Medical Management of Ocular Surface Disease

Published on 08/03/2015 by admin

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Last modified 08/03/2015

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34

Medical Management of Ocular Surface Disease

Introduction

As an orchestra is composed of various instrumentalists playing together to form a unified sound, optimal management of the ocular surface entails fine tuning the performance of its collective players (lids, lacrimal gland, cornea, conjunctiva). Recognized as an integrated system working in concert for quality of ocular surface health and vision, the burgeoning field of ocular surface disease (OSD) has witnessed an explosion in the literature. Advances in our understanding of the pathophysiology driving various conditions affecting the health of the ocular surface has helped clinicians develop and broaden medical and surgical therapies, leading to improved outcomes. This chapter will focus primarily on medical treatment, including topical and systemic regimens.

The medical management of OSD is required prior to surgical intervention. In our understanding of OSD, numerous factors are intertwined. Inflammation, anatomical malpositioning, systemic hormonal levels, and changes in the ocular tear film are individual causative factors that play a role in this complex disease. Central to each of these factors is an underlying inflammatory state, as seen in blepharitis, meibomitis, conjunctivitis, and keratitis. The medical management of OSD requires controlling the inflammation and restoring the normal anatomy and tear film to promote healing of the ocular surface. Careful attention to the medical management of the ocular surface is paramount to the outcomes of any surgical intervention and may indeed preclude its necessity.

Topical Treatment

Artificial Tears

Method of Action

The tear layer represents a complex mixture of mucins for increased viscosity, antimicrobial proteins, growth factors, inflammatory suppressors, and electrolytes for proper osmolarity (Fig. 34.1). Artificial tears cannot completely substitute this complex composition of human tears. Their mechanism of action includes adding volume to the tear film while in contact with the ocular surface. In order to remain in contact with the ocular surface, hydrogels are an essential ingredient of artificial tears. Hydrogels are polymers that swell in water and retain moisture to increase viscosity. The mucous adhesive properties of hydrogels prolong the contact time of artificial tears on the eye. The following hydrogels have been used in artificial tears: hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC), polyvinyl alcohol (PVA), carbopol, polyvinyl pyrrolidone, polyethylene glycol (PEG), polyvinyl alcohol (PVA), dextran, hyaluronic acid, glycerin, and carbomer 940 (polyacrylic acid). There have been no large scale, masked, comparative clinical trials to evaluate the wide variety of hydrogels available. However, using wavefront sensing and ocular coherence tomography, PEG drops showed significant worsening of visual quality, compared with CMC, PVA, and glycerin-containing artificial tears.1

There are many different types of preservatives in artificial tears. Benzalkonium chloride (BAK) and chlorobutanol, which can be toxic when used more than four times a day, are older preservatives. Preservatives, such as GenAqua (Sodium Perborate), Purite (sodium chlorite) and Polyquad (Polyquaternium-1) are less damaging to the ocular surface than BAK.2,3 Purite degrades to chloride ions and water after instillation. GenAqua is converted to water and oxygen on contact with the tear film.

The presence of ‘inactive ingredients’ provides unique surface protective properties to artificial tears. For example, compatible solutes may help surface healing by osmoprotection. HP-Guar forms a cross-linked viscoelastic gel when exposed to eye surface (pH 7.5). This gel increases viscosity and bioadhesive properties while promoting the retention of its two demulcents (polyethylene glycol 400 and polypropylene glycol). It has been suggested that HP-guar preferentially binds to the more dry or damaged areas of the surface epithelial cells, providing protection for these cells.46

Viscous tears have a longer retention time, as they are not easily drained out of the eye through the lacrimal outflow system. Oil-containing eye drops may be added if meibomian gland dysfunction is present. These eye drops will replenish the lipid layer of the tear film and prevent tear evaporation. Moderately hypotonic artificial tears containing PVA, as well as bicarbonate-containing tears have been shown to promote OSD healing in severe dry eyes.710

Dosage

Artificial tears may be dosed on many different schedules, including an as-needed basis. BAK-preserved drops are usually well tolerated when used four times a day or less. If artificial tears are needed more than four times a day then GenAqua or Polyquad preserved tears are better choices, avoiding the toxicity of BAK. In moderate to severe OSD, preservative-free solutions should be used. It is apparent that there is no single artificial tear eye drop that provides the entire surface healing strategies required in OSD (bicarbonate ions, hypotonicity, viscosity, non-preserved). However, understanding of the mechanism of action of the different hydrogels, additives and preservatives in artificial tears will aid the clinician in directing the OSD patient to the optimal tear substitute.

