• Therapy is based on the severity of patient’s symptoms & is adjusted depending on the response
• Medication’s efficacy & safety, & patient’s convenience should be taken into consideration when subjecting the patient to long-term treatment

Goals:

• To relieve symptoms of patients
• To improve visual acuity & quality of life of patients
• To restore ocular surface & tear film to normal homeostatic state
• To correct the underlying defect

Tear Supplementation (Lubricants or Artificial Tears)

• Hypotonic or isotonic solutions that contain electrolytes, surfactants, & different types of viscosity agents
• Ideally, should be preservative-free, contains potassium, bicarbonate & other electrolytes, & have polymeric system that increases retention time
  
  • Non-BAK (benzalkonium chloride) preserved drops may still be used in mild to moderate dry eye syndrome (DES)
• Mainly used to lubricate the ocular surface through their viscosity & mucoadhesive properties
• Replace tear volume
• Provide short-term, palliative relief of dry eye symptoms
• Do not replace the cytokines & growth factors, & have no anti-inflammatory properties but aids in decreasing inflammation by diluting or washing away inflammatory agents
• In general, do not alter ocular pathology
  
  • Studies have shown that regular use improves tear break up time & eliminate dry spots, implying a reparative effect on superficial corneal epithelial cells & their glycocalyx 
• Selected based on concentration & choice of electrolytes, osmolarity & type of viscosity or polymeric system, presence & type or absence of preservative
• No evidence yet has shown that any agent is superior to another

Preservative-free Lubricants

• May be used more frequently w/o thinking about possible toxic effects of preservatives
  
  • Preservatives [eg benzalkonium chloride (BAK), disodium (EDTA)] can irritate the eye & aggravate dry eye symptoms
    
    • Toxicity of BAK depends on its concentration, dosing frequency, tear secretion level, & ocular surface disease severity
    • May be tolerated by patients w/ mild DES when used for ≤4-6x/day
• More important characteristic of lubricants to consider when managing patients w/ moderate to severe DES than the type of polymeric agent used
  
  • BAK toxicity may be high in patients w/ moderate to severe DES due to reduced tear secretion & turnover
• Highly recommended in patients w/ severe dry eye w/ ocular surface disease & impaired lacrimal gland secretion, & in patients on various preserved topical medications for chronic eye disease
• Maybe available as liquid drops, gels, ointments, or ocular inserts
  
  • Gels contain high molecular weight cross-linked polymers that have longer retention times than liquid preparations
  • Ointments contain mineral oil & petrolatum that have longer retention times but produce more significant effects on vision than gels, hence should be applied at bedtime
  • Ocular inserts are long-acting slow-release ocular rods of hydroxypropyl cellulose that is used to decrease repeated instillation of artificial tears; however, is limited by the discomfort of placing a foreign body in the inferior conjunctival sac

Electrolyte- or Ion- (eg Potassium, Bicarbonate) containing Lubricants

• Shown to be useful in treating ocular surface damage caused by dry eye
• Potassium is vital in maintaining corneal thickness
• Bicarbonate promotes the recovery of epithelial barrier function in damaged corneal epithelium & helps in maintaining normal epithelial ultrastructure
  
  • Also maintains the mucin layer of the tear film
• Most artificial tears do not have the same composition as human tears, although some new formulations mimic the human tears’ electrolyte component

Hypo-osmotic Lubricants

• Important since increased tear film osmolarity (crystalloid osmolarity), which is commonly seen in patients w/ dry eyes, causes morphological & biochemical changes to the corneal & conjunctival epithelium, & is pro-inflammatory
• Solutes like glycerin, erythritol, & levocarnitine were added in ophthalmic drops to protect against high osmolarity adverse effects w/ the theory that it:
  
  • Distribute between the tears & intracellular fluids which may help protect against cellular damage due to hyperosmolar tears
• Also, lubricants w/ high colloidal osmolality may be of value because addition to damaged cell surface may cause deturgescence which may lead to return of normal cell physiology
  
  • Colloidal osmolality difference affects the net flow of water across membranes

Viscosity Agents of Lubricants

• Eg Carboxymethylcellulose (CMC), hydroxymethylcellulose (HMC), polyvinyl alcohol, polyethylene glycol, glycol 400, propylene glycol HMC, hydroxypropyl cellulose
• Macromolecular components added to tear supplements that cause increase in residence time which provide longer interval of patient’s comfort
  
  • CMC was shown to bind & be retained by human epithelial cells
• Helps protect the ocular surface epithelium
  
  • HMC coats & protects the surface epithelium, or helps restore protective effect of mucins
  • CMC was shown to have cytoprotective properties that may promote re-epithelialization of corneal wounds
• Viscoelasticity of lubricant drop is important
  
