Conjunctival epitheliopathy revealed with lissamine dye

ICD-10 Diagnosis Codes:

H16.221–Keratoconjunctivitis Sicca, right eye
H16.222–Keratoconjunctivitis Sicca, left eye
H16.223–Keratoconjunctivitis Sicca, bilateral


Title

Keratoconjunctivitis Sicca  


Category

Keratitis


Description

A disease of the surface of the eye that arises due to either decreased tear film production or increased tear film evaporation. 

The modern model of dry eye syndrome describes a collection of disorders that interfere with the ability of the lacrimal apparatus to maintain a healthy tear film over the ocular surface.  The common link between the various disorders is that they all end up with a loss of water from the tear film.

The loss of water from the tear film increases its osmolarity above the normal limit of 311 mOsm/L.  The increase in tear film osmolarity is the link between changes in the lacrimal glands, changes in the eyelids, and disease of the ocular surface.

Ocular Surface Anatomy and Physiology

  • The goal is to keep the cornea clear and healthy
  • Maintenance of physiology requires harmonization betwen the ocular surface epithelium and the tear film
  • Normal ocular surface-tear film interaction is controlled by a neural reflex loop that depends upon intact nerve endings at the ocular surface
  • Maintenance of physiology also requires that secretory and excretory systemsbe intact and functioning
  • Normal motor function of the eyelids and periorbital musculature is essential for tear film stability

Keratoconjunctivitis sicca (dry eye syndrome) evolves through a sequence of four milestones.

  • Loss of water from the tear film with an increase in tear film osmolarity
  • Decreased conjunctival goblet cell density and decreased corneal glycogen
  • Increased corneal epithelial desquamation
  • Destabilization of the cornea-tear interface


1st Milestone –
Loss of water from the tear film with an increase in tear film osmolarity

The tear film is a balanced mixture of water, mucin, lipids, electrolytes, proteins, and immunoglobulins.  When water is lost from a balanced tear film, it produces an imbalance that is characterized by an increase in tear film osmolarity.  The osmolarity changes when water is lost from the tear film while solutes such as sodium and potassium are not.  The first milestone may be accompanied by mild to moderate patient symptoms and no clinical signs.  If left untreated, the disease is likely to progress.


2nd Milestone – Decreased conjunctival goblet cell density and decreased corneal glycogen  

Conjunctival epithelial cells secrete transmembrane mucins that form the glycocalyx.  The glycolcalyx is a glycoprotein (mucin) coating that covers the corneal and conjunctival epithelium.  The function of the glycocalyx is to allow the tear film to bond to the surface of the eye.  The conjunctiva also contains specialized goblet cells that secrete a gel-forming mucin that floats free in the tear film to help stabilize it after the blink.  When tear film osmolarity is chronically elevated, goblet cells become damaged by the high sodium levels associated with high tear film osmolarity.

High tear film osmolarity also produces an osmotic gradient beween the tear film and the ocular surfce.  The osmotic graient is an attempt by the tear film to replace some of the water that is being lost.  The mechanism of the osmotic gradient pulls water from the conjunctival and corneal cells into the tear film.  This pulling action of the gradient produces a type of osmotic shock that damages some of the cells.  As the disease progresses, the level of damage increases.  Eventually, enough cells are damaged to produce a clinically significant loss of the inter-cellular attachments between some of the conjunctival epithelial cells.  As increasing numers of inter-cellular attachments are damaged, conjunctival epithelial cells begin to slough away at an abnormally high rate.  This abnormal sloughing of epithelial cells is called conjunctival epithelial desquamation.

Conjunctival Epithelial Desquamation

  • Abnormal increase in epithelial sloughing results in immature conjunctival epithelial cells moving onto the surface of the eye
  • Immature cells do not have the surface cell coating of glycoprotein (mucin) needed for tear film bonding
  • Uncoated cells are subject to an increase in dessication and injury due to poor tear film bonding
  • Lissamine green dye stains the areas of the conjunctival surface that are not protected by mucin
  • As the conjunctival desquamation accelerates, the damaged cells release inflammatory mediators onto the surface of the eye and the inflammatory process begins

3rd Milestone – Increased corneal epithelial desquamation

Continued exposure to the osmotic gradient produced by high tear film osmolarity will eventually damage the cornea.  The osmotic shock that increases the rate of conjunctival epithelial desquamation eventually increases the rate of corneal epithelial desquamation.  The result is also the same – immature corneal epithelial cells reaching the ocular surface without a glycoprotein surface coating. 

