Figure 1. Mechanism of type I allergic reactions.
Figure 2. Mast cells degranulating and releasing vasoactive amines.
By Diane P. Yolton, PhD, OD
Glucocorticoids, commonly referred to as corticosteroids or steroids, are used by the body to:
In the early 1940s, it was discovered that the naturally occurring glucocorticoid, cortisol, and its synthetic derivatives could be administered as drugs to replace naturally occurring steroids and also to reduce undesirable consequences of inflammation and allergy.
This course describes how topical steroids can be used to treat inflammatory and allergic diseases of the eye’s anterior segment. It begins with a basic science review of inflammation and allergy and then discusses how steroids can be used to suppress these processes. It also provides information on specific topical steroids that are available for ocular use and reviews anterior segment diseases that can be managed by the use of topical steroids.
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Topical Steroids Available for Ophthalmic Application
Steroid/Antibiotic Combinations
Management of Anterior Segment Ocular Diseases with Topical Steroids
Acute inflammation begins within seconds to minutes after tissue damage produced by injuries and diseases such as infections and certain autoimmune processes. It is part of the body’s defense against these insults and results in additional blood to the affected area, movement of fluids, proteins, and cells from the blood into the tissues, and release of substances to fight infection.
Three main processes occur during inflammation:
The effects of inflammation can be summarized by remembering the words:
The effects of inflammation can readily be seen by considering anterior uveitis, which is an inflammatory process affecting the eye. Dilated blood vessels in the limbal area produce a ciliary flush, and proteins that leak into the anterior chamber due to increased capillary permeability cause aqueous flare. As a result of the inflammation, white blood cells also migrate from the blood vessels into the anterior chamber. Topical steroids are used to treat anterior uveitis by suppressing the inflammation and thus prevent damage to the iris, ciliary body, lens, and anterior chamber.
Effects of Steroids on Inflammation
In the eye and elsewhere in the body, inflammation is mediated by chemical molecules that are released from various cells. Inflammatory mediators include metabolites of arachidonic acid, prostaglandins (notably PG D2), and leukotrienes. These substances are released from blood vessel endothelial cells, fibroblasts, and white blood cells including macrophages, monocytes, and lymphocytes.
Prostaglandins and leukotrienes participate in the inflammatory process by causing vasodilatation and increased capillary permeability. Cytokines, including interleukins and alpha tumor necrosis factor, are also released from blood vessel endothelial cells and from macrophages, monocytes, and lymphocytes. Like prostaglandins and leukotrienes, they cause vasodilatation and increased capillary permeability.
Steroids increase the production of a protein that inhibits phospholipase A, which decreases the creation of prostaglandins and leukotrienes. This suppresses inflammation. Steroids also block the production and release of cytokines, which also suppresses the inflammatory process.
Another substance associated with inflammation is complement component C3a. It can bind to receptors on mast cells and basophils, triggering them to release vasoactive amines such as histamine. Steroids inhibit the action of C3a, which reduces the effects of inflammation.
Blood vessel endothelial cells produce several different adhesion molecules during inflammation and they allow leukocytes to migrate from the blood into the tissues. Steroids block the action of these molecules and suppress this inflammatory mechanism.
In summary, steroids inhibit the production or action of numerous molecules that are critical to generating an inflammatory response. As a result of steroid application, there is decreased vasodilatation and capillary permeability, diminished secretion of lipolytic and proteolytic enzymes, decreased movement of leukocytes from the blood to areas of injury, and, ultimately, decreased damage such as fibrosis produced by the inflammation.
Steroids are usually given as a palliative, nonspecific treatment for inflammation. It is important to keep in mind that they attack the inflammation that results from a disease process and do not affect the underlying disease. In fact, the use of steroids can actually work against the body's infection defense.
Inflammation is treated with steroids because the inflammatory process (especially if it results from an autoimmune disease in which the body is attacking itself) can cause permanent tissue damage such as scarring. In selected cases, steroids are also used to enhance patient comfort and appearance, i.e., to suppress redness, swelling, and pain.
Effects of Steroids on Allergies
Another type of inflammatory process occurs during a type I allergic reaction. An allergic response is an unwarranted over-reaction of the body’s immune system to foreign substances, known as allergens, which the body wrongly perceives as threats, e.g., an excessive reaction to pollen that causes allergic rhinitis. Allergies are not only nuisances, but they can damage tissues, so they are often suppressed with steroids.
During a type I allergic reaction, mast cells are triggered by the immune system to release vasoactive amines (e.g., histamine) which cause blood vessels to dilate and become more permeable. Histamine also stimulates nerve endings creating a sensation of itching.
Eosinophilic chemotactic factors are also released from mast cells and they induce eosinophils to move out of the blood and into the tissues. These eosinophils then release more vasoactive amines. In addition to the mast cells releasing mediators, they also produce arachidonic acid and facilitate its conversion into prostaglandins and leukotrienes.
Figures 1 and 2 show the events that trigger an allergic reaction and the release of amines by the mast cells in response to an allergen.
Figure 1. Mechanism of type I allergic reactions.
Figure 2. Mast cells degranulating and releasing vasoactive amines.
Steroids inhibit degranulation of mast cells, basophils, and eosinophils, which decreases the amount inflammatory amines in the tissue. Steroids also suppress allergic reactions by indirectly inhibiting the synthesis of phospholipase A, which catalyzes the production of arachidonic acid. As a result, less prostaglandins and leukotrienes are produced.
For reasons that are not entirely understood, occasionally the body's immune system malfunctions and fails to recognize certain cells or organs as self. Because it regards these cells or organs as foreign, an inflammatory process is set up as part of an attempt to destroy them. Examples include myasthenia gravis and ocular pemphigoid. Steroids can suppress the inappropriate inflammation and partially protect the cells or organs being attacked. Typically, this requires large initial systemic steroid doses followed by chronic steroid doses to keep the inflammation under control.
After an acute inflammatory response, resolution and complete restoration of tissues to normal often occurs. When acute inflammation does not resolve the tissue injury that triggered it, chronic inflammation may occur. Chronic inflammation can be caused by persistent injury or infection (e.g., ulcer or tuberculosis), prolonged toxic agent exposure (e.g., silica), or autoimmune diseases (e.g., rheumatoid arthritis and lupus erythematosus).
During chronic inflammation, macrophages may differentiate into epitheloid cells leading to granulomatous chronic inflammation. Steroids can inhibit macrophage activity and thus decrease the chronic inflammatory response that can be associated with tissue damage, e.g., scarring.
Tables 1 and 1A show some of the many topical steroid formulations that are available for the treatment of ocular inflammation and allergy.
Table 1. Topical Ophthalmic Steroid Solutions and Suspensions
| Steroid | Derivative* | Trade Name (Manufacturer) |
| Prednisolone 1% | Acetate | Generic (various), Pred Forte® (Allergan), Econopred Plus® (Alcon) |
| Prednisolone 1% | Phosphate | Generic (various), Inflamanase Forte® (Novartis), AK-Pred® (Akorn) |
| Prednisolone 0.125% | Acetate | Pred Mild® (Allergan), Econopred® (Alcon) |
| Prednisolone 0.125% | Phosphate | Inflamase Mild® (Novartis), AK-Pred® (Akorn) |
| Dexamethasone 0.1% | Alcohol | Maxidex® (Alcon) |
| Dexamethasone 0.1% | Phosphate | Generic (various), Decadron Phosphate® (Merck), AK-Dex® (Akorn) |
| Fluorometholone 0.1% | Alcohol | Generic (various), Fluor-Op® (Novartis), FML® (Allergan) |
| Fluorometholone 0.1% | Acetate | Flarex® (Alcon), EFlone® (Novartis) |
| Fluorometholone 0.25% | Alcohol | FML Forte® (Allergan) |
| Medrysone 1% | Alcohol | HMS® (Allergan) |
| Loteprednol 0.5% | Etabonate | Lotemax® (Bausch & Lomb) |
| Loteprednol 0.2% | Etabonate | Alrex® (Bausch & Lomb) |
| Rimexolone 1% | Vexol® (Alcon) |
*(Acetate, Alcohol, and Etabonate derivatives are suspensions; Phosphate derivatives are solutions)
Table 1A. Topical Ophthalmic Steroid Ointments
| Steroid | Derivative | Trade Name (Manufacturer) |
| Dexamthasone 0.05% | Phosphate | Generic (Bausch & Lomb), AK-Dex® (Akron) |
| Fluorometholone 0.1% | Alcohol | FML SOP®(Allergan) |
The steroids shown in Tables 1 and 1A are not all equal with regard to their effectiveness in treating inflammation and their potential for producing side-effects, e.g., increasing IOP.
Efficacy of Steroid Formulations
Results from early experiments evaluating the effectiveness of several steroid formulations are summarized in Table 2 (1). Data in this table were derived by creating corneal infections and then assessing the percentage reduction in inflammation produced by the various steroid formulations shown.
