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Documenta Ophthalmologica 83: 33-41, 1993. © 1993 Kluwer Academic Publishers. Printed in the Netherlands. Infectious scleritis: Report of four cases MAITE SAINZ DE LA MAZA, RAMZY K. HEMADY & C. STEPHEN FOSTER Ocular bnmunology Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA Accepted 30 December 1992 Key words: Antimicrobial therapy, Corneoscleritis, Infection, Scleral biopsy, Scleritis Abstract. While systemic autoimmune diseases are the main possibilities in the differential diagnosis of scleritis, other less common etiologies such as infections must also be considered. The authors report four cases of infectious scleritis to review predisposing factors, clinical characteristics, methods of diagnostic approach, and response to therapy. Two patients had primary scleritis and two patients had secondary scleritis following extension of primary corneal infection (corneoscleritis). Diagnoses included three local infections (one each with Staphylo- coccus. Acanthamoeba, and herpes simplex) and one systemic infection (Lyrne disease). Stains, cultures, or immunologic studies from scleral, conjunctival, and/or corneal tissues, and serologic tests were used to make the diagnosis. Medical therapy, including antimicrobial agents, was instituted in all patients, and surgical procedures were additionally required in two patients (scleral grafting in one and two penetrating keratoplasties in another); the patient who required two penetrating keratoplasties had corneoscleritis and underwent eventual enuclea- tion. Infectious agents should be considered in the differential diagnosis of scleritis. Introduction Although scleritis is commonly associated with systemic autoimmune dis- eases [1-4], it is rarely described as a result of an infectious process. Multiple microorganisms, including bacteria, fungi, viruses, and parasites, are capable of establishing a focus of infection in the sclera following the spread of a local or systemic process if normal host barriers or defense mechanisms are compromised [5-35]; these microorganisms may involve the sclera either through direct invasion or through induction of an immune- mediated response [20]. Infectious scleritis may be primary, in which case it usually follows accidental or surgical injuries, or a severe endophthalmitis [5, 6, 20-30]. Accidental injuries include trauma, especially with vegetable matter or soil, and surgical injuries include pterygium excision followed by/3 ir;adiation or topical thiotepa, retinal detachment repair with buckling procedures and/or diathermy, or strabismus surgery. Infectious scleritis also may be secondary, in which case it follows the extension of primary corneal infections

Infectious scleritis: Report of four cases

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Page 1: Infectious scleritis: Report of four cases

Documenta Ophthalmologica 83: 33-41, 1993. © 1993 Kluwer Academic Publishers. Printed in the Netherlands.

Infectious scleritis: Report of four cases

M A I T E S A I N Z D E L A M A Z A , R A M Z Y K. H E M A D Y & C. S T E P H E N F O S T E R Ocular bnmunology Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA

Accepted 30 December 1992

Key words: Antimicrobial therapy, Corneoscleritis, Infection, Scleral biopsy, Scleritis

Abstract. While systemic autoimmune diseases are the main possibilities in the differential diagnosis of scleritis, other less common etiologies such as infections must also be considered. The authors report four cases of infectious scleritis to review predisposing factors, clinical characteristics, methods of diagnostic approach, and response to therapy. Two patients had primary scleritis and two patients had secondary scleritis following extension of primary corneal infection (corneoscleritis). Diagnoses included three local infections (one each with Staphylo- coccus. Acanthamoeba, and herpes simplex) and one systemic infection (Lyrne disease). Stains, cultures, or immunologic studies from scleral, conjunctival, and/or corneal tissues, and serologic tests were used to make the diagnosis. Medical therapy, including antimicrobial agents, was instituted in all patients, and surgical procedures were additionally required in two patients (scleral grafting in one and two penetrating keratoplasties in another); the patient who required two penetrating keratoplasties had corneoscleritis and underwent eventual enuclea- tion. Infectious agents should be considered in the differential diagnosis of scleritis.

Introduct ion

Al though scleritis is c o m m o n l y associated with systemic a u t o i m m u n e dis- eases [1-4] , it is rarely described as a result of an infectious process. Multiple microorganisms, including bacteria, fungi, viruses, and parasites, are capable of establishing a focus of infection in the sclera fol lowing the spread of a local or systemic process if normal host barriers or defense mechanisms are compromised [5-35]; these microorganisms may involve the sclera ei ther th rough direct invasion or th rough induct ion of an immune- media ted response [20].

