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

Figure 28-5 Focal scleral and episcleral inflammation seen in nodular scleritis.

Approximately one-half of affected patients have a bilateral occurrence. Scleral inflammation typically does not extend beyond the nodule,and the sclera usually does not become necrotic. However, rarely, the nodule may become avascular, leading to necrosis that may cause the sclera to become thin and transparent beneath the nodule. In rare worst-case scenarios up to a 26% incidence of vision loss may be seen, but usually only in older patients with associated systemic disease.

In contrast to the non-necrotizing classifications, necrotizing scleritis with inflammation, although rare, is more severe, more likely to cause permanent tissue destruction including vision loss, and carries a 45% to 54% mortality rate over 5 to 10 years. Necrotizing scleritis may indicate a potential lethal underlying systemic vasculitis. The pain from this form of scleritis is the most devastating of all types. More than 60% of patients develop complications other than scleral thinning, and 40% to 74% have loss of visual acuity.The sclera can become transparent with visible choroid and rapid progression over the course of a few weeks. Perforation is a possibility, and the entire anterior segment can become involved without prompt treatment. Even with successful treatment,small areas of uvea may be covered by only a thin layer of conjunctiva or episclera. The actual uvea may be exposed, which if small enough can be covered by new collagen growth; large defects may require a scleral graft.

Unlike other types of scleritis, scleromalacia perforans is minimally symptomatic and insidious in onset. Scleromalacia perforans is bilateral more than 90% of the time and is almost always associated with longstanding rheumatoid arthritis.There is little to no pain or visible inflammation; however, the eye undergoes the same destruction of the sclera as in scleritis with inflammation. Patients may not present until advanced stages of their disease, often not until the characteristic gray or blue-gray of scleral thinning becomes readily evident.

Globe perforation can occasionally occur asymptomatically.

Patients may not be compliant with drug therapy due to side effects, the need for follow-up visits, and a lack of perceived need. Thorough patient education is critical. The 5-year mortality rate associated with scleromalacia perforans is as high as 73%; therefore appropriate and timely referral and comanagement with the appropriate medical specialist is important in minimizing mortality.

Clinical Evaluation

Scleritis can be an extremely destructive disease; therefore early diagnosis is crucial, yet challenging, as demonstrated by reported misdiagnosis as high as 40%.A thorough and detailed history is necessary, including a comprehensive review of systems,to uncover any likely ocular or systemic etiologies for scleritis. A number of time-honored techniques are useful in diagnosing scleritis.

Topical anesthetic installation followed by applied pressure with a cotton swab to the inflamed site can be useful in diagnosis. If this elicits a pain response, scleritis or episcleritis should be suspected, whereas the absence of pain suggests conjunctivitis or uveitis. If 10% phenylephrine or epinephrine 1:1,000 blanches all episcleral vessels, then a scleritis is not present; however, these drugs do not constrict the deep episcleral vascular plexus that is dilated in scleritis.

Lesion color and examination lighting can play a crucial role in scleritis evaluation. For example, red-free light can be used to enhance blood vessels and may allow the clinician to observe areas of vascular closure (Figure 28-6) within a scleritis lesion. These areas represent vascular occlusion and destruction from progressive infiltrative inflammation. Except in scleromalacia perforans, anterior scleritis creates a characteristic bluish red or purplish (violaceous) color in contrast to the salmon red or bright red injection observed in episcleritis. This violaceous

Figure 28-6 Scleritis with areas of vascular closure

(arrows).

582 CHAPTER 28 Diseases of the Sclera

color is seen far more easily in daylight and is often overlooked in tungsten or fluorescent light and the light of the slit lamp. As such, examinations should include evaluation in daylight, actually outside or at least next to a window. When scleral thinning occurs, such as in necrotizing forms of anterior scleritis, visible choroid can create a blue-gray or light gray tone to areas of the sclera. Examination with an overly bright slit lamp can obscure these colors, whereas examination outside the slit lamp may make these areas easier to visualize.

Comprehensive assessment of the eye, including the cornea and the uveal tract, is indicated at the initial examination and follow-up visits for scleritis because complications are extensive and can include uveitis, glaucoma, keratitis, corneal ulceration, proptosis, cataract, extraocular muscle paresis, myositis, and orbital cellulitis. Corneal involvement in scleritis is reported to be 29% to 43% and usually indicates a severe and active systemic disease that requires immediate treatment. Scleritis-related corneal involvement can occur as an infiltrative keratitis, termed sclerokeratitis (Figure 28-7), or noninflammatory corneal thinning such as peripheral ulcerative keratitis. Patients with rheumatoid arthritis and peripheral ulcerative keratitis require prompt immunosuppressive therapy due to the high association of life-threatening vasculitis. Uveitis is associated with scleritis in up to 42% of patients and in almost all patients with posterior scleritis or scleromalacia perforans. Uveitis is viewed as a negative prognostic indicator.