Table 2. The Effectiveness of Steroids
| Steroid and Derivative | Decrease in Corneal Inflammation |
| Prednisolone acetate 1% | 51(%) |
| Prednisolone phosphate 1% | 28(%) |
| Dexamethasone alcohol 0.1% | 40(%) |
| Dexamethasone phosphate 0.1% | 19(%) |
Table 2 indicates that the steroid and derivative combination (i.e., acetate, phosphate, or alcohol) used to treat corneal inflammation is important, in part, because there are differences in the abilities of the drugs to penetrate into the cornea. The acetate derivative of prednisolone and the alcohol derivative of dexamethasone penetrate the corneal epithelium most effectively because they are biphasic and can become alternatively water-soluble and lipid-soluble. In contrast, phosphate derivatives are highly water-soluble and poorly lipid-soluble which means that they cannot easily penetrate through the corneal epithelium.
Table 2 also shows that prednisolone acetate 1% has the greatest anti-inflammatory efficacy of the topical ocular steroids tested. It remains the best choice for severe ocular inflammation. Dexamethasone alcohol is the second–most effective steroid. Prednisolone phosphate is not as effective as the acetate form and is most appropriate for use with moderate inflammations. Dexamethasone phosphate preparations are potent agents for surface inflammation, but they do not penetrate well and thus are not good choices for treatment of intraocular inflammation.
Increases in IOP Produced by Topical Steroid Use
Topical ophthalmic steroids can elevate IOP in some patients, and this can potentially produce glaucoma. Approximately two-thirds of people are genetic steroid-responders, but only 5% will experience a dramatic IOP increase (i.e., greater than 15 mm Hg) (2) as a result of prolonged topical steroid application. Individuals with pre-existing personal or family histories of primary open angle glaucoma are more likely to demonstrate a rise in IOP resulting from steroid use (3). Although IOP elevations resulting from steroid use can occur as soon as one week after the start of therapy, a steroid-produced increase in IOP typically takes 4 to 5 weeks. Thus, short-term steroid use is unlikely to result in a significant IOP increase.
Steroid-induced ocular hypertension appears to be related not only to the individual patient but also to the specific steroid used. In general, dexamethasone and prednisolone are the most likely ophthalmic steroids to induce a significant IOP increase.
The management of patients with steroid-induced glaucoma typically requires discontinuation of the steroid. When steroid treatment has not exceeded 12 months, discontinuation of the steroid will usually result in a return to pre-treatment IOP levels.
If steroid discontinuation is not an option, switching to loteprednol 0.5% should be considered because this drug has a lower potential for producing steroid-induced IOP changes (4). If switching to loteprednol is not successful or if changing steroids is unacceptable, IOP elevation can be treated with anti-glaucoma drugs that suppress aqueous production, e.g., beta-blockers.
The Balance Between Steroid Efficacy and Potential Side-Effects
When selecting a steroid for treating significant ocular inflammation, the ideal formulation would be one with the lowest potential for causing an IOP increase, the best corneal penetrating ability, and the greatest ability to suppress inflammation. Most topical ocular steroids have not been tested using the procedure that was used for prednisolone and dexamethasone (Table 2), so information about the effectiveness and potential for IOP increases of these steroids has been derived from clinical studies.
Fluorometholone is formulated as both alcohol and acetate derivatives. Fluorometholone alcohol does not penetrate the cornea well and so is effective for mild surface inflammation. In contrast, fluorometholone acetate 0.1% has better penetration and is effective for management of moderate inflammation. Fluorometholone alcohol is a good choice for long-term therapy because of its low propensity for inducing an IOP response.
Medrysone is the weakest anti-inflammatory steroid readily available. It can be used for management of superficial ocular inflammations including allergic and atopic conjunctivitis, but intraocular inflammatory conditions generally do not respond to application of this drug. Medrysone also is less likely to cause a significant rise in IOP.
Recently several "soft" steroids with good anti-inflammatory activity and lower propensity to raise intraocular pressure have been synthesized. A soft drug is a biologically active drug that is metabolically unstable so that it undergoes a predictable, one-step transformation to an inactive metabolite after its pharmacologic effects have been expressed at or near the site of application. This means that these drugs are much less likely to raise intraocular pressure after administration, even in steroid responders.
Loteprednol is a soft steroid. In its 0.5% concentration (Lotemax®), it is indicated for the treatment of ocular inflammation including giant papillary conjunctivitis, inflammation following cataract surgery, and seasonal allergic conjunctivitis. In its 0.2% concentration (Alrex®), it is indicated for seasonal allergic conjunctivitis and other mild, non-vision-threatening conditions. Although loteprednol 0.5% is indicated for inflammatory conditions of the lids and anterior segment of the eye, studies have shown that loteprednol is less effective than prednisolone acetate 1% for the treatment of anterior uveitis (5). Because it is a soft steroid, loteprednol has a low potential for raising IOP in steroid responders (4). Thus, for the management of uveitis the favorable profile with respect to intraocular pressure increase may make this drug useful for many patients.
Rimexolone is another newer steroid. It is indicated for treatment of anterior uveitis and for postoperative inflammation following cataract surgery. Rimexolone 1% has similar effectiveness to prednisolone acetate 1% for the treatment of anterior uveitis (6). However, rimexolone has a lower potential for raising IOP (7).
When the relationship between administration frequency of prednisolone acetate 1% and its anti-inflammatory effect on the cornea was investigated, it was found that inflammation decreased as the dosage was increased from one drop every four hours up to one drop every 15 minutes (1). Thus, prednisolone acetate (and probably the other steroids) has a therapeutic effect that exceeds a reasonable clinical dosage regimen. For this reason it is prudent to prescribe a steroid at a high enough initial dose to hit the inflammation hard and fast, even if this means the initial dose is q30 min or q1h.
There are many topical steroid/antibiotic combinations available for ophthalmic use (Tables 3 and 3A).
Table 3. Antibiotic-Steroid Solution and Suspension Combinations Available for Topical Ocular Therapy
| Steroid | Antibiotic | Antibiotic Trade Name (Manufacturer) |
| Dexamethasone 0.1% | Neomycin 0.35% | Generic (Various), NeoDecadron® (Merck), Neo-Dexameth® (Major) |
| Dexamethasone 0.1% | Neomycin 0.35% and Polymyxin B 10,000 U/ml | Generic (Various), Maxitrol® (Alcon), AK-Trol® (Akorn) |
| Hydrocortisone 1% | Neomycin 0.35% and Polymyxin B 10,000 U/ml | Generic (Various), Cortisporin® (Monarch), AK-Spore HC Ophthalmic Suspension® (Akorn) |
| Prednisolone 0.5% | Neomycin 0.35% and Polymyxin B 10,000 U/ml | Poly-Pred® (Allergan) |
| Prednisolone 1% | Gentamicin 0.3% | Pred-G® (Allergan) |
| Dexamethasone 0.1% | Tobramycin 0.3% | TobraDex® (Alcon) |
| Loteprednol 0.5% | Tobramycin 0.3% | Zylet® (Bausch & Lomb) |
Table 3A. Antibiotic-Steroid Ointment Combinations Available for Topical Ocular Therapy
| Steroid | Antibiotic | Trade Name (Manufacturer) |
| Dexamethasone 0.1% | Neomycin 0.35% and Polymyxin B 10,000 U/g | Generic (Various), AK-Trol® (Akorn), Dexacidin® (Novartis) |
| Hydrocortisone 1% | Neomycin 0.35, Bacitracin 400 U/g, Polymyxin B 10,000 U/g |
Generic (Various), Cortisporin® (Monarch), AK-Spore HC® (Akorn) |
| Prednisolone 0.6% | Gentamicin 0.3% | Pred-G SOP® (Allergan) |
| Dexamethasone 0.1% | Tobramycin 0.3% | TobraDex® (Alcon) |
Steroid-antibiotic combination drugs are useful in the management of certain conditions in which it is necessary to suppress inflammation as well as prevent infection. The steroid component of the drug will reduce injection and edema and improve the appearance of the eye during the healing process. It must be remembered that inflammation is one of the body's defenses against infection so use of a steroid-antibiotic combination drug is not generally indicated for treatment of an infection.
When prescribing a steroid-antibiotic combination, the potential adverse reactions of the steroids must be kept in mind. Many combination products are used for treatment of chronic conditions and this puts the patient at risk for adverse side-effects from the steroids. For most conditions, there is not a significance difference in efficacy between the available steroid/antibiotic combinations.
In addition to the older steroid/antibiotic steroid combinations, loteprednol combined with tobramycin (Zylet®) is now on the market. Loteprednol is a soft steroid that is less likely to elevate IOP than other steroids, and this makes Zylet® somewhat safer for long-term use.
