Dry Eye SyndromeDry Eye Syndrome

Dr Humberto ValbuenaDr Humberto Valbuena

INTRODUCTIONINTRODUCTION BackgroundBackground: : Dry eye is a common disorder of the Dry eye is a common disorder of the

tear film that results from decreased tear tear film that results from decreased tear production, excessive tear evaporation, or production, excessive tear evaporation, or abnormality in mucin or lipid components of the abnormality in mucin or lipid components of the tear film. Generally, it is accepted that the tear tear film. Generally, it is accepted that the tear film is made up of 3 intertwined layers, as film is made up of 3 intertwined layers, as follows: follows:

1- 1- A superficial thin lipid layerA superficial thin lipid layer is produced by the is produced by the meibomian glands, and its principal function is meibomian glands, and its principal function is to retard tear evaporation and to assist in to retard tear evaporation and to assist in uniform tear spreading. uniform tear spreading.

2- 2- A middle thick aqueous layerA middle thick aqueous layer is produced by is produced by the main lacrimal glands (reflex tearing), as the main lacrimal glands (reflex tearing), as well as the accessory lacrimal glands of well as the accessory lacrimal glands of Krause and Wolfring (basic tearing). Krause and Wolfring (basic tearing).

3- 3- An innermost hydrophilic mucin layerAn innermost hydrophilic mucin layer is is produced by both the conjunctiva goblet cells produced by both the conjunctiva goblet cells and the ocular surface epithelium and and the ocular surface epithelium and associates itself with the ocular surface via associates itself with the ocular surface via its loose attachments to the glycocalyx of the its loose attachments to the glycocalyx of the microplicae of the epithelium.microplicae of the epithelium.

Mucin deficiency, as seen in Mucin deficiency, as seen in Stevens-Johnson syndromeStevens-Johnson syndrome or or after a after a chemical burnchemical burn, leads to poor wetting of the corneal , leads to poor wetting of the corneal surface with subsequent desiccation and epithelial damage. surface with subsequent desiccation and epithelial damage.

Keratoconjunctivitis sicca (KCS)Keratoconjunctivitis sicca (KCS) is the name given to the is the name given to the ocular surface disorder that develops in patients with ocular surface disorder that develops in patients with aqueous tear deficiency (ATD),aqueous tear deficiency (ATD), and it is the most common and it is the most common cause of dry eye.cause of dry eye.

KCS is subdivided into KCS is subdivided into Sjögren syndromeSjögren syndrome (SS)(SS) associated associated KCS and non-SS associated KCS. Evaporative loss is due KCS and non-SS associated KCS. Evaporative loss is due predominantly to predominantly to meibomian gland dysfunction (MGD).meibomian gland dysfunction (MGD).

Patients with Patients with primary SSprimary SS have evidence of a systemic have evidence of a systemic autoimmune disease as manifested by the presence of serum autoimmune disease as manifested by the presence of serum autoantibodies and very severe ATD and ocular surface autoantibodies and very severe ATD and ocular surface disease. disease. Secondary SSSecondary SS is defined as KCS associated with a is defined as KCS associated with a diagnosable connective tissue disease, most commonly diagnosable connective tissue disease, most commonly rheumatoid arthritis.rheumatoid arthritis.

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.

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.

- 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.

Mucin synthesizing genesMucin synthesizing genes, designated , designated MUC1-MUC8MUC1-MUC8, have , have been isolated, and their role in hydration and stability of the been isolated, and their role in hydration and stability of the tear film are being investigated in patients with dry eye tear film are being investigated in patients with dry eye syndrome. syndrome.

Particularly significant is Particularly significant is MUC5AC,MUC5AC, expressed by stratified expressed by stratified squamous cells of the conjunctiva and whose product is the squamous cells of the conjunctiva and whose product is the predominant component of the mucous layer of tears predominant component of the mucous layer of tears

A A defect in this genedefect in this gene may be a factor in dry eye syndrome may be a factor in dry eye syndrome development. development.

Frequency:Frequency:

In the USIn the US: : Dry eye is a very common disorder Dry eye is a very common disorder

affecting a significant percentage of the affecting a significant percentage of the population, especially those older than 40 years. population, especially those older than 40 years. The estimated number of people affected ranges The estimated number of people affected ranges from 10-14 million in the US.from 10-14 million in the US.

