necrotizing vasculitis affecting large arteries, which is manifested by proximal aortitis, aortic insufÞciency, and infarction of other organ systems [418Ð424]. Other abnormalities include myalgias, arthralgias, and arthritis. Whereas severe hearing loss occurs in 60% of patients without treatment, prednisone therapy preserves hearing in 80% of patients [425]. CoganÕs syndrome has been described in patients diagnosed with other systemic diseases, such as RA or PAN [422, 423, 426].

An atypical form of CoganÕs syndrome, accounting for about 30% of the cases, consists of vestibuloauditory dysfunction associated with ocular manifestations other than keratitis (scleritis, episcleritis, anterior uveitis, posterior uveitis, optic neuritis, and orbital pseudotumor) [426Ð 431]. Atypical forms of CoganÕs syndrome often overlap with other systemic diseases, such as GPA (Wegener), PAN, rheumatoid vasculitis, sarcoidosis, or VogtÐKoyanagiÐHarada syndrome. Patients with the atypical form of CoganÕs syndrome are more likely to develop a systemic necrotizing vasculitis (21%) [421].

Scleritis

The atypical form of CoganÕs syndrome may become manifest with vestibuloauditory dysfunction and scleritis [426Ð428, 431]. Keratitis may or may not be present. Vestibuloauditory symptoms may be present before or after the scleritis, but usually both events are not separated by more than a few months. Although nodular anterior scleritis is a frequent type of scleritis in CoganÕs disease, other varieties, such as diffuse anterior scleritis and necrotizing anterior scleritis, may occur [204, 428].

In our series of 500 patients with scleritis, one patient had CoganÕs syndrome (0.2%). The patient was a 69-year-old male who had recurrent diffuse anterior scleritis in his right eye 1 month before developing bilateral progressive hearing loss. There was no keratitis, anterior uveitis, glaucoma, or loss of vision. Review of systems revealed arthritis, and laboratory tests disclosed an elevated sedimentation rate and positive CICs detected by Raji cell assay. Tests for rheumatoid factor, ANAs, and ANCAs were negative.

Prednisone therapy seemed to halt both recurrent scleritis and hearing loss.

Episcleritis

Episcleritis with or without keratitis may also occur in association with vestibuloauditory symptoms as part of atypical CoganÕs syndrome [426, 429]. There were no patients with Cogan«s syndrome in our series of patients with episcleritis. However, in our prior series of 94 patients with episcleritis [123], one patient had CoganÕs syndrome (1.06%). The patient was a 39-year-old woman who developed recurrent simple episcleritis in her left eye one month after the onset of progressive sensorineural hearing loss. Systemic evaluation did not show evidence of aortic involvement or systemic vasculitis. Tests for ANAs, rheumatoid factor, ANCAs, and cryoglobulins were negative; ESR and CICs were elevated and complement levels were decreased. Prednisone controlled recurrences of episcleritis and progression of hearing loss.

6.1.13.2 Laboratory Findings

There are no speciÞc diagnostic tests for CoganÕs syndrome. ESR and CICs are typically elevated. Leukocytosis and, occasionally, eosinophilia may occur. No evidence of syphilis infection is found.

6.1.14Systemic Immune-Mediated Diseases Associated with Scleritis: Atopy

Atopy (a means Òwithout,Ó topos means ÒplaceÓ) is a term coined by Coca and Cooke [432] in 1923, which refers to Òstrange reactivityÓ or ÒhypersensitivityÓ to environmental antigens in patients with hereditary backgrounds of allergic disease. The major atopies are seasonal rhinitis (hay fever), perennial rhinitis, bronchial asthma, and atopic dermatitis (eczema). The minor atopies include food allergy, urticaria, and nonhereditary angioedema.

