Fig. 5.25 Fifty-Þve-year-old patient with rheumatoid arthritis, associated necrotizing scleritis, and peripheral ulcerative keratitis: right eye

Fig. 5.26 Same patient as in Fig. 5.25: The left eye shows nodular scleritis

institution for further assessment. Slit-lamp examination revealed necrotizing scleritis with peripheral ulcerative keratitis supratemporally in the right eye and nodular scleritis temporally in the left eye (Figs. 5.25 and 5.26). Visual acuity was 20/50 in the right eye and 20/20 in the left eye. Past history included frequent respiratory infections, pleural effusions, and multiple surgical procedures for her joint disease, including hip replacement and neck fusion. Review of systems conÞrmed severe crippling arthritis and revealed mitral valve prolapse and rheumatoid nodules. Rheumatoid vasculitis associated with her rheumatoid arthritis was suspected. Investigations disclosed an RF of 10,240, a CIC of 550 (Raji assay; normal, 0Ð50), and an ANA of 1:16,384. Local measures for her peripheral ulcerative keratitis included keratectomy, cyanoacrylate

adhesive application, and soft contact lens Þtting; resection of the adjacent conjunctiva overlying the necrotic sclera also was performed, at which time necrotic scleral tissue was biopsied. Histopathological and immunoßuorescence studies revealed necrotizing granulomatous inßammation with scattered giant cells in both tissues, with associated inßammatory microangiopathy in the sclera. The patient was diagnosed as having rheumatoid vasculitis, and treatment with cyclophosphamide was instituted. Necrotizing scleritis and peripheral ulcerative keratitis resolved and were quiescent for 18 months, at which time cyclophosphamide was discontinued. Seven months later the patient returned with a recurrence of her necrotizing scleritis with supratemporal bulging uvea in the right eye. Visual acuity had not changed. Review of systems disclosed skin grafts for ulcerative skin lesions in her right leg and foot. A tectonic scleral graft was performed and conjunctival and scleral necrotic tissues were obtained for histopathology and immunoßuorescence. Biopsy results showed necrotizing granulomas with giant cells and inßammatory microangiopathy in both tissues. Therapy with cyclophosphamide was resumed and maintained. The scleral graft remained stable and no evidence of additional necrotizing scleritis was seen.

Clinicopathological Correlates in Infectious Scleritis

Although rare, episcleritis and scleritis may appear in systemic and local infectious diseases, either as a direct invasion by organisms that cause the systemic and local signs, or as a result of the immune response induced by the infectious agent. Improvement in detection of previously unrecognized disease entities and changes in epidemiological trends in the population appear to have played major roles in the decline or emergence of some of the systemic or local diseases that may cause scleritis. The most common systemic infection that may involve the sclera today is herpes zoster [123Ð125]; occasionally herpes simplex, tuberculosis [126], and syphilis [127, 128] may cause scleritis. The most common cause of local infectious scleritis is Pseudomonas aeruginosa

[129Ð133]. Other microorganisms, such as

Streptococcus, Staphylococcus, Proteus, atypical mycobacteria, Borrelia, Nocardia, Apergillus, Acanthamoeba, Toxoplasma, and Toxocara have also been implicated [129, 133Ð137]. In the following sections, we review the pathology of some of these infections.

Systemic Infections

1.Herpes zoster. Herpes zoster episcleral and scleral infections may be the result of a direct viral infection and an autoimmune process induced by the virus, either separately or in combination [125, 138]. Varicella-zoster virus (VZV) has been identiÞed by immunoßuorescence or electron microscopy and viral culture in some areas of the body, including the skin, central nervous system, sensory ganglia, and corneal epithelium [135Ð147]. However, in spite of some efforts to try to identify the virus intraocularly [125], herpes-like particles have been observed only on a few occasions and never in sclera [148, 149] (Witmer R, 1980, Personal communication). In one of these cases, subsequent culture proved that the her- pes-like particles were VZV [149] (Witmer R, 1980, Personal communication). VZV and herpes simplex virus (HSV) are indistinguishable by electron microscopy [147]. However, in contrast to HSV, VZV does not grow in ordinary tissue culture although it does grow in tissue culture containing human embryonic lung diploid cells [146], human fetal diploid kidney cells [147, 150], or human foreskin Þbroblasts [151]. Also, whereas HSV is a pathogen in some animals (rabbit), VZV is not pathogenic in any animal [152]. Furthermore, HSV and VZV differ in their antigenicity so that immunoßuorescence testing with HSVand VZV-speciÞc antibody probes may help in the identiÞcation [139]. Histopathological studies of scleral and conjunctival specimens from patients with VZV scleritis do not show differences from the specimens from patients with scleritis associated with systemic autoimmune diseases. They reveal a granulomatous inÞltration with multinucleated giant cells and epithelioid cells around the necrotic sclera

