EPISCLERITIS Epidemiology and Pathogenesis Episcleritis refers to inflammation of the loose connective tissue between the sclera and

the conjunctiva; it is a much more benign condition than scleritis. Patients with episcleritis usually complain of discomfort or irritation rather than true pain. Slit-lamp examination usually localizes any edema to the area that overlies the sclera. The sclera itself is not thickened, and accompanying uveitis is very rare. Episcleritis is a self-limited condition. Untreated, simple episcleritis generally runs its course in a few days, although nodular disease may last for weeks. Recurrence is common but structural damage of 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 a welldefined red nodule. The nodule can be differentiated from a conjunctival nodule, such as a phlyctenule, because the nodule of episcleritis is not mobile with the conjunctiva. Nodular episcleritis is often associated with more discomfort and a more prolonged course than is simple episcleritis. Topical phenylephrine blanches overlying conjunctival vessels and inflamed episcleral vessels. Differential Diagnosis The differential diagnosis includes conjunctivitis, which is more superficial, and scleritis, which is deeper. Systemic Associations An underlying cause for episcleritis is found in only one third of cases. In one series of 94 patients who had episcleritis, 68% were found to have no associated disease, 13% had a connective tissue or vasculitic disease, 7% had rosacea, and 7% had atopy. Herpes zoster, herpes simplex, chemical injury, and gout were believed to be responsible in one case each.[1]

Treatment Only certain patients may require treatment for cosmesis or for the alleviation of discomfort. Many physicians elect to treat with topical corticosteroids, as these were demonstrated in a randomized double-blind trial to be superior to placebo for the treatment of episcleritis.[2] It also has been suggested, however, that the use of topical

corticosteroids may be detrimental, with

significant rebound inflammation when corticosteroids are tapered.[1] Some patients with episcleritis 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 the section on scleritis). Treatment of underlying blepharitis is important. SCLERITIS Epidemiology and Pathogenesis Scleritis, a rare condition, is associated with different systemic diseases than is uveitis, so the evaluation and treatment of these patients differ. Most scleral inflammation is noninfectious. However, scleral infection by bacterial or fungal organisms, such as Pseudomonas or Aspergillus, may cause a severe scleritis that is difficult to treat. On rare occasions, tuberculosis may be the cause of scleral nodules.[3] Histopathology may show granulomatous or nongranulomatous inflammation, vasculitis, and scleral necrosis.[1] Antigenantibody complexes appear to play a role in many cases of scleritis, although T cells have been implicated in some cases of posterior scleritis. [4] [5] [6] Of patients who have scleritis, 50% appear to have no underlying systemic disease. In the other 50%, an underlying systemic disorder, usually a connective tissue disease, is present. Ocular Manifestations Scleritis may be unilateral, simultaneously bilateral, or alternate from eye to eye. The duration of inflammation is variable active inflammation may last only a few months or persist for years. The involved area may appear violaceous, because the inflammation is in deeper tissues ( Fig. 411-1 ). The whole eye may be involved, or the inflammation may be limited to one or more

quadrants. The involved area is usually tender to palpation, although pain may occur even in seemingly uninvolved areas. The pain typically is deep and boring in nature and often wakes the patient from sleep

Fig. 4-11-1 Diffuse scleritis with a violaceous hue due to deep inflammation. Vessels do not blanch with topical phenylephrine.

On slit-lamp examination, the overlying conjunctival vessels are usually found to be engorged. The episclera may also be edematous and inflamed. At times, the secondary inflammation in the conjunctiva and episclera makes it difficult to determine whether there is underlying scleral inflammation. Topical phenylephrine 2.5% or 10% blanches the overlying conjunctiva and, to a much lesser extent, the episclera. This may permit better delineation of the depth of inflammation. The red-free (green) light on the slit lamp may also be used to clear overlying haze and better determine the level of inflammation. Anterior scleritis is classified as diffuse or nodular. It also may be necrotizing or non-necrotizing. Necrotizing scleritis usually is extremely painful and presents with areas of avascularity in the sclera. Avascular areas may slough to leave scleral thinning, which can progress to staphyloma formation and exposure of bare uvea ( Fig. 4-11-2 ).

Scleromalacia perforans is a type of painless necrotizing scleritis that typically occurs in women with a long-standing history of rheumatoid arthritis. In these cases, yellow scleral nodules develop without much redness or pain. These nodules, which are histopathologically very similar to rheumatoid nodules, may necrose and slough to leave defects in the sclera[7] ( Fig. 4-11-3 ). The term posterior scleritis refers to inflammation behind the equator of the globe. If anterior scleritis is also present, the diagnosis is not difficult. However, in the case of purely posterior

scleritis with a quiet anterior segment, the diagnosis is often missed. Symptoms of posterior scleritis may include pain, blurred vision, and photophobia, although the patient also 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. Chorioretinal changes may consist of subretinal exudates and hemorrhages, as well as a stippled appearance to the retinal pigment epithelium in long-standing disease ( Fig. 4-11-4 ).