SIDE-EFFECTS AND CONTRAINDICATIONS TO THE USE OF TOPICAL OPHTHALMIC STEROIDS IN ADDITION TO THE RISK OF IOP INCREASE
Because steroids suppress immune system function, these drugs lower resistance to infection. Topical ocular steroid therapy can retard corneal healing and can thus cause perforation of the globe if there is thinning of the cornea or sclera.
Topical use of steroids can enhance ocular susceptibility to and severity of fungal and viral infections. For example, steroid therapy can trigger herpes simplex corneal infection and can make the infection worse if used for treatment. For these reasons, ophthalmic steroids are contraindicated in most viral diseases of the cornea and conjunctiva. These include epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella.
Topical steroids are also contraindicated in mycobacterial infections of the eye and fungal diseases of the ocular structures.
Allergy to any ingredients in the steroid preparations is also a contraindication.
Posterior subcapsular cataract formation (Figure 3) can occur as a result of topical steroid use. For most patients, lens changes from steroid therapy do not significantly impair visual acuity. However, if vision is affected reduction or cessation of steroid therapy seldom resolves the opacity, but it typically halts its progression.
Figure 3. Posterior subcapsular cataract associated with steroid use.
MANAGEMENT OF ANTERIOR SEGMENT OCULAR DISEASES WITH TOPICAL STEROIDS
There are many diseases for which a topical steroid is indicated as part of the management strategy. Some of these diseases are described below along with the suggested treatment regimens. Although suggested regimens are listed, selection of other steroids and/or regimen alternatives should be considered depending on the specific disease, its severity, and individual patient characteristics.
For example, a patient with a severe anterior uveitis might require the use of prednisolone acetate 1% administered one drop per hour during waking hours. If no improvement was noted at a one-day follow-up, the dose might need to be increased to one drop every half hour, or the use of systemic steroids might need to be considered. If improvement was noted at the follow-up examination, the dose could be reduced to one drop every 2 hours and reduced again a day later if improvement continued. The object of steroid therapy is to use enough of the drug for long enough to suppress inflammation while at the same time avoiding side-effects.
For some conditions, long-term therapy might be required to maintain inflammation suppression. The newer soft steroids work well for this with the dosing titrated to the level just sufficient to keep the inflammation under control.
When systemic steroids are given, there is considerable concern for a dose tapering schedule. This is partially because systemic steroids tend to suppress production of the body's natural steroids and the body needs time to resume steroid production when steroids drugs are no longer being given. With topical ocular steroid use, there is less concern for suppressing the body's own steroid production because the amounts given are relatively small and systemic absorption is limited. However, discontinuing topical steroid use too abruptly (and before the cause of the inflammation has been eliminated) can lead to rebound inflammation and might require a return to a larger dose. In the case of topical steroid use, the taper rate is usually determined by the clinical appearance of the eye. The dosage should be reduced just fast enough to keep inflammation in check.
Several anterior segment ocular diseases with inflammatory and/or allergic components are described below along with recommended treatment regimens. For almost all of these diseases, steroids are not the drug of first choice for management. If an infection is present, it must be treated before (or rarely along with) the use of steroids. When a steroid-antibiotic combination is used, it is typically given to prevent the development of an infection in compromised tissue.
If the disease is allergy related, environmental changes (e.g., avoiding the allergen) and/or mast-cell stabilizers are mainstays of treatment. However, steroids can be used to provide initial patient comfort for several days until the stabilizers take effect.
Blepharitis is a generic term used to describe several forms of eyelid inflammation that includes both infectious and non-infectious etiologies. Chronic blepharitis is often linked to an occupation or life-style that is associated with dirty hands or poor general hygiene.
There are two common forms of blepharitis that may occur alone or together. The first is staphylococcal blepharitis. In this condition, the eyelid margins and lash follicles are infected with Staphylococcal aureus or there is an increase in the normal flora bacteria, predominantly Staphylococcus epidermidis. These bacteria produce an enzyme called lipase that breaks down lipids in the tears to form free fatty acids, which are toxic and inflammatory.
The presentation of staphylococcal blepharitis is typically bilateral. Symptoms vary but can include itching, burning, scratchiness, foreign body sensation, and excessive tearing. The most typical signs are crusts composed of inflammatory debris along the lid margins. Sometimes the inflammatory debris encircles eyelashes forming collarettes.
Other ocular signs include lid erythema, madarosis (missing lashes), trichiasis (in-turned lashes), plugged meibomian glands, conjunctival injection, and superficial punctate keratitis on the lower third of the cornea. There is often an associated conjunctivitis with papillary hypertrophy of the palpebral conjunctiva. Some of these signs can be caused by an allergic reaction to products the bacteria release from their cells.
Figure 4. Staphylococcal blepharitis with hyperemic eyelid margins and crusts. Trichiasis and madarosis are also present.
Figure 5. Staphylococcal blepharitis with inflamed lash follicles.
The second form of blepharitis involves meibomian gland dysfunction (meibomianitis). It is characterized by excess lipid production from the meibomian glands, which are often inflamed. An excess quantity of oil on the lid margin promotes formation of crusty debris in and around the meibomian glands. This eventually clogs the gland orifices, or, at the very least, interferes with meibomian secretion. Sebum from the glands becomes thickened and may eventually become so thick that it cannot be expressed. In most cases, patients with this form of blepharitis complain of dry, irritated eyes.
The oily deposits on the lid margin provide bacteria with an ideal environment for multiplication and the indigenous staphylococci often multiply out of control. These bacteria produce increased amounts of lipase, which causes toxic and inflammatory reactions on the lids, conjunctiva, and cornea.
Figure 6. Meibomian gland dysfunction with thickened meibomian gland secretions produced by gland expression.
Figure 7. Meibomian gland dysfunction (meibomianitis) with thickened meibomian gland secretions seen in the tear film after gland expression.
The mainstay of therapy for blepharitis is improved lid hygiene. Warm compresses followed by eyelid scrubs using a mild, deodorant-free soap or tearless baby shampoo will resolve or ameliorate most cases.
For moderate, severe or chronic cases, topical and/or oral antibiotic medications might be needed. A topical antibiotic ointment such as bacitracin or erythromycin applied to the lid margins can decrease the number of bacteria and thus improve the blepharitis.
Topical steroids can also be useful for controlling the allergic component of blepharitis and for reducing any inflammation and irritation that are present. An antibiotic-steroid combination such as tobramycin and dexamethasone alcohol (Tobradex®), gentamicin and prednisolone acetate (PredG®), or loteprednol and tobramycin (Zylet®) may provide an effective topical treatment, but, in recalcitrant cases, oral tetracycline 250mg qid or doxycycline 100 mg bid can be tried. Although these drugs may not kill the bacteria (many bacteria are resistant to them), they inhibit bacterial production of lipases, which decreases the toxic and inflammatory components of blepharitis.
Patients using on non-steroidal medications should be checked in seven to 10 days and those using antibiotic-steroid combinations should be checked within three to five days to determine if an IOP response is occurring. After resolution of acute blepharitis, non-medicated patients should be checked every six months, or as needed.
Left untreated, chronic blepharitis can cause degenerative changes in the skin (e.g., ulcerative blepharitis), meibomianitis, hordeola, chalazia, and marginal sterile keratitis.
Patients with a chronic or recurrent history of blepharitis or those who fail to respond to medical therapy might be suffering from acne rosacea. These patients need oral antibiotics (e.g., tetracycline) and possibly a dermatologic consult.
Marginal Corneal Infiltrate/Ulcer
A marginal corneal infiltrate/ulcer is found in the corneal periphery, and no bacteria can be cultured from the cornea. The most common etiology is an allergic reaction to material produced by staphylococci growing on the lid margin and getting into the tears. The immune system responds by producing antibodies, which trigger an allergic reaction that draws white cells into the cornea producing an infiltrate. The infiltrate is subepithelial (i.e., it is located just under the corneal epithelium). If some of the white cells lyse, they released enzymes that destroy epithelial cells and an epithelial defect on the corneal surface can occur. One distinct characteristic of a marginal infiltrate is the notable clear zone that lies between the infiltrate and the limbus.
Patients with a marginal sterile corneal infiltrate/ulcer usually present with mild conjunctival injection, little to no conjunctival chemosis, ocular irritation, and normal acuity.
Figure 8. Marginal corneal infiltrates (arrows).
The treatment strategy for marginal sterile keratitis is two-fold: (1) manage the staphylococcal blepharitis, and (2) treat the corneal inflammation. Prednisolone acetate 1% qid can be used to reduce inflammation and aid in resolution of the infiltrate. A topical antibiotic can be added to protect against infection if an epithelial defect is present.
Pingueculae are yellowish, slightly raised, interpalpebral deposits of abnormal collagen that occur on the nasal and temporal limbal conjunctiva. They are frequently found in middle-aged individuals who experience chronic exposure to the sun. There is no predilection with regard to sex or race.