  • Must be viscous enough to remain on the corneal surface, w/o being washed away
  • At the same time, it has to be elastic enough to maintain a coating on the ocular surface w/o breaking up due to the action of the opening & closing of the eyelids
• Another important property is “lubricity” or the ability of the lubricant to decrease the friction that occurs between the ocular surface & the eyelid margin as it goes up & down over the eye during blinking
• Blurring of vision, caking & drying on eyelashes are the limiting factors of high molecular weight viscous agents especially for patients w/ mild to moderate dry eye
• Castor oil or mineral oil are used to restore or increase the lipid layer of the tear film
• Hyaluronic acid (0.2%) was shown by studies to have longer ocular surface residence time than HPMC (0.3%) or polyvinyl alcohol (1.4%)

Anti-Inflammatories

• Indicated in patients w/ corneal disease who have persistent symptoms despite extensive use of artificial tears

Corticosteroids (Ophthalmic)

• Inhibit inflammatory response w/ fast onset of action
• Improves signs & symptoms of patients w/ or w/o Sjogren syndrome
• Studies have shown improvement of symptom severity scores, reduction of fluorescein & rose bengal staining, decrease in human leukocyte antigen-DR-positive cells, & increase in the number of goblet cells after 2-4 weeks of treatment of patients w/ moderate to severe dry eye
• Should not be recommended for long-term use due to its possible serious side effects
• Pulse therapy may be given to control exacerbations
  

Cyclosporine

• Inhibits T lymphocyte activation but does not affect activated T lymphocytes
• Reduces fluorescein staining of the cornea & increases basal & reflex tear secretion
• Alleviates symptoms of blurred vision, decreases need for artificial tears, & improves evaluation of global response to treatment
  
  • Requires 2-4 weeks of continuous administration before significant improvement in symptoms is noted
  • Improvement was noted for ≥6 months even when medication has been stopped
• An effective & less toxic alternative to ophthalmic corticosteroids
• When combined w/ ophthalmic corticosteroids, produces a faster anti-inflammatory response by stimulating lymphocyte apoptosis
• Optimizes ocular surface to prevent or reduce severity of LASIK-associated dry eye when used w/ lubricants & nutritional supplements in patients who are candidates for refractive surgery w/ dry eye
  
  • May also improve corneal nerve regeneration or nerve sensitivity, & promote better & faster recovery of visual acuity

Tetracyclines

• Eg Doxycycline, Minocycline
• May help improve dry eye symptoms of patients w/ ocular rosacea or meibomian gland dysfunction
• Reduce inflammatory cytokines’ production (interleukin-1 & tumor necrosis factor α), restrain collagenase & matrix metalloproteinases’ activity, & have antiangiogenic properties
• Also reduce the load of bacteria on the eyelids

Secretagogue

Pilocarpine

• Muscarinic agonist used to stimulate production & secretion of tears & saliva in patients w/ Sjogren syndrome
  
  • Noted to be more effective for dry mouth than for dry eye symptoms
  • Dry eye symptom improvement was seen after 6-12 weeks of treatment
• May cause transient increase in numbers of goblet cells
• Reserved for patients w/ moderate to severe symptoms who can tolerate its cholinergic side effects

Biological Tear Substitutes

Autologous Serum

• Contains fibronectin, vitamin A, cytokines, growth factors, & anti-inflammatory substances
• Shown to be beneficial in patients w/ Sjogren syndrome, graft-vs-host disease, Stevens-Johnson syndrome, cicatricial pemphigoid, etc
• Improves dry eye symptoms, tear film break-up time (TFBUT) & rose-bengal staining scores as evidenced by studies compared to artificial tears

Salivary Gland Autotransplantation

• May replace deficient mucin & aqueous tear film phase
• Recommended only in patients w/ end-stage DES w/ absolute tear deficiency, conjunctivalized surface epithelium, & persistent severe pain despite punctal occlusion & hourly application of preservative-free lubricants
  
  • Causes significant improvement in Schirmer test, TFBUT, & rose bengal staining
  • Reduces discomfort & need of pharmaceutical ophthalmic lubricants

Punctal Plugs

• Recommended in patients w/ symptomatic dry eyes, Schirmer test (w/ anesthesia) <5 mm at 5 minutes, & has evidence of ocular surface dye staining
• Studies have shown significant decrease in tear production in patients w/ normal tear production for up to 2 weeks after plug insertion
• Should be avoided by patients w/ allergy to components of the plug, punctal ectropion, pre-existing nasolacrimal duct obstruction, untreated clinical ocular surface inflammation, or in patients w/ acute or chronic lacrimal canaliculus or sac infection
• Complications may include spontaneous plug extrusion, internal migration of a plug, biofilm formation or infection, or pyogenic granuloma formation

Moisture Chamber Spectacles

• Alleviates ocular discomfort due to dry eye
• Shown to increase interblink intervals

Contact Lenses

• Eg hydrophilic bandage contact lenses
• May be used to protect & hydrate the corneal surface in patients w/ severe dry eye syndrome (DES)
  
  • Have been shown to improve visual acuity & comfort, decrease corneal epitheliopathy, & heal persistent corneal epithelial defects
• May be associated w/ small risk of corneal vascularization & corneal infection when used by patients w/ dry eyes