and/or conjunctiva. Neutrophils, lymphocytes, and plasma cells may be seen around the granuloma and around vessels. In some cases, a neutrophilic invasion of the vessel wall can be seen. In our series, one of the two patients with VZV scleritis underwent conjunctival and scleral biopsy. Both tissues showed multiple granulomas with giant cells surrounded by massive inÞltration with mononuclear cells and neutrophils; in addition, an inßammatory microangiopathy was also seen. Indirect immunoßuorescence techniques were used in an effort to identify the viral antigen in cells infected with VZV. The primary antibody used was mouse antihuman monoclonal antibody directed against VZV (wild strain) (1:30; Chemicon International, Temecula, CA); results were negative. Differences (as determined by light microscopy) between VZV scleritis and scleritis associated with systemic autoimmune diseases may exist, however, if other ocular tissues are available for histopathological study, because the combination of necrosis of iris, ciliary body, choroid, retina, and optic nerve, as well as marked inßammation of the posterior ciliary nerves [125] are not seen in scleritis associated with autoimmune diseases but may be seen in VZV scleritis.

2.Herpes simplex. Episcleritis and scleritis are rare entities ocurring either as a result of direct viral invasion during the course of a herpes simplex infection, or as a result of an autoimmune response to the virus, months after the initial viral encounter. Conjunctival and scleral specimens in HSV scleritis show granulomatous inßammation with multinucleated giant cells and epithelioid cells, perivasculitis, and inßammatory microangiopathy. HSV has a cytopathogenic effect in culture on several cell culture lines (HeLa cells, human amnion cells, and Þbroblasts). Herpes simplex virus type 1 (HSV type 1) can also be directly identiÞed by immunological methods in different tissues of the body, including conjunctiva and sclera (indirect immunoßuorescence or immunoperoxidase testing) [153Ð156]. Whereas histopathological features of HSV scleritis are varied and nonspeciÞc, immunoßuorescent

Fig. 5.27 Forty-nine-year-old man with scleritis and associated keratitis. Note the feathery central advancing edge of the keratitis (arrow)

Fig. 5.28 Same patient as in Fig. 5.27: different area and view. Note the intense scleritis

demonstration of HSV protein can make a deÞnitive diagnosis. Prolonged administration of acyclovir is required for effective therapy [156]. We use indirect immunoßuorescence techniques on ocular tissues, including conjunctiva and sclera, to identify viral antigen in cells infected with HSV. The primary antibody used is mouse monoclonal antibody directed against HSV type 1 (1:20; Chemicon International). One of our cases is described as follows:

A 49-year-old white male with a history of right maxilla osteosarcoma underwent facial bone surgical removal and replacement with right Þbular bone grafting. Several days postoperatively he developed right facial and right leg osteomyelitis which was treated with systemic antibiotics. Two months later, debridement of the previous right facial graft was performed and replaced with left Þbular bone grafting. A new focus of left Þbula osteomyelitis prompted his doctors to place a continuous intravenous central line antibiotic pump containing oxacillin and ceftazidime. During this treatment, the patient noticed discomfort and redness in his left eye. Keratitis was diagnosed and treatment with tobramycin drops and gentamicin ointment was instituted. Two weeks later, the eye had deteriorated and the patient was sent to our institution for further studies. At the time of his Þrst examination by us, visual acuity was 20/40 in the right eye and 20/80 in the left eye. Slit-lamp examination revealed blotchy white inÞltrates in corneal stroma, extending from 4 to 5 oÕclock, 4Ð5 mm

