stain, acid-fast stain, and Gomori methenamine silver stain were negative. Proteus mirabilis was identiÞed from cultures of the scleral tissue after biopsy and homogenization. This Proteus scleritis responded well to early and aggressive therapy with topical and intravenous vancomycin and gentamicin. Visual acuity improved to 20/30 and there were no recurrences of infection.

Our second patient was a 60-year-old woman with quiescent ulcerative colitis who developed necrotizing scleritis in her left eye after recurrent and persistent S. aureus infections following a scleral buckling procedure for retinal detachment. Prolonged treatment with aggressive topical bacitracin and oral erythromycin decreased suppuration but did not halt the progression of the scleral necrosis. Visual acuity at that time was hand motions. Excisional scleral biopsy with scleral homografting was performed (Fig. 7.1). Cultures from scleral tissue were negative but histopathological study showed a granulomatous inßammatory reaction, inßammatory microangiopathy, perivascular eosinophils, and a large mast cell population. Immunosuppressive therapy and antibiotic coverage were instituted. The scleral graft remained stable without further scleral melting, although the patient did not regain vision because of retinal problems. Whether necrotizing scleritis was the result of an immune-mediated response induced by S. aureus products, by the potentially vasculitic disease ulcerative colitis after surgical trauma, or by both, is unknown.

In our current series of 500 patients with scleritis, Þve patients had gram-positive coccus or gram-negative rod scleritis (1%). There were three patients with P. aeruginosa scleritis, one patient with S. pneumoniae scleritis, and one patient with Morganella morganii scleritis. One of the patients with P. aeruginosa scleritis was a 48-year-old white female with diabetes mellitus, dyslipidemia, hypertension, and ischemic cardiopathy, who developed a large central corneal ulcer with a scleral abscess with necrosis at the superior nasal sclera, and a 2-mm central descematocele with hypopyon 2 weeks after trauma in her left eye. GramÕs stain showed gramnegative rods and subsequent cultures were positive to P. aeruginosa. FortiÞed ceftazidime

Fig. 7.1 Intraoperative photograph of excisional biopsy of sclera. Lamellar dissection has been carried out down to healthy-appearing sclera, and the entire geographic extent of the area affected by the infection is excised

drops hourly, subconjunctival tobramycin, and intravenous ceftazidime was started and debridement of the scleral abcess was performed. Keratitis and necrotizing scleritis resolved during the next 2 months. She developed cataract and corneal scar with vision of 20/400. Six months later she underwent penetrating keratoplasty and cataract removal and at last follow-up the graft was clear with best-corrected vision of 20/50.

The patient with S. pneumoniae scleritis was a 42-year-old white male without prior systemic or ocular disease who developed a suppurative necrotizing scleritis and keratitis in his right eye 3 weeks after pterygium excision with intraoperative and topical postoperative (3 days) mitomycin. Smears and cultures from cornea and conjunctiva were positives. The patient responded well to early and aggressive therapy with fortiÞed vancomycin drops hourly, subconjuntival vancomycin, and oral levoßoxacin for 10 days. At the last follow-up visit, he had a stable area of scleral thinning without inßammation and his visual acuity was 20/60.

7.1.2Mycobacterial Scleritis

Although ocular lesions, including scleritis and episcleritis, are now rarely caused by

Mycobacterium tuberculosis, the number of ocular infections caused by atypical mycobacteria, such as Mycobacterium chelonae,

Mycobacterium marinum, Mycobacterium fortuitum, or Mycobacterium gordonae, has increased over the past decade [1, 22Ð29]. Keratitis and scleritis are the most common ocular manifestations caused by atypical mycobacteria.

