Dry%20eye%20syndrome Treatment

• Goals of treatment:
  • To relieve symptoms of patients
  • To improve visual acuity and quality of life of patients
  • To restore ocular surface and tear film to normal homeostatic state
  • To correct the underlying defect
• Therapy is based on the severity of patient’s symptoms and is adjusted depending on the response
• Medication’s efficacy and safety and patient’s convenience should be taken into consideration when subjecting the patient to long-term treatment

Tear Supplementation (Lubricants or Artificial Tears)

• Hypotonic or isotonic solutions that contain electrolytes, surfactants, and different types of viscosity agents
• Ideally, should be preservative-free, contain potassium, bicarbonate and other electrolytes, and have polymeric system that increases retention time
  
  • Non-benzalkonium chloride (BAK) preserved drops may still be used in mild to moderate DES
• Mainly used to lubricate the ocular surface through their viscosity and mucoadhesive properties
• Replace tear volume and target ≥1 tear film layer
• Provide short-term palliative relief of dry eye symptoms
• Do not replace the cytokines and growth factors and have no anti-inflammatory properties but aid in decreasing inflammation by diluting or washing away inflammatory agents
• In general, these do not alter ocular pathology
  
  • Studies have shown that regular use improves tear break up time and eliminate dry spots, implying a reparative effect on superficial corneal epithelial cells and their glycocalyx 
• Selected based on concentration and choice of electrolytes, osmolarity and type of viscosity or polymeric system, presence and 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 without the possible toxic effects of preservatives
  
  • Preservatives [eg BAK, disodium ethylenediaminetetraacetic acid (EDTA)] can irritate the eye and aggravate dry eye symptoms
    
    • Toxicity of BAK depends on its concentration, dosing frequency, tear secretion level, and ocular surface disease severity
    • BAK may induce corneal and conjunctival epithelial cell apoptosis, corneal nerve damage, impair wound healing and disturb tear film stability
    • May be tolerated by patients with mild DES when used for ≤4-6x/day
• More important characteristic of lubricants to consider when managing patients with moderate to severe DES than the type of polymeric agent used
  
  • BAK toxicity may be high in patients with moderate to severe DES due to reduced tear secretion and turnover
• Highly recommended in patients with severe dry eye with ocular surface disease and impaired lacrimal gland secretion, and in patients on various preserved topical medications for chronic eye disease
• May be 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 and 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 are used to decrease repeated instillation of artificial tears; however, these are limited by the discomfort of placing a foreign body in the inferior conjunctival sac

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

• Shown to be useful in treating ocular surface damage caused by dry eye
• Buffered solutions containing potassium, calcium, magnesium, phosphate, bicarbonate and sodium chloride are used to maintain the epithelial surface
• Potassium is vital in maintaining corneal thickness
  • Tears with high potassium levels may protect the corneal epithelium from ultraviolet B (UVB) radiation
  • Decreased potassium may increase corneal thickness
• Bicarbonate promotes the recovery of epithelial barrier function in damaged corneal epithelium and 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 with dry eyes, causes morphological and biochemical changes to the corneal and conjunctival epithelium and is pro-inflammatory
• Solutes like glycerin, erythritol, and levocarnitine were added in ophthalmic drops to protect against high osmolarity adverse effects with the theory that it distributes between the tears and intracellular fluids which may help protect against cellular damage due to hyperosmolar tears
• Lubricants with 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
• Under hyperosmotic stress, lubricants may inhibit inflammation

Viscosity Agents of Lubricants

• Eg Carboxymethylcellulose (CMC), Hydroxymethylcellulose (HMC), Polyvinyl alcohol, Polyethylene glycol, glycol 400, Propylene glycol HMC, Hydroxypropyl methylcellulose (HPMC), Carbomer (Polyacrylic acid)
• 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 and be retained by human epithelial cells and promote cell healing
• Help protect the ocular surface epithelium
  
