Dry Eye Syndrome Management

The goals of treatment are the following:

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

Pharmacological therapy in DES is based on the severity of patient’s symptoms and is adjusted depending on the response. The medication’s efficacy and safety, and the patient's convenience are taken into consideration when subjecting the patient to long-term treatment. 

Tear Supplementation (Lubricants or Artificial Tears)  

These are hypotonic or isotonic solutions that contain electrolytes, surfactants, and different viscosity agents. Ideally, these should be preservative-free, contain potassium, bicarbonate, and other electrolytes, and have polymeric system that increases retention time. For example, nonbenzalkonium chloride (BAK) preserved drops may still be used in mild to moderate DES.  

They are mainly used to lubricate the ocular surface through their viscosity and mucoadhesive properties. They replace the tear volume and target ≥1 tear film layer. They are also able to provide short-term palliative relief of dry eye symptoms and aid in decreasing inflammation by diluting or washing away inflammatory agents.  However, these drugs do not replace the cytokines and growth factors and have no anti-inflammatory properties.  

In general, these do not alter ocular pathology but there are some studies showing that regular use of these agents leads to improvement in the tear break up time (TBUT) and eliminate dry spots, thus implying a reparative effect on superficial corneal epithelial cells and their glycocalyx.  

Agents are selected based on concentration and choice of electrolytes, osmolarity, and type of viscosity or polymeric system, presence and type or absence of preservative. Lastly, there is no evidence yet that any agent is superior to another.  

 

Preservative-free Lubricants  

Preservative-free lubricants may be used more frequently without the possible toxic side effects of preservatives. Preservatives such as BAK, disodium ethylenediaminetetraacetic acid (EDTA) can irritate the eye and aggravate dry eye symptoms. The toxicity of BAK depends on its concentration, dosing frequency, tear secretion level, and ocular surface disease severity. BAK may also induce corneal and conjunctival epithelial cell apoptosis, corneal nerve damage, impair wound healing, and disturb tear film stability. These agents with preservatives may be more tolerated by patients with mild DES when used for ≤4-6 times a day.  

When managing patients with moderate to severe DES, a more important characteristic to be considered is the presence or absence of preservatives rather than the type of polymeric agent used. For example, BAK toxicity may be high in patients with moderate to severe DES due to reduced tear secretion and turnover.  

Preservative-free lubricants are highly recommended in patients with severe dry eyes with ocular surface disease and impaired lacrimal gland secretion, and in patients on various preserved topical medications for chronic eye disease.  

Perfluorohexyloctane is a novel, preservative-free lubricant that has obtained recent approval from the FDA for the management of DES. Studies show that there is marked improvement in the symptoms of dry eye syndrome secondary to meibomian gland dysfunction.

These agents may be available as liquid drops, gels, oils, 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, these are applied at bedtime. Lastly, ocular inserts are long-acting, slow-release ocular rods of hydroxypropyl cellulose that are used to decrease repeated installation of artificial tears. However, they are limited by the discomfort of placing a foreign body in the inferior conjunctival sac.  

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

Electrolyte- or ion-containing lubricants have shown to be useful in treating ocular surface damage caused by dry eye. They are buffered solutions containing Potassium, Calcium, Magnesium, Phosphate, Bicarbonate, and Sodium chloride that are used to maintain the epithelial surface. In the case of Potassium, it is vital in maintaining corneal thickness. Tears with high Potassium levels may protect the corneal epithelium from ultraviolet B (UVB) radiation. It is noted that decreased Potassium may increase corneal thickness. While Bicarbonate promotes the recovery of the epithelial barrier function in damaged corneal epithelium and helps in maintaining normal epithelial ultrastructure. It also maintains the mucin layer of the tear film. Lastly, it must be noted that 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  

Hypo-osmotic lubricants are important since increased tear film osmolarity (crystalloid osmolarity), commonly seen in patients with dry eyes, causes morphological and biochemical changes to the corneal and conjunctival epithelium and is proinflammatory. 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 then lead to return of normal cell physiology as colloidal osmolality difference affects the net flow of water across membranes. Importantly, under hyperosmotic stress, these lubricants may inhibit inflammation.  

Viscosity Agents of Lubricants

Examples: Carboxymethylcellulose (CMC), Hydroxymethylcellulose (HMC), Polyvinyl alcohol, Polyethylene glycol, Glycol 400, Propylene glycol HMC, Hydroxypropyl methylcellulose (HPMC), Carbomer (Polyacrylic acid)  

Addition of macromolecular components to tear supplements leads to increased residence time which provides longer interval of the patient’s comfort. For example, CMC was shown to bind and be retained by human epithelial cells and promote healing. These agents also help protect the ocular surface epithelium. HMC coats and protects the surface epithelium or helps restore the protective effects of mucins. While CMC was shown to have cytoprotective properties that may promote re-epithelialization of corneal wounds.  