Traditional examination alone may not always be adequate to diagnose or manage scleritis, to identify areas of early vascular closure (see Figure 28-6), to differentiate benign nondestructive scleritis from necrosis, or to adequately monitor the success of treatment. Although not readily available, high-frequency ultrasound biomicroscopy

Figure 28-7 Sclerokeratitis adjacent to an area of scleritis

(arrows).

is able to image the anterior segment in fine detail. The ultrasound biomicroscopy can be used to detect and monitor scleral inflammatory diseases at the anterior segment, allowing the differentiation of episcleritis and scleritis and measurement of scleral tissue thickness. These properties make it particularly useful for diagnosis and monitoring of anterior scleritis.

Low-dose fluorescein angiography of the anterior segment, alone or in combination with indocyanine green angiography, provides detailed studies of vascular filling and leakage patterns in episcleritis and scleritis. Angiography can identify which vessels, episcleral or scleral, are leaking and if there are areas of vascular closure, making this procedure particularly useful for diagnosing and monitoring anterior scleritis. Fluorescein angiography can assist in confirming necrotizing scleritis and differentiating early necrotizing scleritis from diffuse and nodular forms.Angiography may be particularly useful in challenging cases, including posterior scleritis, and is also helpful in monitoring the effectiveness of treatment.

Laboratory tests are often indicated to exclude an underlying systemic disease. However, tests are expensive and may not be successful in making a definitive diagnosis; therefore they should be ordered in a focused fashion, based on the clinical presentation and a thorough history. The eye care practitioner may prefer to send a scleritis patient to an internist for laboratory testing because a physical examination of the patient is also indicated. Clear communication of the suggested tests and systemic diseases to be considered is recommended if this is the chosen path for further assessment.Table 28-1 lists some of the laboratory tests used in exploring the systemic etiologies of scleritis.

Posterior Scleritis

Posterior scleritis is defined as scleritis occurring posterior to the ora serrata. The mean age at onset is 49; however, 30% are under the age of 40, and children may present as well. Posterior scleritis is severe and potentially blinding with complications that include uveitis, retinal and choroidal detachments, choroidal thickening, optic disc or macular edema, retinal hemorrhages, proptosis, subretinal mass, and ophthalmoplegia. Misdiagnosis of posterior scleritis is common, and it can mimic a subretinal mass, such as a choroidal melanoma or hemangioma, metastatic carcinoma, or uveal lymphoid hyperplasia. It is not uncommon for an eye to be enucleated because of a suspected intraocular tumor that later was shown to be posterior scleritis. Conversely, intraocular tumors have been misdiagnosed as posterior scleritis. Dilation and evaluation of the posterior segment at regular intervals are indicated.

Posterior scleritis is more difficult to diagnose than anterior scleritis because it is harder to visualize and can present with few to no clinical signs.The underestimation of posterior scleritis is high, as demonstrated by studies in which 43% to 100% of enucleated eyes with histologic

Table 28-1

Diagnostic Laboratory Testing in Scleritis

ACE = angiotensin-converting enzyme; ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic antibody; BUN = blood urea nitrogen; CBC = complete blood count; ELISA = enzyme-linked immunoassay assay; ESR = erythrocyte sedimentation rate; FTA-ABS = fluorescent treponemal antibody absorption; HLA = human lymphocyte antigen; MHA-TP = micro- hemagglutination-Treponema pallidum; PPD = purified protein derivative; RPR = rapid plasma reagin; VDRL = venereal disease reference laboratory.

Adapted with permission from Castells DD. Anterior scleritis: three case reports and a review of the literature. Optometry 2004;75:433.

evidence of posterior scleritis did not have a previous diagnosis. Posterior scleritis should be suspected in the above-mentioned complications, all cases of anterior scleritis, unexplained reduction in vision, and when unexplained pain is present. However, it is important to note that only 55% of patients with posterior scleritis report severe pain.When pain is present, it is of the same nature as anterior scleritis.

Posterior scleritis is associated with anterior scleritis 60% of the time. Monitoring for change in visual acuity is important in scleritis because it may indicate new or progressive posterior involvement. Serial refractions can reveal scleritis-induced refractive error changes and scleral depression can identify and localize an area of posterior scleritis by eliciting intense pain when applied to the involved site.

