Introduction
The sclera is a dense, poorly vascularized connective tissue structure composed of collagen, elastin, proteoglycans, and glycoproteins. It is embryologically derived from the neural crest and the mesoderm.
The sclera may be affected by a number of inflammatory and noninflammatory processes. This chapter will describe episcleritis, focusing on scleritis, a more serious and often vision-threatening condition.
Inflammatory Diseases
Episcleritis
Epidemiology and Pathogenesis
Episcleritis refers to inflammation of the loose connective tissue between the sclera and the conjunctiva. Patients often complain of discomfort or irritation rather than true pain. Slit-lamp microscopic examination usually localizes any edema to the area that overlies the sclera. The sclera itself is not thickened. Accompanying uveitis is very rare.
Episcleritis is a self-limiting condition, generally running its course in a few days, although nodular disease may last for weeks. Recurrence is common, but structural damage to the eye does not occur.
Diagnosis and Ocular Manifestations
Episcleritis can be described as simple , in which all or part of the episclera is diffusely inflamed, or nodular , in which inflammation is confined to a localized area with the presence of well-defined, red nodules. Nodular episcleritis often is associated with a more discomfort and a more prolonged course compared with simple episcleritis. Bilateral inflammation is seen in 40% of patients. Topical phenylephrine blanches overlying conjunctival vessels and inflamed episcleral vessels.
Differential Diagnosis
The differential diagnosis includes conjunctivitis, which is more superficial; phlytenulosis, which is typically mobile; and scleritis, which is deeper and more painful.
Systemic Associations
An underlying cause for episcleritis is found in approximately one third of cases. In two series of 94 and 85 patients with episcleritis, 68%–73% were found to have no associated disease; 13%–15% had a connective tissue or vasculitic disease; 7% had rosacea; 1%–7% had atopy; and 1%–6% had an associated infection (herpes zoster, herpes simplex, cat scratch disease, Lyme disease).
Treatment
Some patients may benefit from treatment for cosmesis or alleviation of discomfort. Many physicians elect to treat with topical corticosteroids, demonstrated in a randomized double-masked trial to be superior to placebo for the treatment of episcleritis. However, the use of topical corticosteroids may be detrimental because of the risk of rebound inflammation when the drugs are tapered. Some patients respond well to topical nonsteroidal anti-inflammatory drugs (NSAIDs). Systemic NSAIDs also may be used for the treatment of severe or recurrent episcleritis, although significant side effects may be associated with their use (see section on scleritis ). Treatment of underlying blepharitis is important.
Scleritis
Epidemiology and Pathogenesis
Scleritis is more associated with different systemic diseases compared with uveitis, so the evaluation and treatment for both conditions differ. In most cases, scleral inflammation is noninfectious. However, scleral infection caused by bacterial, protozoan, or fungal organisms, such as Pseudomonas , Mycobacterium , Acanthomoeba , or Aspergillus , may cause severe scleritis that is difficult to treat ( Fig. 4.11.1 ). Scleritis typically occurs in the sixth decade of life, but may occur in adolescents and in very old adults. Females are more commonly affected, and bilateral inflammation occurs in nearly 40% of cases.
Ocular Manifestations
Scleritis may be unilateral, bilateral, or alternate from eye to eye. The duration of inflammation is variable and may last only a few months or persist for years. The involved area may appear violaceous because the inflammation occurs in deeper tissues ( Fig. 4.11.2 ). The whole eye may be involved, or inflammation may localize to one or more quadrants. The involved area usually is tender to palpation, although pain may occur in seemingly uninvolved areas. The pain typically is deep and boring in nature and often wakes the patient from sleep.
On slit-lamp microscopy, the overlying conjunctival vessels usually are found to be engorged. The episclera may be edematous and inflamed. At times, the secondary inflammation in the conjunctiva and episclera makes it difficult to appreciate the underlying scleral inflammation. Topical phenylephrine blanches the overlying conjunctiva and, to a much lesser extent, the episclera and may permit better delineation of the depth of inflammation. The red-free (green) light on the slit lamp may be used to determine the level of inflammation.