In most cases, pingueculae are an ancillary finding, causing few if any ocular symptoms. Occasionally, a pinguecula can lead to the formation of a pterygium, which is a raised, whitish, triangular-shaped wedge of fibrovascular tissue. The base of a pterygium typically lies within the interpalpebral conjunctiva and the apex grows onto the cornea. The majority of pterygia are located with their bases oriented nasally.
Figure 9. Pterygium.
Both pingueculae and pterygia are usually discovered during routine ocular examinations of asymptomatic individuals. However, they can become red and irritated, thus motivating a patient to seek care. In addition, a pterygium can be associated with corneal punctate epitheliopathy and corneal dellen (i.e., corneal thinning secondary to dryness).
Ultraviolet light exposure is the most significant contributory factor in the development of both pingueculae and pterygia. Other contributing factors include allergens, noxious chemicals, and irritants such as wind, dirt, dust, and air pollution.
Because pingueculae and pterygiae are linked to environment exposure, initial management for asymptomatic or mildly irritated lesions involves the use of UV-blocking spectacles and liberal lubrication. Patients should be advised to avoid smoky or dusty areas or to use goggles.
Inflamed or irritated pingueculae and pterygia can be treated with a short topical steroid course (e.g., prednisolone, loteprednol, fluoromethone, or rimexolone) qid in the affected eye. Treatment duration and dose levels are determined by the clinical appearance of the lesion. It is important to inform the patient that steroid treatment will not make the lesion go away, it will only reduce inflammation and possibly slow its development.
Surgical excision of a pterygium is usually indicated only when significant induced astigmatism and/or significant threat to the visual axis occurs.
Seasonal or Perennial Allergic Conjunctivitis
Patients with ocular allergy usually present with itchy, watery eyes, and mild hyperemia. In most cases, the patient will report a history of personal and/or family seasonal allergies. The important observable clinical signs include conjunctival swelling (chemosis) and hyperemia, and red, edematous eyelids.
Figure 10. Seasonal allergic conjunctivitis.
Allergens producing ocular allergy include airborne tree and grass pollens, mold spores, and dust mites. They trigger mast cell degranulation via IgE with the release of vasoactive amines such as histamine, which can cause inflammation and irritation.
Because allergy cannot typically be cured, management is primarily directed toward reducing symptoms. The most effective treatment for allergic conjunctivitis is to eliminate the offending allergens through air conditioning and filtering. Cold compresses, artificial tears, and ointments to soothe, lubricate, and wash away or dilute antigens can be used on an as-needed basis. Topical over-the-counter decongestants can be used to produce vasoconstriction, and to reduce hyperemia and chemosis.
Topical antihistamines such as emedastine (Emadine®) and levocabastine (Livostin®) can be used to block the actions of histamine. Mast-cell stabilizers including pemirolast (Alamast®), nedocromil (Alocril®), lodoxamide (Alomide®), and cromolyn can also be used to stabilize mast cells and inhibit release of the histamine. Dual action medications such as olopatadine (Patanol®), ketotifen (Zaditor®), and azelastine (Optivar®) combine antihistamine and mast-cell stabilizing properties. They are widely used for managing symptoms associated with seasonal allergies.
For more severe allergy presentations, a topical steroid such as loteprednol 0.2% (Alrex®) one drop qid can be used. This medication is effective even in severe ocular allergic responses and appears to be safe for long-term management of allergies. However, IOP should still be monitored in patients who take any steroid for 10 days or more.
One approach to treating allergic conjunctivitis is to start the patient on both loteprednol 0.2% one drop qid and a mast cell stabilizer. The steroid will take effect quickly whereas the mast-cell stabilizer may take up to a week to become fully effective. The steroid can then be tapered off and the patient can be maintained on the mast cell stabilizer.
Vernal Keratoconjunctivitis (VKC)
Vernal keratoconjunctivitis (VKC) is an uncommon ocular allergic disorder that is more prevalent in warmer climates. It consists of a chronic, bilateral inflammation of the superior palpebral and limbal conjunctiva. Symptoms often include severe itching and thick, ropy discharge. The important clinical signs include large conjunctival papillae on the superior tarsus; raised Horner-Trantas dots (i.e., gelatinous, white clumps of degenerated eosinophils usually located at the superior limbus); areas of superficial punctate keratitis (SPK); and, in severe cases, well-demarcated, sterile corneal shield ulcers located superiorly.
VKC is typically seasonal, occurring during the months of April to August. The initial onset of VKC is usually before puberty and disease intensity reaches a peak at around 11 to 13 years of age. VKC is a self-limited disease with a duration ranging from 2 to 10 years. Males typically are affected more than females, and there is usually a family history of atopic (allergic) disease.
Figure 11. Large papillae on the upper tarsus in vernal keratoconjunctivitis.
Figure 12. Horner-Trantas dots at the superior limbus in vernal keratoconjunctivitis.
Vernal shield ulcers can develop in the upper regions of the cornea. The base of the ulcer is composed of abnormal mucus, fibrin, and serum, deposited as a gray plaque. Friction secondary to the roughened superior conjunctiva erodes the corneal epithelium and can produce these ulcers.
Figure 13. A corneal shield ulcer in vernal keratoconjunctivitis.
Management of VKC is primarily directed at reducing symptoms and preventing serious vision-threatening sequelae. In mild cases, cold compresses, ocular lubricants, and decongestants may be sufficient.
In moderate to severe cases, topical and oral antihistamines, mast cell stabilizers, non-steroidal anti-inflammatory drugs (NSAIDs), and topical steroids are treatment options.
Dosage for topical steroid treatment is adjusted depending on severity of the clinical presentation. Prednisolone (acetate or phosphate) 1% one drop q1h to qid can be used during the first few days with the dosage tapered over 1 to 2 weeks. Maintenance therapy includes one drop of prednisolone 1% or fluorometholone 1 to 3 times per day. Topical cyclosporine A is also an effective treatment option for VKC.
A steroid (e.g., prednisolone acetate 1% q2h for 1 week with a rapid taper) in conjunction with a topical antibiotic for infection prevention and a cycloplegic agent are typically used for treatment of a shield ulcer.
Atopic Keratoconjunctivitis (AKC)
Atopic keratoconjunctivitis (AKC) is one of the most serious of the ocular allergies because of the potential for loss of vision caused by corneal involvement. AKC is not seasonal and occurs throughout the year. It is typically an adult disease affecting those aged 30 to 50 years. The disease is often associated with atopy; eczema is found in most cases and allergic rhinitis in about two-thirds of the patients with AKC.
AKC is typically bilateral with symptoms of itching, burning, mucous discharge, and photophobia. Lid involvement includes dermatitis, blepharitis, and meibomianitis. The conjunctiva will be hyperemic and chemotic with diffuse papillae in the superior palpebral conjunctiva. Punctate epithelial erosions occur in most patients with more serious ulceration, vascularization, pannus, and scarring occurring in about three-fourths of patients. Reduction in visual acuity caused by corneal changes occurs in 70% of AKC patients, and cataracts occur in about 10% of cases.
Figure 14. Atopic keratoconjunctivitis with conjunctival papillae in the left image and conjunctival cicatricial changes in the right image.
Mild AKC can be managed with environmental controls, cold compresses, vasoconstrictors, and topical antihistamines. Mast cell stabilizers also have an important role in the management of AKC and are sometimes required for long-term use.
A topical steroid (e.g., prednisolone acetate 1% q1h to qid) is often essential for the treatment of atopic keratoconjunctivitis. Because cicatricial changes in the conjunctiva and cornea can be a part of the disease process, a steroid is required to reduce inflammation and prevent scarring.
AKC can last a long time so the patient will typically require long-term steroid therapy. Because rimexolone and loteprenol are “safer” steroids in terms of IOP changes, they are good choices for chronic treatment. In sight-threatening cases of AKC, cyclosporine A is a treatment option in addition to steroids.
Giant Papillary Conjunctivitis
Giant papillary conjunctivitis (GPC) is a condition seen in soft contact lens patients, patients with exposed suture knots, and those with prostheses. A current theory is that some forms of GPC are immune system reactions triggered by contact lens deposits (e.g., denatured proteins) that act as allergens. Patients with asthma, hay fever, or animal allergies may be at greater risk for developing GPC.
Initial GPC presentation may occur months or even years after lens wear has been initiated. Papillae associated with GPC can be observed on the superior tarsus. Ocular itching after lens removal, increased mucus discharge in the morning, photophobia, and decreased lens tolerance are all initial symptoms. Vision can be affected by deposits on the lens, by lens displacement secondary to superior lid papillary hypertrophy, or by repetitive mechanical corneal abrasion causing infiltration (e.g., shield ulceration).
Figure 15. Giant papillae.
Management is primarily directed at reducing symptoms. Discontinuing contact lens wear is usually needed for moderate and severe giant papillary conjunctivitis. After lens removal, the treatment is very similar to that for seasonal allergic conjunctivitis with topical mast cell stabilizers being the mainstay.