In up to 15% of patients there are no presenting signs of posterior scleritis, and the diagnosis must be made on imaging studies of the orbit such as with B-scan ultrasonography or computed tomography. Magnetic resonance imaging is not useful for detecting soft tissue masses within or next to the sclera. Ultrasonography shows a thickened sclera and a possible clear zone immediately posterior to the globe (Figure 28-8).The normal thickness of the sclera varies from 0.3 to 1.0 mm, but in scleritis it can become as thick as 6 mm. Computed tomography can also reveal the inflammation as a thickening of the sclera and a separation between the sclera and Tenon’s capsule.The thickening of the sclera is rendered obvious by comparing it with the fellow globe on computed tomography. Unfortunately, there may be no way to detect posterior scleritis of the painless necrotizing variety.

Management

Appropriate management of scleritis requires accurate classification and diagnosis plus appropriate identification

584 CHAPTER 28 Diseases of the Sclera

of etiology and any associated complications or systemic disease. Aggressive treatment is important to minimize potential complications that contribute to loss of vision or damage to the globe. Decreasing pain is the key indicator of improvement, whereas other parameters of effective treatment include a decrease in episcleral and scleral injection, tenderness, and corneal and intraocular involvement. Smoking has been shown to necessitate higher drug treatments and delay response to treatment by a month or more; therefore any scleritis patient who is an active smoker should be counseled to quit immediately.

Systemic therapy is usually required to control all but the mildest cases of scleritis. These treatments include NSAIDs, corticosteroids, and immunosuppressive agents. Because these agents have significant potential side effects, it is prudent to discuss the risks and benefits with the patient and to monitor closely for toxicity. Appropriate management of any underlying systemic condition may not only treat the scleritis but extend life. Particularly, in the case of underlying active vasculitic disease, delay in diagnosis and treatment may lead to death. As such, appropriate and timely comanagement between the eye care practitioner and the patient’s physician is paramount. Although complications and vision loss are common with scleritis, early and intensive systemic treatment is often successful in preserving the eye and vision. Treatment is primarily determined by the etiology and severity of the inflammation.

An infectious etiology has been found in 6% to 18% of patients with scleritis. Many infectious agents have been reported to cause scleritis (see Box 28-2), with varicella zoster being the most common. A known infection should be treated with a targeted therapeutic regimen; however, infectious scleritis is difficult to treat due to the poor antimicrobial penetration into the avascular sclera and to the ability of some microorganisms to persist within the avascular intrascleral lamellae for long periods without inciting an inflammatory response. Often, when the sclera develops an infectious inflammation, medical treatment alone is not effective and surgical intervention is necessary. Cryotherapy may be useful in the treatment of infectious scleritis due to mechanical destruction of the microorganisms by the extracellular ice or enhancement of antibiotic absorption through damage to bacterial cell walls or disrupted scleral tissue. Prognosis is better if the cornea is not involved. Approximately 60% of eyes with infectious sclerokeratitis require evisceration or enucleation or are left blind.

Topical ocular steroids are often not effective alone in treating scleritis; however, up to 47% of patients with diffuse or nodular scleritis may recover with only 1% topical prednisolone acetate. Therefore, topical steroids may be appropriate in treating mild inflammation and pain, to maintain a state of remission between exacerbations, and as adjunctive therapy to oral agents.Topical cyclosporine A may also be effective in treatment of scleritis, either alone or as an adjunctive agent to systemic treatment.

Oral NSAIDs

Oral NSAIDs are the established first-line treatment for non-necrotizing classifications of scleritis, providing control for up to 90% of cases. The initial drug choice should be one with established efficacy in treating scleritis as not all NSAIDs are equally effective. Individual patient response to NSAIDs is variable; therefore, if the initial drug is not effective, a different classification of NSAID should be tried before progressing to another form of medication. Failure of three different NSAIDs constitutes failure of the drug category. Some NSAIDs are available with an enteric coating (EC) or sustainedreleased (SR) formulations, such as Naprosyn EC and Indocin SR. Such preparations may reduce gastric side effects. One needs to seriously consider the risks and contraindications associated with NSAIDs, such as gastrointestinal bleeding, myocardial infarction, and stroke, when choosing this drug class.

Flurbiprofen, 100 mg three times daily, is a wellestablished first-line NSAID providing there is no evidence of vascular closure or scleral destruction on biomicroscopy. Flurbiprofen should provide pain relief within 2 days and improvement in clinical signs within 1 week. Indomethacin SR formulation, 75 mg twice daily, is a well-established second-choice drug when flurbiprofen is not effective but has also been used as first line. NSAIDs that have shown efficacy and are now available in over-the-counter formulations include naproxen, 500 mg twice daily, and ibuprofen, 600 mg four times daily. If a simplified dosing schedule is a consideration, then piroxicam, 20 mg/day, may be considered. Once effective control is established, a lower maintenance dose may suffice until the scleritis enters remission. To reduce the risk of gastrointestinal side effects, patients should be instructed to take NSAIDs with food or antacids.

