Dry eye disease is one of the most common eye conditions encountered in primary eye care practice, and seriously affects the well being of the patient. It has been defined by the International Dry Eye Workshop (DEWS) as a ‘multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance and tear film instability with the potential to damage the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface’.1 Dry eye disease is believed to affect 5 to 35% of the general population,2 giving symptoms of discomfort, tired eyes, dryness, burning of the eyes and reduction of vision. Typically it becomes more severe towards the end of the day.3 Several factors have been identified as increasing the risk of developing dry eye, including being female, increasing age,4 hormonal dysfunction,5 contact lens use,6 systemic medication 7 and laser refractive surgery.8 The reduction in quality of life caused by dry eye has been compared to angina 9 in its severity.
Blepharitis is an often chronic inflammatory condition, leading to itching, crusting, and redness of the eye lids,10 and is often associated with dry eye disease. One sub-type, meibomian gland dysfunction (MGD), is considered responsible for up to 86% 11 of dry eye disease due to disruption of lipid production.12
Dry Eye: Anatomy and physiology
The pre-corneal tear film serves a number of purposes: it provides a smooth uniform surface to the cornea, supplies essential nutrients to the corneal surface, allows a fluid movement of the eyelid over the cornea, removes metabolic corneal waste products and contains bactericidal antibodies, proteins and phagocytes to provide immuno-protection. While it is understood to have a complex mixed structure, the pre-corneal model most widely recognized is that of the tri-lamellar tear film,13 consisting of a mucous, aqueous and lipid phase. The typical tear film has a volume of 7.1µl,14 most of which will be concentrated in the tear menisci and having an average thickness over the cornea of just under 5µm.15 Normal osmolarity of this structure is in the region of 285-295 mOsm/L,16 with a pH of 7.6. 17
The mucous phase of the tear film adheres to the corneal epithelial cells. It is made up of mucins, inorganic salts, immunoglobulins and glucose suspended in water.18 Mucus is primarily secreted by conjunctival goblet cells, although small amounts are also secreted by corneal epithelial cells.19 The mucous phase of the tear film is polar and so allows the tear film to adhere to the hydrophobic epithelium, protecting the ocular surface from the shear forces of the eyelid. The mucous phase may also prevent bacterial adhesion to the corneal surface by trapping debris and facilitating their removal by the blinking process.20
The aqueous phase constitutes the main component of the tear film. It is responsible for the lubrication and the provision of nutrients to the ocular surface. Aqueous contains lysozyme, lactoferrin, immunoglobulins, albumin, glycoproteins, and carries oxygen to nourish the corneal surface. 21 Aqueous is secreted by the lacrimal gland, this gland is innervated by both divisions of the autonomic nervous system, with parasympathetic innervation responsible for basal and reflex tearing.
The lipid phase constitutes the outer aspect of the tear film. Its purpose is to retard the evaporation of the aqueous phase, provide a smooth refractive surface to the eye and to form a protective barrier against microbes and debris. The lipid phase is secreted from the meibomian glands in the eye-lids; these secretions are made up of both polar and non-polar components and contain cholesterol, wax esters, free cholesterol, free fatty acids and phospholipids.22 Meibomian secretion is influenced by hormonal, neural and the mechanical force of the eye lid contraction.23
The tear film is spread over the ocular surface by the eye during blinking of the eyelid.24 The other purposes of this action are to remove alien particulate matter and metabolites and to facilitate tear exchange. Blinking is accomplished by contracture of the orbicularis oculi. During this action, the lids move together closing first at the temporal canthus and then the medial canthus, encouraging tear fluid to move down the lacrimal puncta. The compression of the lacrimal ampulla further serves to encourage tear fluid to drain from the ocular surface.12 The average person carries out a blink once every four seconds.25 It is believed that the rate of blinking may in part be mediated by the pre-corneal tear film rupture, suggesting that the blink rate may be timed to avoid tear film destabilisation. A detailed discussion of the lacrimal apperatures will be published in a forthcoming issue of Optician.
