Infectious Scleritis

Etiology

The etiology of infectious scleritis can be primary or secondary. Primary scleritis occurs following an accidental or surgical injury (58.5 to 88%).[10][11] Infectious scleritis can follow trauma (10%), infectious endophthalmitis, or adjacent keratitis. Predisposing factors to a primary infection include systemic infection, systemic/topical steroid use (39%), and previous diagnosis of autoimmune scleritis. Ocular surgery such as pterygium surgery (57%), scleral buckle (8%), cataract removal (10%), strabismus, glaucoma filtration surgery, suture removal, and vitreoretinal procedures have all been implicated for infectious scleritis.[12][13][14][15][16] 

A cosmetic ocular-whitening procedure, popularized in South Korea, has also been noted to lead to infectious scleritis. The procedure involves the removal of pinguecula or pterygium and is followed by an amniotic membrane graft. One severe post-procedural complication is a scleral melt, which puts the patient at high risk for infectious scleritis.[17] Secondary infectious scleritis refers to the extension of a primary corneal infection (corneoscleritis). Risk factors for corneoscleritis include similar risk factors for primary infectious scleritis, such as suture removal or ocular surgeries. Further risk factors noted specifically for secondary infectious scleritis are contact lenses use, debilitating systemic diseases, and corneal tissue devitalization.

Epidemiology

One study reported that in 56 eyes with infectious scleritis, the median time from the inciting event was 1.9 months. Patients with a history of pterygium surgery had a median time of 49 months (range 0-183 months) after surgery before developing infectious scleritis. This duration is significantly longer than those with glaucoma, cataracts, and retinal surgery (median 1.0 to 1.6 months). The study also noted a median age of 70, suggesting that age might be a factor in developing this condition.[7] The pathogens more commonly responsible for infectious scleritis are Pseudomonas aeruginosa in developed countries and Nocardia or fungi in developing countries.[1]

Pathophysiology

The most common cause of infectious scleritis is Pseudomonas spp, with Pseudomonas aeruginosa being the most frequent. This pathogen uses collagenases to destroy the scleral tissue.[18] This microbe is the etiologic agent for 25-85% of cases in some studies.[5][6] The next common cause of bacterial scleritis is gram-positive cocci. Staphylococcus aureus causes localized scleral thinning and inverse hypopyon.[19] Methicillin-resistant Staphylococcus aureus (MRSA) has also been noted in cases of post-surgical infectious scleritis, incorrectly diagnosed as Pseudomonas.[20] Streptococcus has been noted in patients with simultaneous cardiovascular, gastrointestinal, and genitourinary infections. Additional predisposing factors are the use of radiation and mitomycin C.[8] 

Several cases due to S. pneumoniae were refractory to antibiotics and resulted in enucleation, suggesting an aggressive form of infectious scleritis. Gram-negative bacilli are another common cause of infectious scleritis. One patient with a gram-negative bacilli infection presented with a mass over an area of the sclera, which was discovered by ultrasound biomicroscopy (UBM) 18 years after pterygium surgery. Other reported etiologic agents for infectious scleritis are Mycobacterium tuberculosis, Klebsiella, Rhodtrula, and other Mycobacterial infections in the immunocompromised.[10]

Fungal infectious scleritis has a worse outcome compared to bacterial or viral scleritis. Poor outcomes for fungal scleritis may be explained by the following:

• Fungal infections take longer to diagnose than bacterial infections.
• Antifungals have poor penetration into the sclera.
• Fungal infections are more aggressive.

A majority of cases progress to the evisceration of the eye.[6][10] Nocardia is classified with fungal scleritis because the findings are more similar to fungal scleritis than bacterial scleritis. Additionally, fungal etiology should be considered in developing countries. The study hypothesized that fungal infections are more likely to occur in hot/arid climates, allowing for a higher presence in the soil, and are due to inciting factors of trauma or surgery. Signs of fungal scleritis include full-thickness corneal inflammation with scleral lesions, rapidly progressive cataracts, and serous retinal detachment.[5][9] Exposure to agricultural soil or plant matter is an inciting factor for infections with Nocardia, Psuedallescheria boydii, and Paecilomyces lilacinus. Aspergillus was noted to be found in a patient with a history of intravenous drug use (IVDA). Scedosporium is another fungal vector.