InternationallyInternationally: : The frequency of dry eye in The frequency of dry eye in

other countries closely parallels that of the US. other countries closely parallels that of the US.

Mortality/Morbidity:Mortality/Morbidity: Dry eye may be complicated by Dry eye may be complicated by sterile or infectious corneal ulcerationsterile or infectious corneal ulceration. Occasionally, corneal . Occasionally, corneal perforation may occur. In rare cases, sterile or infectious perforation may occur. In rare cases, sterile or infectious corneal ulceration in dry eye syndrome can cause blindness.corneal ulceration in 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. KCS Dry eye may be slightly more common in women. KCS associated with SS (a type of dry eye) is believed to affect 1-associated with SS (a type of dry eye) is believed to affect 1-2% of the population, and 90% of those affected are women. 2% of the population, and 90% of those affected are women.

CausesCauses A classification system formulated by the National Eye A classification system formulated by the National Eye

Institute distinguishes 2 main categories (or causes) of dry Institute distinguishes 2 main categories (or causes) of dry eye states, an aqueous deficiency state and an evaporative eye states, an aqueous deficiency state and an evaporative state. 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 ablation Lacrimal ablation Congenital alacrima (Riley-Day syndrome) Congenital alacrima (Riley-Day syndrome) Primary lacrimal deficiency Primary lacrimal deficiency Graft-versus-host disease Graft-versus-host disease

– Infiltrative processesInfiltrative processes Lymphoma Lymphoma Amyloidosis Amyloidosis Hemachromatosis Hemachromatosis Sarcoidosis Sarcoidosis

– Infectious diseasesInfectious diseases HIV diffuse infiltrative lymphadenopathy syndrome HIV diffuse infiltrative lymphadenopathy syndrome Trachoma Trachoma

– Lacrimal obstructive diseaseLacrimal obstructive disease Trachoma Trachoma Ocular cicatricial pemphigoid Ocular cicatricial pemphigoid Erythema multiforme and Stevens-Johnson syndrome Erythema multiforme and Stevens-Johnson syndrome Chemical burns Chemical burns Endocrine imbalance Endocrine imbalance

– Anticholinergic medicationsAnticholinergic medications

– Decreased corneal sensationDecreased corneal sensation Neurotrophic keratitis Neurotrophic keratitis Corneal surgery Corneal surgery Herpes simplex Herpes simplex Contact lens wear Contact lens wear Cranial nerve VII (CN VII) palsy Cranial nerve VII (CN VII) palsy Diabetes Diabetes Aging Aging

Sjögren syndromeSjögren syndrome

– PrimaryPrimary (no associated connective tissue disease (no associated connective tissue disease [CTD])[CTD])

– SecondarySecondary (associated CTD) (associated CTD) Rheumatoid arthritis Rheumatoid arthritis Systemic lupus erythematosus Systemic lupus erythematosus Progressive systemic sclerosis (scleredema) Progressive systemic sclerosis (scleredema) Primary biliary cirrhosis Primary biliary cirrhosis Interstitial nephritis Interstitial nephritis Polymyositis and dermatomyositisPolymyositis and dermatomyositis

Evaporative lossEvaporative loss

– Blepharitis-associated - Obstructive meibomian gland Blepharitis-associated - Obstructive meibomian gland diseasedisease

– Blink disordersBlink disorders

– Disorders of eyelid aperture and eyelid/globe congruityDisorders of eyelid aperture and eyelid/globe congruity

CLINICALCLINICAL Ocular irritation of dry sensation, burning, itching, Ocular irritation of dry sensation, burning, itching,

foreign body sensation, photophobia, and blurred foreign body sensation, photophobia, and blurred vision are common in patients with dry eye.vision are common in patients with dry eye.

In KCSIn KCS, symptoms tend to be worse toward the end , symptoms tend to be worse toward the end of the day, with prolonged use of the eyes, or with of the 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 the may complain of redness of the eyelids and conjunctiva, but, in these patients, the eyelids and conjunctiva, but, in these patients, the symptoms are worse on awakening in the morningsymptoms are worse on awakening in the morning..

