Ординатура / Офтальмология / Английские материалы / Clinical Ocular Pharmacology 5th edition_Bartlett, Jaanus_2008

preservatives used in ophthalmic agents, medications, cosmetics, and hair and skin care products. Prevalent among offending antigens and a well-documented cause of allergic dermatitis are parabens, a frequent preservative in many facial creams and lotions, as well as nickel, chromates, foam rubber, fragrances, and surfactants. Brimonidine can cause an allergic response in up to 25.7% of patients. Hyperemia and dermatitis may manifest within 2 weeks of treatment initiation (Figure 27-9).

Diagnosis

The overlap in signs, symptoms, and the offending substances involved in both allergic and irritant contact dermatitis can make the diagnosis difficult. A careful history assists in the diagnosis by providing information about occupational or domestic exposure to relevant allergens. Signs and symptoms include itching, eczema, blepharitis, follicles, or papules and hyperemia.

The primary signs of irritant dermatitis are erythema and edema, which are often localized to the skin of the eyelid, with associated symptoms of burning and stinging more common than itching. The skin usually is flat and dry, with scaling (Figure 27-10).

In contrast, a predominant feature of allergic contact dermatitis is pruritus, rather than burning, and in severe cases marked periorbital edema is present. A papillary conjunctivitis, with hyperemia, chemosis, and serous discharge, can occur.An erythematous blepharitis and, in severe cases, a superficial punctate keratitis can develop. When allergic contact conjunctivitis is present before lid involvement, the likely cause is a topical ophthalmic medication, as opposed to a cosmetic or hair product. Eyelid findings in chronic allergic contact dermatitis are similar to those in atopic dermatitis. Here lichenification, erythema, hyperpigmentation, and scaling are present.

Figure 27-9 Allergic response secondary to use of brimonidine 0.2%.

Allergic contact dermatitis may occur in the presence of treatment with topical corticosteroids.

Allergic contact dermatitis may be diagnosed with the assistance of patch testing. Although patch testing is not diagnostic for irritant dermatitis, a negative patch test in combination with clearing of the dermatitis after removal of the offending agent is indicative of an irritant cause. Common agents producing allergic contact dermatitis include nail polish, rubber, nickel, mascara, eye liners and eye shadow, and drugs such as neomycin.

Management

Contact dermatitis may resolve without treatment within days but may take up to 3 weeks in allergic cases. In contrast, in toxic cases resolution may take 3 to 6 weeks. Avoidance of the offending agent is the first step in the treatment of contact dermatitis, with emphasis given to decreasing rubbing and scratching. Supportive therapy includes cool compresses. In addition, application of topical steroid ointment or cream preceded by cool compresses temporarily relieves symptoms. Steroid use should be limited to 5 to 10 days due to the risk of tachyphylaxis, atrophy of the skin, and increased risk of infection.

Urticaria

Urticaria, also known as hives, involves the outer dermis and is characterized by wheals and itching.The diagnosis is critical because acute asthma and anaphylaxis can occur. Angioedema is similar to urticaria but differs in that the deeper layers of the skin, the deep dermis or subcutaneous areas, are involved. Angioedema is present with urticaria in 40% of patients and without urticaria in 20%; urticaria presents alone in 40%.

Figure 27-10 Contact dermatitis.

572 CHAPTER 27 Allergic Eye Disease

Etiology

Urticaria may occur as a result of immune mediation (type I, IgE-mediated), nonimmune mechanisms (involving mast cell mediators), offending physical agents, psychogenic causes, or stress or it may be idiopathic. Precipitating factors may include cold air, water, or objects; high temperatures; heat; sunlight; and pressure to the skin. Urticaria may also be a result of insect bites, drugs, cosmetics, hair products, ophthalmic agents, latex, or formaldehyde.

Diagnosis

The clinical manifestations of urticaria include itching, papules, and plaques. In contrast, angioedema consists of deeper swelling, without itching.