Maintenance of this delicate homeostasis is required in order to avoid disruption of the tear film and the descent into ocular surface disease.
Methods of insult
Dry eye may be caused by a number of factors (Figure 1). Typically these are broken down by the nature of the dry eye disease they are responsible for. Dry eye disease may be defined as; aqueous-deficient dry eye, where reduction in aqueous production is responsible for the reduction in tear volume; evaporative dry eye, where the regulation of tear film evaporation is disrupted causing excessive evaporation, and when it is advanced;26 a mixed aqueous-deficient/meibomian gland dysfunction dry eye, where the tear film is compromised by both reduced aqueous production and increased tear fluid evaporation.27
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Aqueous deficient dry eye disease may be thought of as a disruption to the normal regulation of the lacrimal gland. This may be due to a number of inflammatory and auto-immune conditions such as Sjögren’s syndrome.28 In these conditions the lacrimal gland is infiltrated by activated T-cells and this induces cell death of the ductal cells and hyposecretion of aqueous fluid.29 Aqueous deficiency may also occur in the absence of inflammatory conditions; the normal function of the lacrimal apparatus can decrease with advancing age due to periductal fibrosis and blood vessel loss,1,30 by hormonal dysfunction 5, or can be affected by other conditions damaging the ocular surface and inhibiting the corneal sensory reflex.
Evaporative dry eye occurs due to excessive evaporation of ocular tear fluid and may be thought of as being intrinsic (due to a loss of tear film evaporative regulation) or extrinsic (where evaporation is increased by the pathological effects of other conditions).1 Common intrinsic disorders include posterior blepharitis, MGD, disorders of the eye lid and reduced blink rate. Extrinsic causes of dry eye may include preservative toxicity,31,32 contact lens wear,33 allergic response, and goblet cell loss in ocular surface disease.34
The common feature of all forms of dry eye is tear film hyperosmolarity1. This occurs due to a reduction (through evaporation, reduced secretion or a combination of both) of tear volume.35 This hyperosmolarity of the tear film typically ranges from 308-360 mOsm/L16,36 and induces hyperosmolarity in the epithelial cells of the cornea and conjunctiva. Exposure to raised osmolarity leads the epithelial cells to stimulate an inflammatory response, resulting in an increase in inflammatory cytokines, such as metalloproteinases,37 interleukin and tumour necrosis factor alpha.38,39 The inflammation leads to cell apoptosis of conjunctival, corneal and lacrimal gland cells,40 and when coupled with the raised osmolarity leads to a decline in the goblet cell population,41 reducing mucin levels1,42,43 and further destabilisation of the tear film.1
Tear film instability may be the initiating cause of dry eye in many cases,10 with disruption of the lipid layer leading to an increase in evaporation. It may also be initiated by a reduction in corneal sensitivity 44 caused by the use of contact lenses 45 or corneal surgery. It is now widely accepted that, whatever the initial cause, untreated dry eye disease may lead to a cycle of tear film instability, hyperosmolarity, inflammation, further tear film instability, resulting in damage to the ocular surface and exacerbation of the original symptoms (Figure 2). 1, 46
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Clinical treatment
Treatment of dry eye aims to both alleviate symptoms, and to return the ocular surface to homeostasis.
Patient Education
The first line of treatment is patient education. After a thorough examination outlining tear volume, stability, production, osmolarity and ocular surface damage,46 the condition of the ocular surface may be well attained. Education of the patient as to what is occurring not only gives them confidence in their practitioner but also reduces the risk of non-compliance to treatment regimes. By taking a thorough history, precipitating factors such as exposure to air conditioning, extensive digital screen use or extended wear contact lens use may be identified as causative factors and patients may be advised to avoid or minimize these appropriately.
Ocular Lubricants and Other Drops
The first intervention for dry eye recommended by practitioners is the use of ocular lubricants. These are usually well accepted and are relatively non-invasive.