Topical CorticoSteroids

Mechanism of Action

Topical corticosteroids are currently the most effective, potent treatment modalities for the medical management of ocular inflammation, an important hallmark of OSD. Although there is no generally accepted explanation for the mechanism of action of ocular corticosteroids, they are thought to act by inducing lipocortins, proteins that inhibit phospholipase A2. It is postulated that these proteins control the biosynthesis of potent inflammatory mediators, including prostaglandins and leukotrienes by inhibiting the release of arachidonic acid, their common precursor. Corticosteroids inhibit the inflammatory response to a variety of inciting agents that may delay wound healing. They inhibit fibrin and collage deposition, capillary dilation, capillary proliferation, leukocyte migration, fibroblast proliferation, and scar tissue formation associated with the process of inflammation. The two traditional groups of corticosteroids are the ketone steroids (prednisolone, dexamethasone, fluorometholone, medrysone, rimexolone, and difluprednate) and the ester steroids (loteprednol).

Delivery System

Corticosteroids are available in a diverse range of preparations, including solutions, suspensions, emulsions and ointments (Table 34.1). Topical steroids in a suspension, or viscous formulation have increased ocular contact time and can thereby double the corneal and aqueous steroid concentrations, compared with the same drug used as a solution.11 There is no prospective clinical trial comparing the relative efficacy of generic with branded topical steroids, though studies point to the possible advantage of smaller particle size in branded drops conferring greater efficacy and bioavailability.12 The relative potency of corticosteroids depends on the molecular structure, concentration, and release from the vehicle. For example, dexamethasone is a very potent steroid, but does not penetrate ocular tissues well. In contrast, prednisolone is less potent and has better ocular penetration. Steroids, such as loteprednol etabonate and fluorometholone are less potent, but have safer side effect profiles. Compared to dexamethasone and prednisolone, loteprednol etabonate and fluorometholone are reported to have lower rates of intraocular pressure (IOP) spikes. A retrospective review of 30 patients with IOP elevation to a mean of 31.1 millimeters of mercury after prednisolone acetate use for keratoplasty reported a 41% reduction in IOP after switching to loteprednol etabonate. Yet in one study, IOP elevations with loteprednol occurred more commonly in females after an average of 2 months of treatment.13

Table 34.1

Active Ingredients and Available Formulations for Topical Ophthalmic Steroid Preparations

Topical Ocular Steroid Concentration/Formulation
Prednisolone acetate 0.125, 1.0% suspension
Difluprednate 0.05% emulsion
Prednisolone sodium phosphate 0.125, 0.5 1.0% solution
Dexamethasone alcohol 0.05–0.1% susp, ointment
Fluorometholone acetate 0.1% suspension
Fluorometholone alcohol 0.1% suspension, ointment
0.25% suspension
Rimexolone 0.5–1% suspension
Medrysone alcohol 1.0% suspension
Lotoprednol etabonate 0.2, 0.5% suspension

Dosage

To our knowledge, no studies have conclusively outlined the optimal steroid concentrations for treating various OSD conditions. Studies have evaluated topical corticosteroid penetration into human aqueous humor (Fig. 34.2).14 For conditions primarily affecting the ocular surface where intraocular antiinflammatory therapy is not needed, fluorometholone alcohol 0.1%, loteprednol etabonate 0.5% and prednisolone sodium phosphate 0.5% are viable options. When intraocular penetration is indicated, the more potent prednisolone acetate, dexamethasone or difluprednate emulsion should be considered. In randomized, controlled studies, loteprednol etabonate has demonstrated excellent results in treating external inflammation, such as seasonal allergic conjunctivitis and giant papillary conjunctivitis with a favorable side effect profile.15,16 Topical corticosteroids with lower aqueous penetration are not as effective as those with higher intraocular penetration in the management of intraocular inflammation.14 Compared to prednisolone acetate 1%, loteprednol etabonate 0.5% has been found to be less effective in patients with acute anterior uveitis.17

Side Effects

Prolonged administration of corticosteroids may result in a rise in IOP with subsequent damage to the optic nerve. In glaucoma patients or patients with a previous steroid response, close monitoring of the IOP is extremely important. Use of corticosteroids may also result in formation or progression of posterior subcapsular cataracts. Additional side effects include delayed wound healing, corneal and scleral thinning or perforation. Prolonged treatment with corticosteroids may suppress the host response and thus increase the susceptibility of secondary ocular infections, including bacterial, viral, fungal, and parasitic infections. In patients whose symptoms worsen with attempted corticosteroid weaning, switching to less potent antiinflammatory therapy is a viable alternative. Due to the well-known complications associated with prolonged corticosteroid therapy, long-term treatment should be reserved for severe, disabling OSD, and such patients must be closely monitored. Compared to dexamethasone, difluprednate, and prednisolone, loteprednol and fluorometholone have lower rates of these complications. Patients with corneal disease that may affect the measurement of IOP need be closely followed for side effects of corticosteroid use, as these measurements may be inaccurate in cases of corneal thinning or edema.

