The initial management of dry eye disease relies on the use of artificial tear substitutes and the conservation of natural tears. Most artificial tears are lubricants with an electrolyte content that is only an approximation of normal tears. Viscosity agents are often added to artificial tears to increase the ocular surface residence time. An understanding of the complex interactions between aging, hormonal change, the environment, and the immune system has lead to new therapies to treat dry eye disease. Treatments that reduce associated con-junctival inflammation and stimulate the production of normal tear components may become increasingly important for the management of severe disease. An understanding of the behaviour of normal tears and the aetiology of dry eye is fundamental to the development of an effective treatment strategy.

Rational for Medical Management


Structure of the Tear Film
The tear film is part of a functional unit that comprises the tears, corneal and conjunctival epithelium, lacrimal glands, and lids. Disturbance of one or more of these interrelating structures can result in characteristic symptoms and signs of dry eye disease. This disease acts through the common disease mechanisms of hyperosmolar tears and surface drying that damages the epithelial cells, with associated inflammation and a susceptibility to infection. The terms dry eye disease, dysfunctional tear syndrome, and keratoconjunctivitis sicca are synonymous.

Tears are mechanically spread over the ocular surface by upper lid blinking, but the development of an effective tear film depends upon surfactant phospholipids in the surface layer and mucous in the basal layer that allows the fluid to adhere to the hydrophilic epithelial cells. The lubricating action of the tear film disperses the shearing forces on the epithelium caused by blinking. Finally, the tear film provides a smooth optical interface, transports metabolites, and freely transmits oxygen and carbon dioxide to the cornea.

The structure of the tear film consists of an outer lipid layer lying on an aqueous layer that contains mucus. The meibomian glands secrete the lipid, which is released from the glands by lid movement. The lipid layer is composed of two phases: (1) an outer surface non polar phase that contains waxes, cholesterol esters, and triglycerides and (2) an inner polar aqueous-mucin phase that has surfactant properties. The inner polar phospholipids are bound to protein lipocalins within the aqueous layer that bind hydrophobic molecules and contribute to tear viscosity. The lipid layer reduces evaporation from the aqueous layer and dysfunction may result in an evaporative dry eye state.

The aqueous layer is secreted by the main and accessory lacrimal glands and consists of water, electrolytes, dissolved mucins, and proteins. It has antibacterial properties due to the presence of IgA, lysozyme and lactoferrin, and it contains growth factors (EGF, TGF-a, HGF) secreted from the lacrimal gland in response to injury. It also contains leukocytes and pro-inflammatory cytokines that accumulate when tear production is reduced during sleep. The aqueous phase can physically wash away debris and toxic agents that may cause inflammation. Deficiency of this layer results in an aqueous deficiency dry eye.

Mucins are at their highest concentration internally in the aqueous phase and they serve to increase viscosity and anchor the aqueous phase to the glyco-calyx of the external cells of the epithelium. Each mucin is a high-molecular-weight glycoprotein containing a protein core with radially linked carbohydrate side chains. The protein core forms the basis of further classification (e.g. MUC1, MUC2, etc.). Human mucins are classified according to anatomical distribution as transmembrane or secretory, and the secretory mucins are further classified according to their physical properties as gel-forming or soluble. Secretory ocular mucins are principally produced by the conjunctival goblet cells (MUC5AC) but also by the lacrimal glands (MUC7).

The glycocalyx of the superficial epithelial cells of the cornea and conjunctiva is formed of trans-membrane mucins (MUC1, MUC2, and MUC4). MUC1 is essential to aid spreading of the secretory gel mucin produced by goblet cells and it also prevents pathogens binding to the ocular surface. Damage to the mucus-binding complex will change the cell membrane from a hydrophihc to a hydrophobic surface and prevent normal tear film adherence. Loss of goblet cells and ocular surface mucus is a feature of cicatrising conjunctivitis, vitamin A deficiency, and chemical burns. Almost all of this complexity of structure is absent from artificial tears.