Anterior scleritis is classified as diffuse ( Fig. 4.11.3A ) or nodular ( Fig. 4.11.4 ). It also may be necrotizing or nonnecrotizing. Necrotizing scleritis usually is extremely painful and presents with areas of avascularity in the sclera. Avascular areas may result in scleral thinning, which can progress to staphyloma formation and exposure of bare uvea ( Fig. 4.11.5 ). A simple grading system for scleritis, which has been described in the literature, has helped standardize the assessment of scleritis ( Fig. 4.11.6 ).
Scleromalacia perforans is a very rare type of painless necrotizing scleritis, which typically occurs in women with a long-standing history of rheumatoid arthritis.
Posterior scleritis refers to inflammation behind the equator of the globe and may be difficult to diagnose if anterior scleritis is not also present. Symptoms of posterior scleritis may include pain, blurred vision, and photophobia, although the patient may be fairly asymptomatic. Some patients with posterior scleritis develop proptosis, shallowing of the anterior chamber, exudative retinal detachments, choroidal detachments, disc swelling, and chorioretinal changes ( Figs. 4.11.7A and 4.11.8A ). Chorioretinal changes may consist of subretinal exudates and hemorrhages, as well as a stippled appearance to the retinal pigment epithelium in long-standing disease.
Scleral inflammation may cause structural damage to the eye, resulting in scleral translucency and thinning (see Fig. 4.11.5 ). Ocular complications were encountered in nearly 45% of cases in one study, including anterior uveitis (26%), decreased vision (16%), peripheral keratitis (13%), and ocular hypertension (14%). Decreased vision is associated most with necrotizing and posterior scleritis, although vision may be decreased as a result of cystoid macular edema in any type of scleritis. Significant amounts of induced astigmatism necessitate performance of retinoscopy in all patients with anterior scleritis and reduced vision.
Scleritis adjacent to the cornea may be associated with a focal or diffuse keratitis. Focal keratitis may manifest as a ring infiltrate at the limbus, without the peripheral clear zone that is seen with staphylococcal marginal infiltrates ( Fig. 4.11.9 ). Sclerokeratitis also may present with crystalline deposits that have the appearance of spun sugar or cotton candy in the deep cornea ( Fig. 4.11.10 ). This variant is known as sclerosing keratitis .
A number of mechanisms may result in elevation of intraocular pressure (IOP). Inflammatory cells may block scleral emissary vessels, which results in elevated episcleral venous pressure and hence elevated IOP. Ciliary body effusion may cause angle closure as the lens–iris diaphragm rotates anteriorly. Accompanying uveitis may be responsible for glaucoma if the trabecular meshwork is clogged with inflammatory cells and debris. Corticosteroid use may result in secondary elevation of IOP.
Differential Diagnosis
Conjunctivitis usually can be differentiated from scleritis by the presence of discharge, superficial inflammation, and the lack of severe aching or pain. Episcleritis may sometimes be confused with scleritis, although the two conditions can usually be differentiated based on history and clinical examination.
Ciliary flush (injection) that accompanies acute iritis may be confused with scleritis. However, the ciliary flush usually is restricted to the area adjacent to the limbus, and iritis appears to be the predominant finding.
Solid-appearing subretinal masses that mimic melanomas can occur in patients with scleritis ( Fig. 4.11.11 ). Computed tomography (CT) may be helpful in making the diagnosis of scleritis in these cases, demonstrating a contrast-enhancing mass that is uniformly isodense with sclera. A-scan ultrasonography usually demonstrates high internal reflectivity in scleritis (as opposed to low internal reflectivity in melanoma), and a B-scan may demonstrate thickened sclera.
Diagnosis and Ancillary Testing
The diagnosis of anterior scleritis is clinically based. It is important to examine the patient with the room lights on. The lid should be lifted and the eyes examined from a distance, as scleritis may be missed if the patient is examined only at the slit lamp in a dark room.
The diagnosis of posterior scleritis can be difficult. Fluorescein angiography may be helpful because it may demonstrate characteristic subretinal leakage spots that coalesce as the study progresses (see Fig. 4.11.8B ). Only Vogt–Koyanagi–Harada syndrome has a similar picture on fluorescein angiogram.