Oral Steroids

Systemic corticosteroid therapy is usually considered as the second-line treatment when NSAIDs are not effective, when NSAIDs are contraindicated, in cases of severe or necrotizing scleritis, and when vascular closure is evident. Sufficiently high initial dosage must be given to control the scleritis, and then the drug should be rapidly tapered to the minimal maintenance dose. Oral steroids control scleritis in almost all patients who can tolerate the appropriate dosage and duration of therapy. NSAIDs, even if not effective alone, may be useful when used in combination with steroids; however, this poses an additive risk of gastrointestinal side effects. Injectable steroids have been used effectively including intravenous, intramuscular, subconjunctival and orbital floor. These routes of administration may increase effectiveness but carry unique risks that must be carefully considered.

Although steroid therapy must be individualized, a typical prednisone dosage is 1 mg/kg/day (usually 60 to

100 mg daily in adults), initially tapered to 20 mg over the first week. The dose is then reduced by 5 to 10 mg per week (often 2.5-mg steps every other day) until the drug is discontinued without incident or an acceptable maintenance dose is achieved (typically 10 to 20 mg/day), which is usually required for a few weeks before a final taper. NSAIDs should be used to maintain a patient off steroids when possible. Because of the high rate of gastrointestinal side effects, prophylactic gastric acid suppressors are often given in conjunction with steroids. These drugs include esomeprazole, omeprazole, and ranitidine.

Immunosuppressants

Immunosuppressive drugs are a third-line therapy in nonnecrotizing scleritis, but the first choice in necrotizing forms of scleritis. In patients with necrotizing scleritis, up to 100% and 91% will fail initial treatment with NSAIDs or steroids, respectively, whereas only 26% of patients will fail initial treatment with immunosuppressive drugs.This treatment may also aid in minimizing the mortality rate. For example, in patients with rheumatoid arthritis or peripheral ulcerative keratitis and rheumatoid arthritis it was shown to decrease mortality from 54% for patients receiving NSAID and steroidal therapy to zero for patients who consistently remained on immunosuppressive drugs. The side effects of immunosuppressive agents are unique to the drug and can be severe; thus this therapeutic strategy is best administered and monitored by a specialist familiar with these therapeutic regimens. Drugs in this group include cyclophosphamide, methotrexate, azathioprine, and cyclosporine.

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Uveitis, by definition, describes an inflammatory state affecting the uveal tissues of the eye; these include the iris, ciliary body, and choroid. Any or all of these structures may be involved in uveitis, a potentially blinding disorder that has great potential impact from both a medical and socioeconomic standpoint. This chapter reviews the classification, pathophysiology, epidemiology, diagnostic considerations, and medical management of uveitis.

PERTINENT ANATOMY

The uveal tract constitutes the middle tunic of the eye, located between the innermost retina and the outer protective scleral coat. This tissue and its constituent parts are both richly vascularized and highly innervated. The iris defines the anterior-most part of the uvea. It serves primarily as a diaphragm to admit light into the eye. Just posterior to the iris is the ciliary body, responsible for aqueous production and accommodation of the lens. Finally, the choroid defines the posteriormost aspect of the uvea. The choroid, via the choriocapillaris, is responsible for blood supply to the outer one-third of the retina. It also serves as a pathway for numerous sensory and autonomic neurons traveling to the anterior eye.

DESCRIPTION AND CLASSIFICATION OF UVEITIS

Uveitis has been historically described in a variety of ways. Duration of the inflammation—essentially, acute versus chronic—is one way of classifying uveitis. Another is the nature of the underlying etiology, that is, traumatic, inflammatory, immune-related, infectious, or idiopathic uveitis. Additionally, when the uveitis is associated with systemic inflammatory conditions such as tuberculosis or sarcoidosis, the condition may be described by pathologic features, such as “granulomatous.” Granulomatous disorders typically are associated with specific clinically detectable signs, such as “mutton-fat” keratic precipitates

(KPs) and/or iris nodules. The final way of classifying

uveitis is by location (anterior, intermediate, or posterior) and the involved ocular structures (e.g., iritis, cyclitis, choroiditis, etc.).

Throughout the years this lack of consistency in the classification of uveitis has been a source of confusion to students, clinicians, and researchers alike. Fortunately, today, terms like nongranulomatous iridocyclitis are used somewhat sparingly. Uveitis now tends to be classified according to the International Uveitis Study Group recommendations, which describe the condition in terms of symmetry (unilateral or bilateral), course (acute, i.e., <12 weeks, or chronic, i.e., >12 weeks), and most importantly, anatomic location. Recognized International Uveitis Study Group categories of uveitis are as follows:

1.Anterior uveitis: Involves the anterior-most portion of the uvea, that is, the iris and/or the anterior aspect of the ciliary body (pars plicata). The terms iritis and iridocyclitis, although more descriptive of the specific tissues involved, are less favorable today in the formal classification scheme. In the United States anterior uveitis is the most common form of uveitis encountered in clinical practice.