Mechanical Behaviour of the Tear Film
Fluids can be classified according to the way they behave under sheer stress. A perfect fluid has no resistance to shear stress and therefore lacks viscosity. Fluids that are not perfect are classified as either newtonian if their viscosity is constant for different rates of shear, or non-newtonian if they become less viscous over time when a shear force is applied. This property of non-newtonian fluids is termed thixotropy - these are fluids that are both viscous and elastic. Tears have thixotropic properties but most artificial tears do not. The linear charged polymers (carboxymethylcellulose and hyaluronic acid) are the only agents used in artificial tears that have shear-thinning characteristics of non-newtonian fluids. It has been proposed that tears behave like a fluid during blinking but more like a gel between blinks.

Regulation of Tear Film Components
Regulation of the stability of the tear film is under hormonal and neuronal control. Androgen receptors have been identified in meibomian tissue, while oestrogen and progesterone receptors have been identified in conjunctiva and lacrimal gland. Postmenopausal women and the elderly may be relatively androgen-deficient and this may account for some of the involutional changes seen in periocular tissue. Androgens (testosterone) may also act as a natural suppressor of inflammation. Hormone treatments have been evaluated to treat some of the involutional changes associated with dry eye disease. Nerve fibres have been demonstrated adjacent to the lacrimal gland, goblet cells, and meibomian glands. The role of these fibres in maintaining the tear film is unclear although parasympathetic (acetylcholine- and VIP-dependent) fibres stimulate aqueous and protein secretion from the lacrimal gland, and VIP endings at the basement membrane may stimulate mucus secretion from the goblet cells.

Inflammation and Dry Eye Disease
A T-lymphocyte infiltrate is present in the conjunctiva and accessory glands of 80% of patients with dry eye disease. There is also an increased expression of HLA class II antigens, markers of apoptosis (Fas-Fas ligand), and inflammatory cytokines in the epithelium. Although this is thought to be a primary event in Sjógren's syndrome, secondary inflammation from surface friction during blinking is probably an aggravating factor in the majority of patients with dry eye disease. Inflammation may thus be both the cause and the result of dry eye, amplifying and perpetuating disease. The presence of inflammation is the rationale for the use of steroid and immunosuppression in the treatment of dry eye disease in patients with and without Sjógren's syndrome.

Guidelines for Clinical Management
Dry eye disease is generally not curable and management is structured around the control of symptoms and the prevention of surface damage. Clinical tests have a low sensitivity and specificity and they are not a reliable basis for management. Fortunately, in the great majority of patients the disease is not sight threatening. The choice of treatment depends on the severity of the disease, and one or more of the following measures may be used alone or in combination. Initial treatment is with artificial tears that lubricate the surface and reduce lid friction, although they usually only provide relief for a short time period after drop instillation. The goal of treatment is to improve eye comfort and vision at a frequency of treatment that can be reduced to a minimum. Guidelines have been produced to indicate the level of management that is appropriate according to the severity of disease. There is a placebo effect and some patients wish to continue using artificial tears without clinical signs of dry eye. A benefit with regard to patient symptoms is more difficult to achieve than a resolution of ocular signs.

General Measures

Patient education. Discuss the nature of the condition to establish a realistic expectation of outcome, provide reassurance, and encourage compliance with treatment.

Review of the home and work environment. Emphasize the importance of blinking when reading or using a video display unit. Eliminate dry air conditioning and wind if possible. A reduction in room temperature and central heating will minimize tear evaporation. Humidifiers are usually disappointing because they do not increase room humidity sufficiently. Working directives and open plan offices can limit the ability of employers to implement these recommendations. A local increase in humidity can be achieved with moist chamber goggles or side shields to glasses if this is cosmetically acceptable.

Discontinue toxic topical treatments if possible. Numerous systemic treatments have been associated with symptoms of dry eye, e.g. thiazide diuretics, anticholinergics, tricyclic antidepressants, (3-blockers, isotretinoin (13-cis-retinoic acid), and antihistaminines (loratadine, cetrizine). The excipients (e.g. benzalkonium chloride, EDTA) in drops used for other reasons, e.g. glaucoma medications, may aggravate surface damage. The preservative benzalkonium chloride can be particularly toxic to the epithelium.