ParadoxicallyParadoxically, some patients with dry eye , some patients with dry eye syndrome complain of syndrome complain of too much tearingtoo much tearing. When . When evidence of dry eye syndrome exists, this evidence of dry eye syndrome exists, this symptom often is explained by excessive reflex symptom often is explained by excessive reflex tearing due to severe corneal surface disease tearing due to severe corneal surface disease from the dryness.from the dryness.

Certain systemic medications also decrease tear Certain systemic medications also decrease tear production, such as antihistamines, beta-production, such as antihistamines, beta-blockers, and oral contraceptives.blockers, and oral contraceptives.

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 an In severe cases, there may be an epithelial defect or a sterile epithelial defect or a sterile corneal infiltrate or ulcercorneal infiltrate or ulcer. Secondary infectious keratitis also . Secondary infectious keratitis also can develop. Both sterile and infectious corneal perforations can develop. Both sterile and infectious corneal perforations can occur.can occur.

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.

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.

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

WORKUPWORKUP Lab Studies:Lab Studies:

Conjunctival impression cytology can be used to monitor the Conjunctival impression cytology can be used to monitor the progression of ocular surface changes.progression of ocular surface changes.

Serology for circulating autoantibodies, including ANA or SS Serology for circulating autoantibodies, including ANA or SS antibodies (ie, SS-A, SS-B), may be indicated.antibodies (ie, SS-A, SS-B), may be indicated.

Other Tests:Other Tests: Dry eye is essentially a Dry eye is essentially a clinical diagnosisclinical diagnosis, combining information , combining information

obtained from both the history and the examination and performing obtained from both the history and the examination and performing 1 or more tests to lend some objectivity to the diagnosis. No one test 1 or more tests to lend some objectivity to the diagnosis. No one test is sufficiently specific to permit an absolute diagnosis of dry eye.is 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 is determined by measuring the time lapse between instillation of fluorescein and appearance of the first lapse between instillation of fluorescein and appearance of the first dry spots on the cornea. Decreased TBUT of less than 10 seconds is dry spots on the cornea. Decreased TBUT of less than 10 seconds is considered abnormal, indicative of tear instability.considered abnormal, indicative of tear instability.

Use rose bengal and fluoresceinUse rose bengal and fluorescein staining to staining to evaluate epitheliopathy. Rose bengal stains not only dead and evaluate epitheliopathy. Rose bengal stains not only dead and devitalized cells but also healthy cells that are protected devitalized cells but also healthy cells that are protected inadequately by a mucin coating. Fluorescein pools in epithelial inadequately by a mucin coating. Fluorescein pools in epithelial erosions and stains exposed basement membrane. erosions and stains exposed basement membrane.

– Early or mild cases of KCSEarly or mild cases of KCS are detected more easily with are detected more easily with rose bengal than with fluorescein staining, and the conjunctiva rose bengal than with fluorescein staining, and the conjunctiva usually is stained more intensely than the cornea. usually is stained more intensely than the cornea. Interpalpebral staining of the nasal and/or inferior paracentral Interpalpebral staining of the nasal and/or inferior paracentral cornea is seen in KCS. A linear pattern of inferior conjunctiva cornea is seen in KCS. A linear pattern of inferior conjunctiva and corneal staining by rose bengal is characteristic of MGD.and corneal staining by rose bengal is characteristic of MGD.

– Van Bijsterveld developedVan Bijsterveld developed a scoring system for rose a scoring system for rose bengalbengal that evaluates the intensity of staining based on a that evaluates the intensity of staining based on a scale of 0-3 in 3 areas: nasal conjunctiva, temporal scale of 0-3 in 3 areas: nasal conjunctiva, temporal conjunctiva, and cornea. With this system, the maximum conjunctiva, and cornea. With this system, the maximum possible score is 9. According to this system, a score of 3.5 or possible score is 9. According to this system, a score of 3.5 or greater is considered positive for KCS.greater is considered positive for KCS.