Although conjunctivitis or keratoconjunctivitis (allergic, giant papillary, vernal, and atopic) is the most characteristic ocular manifestation in atopy, scleritis, and particularly episcleritis, also may

occur. Exposure to airborne allergens, occasional (e.g., vapor of printing inks), seasonal (e.g., pollen), or perennial (e.g., house dust mite), may trigger recurrent attacks of episcleritis [114, 122, 204, 433]. Skin testing was investigated by McGavin et al. [114] in 23 patients (17 patients with episcleritis and six patients with scleritis). Of the eight patients with episcleritis and one patient with scleritis who had a positive reaction to some allergen, only three gave a clear history of either hay fever or asthma. In the Watson and Hayreh series [122], 12% of patients with episcleritis and 0.96% of patients with scleritis had a history of asthma or hay fever. Although several of our patients with episcleritis and scleritis had positive skin tests result to multiple allergens, only seven patients with episcleritis (7.44%) and one patient with scleritis (0.58%) had a clear history of major atopies with bronchial asthma (four patients), hay fever (four patients), eczema (two patients), and perennial rhinitis (two patients). In two patients, episcleritis was associated with a past history of perennial keratoconjunctivitis and giant papillary conjunctivitis. Episcleritis was recurrent, almost always bilateral, and simple or nodular. Scleritis was recurrent, bilateral, and diffuse. There were no corneal lesions, cataract, or glaucoma, and the visual acuity was not affected.

The incidence of atopy in patients with episcleritis or scleritis in these studies is not higher than that expected in patients without episcleritis or scleritis (10Ð20% of the general population) [434, 435], indicating that there is no signiÞcant relationship between atopy and episcleritis or scleritis.

6.1.15Other Systemic ImmuneMediated Diseases That Rarely May Be Associated with Scleritis and Episcleritis

Juvenile idiopathic arthritis (JIA) is diagnosed in patients under 16 years of age who have had arthritis for 3 months or more. JIA may be classiÞed into three groups, depending on the number of involved joints at the onset: systemic onset group, polyarticular onset group, and pauciarticular onset

group [436]. Patients with polyarticular onset of JIA follow a clinical course similar to that of adults with RA. Ocular involvement in JIA occurs most commonly in the pauciarticular onset group of JIA; it is characterized by anterior uveitis, which may lead to band keratopathy, cataracts, or secondary glaucoma [437]. However, ocular involvement also may occur in the polyarticular onset group of JIA [438]; it is characterized by scleritis, usually of the diffuse or nodular variety, and episcleritis [121, 204]. JIA patients with episcleritis or scleritis are usually girls who are seropositive for rheumatoid factor. Patients with the systemic onset of JIA (StillÕs disease) do not develop ocular manifestations. Patients with the pauciarticular onset of JIA do not develop scleritis or episcleritis [242]. In our series of 500 patients with scleritis, one patient had JIA (0.2%). The patient was a 17-year-old female with polyarticular JIA for 10 years. She had had previous episodes of anterior uveitis. She developed unilateral diffuse scleritis with anterior uveitis without other complications, including keratitis, glaucoma, or loss of vision.

Occasionally, scleritis has been associated with dermatomyositis [439], SjšgrenÕs syndrome [439], TakayasusÕ arteritis [121], and thyroid diseases, including HashimotoÕs thyroiditis or thyrotoxicosis [204]. Simple episcleritis may, although rarely, accompany the onset of SchšnleinÐHenoch purpura, a small-sized vessel vasculitis, which commonly affects young children, especially boys [204].

Ocular manifestations of sarcoidosis include conjunctival granulomas, inÞltration of the lacrimal gland, KCS, anterior, intermediate, or posterior uveitis, retinal vasculitis, and optic nerve involvement. Scleral and episcleral nodules occur rarely; these may recur when the systemic condition exacerbates [123, 132, 440Ð444]. Anterior staphyloma has occasionally been found to be the Þrst ocular manifestation of sarcoidosis [445].