It must be remembered that an important factor of a lubricant is its viscoelasticity. Lubricants must be viscous enough to remain on the corneal surface without being washed away. At the same time, they must 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. For overnight use, very high viscosity eye drops are recommended while during low viscosity ones are 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 the eyelashes are limiting factors of high molecular weight viscous agents especially for patients with mild to moderate dry eye. Castor oil or mineral oil can be 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 have also shown that the combination of CMC and Hyaluronic acid improves signs and symptoms of DES compared to CMC alone.  

Anti-inflammatory Agents  

Anti-inflammatory agents are indicated in patients with corneal disease who have persistent symptoms despite extensive use of artificial tears.  

Corticosteroids (Ophthalmic)  

Ophthalmic corticosteroids inhibit inflammatory response with fast onset of action. They improve signs and symptoms of patients with or without Sjögren syndrome. Studies have also 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 to 4 weeks of treatment of patients with moderate to severe dry eye. They should not be recommended for long-term use due to possible serious side effects. However, 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  

Cyclosporine inhibits T lymphocyte activation but does not affect T lymphocytes. It reduces fluorescein staining of the cornea and increases the basal and reflex tear secretion. It also alleviates symptoms of blurred vision, decreases the need for artificial tears, and improves evaluation of global response to treatment. Cyclosporine requires 2-4 weeks of continuous administration before significant improvement of symptoms is noted. Improvement was also noted for ≥6 months even when medication had been stopped.  

Early initiation may be considered to manage inflammation in patients with risk factors for developing severe dry eye syndrome. Patients should be examined ideally after a month and then every 3 months of treatment. The dose may be decreased to once a day regimen after a full year of therapy without a decrease in beneficial effects. Studies demonstrate long term tolerability (24 months) with no reports of systemic adverse events. 

It is an effective and less toxic alternative to ophthalmic corticosteroids. Cyclosporine, when combined with ophthalmic corticosteroids, produces a faster anti-inflammatory response by stimulating lymphocyte apoptosis. Initiation of short-term treatment with corticosteroids at the same time, or shortly before Cyclosporine leads to better clinical outcomes. It may also be given to patients with dry eyes who underwent punctal occlusion. It optimizes the 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. Cyclosporine may also improve corneal nerve regeneration or nerve sensitivity and promote better and faster recovery of visual acuity.  

Lifitegrast  

Lifitegrast is a lymphocyte function-associated antigen 1 (LFA-1) antagonist which blocks lymphocyte interaction to upregulated adhesion molecules. It improves signs (eg corneal and conjunctival) and symptoms (eg eye dryness score and ocular discomfort) of dry eye after 3 months of use. However, further studies are still needed to establish long-term effectiveness and safety.  

Macrolides

Example drug: Azithromycin  

Macrolides significantly reduces cellular accumulation of cholesterol, cholesterol esters, phospholipids, and lysosomes on human meibomian gland epithelial cells compared with Doxycycline, Minocycline, and Tetracycline. Their anti-inflammatory properties may reduce bacterial flora and lid inflammation in meibomian gland dysfunction associated with rosacea.  

Tetracyclines

Example drugs: Doxycycline, Minocycline  

Tetracyclines are broad-spectrum antibiotics which inhibit protein synthesis by binding aminoacyl-transfer ribonucleic acid (tRNA) to the messenger RNA (mRNA)-ribosome complex. They reduce inflammatory cytokine production (eg interleukin-1 [IL-1], and tumor necrosis factor α [TNF-α]), restrain collagenase, phospholipase A2, and matrix metalloproteinases’ activity, and have antiangiogenic properties. They may also help improve dry eye symptoms of patients with ocular rosacea or meibomian gland dysfunction.  

Secretagogues  

Cevimeline  

Cevimeline is a muscarinic acetylcholine receptor agonist that is used for the treatment of Sjögren syndrome-associated DES. Studies have shown significant improvement in ocular dryness and dry mouth with increased lacrimal and salivary flow rates. Long-term compliance to Cevimeline compared to Pilocarpine is due to the lesser reported adverse effects in the former.   

Diquafosol  

Diquafosol is a purinergic P2Y2 receptor agonist that stimulates water and mucin secretions from conjunctival epithelial cells and goblet cells. Studies have also shown significant improvement in TBUT, corneal and conjunctival fluorescent staining, and Schirmer score. Three percent ophthalmic solution is approved for the treatment of DES in several Asian countries.  