The diagnosis of urticaria involves taking a thorough history of insect bites, use of medications or cosmetics, specific types of food intake, and use of occupational agents (e.g., latex gloves). Clinical findings indicative of urticaria include the characteristic wheals, edema, burning, stinging, and itching. When urticaria is a result of an allergen, the clinical presentation occurs as early as 30 to 60 minutes after exposure, with a delayed reaction occurring 4 to 6 hours later. Additional clinical findings may include angioedema, rhinitis, conjunctival injection, and chemosis. Severe clinical manifestations may result in syncope, asthma, hypotension, and anaphylaxis.

Diagnostic evaluation using patch testing should be done with caution and only with the ability to manage a severe reaction such as anaphylaxis. Patch testing may be done by a dermatologist or an allergist.An open patch test may be performed in which small amounts of the offending agent are placed on the flexor forearm for only 15 minutes. The area is evaluated every 15 minutes for 1 hour.The presence of follicular erythema or wheal indicates a positive finding. If a negative result is found with the open patch test, a closed patch test may be performed for only 15 minutes. If negative findings persist, prick or scratch testing may be done.

Management

Application of cool compresses for 10 to 15 minutes four times a day for 1 to 2 days and use of topical steroids and systemic antihistamines may provide relief of acute symptoms of urticaria. In cases of allergen-related urticaria, determination of the cause, followed by its subsequent avoidance, is essential to management. Urticaria, however, carries the risk of serious sequelae,including anaphylaxis.

Oral antihistamines can be effective in alleviating the itch as well as assisting in the resolution of the wheals. When urticaria or angioedema has a severe presentation, diphenhydramine or oral steroids can be effective.

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574 CHAPTER 27 Allergic Eye Disease

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The episclera is a fully vascularized fibroelastic tissue loosely overlying yet tightly attached to the sclera. Disease of the episclera tends to be transient and of minimal impact to the patient. The sclera, along with the cornea, serves as the protective shell of the eye and is composed chiefly of various types of collagen, elastin, and proteoglycans arranged in an extracellular matrix with little vascular supply. Diseases of the sclera tend to be serious, painful and of significant consequence to the patient.This chapter discusses inflammation of these tissues, termed episcleritis and scleritis. Both are rare, episcleritis less so; therefore limited large-scale studies exist and no true prevalence studies have been done. However, the literature provides significant understanding and management standards.

VASCULATURE OF THE EPISCLERA AND SCLERA

The sclera is considered avascular because it contains no capillary beds. It obtains sufficient nutrition to meet its low metabolic requirements from the episcleral and choroidal blood supplies. The episclera obtains a rich blood supply from the anterior and posterior ciliary arteries.The episclera contains two vascular supplies, a superficial vascular plexus and a deep vascular plexus.

Episcleritis is characterized by a vasculitis of the superficial episcleral vascular plexus and edema of the episcleral tissue. The deep vascular plexus and sclera are not involved and remain flat in episcleritis.This is in contrast to scleritis, in which vasculitis involves the deep episcleral vascular plexus and scleral edema. Although scleritis may potentially occur in the absence of episcleritis, it is usually associated with varying degrees of episcleritis. This associated involvement of the superficial vascular plexus may present a challenge in visualizing and excluding scleritis from the diagnosis.

EPISCLERITIS

Episcleritis is a somewhat uncommon and usually benign self-limiting inflammation of the episcleral tissues. Of new

patient referrals to specialty clinics, the incidence of episcleritis was 0.08% to 1.4%. However, true incidence is probably considerably higher because most occurrences are mild and do not require treatment.Although episcleritis can affect any age group, it is most often found in younger adults, with a smaller grouping in older adults, and it rarely affects children. Episcleritis affects women up to 75% of the time. Involvement is unilateral in approximately two-thirds of cases, and the risk of second eye involvement is approximately 12%. Over 50% of patients have recurrence that often continue up to 6 years, but recurrences can occur as long as 30 years after the initial event.