7.1.2.1 Atypical Mycobacterial Disease

Atypical mycobacterial scleritis has been reported following extension of severe infectious keratitis into the sclera, resulting in keratoscleritis [1, 29], or following procedures done on an outpatient basis, such as removal of an extruded scleral buckle [28]. Certain concentrations of standard disinfectants used in minor ofÞce procedures have been shown to permit Mycobacterium growth; some of these are 2% aqueous formaldehyde, 2% alkaline glutaraldehyde, and 0.3Ð0.7 mg of free chlorine/ml [30]. Atypical mycobacterial scleritis with or without keratitis is characterized by nodular or necrotizing slowly progressive lesions over several months, often accompanied by mild mucopurulent discharge. The most common Mycobacterium causing scleritis is M. chelonae [1, 25, 27, 28], a rapidgrowing Mycobacterium (Runyon group IV), which may be associated with minor ofÞce ophthalmic procedures [25], or abscesses following intramuscular injections. Scleritis also may be caused by M. marinum [29], a slow-growing Mycobacterium

(Runyon group I), that is often linked with skin diseases, such as swimming pool, aquarium, or Þsh tank-granuloma; [31, 32] M. marinum keratoscleritis has also been associated with systemic

Mycobacterium leprae infections [33].

Standard smears and cultures are not helpful in the isolation of mycobacteria from corneal and scleral biopsy specimens; however, Ziehl-Neelsen stain demonstrates the presence of acid-fast bacilli, and culture on LšwensteinÐJensen culture medium at 30¡C (poor growth at 37¡C) yields the organisms [34, 35]. Because cultures on LšwensteinÐJensen culture medium may take several weeks to become positive, the Þnding of characteristic acid-fast bacilli in the biopsy is sufÞcient for making the diagnosis of mycobacterial infection. Thus, treatment with amikacin may be undertaken weeks before deÞnitive mycobacterial identiÞcation by culture is achieved (Table 7.2). Although intradermal skin tests may

be positive for a speciÞc atypical Mycobacterium and negative for others, a tuberculin protein-puri- Þed derivative (PPD) skin test often turns positive. Tissue debridement associated with topical and systemic medical therapy may be effective in curing mycobacterial scleritis and keratitis. Pharmacological possibilities after deÞnitive mycobacterial identiÞcation include rifampin, ethambutol, isoniazid, streptomycin, kanamycin, minocycline, cefoxitin, or sulfamethoxazol singly or in combination; the choice depends on in vitro sensitivity laboratory studies.

Differential diagnosis of infectious scleritis with or without keratitis must include atypical mycobacteria, particularly if the scleritis appears following either minor ofÞce ophthalmic procedures, or ocular injuries associated with soil or contaminated water (swimming pool, aquarium, other water containers). Laboratory studies of scleral or corneal biopsy specimens from patients with infectious scleritis must include acid-fast stain and cultures at 30¡C for exclusion of atypical mycobacterial disease.

7.1.2.2 Tuberculosis

Although the incidence of pulmonary and extrapulmonary tuberculosis has decreased in the USA since the last century, infection by M. tuberculosis still remains a major medical problem in certain immigrant and underprivileged groups. The apices of the lungs are involved commonly in pulmonary tuberculosis, but the lower lobes or any other site may be affected. Most cases are believed to be a reactivation of M. tuberculosis that was acquired months to years earlier rather than reinfection or initial infection by this Mycobacterium. Pulmonary tuberculosis may spread to distant organs, such as the eye by lymphatics or via the bloodstream, causing scleritis and episcleritis. Only about 40% of patients with extrapulmonary tuberculosis have clinical or radiographic evidence of lung disease.

The incidence of ocular involvement in a tuberculosis sanatorium ranged from 0.5 to 1.4% from 1940 to 1966 (14 cases with scleral tuberculosis) [36] and the incidence of tuberculosis in patients with scleritis was 1.92% in 1976 [37]. Occasional cases have been reported more recently [17, 38].

Tuberculous scleritis may be the result either of a direct M. tuberculosis scleral invasion or of an immune-mediated reaction to circulating tuberculoproteins. Early diagnosis may minimize ocular and systemic complications.