Aids should be provided for patients with a loss of dexterity (e.g. rheumatoid arthritis). Single unit dose dispensers for preservative free drops may not be appropriate. Stiff plastic dropper bottles can be held and squeezed in a nutcracker or an eyedrop bottle squeezer (available commercially).

Identify and Treat Associated Conditions


Local Factors Associated with Dry Eye
These factors include: Posterior lid margin disease (blepharitis) may exacerbate evaporative dry eye. This may be associated with rosacea and allergic eye disease, Corneal exposure from lagophthalmos, lid margin defects, or seventh nerve palsy allows excessive evaporation. Abnormal globe position, lid retraction or exophthalmos from thyroid eye disease should be treated, Relative corneal anaesthesia with reduced reflex tearing following LASIK may precipitate dry eye symptoms.

Systemic Disease
A number of systemic conditions also cause ocular surface disease and severe dry eye, although dry eye disease is rarely the presenting symptom. These conditions should be investigated and treated appropriately, but the treatment of the associated dry eye disease is then usually still based on ocular signs rather than the underlying condition. These diseases include: (i) Sjógren's syndrome; (ii) rheumatoid arthritis; (iii) scleroderma (crest syndrome - calcinosis, Reynaud's phenomenon, oesophageal hypomotility, sclerodactyly, and telang-iectasia); (iv) systemic lupus erythematosis; (v) retroviral infection: infection with HTLV1, HIV, hepatitis C, or chronic Epstein-Barr virus (EBV) infection -EBV infection has been proposed as a trigger for the onset of Sjógren's syndrome, and (vi) cicatricial conjunctivitis (mucous membrane pemphigoid, Stevens-Johnson syndrome, atopic keratoconjunctivitis, graft-versus-host disease).

Tear Substitutes
These have a relatively simple formulation compared to normal tears and their delivery is periodic rather than continuous. Although continuous delivery pumps are available, they are usually restricted to the treatment of extreme dry eye. The relative contribution of their individual components to the overall desired effect - lubrication, replacing tear components, reducing osmolarity, or diluting inflammatory agents - is difficult to prove. Slightly alkaline pH drops are better tolerated than neutral or acidic drops.

Almost all artificial tears aim to replace the aqueous phase of the tear film. There are no mucus substitutes, and oils and lipids are only an approximation to the action of tear lipid layer. Simple electrolyte solutions and saline are rapidly lost from the ocular surface and attempts have therefore been made to increase the ocular surface residence time by adding macromolecules that increase the viscosity or gel properties of the solution, contribute a demulcent effect, and potentially combine with the mucus component of the tear film. These viscous or gel agents are otherwise inactive components of the drop. For example, the ocular surface residence time of carboxymethylcellulose is significantly longer than smaller molecule hydroxypropylmethylcellulose, although it is uncertain whether this fact fully explains the difference in effect. Because relative efficacy or artificial tear drops is difficult to compare the principal categories are listed in alphabetical order below and in table.

Acetylcysteine 5% drops are commercially available and are useful in patients with filamentary keratitis and mucous plaques secondary to dry eye. They are used 4 times daily and may cause stinging following instillation if there is epithelial disease. Acetylcysteine 10 and 20% is not available commercially and they have a limited bottle life even if kept refrigerated.

Cellulose based products have been the mainstay of artificial drop treatment for years. Except for carmellose they have a short ocular surface residence time.

Carbomers 974P and 980 make a relatively viscous solution, which increases ocular residence time.

Electrolyte solutions are marketed to treat the 'electrolyte toxicity' from hypertonic tears. Their constituents are usually not provided. They may have added w-3, flaxseed or evening primrose oil, and vitamins A or E of unknown effect. They are not CE marked and have not been evaluated by the FDA but are available on the Internet. Saline (0.9%) drops are effective but very short acting.

Hydroxypropyl (HP) guar is not listed in pharmacopeias. It is marketed as Systane® (Alcon), which also contains polyethylene glycol 400 and propy-lene glycol. It is proposed that HP-guar becomes a viscous gel on combination with the patient's tears and binds to the hydrophobic epithelial surface to form a protective layer.