2.Intermediate uveitis: Describes inflammation confined to the posterior aspect of the ciliary body (pars plana) and/or the peripheral choroid. Secondary involvement of the retina and vitreous may also be seen. The most common form of intermediate uveitis in the United States is pars planitis.

3.Posterior uveitis: Involves the choroid, overlying retina, and vitreous. The terms choroiditis, chorioretinitis, and retinochoroiditis are still used to describe specific conditions, for example, ocular histoplasmosis or acute retinal necrosis, but these conditions both technically constitute a posterior uveitis.

4.Panuveitis: Describes the situation in which all aspects and structures of the uvea are inflamed. This form of uveitis, rare in the United States, is most commonly encountered with widespread ocular infection (e.g., infantile toxocariasis) or severe autoimmune disease (e.g.,Vogt-Koyanagi-Harada syndrome).

588 CHAPTER 29 Uveitis

ETIOLOGY AND PATHOPHYSIOLOGY

Uveitis should not be thought of as a singular ocular disorder but rather as a diverse collection of pathologic conditions with similar clinically observable signs. A vast multitude of etiologies may induce uveitis, ranging from blunt trauma to widespread systemic infection (e.g., tuberculosis) to generalized ischemic disorders (e.g., giant cell arteritis). Some other well-known systemic etiologies include ankylosing spondylitis, rheumatoid arthritis, sarcoidosis, multiple sclerosis, syphilis, Lyme disease, and histoplasmosis. A more thorough compilation of etiologic conditions is listed in Box 29-1. Of course, not all forms of uveitis are associated with systemic illness. Localized inflammations may occur as well, either by iatrogenic or idiopathic means. Some primary uveitic syndromes include Fuchs’ heterochromic iridocyclitis and PosnerSchlossman syndrome. In addition, various retinal “white dot syndromes,” such as bird-shot choroiditis, acute

Box 29-1 Systemic Disease Associations in

Uveitis

Adapted from Wade NK. Diagnostic testing in patients with ocular inflammation. Int Ophthalmol Clin 2000;40:37–54.

posterior multifocal placoid pigment epitheliopathy, multiple evanescent white dot syndrome, and serpiginous choroiditis are also associated with uveitis.

Although the precise pathophysiology of uveitis has not been entirely elucidated, we do have a basic understanding of the cascade of events involved during this inflammatory state. In the normal human eye, the intraocular space remains free of inflammatory cells and plasma proteins by virtue of the blood–aqueous barrier anteriorly and the blood–retina barrier posteriorly. The blood–aqueous barrier is comprised of tight junctions between the endothelial cells of the iris vasculature and between the apicolateral surfaces of the nonpigmented epithelium of the ciliary body. Tight junctions between the retinal pigment epithelial cells and between endothelial cells of the retinal vasculature constitute the blood–retina barrier. In an inflammatory ocular state, cytokines mediate numerous tissue changes, among them vasodilation and increased vasopermeability. When the uveal vessels dilate, exudation of plasma, white blood cells, and proteins into the extravascular spaces (e.g., the anterior chamber) becomes possible. Small-molecular- weight proteins may cloud the ocular media but have little impact otherwise; however, as larger molecular weight proteins like fibrinogen accumulate in the aqueous and/or vitreous, pathologic sequelae follow. Fibrinogen is ultimately converted into fibrin, an insoluble protein involved in the blood-clotting process. In the anterior chamber fibrin acts as a glue, binding with cellular debris to form KPs; more importantly, fibrin facilitates the adhesion of adjacent ocular structures, such as the peripheral iris and cornea (anterior synechia) or the pupillary margin and anterior lens surface (posterior synechia).With synechiae comes the risk of secondary glaucomas, in particular angle closure with or without pupillary block. In the posterior segment, transudation of fluid and cells from the choroid can result in cystoid macular edema (CME) and, in extreme cases, exudative retinal detachment. The accumulation and contraction of fibrin within the vitreous cavity can initiate a tractional retinal detachment. Additionally, chronic uveal inflammation results in an increased concentration of vasoproliferative mediators, promoting angiogenesis or neovascularization. Neovascular changes in the iris and angle can further predispose an individual to secondary glaucoma, whereas in the posterior segment neovascularization of the retina enhances the risk of hemorrhage and tractional detachment.