Infect ious scleritis may be pr imary, in which case it usually follows accidental or surgical injuries, or a severe endophthalmi t i s [5, 6, 20-30] . Accidenta l injuries include t rauma, especially with vegetable mat te r or soil, and surgical injuries include p terygium excision fol lowed b y / 3 i r ;adiat ion or topical thiotepa, retinal de t achmen t repair with buckling p rocedures a n d / o r d ia thermy, or strabismus surgery. Infect ious scleritis also ma y be secondary , in which case it follows the extension of pr imary corneal infections

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(corneoscleritis) [5, 31-35]. Risk factors in corneoscleritis usually include contact lens wear, recent ocular surgery or suture removal, use of topical medications (corticosteroids, beta-blockers), neovascular or phacomorphic glaucomas, adnexal disease, corneal tissue devitalization (recurrent attacks of herpes simplex or zoster keratitis, corneal exposure), and debilitating systemic diseases (AIDS, diabetes). Untreated, primary or secondary infectious scleritis may result in loss of the eye through extension of the infection to adjacent structures and eventual phthisis or perforation.

Since infectious scleritis may be clinically identical to that caused by systemic autoimmune diseases, a specific diagnostic approach is important to differentiate both groups of scleritis; infectious etiologies are usually treatable with specific therapy whereas steroid therapy or immunosuppres- sire therapy, often used in scleritis associated with immune-mediated diseases, are contraindicated in active infection.

We report our experience in the management of four patients with infectious scleritis emphasizing the historical, clinical, laboratory, and biopsy features which led to a specific diagnosis, the medical and surgical therapies, and the outcomes.

Case reports

Case information, including patient demography, predisposing factors, diagnoses, associated systemic disease, corneal involvement, need of surgi- cal therapy, and outcomes, is summarized in Table 1.

Patient 1. A 60 year old woman with quiescent ulcerative colitis developed necrotizing scleritis in her left eye after recurrent and persistent Staphylo- coccus' 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. Cultures from

T a b l e 1. Infectious scleritis characteristics

Patient Contributory past Hx Diagnosis Local- Cornea Surgery Outcome Sex or systemic Age (Yr) review of systems

1/F/60 Scleral Buckling x RD Staphylococcus Local No Yes Stable Ulcerative Colitis aureus

2/M/49 Presumed past HSK Acanthamoeba Local Yes Yes Enucleation 3/M/49 Maxilla osteosarcoma Herpes simplex Local Yes No Stable

type 1 4/F/57 Migratory Borrelia Systemic No No Stable

osteoarthritis burgdorferi

RD: retinal detachment; HSK: herpes simplex type I keratitis.

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scleral tissue were negative but histopathologic study showed a granulomat- ous inflammatory reaction, inflammatory microangiopathy, perivascular eosinophils, and a large mast cell population. Immunosuppressive therapy and antibiotic coverage was instituted. The scleral graft remained stable without further scleral melting although the patient did not regain vision because of retinal problems.

Patient 2. A 51 year old male with a presumed past history of herpes simplex keratitis, developed a persistent corneal epithelial defect, a suppurative stromal keratitis, and a nodular scleritis in his right eye which rapidly progressed to necrotizing scleritis. Review of systems was unrevealing. Corneal scrapings were taken for Gram's stain and standard cultures which were negative. Conjunctival and episcleral biopsy showed nongranulomat- ous inflammation; Gram's stain was negative. Progressive corneal thinning necessitated penetrating keratoplasty. Corneal button histopathologic ex- amination disclosed numerous basophilic cysts with darkly staining capsules, clear periphery, and darkly staining centers compatible with Acantharnoeba cysts as well as stromal necrosis. Culture on nonnutrient agar with E, coli identified Acantharnoeba polyphaga. Therapy with intensive topical 1% propamidine isethionate (Brolene), neomycin, and miconazol, and oral ketoconazol was instituted. The postoperative course was complicated by glaucoma. Two weeks after surgery the patient developed progressive graft tissue necrosis with wound leak and further scleral thinning. Penetrating keratoplasty was repeated and therapy for Acantharnoeba corneoscleritis was continued; two months later the eye became phthisical and was enucleated.

Patient 3. A 49-year-old white male with a history of right maxilla osteosarcoma required facial bone surgical removal and replacement with right fibular bone grafting. Several days post-operatively 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 fibular bone grafting. A new focus of left fibula osteomyelitis prompted his doctors to place a continuous intravenous central line antibiotic pump containing oxacillin and ceftazidime. While with this treatment, the patient noticed discomfort and redness in his left eye. Keratitis was diagnosed and treatment with tobramycin drops and gen- tamicin 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 first 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 infiltrates in corneal stroma extending from 4 to 5 o'clock, 4 to 5 mm from periphery to the center, and without anterior chamber reaction. Episcleral and scleral diffuse edema and redness were observed adjacent to the corneal stromal infiltration. Infectious corneoscleritis was diagnosed and possible