Oils and ointments contain petrolatum mineral oil (paraffin) and wool fat. Castor oil emulsion is marketed as Refresh Endura™ (Allergan) in the USA. Ointments can be useful for extreme dry eye disease and they can be used at bedtime to supplement other treatments given during the day. They can blur vision, which limits their use in mild dry eye. Clarymist™ is a spray that contains soy lecithin 1.0% incorporated in liposomes. The phosphatidylcholine polar molecule consisting of a fatty acid component that is lipid-soluble and a charged phosphate group that is water-soluble. It is proposed that this mimics the function of the tear lipid layer.

Polyvinyl alcohol and povidone are viscous additions to a balanced saline solution. They are available as non-preserved drops.

Autologous serum (20-100%) contains surface-acting proteins, cytokines, and inhibitors of inflammation. They are effective in severe dry eye disease such as graft-versus-host disease or ocular cicatricial pemphigoid and for in the management of associated epithelial breakdown. Recent European legislation has limited the manufacture of blood products to accredited laboratories and blood banks. The manufacture is therefore expensive.

Sodium hyaluronate is available from several manufacturers as unit doses or as a spray (Hycosan®, Vismed®, Hyabak®, HyloVision HD®) with a sufficient amount to last several weeks. It has a relatively long surface residence time and is particularly effective in the management of severe dry eye states. Concerns have been raised that phosphate-buffered solutions of sodium hyaluronate can cause corneal calcium precipitation in severe dry eye disease.

The excipients (stabilizers, buffering systems, etc.) and preservatives in many formulations are a potential source of corneal toxicity, especially if there is delayed tear clearance after punctal occlusion. Preservative-free drops are essential if there is severe dry eye, and the intensive use of drops containing benzalkonium chloride in severe dry eye can cause central corneal melt. It is recommended that non-preserved drops be used whenever possible, particularly if treatment is required more than 4 times daily.

Management of Dry Eye with Contact Lenses
Contact lenses can be used as an aid to manage dry eye disease or ocular surface exposure by preventing or reducing surface evaporation. They can help reduce surface discomfort from keratinisation or filamentary keratitis, and rigid lenses can overcome the effects of irregular astigmatism. Their use is normally reserved for patients with moderate to severe dry eye liable to epithelial breakdown and unresponsive to topical treatment, and their use is supplemented with ocular lubricants. In patients with Stevens-Johnson syndrome and ocular cica-tricial pemphigoid, shallow fornices and symblepharon may mean that large diameter lenses cannot be used. Hydrogel, silicone hydrogel, and silicone rubber lenses have been evaluated, but there is an increasing interest in the use of rigid corneal and scleral lenses.

For each lens the potential benefit of a reservoir of fluid trapped behind the lens and the mechanical protection provided has to be weighed against the increased evaporation from the surface of the lens, reduced tear flow, and the risk of infection. The key properties of lens fit, the resistance to spoliation, and the oxygen transmission of the available contact lenses are listed below and in table. Oxygen transmission is measured as the Dk/t of the lens - where Dk is the oxygen permeability of the lens material and (t) the lens thickness. To limit overnight corneal swelling to <4%, it has been estimated that a lens should have a Dk/t of 87.0 ± 3.3 X 10~9 units, where the units are (cm/s) (ml 02/ml X mm Hg). Hydrogel Lenses These are available in a wide range of parameters. The use of a thin lens made of a high water content material increases the oxygen transmission, although they are not recommended for overnight wear as they do not achieve the required Dk/t.

The lens material may carry an electronic charge such that an ionic material attracts positively charged proteins, while non-ionic materials tend to attract lipids. If there is decreased tear production with a high concentration of protein and mucin in the tear film a non-ionic material may be preferable. Omafilcon A (Proclear, Coopervision) contact lenses have a high water content and incorporate phosphorylcholine that creates a biocom-patible layer of synthetic lipid on the surface that makes the lens hydrophilic, increases the surface wettability, and reduces the rate of protein adsorption. The Benz 3X lens material has similar properties (Igel®, Ultravision). High water content lenses can cause corneal dehydration by absorbing water from the tear film, and with a poor tear film the lens is prone to drying and discomfort. For more severe dry eye conditions a thin low water content lens should be considered although they carry a greater risk of epithelial hypoxia.