EPIDEMIOLOGY

Because uveitis represents a group of vastly heterogenous ocular disorders with a multitude of etiologic factors, epidemiologic studies of this entity prove to be somewhat challenging. The incidence and prevalence of uveitis, as well as its clinical presentation, may vary widely with regard to geographic location, age, medical history, and

other factors. Crucial considerations in the epidemiology of uveitis are as follows:

1.Geography: The worldwide annual incidence of uveitis is between 14 and 52 per 100,000 population. However, vast differences exist between and within countries. For example, a French study in 1984 revealed a prevalence of 38 per 100,000, whereas a 1962 U.S. study noted 200 cases per 100,000. A study from India in 2000 indicated an overwhelming 730 cases per 100,000 population. Most likely, these discrepancies are due to differences in reporting, access to medical care, and inclusion/exclusion criteria of the different studies. In addition, there are significant variations in the presentation of uveitis based on geographic location. In the United States, Europe, and Australia anterior uveitis is most prevalent, followed by posterior uveitis. In Argentina and Western Africa, however, panuveitis is the most common presentation of uveitis. These differences may be attributable to the high rate of endemic infection by toxoplasmosis and onchocerciasis in these regions, respectively. Similarly, panuveitis and posterior uveitis may be more common in Asian countries such as Japan and Korea because of the high incidence of Vogt-Koyanagi-Harada disease. Regional differences within countries also account for wide variations in uveitis epidemiology. In the United States, for example, uveitis associated with ocular histoplasmosis is more frequently observed in patients from the Ohio–Mississippi River valley.

2.Age: Uveitis is most commonly encountered in persons between ages 20 and 59 years. Interestingly, this period corresponds with an individual’s peak T-cell activity. It unfortunately also coincides with the greatest potential earning period of a person’s life and hence can have significant economic impact in terms of disability. Children and the elderly are rarely affected by uveitis; however, when individuals in these age groups are encountered, specific disorders must be considered. In those under the age of 16, juvenile idiopathic arthritis (JIA) is responsible for nearly 40% of anterior uveitis cases. Posterior uveitis in children is typically associated with toxoplasmosis. In those over age 60 presenting with uveitis, common causes include herpes zoster, Acute Retinal Necrosis (ARN), serpiginous chorioretinopathy, bird-shot retinopathy, and herpes simplex. Giant cell arteritis and other ischemic disorders must be considered as well.

3.Gender: Overall, uveitis does not tend to favor either gender; however, certain predisposing conditions may have a predilection for males or females. For example,

HLA-B27–associated uveitis (e.g., ankylosing spondylitis, Reiter’s syndrome) is encountered more commonly in males (3:1), whereas uveitis of JIA shows a distinct female preponderance (5:1).

4.Race: There is no known racial predilection associated with uveitis as a diagnosis. However, in the same way

that gender-specific etiologies may be identified, racespecific disorders are known to occur in uveitis patients. In the white population, for example, both the HLA-B27 conditions and ocular histoplasmosis are encountered more commonly than in other races. Individuals of African descent are at greater risk for sarcoidosis, whereas Asian individuals demonstrate a higher frequency of Vogt-Koyanagi-Harada syndrome and Behçet’s disease.

5.History: Numerous factors in a patient’s history can be contributory to uveitis. The ocular history is paramount, and factors such as trauma, surgery, and infection must be considered. Numerous systemic illnesses associated with uveitis have already been discussed and listed in Box 29-1. It is important for the clinician to probe the history for symptoms or signs that might be pertinent to these disorders, such as joint pain or joint deformities, lower back pain, gastrointestinal disturbances, respiratory problems, oral or genital lesions, rashes, and nail pitting. Any prior hospitalizations should be elucidated, as well as the reason and duration. Sexual history must also be taken into account, because syphilis, herpes simplex, and human immunodeficiency virus (HIV) infection in particular may be associated with uveitis. Reiter’s syndrome (or reactive arthritis), with its characteristic findings of conjunctivitis, uveitis, arthritis, and urethritis, often follows a chlamydial or dysentery infection. Likewise, a thorough review of the drug history is important in patients with uveitis, not only to determine prior therapy for systemic illness but also to ascertain clues as to other potential etiologies. Numerous drug therapies have been associated with uveitis, among them topical agents such as latanoprost and metipranolol; systemic drugs purported to cause uveitis include rifabutin, cidofovir, the sulfonamides, and the family of drugs known as the bisphosphonates, used in the treatment of osteoporosis.