B-scan ultrasonography is extremely useful in the diagnosis of posterior scleritis. The T-sign, representing fluid in Tenon’s capsule, is highly characteristic of posterior scleritis, although it is not always present (see Fig. 4.11.7C ). Thickening of the posterior sclera usually can be demonstrated on B-scan. CT of the orbits with contrast material may show the so-called ring sign of enhancement of the sclera, suggestive of posterior scleritis. Magnetic resonance imaging has not proved to be any more useful than CT and may even be less helpful, although it avoids the radiation risks associated with CT. Ultrasound biomicroscopy and anterior segment optical coherence tomography may help characterize severity and extent of disease (see Figs. 4.11.3B and 4.11.4B ).
The workup of a patient with scleritis includes an evaluation for systemic vasculitis, connective tissue disease, and infection. Much of this information can be gained from a detailed history. Laboratory tests might include erythrocyte sedimentation rate, rheumatoid factor, anticitrullinated protein antibody, antineutrophil cytoplasmic antibodies (C- and P-ANCA), antiproteinase 3, antimyeloperoxidase antibodies (anti-PR3, anti-MPO), and antinuclear antibody. Review of systems and a relevant family history may prompt the clinician to order human leukocyte antigen B27 or inflammatory bowel serology. Specific serological test for syphilis (including fluorescent treponemal antibody absorption test, microhemagglutination test for Treponema pallidum , syphilis immunoglobulin G enzyme immunoassay) should be obtained for all patients with ocular inflammation. A complete blood count and urinalysis may be considered. Chest radiography may be performed to look for evidence of tuberculosis, sarcoid, or granulomatosis with polyangiitis (GPA). ANCA, anti-PR3, and anti-MPO testing often is positive in cases of GPA, microscopic polyarteritis, and other related vasculitides. Two different patterns of immunofluorescence staining have been identified. Classic ANCA (C-ANCA) and anti-PR3 are more specific for GPA and other closely related vasculitides. The positivity of this test may depend, in part, on disease activity; in some patients, the test becomes negative with treatment or a decrease in disease activity.
Systemic Associations
Underlying systemic disease is present in approximately 35%–50% of patients with scleritis. Rheumatoid arthritis is the most frequently associated condition, and scleritis may be the first manifestation, preceding joint disease. Other connective tissue diseases that can present with scleritis include GPA, polyarteritis nodosa, systemic lupus erythematosus, and relapsing polychondritis ( Fig. 4.11.12 ).
Psoriatic arthritis and ankylosing spondylitis, although usually associated with acute iritis, can at times be associated with scleritis. Inflammatory bowel disease, especially Crohn’s disease, can be associated with scleritis. Scleritis has been observed in 18% of patients with inflammatory bowel disease and may correspond to gastrointestinal (GI) disease activity, as does accompanying large joint peripheral arthritis. Pyoderma gangrenosum and Cogan’s syndrome can be associated with scleritis. Sarcoidosis can cause granulomatous scleritis.
Infectious conditions, such as tuberculosis, acanthomoebiasis, syphilis, and leprosy, may result in granulomatous, nodular scleritis (see Fig. 4.11.1A ). Herpes zoster and herpes simplex may cause scleritis ( Fig. 4.11.13 ). When herpesviruses cause scleritis, it usually is in the late recovery phase of the disease rather than during acute infection.
Necrotizing scleritis can be triggered by ocular surgery ( Fig. 4.11.14 ); it has been reported weeks to months after cataract surgery, penetrating keratoplasty, muscle surgery, glaucoma surgery, and even pterygium surgery. Evidence exists of underlying connective tissue disease in some of these patients, but in others, no causative factor can be found. Infectious causes must be sought in all patients with postoperative scleritis.
Pathology
Scleral biopsy should be done only in exceptional circumstances. The surgeon should be prepared either to place a scleral reinforcement graft or use some other tissue, such as periosteum, to replace the sclera that has been sampled for biopsy, as severe thinning of the sclera can result in an unexpected encounter with intraocular contents.
Histopathological examination may reveal one of four patterns of inflammation, which can correlate with disease etiology : zonal, necrotizing granulomatous; diffuse, nonnecrotizing; necrotizing with microabscesses; and nonzonal, nondiffuse granulomatous. Antigen–antibody complexes mediate zonal, necrotizing granulomatous inflammation, which is most often associated with systemic disease. Lymphocytes and plasma cells appear in diffuse nonnecrotizing inflammation, which is often idiopathic. Necrotizing inflammation with microabscesses is observed in infectious scleritis.