Silicone Hydrogel Lenses These have high oxygen transmissibility due to the silicone component of the lens material, and because the water content can be reduced the potential for lens dehydration is also reduced. They meet the minimum recommended oxygen transmission for overnight wear. The lens is less flexible than a hydrogel lens and sometimes may be less comfortable due to the higher modulus. Until recently, silicone hydrogel lenses were only available in a limited number of parameters. Second-generation silicone hydrogel materials such as Galyfilcon A (Acuvue® Advance™, Johnson & Johnson) and Iotrafilcon B (02 Optix™, CIBA Vision) have a higher water content and although they have a lower Dk/t their increased flexibility may increase comfort. These new lenses have a Dk/t of>130.

Silicone Rubber
Silicone rubber lenses have previously been used extensively for managing severe dry eye disease. They have an extremely high oxygen transmissibility of 200-400 and can be worn overnight without hypoxia. They do not contain water and cannot dehydrate but they are prone to surface spoliation. They can also tighten unpredictably after fitting, which can result in lens binding. They are semi-rigid and do not drape well over an irregular cornea. Two types of silicone rubber lenses have been marketed, Silflex (Wóhlk) and Silsoft (Elastofilcon A, Bausch & Lomb). Unfortunately, Silflex lenses have been withdrawn and Silsoft™ lenses are only available in high positive powers for aphakia or high hypermetropia.

Limbal Diameter Rigid Gas-Permeable Lenses (RGP)
Limbal diameter rigid lenses are particularly useful in cases of exposure or moderate to severe dry eye (e.g. Stevens-Johnson syndrome). They protect the entire corneal surface by retaining a tear reservoir. They flex less than silicone lenses so the chances of binding are reduced. The oxygen transmission is not as high as silicone rubber, but greater than hydrogels. Although they may not be as comfortable as hydrogel or silicone hydrogel lenses in mild dry eye, they do not dehydrate and may be more comfortable in severe dry eye.

Scleral Lenses
Scleral contact lenses have an important role in the management of severe dry eye disease, exposure, and trichiasis. With the introduction of RGP materials the first choice for fitting is with a non-ventilated design. They have a large diameter (typically between 16 and 23 mm) and the bearing surface for the lens is the sclera rather than the cornea. The lens retains a precorneal fluid reservoir of saline or non-preserved artificial tear solution that maintains corneal hydration and physically protects the entire ocular surface. They can be comfortable to wear without adaptation because there is little movement and thus minimal lid sensation. Although fitting sets are available, specialist knowledge of their use is necessary. Overnight wear is possible although there is significant hypoxia, and this is only indicated if there is nocturnal exposure.

Collagen Shields
These have been evaluated for dry eye but are now generally unavailable. They contain porcine or bovine collagen and are packed dry and hydrated with saline before inserting. They can help re-epithelialisation of the severe dry eye, although they are not licensed for the treatment of dry eye. They dissolve over time although the rate can vary. They can be uncomfortable, vision is usually reduced to at least 6/36 and corneal visualisation is difficult. The oxygen permeability of a new lens is similar to a hydrogel lens, but this increases dramatically as the lens dissolves.

Contact Lens Selection
The type of contact lens used is dependent on the severity of the ocular surface disease and the aetiology. Table summarises the different lens types and provides a guideline for lens selection dependent on the severity of dry eye. A silicone hydrogel lens can be used across the whole spectrum of disease as long as the fornices are not severely contracted. Table shows the compatibility between eyedrops and contact lenses. If treatment with topical medication is required the use of a non-fenestrated scleral lens may prevent effective drug penetration.