Because VogtÐKoyanagiÐHarada syndrome is caused by an autoimmune attack directed against organs containing melanocytes, ocular involvement is usually characterized by bilateral progressive panuveitis affecting the choroid, ciliary body, and iris. The sclera may contain some melanocytes, especially at the site of emergence of

long ciliary nerves anterior to the insertion of the recti muscles. Although uncommon, focal necrotizing scleritis in VogtÐKoyanagiÐHarada syndrome may occur and may lead to uveal show and anterior staphyloma [446]. Scleritis also may be caused by an extension of an orbital granulomatous process or a uveal granulomatous process, such as sympathetic ophthalmia [439].

Tubulointerstitial nephritis and uveitis (TINU) is an uncommon syndrome involving the kidney and the eye. It occurs mainly in children and young adults, and females are affected more often than males. Patients usually present with systemic symptoms, including fatigue, malaise, anorexia, abdominal pain, fever, and anemia. The neprhitis usually precedes the uveitis, although simultaneous onset in both organs has been described. The nephropathy typically resolves spontaneously or responds favorably to systemic steroid therapy, but the uveitis may become chronic and treatment resistant. Laboratory Þndings of high ESR, normochromic normocytic anemia, elevated serum creatinine and BUN levels, and abnormal urinalysis Þndings (glycosuria, proteinuria, aminoaciduria, microhematuria, b2 microglobulinuria) support the diagnosis, although deÞnitive diagnosis is established by kidney biopsy [447].

Although uncommonly, scleritis may occur with TINU syndrome [448]. In our series of 500 patients with scleritis, two patients had TINU (0.4%). They were two females, with a mean age of 30 years. One patient had diffuse anterior and posterior scleritis with anterior uveitis, posterior uveitis, and optic neuritis. The other patient had diffuse anterior scleritis with anterior uveitis. Any patient who develops scleritis with elevated serum creatinine and BUN levels should be examined for TINU syndrome.

6.1.16Systemic Immune-Mediated Disease-Associated Scleritis After Ocular Surgery

Scleritis, particularly necrotizing anterior scleritis, may appear following surgical trauma of the sclera in patients with autoimmune vasculitic

diseases, such as RA, GPA (Wegener), or IBD [449, 450]. Surgical trauma may favor CICs becoming entrapped in episcleral vessels and perforating scleral vessels. Inßammatory microangiopathy may lead to scleral destruction [451, 452]. Subcutaneous nodules in RA usually appear in areas subjected to mechanical trauma, such as the olecranon, the buttock, or the Þngertip pads. Pathological studies show vasculitis and Þbroblast proliferation; vessel thrombosis and collagenase production result in tissue destruction [453Ð455]. Cutaneous vascular lesions, such as purpura, pustules, vesicles, and ulcers, most often appear in areas of repeated low-grade trauma. Pathological studies show cutaneous necrotizing venulitis [456, 457].

In our prior series of scleritis [123], 10 of 11 patients (90.9%) who developed necrotizing scleritis up to 6 months after ocular surgery (interval range, 2Ð4 weeks) had an underlying systemic autoimmune vasculitic disease; these diseases included RA, GPA (Wegener), and IBD. Appropriate studies led to the discovery and subsequent treatment of the systemic diseases in Þve patients; the other Þve had been previously diagnosed. These results emphasize the need for meticulous diagnostic pursuit of systemic autoimmune vasculitic diseases in patients with necrotizing scleritis following intraocular surgery.

Sclerokeratitis may appear following keratoplasty in patients with severe atopy. Lyons et al. [458] reported a series of Þve severe atopic patients in whom sclerokeratitis developed 1Ð4 weeks after keratoplasty. Serum IgE levels were elevated in all these patients. The scleritis was of the diffuse type and the keratitis was characterized by host stromal inßammation, which, through loosening of the graft sutures, caused protrusion of the graft or incompetence of the graftÐ host interface. The authors proposed that IgE binding on the surface of mast cells in the conjunctiva with subsequent degranulation could be involved in the pathogenesis of the sclerokeratitis. These results emphasize that severe atopic patients undergoing keratoplasty require prophylactic measures for stabilization of the atopic ocular disease (seasonal timing of the operation, cromolyn sodium, and, if necessary, topical steroids), use of

interrupted sutures, and frequent postoperative follow-up for detection of sclerokeratitis. Highdose oral steroids at the onset of the condition may adequately suppress the ocular inßammation.