Treatment
Medical Treatment
Most patients who have active scleritis require therapy. Some physicians recommend that treatment be continued until all redness is gone from the eye. However, if no pain and no evidence of any damage to the eye exist, the side effects of the therapy may outweigh the benefits. Some patients who have only mild redness, no active secondary uveitis or keratitis, and no visual problems may not require therapy, but must be closely monitored.
Topical nonsteroidal agents may be of some benefit in patients who have mild episcleritis, but they are of no benefit in true scleritis. Most topical corticosteroids do not have any marked beneficial anti-inflammatory effect in cases of true scleritis, although they may be helpful in controlling secondary uveitis. Difluprednate, a newer topical corticosteroid, has been shown to have scleral penetration in rabbit models and may be a useful therapeutic agent in scleritis, but clinical data on its use in human scleritis are lacking.
Oral NSAIDs should be considered the first line of treatment in patients with mild and moderately severe scleritis. They have been reported to be effective in diffuse scleritis and mild nodular scleritis. Indomethacin 50 mg three times a day or, in the sustained-release form, 75 mg twice a day, can be very effective. Other nonsteroidal agents that appear to work well are piroxicam and naprosyn. Ibuprofen, diclofenac, tolmetin, sulindac, and others also may be of benefit.
All systemic nonsteroidal agents carry the risk of significant side effects. Long-term therapy may result in allergic reactions, GI problems, and kidney damage. An increased risk of cardiac events has been reported with both cyclooxygenase-2 (COX-2)–specific and COX-2–nonspecific NSAIDs. These medications should be avoided in those patients with significant cardiac risk factors, especially in patients with prior myocardial infarction, prior stroke, or recent cardiac arrhythmias. Patients who take NSAIDs may require other medications to prevent or treat GI side effects. Options include histamine 2 (H 2 ) receptor antagonists (e.g., ranitidine, famotidine, cimetidine), coating agents (e.g., sucralfate), gastric acid secretion inhibitors (e.g., the synthetic prostaglandin E 1 analogue misoprostol), and proton pump inhibitors (e.g., omeprazole). The NSAIDs that are selective COX-2 inhibitors may have fewer GI side effects but appear to be less potent antiinflammatory agents.
Systemic corticosteroids often are used as initial therapy for patients with moderate to severe scleritis. The usual starting dose is 1 mg/kg/day of prednisone, but in severe cases, doses up to 1.5 mg/kg/day or even intravenous pulse corticosteroids may be required. The prednisone is then slowly tapered to a best-tolerated dose. Many patients require therapy for 6 months to a year or longer. Patients who require more than 3 months of treatment or 5 mg of chronic daily prednisone should be considered for corticosteroid-sparing agents. Occasionally, patients who take their full dose of oral prednisone in the morning experience pain at night. If the dose is divided and taken twice a day, this night pain may be relieved without increasing the total dose.
Pulse intravenous methylprednisolone at 0.5–1 g may be required in some patients with severe scleritis. This high dose may be used once a day for 3 days or once every other day for three doses and then reduced to once a week. Oral prednisone is often required to supplement the pulses.
All systemic corticosteroids may result in adrenal suppression, weight gain, mood changes, blood pressure elevation, blood sugar elevation, osteoporosis, and aseptic necrosis of the femoral head. Any patient who is on oral prednisone for longer than 1 year, even on an every-other-day schedule, should have a bone density evaluation.
Subconjunctival injection has been proposed as a method of corticosteroid delivery in cases of nonnecrotizing anterior scleritis. Its use typically is limited to adjunctive therapy in cases of nonnecrotizing localized disease, cognizant of the at least theoretical risk of scleral thinning and perforation.
Immunosuppressive or immunomodulatory therapy may be required in patients with scleritis who are unresponsive to or intolerant of prednisone, or who require long-term therapy (see Fig. 4.11.5 ). In patients with severe rheumatoid arthritis and GPA, morbidity and mortality are reduced with the use of immunosuppressive agents. Many patients with necrotizing scleritis require immunosuppressive therapy to preserve vision. Evidence exists that well-managed immunosuppressives have less long-term toxicity compared with high- or moderate-dose prednisone. All immunomodulatory therapy for scleritis is used off label.