Direct M. tuberculosis scleral invasion is usually due to hematogenous miliary spread of pulmonary tuberculosis; [36, 39Ð42] occasionally, scleritis may occur from local infection caused by direct injury [43] or by extension of lesions in adjacent tissues, such as cornea, conjunctiva, or iris [44, 45]. Direct M. tuberculosis scleral invasion may appear as nodular scleritis that, untreated, may progress to necrotizing scleritis [42, 43, 46, 47]. Tuberculous posterior scleritis has also been described [48]. The marginal cornea may be secondarily involved with inÞltrates and neovascularization, and there may be mucopurulent discharge. Occasionally, M. tuberculosis may involve episclera, causing simple or nodular episcleritis [37, 49]. Tuberculosis may be diagnosed from sputum, urine, ocular tissue, or other body ßuids by demonstrating acid-fast bacilli on Ziehl-Neelsen stain and by identiÞcation of M. tuberculosis on LšwensteinÐJensen culture media at a temperature optimum of 37¡C. Intradermal skin testing (PPD) and chest X-rays may aid in the diagnosis. Diagnosis of tuberculous scleritis requires scleral biopsy; scleral specimens show caseating granulomas with multinucleated giant cells and characteristic acidfast bacilli. Because cultures may become positive after several weeks, detection of acid-fast bacilli in scleral tissue and in sputum enables the presumptive diagnosis of systemic tuberculosis, allowing institution of adequate therapy with ethambutol (400 mg orally twice a day), isoniazid (300 mg orally once a day), rifampin (600 mg orally once a day), and pyridoxine (50 mg orally once a day) for 6Ð12 months [18]. Detection of acid-fast bacilli in scleral tissue but not in sputum or other body ßuid is regarded as characteristic of localized mycobacterial disease, allowing institution of amikacin before deÞnitive mycobacterial identiÞcation by culture (Table 7.2). If M. tuberculosis is identiÞed, therapy should include concomitant use of two or more systemic drugs (isoniazid, rifampin, ethambutol, streptomycin,

pyridoxine), depending on antibiotic sensitivities. Streptomycin may be applied topically and subconjunctivally [42]. Systemic or topical steroids may worsen the active infection [38]. Recently, interferon-gamma release assays (IGRAS) have become commercially available. There are two in vitro assays that measure T cell release of interferon gamma (IFN-g) in response to stimulation with the highly tuberculosis-speciÞc antigens ESAT-6 and CFP-10. QuantiFERON-TB Gold¨ (Cellestis Ltd., Carnegie, Australia) is a whole-blood ELISA for the measurement of IFN-g, and T-SPOT.TB¨ (Oxford Immunotec, Oxford, UK) is an enzyme-linked immunospot (ELISpot) assay. IGRAs are more speciÞc than the intracutaneous tuberculin-puriÞed protein derivative (PPD) as a result of less cross-reactiv- ity due to BCG vaccination and sensitization by nontuberculous mycobacteria. IGRAs also appear to be at least as sensitive as the PPD for active tuberculosis (used as a surrogate for latent M. tuberculosis infection). Although diagnostic sensitivity for latent infection cannot be directly estimated because of the absence of a gold standard, these tests have shown better correlation than the PPD with exposure to M. tuberculosis in contact investigations in low-incidence settings. Other potential advantages of IGRAs include logistical convenience, the need for fewer patient visits to complete testing, the avoidance of unreliable and somewhat subjective measurements, such as skin induration, and the ability to perform serial testing without inducing the boosting phenomenon (a spurious PPD conversion due to boosting of reactivity on subsequent PPDs among BCGvaccinated persons and those infected with other mycobacteria). Because of the high speciÞcity and other potential advantages, IGRAs are likely to replace the PPD for latent infection diagnosis in low-incidence, high-income settings where cross-reactivity due to BCG might adversely impact the interpretation and utility of the PPD. Direct comparative studies in routine practice thus far suggest that the ELISpot has a lower rate of indeterminate results and probably a higher degree of diagnostic sensitivity than the wholeblood ELISA. Further studies are under way to assess the performance of these tests in contact

investigations and in persons with suspected tuberculosis disease, health care workers, HIVinfected individuals, persons with iatrogenic immunosuppression, and children.