Considered a corticosteroid primarily targeting ocular surface inflammation, fluorometholone alcohol 0.1% may adequately control signs and symptom of dry eyes in patients with keratoconjunctivitis sicca (KCS). In a randomized, controlled trial, fluorometholone alcohol 0.1% used q.i.d. for 30 days demonstrated a beneficial effect on both subjective and objective clinical parameters of moderate-to-severe KCS patients, reportedly without complications.18 A mild corticosteroid with low intraocular penetration, fluorometholone alcohol 0.1% may have a lower likelihood of increasing intraocular pressure, compared to prednisolone or dexamethasone.14 A short-term treatment option for patients with moderate keratoconjunctivitis sicca, topical loteprednol etabonate 0.5% used four times a day for 4 weeks may be beneficial in improving objective clinical parameters with an acceptable benefit–risk ratio. A randomized, masked clinical trial comparing loteprednol to vehicle reported greater improvement in objective variables, including corneal fluorescein staining and conjunctival injection, particularly in a subset of patients with more severe clinical findings of inflammation.19

Topical Cyclosporine

Dosage

In severe cases, higher concentration cyclosporine A 2% can provide symptomatic relief. A double-masked, placebo-controlled trial to evaluate the short-term efficacy and safety of topical 2% cyclosporine A in a preservative-free vehicle for patients with severe VKC demonstrated a statistically significant decrease in both signs and symptoms with no observed side effects over the course of the study.21 For the treatment of patients with steroid-dependent atopic keratoconjunctivitis (AKC), cyclosporine A 2% dissolved in maize oil and dosed four times daily to both eyes appears to be an effective means to improve signs and symptoms, allowing patients to be weaned off topical corticosteroids.22

Cyclosporine 0.05% may lead to improved tear film regularity and ocular surface health. In a randomized clinical study of moderate to severe dry eye patients, baseline tear production, as determined by Schirmer testing (with anesthesia), increased to a significantly greater degree in the cyclosporine 0.05% group than in the vehicle group. Also, compared to vehicle, patients treated with cyclosporine 0.05% demonstrated greater improvements in blurred vision that could be explained by the improvement in corneal fluorescein staining.23 Combination therapy with topical cyclosporine A and topical steroids has been successfully used in treating moderate to severe DES. While cyclosporine does not contribute to the rapid anti-inflammatory effect of corticosteroids, it has a better side effect profile and is safer for long-term use. It is possible to begin treatment of the ocular surface by prescribing both topical steroids and cyclosporine at the same time. The concurrent short-term use of a topical steroid tapered over 1–2 months provides the benefit of faster symptom relief and improvement of ocular signs without accompanying serious complications.24

Azithromycin

Mechanism of Action

Azithromycin is a broad-spectrum macrolide antibiotic that contains nitrogen on its macrolide ring. It inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit of susceptible microorganisms. It has high tissue penetration and a prolonged half-life. Macrolide antibiotics, such as azithromycin exhibit antiinflammatory properties. Studies have demonstrated that they can inhibit the production of proinflammatory cytokines and the production of matrix metalloproteinases (MMPs).25

Although the specific antiinflammatory mechanism of action remains unknown, the suppression of the nuclear transcription factor nuclear factor kappa B (NF-κB) has been shown to play a role. Furthermore, the concentration of macrolide antibiotics, such as azithromycin within polymophonuclear leukocytes (PMNs) may also modulate their role in infection-mediated inflammation.26,27 With respect to ocular inflammatory diseases, an in vitro study found azithromycin in DuraSite as effective in suppressing MMPs in the corneal epithelium and endothelium as doxycycline (a tetracycline analog with known antiinflammatory properties, see below) in both human and bovine cells.28

Dosage

The recommended dose of azithromycin is one drop twice a day for the first 2 days and then one drop a day for the next 5 days. A single topical dose in healthy individuals demonstrated azithromycin achieved significant tissue concentrations and maintained those levels for up to 24 hours.31 Peak concentrations of azithromycin of more than 200 µg/g of tissue were achieved in human eyelid tissue as the drug accumulated over the 7 days of therapy. Furthermore, 5 days after discontinuing the medication, tissue concentrations of azithromycin of more than 50 µg/g were still present in the eyelids. Similar results were found for corneal and conjunctival samples.30

Topical Vitamin A

Mechanism of Action

Vitamin A is essential for maintaining the health of epithelial cells throughout the body. Vitamin A deficiency adversely affects conjunctival and corneal epithelial cells, causing loss of goblet cells and leading to increased epidermal keratinization and squamous metaplasia of the mucous membranes.32 Vitamin A can exist in three forms: retinol, retinal, and retinoic acid. Many tissues requiring vitamin A store the vitamin as an ester of retinal. Vitamin A is stored as fatty acyl esters of retinol in the lacrimal gland. It is also present as retinol in the tears of rabbits and humans. Its presence in tears provides the rationale for treating OSD with vitamin A.32