Other forms of infectious scleritis result from viruses and parasites. Among the parasites, the most notable is Toxoplasma gondii. In one study, patients with this pathogen had retinochoroiditis and were immunosuppressed on the diagnosis.[21] Viral scleritis has been noted with both VZV and HSV, typically with unilateral symptoms. The severity of symptoms in viral scleritis has been variable, but most studies describe the presence of a diffuse anterior scleritis, perilimbal devascularization, and corneal thinning.[22]

History and Physical

Patients suspected of having scleritis should have a thorough systemic evaluation and a full ophthalmic examination.[22] A history of trauma or ocular surgery should alert the physician. Patients presenting with infectious scleritis usually complain of redness, watery eyes, and pain.[13] Patients with infectious scleritis and history of retinal surgery generally have a more rapid onset when compared to other groups.[14]

On examination, patients commonly have episcleral and conjunctival hyperemia (98%), and scleral necrosis (93%). Patients additionally present with calcified plaques (38%), anterior segment inflammation (25%), corneal involvement (25%), and multifocal scleral abscesses (23%).[4] Studies also report cases with adjacent structure involvement or endophthalmitis on presentation. One study noted that the mean necrotic area was 3.6 clock hours. The area was smaller in patients that lacked an inciting event. Bacterial scleritis was also reported to have a larger necrotic area when compared to fungal scleritis on presentation.[4] Peripheral keratitis was more frequently seen in patients with infectious scleritis than those with idiopathic scleritis (22.9%/10.3%).[22] Unilateral sclerouveitis or sclerokeratitis may have an underlying infection, especially if there are no symptoms of systemic disease.

The use of ultrasound biomicroscopy (UBM) has also been used for the examination of infectious scleritis. UBM allows for early detection of choroidal and retinal detachment, ciliary body rotation, and elimination of the ciliary sulcus due to infectious scleritis.[23] Additionally, imaging via optical coherence tomography could also allow for the visualization of vitreous opacities and subretinal deposits, suggestive of lipofuscin-laden macrophages.

Evaluation

Patients with newly-diagnosed scleritis should undergo clinical and laboratory evaluation for vasculitis, including CBC, CMP, urinalysis, P-ANCA, C-ANCA, ESR, C-reactive protein, and chest x-ray. Systemic infections such as Lyme disease or syphilis must also be ruled out.[24] 

Patients with a high-risk history should be further evaluated for infectious scleritis. Infectious scleritis should be cultured by swab, spatula, or biopsy of the sclera. Specimens should be cultured on blood and chocolate agar, thioglycolate, Sabourad dextrose agar, non-nutrient agar with E.Coli, and brain- heart infusion broth.[6] Additional methods, such as immunohistochemistry and titers, should also be utilized for culture-negative results.[14][22]

Treatment / Management

Studies have highlighted the importance of the prevention of infectious scleritis.[6] Measures like adjunctive therapy or avoiding overuse of cautery during surgery might spare episcleral blood flow, allowing for better wound healing.[25] Studies also advise against the bare sclera techniques as these leave the surface vulnerable to infection. Studies also advise against the use of an amniotic membrane over an area of debridement as it affects the penetration of antimicrobial agents, though they advocate the combined use of an amniotic membrane and fascia lata grafts over an area of debridement.[6] Recommendations for infectious scleritis treatment are not well established before a specific antimicrobial diagnosis.[5] Initial treatment with a broad-spectrum antibiotic coverage for Pseudomonas, both topical (gatifloxacin 0.3% and amikacin 2.5%) as well as systemic (gatifloxacin 400mg twice daily), maybe started to address a clinical suspicion of Pseudomonas.[4][13] (B2)

If history is indicative of trauma with agricultural material, a topical and systemic antifungal should be used.[10] There is no strict guideline for the duration of the antimicrobial medication. One source states a median amount of 50 days for infectious scleritis while another recommends a “prolonged” course.[5][25](B2)

