bacilli on scleral biopsy specimen. Therapy consists of a combination of oral dapsone, clofazimine, and rifampin. This is supplemented by prolonged treatment with local steroids, which must be carefully monitored and slowly tapered.

7.1.3Spirochetal Scleritis

The spirochetes that most frequently cause scleritis or episcleritis are Treponema pallidum and Borrelia burgdorferi, etiological agents of syphilis and Lyme disease, respectively. Because syphilis and Lyme disease have increasingly been detected for the past decade in the USA and Europe, both entities must be included in the differential diagnosis of patients with scleritis and episcleritis. Past history, review of systems and laboratory testing are important contributors to the diagnosis of spirochetal scleritis or episcleritis.

7.1.3.1 Syphilis

Scleritis and episcleritis may be ocular manifestations of syphilis, a sexually transmitted disease caused by the spirochete T. pallidum.

Epidemiology

Syphilis was considered to be one of the most common causes of intraocular inßammation before 1925. The advent of antibiotic therapy led to a marked decrease in syphilitic infections and, in 1955, it was believed that syphilis had been eradicated [63]. However, since the late 1970s the incidence of syphilis, and therefore of its ocular manifestations, has been steadily increasing in the USA [64]. Syphilis now accounts for approximately 100,000 new sexually transmitted diseases annually. The association of ocular syphilis, particularly uveitis, retinitis, or optic neuritis, and human immunodeÞciency virus (HIV) infection has been reported [65Ð76].

Pathogenesis and Clinical Features

Syphilis is transmitted either by venereal contact or transplacentally by an infected mother to her unborn child (congenital syphilis) [77]. Primary syphilis appears as an ulcerated, painless chancre at the point of T. pallidum inoculation, usually in

the genital area, with regional lymphadenopathy. One month to 3 years later, hematogenous spread of T. pallidum leads to secondary syphilis characterized by skin and mucous membrane lesions, as well as generalized lymphadenopathy. The humoral and cellular immune responses can suppress the treponemes in an immunocompetent individual, resulting in a latent stage. In one third of affected individuals, often after latent periods of 1Ð30 years, tertiary syphilis develops. Tertiary syphilis consists of an immune-mediated response to T. pallidum and its metabolic products, leading to the formation of gummas. Although gummas may appear in any organ, they usually cause cardiovascular lesions (aortic aneurysms) and central nervous system involvement (paralysis). Treponemes may be found in the gummas.

T. pallidum dissemination through transplacental passage from an infected mother, followed by hypersensitivity reactions, causes congenital syphilis. Interstitial keratitis, peg top teeth, and deafness, considered the cardinal signs, are late manifestations of the disease. Other, less common manifestations are saddle nose deformity, skull abnormalities, and arched palate.

Scleritis and Episcleritis

The reported incidence of syphilis in patients with scleritis is 2.89% [37]. Not infrequently, scleritis is the initial manifestation of the disease [65, 78]. Scleritis usually occurs during the course of secondary, tertiary, or congenital syphilis. Episcleritis also may occur during the primary stage. Therefore, the pathogenesis of syphilitic scleritis or episcleritis may be related either to a direct invasion of Treponema (primary or secondary) or to an immune-mediated response to Treponema or its metabolic products (tertiary or congenital).

1.Primary Syphilis: Episcleritis during primary syphilis is usually secondary to an overlying conjunctival chancre. Preauricular and submaxillary lymphadenopathy also may occur [79].

2.Secondary Syphilis: Scleritis and episcleritis during secondary syphilis appear at the same time as or after the onset of skin rash. They are often associated with conjunctival involvement. Scleritis or episcleritis and conjunctivitis are

characteristically localized at the limbus. Limbal swelling may overlap the corneal margin.