A steroid can also be used in the treatment of giant papillary conjunctivitis; an excellent steroid choice is loteprednol 0.5% (Lotemax®) qid. Improvement in symptoms and signs can often be seen in one week at which time a taper can be started.
After the disease is under control, fitting susceptible patients with daily disposable or rigid gas-permeable lenses may prevent another GPC flare-up.
The most common cause of viral conjunctivitis is adenovirus, with the two most frequently occurring types being epidemic keratoconjunctivitis and pharyngoconjunctival fever.
Pharyngoconjunctival fever (PCF) is characterized by fever, sore throat, and follicular conjunctivitis. Patients should be told to expect their ocular symptoms to get worse for about seven to ten days before getting better and that the infection won’t completely go away for three to six weeks.
Epidemic Keratoconjunctivitis (EKC) is characterized by a follicular conjunctivitis with epithelial and stromal keratitis. Subepithelial corneal infiltrates, typically concentrated in the central cornea, can be seen two or more weeks after the follicular conjunctivitis starts.
Figure 16. Subepithelial infiltrates in epidemic keratoconjunctivitis.
Key clinical signs of both conditions include conjunctival injection, serous discharge, edematous eyelids, pinpoint subconjunctival hemorrhages, pseudomembrane formation, and palpable preauricular lymph nodes.
Both conditions are highly contagious. Patients will usually report recent contact with someone who had either red eyes or an upper respiratory infection. Both forms tend to start in one eye and then spread to the other eye within a few days.
Because EKC and PCF are contagious and self-limiting, primary treatment involves patient education and comfort. Patients should be told to stay home from work or school until there is absolutely no discharge. They should also be instructed not to share utensils, glasses, linens or washcloths with others.
Medical management involves symptomatic relief and can range from cold compresses and artificial tears to topical vasoconstrictors. A topical antibiotic can be used as a prophylactic to prevent bacterial infections when corneal epithelial defects present.
If subepithelial infiltrates affect vision, a mild topical steroid (e.g., fluorometholone alcohol 0.1% one drop 2 to 4 times daily) can be used to help resolve them. The steroid may be needed for months, and, even with a very slow taper, infiltrates may recur and be more prolonged.
Dry eye is a multifactorial ocular surface disease with various manifestations and degrees of severity. Some individuals manifest mild or episodic symptoms that are easily controlled with an ocular lubricant. Others present with severe complications from keratoconjunctivitis sicca.
Figure 17. Dry eye stained with rose bengal showing patches of devitalized epithelial cells.
Although dry eye is associated with many conditions including ocular allergy and infection, there is evidence that decreased tear secretion, decreased tear turnover, and desiccation can promote inflammation of the ocular surface, even in the absence of infection (8). Pro-inflammatory cytokines and activated T-cells in the conjunctiva have been found in dry eye patients, both with and without Sjogren's syndrome. These inflammatory products not only cause irritation but can also create excess mucus production, which can precipitate in the form of filaments.
Chronic inflammation can damage the cornea's nerve fibers, which can lead to neurotrophic keratitis. Inflammatory stimulation of corneal neural receptors can also feed back to the lacrimal glands via efferent nerves resulting in decreased tear production.
There are many management options for dry eye. Simple artificial tears replenish moisture and perhaps wash away accumulated debris. Newer products have additional features that enhance their function in treatment of dry eye. TheraTears® (Advanced Vision Research) can reduce the osmolarity of the tear film (in dry eye, tears can become hyperosmotic). Refresh Endura® (Allergan) and Smoothe Emollient Eye Drops® (Alimera Sciences) contain both an aqueous and a lipid component (in many dry eye states, such as meibomian gland dysfunction, the lipid layer of the tears is reduced leading to evaporative dry eye). Systane® (Alcon) incorporates hydroxypropyl guar that increases tear viscosity and residence time on the eye's surface.
Punctal occlusion can preserve the tears already on the ocular surface, however patients with an inflammatory component to their dry eye might actually get worse as a result of occlusion. Decreased tear clearance can result in accumulation of inflammatory cytokines in the tear film and/or a rise in osmolarity. This could affect the corneal nerves and cause a decrease in tear production. Identification and treatment of any underlying inflammation should be done before considering punctul occlusion.
Cyclosporine® (Allergan) is an immunomodulator and was the first drug specifically indicated for the treatment of keratoconjunctivitis sicca. Cyclosporine works by reducing immune-mediated inflammation at the ocular surface. Patients typically respond well to cyclosporine although it may take three to six months to achieve maximum response.
Topical steroids can also be used to treat dry eye signs and symptoms. Steroids help increase goblet cell density and reduce the accumulation of inflammatory cells within ocular surface tissues. For example, topical loteprednol 0.5% (Lotemax®) qid can benefit patients with keratoconjunctivitis sicca when there is at least a moderate inflammatory component present (9).
The diagnosis of chemical trauma to the eye is usually based on history rather than on signs and symptoms. Patients will generally report a varying degree of pain, photophobia, reduced vision, and colored haloes around lights. In mild to moderate burns, the eye is hyperemic and may display conjunctival chemosis, eyelid edema, first degree burns to the skin (i.e., reddening), and cells and flare in the anterior chamber. Corneal findings can range from diffuse punctate keratopathy to focal epithelial erosion with mild stromal haze.
When the chemical injury is more severe, the eye is not red but appears white because of conjunctival vessel ischemia. Chemosis of the lids and conjunctiva is present, and the surrounding facial areas may have second or third degree burns. Corneal findings can include total epithelial erosion with edema and dense stromal hazing, sometimes to the point of complete opacification.
Figure 18. Alkali burn.
Chemical burns constitute ocular urgencies. When chemical exposure occurs, prompt, copious fluid irrigation of the affected eye is critical to successful management. Flushing the eye with either water (by the patient) or saline (by the doctor) for 20 to 30 minutes and then checking with litmus paper to assure neutrality is the initial treatment. Any necrotic tissue should be debrided using a cotton-tipped applicator moistened with antibiotic solution. The fornices should be swabbed in a similar fashion. A cycloplegic and a broad-spectrum antibiotic should then be instilled. If significant epithelial erosion has occurred, a bandage contact lens must be considered.
In cases when inflammation is severe, a topical steroid such as prednisolone acetate 1% one drop q2h to q4h can be used during the first week following trauma. Use of a steroid beyond 10 days puts the patient at risk for a corneal melt (keratolysis). Depending on the level of pain, topical and oral non-steroidal drugs or narcotic analgesics can be used.
Hyperosmotic sodium chloride can be used during and following corneal re-epithelialization to encourage adhesion of the epithelium to Bowman's layer. If there is loose epithelium, it should be debrided with a cotton swab. Patients should be evaluated daily including measurement of IOP because the trabecular meshwork can become blocked with inflammatory debris causing a secondary glaucoma.
Thygeson's Superficial Punctate Keratitis
The signs and symptoms of Thygeson's superficial punctate keratitis are minimal. Patients usually report only a mild to moderate foreign body sensation, tearing, and occasionally photophobia. The eye appears white and quiet, and there is no history of recent inflammation or any associated systemic illness. The condition is usually bilateral and typically occurs in the second to third decade of life. The etiology of Thygeson's is unknown.
Biomicroscopy reveals numerous round or stellate areas of coarse, gray, slightly elevated intraepithelial opacities. These lesions resemble subepithelial infiltrates but are more superficial, duller in color, and less well organized. Also, these areas may demonstrate variable central staining with fluorescein, whereas subepithelial infiltrates typically do not stain. Inspection of the anterior chamber shows no cells or flare.
Figure 19. Thygeson’s superficial punctate keratitis. Left image shows rose bengal staining of corneal lesions. Right image shows the corneal lesions magnified.
Visual acuity may be normal or mildly reduced, depending upon the density and location of the opacities. Because Thygeson's superficial punctate keratitis tends to run a chronic course with remissions and exacerbations, the patient may report having had similar experiences in the past. The clinical presentation, although bilateral in nature, may be asymmetric or involve only one eye at a time.
In most cases, Thygeson's superficial punctate keratitis presents with an insidious onset. The disease often continues to plague patients for months or even years, with sporadic exacerbations. The trigger mechanism for these flare-ups appears to be idiopathic.
Thygeson's superficial punctate keratitis is a self-limiting disorder, but intervention usually speeds resolution and enhances patient comfort. Mild cases can be managed with topical lubrication.
Moderate to severe cases may require topical steroids for relief of symptoms. A mild steroid such as prednisolone acetate 0.12% or fluorometholone 0.1% can be used qid for one week and then tapered slowly as signs and symptoms resolve.