Corneal Epithelial Desquamation

  • Abnormal increase in sloughing results in immature corneal epithelial cells moving onto the surface of the eye
  • Immature cells do not have the surface cell coating of glycoprotein (mucin) needed for tear film bonding
  • Uncoated cells are subject to an increase in dessication and injury due to poor tear film bonding
  • Lissamine green dye stains the areas of the corneal surface that are not protected by mucin
  • As the corneal desquamation accelerates, the damaged cells perpetuate the inflammatory process by releasing additional inflammatory mediators onto the ocular surface
Corneal Epithelial Desquamation

  • Cornea is not clear and healthy
  • Corneal epitheliopathy stains with fluorescein dye
  • Decreased corneal glycogen reduces the amount of energy available for epithelial wound repair and leads to punctate keratopathy
  • Puntate keratopathyon the central cornea is enhanced with fluorescein dye and cobalt blue filter
  • Dye staining reveals damaged epithelial cells and/or areas of abnormal epithelial cell sloughing
  • Interpalpebral location of the dye staining pattern suggests an aqueous deficiency dry eye syndrome
  • Central corneal location of the dye staining pattern suggests moderate-to-advanced dry eye disease

4th Milestone – Destabilization of the cornea-tear interface

The decrease in corneal glycogen precipitates the last milestone in the natural history of dry eye syndrome – destabilization of the cornea-tear interface secondary to the loss of epithelial microvilli.  As changes in the corneal epithelial cell surface become more severe, surface glycoproteins are lost.  The lost of these glycoproteins (primarily mucins) degrade the glycocalyx and further destabilize the cornea-tear interface.

Destabilization of the Cornea-Tear Interface

  • Damaged epithelial cells stain with fluoescein dyeDry spots form overdamaged areas of the corneal epithelium
  • Geographic areas of abnormal epithelial sloughing stain with fluorescein dye
  • Fluorescein dye staining indicate areas of the corneal epithelium without microvilli to interface with the tear film
  • When large areas of the corneal epithelium are damaged or missing, the lack of microvilli to create a cornea-tear interface leads to areas of poor corneal wetting
  • Areas of poor corneal wetting are indicated by dark spots or streaks (dry spots)visible in the tear film after the blink

The main goal of the diagnostic evaluation in a patient with keratoconjunctivitis sicca is to accomplish the following:

  • To establish the diagnosis of keratoconjunctivitis sicca
  • To determine WHY there is a loss of water from the tear film
  • To establish appropriate therapy
  • To relieve discomfort
  • To prevent complications
  • To educate patients and involve them in managing their dry eye disease

To obtain the information required to determine a clinical diagnosis of keratoconjunctivitis iscca and to prescribe a treatment plan, the following service components of a medical eye examination should be performed.

  • Patient history
  • General medical observation
  • Adnexal examination
  • External ocular examination with biomicroscopy


Patient History

Patients with keratoconjunctivitis sicca may present with any of the following abnormal clinical symptoms:

  • Dry eyes
  • Itchy eye
  • Burning eyes
  • Scratchy eyes
  • Stinging eye
  • Watery eyes
  • Light sensitivity
  • Gritty sensations
  • Eye pain
  • Blurred vision

In addition to physiological conditions, symptoms can be worsened by exposure to environmental conditions such as wind, air conditioning, and temperature extremes.  Activities that reduce blink rate (e.g., extended periods of reading, computer viewing, or driving) can produce more severe symptoms.

External Ocular Examination with Biomicroscopy

Patients with keratoconjunctivitis sicca may present with abnormal clinical signs in any of the following anatomical areas:

  • Tear film
  • Eyelid
  • Conjunctiva
  • Cornea
Clinical Appearance of the Tear Film

  • To evaluate the tear film touch a wet fluorescein strip to the patient’s inferior tarsal conjunctiva
  • Lack of spontaneous fluorescence indicates decrease tear film volume
  • Mucous strands in an abnormal tear film stain with fluorescein dye
Clinical Appearance of the Tear Film

  • Loss of water from the tear film results in decreased tear volume
  • Decrease tear volume is associated with debris in the tear film
  • Dehydrated mucus that has precipitated in the inferior fornix indicates a severe loss of water from the tear film
Clinical Appearance of the Tear Film

  • Rapid development of dark spots in the precorneal tear film after the installation of fluorescein dye
  • Finding is used diagnostically as the tear film breakup time measurement
  • Abnormal tear film breakup time indicates tear film instability
  • Up to 50% of all patient with dry eye syndrome will have normal tear film stability
  • The corneal epithelial changes required to cause tear film instability occur late in the natural history of dry eye syndrome
Clinical Appearance of the Tear Film

  • In patient’s with evaporative dry eye syndrome secondary to posterior blepharitis, the appearance of the tear film has a watery quality
  • Patients may report their eyes feel like they are tearing
  • The tears tend to splash around more on the surface of the eye because the lack of meibum secondary to the blepharitis increases the surface tension of the tear film
  • This sensation occurs because the oil barrier created by the secretion of meibum onto the lid margin is missing
  • As a result, tear fluid can touch the cutaneous portion of the muco-cutaneous junction, making it feel as if the eyes are tearing
DG37515Pic06
DG37515Pic12 Clinical Appearance of the Eyelid

  • The muco-cutaneous junction is a line of squamous cells that runs along the entire length of the upper and lower eyelid margin
  • This line of demarcation between the palpberal conjunctiva and the outer eyelidis also known as Marx’s line
  • Anterior displacement of Marx’s line is visible with lissamine green staining
  • This clinical finding is associated with blepharitis-induced evaporative dry eye syndrome
Clinical Appearance of the Conjunctiva

  • Conjunctival staining occurs relatively early in the natural history of dry eye syndrome
  • The paternal of conjunctival staining is more useful than the presence or absence of staining
  • In patients with dry eye syndrome, the nasal conjunctiva usually stains more than the temporal conjunctiva

 

DG37515Pic05
DG37515Pic03 Clinical Appearance of the Cornea

  • Central corneal staining is a clinical sign of moderately- severe dry eye syndrome
  • This clinical finding occurs late in the natural history of the disease

 

According to the 2004 recommendations from the Delphi Panel, dry eye syndrome can also be classified by the stage of the disease. 