3.Tertiary Syphilis: Scleritis and episcleritis during tertiary syphilis are not clinically different from that caused by any other disease. Scleritis in this stage has an insidious onset, may be of the diffuse anterior, nodular anterior, necrotizing anterior, or posterior type, and is often

recurrent [78Ð80]. Immune-mediated mechanisms lead to scleral granulomatous inßammation and inßammatory microangiopathy [81]. Occasionally, scleritis is associated with interstitial keratitis. Interstitial keratitis often is unilateral, localizes in the superior sector, and appears as tiny stromal opacities, mild endothelial edema, and keratic precipitates 5 months to 10 years following primary infection. Stromal opacities may coalesce, affecting either a localized area or the entire cornea, giving a ground-glass appearance. Later, vessels arrive and invade the deep stroma. Once the inßammation subsides, vascular ßow diminishes, leaving behind the empty ghost vessels. Anterior uveitis may occasionally occur. Episcleritis in this stage may be simple or nodular [78]. The presence of ocular involvement in tertiary syphilis may be associated with other systemic lesions characteristic of this stage, such as neurosyphilis [65] or cardiovascular involvement.

4.Congenital Syphilis: Scleritis in congenital syphilis develops many years after the cardinal characteristics appear and is usually of long duration, mild severity, and resistant to treatment. Scleritis is usually of the diffuse anterior or posterior type [80]. Interstitial keratitis in congenital syphilis usually begins between the ages of 5 and 20 years and may reappear at the same time as the onset of scleritis. It is eventually bilateral and is more severe and diffuse than the interstitial keratitis seen in tertiary syphilis [82]. Anterior uveitis is often associated.

In our prior series of 172 patients with scleritis

[13], one patient had syphilis (0.58%). The patient was a 63-year-old black female with a 1-year history of nodular scleritis in her right eye, which was unresponsive to systemic prednisone and

azathioprine and to local steroid therapy. At the moment of her Þrst examination by us, visual acuity was 20/25 in the right eye and 20/20 in the left and slit-lamp examination revealed nodular scleritis and mild anterior uveitis. Past history review did not reveal any prior disease or speciÞc treatment, and review of systems did not disclose teeth, hearing, skull, or nose abnormalities. Serological tests were unremarkable and scleral biopsy disclosed only subacute inßammation. No silver stains or immunostains were performed on the specimen. Prednisone was slowly tapered and oxyphenbutazone was begun. The inßammation resolved but the patient returned again 3 months later with a nodular scleritis in her left eye. This new episode prompted repeat laboratory studies, including tests for syphilis. The ßuorescent treponemal antibody absorption (FTA-ABS) test was positive. Retrospective indirect immunoßuorescence testing in an attempt to demonstrate T. pallidum in the prior scleral biopsy (rabbit antitreponemal antibody and ßuorescein-labeled sheep anti-rabbit antibody) was negative. The patient was advised to begin therapy for syphilis but she did not return until 7 months later, when she had a nodular scleritis recurrence in her left eye. She refused spinal tap. The patient was hospitalized and treated with intravenous penicillin (24 million units of aqueous penicillin G daily for 10 days), topical prednisolone acetate (1%, four times daily), and scopolamine (0.25%, twice daily). Therapy was continued on an outpatient basis with penicillin (2.4 million units of penicillin G benzathine, intramuscular, once a week for 3 weeks); topical steroid was tapered and discontinued after 8 weeks. The scleritis resolved within 2 weeks after the onset of therapy. The patient did not have recurrences of her scleritis during the following 2 years. The presence of scleritis in this patient was the Þrst manifestation whose study led to the diagnosis and treatment of syphilis.

Diagnosis

Because treponemes may be scant in sclera, particularly in tertiary or congenital syphilis, their identiÞcation with silver stains (LevaditiÕs stain or WarthinÐStarry stain) or by immunological methods (direct or indirect immunoßuorescence

or immunoperoxidase testing) may be difÞcult [83Ð86].