Fig. 4-11-4 Subretinal hemorrhage and exudate in a patient who has necrotizing scleritis.

Scleritis frequently is associated with a secondary uveitis either iritis or choroiditis. Patients who have sclerouveitis may develop keratic precipitates, posterior synechiae, and, if posterior scleritis is present, exudative retinal changes, hemorrhage, and retinal pigmentary changes. Scleral inflammation may cause structural damage to the eye. Scleral translucency and thinning regularly occur (see Fig. 4-11-2 ). 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. 4-11-5 ). Sclerokeratitis also may present with crystalline deposits that have the appearance of spun sugar or cotton candy in the deep cornea. This variant is known as sclerosing keratitis[7] ( Fig. 4-11-6 ).

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 detachment adjacent to areas of active scleritis may cause angle closure as the lensiris diaphragm rotates anteriorly. Topical corticosteroids also may induce an elevation in IOP. Accompanying uveitis may be responsible for glaucoma if the trabecular meshwork is clogged with inflammatory cells and debris. Whatever the mechanism, scleritis frequently is associated with secondary glaucoma. Diagnosis and Ancillary Testing The diagnosis of anterior scleritis is a clinical one. 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, as it may demonstrate characteristic subretinal leakage spots that coalesce as the study progresses ( Fig. 4-11-7 ). Only Vogt-Koyanagi-Harada syndrome has a similar picture on fluorescein angiogram.[8]

Fig. 4-11-7 Fluorescein angiography. (A) Exudative retinal detachment and choroidal folds in posterior scleritis. (B) The same eye shows choroidal folds and areas of subretinal leakage, which increase in intensity in the late phases of the angiogram. Only Vogt-Koyanagi-Harada syndrome and posterior scleritis exhibit this subretinal leakage pattern. Many patients with posterior scleritis do not have this leakage pattern, however.

B-scan ultrasonography also may be helpful in the diagnosis of posterior scleritis. The T-sign, representing fluid in Tenon's capsule, is said to be highly characteristic of posterior scleritis, although it is not always present ( Fig. 4-11-8 ). Thickening of the posterior sclera can usually be demonstrated on B-scan.[9]

Fig. 4-11-8 B-scan ultrasonography showing the dark area behind Tenon's capsule. This forms the T-sign with the dark optic nerve pattern, which is believed to be due to fluid in Tenon's capsule and is very characteristic of posterior scleritis, but it is not always present.

Computed tomography (CT) scan of the orbits with contrast material may show the so-called ring sign of enhancement of the sclera, suggestive of posterior scleritis ( Fig. 4-11-9 ). However, scleritis patients can have negative CT scans with contrast. Magnetic resonance imaging (MRI) has not proved to be any more useful than CT scans, and evidence exists that MRI may even be less helpful than CT.[10]

Fig. 4-11-9 Computed tomography scan of orbits with infusion in a patient with posterior scleritis. On the right (arrow), the ring sign, due to the concentration of contrast material in the sclera, is present.

The work-up of a patient with active scleritis includes an evaluation for evidence of vasculitis, connective tissue disease, and infection. Much of this information can be gained from a detailed history. Appropriate laboratory tests might include erythrocyte sedimentation rate, rheumatoid factor, and antinuclear antibody to look for evidence of systemic connective tissue disease. A fluorescent treponemal antibody absorption (FTA-ABS) test, MHA-TP (microhemagglutination test for Treponema pallidum), or other specific serological test for syphilis should be done on all patients to rule out latent syphilis. A complete blood count and urinalysis may be considered. A chest radiograph may be obtained to look for evidence of tuberculosis, sarcoid, or Wegener's granulomatosis. An antineutrophil cytoplasmic antibody (ANCA) test should be carried out for all patients suspected of having vasculitic disease. It is often positive in cases of Wegener's granulomatosis, microscopic polyarteritis, and other related vasculitides.[11] Two different patterns of immunofluorescence staining have been identified. Classic ANCA (C-ANCA)

produces a coarsely granular, centrally attenuated immunofluorescence, and perinuclear ANCA (P-ANCA) produces a perinuclear staining pattern. Of these, C-ANCA is more specific for Wegener's granulomatosis and other closely related vasculitides and is rarely positive in other patients, whereas P-ANCA is less specific and may be positive in patients with inflammation of nonvasculitic cause. The positivity of this test may depend, in part, on disease activity; in some patients, the tests become negative with a decrease in disease activity.[12] Differential Diagnosis Conjunctivitis usually can be differentiated from scleritis by the presence of discharge, superficial inflammation that clears with topical phenylephrine, and the lack of severe aching or pain. Episcleritis is the most challenging differential diagnosis in patients who have scleritis; differentiating features were discussed earlier. The ciliary flush that accompanies acute iritis may be confused with scleritis. However, the ciliary flush is usually 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. 4-11-10 ). [13] [14] CT scanning 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.