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etiologic agents considered included fungus, herpes virus type 1, spirochetes (Treponema pallidum), Acanthamoeba, and bacteria. Although unlikely, an autoimmune process was not discounted. A scleral-conjunctival-corneal biopsy was performed and specimens were sent for fungal, bacterial, and acanthamoebal cultures (tissue homogenates) as well as for histopathology and for immunofluorescence (antiimmunoglobulins and anticomplement antibodies, and anti-herpes simplex virus (HSV) type 1 antibodies) studies. Conventional blood work included fluorescent treponemal antibody absor- tion test (FTA-ABS) which was negative. Gram's stain, calcofluor white stain, and appropriate cultures for fungus, bacteria, and Acanthamoeba were negative. Histopathology studies revealed a chronic nongranulomatous inflammation, and direct immunofluorescent studies (antiimmunoglobulins and anticomplement antibodies) were negative for detection of vasculitis. Indirect immunofluorescent technique using monoclonal antibodies directed against HSV type 1 was dramatic, revealing positive detection of the viral antigen in cornea, conjunctiva, and sclera, with the appropriate negative controls. The patient was diagnosed with HSV type 1 corneoscleritis and treatment with acyclovir and steroids was instituted. Four weeks later the ocular infection had resolved and visual acuity had improved to 20/30.

Patient 4. A 57 year old female who had been living in New England for the past five years had had recurrent episodes of diffuse scleritis in her left eye along with mild anterior uveitis, disc edema, and cystoid macular edema. The patient did not recall being bitten. Review of systems disclosed a migratory oligoarthritis. Laboratory tests revealed a Lyme titer of 1:640 by ELISA and elevated circulating immune complexes by Raji cell assay; FTA-ABS test was negative. No scleral biopsy for silver stains or immuno- stains was performed. Therapy with intravenous ceftriaxone 2 mg a day for 14 days and topical steroids controlled the scleritis without further recur- rences.

Discussion

Infectious scleritis should be suspected in those cases of progressive scleral inflammation where the past and present history reveals accidental trauma, ocular surgical procedures, and debilitating past ocular (recurrent attacks of herpes simplex or zoster keratitis) or extraocular (autoimmune diseases, neoplasias) conditions; they also should be suspected if the review of systems reveals multisystem findings compatible with a systemic infection. Historical aspects and review of systems were contributory to the diagnosis in all patients: ocular surgical procedure in patient 1 (scleral buckling for retinal detachment surgery one week before the onset of scleritis), past ocular condition in patient 2 (presumed herpes simplex keratitis), extra-

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ocular diseases in patient 1 (ulcerative colitis) and patient 3 (maxilla osteosarcoma), and systemic findings in patient 4 (migratory oligoarthritis).

Infectious scleritis may be clinically identical to that caused by systemic autoimmune diseases. All patients showed an indolent progressive anterior scleritis: patients 1 and 2 had necrotizing scleritis and patients 3 and 4 had diffuse scleritis. Associated ocular findings included primary stromal keratitis in patients 2 and 3 and uveitis, disc edema, and cystoid macular edema in patient 4.

All classes of microbial organisms can infect the sclera, including bacteria, fungi, viruses, and parasites [20]. In exogenous and endogenous infections, conjunctival scrapings for smears and cultures, and serologies must be obtained, and antimicrobial therapy (fortified topical, intravenous, and often subconjunctival), depending on results, must be initiated as soon as possible. If scleral infection is the primary clinical suspicion, but smears and cultures (at 48 hours), and serologies are negative, and the patient is not improving on the initial broad spectrum antibacterial therapy chosen, scleral or corneoscleral biopsy is recommended. Biopsied tissue may be homogen- ized and cultured in the usual media, evaluated histopathologically with special stains, or analyzed by immunofluorescence techniques. If the microorganism cannot be isolated and the patient continues to worsen, surgical procedures may be considered for isolation and therapeutic pur- poses. Definitive excisional biopsy includes deep scleral dissection with subsequent scleral graft and/or lamellar or penetrating keratoplasty. Stains, cultures, or immunologic studies from scleral, conjunctival, and/or corneal tissues, and serologic tests were used to make the diagnosis in all patients: Gram's stain (positive cocci) and standard cultures in patient 1 after conjunctival scrapings; calcofluor white stain (cysts compatible with Acan- thamoeba) and culture in nonnutrient agar with E. coli (Acanthamoeba) in patient 2 after corneal button examination following penetrating keratoplas- ty; immunofluorescence studies with anti-HSV type I antibodies in patient 3 after scleral-conjunctival-corneal biopsy; and serology for anti-BorreIia burgdorferi antibodies through ELISA in patient 4.