Oral or subcutaneous methotrexate (7.5–25 mg weekly) has been reported to be of benefit in reducing or eliminating the need for systemic corticosteroid therapy. Azathioprine at a dose of 1.5–2 mg/kg/day also may reduce or eliminate the need for corticosteroids. However, both these agents can result in hepatic and hematological toxicity. Mycophenolate mofetil, another antimetabolite drug, may have lower toxicity and higher efficacy.
Cyclosporine, which acts in part by interfering with interleukin-2, has been used with some success in the treatment of scleritis. At doses of 10 mg/kg/day, it is nephrotoxic, so it is almost always used at lower doses, such as 5 mg/kg/day as an initial dose and 3–5 mg/kg/day as a maintenance dose. However, at these doses, it may be impossible to discontinue the use of corticosteroids. As such, cyclosporine is used as an adjunctive therapy, permitting lower doses of systemic corticosteroids, or in combination with other agents such as antimetabolites. Systemic hypertension, renal failure, hirsutism, and gingival hyperplasia all may occur with cyclosporine. Tacrolimus (FK-506) has a different structure from that of cyclosporine but has similar intracellular actions and is supplied in a topical ointment that has been shown to be effective in a small number of scleritis cases.
Biological medications have been shown to be particularly effective in treating scleritis. Tumor necrosis factor inhibitors, which include infliximab, adalimumab, etanercept, certolizumab, and golimumab, typically act rapidly in controlling inflammation. The majority of data in uveitis and scleritis are for infliximab and adalimumab. Although adalimumab recently received U.S. Food and Drug Administration approval for the treatment of noninfectious intermediate, posterior, and panuveitis in adults, its use in scleritis is still off label. In addition, rituximab has been shown to have excellent efficacy in refractory cases of scleritis. These agents are usually prescribed and monitored in conjunction with a rheumatologist.
Alkylating agents, such as chlorambucil and cyclophosphamide, may be of benefit and usually enable oral prednisone to be tapered or discontinued. In some cases, a 3- to 6-month course of chlorambucil, with reduction of the white blood cell count to 2400–3500, results in prolonged remission of ocular inflammatory disease. Alkylating agents may have hematological toxicity, and blood counts must be monitored frequently. Cyclophosphamide has the added risk of hemorrhagic cystitis, so adequate hydration is imperative. Cyclophosphamide works more rapidly (frequently within a few days to a week) compared with chlorambucil. Pulse intravenous cyclophosphamide also has been used in severe sight- or life-threatening disease. Because alkylating agent use may increase the risk of late malignancy and sterility, detailed informed consent should be obtained before starting therapy. These agents may result in premature gonadal failure in males and females and are also teratogenic, so patients must be counseled carefully.
Surgical Treatment
Surgery for scleritis may be performed when scleral perforation or extensive thinning exists with significant risk for scleral rupture. However, most patients who have thin sclera and even staphyloma formation do not require structural reinforcement. If the decision is made to reinforce the sclera, available agents include fresh or preserved donor sclera, periosteum, or fascia lata. Donor sclera is relatively easy to use, but after several months, it may start to dissolve, as did the originally diseased tissue. Autologous periosteum can be harvested from the tibial crest and may be a better agent to use, as it may be less likely to necrose compared with donor sclera.
Many patients who have scleritis develop cataracts. Surgery for cataracts in such patients should be undertaken only when the disease has been in remission for at least 3 months. The physician should be alert to recognize recrudescence of scleral inflammation after surgery.
Course and Outcome
Most patients with mild or moderate scleritis maintain excellent vision. The length of time during which scleritis is active varies from patient to patient. In a minority of patients, the disease is active for months and then goes into long-term remission. In other patients, the disease is active for several years. In some patients, the disease seems to move from eye to eye or to move from one area of sclera to another.
Necrotizing scleritis portends a worse prognosis compared with nonnecrotizing disease. Patients with necrotizing scleritis have a high incidence of visual loss and a 21% 8-year mortality. Immunosuppressive therapy appears to lessen these risks.
Episcleritis
Epidemiology and Pathogenesis
Episcleritis refers to inflammation of the loose connective tissue between the sclera and the conjunctiva. Patients often complain of discomfort or irritation rather than true pain. Slit-lamp microscopic examination usually localizes any edema to the area that overlies the sclera. The sclera itself is not thickened. Accompanying uveitis is very rare.