Alleviation of symptoms with lubricants depends on the severity of dry eye and the frequency of lubrication. While there are many different ocular lubricants on the market, the main types in use are those based on carboxymethylcellulose (CMC), polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), propylene glycol (PG), carbomers, lipid formulations and ointments. Different lubricants have different retention times on the ocular surface, with the effect of more viscous formulations lasting longer.47,48 Generally the mild to moderate dry eye sufferer will be required to insert drops four times per day to experience sufficient comfort.49 With frequent instillation of lubricants the treatment must remain sterile in order to avoid microbial contamination. It is widely accepted that single dose preservative-free lubricants be used so as to avoid solution toxicity and that preserved solutions (particularly those preserved by benzalkonium chloride) should be avoided.50,51 For a list of available ocular lubricants in the UK go to http://www.opticianonline.net/tear-products-management-dry-eye-2015/.
Traditional models for treating dry eye have suggested selecting a drop formulated specifically to reduce osmolarity.52 Hypotonic lubricants, usually formulated with unpreserved hyaluronic acid or CMC, have been found to effectively reduce inflammation and osmolarity in dry eye disease.53,54,55 More recent work has found that as dry eye is often due to a loss in the lipid layer10 a lipid-replacing lubricant may, by increasing the lipid layer thickness, more successfully alleviate the symptoms of the condition.56
For severe cases of dry eye, where frequent application of lubricants does not alleviate symptoms, autologous serum drops may be considered. These are produced from components of the patient’s own blood and mimic the natural tears. Current research is unclear of how effective these may be,57 and for the moment this treatment option remains the preserve of the hospital eye service.
Contact Lenses
While dry eye is usually considered a contraindication for contact lens wear, high DK/T scleral and semi-scleral lenses may be used for the therapeutic alleviation of dry eye disease.58,59 They do this by trapping a tear reservoir behind the lens surface, providing continuous nourishment to the ocular surface. Use of CMC containing agents with silicone hydrogel lenses has also been found to provide an effective form of protection to the corneal surface 60,61 providing the dual ability to correct refractive error and to provide comfort.
Punctal Occlusion
Occlusion of the lacrimal drainage system has been suggested as a way of providing a long-term solution to the problem of tear film insufficiency and return some stability to the lipid layer 62 (Figure 3). Occlusion may be carried out using a number of different types of punctal plugs. The most common, the Freeman-style plug, may be fitted directly to the opening of the lacrimal puncta, while other types of intra-canalicular plugs may be fitted further down the canaliculus. Silicone plugs may be inserted in practice under topical anaesthesia; however, it is important to ensure that the canaliculus is patent prior to insertion of the plug. Collagen plugs, which dissolve over the course of a few week, may also be fitted within practice, in order to identify the tear film’s response to occlusion. While punctal occlusion has been seen as a method for treating advanced aqueous-deficient dry eye disease, little research has been carried out to measure its effectiveness.63 While practitioners must carry out patient-centred care, this is an area where additional research would be beneficial.
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Therapeutics
An extended ability to prescribe preparations for the therapeutic treatment of dry eye disease is available to those with qualifications in supplementary prescribing. In severe cases of dry eye disease or cases of reduced mucous production, acetylcystine 5% may be prescribed for use to improve tear film adherence to the eye or for the removal of corneal filaments.64
Independent prescribing optometrists may prescribe off-label products for the treatment of dry eye. As damage of the ocular surface is due to increased inflammation1 many of these therapies contain agents aimed at reducing surface inflammation.