DIAGNOSIS

The diagnosis of uveitis is typically based on the clinical presentation, including symptoms and signs specific to this immune-mediated ocular response. Most, though not all, patients with anterior uveitis present with pain. The pain tends to be a dull ache deep within the eye, which may radiate to the surrounding orbit and face. Typically, this discomfort is exacerbated by bright light (photophobia), which induces miosis and stretches the inflamed uveal tissues. Lacrimation is another common symptom. Visual acuity is variably affected; anterior uveitis usually displays only mild visual impairment; however, in cases of posterior uveitis the deficit may be profound. In most cases a visible inflammatory response involving the conjunctiva and episclera is observable on gross examination. Perhaps the most recognizable signs associated with

590 CHAPTER 29 Uveitis

uveitis are “cells and flare.” Cells represent leukocytes, liberated from dilated blood vessels in the iris and ciliary body. Flare is the visibly observable accumulation of plasma protein. Both cells and flare may be observed readily in the anterior chamber, becuase the aqueous is normally optically empty. In the vitreous it may be more difficult to observe cells and flare; however, specific presentations, such as “snow banking” and “strings-of- pearls,” can be pathognomonic for intermediate or posterior uveitis. More distinct findings may be seen with biomicroscopy and/or funduscopy, depending on the tissues involved.

Anterior Uveitis

Anterior uveitis accounts for approximately 90% of uveitis cases seen in the primary care setting and roughly 50% to 60% of uveitis managed at the tertiary care level.

Anterior uveitis may be acute or chronic; acute cases tend to be unilateral and devoid of “granulomatous” changes, whereas chronic uveitis may be bilateral and usually has more significant pathology. Etiologies abound in anterior uveitis, but the most common identifiable cause is HLA-B27–associated disease.

Visual Acuity

The evaluation of any ocular malady begins with visual acuity assessment, performed in both the involved and uninvolved eye. In the earliest stages of anterior uveitis, visual acuity is minimally compromised. However, as the condition persists over days to weeks, accumulation of cells and flare, as well as photophobia and lacrimation, may result in subjectively blurred vision. Pigment accumulation on the anterior lens capsule and corneal endothelium may further compromise acuity and may serve to disrupt the endothelial pumps, resulting in corneal edema. At this stage visual acuity may be impaired on the order of 20/60 or worse. Over months to years, chronic inflammation and corticosteroids can induce cataract formation, leading to a precipitous drop in visual acuity. Secondary glaucomas, such as those encountered in synechiae-induced angle-closure or neovascular glaucoma, can result in profound irreversible vision loss.

External Examination

The patient with anterior uveitis may display a sluggish, fixed, and/or irregular pupil on the involved side. Typically, the pupil is miotic secondary to ciliary spasm, though it may assume a larger more irregular shape due to synechia formation. Ocular motility is generally intact. Gross observation may reveal a pseudoptosis, secondary to photophobia; there is not typically any notable lid edema. Conjunctival and episcleral vessels are characteristically dilated, often profoundly, so that a unilateral “red eye” presentation is seen. Except in rare cases, there is no ocular discharge or palpable preauricular lymphadenopathy

associated with anterior uveitis.Vesicular lesions near the eyes may signify a herpetic etiology.

Biomicroscopy

Biomicroscopy is critical in the uveitis assessment. It allows for accurate diagnosis as well as identification of potentially sight-threatening complications. The following structures and areas should be given special attention:

1.Redness: Anterior uveitis typically presents with a characteristic circumlimbal hyperemia, or “ciliary flush” as it is sometimes described. This pattern corresponds to the inflammation of the underlying ciliary body. In more profound reactions, however, the redness may be diffuse.

2.Cornea: The cornea is often involved in anterior uveitis. KPs, inflammatory cells that accumulate and coalesce, are often seen to deposit on the endothelium. In acute, traumatic, and idiopathic anterior uveitis

KPs take the form of a fine powdery-white dusting. In anterior uveitis associated with granulomatous disorders, however, KPs tend to be larger and denser. In newly active cases these “mutton-fat” KPs may appear somewhat three-dimensional and “greasy” in consistency. Over time they become more densely pigmented, ranging from yellow to dark brown in color, and tend to flatten. Mutton-fat KPs suggest a more chronic recalcitrant course of uveitis.

3.Anterior chamber: The finding of cells and flare in the anterior chamber is crucial to a diagnosis of anterior uveitis. It is important to assess the anterior chamber before instilling any diagnostic dyes or drugs; dyes such as fluorescein can penetrate the cornea and simulate flare, whereas pharmacologic dilation can release pigment from the iris, which may be mistaken for white cells. Proper technique also requires that the

anterior chamber be viewed in a completely dark room under high magnification (25 to 40×) with a small

intense beam of white light directed obliquely through the aqueous (45to 60-degree angle). Because of the Tyndall effect, cells and flare become visible in the anterior chamber and are reminiscent of smoke or dust circulating within a sunbeam. Grading schemes for cells and flare are shown in Tables 29-1 and 29-2, respectively. The grading of cells and flare is useful in determining the severity of the anterior uveitis and for monitoring the response to therapy.