As soon as the microorganism is isolated by culture, therapy may be refined with antibiotic sensitivity results. Antimicrobial agents (antibiotics, antiprotozoal, antivirals) were instituted in all paticnts, and surgical proce- dures were additionally required in two patients: one scleral grafting in patient 1 following scleral biopsy and two penetrating keratoplasties in patient 2. Isolated infectious scleritis has a better prognosis than infectious corneoscleritis [5, 6]. Three patients remained stable after medical and surgical procedures: patients 3 and 4 improved final vision and patient 1 had unchanged final vision. The remaining patient (patient 2) required enuclea- tion following two unsuccessful penetrating keratoplasties; he had primary stromal keratitis with subsequent scleral extension.

Athough Pseudornonas aeruginosa is the most common bacterial cause of scleral infections, Staphylococcus aureus scleritis also has been reported

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[5, 36]. Bacteria are capable of establishing a focus of infection in the sclera if normal host barriers or defense mechanisms are compromised. They also may cause scleritis by inducing immune-mediated responses in the vessel wall (inflammatory microangiopathy), such as formation and deposition of immune complexes containing bacterial products. The scleritis then becomes autoimmune, and thereafter, independent of the presence of the initiating organism. In these cases, high dose oral steroids or other immunosuppres- sive agents must be instituted; continued antibiotic coverage is recom- mended.

Acanthamoeba is a small amoeba which may be found in soil, contami- nated water, contact lenses, and solutions used to rinse contact lenses [37]. Scleritis due to Acanthamoeba is usually the result of scleral extension of primary corneal infections [16, 17]. Scleritis may be caused by either a direct infection by the microorganism or by an immune-mediated reaction to killed microorganisms [16]. Risk factors include history of minor corneal trauma, direct exposure to soil or contaminated fluids, or contact lens wear [38-40]. Scleritis is usually diffuse or nodular, although it may progress to necrotiz- ing, and lead to scleral ectasia [16]. Scleritis is accompanied by a ring-shaped infiltrative stromal keratitis [41], sometimes with persistent or recurrent pseudodendritic or punctate epithelial erosions. Diagnosis of corneoscleritis due to Acantharnoeba is usually missed because the infection is uncommon; HSV corneoscleritis is the most frequent misdiagnosis.

However, even if the infection is considered initially, Acanthamoeba may still be difficult to isolate; superficial scrapings of the cornea may not include the parasite if it is located only in corneal stroma. Since Acanthamoeba corneoscleritis has a poor prognosis, a meticulous past history, slit lamp examination, smears with calcofluor white stain, and cultures with nonnut- rient agar with E. coli from scrapings or biopsy, may be contributory to early diagnosis.

HSV scleritis is uncommon. It may be caused by either a direct HSV invasion [2], often with epitelial infectious ulceration or necrotizing stromal disease, or by an immune-mediated reaction to the virus, often with necrotizing or interstitial stromal keratitis, immune rings, limbal vasculitis, disciform keratitis, or peripheral ulcerative keratitis. Since clinical features of corneoscleritis may not be characteristic of active HSV infection, immunofluorescence studies with anti-HSV type i antibodies on corneos- cleral tissue may be very helpful in reaching the diagnosis.

Lyme disease is acquired by the bite of Ixodes damrnini, a well recognized tick vector for the spirochaete Borrelia burgdorferi [42]. However, only aproximately 30% of persons recall being bitten [43]. Lyme disease has three defined clinical stages [44]. Stage 1 appears within one month of an infected tick bite, usually in the summer, and is characterized by a skin macular rash known as erythema chronicum migrans. Stage 2 begins after several weeks to months after the tick bite and is characterized by neurologic and cardiac manifestations. Stage 3 occurs up to two years after

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the tick bite and is characterized by a migratory oligoarthritis sometimes accompanied by neurologic manifestations. Ocular manifestations may appear at any stage but are more common in the last two stages. They include involvement of cranial nerves (third, sixth, and seventh), optic nerve (optic neuritis and perineuritis, papilledema, ischemic optic neuropathy, optic nerve atrophy), and retina (retinal hemorrhages, exudative retinal detachments, cystoid macular edema) [45]. Other reported ocular findings are anterior and posterior uveitis, endophthalmitis, keratitis, conjunctivitis, blepharitis, and episcleritis [46, 47]. Scleritis has not been previously reported in Lyme disease. The pathogenesis of Lyme scleritis may be related either with direct invasion of the Borrelia or with immune-mediated response to BorreIia or its metabolic products. Our patient had recurrent episodes of scleritis associated with optic neuritis. Lyme disease must always be considered in the differential diagnosis of scleritis associated with neuroophthalmologic findings.

Since early, aggressive, and prolonged appropriate antimicrobial therapy may improve outcome, early diagnosis is essential in order to institute early treatment to halt the progression of infectious scleritis or corneoscleritis.

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Address for correspondence: Maite Sainz de la Maza, MD, Urgel 224, E-08036 Barcelona, Spain. Phone: (343) 430 9540; Fax: (343) 209 8429