Cyclosporine 0.05% ophthalmic emulsion has been licensed by the FDA for the effective treatment of moderate-to-severe dry eye disease.65,66 It acts by inhibiting T-cell activation and cellular apoptosis,67 leading to reduced inflammation and an increase in tear production.68 Cyclosporine has the advantage of having few systemic side effects due to its low penetration.69
In cases of severe dry eye, therapeutic practitioners working in conjunction with ophthalmology partners may choose to prescribe a course of topical dexamethasone to reduce inflammation; this course of action has been found to ameliorate symptoms in as little as one week.70 Care must be taken to monitor intraocular pressure and crystalline lens integrity over the duration of use due to the increased risk of glaucoma and cataract development.71 Research for further treatment of aqueous deficiency has been carried out to improve the function of the lacrimal gland. While it has been known that oral pilocarpine can improve the symptoms of dry eye in patients with Sjögren’s syndrome,72 future research is looking into the possibility of bioengineering new lacrimal apparatus for those with severe dysfunction.73
Blepharitis: anatomy and physiology
The eyelids consist of two thin pieces of skin that protect the eye,. On their outside they project a series of fine lashes which further serve to protect the surface from dust. At the base of these lashes there are a series of modified sebaceous glands, both secreting directly onto the lash follicle and in the vicinity of the follicle onto the surface of the skin.
Both upper and lower lids surround collagenous tarsal plates, containing a series of meibomian glands (with approximately 31 and 26 glands respectively) opening onto the lid margin, a specialized sebaceous gland that express meibum, which is the main constituent of the lipid phase of the tear film.23 The inside of the eyelid connects to the palpebral conjunctiva, a loose stratified squamous epithelium, which serves to evenly spread the tear film while blinking.
Method of insult
Blepharitis is most commonly described by the anatomical location of the affected eyelid. Blepharitis may be described as being anterior, affecting the anterior lid margin, posterior, affecting the posterior lid margin, mixed anterior and posterior blepharitis and meibomian gland dysfunction (MGD).
Anterior blepharitis is typically characterized by an inflammation of the anterior eyelid margin, the formation of oily collarettes and crusting at the base of the eye lashes,74 with chronic inflammation leading to madarosis or trichiasis. Like dry eye disease, blepharitis may have a number of aitieologies; the majority of cases are believed to be due to Staphylococcus epidermis or Staphylococcus aureus.75 Although the exact mechanism of their action remains unknown, it is widely believed that the inflammatory response is due to direct infection of eyelid follicles. Alternative explanations, including inflammation as an automatic response to the biomarker of a bacterial endotoxin, have also been postulated.76
Recent interest has led to the investigation of the infestation of the lid margin by demodex mites as a possible cause of blepharitis (Figure 4). These ubiquitous mites 77 can infest the lash follicles, causing lid, conjunctival and corneal irritation through destabilization of the tear film.78
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Skin disorders such as seborrhoeic dermatitis, eczema or psoriasis may also cause inflammation of the lid margin. In these conditions the homeostasis of the skin surface is disrupted and can lead to insufficient or excess oils in the skin, both of which may lead to irritation of the lid margin.
Posterior blepharitis is an inflammation of the posterior portion of the lid margin, and may be caused by MGD, allergic or infectious conjunctivitis or even acne rosacea.10 MGD is a condition where the normal output of the lipid producing meibomian glands are disturbed, leading to reduced output of lipids or a production of poor quality lipids. MGD may be caused by a number of factors such as gland obstruction (due to keratinisation), replacement of glands, infection, toxicity and systemic conditions.79
Clinical treatment
Treatment of disorders of the eye-lids and lashes, including blepharitis, centres on the maintenance of good ocular hygiene. To this end many products have emerged in the market to treat disorders of the lid margin.
Ocular hygiene
UK College of Optometrists guidelines recommend the use of diluted baby shampoo or sodium bicarbonate solution to cleanse the lid surface.80 These however, like bacterial lipases, may break down meibomian lipids, destabilizing the tear film.81 There are now many lid cleansing agents containing dilute antimicrobials, which aim to cleanse the lid surface whilst minimising insult to the ocular surface. Unpreserved solutions have been shown to minimize irritation with chronic use,82 these solutions may be used on their own or in combination with sterile wool cleaning pads to gently cleanse the lid margin.