Episcleritis is a self-limiting condition, generally running its course in a few days, although nodular disease may last for weeks. Recurrence is common, but structural damage to the eye does not occur.
Diagnosis and Ocular Manifestations
Episcleritis can be described as simple , in which all or part of the episclera is diffusely inflamed, or nodular , in which inflammation is confined to a localized area with the presence of well-defined, red nodules. Nodular episcleritis often is associated with a more discomfort and a more prolonged course compared with simple episcleritis. Bilateral inflammation is seen in 40% of patients. Topical phenylephrine blanches overlying conjunctival vessels and inflamed episcleral vessels.
Differential Diagnosis
The differential diagnosis includes conjunctivitis, which is more superficial; phlytenulosis, which is typically mobile; and scleritis, which is deeper and more painful.
Systemic Associations
An underlying cause for episcleritis is found in approximately one third of cases. In two series of 94 and 85 patients with episcleritis, 68%–73% were found to have no associated disease; 13%–15% had a connective tissue or vasculitic disease; 7% had rosacea; 1%–7% had atopy; and 1%–6% had an associated infection (herpes zoster, herpes simplex, cat scratch disease, Lyme disease).
Treatment
Some patients may benefit from treatment for cosmesis or alleviation of discomfort. Many physicians elect to treat with topical corticosteroids, demonstrated in a randomized double-masked trial to be superior to placebo for the treatment of episcleritis. However, the use of topical corticosteroids may be detrimental because of the risk of rebound inflammation when the drugs are tapered. Some patients respond well to topical nonsteroidal anti-inflammatory drugs (NSAIDs). Systemic NSAIDs also may be used for the treatment of severe or recurrent episcleritis, although significant side effects may be associated with their use (see section on scleritis ). Treatment of underlying blepharitis is important.
Epidemiology and Pathogenesis
Episcleritis refers to inflammation of the loose connective tissue between the sclera and the conjunctiva. Patients often complain of discomfort or irritation rather than true pain. Slit-lamp microscopic examination usually localizes any edema to the area that overlies the sclera. The sclera itself is not thickened. Accompanying uveitis is very rare.
Episcleritis is a self-limiting condition, generally running its course in a few days, although nodular disease may last for weeks. Recurrence is common, but structural damage to the eye does not occur.
Diagnosis and Ocular Manifestations
Episcleritis can be described as simple , in which all or part of the episclera is diffusely inflamed, or nodular , in which inflammation is confined to a localized area with the presence of well-defined, red nodules. Nodular episcleritis often is associated with a more discomfort and a more prolonged course compared with simple episcleritis. Bilateral inflammation is seen in 40% of patients. Topical phenylephrine blanches overlying conjunctival vessels and inflamed episcleral vessels.
Systemic Associations
An underlying cause for episcleritis is found in approximately one third of cases. In two series of 94 and 85 patients with episcleritis, 68%–73% were found to have no associated disease; 13%–15% had a connective tissue or vasculitic disease; 7% had rosacea; 1%–7% had atopy; and 1%–6% had an associated infection (herpes zoster, herpes simplex, cat scratch disease, Lyme disease).
Treatment
Some patients may benefit from treatment for cosmesis or alleviation of discomfort. Many physicians elect to treat with topical corticosteroids, demonstrated in a randomized double-masked trial to be superior to placebo for the treatment of episcleritis. However, the use of topical corticosteroids may be detrimental because of the risk of rebound inflammation when the drugs are tapered. Some patients respond well to topical nonsteroidal anti-inflammatory drugs (NSAIDs). Systemic NSAIDs also may be used for the treatment of severe or recurrent episcleritis, although significant side effects may be associated with their use (see section on scleritis ). Treatment of underlying blepharitis is important.
Scleritis
Epidemiology and Pathogenesis
Scleritis is more associated with different systemic diseases compared with uveitis, so the evaluation and treatment for both conditions differ. In most cases, scleral inflammation is noninfectious. However, scleral infection caused by bacterial, protozoan, or fungal organisms, such as Pseudomonas , Mycobacterium , Acanthomoeba , or Aspergillus , may cause severe scleritis that is difficult to treat ( Fig. 4.11.1 ). Scleritis typically occurs in the sixth decade of life, but may occur in adolescents and in very old adults. Females are more commonly affected, and bilateral inflammation occurs in nearly 40% of cases.