Episcleritis is clinically classified as either simple or nodular. Simple episcleritis is usually the milder form, being limited to a sector of the eye in approximately two-thirds of cases, but can affect the entire episclera in approximately one-third of cases. Nodular episcleritis is usually more serious and involves the presence of a definitive nodule and mild to moderate discomfort. Approximately 20% to 25% of cases present as nodular. Only 2% to 5% of episcleritis progresses to scleritis. Simple episcleritis usually lasts 1 to 3 weeks, whereas nodular episcleritis has a more variable course, in some cases lasting up to 2 months. Both forms periodically recur but become less frequent with time until the disease no longer remits. Either form may recur as the other.

Episcleritis is idiopathic approximately 70% of the time. Mild, nonrecurring, and resolving presentations do not require further assessment. However, about 30% of patients with episcleritis have an underlying condition. These individuals tend to be older with a history of systemic disease.The episcleritis tends to last longer than usual and may not respond to topical steroid treatment.

There are a wide range of reported rates of association with systemic disease most likely representing practice modality bias. Seven percent of patients with episcleritis demonstrate hyperuricemia even in the absence of clinical gout and 15% demonstrate serologic indications of connective tissue disease. The most commonly associated systemic diseases are shown in Box 28-1; however, theoretically,

576 CHAPTER 28 Diseases of the Sclera

Box 28-1 Common Diseases Associated With

Episcleritis

Inflammatory/immunologic

Inflammatory bowel disease

Relapsing polychondritis

Rheumatoid arthritis

Systemic lupus erythematosus

Infectious

Herpes zoster

Lyme disease

Syphilis

Other

Idiopathic (most common)

Atopy

Gout

all the disorders that can cause scleritis (Box 28-2) can also cause episcleritis. Episcleritis can be the initial sign of a systemic vasculitic disease; therefore, a careful review of systems is recommended at initial and yearly evaluations.

The underlying cause of episcleritis often remains elusive but has been associated with stress. Pathologically, the involved area shows a heavy primarily lymphocytic infiltration devoid of polymorphic cells. Because of the loose richly vascularized nature of the episclera, inflammation can spread quickly, leading to vessel dilation, edema, cellular infiltrate, and discomfort (Figure 28-1). In some patients a migrainous etiology has been identified. Episcleritis has shown an association with antigenantibody reactions, as in those with penicillin sensitivity. There is controversy about whether the rate of atopy for family or patient is greater than in the general population.

It has also been hypothesized that a type I hypersensitivity reaction may be involved in some patients. A definitive pathogenic mechanism for episcleritis has still not been established.

Diagnosis

The hyperemia of simple episcleritis is often seen in one or more sectors within the interpalpebral fissure (see Figure 28-1), usually developing within 1 hour. The vessels are usually tortuous and often demonstrate saccular dilatations (Figure 28-2). The vessel injection in simple episcleritis can vary from a mild red flush to an intense fiery red. For diagnosis of episcleritis versus scleritis, natural daylight examination is highly recommended over the slit lamp because the former brings out the colors whereas the latter diminishes them. Episcleritis presents a salmon red or bright red color versus the bluish-red or purplish tones of scleritis. If daylight examination is not readily available, then incandescent light is the next best choice. Excluding involvement of the deep episcleral vascular plexus is another way to rule out scleral involvement.This is often accomplished with the red free filter in the slit lamp or after application of 10% phenylephrine to constrict the conjunctival and superficial episcleral vascular plexus, allowing clear visualization of the deep episcleral vascular plexus that is not blanched by phenylephrine.

In nodular episcleritis there is usually only a single distinct, elevated, red, edematous nodule with surrounding congestion (see Figure 28-1). This classification is localized to discrete areas, each of which consists of an elevated nodule that is mobile over the underlying sclera. Because edema is isolated to the episclera, a biomicroscope slit beam does not show any upward deviation of the underlying sclera. Nodules vary in size and elevation,

Figure 28-1 Nodular episcleritis in sectorial configuration. Arrow points to elevated edematous nodule.

Figure 28-2 Diffuse episcleritis demonstrating vessel injection, tortuosity, and saccular dilatations (arrows).