4.Iris: In cases of granulomatous disease, inflammatory nodules may be detected in the iris. Nodules seen at the pupillary margin are termed Koeppe nodules, whereas Busacca nodules occur within the iris stroma.

Iris nodules have been identified in association with a variety of disorders, including sarcoidosis, tuberculosis, leprosy, syphilis, multiple sclerosis, Vogt-Koyanagi-Harada syndrome, and Fuchs’ heterochromic iridocyclitis. The pupillary margin and iris surface should also be examined for neovascular membranes in cases of chronic uveitis. Additionally, iris

Table 29-1

Grading Scheme for Anterior Chamber Cells

aField size is a 1 mm × 1 mm slit beam.

Adapted from The Standardization of Uveitis Nomenclature (SUN) Working Group.

atrophy may be noted in chronic or recurrent anterior uveitis, particularly Fuchs’ heterochromic iridocyclitis, cytomegalovirus, and herpes zoster infections. It is also crucial to evaluate the iris for areas of synechiae. Posterior synechia is noted at the pupillary margin, though it may be difficult to detect when the pupil is miotic. Pharmacologic dilation facilitates the diagnosis of posterior synechia and often helps to break areas of adhesion as well. Peripheral anterior synechia may be seen in some cases by direct illumination of the limbus; however, peripheral anterior synechia should always be confirmed by gonioscopic evaluation.

5.Lens: Pigment and cellular debris, similar to KPs, are often detected on the anterior lens surface. Faint fibrin membranes at the pupillary margin may precede areas of posterior synechiae. Cataracts are an important consideration in chronic recalcitrant uveitis and for those on long-term corticosteroid therapy, because the latter is also linked with the development of posterior subcapsular cataracts.

6.Vitreous: In all cases of uveitis it is important to evaluate the vitreous by direct and indirect means. Occasionally, a presumed anterior uveitis may simply represent “spillover” of inflammatory cells from an intermediate or posterior uveitis or a“masquerade syndrome.”

Table 29-2

Grading Scheme for Anterior Chamber Flare

Adapted from Jabs DA, Nussenblatt RB, Rosenbaum JT, et al. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Standardization of Uveitis Nomenclature (SUN) Working Group. Am J Ophthalmol 2005;140:509–516.

Comparison of the aqueous versus vitreous response is critical. In most cases of truly anterior uveitis, there are minimal to no cells in the vitreous.

Tonometry

The measurement of intraocular pressure (IOP) is essential in the initial assessment and ongoing management of uveitis. In the early stages of uveitis the IOP is typically low, due to secretory hypotony within the ciliary body. Over time, however, the IOP may normalize or rise to abnormal levels due to numerous mechanisms, including trabecular blockage by inflammatory debris and synechia formation. Elevated IOP usually indicates a more chronic condition.

Gonioscopy

Gonioscopy is crucial to confirm the presence of peripheral anterior synechia. Even angles that appear deep centrally may have peripheral anterior synechia, because the pathogenesis of these adhesions involves an inflammatory etiology rather than an anatomic anomaly. Gonioscopy may also reveal neovascularization of the angle (NVA) and in cases of posttraumatic uveitis, angle recession.

Fundus Examination

All patients with anterior uveitis should undergo dilated funduscopy. Such examination should be attempted on the initial visit, although it may be difficult because of patient discomfort and/or posterior synechia. In such cases, ophthalmoscopy on the first follow-up visit may yield more useful information. Without adequate careful examination of the peripheral fundus and posterior pole, one cannot rule out the possibility of posterior involvement or masquerade syndromes. Masquerade syndromes are disorders that present as uveitis but do not have an inflammatory etiology. Such diseases either cause a secondary uveitis or are mistaken for a primary uveitis, because of the presence of white cells, red blood cells, pigment, or tumor cells. Examples of masquerade syndromes may include lymphoma, leukemia, retinoblastoma, malignant choroidal melanoma, retinal detachment, and intraocular foreign body.

Intermediate Uveitis

Intermediate uveitis tends to affect younger patients, ranging from their teens to early forties. The most common presentation involves vague complaints of blurry vision and persistent floaters, with a slow insidious onset. Pain and photophobia are uncommon symptoms. Whereas the signs of anterior uveitis are primarily seen in the aqueous and iris, the diagnosis of intermediate uveitis typically involves evaluation of the vitreous and peripheral retina. Bilateral involvement at initial presentation is near 80%, and approximately one-third of unilateral cases ultimately become bilateral. Intermediate uveitis has been reported