As broad-spectrum antibiotic coverage is generally used for the most common causative organisms, studies recommend tailoring the treatment to culture results. Scleritis due to Staphylococcus and Streptococcus may be treated with topical antibiotics such as fortified cefazolin (50 mg/mL) and topical fluoroquinolones (ciprofloxacin 0.3%/gatifloxacin 0.3%).[13] Patients refractory to fortified antibiotic therapy or culture positive for MRSA may be admitted and treated with subconjunctival and IV vancomycin.[5] 

Tuberculosis therapy is recommended for patients with M.tuberculosis scleritis. However, those with other Mycobacterium do not respond well to antituberculosis medications and should be treated with topical amikacin (25 mg/mL) and a systemic medication such as doxycycline (200 mg) or clarithromycin (500 mg). It is also recommended to continue the medication four to six weeks after the resolution of symptoms. Topical natamycin 5% and systemic itraconazole (100 mg) or systemic ketoconazole (200 mg) twice daily are recommended for patients with a fungal scleritis. Nocardia shows good resolution with the use of systemic trimethoprim/sulfamethoxazole (160 mg/800 mg twice daily), but some studies have also shown sensitivity to topical amikacin.[5][6] 

Patients diagnosed with Toxoplasmosis gondii show good resolution with an oral trimethoprim/sulfamethoxazole (160 mg/800 mg twice daily) and azithromycin (500 mg); however, no topical application was reported.[26] varicella-zoster virus (VZV) or herpes simplex virus (HSV) scleritis showed resolution with acyclovir treatments (initial 800 mg five times daily with lower maintenance dose).[22] It is noted that while an oral steroid with antimicrobials has varying success, it has been detrimental for cases of Nocardia and HSV.[6](B2)

Studies indicate that a variety of antimicrobial treatment regimens have been utilized (95% topical, 77% oral, 11% intravitreal). However, in only 18% of patients (n=56), was this sole treatment adequate, most who received this treatment required surgical intervention.[7] Another study (n=28) found that three out of four patients receiving medical therapy alone (n=16) result in enucleation or evisceration of the eye, whereas combined intervention (n=11) results in two out of eleven patients needing enucleation or evisceration of the eye.[12] Most patients with a diagnosis of infectious scleritis should undergo early and repetitive surgical debridement.[4][8][13] (B2)

Cryotherapy, corneoscleral grafts, or removal of hardware (scleral buckle and glaucoma drainage device), in addition to antimicrobial medication, may be necessary.[6][7] Surgeries are adjunctive methods to overcome the poor penetration of the antimicrobial agent. Studies show that if patients were diagnosed and started on surgical treatment within a specific time frame (2.5 days) from diagnoses, patients had a 100% globe preservation rate.[27](B2)

Differential Diagnosis

The most common differential diagnosis for patients with suspected infectious scleritis is autoimmune scleritis, as both manifest with similar signs and symptoms.[2][10] Alternate diagnoses include episcleritis and anterior uveitis.[15][28] Patients with systemic diseases such as vasculitis and syphilis have also been known to show symptoms similar to scleritis. A systemic workup can differentiate these from scleritis.[24]

Prognosis

Worse visual outcomes are correlated with poor visual acuity at presentation, endophthalmitis, keratitis, isolated medical therapy, and fungal infections.[29] The dissemination of the infection also leads to a worse outcome. A study reported that 50% of eyes lost function vision, meaning best-corrected visual acuity of less than 20/200. No difference in outcome has been noted for the duration of treatment, bacterial infection/fungal infection, or inciting event.[7]

Complications

Poorly managed cases or undiagnosed infectious scleritis may result in poor outcomes for patients. As previously stated, treatment with steroids may worsen the infection. Recurrence of infectious scleritis, defined as new nodules or necrotic areas, were seen in 9.52% of patients, most of which had fungal scleritis.[6][10][30] Other complications included cataracts, glaucoma, epithelial defects, fibrotic pupillary membrane, corneal opacities, retinal detachment, choroidal detachment, and globe perforation. Some complications may require enucleation.[10][13]