Use the Schirmer test to test aqueous Use the Schirmer test to test aqueous tear productiontear production. . Traditionally, the basic secretion Traditionally, the basic secretion test is performed following the instillation of topical test is performed following the instillation of topical anesthetic and the placement of a thin strip of filter paper anesthetic and the placement of a thin strip of filter paper in the inferior cul-de-sac. Measurement of less than 5 mm is in the inferior cul-de-sac. Measurement of less than 5 mm is abnormal; 5-10 mm is equivocal.abnormal; 5-10 mm is equivocal.

– The Schirmer I testThe Schirmer I test, , which measures both basic which measures both basic and reflex tearing, consists of the same test without the and reflex tearing, consists of the same test without the use of a topical anesthetic agent. Less than 10 mm of use of a topical anesthetic agent. Less than 10 mm of wetting after 5 minutes is diagnostic of ATD. The test is wetting after 5 minutes is diagnostic of ATD. The test is relatively specific, but it is poorly sensitive.relatively specific, but it is poorly sensitive.

– The Schirmer II testThe Schirmer II test measures reflex tearing. measures reflex tearing. It is performed similar to the basic secretion test, with It is performed similar to the basic secretion test, with the addition of nasal mucosal irritation with a cotton tip the addition of nasal mucosal irritation with a cotton tip applicator. Wetting of less than 15 mm after 5 minutes is applicator. Wetting of less than 15 mm after 5 minutes is consistent with abnormalities of reflex secretionconsistent with abnormalities of reflex secretion

Additional tests include tear film Additional tests include tear film osmolarityosmolarity, tear lysozyme, and tear lactoferrin. , tear lysozyme, and tear lactoferrin. Tear film osmolarity has been shown to be Tear film osmolarity has been shown to be elevated in patients with dry eyes. elevated in patients with dry eyes.

It is a very sensitive test for identifying a dry eye It is a very sensitive test for identifying a dry eye but lacks specificity. The test often is not used but lacks specificity. The test often is not used because of the lack of commercially available because of the lack of commercially available equipment for its measurementequipment for its measurement..

Procedures:Procedures:

Lacrimal gland or minor (salivary) gland biopsy Lacrimal gland or minor (salivary) gland biopsy may be performed to aid in diagnosing SS.may be performed to aid in diagnosing SS.

Histologic FindingsHistologic Findings:: Histopathologically, Histopathologically, squamous metaplasia with loss of goblet cells, squamous metaplasia with loss of goblet cells, cellular enlargement, and increase in cellular enlargement, and increase in cytoplasmic/nuclear ratio of the superficial cytoplasmic/nuclear ratio of the superficial conjunctival epithelial cells are present in conjunctival epithelial cells are present in patients with KCS. patients with KCS.

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 Hot compresses and eyelid massage, especially if

associated with MGDassociated with MGD

Moderate Moderate – Artificial tears without preservatives 4 times daily to Artificial tears without preservatives 4 times daily to

hourly hourly – Lubricating ointment at bedtime Lubricating ointment at bedtime – Doxycycline 100 mg qd/bid if indicated for MGD Doxycycline 100 mg qd/bid if indicated for MGD – Lower punctal occlusionsLower punctal occlusions

Severe Severe – Perform all of the above treatments Perform 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 tarsorrhaphy Lateral tarsorrhaphy

Emerging therapy Emerging therapy – Immunomodulatory agents (eg, topical cyclosporine A) Immunomodulatory agents (eg, topical cyclosporine A) – Topical androgens Topical androgens – Secretagogues (substance that increases acinar cell Secretagogues (substance that increases acinar cell

activity and protein synthesis, eg, oral pilocarpine) activity and protein synthesis, eg, oral pilocarpine) – Cytokine-blocking agentsCytokine-blocking agents

Consultations:Consultations: A rheumatologist can be consulted A rheumatologist can be consulted if a systemic collagen vascular disease is if a systemic collagen vascular disease is suspected.suspected.

Further Outpatient Care:Further Outpatient Care:

Follow-up care is based on the severity of Follow-up care is based on the severity of symptoms.symptoms.

Complications: Complications:

Decreased visual acuityDecreased visual acuity BlindnessBlindness

Prognosis: Prognosis:

In general, prognosis for visual acuity in patients In general, prognosis for visual acuity in patients with dry eye syndrome is good.with dry eye syndrome is good.

Gracias………Gracias………