Immune-mediated tuberculous scleritis, usually with interstitial or phlyctenular keratitis or phlyctenular keratoconjunctivitis, is considered to be a host immune response to cell wall components of M. tuberculosis proteins. Occasionally, episcleritis may occur [37]. The pathogenesis appears to be related to a cell-mediated type IV hypersensitivity reaction to these antigens. Although there is no mycobacterial invasion of sclera, immune-mediated tuberculous scleritis often occurs in conjunction with active systemic disease. Histologically, scleral specimens show a granulomatous reaction without acid-fast bacilli. Interstitial keratitis associated with scleritis tends to be peripheral and sectorial. Unlike luetic interstitial keratitis, in which the deep stroma is involved, tuberculosis interstitial keratitis affects the superÞcial and midstromal layers. There are often nodular inÞltrates with superÞcial stromal vascularization. The clinical course is prolonged, with residual corneal scarring. Phlyctenular keratoconjunctivitis develops as a small vesicle in peripheral cornea, bulbar conjunctiva, or tarsal conjunctiva. The vesicle progresses to a nodule, which degenerates and heals. Resolution of corneal phlyctenules involves scarring and neovascularization; resolution of conjunctival phlyctenules does not involve scarring. Corneal phlyctenules may spread centrally, leaving a characteristic leash of vessels from the central lesions to the healed peripheral areas marking its path. The diagnosis of tuberculosis as the cause of immune-mediated scleritis with or without keratitis is in most cases difÞcult or impossible to conÞrm. It depends on the associated ocular Þndings and evidence of previous or present systemic tuberculosis demonstrated by a positive PPD test, chest X-ray compatible Þndings, and positive sputum culture. Treatment must include topical corticosteroids with meticulous tapering and systemic tuberculostatic drugs if there is evidence of active disease [50, 51].

In our prior series of 172 patients with scleritis [13], one patient had scleritis associated with systemic tuberculosis (0.57%). The patient was a

55-year-old black Haitian female with a 4-year history of intermittent redness without pain and gradual decrease in vision in her right eye. Past family history disclosed a member with tuberculosis and review of systems revealed constitutional symptoms and productive cough. At the moment of her Þrst visit with us, the visual acuity was hand motions in the right eye and 20/50 in the left eye. Slit-lamp examination showed diffuse scleritis associated with adjacent interstitial keratitis in the right eye. A PPD intradermal skin test was reactive and the chest X-ray showed extensive left lower and middle lobe inÞltrates. Her sputum contained acid-fast bacilli and M. tuberculosis grew when cultured. Systemic tuberculosis was diagnosed and systemic tuberculostatic agents were instituted. Sclerokeratitis was believed to be due to tuberculosis, probably secondary to an immune-mediated reaction, and topical steroids were begun. Ocular inßammation subsided 2 months after the initiation of systemic and topical treatment. Visual acuity was at the level of counting Þngers at 4 ft, due to corneal scarring. Tapering and discontinuation of topical steroids was followed by a recurrence of the sclerokeratitis; reinstitution of topical steroids with a slow taper halted the process without further recurrences.

In our current series of 500 patients with scleritis, Þve patients had scleritis associated with tuberculosis (1%). They were three males and two females with a mean age of 53 years (range 35Ð72 years). Three patients had recurrent nodular scleritis, one patient had recurrent diffuse scleritis, and one patient had recurrent necrotizing scleritis. Past family history of a member with tuberculosis was found in two patients and review of systems revealed constitutional symptoms and productive cough in all patients. PPD intradermal skin test and QuantiFERON-TB Gold¨ were positive in all patients. T-SPOT.TB¨ was also positive in the three tested patients. Chest X-ray revealed compatible Þndings in all patients and positive sputum smears and cultures contained acid-fast bacilli and M. tuberculosis in three patients. Systemic tuberculostatics agents were instituted associated with topical steroids. Scleral inßammation subsided without further recurrences.