The presumed diagnosis of acquired syphilitic scleritis when scleral treponemes cannot be demonstrated is made on the basis on the histological conjunctival or scleral granulomatous inßammatory reaction with obliterative endarteritis [80, 87, 88] associated with a positive FTA-ABS test or microhemagglutination assay for T. pallidum (MHA-TP). Past history of venereal disease and signs of CNS or cardiovascular involvement also support the diagnosis.

Scleritis due to congenital syphilis is suggested by a history of ocular inßammation in childhood, previous therapy for syphilis, a maternal history of a positive syphilis serology, other ocular signs, such as salt-and-pepper chorioretinitis or optic atrophy, or the presence of late clinical manifestations of syphilis, such as deafness, teeth abnormalities, palatal perforation, or saddle nose deformity, and a positive FTA-ABS test or MHA-TP.

The FTA-ABS or MHA-TP tests are the most sensitive tests for any stages of syphilis except primary, early secondary, and early congenital forms. The FTA-ABS test is 98% sensitive and the MHA-TP test is 98Ð100% sensitive in tertiary syphilis [63, 89Ð91]. The MHA-TP is more speciÞc than the FTA-ABS, with only 1% or less of false-positive reactions in leprosy, relapsing fever, systemic lupus erythematosus, rheumatoid arthritis, or yaws [91]. The Venereal Disease Research Laboratory (VDRL) quantitative test is not reliable in late congenital or tertiary syphilis and has a high incidence of false-positive reactions [89, 90]. Therefore, the FTA-ABS and MHA-TP are preferred for episcleritis and scleritis suspected to be caused by syphilis. However, the FTA-ABS and MHA-TP do not indicate active, as opposed to previous, disease; patients with scleritis or episcleritis and positive FTAABS or MHA-TP tests could have had syphilis in the past, which was treated, or could have latent syphilis and coincidentally develop idiopathic scleral or episcleral inßammation. The clinical response after adequate therapy for syphilis suggests that scleritis or episcleritis in patients with positive FTA-ABS and MHA-TP tests is caused by syphilis.

The presence of ocular lesions, including scleritis and episcleritis, in tertiary syphilis requires a careful search for evidence of neurosyphilis through a cerebrospinal ßuid examination for cells and protein, and a VDRL test [63].

Because ocular syphilis may occur concomitantly with HIV infection, we believe that all patients with ocular syphilis should now be evaluated for HIV and vice versa [63].

Therapy

Once the diagnosis of syphilitic scleritis or episcleritis has been established and a history of possible penicillin allergy discarded, therapy with penicillin G benzathine (2.4 million units, intramuscularly once a week for 2 weeks in secondary syphilis; the same regimen for 3 weeks in tertiary or congenital syphilis) may be instituted. However, because of previous reports of therapeutic failures with intramuscular penicillin G benzathine and experimental data suggesting that complete spirochetal sterilization from the eye may be impossible unless high dosages and prolonged periods of treatment are used [92], we prefer to treat patients, particularly those with tertiary syphilis, with the neurosyphilis regimen of intravenous penicillin (24 million units of aqueous penicillin G, intravenous, daily for 10 days) followed by intramuscular penicillin (2.4 million units of penicillin G benzathine, intramuscular once a week for 3 weeks) [89]. Tetracyclin or erythromycin (500 mg, four times a day for 4 weeks) has been used in penicillinallergic patients; there are no properly controlled studies to test the efÞcacy of these treatments. We prefer instead to have penicillin-allergic patients undergo penicillin desensitization before treating with penicillin. Some patients who give a history of penicillin allergy prove negative when skin tested for immediate hypersensitivity to penicillin and could be given aqueous crystalline penicillin G under close supervision in the hospital.

Scleritis in tertiary or congenital syphilis with or without interstitial keratitis requires topical corticosteroids with careful clinical monitoring and slowly progressive dose reduction.

There is evidence that syphilis may pursue a more aggressive course in patients who are concurrently infected with HIV, rendering standard