Interstitial keratitis is a diffuse or sectorial vascularization and scarring of the corneal stroma. The most common etiology is congenital syphilis (90% of patients) followed by tuberculosis and herpes simplex. Symptoms of the acute form include decreased vision, pain, photophobia, and red eye. Signs include conjunctival injection, corneal stromal vascularization, stromal edema, anterior chamber cells/flare, and keratic precipitates.
Figure 20. Interstitial keratitis.
Evaluation should include laboratory tests for syphilis (e.g., the Venereal Disease Research Laboratory (VDRL) test and/or the fluorescent-treponema antibody-absorption (FTA-ABS) test). The purified protein derivative (PPD) skin test and chest radiographs should also be done to rule out tuberculosis.
After treating the underlying cause, acute interstitial keratitis can be managed with a topical steroid such as prednisolone acetate 1% qid along with a cycloplegic. Again, the steroid dosage can be adjusted and the drug should be used as long as necessary. When the condition improves, the dosage can be reduced.
Rosacea is an idiopathic, chronic, facial inflammatory disorder of adults. Characteristic features include erythema, pustules, papules, and telangiectasia of the nose, chin, forehead, and cheeks. Rhinophyma (redness, enlargement of the sebaceous glands, and nodular swelling of the skin on the nose) can occur late in the course of rosacea.
Frequent ocular manifestations include blepharitis, chalazia, conjunctival infection, and dry eye. The cornea is rarely involved but punctate epithelial erosions, sterile peripheral infiltrates, corneal neovascularization, and corneal thinning have been reported.
Figure 21. Corneal vascularization and infiltration at the left limbus in acne rosaea.
Treatment for rosacea involves systemic tetracycline or doxycycline administration. Topical metronidazole is also effective for facial skin eruptions. Moderate to severe keratitis requires topical steroid treatment with prednisolone acetate one drop 1% qid for 1 to 2 weeks as an initial therapy. As the keratitis improves, the dosage should be tapered.
A phlyctenule is a nodular infiltrate on the bulbar conjunctiva, at the limbus, or on the cornea. It is a vascularized lesion and when it marches across the cornea, it causes vascularization and scarring.
Figure 22. Phlyctenule located at about 5 o’clock.
Patients with a phlyctenule present with a red eye, itching, and foreign body sensation. They may also have photophobia, tearing, and discharge.
Phlyctenulosis is an allergic reaction to Staphylococcus species, Mycobacterium species, Candida species, Coccidioides, or Chlamydia.
Ocular management starts with treatment of the underlying etiology. If the phlyctenulosis is associated with staphylococcal blepharitis, management of the blepharitis with warm compresses, lid scrubs, and antibiotics is appropriate. The resurgence of tuberculosis makes tuberculosis testing appropriate for patients with phlyctenulosis.
The ocular lesions are treated with topical steroids. Patients typically respond well to prednisolone acetate 1% one drop q2h to q4h for the first 24 to 48 hours. Subsequently, the dose should be tapered rapidly on the basis of clinical response. In most cases, patients obtain dramatic relief from symptoms and can taper the drug in 7 to 10 days. Cycloplegia is only necessary if there is an associated iritis.
Herpes zoster ophthalmicus (HZO) typically presents with nondescript facial pain, fever, and general malaise. About four days after onset, a vesicular skin rash appears along the distribution of the fifth cranial nerve, characteristically respecting the vertical midline. The vesicles discharge fluid and begin to scab over after about one week. Pain can be extreme during the inflammatory stage, and patients are extremely symptomatic.
Ocular involvement can include follicular conjunctivitis, epithelial and/or interstitial keratitis, pseudodendritic keratitis, uveitis, scleritis or episcleritis, chorioretinitis, optic neuropathy, and even neurogenic motility disorders (especially fourth cranial nerve palsy).
If there are vesicles at the tip of the nose (known as Hutchinson’s Sign), there is a 75 percent likelihood of ocular sequelae.
Figure 23. Micropseudodendrites in herpes zoster ophthalmicus.
Figure 24. Disciform keratitis in herpes zoster ophthalmicus.
Herpes zoster ophthalmicus is caused by the varicella/zoster virus. The trigeminal ganglion or other ganglia in the body are initially infected by this virus during the childhood disease chickenpox. The virus remains dormant in ganglion cells, but, if it is reactivated years later, it can cause herpes zoster ophthalmicus if the eyes are involved or shingles if other parts of the body are involved.
Herpes zoster ophthalmicus is typically treated with oral acyclovir (Zovirax®), 600 to 800 mg five times a day for seven to 10 days. The treatment is most effective when started within 72 hours of skin lesion onset. Systemic acyclovir promotes resolution of the skin lesions and decreases the incidence and severity of dendriform keratopathy, uveitis, and stromal infiltrates. Alternative drugs that are also effective include famciclovir (Famvir®) and valacyclovir (Valtex®).
Ocular management depends on severity and the specific tissues involved. Prednisolone acetate 1% can be used one drop qid for corneal changes caused by inflammation, stromal infiltrates, serpiginous ulceration, and disciform keratitis. Steroids can also be used to suppress anterior uveitis. If they are used, steroids must be tapered very slowly to avoid recurrences of inflammation.
Before a topical steroid is used, it is essential herpes simplex keratitis has been ruled out as the cause of ocular involvement. A prophylactic antibiotic should be considered in cases of corneal epithelial disease. In cases that involve uveitis, a cycloplegic drug should also be used.
Pain relief is usually needed for the management of herpes zoster ophthalmicus. This might include the use of cool compresses and oral analgesics. Cimetidine 400mg bid can also provide some relief from the neuralgia.
Herpes simplex virus is usually acquired in childhood during a flu-like illness. The virus then becomes dormant in the trigeminal ganglion from which it can reactivate to multiply in the corneal nerves and epithelial cells.
Epithelial herpes simplex keratitis can present as a superficial punctate keratitis, a dendrite (ulcerated, classically with terminal bulbs), or a geographic ulcer. Viral multiplication in the corneal nerves causes decreased corneal sensation. Treatment with topical trifluridine will shorten the time to resolution of the epithelial disease, which usually heals without scarring. However, it often recurs.
Following an episode, the recurrence rate is 25% during the first year and 50% during the second year. Recurrent herpes simplex disease can be triggered by a variety of factors including sun exposure, fever, stress, menses, trauma, illness, and immunosupression.
Except under extreme and very unusual circumstances, a steroid is contraindicated in herpes simplex epithelial keratitis.
Steroid use is a risk factor for stromal involvement that is often vision threatening.
Figure 25. Dendritic epithelial keratitis caused by herpes simplex virus.
Repeated infection of the corneal epithelium with herpes simplex virus and/or use of a steroid to treat the epithelial disease can cause immune-mediated stromal disease such as disciform keratitis (disciform edema). Disciform keratitis is a self-limited, immune reaction with focal, disc-like areas of stromal edema, folds, fine keratic precipitates, and scarring.
Figure 26. Disciform keratitis that was triggered by herpes simplex virus.
The herpes simplex virus can also trigger an immune-mediated inflammatory reaction in the stroma. There will usually be a single or multiple white patches of infiltration within the corneal stroma along with concurrent stromal edema and vascularization. There will also be a severe anterior uveitis. Typically, the overlying epithelium is intact.
Although a steroid should not be used to treat an active herpes simplex epithelial infection (e.g., when a dendrite is present), immune-mediated stromal disease (e.g., disciform keratitis and stromal inflammatory disease) must be treated with a steroid to prevent scarring and vision loss.
Figure 27. Immune-mediated inflammatory stromal keratitis.
For both disciform and stromal keratitis, a steroid can shorten the duration of inflammation. A steroid (e.g., prednisolone acetate 1%) should be applied one drop qd to qid depending on severity of inflammation and then tapered slowly over months depending on response. For management of the associated anterior uveitis, a cycloplegic drug should be considered. Trifluridine qid can be added to treat any active virus infection if epithelial keratitis is present or prophylactically, if higher steroid doses are required.
Long-term suppressive oral therapy with acyclovir 400mg po bid has been shown to significantly reduce the recurrence rate of not only herpes simplex epithelial keratitis, but also of stromal disease.
Episcleritis typically presents with an acute onset of redness, usually in one eye. Often sectorial injection of the episcleral and overlying conjunctival vessels will be noted, although the redness may be diffuse throughout these tissues. Occasionally, there may be a translucent white nodule centrally within the inflamed area (nodular episcleritis). Although some patients complain of mild discomfort including photophobia and/or a sensation of heat or prickling, often there are no associated symptoms. The cornea remains clear in this condition and there is no associated anterior chamber reaction. The disorder is idiopathic in the majority of cases, however occasionally there is an association with an underlying systemic disease, (e.g., rheumatoid arthritis or lupus erythematosus).
Figure 28. Epislceritis.
Most episodes of episcleritis are self-limiting, meaning that they will resolve spontaneously within two to three weeks even if the patient does not receive treatment. However, patients who are experiencing discomfort may benefit from a topical steroid. Prednisolone acetate 1% or dexamethasone 0.1% one drop q1h to q2h can be used until the redness disappears and then 3 or 4 times daily for 4 to 5 days to prevent a recurrence.