For the removal of the surface debris that builds up on the eyelashes, single use pre-impregnated cleansing wipes have been found to be effective while also reducing the irritation caused by lid disease.83
Oils from disrupted meibomian glands are known to have an increased melting point.84 This results in insufficient meibum being secreted onto the ocular surface, destabilizing the tear film. In order to effectively unblock these glands, constant warm compression at 45 0C for at least four minutes is required 85 in order to clear the glands. Maintenance of this temperature over time is difficult and ocular masks dedicated to the treatment of MGD have been developed. These masks have been shown to improve the stability of the tear film 86 and to be effective in the treatment of MGD.87 A new wet chambered goggle device has been developed in an attempt to improve MGD therapy, and has been found to be a safe 88 and effective method for the relief of MGD. It works by providing a moist warm environment around the ocular area, providing constant heat to the meibomian glands, and alleviating dry eye symptoms by increased humidity.89 The advantage of this new device is in its ability to be used with minimal interference in tasks such as reading, watching television or computer use.
Practitioners should be cautious when prescribing warm compresses. It is known that direct heat, like that from MGD treatments, causes the degranulation of mast cells.90 If uncontrolled this may mimic the inflammatory response of the eye and lead to an increase in symptoms. Some practitioners therefore recommend the use of a cold compress shortly after warm compression to reduce the risk of further inflammatory response.
The chronic nature of blepharitis and MGD, combined with the risk of poor compliance with treatment regimes,89 has led to research for the development of clinic-based treatment methods for lid disease. Clinic treatments are being developed to mimic the action of traditional cleaning regimes, reducing the treatment burden on the patient and alleviating symptoms for a longer duration.
Cleaning of the lid margin may now be accomplished in practice by the use of a new lid and lash cleaning device. This device cleans the lid margins with a spinning sterile micro-sponge. One study has shown it to provide symptomatic relief and improved meibomian gland function in sufferers of ocular surface disease.91 However, further investigation of its cleansing ability needs to be carried out. Treatment of demodex infenstation may be achieved by a lid scrub with 50% tea tree oil.80,92 While most components of tea tree oil are toxic to the demodex mite, terpinen-4-ol has been shown to be the most potent component of tea tree oil, successfully eradicating demodex mites when in 1% solution.93 Such solutions are toxic to the ocular surface and should be administered by experienced practitioners.80 The success of tea tree oil in treating demodex infestation has led to the development of lid scrubs with a lower concentration for patients’ home use, however, the success of these lower dose cleansers have been mixed80,94,95 leading to questionable efficacy.
Clearance of the meibomian glands in practice may be carried out by intra-ductal probing. Clearance of the glands has been found in small studies to successfully alleviate the symptoms of ocular surface disease.96,97 Successful long-term alleviation of symptoms of MGD have been reported from a new in-office device. It works by applying heat to the conjunctiva, and delivering thermal pulsation to the meibomian glands. The treatment lasts for 12 minutes and has been reported to be as effective as twice-daily lid cleaning,98 with some studies claiming it able to alleviate the symptoms of MGD for up to one year.99,100 If these results are found to be consistent this device may herald a new age in the treatment of lid disorders.
Therapeutics
Therapeutic management of blepharitis focuses on reduction of both infectious agents and inflammation. Surface treatment of ocular conditions using chloramphenicol has been practiced for many years.101 The recognition that blepharitis is frequently associated with staphylococcal infection of the eye-lid has led practitioners to favour the use of fucidic acid in the treatment of anterior blepharitis.
Independent practitioners may consider prescribing tetracycline antibiotics for the treatment of ocular surface conditions, 40mg doxycycline daily has been shown to effectively reduce inflammation in blepharitis, particularly in patients with rosacea.103,104 It does this by binding to the 30S ribosome subunit of bacterial lipases, inhibiting bacterial protein synthesis, leading to a reduction of parasitic stress and an increase in production of meibum.