Systemic Associations Underlying systemic disease is present in approximately 50% of patients with scleritis.[15] Rheumatoid arthritis is the most frequently associated condition.[16] Other connective tissue

diseases that can present with scleritis include Wegener's granulomatosis, polyarteritis nodosa, systemic lupus erythematosus, and relapsing polychondritis ( Fig. 4-11-11 ).

Fig. 4-11-11 Patients with relapsing polychondritis. Note inflammation of the superior half of the pinna.

Psoriatic arthritis and ankylosing spondylitis, although usually associated with acute iritis, can at times be associated with scleritis.[16] Inflammatory bowel disease, especially Crohn's disease, can be associated with scleritis[17] ( Fig. 4-11-12 ). Patients who have inflammatory bowel disease, especially those that are HLA-B27 positive, may also develop both acute and chronic iridocyclitis. Scleritis is more often associated with inflammatory bowel disease when large joint peripheral arthritis occurs. Iritis is more often associated with inflammatory bowel disease when the patient also has ankylosing spondylitis.[17] Pyoderma gangrenosum and Cogan's syndrome can be associated with scleritis.[18] Sarcoidosis can cause scleral granulomas.

Fig. 4-11-12 Nodular scleritis in patient who has Crohn's disease.

Infectious conditions such as tuberculosis, syphilis, and leprosy have been reported to cause granulomas in the sclera. Herpes zoster and herpes simplex may also cause scleritis ( Fig. 4-1113 ). When herpesviruses cause scleritis, it is usually in the late recovery phase of the disease rather than during the acute infection.[15]

Fig. 4-11-13 Necrotizing anterior scleritis secondary to herpes zoster. The patient underwent extracapsular cataract extraction 2 weeks earlier, which precipitated ophthalmic

zoster and led to anterior segment necrosis.

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. [19] [20] [21] Evidence exists of underlying connective tissue disease in some of these patients, but in others, no causative factor can be found.

Fig. 4-11-14 Necrotizing scleritis induced by trabeculectomy surgery. Note the large conjunctival vessels seen in this 75-year-old woman; these are frequently seen after severe scleritis.

Pathology The histopathology of scleritis appears to be similar whether or not a systemic autoimmune disease is present. Inflammatory cells are seen in the sclera. Nongranulomatous inflammation is composed primarily of mononuclear cells, including lymphocytes, plasma cells, and macrophages. Granulomatous inflammation is characterized by the presence of epithelioid cells, which may coalesce to form multinucleated giant cells. In necrotizing scleritis, one sees eosinophilic fibrinoid material, often in the center of a granuloma. Scleral biopsy should be done only in exceptional circumstances. The surgeon should be prepared to either place a scleral reinforcement graft or use some other tissue, such as periosteum, to replace the sclera that is biopsied, as severe thinning of the sclera can result in an unexpected encounter with intraocular contents. Treatment Medical treatment

Most patients who have active scleritis require therapy. Certainly, patients who have pain and marked redness require therapy to alleviate the pain and prevent structural damage to the eye. Some physicians recommend that treatment be continued until all redness is gone from the eye. However, if there is no pain and no evidence of any damage to the eye, the side effects of the therapy may outweigh the benefits. Patients who have mild redness, no active secondary uveitis or keratitis, and no visual problems may not require therapy. Topical nonsteroidal agents may be of some benefit in patients who have mild episcleritis, but they are of no benefit in true scleritis. Topical corticosteroids seldom have any marked beneficial anti-inflammatory effect in cases of true scleritis, although they may be helpful in controlling secondary uveitis. Oral NSAIDs should be considered the first line of treatment in patients with mild and moderately severe scleritis. Indomethacin 50 mg three times a day or, in the sustained-release form, 75 mg twice a day can be very effective. Another nonsteroidal agent that appears to work well is piroxicam 20 mg daily. Ibuprofen, naproxen, tolmetin, sulindac, and others may be of benefit. All these nonsteroidal agents carry the risk of significant side effects. Allergic reactions, gastrointestinal problems, and kidney damage from long-term therapy can all occur. An increased risk of cardiac events has been reported with some NSAIDs. Patients who take NSAIDs may require other medications to prevent or treat gastrointestinal side effects. Options include histamine H2 receptor antagonists (e.g., ranitidine, famotidine, cimetidine), agents that coat the ulcer site (e.g., sucralfate), gastric acid secretion inhibitors (e.g., the synthetic prostaglandin E1 analog misoprostol), and proton pump inhibitors (e.g., omeprazole). The NSAIDs that are selective COX-2 inhibitors may have fewer gastrointestinal side effects but appear to be less potent anti-inflammatory agents, and seem to have more cardiovascular side effects. Systemic corticosteroids are usually required for patients who have moderately severe 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 may be required. The prednisone is then slowly tapered to a best-tolerated dose.