578 CHAPTER 28 Diseases of the Sclera

potentially causing adjacent dellen formation. Nodular episcleritis may last longer than simple episcleritis. Regression is often within 3 to 4 weeks but can persist up to 2 months, with rare cases requiring anti-inflammatory intervention.

Both types of episcleritis have edema of the episclera and overlying conjunctiva. The edema is distributed diffusely or focally in simple versus nodular episcleritis respectively.There may be grayish infiltrates present that appear yellow in red-free light. In both classifications, the patient may complain of a sensation of heat, prickling, light sensitivity, and/or mild discomfort. Pain is usually absent and rarely significant or radiating.The eye is rarely tender to the touch. Although tearing is common, there is no ocular discharge. In rare instances the eyelids may become edematous, and if photophobia is present an associated keratitis should be suspected. Episcleritis does not affect visual acuity, and intraocular structures are usually not involved.

Nodular episcleritis is similar to diffuse but may have a more insidious onset and longer duration. In severe cases of episcleritis, one may observe rare anterior chamber cells that resolve with the episcleritis and do not represent a true uveitis. In the case of concurrent uveitis and episcleritis, the uveitis treatment may also control the episcleritis, and a systemic evaluation may be indicated to explore the possibility of an underlying etiology.

Episcleritis usually resolves without any permanent effect to the involved tissues, regardless of the severity or number of recurrences. However, multiple attacks of nodular episcleritis in the same location may cause thinning of the superficial scleral lamellae, causing slight transparency. If episcleritis occurs close enough to the cornea, it may cause mild peripheral corneal thinning or vascularization. Neither of these consequences is usually significant.

Management

Episcleritis is a self-limiting disease with minimal symptoms and risk; therefore it generally does not require treatment, and patients should be encouraged to let the condition run its course. Simple anterior episcleritis, in particular, tends to greatly improve within 1 week and resolve by 3 weeks. Lubricants, particularly cold artificial tears, and cold compress can be used as supportive measures. Often, however, patients desire symptomatic relief from the redness and discomfort. In other cases, particularly nodular episcleritis, there may be some discomfort.

Rarely, a history of sensitization to an external agent can be identified. In these cases removal of the offending agent is the recommended treatment. Possible contributory or causal diseases, such as dry eye syndrome, acne rosacea, ocular allergic disease, or blepharitis, have been noted in up to 50% of episcleritis patients.These concurrent conditions should be treated if present. Full response to treatment in any patient who smokes can be delayed by a month or more. For this reason and because episcleritis

is recurrent, patients who smoke should be counseled to stop smoking and given smoking cessation options when necessary.

Vasoconstrictors, such as phenylephrine, naphazoline, oxymetazoline, and tetrahydrozoline, are available over the counter and may be beneficial in mild cases. However, there is no evidence that they shorten the course of the disease and, when abused, they can cause rebound hyperemia and medicamentosa, which can increase the redness or edema in the episclera. For these reasons, vasoconstrictors should be used sparingly.

Topical nonsteroidal anti-inflammatory drugs (NSAIDs), such as bromfenac, diclofenac, ketorolac, and nepafenac, have been advocated, but there is evidence that commercially available preparations do not appear effective in treating episcleritis. Topical flurbiprofen and ketorolac were found to be no more effective than placebo in treating episcleritis; therefore, treatment modalities other than topical NSAIDs should be used.

When intervention is indicated, topical steroids have often been considered the drug of choice. This is a debated treatment, however, not only due to the possible side effects of repeated or long-term topical steroid use, but because topical steroids have been shown to cause a “rebound effect” upon withdrawal of the drug that includes an increase in both the intensity and frequency of future attacks. Treating episcleritis with supportive measures only has been suggested, using drug therapy only if absolutely necessary, and then using NSAIDs as a first-line treatment.