  • Severe symptoms 
  • Severe corneal staining 
  • Corneal erosions 
  • Conjunctival scarring 

 

Dry Eye Severity Level   Clinical Signs And Symptoms 
 Level 1 – Mild    

  • Mild to moderate symptoms
  • No clinical signs
  • Mild to moderate conjunctival signs 
 Level 2 – Moderate    

  • Moderate to moderately-severe symptoms
  • Tear film abnormalities
  • Mild corneal punctate staining
  • Conjunctival staining
  • Visual blur, glare, photophobia
 Level 3 – Moderately-severe    

  • Moderately-severe to severe symptoms
  • Marked corneal punctate staining
  • Central corneal staining
  • Filamentary keratitis
 Level 4 – Severe    

  • Severe symptoms
  • Severe corneal staining
  • Corneal erosions
  • Conjunctival scarring 

 

In addition to disease staging, dry eye syndrome can be classified by etiology or clinical appearance.

Etiology of decreased tear film volume

  • Decreased tear production
  • Increased tear evaporation

Presence of eyelid margin disease

  • Yes
  • No

Presence of clinically apparent inflammation

  • Yes
  • No

This would include other diseases that present with a superficial punctate keratopathy or excess mucus accumulation in the tear film.

Blepharitis

  • Toxins related to the release of inflammatory mediators can produce superficial punctate keratopathy on the inferior cornea
Exposure Keratoconjunctivis

  • Poor eyelid closure or an elevated conjunctival mass can produce a superficial punctate keratopathy that is similar in appearance to the damage caused by dry eye syndrome
Chemical Burn

  • Mild to moderate burns can produce superficial punctate keratopathy or sloughing of the entire epithelium
Topical Drug Toxicity

  • Any eyedrops with preservatives that are used frequently may produce a superficial punctate keratopathy
Contact Lens-Induced Superficial Punctate Keratopathy

  • Contact lens overwear, tight lens sydrome, solution toxicity and giant papillary conjunctivitis can produce a superficial punctate keratopathy
Retained Conjunctival Foreign Body 

  • A foreign body under the eyelid can produce linear epithelial defects in a vertical orientation
Conjunctivitis 

  • Mucous discharge associated with bacterial conjunctivitis can mimic the appearance of dehydrated mucous that collects in the inner canthus of dry eye patients
Trichiasis

  • Misdirected lashes cam produce superficial keratopathy
  • In entropion or ectropion, an eyelid margin turned in or out can mechanically damage the cornea and cause superficial keratopathy
Trauma 

  • Habits such as chronic eye rubbing can mechanically damage the corneal epithelium resulting in superficial punctate keratopathy

To follow best practices treatment guidelines, use the algorithm developed by Delphi Panel.

Level 1 – Mild Dry Eye Syndrome

  • Patient counseling
  • Preserved artificial tears
  • Environmental management
  • Allergy eye drops
  • Increased water intake
  • Use of hypoallergenic products
  • If no improvement, add level 2


Level 2 – Moderate Dry Eye Syndrome

  • Unpreserved artificial tears, gel, ointments
  • Topical immunomodulators (e.g., Restatis Ophthalmic Emulsion)
  • Topical steroids
  • Secretagogues
  • Nutritional support
  • If no improvement, add level 3


Level 3 – Moderately-Severe Dry Eye Syndrome

  • Oral tetracyclines
  • Punctal occlusion
  • If no improvement, add level 4


Level 4 – Severe Dry Eye Syndrome

  • Systemic anti-inflammatory therapy
  • Oral cyclosporine
  • Moisture goggles
  • Acetylcysteine
  • Punctal cautery
  • Eyelid surgery

In 2006, the Asclepius Panel enhanced the Delphi Panel’s recommendation for treating dry eye syndrome.  Their recommendations was to prescribe steroids in conjunction with Restasis earlier in the natural history of the disease.

Their recommendations include the following treatment guidelines:

  • Day 1 – initiate treatment with Lotemax eyedrops 4x per day; use artificial tears as needed
  • Day 14 – reduce Lotemax to twice daily and discontinue over the next 2-4 weeks; begin Restasis twice daily
  • Day 60 – continue with Restasis twice daily; use Lotemax up to 4x per day for breakthrough period
  • Day 180 – monitor patient’s progress

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