from periphery to the center, and without anterior chamber reaction (Fig. 5.27). Episcleral and scleral diffuse edema and redness were observed adjacent to the corneal stromal inÞltration (Fig. 5.28). Infectious keratoscleritis was diagnosed and possible etiological agents considered included fungus, virus (HSV type 1), spirochetes (T. pallidum), Acanthamoeba, and bacteria. Although unlikely, an autoimmune process was not discounted. A corneo-conjunctiva-scleral biopsy was performed and specimens were sent for fungal, bacterial, and Acanthamoeba cultures (tissue homogenates) as well as for histopathology and for immunoßuorescence (anti-immunoglobulin and anti-complement antibodies, and anti-HSV type 1 antibodies) studies. Conventional blood work included a ßuorescent treponemal antibody absorption test (FTA-ABS) which was negative. Gram stain, calcoßuor white stain, and appropriate cultures for fungus, bacteria, and Acanthamoeba were negative. Histopathology studies revealed a chronic nongranulomatous inßammation, and direct immunoßuorescent studies (anti-immunoglobulin and anticomplement antibodies) were negative for detection of vasculitis. Results of immunoßuorescent studies, using monoclonal antibodies directed against HSV type 1, were dramatic, revealing positive detection of the viral antigen in cornea, conjunctiva, and sclera, with the appropriate negative controls (Figs. 5.29 and 5.30). The patient was diagnosed with HSV type 1

Fig. 5.29 Immunoßuorescence microscopy: conjunctival biopsy from the same patient illustrated in Figs. 5.27 and 5.28. Antibody is anti-herpes simplex virus antibody. Note the striking positivity of the nuclei in the epithelial cells and in some of the keratocytes, indicating the presence of herpes simplex virus in the tissue

Fig. 5.30 Negative control for the anti-herpes antibody immunohistochemical staining, eliminating the Þrst (antiherpes) antibody in a two-step, indirect immunoßuorescence technique. This negative control is important: it makes it clear that the Þndings shown in Fig. 5.29 are indeed true positives

keratoscleritis and treatment with acyclovir and steroids was instituted. Four weeks later, the ocular infection had resolved and visual acuity had improved to 20/30.

3.Tuberculosis. Episcleritis and scleritis are rarely caused by Mycobacterium tuberculosis in developed countries today, but when it occurs, it is usually the consequence of a hematogenous miliary spread of pulmonary tuberculosis [157Ð160]. More uncommonly,

tuberculous scleritis may be the result of a local manifestation of a hypersensitivity reaction to circulating tuberculoproteins, or of an exogenous infection caused either by a

direct injury [161], or by a direct spread of a tuberculous lesion in adjacent ocular tissues [162Ð164]. Histologically, the classic pattern of tuberculous scleritis in conjunctival and scleral specimens is a granulomatous inßammation surrounding an area of caseation necrosis in which acid-fast bacilli can be demonstrated by ZiehlÐNeelsen staining or by ßuorescent staining with auramineÐrhodamine [160Ð168]. Perivascular inÞltration with chronic inßammatory cells may be seen. Because the histological changes in tuberculous scleritis are similar to the changes present in scleritis associated with systemic autoimmune diseases, identiÞcation of the microorganism in conjunctival or scleral tissue is important for ascribing the diagnosis of tuberculosis to scleral inßammation. In some cases, however, identiÞcation of the microorganism in ocular tissue cannot be accomplished, in which case the diagnosis of tuberculosis is presumed on the basis of histological ocular granulomatous reaction associated with chest X-ray-compatible Þndings and a positive sputum culture. The diagnosis may be presumed based on the basis of histological ocular granulomatous reaction in association with a strongly positive Mantoux test.

4.Syphilis. Within 3 weeks of the Þrst encounter with the spirochete T. pallidum, usually by sexual contact, primary syphilis occurs, characterized by a chancre of skin or mucous membrane with regional lymphadenopathy. This lesion resolves in 3 weeks. Hematogenous spread of T. pallidum underlies the pathogen-

esis of secondary syphilis, which occurs 2 months to 3 years after the inoculation. In an immunocompetent individual, the humoral and cellular immune responses can suppress the treponemes, resulting in a latent stage. Immune regulation breakdown may occur in about one third of the affected individuals, leading to tertiary syphilis, in which the treponemes can be detected in certain tissues. Treponeme dissemination through placental invasion followed by hypersensitivity reactions causes congenital syphilis. Episcleritis and scleritis may occur during the course of secondary, tertiary, or congenital syphilis.