Topical steroids have been shown effective in treating episcleritis, despite their inherent risks. Prednisolone has been shown effective; however, it may be prudent to use a topical steroid with a lower likelihood to cause an increase in intraocular pressure. These agents include fluorometholone, loteprednol, or rimexolone. Fluorometholone 1% has been shown successful in treating episcleritis and 0.25% can also be used. Loteprednol etabonate (0.2% or 0.5%) shows a minimal risk of raising intraocular pressure and is probably less likely to cause cataract formation than other topical steroids.

Topical steroid dosing is often suggested at four times a day, although more frequent installation may be necessary. Dosing should be tapered over a few days after resolution to avoid rebound.Tapering may not, however, avoid the observed consequences of increasing severity and frequency in future episodes. Another popular dosing approach is to consider a short high-dose steroid pulse over 2 weeks, such as one drop every hour for 2 days, then six drops a day for 2 days, five drops a day for 2 days, and so on until one drop a day for 2 days, and then stop. This strategy is often sufficient to significantly minimize severe episodes. It is prudent to remember that episcleritis is generally self-resolving and that steroid therapy serves only to hasten its resolution.

Oral NSAIDs are useful in the management of episcleritis, either as a first-line treatment or in cases that are

intractable or nonresponsive to topical steroids. Not all oral NSAIDs are effective in treating episcleritis. Patients have variable responsiveness to specific NSAIDs; therefore, if one is not effective another one should be tried. Naproxen, 250 to 500 mg twice daily, or ibuprofen, 200 to 600 mg four times daily, is the recommended NSAID for episcleritis. More potent NSAIDs include flurbiprofen, 100 mg three times daily, and indomethacin, 25 mg four times daily or 75 mg sustained-release capsules twice daily. The side effects and cautions of NSAIDs, which include cardiovascular and gastrointestinal effects, should be carefully considered, explained to the patient, and monitored during therapy.

SCLERITIS

Unlike the more commonly encountered episcleritis, inflammation of the sclera is relatively rare, painful, and capable of extensive and permanent tissue and visual destruction. Scleritis is characterized by an immunemediated vasculitis and inflammatory cell infiltration of the sclera and episclera. Scleritis usually occurs in the fourth to sixth decades of life but can be seen at any age. Peak incidence for men is in the fourth decade, whereas there are two peaks for women: the third and sixth decades. Diffuse scleritis shows a 1:1 distribution, whereas the other forms, particularly necrotizing and posterior scleritis,show a female predilection.Scleritis presents bilaterally about 50% of the time, and unilateral presentations usually

involve the fellow eye within 6 years. Bilateral scleritis is more common when there is an underlying systemic etiology, and scleritis may recur in up to 39% of cases.

The classification for scleritis (Figure 28-3) is an established and substantiated system based on clinical appearance and tissue involvement. This classification also correlates to the severity of ocular and systemic disease states. Approximately 8% of patients change classification during the course of their scleritis. Anterior scleritis is subclassified as diffuse, nodular, or necrotizing. Of patients presenting with scleritis, 39% to 45% present with diffuse and 23% to 45% with nodular. Approximately 4% progress from diffuse to nodular, and 3.4% progress from nodular to necrotizing. Necrotizing anterior scleritis is the most severe form because of active tissue destruction and is further classified as with inflammation or without inflammation. The term necrotizing scleritis without inflammation is based on the lack of clinically visible inflammation compared with the other classifications and can be considered a misnomer because inflammation is still the underlying etiology. For clarity’s sake, some prefer to refer to this classification of scleritis as scleromalacia perforans. Of those with necrotizing scleritis 10% to 23% present with scleromalacia perforans and 3% to 4% present with necrotizing scleritis with inflammation. Two percent to 12% of patients presenting with scleritis manifest the posterior kind, although, due to a high rate of missed diagnosis, it is suggested that up to 20% of presenting scleritis is posterior.

580 CHAPTER 28 Diseases of the Sclera

Up to 57% of scleritis cases are associated with an underlying systemic disease (see Box 28-2). Thus, more commonly than with episcleritis, scleritis may be the initial or only indication of a severe and life-threatening systemic disease. These diseases are usually connective tissue and autoimmune disorders with rheumatoid arthritis being the most common, followed by Wegener’s granulomatosis. Other less frequent underlying diseases include inflammatory bowel disease, systemic lupus erythematosus, relapsing polychondritis, and herpes zoster infection. Five percent to 10% of anterior scleritis cases are infectious,with bacteria,viruses,fungi,and parasites all potential causes.