Because of the possible association with systemic disorders, patients with extremely severe presentations or with more than three recurrences can be referred for a medical evaluation.
Unlike the mild discomfort of episcleritis, scleritis presents with severe, boring ocular pain that may also involve the adjacent head and facial regions. The scleral vessels will be significantly dilated, along with the overlying vessels of the episclera and bulbar conjunctiva.
In some cases, the affected eye may be so injected that it actually takes on a deep red, almost purple, hue. This presentation may be sectorial or diffuse and with or without a nodule.
Figure 29. Scleritis
Patients typically report a gradual onset of pain and redness, with associated photophobia, tearing, and decreased vision. Slip lamp evaluation may reveal scleral nodules (nodular scleritis), peripheral keratitis, and secondary uveitis. In severe cases of necrotizing scleritis, the sclera can become so transparent due to chronic inflammation, that the underlying dark blue of the choroid will be revealed.
Over 50% of scleritis cases are associated with systemic disease such as rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, polyarteritis nodosa, Wegener's granulomatosis, herpes zoster virus, gout, and syphilis.
The first step in the treatment of scleritis is to identify and manage any underlying systemic disease. Delay in the diagnosis of associated vasculitic diseases may lead to patient death.
After the underlying disease has been controlled, the scleritis needs to be treated. Use of topical steroids can relieve pain and dramatically reduce scleral inflammation. Either prednisolone 1% or dexamethasone 0.1% can be used from one drop qid to as often as once every hour depending on severity of the inflammation.
However, topical steroid therapy is usually not adequate by itself to treat scleritis, so the preferred treatment plan also involves uses of systemic anti-inflammatory or immunosuppressive drugs. Oral non-steroidal anti-inflammatory drugs such as ibuprofen, indomethacin, and naproxen, along with steroids such as prednisone, and immunosuppressive drugs such as cyclophosphamide, cyclosporine, azathioprine, methotrexate and clorambucil can be used. Aggressive treatment of scleritis is important to prevent complications (e.g., cell necrosis and collagen degeneration) that occur during the later stages of the disease and vary according to the degree of inflammation.
The typical presentation of anterior uveitis involves pain, photophobia, and hyperlacrimation. Patients report a deep, dull, aching of the involved eye and surrounding orbit. Associated sensitivity to lights may be severe. Excessive tearing occurs secondary to increased neural stimulation of the lacrimal gland and the patient does not report a foreign-body sensation.
Visual acuity is variable ranging from mild blur to significant vision loss if synechiae or cyclitic membranes are present. An examination may reveal mild to moderate lid swelling resulting in pseudoptosis.
A deep, perilimbal injection of the conjunctiva and episclera is typical, although the palpebral conjunctiva is characteristically normal. The cornea may display mild edema.
Figure 30. Anterior uveitis.
The hallmark signs of anterior uveitis include cells and flare in the anterior chamber. If the anterior chamber reaction is significant, small gray to brown endothelial deposits known as keratic precipitates may be present. This can then lead to endothelial cell dysfunction and corneal edema.
Iris findings may include adhesions to the lens capsule (posterior synechiae) or, less commonly, to the peripheral cornea (anterior synechiae). Additionally, granulomatous nodules may appear on the surface of the iris.
Intraocular pressure is initially reduced in the involved eye due to secretory hypotony of the ciliary body. However, as the reaction persists, inflammatory by-products may accumulate in the trabeculum. If this debris builds significantly, and if the ciliary body resumes its normal secretory output, IOP can rise sharply resulting in a secondary uveitic glaucoma.
Uveitis can be idiopathic, it can be associated with underlying systemic disease, or it can occur as a direct result of ocular trauma. Occasionally, inflammatory reactions in adjacent tissues (e.g., keratitis) can induce a secondary uveitis.
Uveitis can be either acute or chronic. The chronic form is more often associated with systemic disorders including ankylosing spondylitis, Behçet's syndrome, inflammatory bowel disease, juvenile rheumatoid arthritis, Reiter's syndrome, sarcoidosis, syphilis, tuberculosis, and Lyme disease.
There are two primary goals when managing anterior uveitis. The first is to immobilize the iris and ciliary body to decrease pain and prevent posterior synechiae. This is achieved by using a cycloplegic drug such as homatropine 5% tid, scopolamine 0.25% tid, or atropine 1% bid.
The second goal is to quell the inflammatory response. This is achieved by using a topical steroid q1h to q2h or more often if the reaction is severe. Prednisolone acetate 1% is often the drug of first choice. Several studies have shown that loteprednol is less effective than prednisolone acetate 1% for the treatment of anterior uveitis. Significant secondary elevations in IOP (e.g., greater than 26 mm Hg) can typically be managed with beta-blockers.
After beginning treatment, the patient should be re-evaluated every one to seven days depending on the severity of the condition. As the uveitis resolves, the cycloplegic can be discontinued and the steroid can be tapered to tid or qid. Generally, it is better to taper slowly rather than abruptly; patients may need to remain on steroid drops daily or every other day for several weeks.
Recurrent uveitis, defined as three or more unexplained episodes, should be considered to be representative of an underlying systemic inflammatory disease until proven otherwise. Identification and management of the underlying disease is essential.
In addition to an anterior segment examination, a dilated fundus evaluation should be done for anterior uveitis patients because the anterior uveitis may actually constitute a "spillover" of posterior ocular inflammation.
Glaucomatocyclitic Crisis (Posner-Schlossman Syndrome)
A patient having a glaucomatocyclitic crisis will present with a recurrent, unilateral red eye, and, at most, very mild discomfort. Acuity will be slightly reduced, and this is often the patient's chief complaint.
The cornea will be mildly edematous, but the anterior chamber will be remarkably clear. Often, the only signs of anterior chamber inflammation will be a rare cell or two in the chamber or, more commonly, a few keratic precipitates on the endothelium. Intraocular pressure can range from 30 to 70mm Hg, but the patient will typically not be in acute distress. The recurrent nature of the attacks predisposes the patient to developing glaucomatous optic atrophy.
Figure 31. Corneal edema and keratic precipitates in glaucomatocyclitic crisis.
Management of glaucomatocyclitic crisis involves use of a cycloplegic in the form of scopolamine 0.25% tid or homatropine 5% tid. In addition, a steroid such as rimexolone, prednisolone acetate, or fluorometholone acetate should be used hourly, and then tapered as the condition resolves.
To reduce IOP, a topical beta-blocker (e.g., Timolol® 0.5% bid) or a topical carbonic anhydrase inhibitor (e.g., Trusopt® tid) can be used provided there are no medical contraindications to these drugs. Avoid pilocarpine because it can increase inflammation and because of the associated miosis can lead to the formation of posterior synechiae. Also avoid using the prostaglandin analogs in these patients because they can potentially break down the blood-aqueous barrier and increase inflammation. Follow the patient every 24 hours, graduallytapering the medications as the condition improves.
Patients with neovascular glaucoma typically present with a chronically red, painful eye, and significant vision loss. Retinal ischemia caused by diabetes, retinal vessel occlusion, giant cell arteritis, or carotid artery disease may also be present.
Visible neovascularization of the iris and angle with angle closure will be present. This leads to corneal edema, anterior segment inflammation (cells and flare in the anterior chamber), and elevated IOP (often exceeding 60 mm Hg).
Figure 32. Neovascular glaucoma. (www.eyeatlas.com)
Initial therapy involves use of a topical cycloplegic such as atropine 1% bid along with a topical steroid such as prednisolone acetate 1% qid. These medications will improve patient comfort, but topical medical therapy with a steroid and a cycloplegic is not sufficient treatment for neovascular glaucoma.
Rather, elimination of the stimulus for neovascularization is the ultimate goal of therapy. This usually requires pan-retinal photocoagulation to destroy a portion of the ischemic retina and reduce oxygen demand. Photocoagulation of the retina can also reduce neovascularization of the iris.
Surgical treatment is often required to control elevated IOP. Trabeculectomy with a drainage device or cyclophotocoagulation may be necessary.
Hyphema (circulating or layered red blood cells in the anterior chamber) can be the result of a concussive injury. Patients typically present with blurred vision, pain, photophobia, and lacrimation. Because the trauma that the produced hyphema can be severe enough to produce other ocular injuries, the visual outcome and prognosis for hyphema cases is typically guarded.
Figure 33. Hyphema showing layered red blood cells in the anterior chamber.
A thorough history and evaluation of the entire eye are critical. Any ocular injury needs to managed independently of the hyphema.
Because many patients with a hyphema have an associated anterior uveitis, treatment with cycloplegics and steroids improves comfort and places the iris at rest during the healing process. Cycloplegia with atropine 1% bid to tid and inflammation control with prednisolone acetate 1% q2h to qid can be used initially. Taper the steroid over 3 to 4 weeks as the uveitis and hyphema resolve.