Some patients require daily prednisone for 6 months to a year or longer. Patients who require more than 5 or 10 mg of chronic daily prednisone should be considered for steroid-sparing agents such as methotrexate (see below). Adrenal suppression can be reduced with an everyother-day dosing regimen. 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 0.51 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 3 days and then reduced to once a week. Oral prednisone is usually required to supplement the pulses.[22] 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 non-necrotizing anterior scleritis.[23] Its use, as the study authors suggest, should probably be limited to adjunctive therapy in select cases of non-necrotizing localized disease, cognizant of the at least theoretical risk of scleral thinning and perforation. Immunosuppressive drugs can be vision saving and even life saving in patients with scleritis who are unresponsive to or intolerant of prednisone ( Fig. 4-11-15 ). The morbidity and mortality of patients with severe rheumatoid arthritis and Wegener's granulomatosis are reduced with the use of immunosuppressive agents.[24] Many patients with necrotizing scleritis require

immunosuppressive therapy to preserve vision. Immunosuppressives also may be required in patients who develop corticosteroid toxicity or who have been on prednisone for more than 36 months. Evidence exists that many immunosuppressives may have less long-term toxicity than high- or moderate-dose prednisone.[25]

Fig. 4-11-15 Necrotizing sclerokeratitis secondary to rheumatoid arthritis. (A) Sixtyyear-old man with necrotizing sclerokeratitis secondary to rheumatoid arthritis. (B) Same patient 6 months later while on cyclophosphamide. Note the scar in the cornea but the lack of scleral inflammation and corneal infiltration. The patient still required cyclophosphamide to keep inflammation in check 1 year after these photographs were taken.

Oral or subcutaneous methotrexate (7.525 mg weekly) has been reported to be of benefit in reducing or eliminating the need for prednisone.[26] Azathioprine at a dose of 1.52 mg/kg/day also may reduce or eliminate the need for corticosteroids.[3] However, both these agents can result in hepatic and hematological toxicity. These drugs may be used alone but are more often used in combination with corticosteroids. Mycophenolate mofetil is in the same family as azathioprine but may have lower toxicity and higher efficacy. Alkylating agents, such as chlorambucil and cyclophosphamide, also may be of benefit[27] and usually enable oral prednisone to be tapered or discontinued. In some cases, a 36-month course of chlorambucil, with reduction of the white blood cell count to 24003500, causes prolonged remission of ocular inflammatory disease.
[28] [29]

Alkylating agents do not cause hepatic problems but do have

hematological toxicity. 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) than does chlorambucil, which has a slower onset. Cyclophosphamide given once a week or once a month may be less toxic than daily oral cyclophosphamide, although it may be less effective. 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. Women must be advised that pregnancy must be avoided, as these agents may be teratogenic.

Ciclosporin, which acts, at least in part, by interfering with interleukin-2, has been used with some success in the treatment of scleritis.[30] 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 35 mg/kg/day as a maintenance dose. However, at these doses it may be impossible to discontinue the use of corticosteroids, so the main use has been as adjunctive therapy, permitting the use of lower doses of systemic corticosteroids. [30] [31] Systemic hypertension, renal failure, hirsutism, and gingival hyperplasia all may occur with ciclosporin. Because ciclosporin is not associated with the development of sterility, it may be an attractive agent to use in young patients. Again, the risk of developing late malignancy is much lower with ciclosporin than with other immunosuppressive agents. Tacrolimus (FK-506) has a different structure than ciclosporin but similar intracellular actions. There are no data on its efficacy in scleritis, but it has been shown to be useful in the treatment of a number of types of uveitis. Tumor necrosis factor inhibitors such as infliximab and adalimumab are used to treat systemic diseases associated with scleritis, such as rheumatoid arthritis and Crohn's disease, and seem to be beneficial in the treatment of scleritis as well. 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 melt, 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 than is donor sclera.[32] 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 23 months. Small incision clear corneal extraction is preferred. The physician should be alert for a recrudescence of scleral inflammation after surgery. Course and Outcome

Most patients who have 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 only a few 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 than does non-necrotizing disease. Patients who have necrotizing scleritis have a high incidence of visual loss[33] and a 21% 8-year mortality.[15] Immunosuppressive therapy appears to lessen these risks.