Tear Stimulation
Cholinergic agonists (secretogogues) such as oral pilocarpine (Salagen® 5 mg orally q.i.d.) and cevimeline (15 mg t.i.d.) that act on the exocrine glands have been shown to reduce the symptoms of dry eye and dry mouth in patients with Sjógren's syndrome, although side effects such as flu-like symptoms, blurred vision, nausea, and sweating in about 40% of patients limits their usefulness. Diquafosol 2%, a topical analogue for the nucleotide receptor P2Y2, has been shown to be capable of increasing the production of ocular surface aqueous and mucous, although it improves corneal signs better than symptoms. Other topical agents (rebamipide, ecebet sodium, gafar-nate) are being assessed as mucous production stimulators. Stimulated secretion of mucin MUC1 from corneal epithelium by topical eicosanoids (15(S)-HETE) has been demonstrated. Topically applied eledoisin (Alcon-Cusi, Spain), a extract from octopus venom glands, stimulates tear flow as a vasodilator and a contraction agent of extravascular smooth muscle and may be useful in volume-deficient dry eyes due to palsy of the major pet-rosal nerve.

Anti Inflammatory Agents

Low dose topical steroid is an effective supplementary treatment for the management of acute exacerbations of dry eye disease. However, the risks of long-term treatment must be balanced against the potential benefits of increased comfort. Intensive topical prednisolone 1% used 4 times daily for 6 weeks was reported to be helpful in severe dry eye associated with graft-versus-host disease.

Topical ciclosporine A 0.05%(Restasis®, Allergan) is a safe, well-tolerated agent that reduces T-cell-mediated inflammation of lacrimal tissue. Treatment is followed by a fall in indictors of inflammation (HLA-DR-positive cells, IL-6 levels, and apoptosis) in the tear film and conjunctiva. An increase in goblet cell numbers and reversal of squamous metaplasia has also been documented, with an improvement in tear flow as assessed by Schirmer's test.

Systemic tetracyclines (doxycycline 50-100mg daily) may help control any blepharitis associated with dry eye disease. It may act as an antibiotic to reduce lipase production that can break down meibomian lipids and exacerbate evaporative dry eye. They may also directly block some inflammatory cytokines and metalloproteinases in the tears.

Other Options

Retinoic acid 0.05% has no demonstrated beneficial effect on dry eye disease apart from reversing squamous metaplasia and keratinisation.

Zidovudine, an antiretroviral agent, has been reported to be effective in primary Sjógren's syndrome.

Postmenopausal women taking oestrogens are at increased risk of developing dry eye disease. Oral oestrogen replacement is not helpful and has potential systemic risks. Although no benefit effect has been demonstrated for topical oestrogens, there may be an effect for combined oral oestrogen and androgen. The role of topical androgens (e.g. testosterone 0.03%) on evaporative dry eye has not yet been fully evaluated.

The effect of flaxseed (w-3) oils taken orally or added to artificial tears is unproven.

Trehalose is a natural disaccharide that protects cells against desiccation. It appears to be clinically effective against signs of dry eye but it is not available commercially.

Patients following acupuncture feel better but lack any objective signs of improvement, suggesting a placebo effect.

Suggested Sequence for the Introduction of Medical Therapy

Symptoms but no signs: (a) environmental measures; (b) preserved artificial drops.

Mild conjunctival and corneal stain: (a) non-preserved drops of increased viscosity; (b) ointment at night.

Confluent central corneal stain: (a) intensive frequency of non-preserved drops; (b) trial of topical anti-inflammatory treatment (cyclosporine A or steroid); (c) temporary punctual occlusion.

Actual or potential epithelial breakdown: (a) intensive non-preserved drops; (b) topical anti-inflammatory treatment; (c) autologous serum (if available); (d) contact lens; (e) immunosuppression for autoimmune disease (rheumatoid arthritis, graft-versus-host disease, OCP, etc).

Conclusions

Medical treatment is central to the management of dry eye disease. Environmental control has an important role in prevention of symptoms.

Use non-preserved viscous preparations wherever possible for moderate to severe dry eye. As the ocular residence time of an agent is increased they tend to become more effective and the frequency of treatment can thus be reduced.

The role of anti-inflammatory agents and topical immunosuppression needs to be better defined.

Contact lenses have a role in the prevention of epithelial breakdown and visual rehabilitation in severely dry eyes.