Recent research has suggested that more successful suppression of bacterial influence may be achieved by systemic azithromycin,105 with one study suggesting that topical therapy may be pereferable.106 Azithromyacin acts by binding to the 50S subunit of the bacterial ribosome, inhibiting mRNA translation. Like doxycycline, the bacterial stress on the ocular surface may be reduced and meibomian gland function improved.
Practitioners should be cautious in prescribing though as frequent use of antibiotics risks increasing the likelihood of medically resistant Staphylococcus aureus (MRSA).102
Nutrition
The role of diet in the treatment of dry eye has traditionally been limited to improvement of hydration to improve symptoms of ocular surface disease. While recent work supports this view,107 the influence of essential fatty acids has also been considered in the process of ocular surface disease.
Essential fatty acids are those that are required for healthy function but cannot be synthesized in the body. They come in two forms: alpha-linolenic acid (an omega-3 fatty acid); and linoleic acid (an omega-6 fatty acid). While modern western diets typically contain omega-6:omega-3 in a ratio of approximately 15-20:1, a more appropriate ratio of consumption of these nutrients has been suggested at 4:1.108,109 Essential fatty acids can be converted into prostaglandins, active molecules in the inflammatory pathway. Prostaglandins come in three varieties, PGE1, PGE2 and PGE3. PGE1 has anti-inflammatory properties as it reduces pain and swelling in mucoidal tissues and inhibits blood clotting, and can only be synthesized from omega 6 fatty acids. PGE2, like PGE1, can only be synthesized from omega-6 fatty acids. PGE2 acts as a pro-inflammatory agent, thereby leading to increased blood clotting and, taken in excess, to chronic inflammatory conditions.
PGE3 is synthesized from omega-3 fatty acids. These agents serve as anti-dash-inflammatory agents, reducing excess inflammation. Docosahexaenoic acid (DHA) a type of omega-3 fatty acid serves to maintain cellular function in the brain and eye,110 and has also been found to serve a beneficial role in systemic cardiovascular and inflammatory conditions. Another omega-3 fatty acid, eicospentenoic acid (EPA) serves an anti inflammatory function by inhibiting the production of arachidonic acid, an intermediary in the production of PGE2, reducing PGE2 formation. It is believed that inflammatory control in the body may be based on a balance of the omega-3 and omega-6 mediators.111
Research has shown that short-term supplementation with omega-3 formulations,112,113 can improve tear film stability, tear volume and reduce symptoms. However, for chronic conditions gamma linolenic acid (GLA) (a mediator in the production of PGE1) is required for the production of the anti-inflammatory PGE1. Formulations containing both omega-3 and omega-6 in are therefore recommended for treating chronic ocular surface disease.114,115 In addition to the reduction of inflammation, increased intake of omega-3 has been shown to improve meibomian lipid secretions,116 and increase the production and volume of the tear film.117 It can be seen that supplementation has an active role to play in the treatment of dry eye and blepharitis.
Conclusion
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Dry eye disease and blepharitis are often comorbid conditions affecting the ocular surface, often due to multifactorial causation, and once initiated lead on to a cycle of dis-regulation. While traditional therapy has focused on treating the initial dysfunction, a more holistic approach to treatment is required (Table 1).
To remove patients from the vicious cycle of ocular surface disease, treatment must be tailored to their needs. The initial cause of the dysfunction may be unclear, and so a combination of therapies may be required 118. Patient education is important to reducing exposure to causative agents and non-compliance to treatments. Treatment of dry eye and blepharitis should consist of a mixed therapy, consisting of frequent lubrication, lid hygiene, nutritional supplementation and, where required, anti-inflammatory intervention. Practitioners must also be aware of the limits of their professional knowledge and be prepared to refer complex cases to more experienced and therapeutically trained colleagues. Treatment of ocular surface disease remains difficult. However, appropriate interventions in most cases will alleviate symptoms of ocular discomfort and improve the quality of life for many patients.
Malcolm Maciver is a clinical optometrist practicing in Hampshire and is a senior lecturer in optometry at the University of Portsmouth
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