If the IOP is above 27 mm Hg, a beta-blocker bid can be added. Patients should be on bed rest with their head elevated at a 30-degree angle. To avoid a re-bleed, acetaminophen (not aspirin) should be used to manage pain. Immediate referral for possible surgical evacuation of the blood is indicated if corneal blood staining has occurred, IOP is over 60 mm Hg, an 8-ball hemorrhage is present, or IOP remains above 35 mm Hg for 7 days.
Lens extraction and insertion of an intraocular lens is indicated when a cataract significantly decreases vision and/or glare interferes with daily activities. Other reasons for cataract extraction involve the presence certain diseases (e.g., phacolytic glaucoma or uveitis) or when the cataract prevents examination or treatment of a pre-existing ocular condition (e.g., diabetic retinopathy, glaucoma).
Figure 34. Cataract surgery. On left phacoemulsification, on right posterior chamber IOL.
Postoperative inflammation is produced by the trauma associated with the surgical procedure as well as an immune response to pseudophakic lens material, viscoelastics, etc. Surgically induced iritis is typically minimal and self-limiting, but it does result from even the most uneventful cataract extraction.
A topical steroid (either alone or in combination with an antibiotic) is the standard treatment for postoperative inflammation. Commonly used steroids include prednisolone acetate 1%, prednisolone phosphate 1%, dexamethasone 0.1%, rimexolone 1.0% , and loteprednol 0.5%.
Steroids are typically administered using a regimen of qid for one or two weeks and then tapered using a variety of schedules. Dosage may be more frequent and the tapering more prolonged if there is significantly increased postoperative inflammation.
Cystoid macular edema (CME) is a well-documented complication of cataract surgery. Pathogenesis of CME includes accumulation of fluid in the macular intracellular and extracellular spaces as a result of increased perifoveal capillary permeability.
Figure 35. Cystoid macular edema as seen in fluorescein angiography. Left image shows early phase, right image shows late phase.
Because CME spontaneously resolves in all but about 25% of patients, treatment is often unnecessary. If treatment is warranted for uncomplicated CME, it usually includes a topical steroid such as prednisolone acetate 1%, prednisolone phosphate 1%, or dexamethasone phosphate 0.1% instilled 4 times per day. Additionally, a topical non-steroidal anti-inflammatory drug and a cycloplegic drug can be added. If no improvement occurs, subconjunctival steroid injection can be considered and an oral steroid may be needed in difficult cases.
Laser vision correction uses ophthalmic lasers to correct myopia, hyperopic, and astigmatism by reshaping the cornea. The most common procedure is LASIK (Laser in Situ Keratomileusis).
Figure 36. LASIK procedure. The corneal flap is being folded back out of the way so that the laser can ablate the corneal stroma.
To achieve a satisfactory result, patients must adhere to a planned postoperative prophylactic regimen. Medications typically include an antibiotic to prevent infection, a steroid (e.g., loteprednol 0.5%) to suppress inflammation, and artificial tears to facilitate corneal lubrication. These medications are continued for the 7 to 10 days at which time the antibiotic and steroid are discontinued but the artificial tears are continued.
Fuch’s Heterochromic Iridocyclitis
The typical patient with Fuch’s heterochromic iridocyclitis is a young adult who presents with unilateral vision loss. There is a predilection for blue-eyed patients and the iris of the affected eye may be lighter in color. A mild anterior chamber reaction and fine stellate keratic precipitates with iris stromal atrophy are usually found. Posterior synechiae are typically not present although anterior synechiae are possible. Cataracts and glaucoma are common sequalae.
Figure 37. Keratic precipitates in Fuch’s heterochromic iridocyclitis.
Because Fuch’s heterochromic iridocyclitis is an inflammation, steroid treatment seems an intuitive choice. However, the condition is not responsive to steroids in any form. No treatment at all is the best management plan for the inflammation.
Cataract extraction can be performed when necessary; patients with Fuch’s tolerate phacoemulsification with posterior IOP implantation well. Glaucoma is the most significant risk of Fuch’s and must be managed aggressively with drugs that lower aqueous production, e.g., beta-blockers. Miotics should never be used and prostaglandin analogs should be considered the last medical option because both can cause increased inflammation and the miotics can cause posterior synechiae in these patients.
Superior Limbic Keratoconjunctivitis (SLK)
Superior limbic keratoconjunctivitis occurs most often in middle-aged females who typically report symptoms of ocular discomfort including burning, foreign-body sensation, and/or non-descript pain. Additionally, they might complain of photophobia and excessive tearing.
Gross clinical signs often include mild lid swelling and pseudoptosis along with blepharospasm. Visual acuity is usually not affected.
Slit lamp examination reveals sectorial inflammation of the superior bulbar conjunctiva. The superior limbal margin of the cornea may be inflamed as well. Fluorescein and rose bengal or lissamine green reveal punctate epithelial disruption of the conjunctiva and cornea. Filaments are encountered within the precorneal tear film in roughly half of all patients with SLK.
Eversion of the upper lid can reveal a uniform papillary hypertrophy along the tarsus, which may be mild to marked. The condition is typically bilateral but often asymmetric. In most instances, the diagnosis of superior limbic keratoconjunctivitis is based solely upon the characteristic presentation.
Figure 38. Superior Limbic Keratoconjunctivitis
Despite the clinical appearance of ocular inflammation in superior limbic keratoconjunctivitis, topical steroids are not effective. Although no specific treatment has yet been shown to be 100 percent effective for the treatment of SLK, many modalities have been employed. For example, application of topical 0.5% or 1.0% silver nitrate solution to the superior bulbar and tarsal conjunctivae chemically cauterizes the irregular tissue and promotes re-growth of new, healthy epithelium. Unfortunately, recurrences can occur after silver nitrate use so re-treatments are common.
Pressure patching has been employed for severely symptomatic cases of superior limbic keratoconjunctivitis, as well as the use of bandage hydrogel lenses to alleviate mechanical irritation. Punctal occlusion, copious lubrication, and topical mast cell stabilizers such as 4% cromolyn or 0.1% lodoxamide (Alomide®) also have been used. Thermocautery and surgical resection are employed only when less invasive means have failed.
Because superior limbic keratoconjunctivitis is often associated with a systemic thyroid problem, patients presenting with SLK should be referred for a systemic workup including a serologic thyroid panel. Other disorders, such as rheumatoid arthritis and Sjögren’s syndrome, may also be associated with superior limbic keratoconjunctivitis.
Inflammation is one of the body's defenses against the effects of trauma and infection, so, in a sense, the use of steroids to block inflammation works against the body as it tries to heal itself. When inflammation is caused by an infection, the infection needs to be treated with antibiotics before the inflammation can be suppressed to prevent further tissue damage and scarring.
When inflammation is the result of an autoimmune or idiopathic disease, a steroid can be a drug of first choice to suppress the inflammation, but it is important to remember that this suppression does not cure the underlying problem.
In terms of steroid choice, dosage, and tapering, clinical judgement plays a major role. Management of more severe inflammation, especially when deeper ocular tissues are involved, requires the use of more potent steroids administered on a frequent dosing schedule. If IOP increases are a concern, one of the newer soft steroids can be used to partially reduce the potential for an IOP rise.
When the inflammation shows signs of being suppressed, the steroid dosage can be decreased or a less potent steroid can be employed. However, dosage should be maintained at a high enough level to prevent a return of the problem.
For steroid use, the best rules of thumb are:
Steroids only suppress signs and symptoms of an underlying problem, but they can be very effective in preventing or reducing tissue damage caused by excessive inflammatory or allergic responses.
CREDITS
Images used in this course have been derived from a variety of sources including: Spalton, Hitchings, Hunter: Slide Atlas of Clinical Ophthalmology, 1994, Mosby Year Book Europe Limited; Kanski: Clinical Ophthalmology Slide Sets; various Web sites including www.eyeatlas.com.
REFERENCES
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9. Pflugfelder SC, Maskin SL, Anderson B, et al. A randomized, double-masked, placebo-controlled, multicenter comparison of loteprednol etabonate ophthalmic suspension, 0.5%, and placebo for treatment of keratoconjunctivitis sicca in patients with delayed tear clearance. Am J Ophthalmol 2004; 138:444-457.
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Diane P. Yolton, PhD, OD Pacific University College of Optometry 2043 College Way Forest Grove OR 97116Pacific University College of Optometry provides On-Line CE as a service to optometrists. The college does not endorse or recommend any products, equipment, or services that might be discussed in the courses. Courses are prepared by individuals believed to be experts in their areas of specialization who are compensated for their efforts. The College relies on their expertise to produce accurate and timely courses. Questions or concerns about courses should be directed to the individual authors and/or the Continuing Education Department at the College of Optometry at kundart@pacificu.edu.
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