Scleritis occurs in 0.3% to 6.3% of rheumatoid arthritis patients, and the incidence of rheumatoid arthritis in scleritis patients is reported as 10% to 33%. In Wegener’s granulomatosis scleritis may be the only clinical sign in up to 16% of patients.These statistics reinforce the importance for patients with systemic autoimmune and collagen vascular disorders to receive routine eye care and to be educated about possible ocular involvement of their diseases. For scleritis patients with an identifiable systemic etiology, up to 84% demonstrate a systemic vasculitis that usually produces the more destructive necrotizing forms of scleritis and scleromalacia perforans in particular. Approximately half of patients with necrotizing scleritis die from systemic vascular events.This fact emphasizes the need for timely referral and adequate comanagement with the appropriate medical specialist to minimize patient morbidity and mortality.

The pathophysiology of scleritis is complex and not fully understood.The main dysfunction is thought to be the deposition of immune complexes in the vasculature of the sclera and episclera, creating a vasculitis. This leads to edema and inflammatory cell infiltration of the sclera and episclera, which in turn cause disorganization and destruction of the collagen lamellae. However, not all presentations of scleritis demonstrate the same pathology.

In idiopathic cases the histology often suggests a type IV delayed hypersensitivity reaction, whereas cases associated with rheumatoid arthritis or systemic vasculitis display histology consistent with a type III immune complex–mediated process. In diffuse and nodular scleritis the inflammatory infiltrate is generally nongranulomatous; however, in necrotizing scleritis the infiltrate is usually granulomatous, and deposition of immune complexes can be seen in the walls of the superficial and deep episcleral vascular plexus. Cell necrosis and collagen degeneration appear to be caused by proteolytic enzymes, which stimulate intracellular tissue digestion. The primary site for vascular occlusion, termed vascular closure, is the venules, except in scleromalacia perforans where it occurs in the capillaries. Whichever of the various pathogenic mechanisms may be involved in a given presentation the result is inflammation and, in the necrotizing classifications, scleral necrosis and thinning.

Diagnosis

The onset of scleritis is usually slow, with symptomatic increase over many days. Tearing and photophobia are common complaints in scleritis, with or without a concurrent keratitis. There should be no discharge, but vision loss is possible. Scleritis may be one of the most painful eye conditions known and, except in the case of scleromalacia perforans, the hallmark symptom of scleritis is severe pain, often described as boring in nature.The pain often prompts the patient to seek care and may be localized to the eye but often radiates to the jaw, temple, or head.The severity can lead to weight loss,interfere with sleep and be only minimally or temporarily relieved by even prescription analgesics.The eye can become exquisitely tender to the touch, with the slightest digital pressure eliciting patient recoil.The pain may appear greatly disproportionate to clinical findings, particularly in posterior scleritis where there are no readily visible findings. The pain is secondary to inflammation, with distention of the sensory nerve endings as they become edematous and damaged. In some cases intractable pain may be relieved only by the use of retrobulbar alcohol injections.

In diffuse anterior scleritis (Figure 28-4), the pain is often less severe.This form of scleritis is the mildest and most common type, and it manifests as an area of sectorial or diffuse dilation of the deep episcleral vascular plexus with overlying and adjacent episcleritis that can affect the whole eye. There can be mild anomalous changes in the blood vessels that may persist even after successful treatment, which is associated with a 9% incidence of vision loss.

Nodular scleritis consists of one or more focal nonmovable nodules of inflamed scleral tissue (Figure 28-5), usually in the interpalpebral region. These nodules are frequently tender to palpation, and nodular scleritis is more likely to cause severe or radiating pain than diffuse scleritis.

Figure 28-4 Diffuse scleritis with deep vessel injection and associated episcleritis.