Suture-related episcleritis may occur after transscleral Þxation of a posterior chamber intraocular lens in a patient with the absence of capsular and zonular support [459].

6.2Dermatological DiseaseAssociated Scleritis

6.2.1Rosacea

Acne rosacea is a chronic disease characterized by skin manifestations, which include persistent erythema, telangiectasias, papules, and pustules in the ßush areas of the face and neck. The classic rhinophyma, caused by sebaceous gland hypertrophy, also is a typical feature of the advanced stage of the disease. Ocular rosacea occurs in 3Ð58% of the cases with acne rosacea, depending on the series, and consists primarily of meibomian gland (modiÞed sebaceous gland) dysfunction associated with the cutaneous disease [460]. Abnormalities in meibomian gland secretions (alteration in melting points of waxes and cholesterol esters, excessive free fatty acids, or biochemical abnormalities) [461] may secondarily inßame the external surface of the eye, causing conjunctivitis, keratitis, and less frequently episcleritis and scleritis [460, 462Ð464]. A type IV hypersensitivity reaction may play a signiÞcant role in the pathogenesis of the disease [464]. Burning, tearing, eyelid swelling, irritation, photophobia, blurred vision, dryness, and mild itching are the usual symptoms.

The reported incidence of rosacea in patients with episcleritis is 1.88% [122]. In our series of 85 patients with episcleritis, four patients had rosacea (0.8%). Rosacea episcleritis may be simple or nodular, and is usually bilateral. The reported incidence of rosacea in patients with scleritis ranges from 0.34 to 0.96% [122Ð124]. In our series of 500 patients with scleritis, Þve patients had rosacea (1%). Rosacea scleritis is usually diffuse or nodular, but scleral perforation

occasionally may occur [132, 463]. Rosacea episcleritis and scleritis are accompanied by meibomianitis (solidiÞed plugs, dilated glands, pouting oriÞces, distorted oriÞces, hordeolum, and chalazion), blepharitis (crusting, decreased cilia, margin thickening or irregularity, and scaling), telangiectasia of lid margins, conjunctivitis (bulbar injection, tarsal papillary hypertrophy, and symblepharon), or keratitis (superÞcial punctate keratopathy, corneal vascularization, PUK, and corneal perforation). Mechanical and hygienic maneuvers with or without doxycycline is the treatment of choice for rosacea episcleritis and scleritis.

The diagnosis of ocular rosacea is made on the basis of skin clinical Þndings, although in 20% of cases the ocular manifestations appear Þrst. Meibomian gland dysfunction is a nonspeciÞc ocular Þnding but, when is seen in combination with characteristic skin manifestations, it allows a Þrm diagnosis of ocular rosacea. Any patient who develops episcleritis or scleritis and meibomian gland dysfunction should be examined for skin manifestations.

6.3Metabolic Disease-Associated Scleritis

6.3.1Gout

Gout is a defect of purine metabolism that is manifest by (1) an increase in the serum urate concentration, (2) recurrent attacks of acute arthritis with deposits of monosodium urate monohydrate (tophi) in and around the joints of the extremities (often the big toe), (3) renal disease, and (4) uric acid urolithiasis.

Deposits of monosodium urate monohydrate may also precipitate in the eye, leading to conjunctivitis, episcleritis, or (less commonly) scleritis [114, 122, 465]. They also may precipitate in the corneal epithelium or BowmanÕs membrane, and in the iris. The reported incidence of highserum uric acid values in patients with episcleritis is 11%, and that of clinical gout is 7% [122]. The onset of episcleritis in gout is sudden and may be triggered by cold, heat, or indiscretions of