Pilocarpine  

Pilocarpine is a muscarinic agonist that is used to stimulate production and secretion of tears, sweat, and saliva in patients with Sjögren syndrome. However, it is more effective for dry mouth than for dry eye symptoms. Dry eye symptoms showed improvement after 6 to 12 weeks of treatment. It may cause transient increase in the number of goblet cells. It is reserved for patients with moderate to severe symptoms who can tolerate its cholinergic side effects.  

Varenicline  

Varenicline is a highly selective nicotinic acetylcholine agonist that acts as a neuroactivator for tear film production. A phase 3 study showed clinically significant improvement in symptoms, with good tolerability.

Biological Tear Substitutes  

Autologous Serum  

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. Autologous serum has been shown to be beneficial in patients with Sjögren syndrome, graft-vs-host disease, Stevens-Johnson syndrome, cicatricial pemphigoid and many more. It improves dry eye symptoms, TFBUT, and rose bengal staining scores as evidenced by studies compared to artificial tears.  

Salivary Gland Autotransplantation  

Salivary gland autotransplantation may replace deficient mucin and aqueous tear film phase. It is only recommended 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. This causes significant improvement in Schirmer test, TFBUT, and rose bengal staining while reducing discomfort and the need for pharmaceutical ophthalmic lubricants.  

Umbilical Cord Serum  

Umbilical cord serum is useful in patients with systemic inflammation, anemia, or chronic diseases who may not be ideal candidates for autologous serum. It improves symptoms, TFBUT, corneal staining, and impression cytology findings in patients with DES resistant to conventional treatment and in ocular graft-host disease. Studies have shown 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)  

SkQ1 is the first topical drug registered in Russia that targets oxidative stress in the mitochondria. Studies show improvement of symptoms, reduced corneal staining, and promotes corneal epithelial wound healing. 

Investigational Agents  

Rebamipide  

Rebamipide is a quinolinone derivative that increases prostaglandin E2 and I1, which stimulates secretion of mucins by the conjunctival goblet cells, causing improved surface healing and tear film stability. A multi-center, randomized, double-blinded, phase IIb/III study showed significant improvement in both TFUT and Shirmer test compared to placebo. 

Patient Education

Patient education is important to discuss the chronic nature and history of DES, setting therapeutic goals and treatment instructions. Additionally, lifestyle and environmental modifications are also effective. Patients are advised to reduce or eliminate exacerbating medications (eg antihistamines, antidepressants) and environmental stresses (eg low humidity, air conditioning). In the case of humidity, a humidified environment decreases tear evaporation. The patient is also encouraged to have regular breaks with eye closure when reading or working on a computer. Patients are instructed to lower screens to below eye level to reduce interpalpebral aperture. It is also advised that patients are to keep away from hot, windy, low-humidity, and high-altitude places. Moisture-retaining glasses may also be recommended. It is also important to educate patients on the 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 the patient’s management. Warm lid eye compresses aid in decreasing meibum viscosity and preventing obstruction of ducts. Proper eyelid hygiene removes irritating debris, increases blood flow, and opens blocked meibomian glands. Symptoms of dry eyes are also influenced by diet. Omega-3 fatty acids are recommended to be increased in the diet, while decreasing omega-6 fatty acid intake. This is due to the fact that 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. Lastly, patients are advised to take supplements that contain linoleic acid and gamma-linoleic acid which were shown to improve symptoms and decrease lissamine green staining. 

Tear Retention Devices

Punctal Plugs  

Punctal plugs provides temporary occlusion of one or both puncta to keep tears on the ocular surface by decreasing tear drainage. They are recommended in patients with symptomatic dry eyes, Schirmer test (with anesthesia) <5 millimeters at 5 minutes and have evidence of ocular surface dye staining. They 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 of punctal plugs include spontaneous plug extrusion, infection, punctal enlargement, internal migration of a plug, biofilm formation or infection, or pyogenic granuloma formation.  

Moisture Chamber Spectacles  

Moisture chamber spectacles are eyeglasses that help slow down evaporation of tears by lessening airflow and providing a humid environment on the ocular surface. They alleviate ocular discomfort due to dry eye and have shown to increase interblink intervals.  

Contact Lenses

Example: Hydrophilic bandage contact lenses  

These may be used to protect and hydrate the corneal surface in patients with severe DES. They have also been shown to improve visual acuity and comfort, decrease corneal epitheliopathy, and heal persistent corneal epithelial defects. However, they may be associated with a small risk of corneal vascularization and corneal infection when sued by patients with dry eyes.