  • HMC coats and 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 without being washed away
  • At the same time, it has to be elastic enough to maintain a coating on the ocular surface without breaking up due to the action of the opening and closing of the eyelids
  • Very high viscosity eye drops are recommended for overnight use and low viscosity for daytime
• Another important property is “lubricity” or the ability of the lubricant to decrease the friction that occurs between the ocular surface and the eyelid margin as it goes up and down over the eye during blinking
• Blurring of vision, caking and drying on eyelashes are the limiting factors of high molecular weight viscous agents especially for patients with mild to moderate dry eye
• Castor oil or mineral oil is 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%)
• Studies also showed combination of CMC and hyaluronic acid improves signs and symptoms of DES compared to CMC alone

Anti-Inflammatory Agents

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

Corticosteroids (Ophthalmic)

• Inhibit inflammatory response with fast onset of action
• Improve signs and symptoms of patients with or without Sjögren syndrome
• Studies have shown improvement of symptom severity scores, reduction of fluorescein and rose bengal staining, decrease in human leukocyte antigen-DR-positive cells, and increase in the number of goblet cells after 2-4 weeks of treatment of patients with moderate to severe dry eye
• Should not be recommended for long-term use due to its possible serious side effects
• Repeated short-term pulse therapy may be given to control exacerbations and for patients with moderate to severe disease who did not respond to other therapies
  

Cyclosporine

• Inhibits T lymphocyte activation but does not affect activated T lymphocytes
• Reduces fluorescein staining of the cornea and increases basal and reflex tear secretion
• Alleviates symptoms of blurred vision, decreases need for artificial tears, and 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 and less toxic alternative to ophthalmic corticosteroids
• When combined with ophthalmic corticosteroids, it produces a faster anti-inflammatory response by stimulating lymphocyte apoptosis
• May be given to patients with dry eye who underwent punctal occlusion
• Optimizes ocular surface to prevent or reduce severity of LASIK-associated dry eye when used with lubricants and nutritional supplements in patients who are candidates for refractive surgery with dry eye
  
  • May also improve corneal nerve regeneration or nerve sensitivity and promote better and faster recovery of visual acuity

Lifitegrast

• Lymphocyte function-associated antigen 1 (LFA-1) antagonist which blocks lymphocyte interaction to upregulated adhesion molecules
• Improvement in signs (corneal and conjunctival staining) and symptoms (eye dryness score and ocular discomfort) was noted after 3 months of use
• Further studies are still needed to establish long-term effectivity and safety

Macrolides

• Eg Azithromycin
• Significantly increase cellular accumulation of cholesterol, cholesterol esters, phospholipids and lysosomes on human meibomian gland epithelial cell compared with Doxycycline, Minocycline and Tetracycline
• Anti-inflammatory properties may reduce bacterial flora and lid inflammation in meibomian gland dysfunction associated with rosacea

Tetracyclines

• Eg Doxycycline, Minocycline
• Broad-spectrum antibiotics which inhibit protein synthesis by binding aminoacyl-tRNA to the mRNA-ribosome complex
• Reduce inflammatory cytokines’ production (interleukin-1 and tumor necrosis factor α), restrain collagenase, phospholipase A2 and matrix metalloproteinases’ activity, and have antiangiogenic properties
• May help improve dry eye symptoms of patients with ocular rosacea or meibomian gland dysfunction

Secretagogues

Cevimeline

• Muscarinic acetylcholine receptor agonist for the treatment of Sjögren syndrome-associated DES
• Studies showed significant improvement in ocular dryness and dry mouth with increased lacrimal and salivary flow rates
• Long-term patient compliance is more likely due to lesser reported adverse events with Cevimeline compared to Pilocarpine

Diquafosol

• Purinergic P2Y2 receptor agonist that stimulates water and mucin secretions from conjunctival epithelial cells and goblet cells
• Studies showed significant improvement in tear break-up time (TBUT), corneal and conjunctival fluorescent staining and Schirmer score
• 3% ophthalmic solution is approved for treatment of DES in several Asian countries

Pilocarpine

• Muscarinic agonist used to stimulate production and secretion of tears, sweat and saliva in patients with Sjögren 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 with moderate to severe symptoms who can tolerate its cholinergic side effects

Biological Tear Substitutes

Autologous Serum

• Contains fibronectin, vitamin A, cytokines, growth factors, and anti-inflammatory substances
  • Studies showed that serum and other blood derivatives may promote corneal healing due to its biochemical characteristics
• Shown to be beneficial in patients with Sjögren syndrome, graft-vs-host disease, Stevens-Johnson syndrome, cicatricial pemphigoid, etc
• Improves dry eye symptoms, TFBUT and rose bengal staining scores as evidenced by studies compared to artificial tears

Salivary Gland Autotransplantation

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

Umbilical Cord Serum

• Useful in patients with systemic inflammation, anemia or chronic diseases who may not be ideal candidates for autologous serum
• Improves symptoms, TBUT, corneal staining and impression cytology findings in patients with DES resistant to conventional treatment and in ocular graft-vs-host disease
• Studies showed lower symptoms and corneal fluorescein staining scores in severe DES and higher goblet cell density in Sjögren syndrome compared to autologous serum

Antioxidants

Skulachev Ions/SkQ1

• 1st topical drug registered in Russia that targets oxidative stress in mitochondria
• Studies show improvement of symptoms, reduced corneal staining and promotes corneal epithelial wound healing

• Patient education is important to discuss the chronic nature and history of DED, setting therapeutic goals and treatment instructions 
• Lifestyle/environmental modifications are effective for most patients with DED
  
  • Advise patient to reduce or eliminate exacerbating medications (eg antihistamines, antidepressants) and environmental stresses (eg low humidity, air conditioning)
    
    • Humidified environment decreases tear evaporation
  • Encourage the patient to have regular breaks with eye closure when reading or working on a computer
  • Instruct the patient to lower computer screens to below eye level to reduce interpalpebral aperture
  • Advise the patient to keep away from hot, windy, low-humidity, and high-altitude places, and to avoid smog, smoke, and vehicle’s exhaust
    
    • Moisture-retaining glasses may be recommended
  • Educate the patient on correct use of contact lenses

• For patients with chronic blepharitis and meibomian gland dysfunction which may be associated with tear dysfunction, eyelid hygiene is an important component of patient’s management
  
  • Removes irritating debris, increases blood flow, and opens up blocked meibomian glands
  • Warm lid compresses aid in decreasing meibum viscosity and preventing obstruction of ducts

• Diet influences dry eye symptoms
  
  • Recommend to increase omega-3 fatty acid in diet (eg fish, fish oil, plants, plant oil) and to decrease omega-6 fatty acid
    
    • Omega-6 fatty acids are precursors of certain lipid-derived proinflammatory mediators, while omega-3 fatty acids inhibit their synthesis and block production of other inflammatory cytokines
  • Advise the patient to take supplements that contain linoleic acid and gamma-linoleic acid which were shown to improve symptoms and decrease lissamine green staining

Punctal Plugs

• Temporary occlusion of one or both puncta to keep tears on the ocular surface by decreasing tear drainage 
• Recommended in patients with symptomatic dry eyes, Schirmer test (with anesthesia) <5 mm at 5 minutes, and have evidence of ocular surface dye staining
• Should be avoided by patients with allergy to components of the plug, punctal ectropion, pre-existing nasolacrimal duct obstruction, untreated clinical ocular surface inflammation, or in patients with acute or chronic lacrimal canaliculus or sac infection
• Complications may include spontaneous plug extrusion, infection, punctal enlargement, internal migration of a plug, biofilm formation or infection, or pyogenic granuloma formation

Moisture Chamber Spectacles

• Eyeglasses that help to slow down evaporation of tears by lessening airflow and providing a humid environment on the ocular surface 
• Alleviates ocular discomfort due to dry eye
• Shown to increase interblink intervals

Contact Lenses

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