Inamoto Y, Chai X, Kurland BF, et al. Validation of measurement scales in ocular graft-versus-host disease. Ophthalmology. 2012;119(3):487–493. Epub 2011 Dec 6.
Jabs DA, Wingard J, Green WR, Farmer ER, Vogelsang G, Saral R. The eye in bone marrow transplantation. III. Conjunctival graft-vs-host disease. Arch Ophthalmol. 1989;107(9):1343–1348.
Malta JB, Soong HK, Shtein RM, et al. Treatment of ocular graft-versus-host disease with topical cyclosporine 0.05%. Cornea. 2010;29(12):1392–1396.
Ogawa Y, Shimmura S, Dogru M, Tsubota K. Immune processes and pathogenic fibrosis in ocular chronic graft-versus-host disease and clinical manifestations after allogeneic hematopoietic stem cell transplantation. Cornea. 2010;29(11):S68–S77.
Figure 7-14 A, Patient with graft-vs-host disease fitted with a therapeutic scleral contact lens. The inferior paracentral cornea demonstrates subepithelial scarring. B, High magnification shows the space between the contact lens and cornea.
(Courtesy of Charles S. Bouchard, MD.)
Other Immune-Mediated Diseases of the Skin and Mucous Membranes
Other immune-mediated disorders that can, in rare cases, affect the conjunctiva include linear IgA bullous dermatosis, dermatitis herpetiformis, epidermolysis bullosa, lichen planus, paraneoplastic pemphigus, pemphigus vulgaris, and pemphigus foliaceus.
Immune-Mediated Diseases of the Cornea
Thygeson Superficial Punctate Keratitis
PATHOGENESIS The etiology of Thygeson superficial punctate keratitis (SPK) is unknown. Although many of the clinical features resemble those of a viral infection of the epithelium, attempts to confirm viral particles by electron microscopy or culture have been unsuccessful. No inflammatory cells are evident. The rapid response of the lesions to corticosteroid therapy suggests that Thygeson keratitis is largely immunopathogenically derived.
CLINICAL PRESENTATION This condition, first reported by Thygeson in 1950, is characterized by recurrent episodes of tearing, foreign-body sensation, photophobia, and reduced vision. It affects children to older adults and is typically bilateral, although it may develop initially in 1 eye or may be markedly asymmetric in some cases. The hallmark finding is multiple (up to 40 but as few as 2–3) slightly elevated corneal epithelial lesions with “negative staining,” which are noted during exacerbations. The epithelial lesions are round or oval conglomerates of gray, granular, or “crumblike” opacities associated with minimal conjunctival reaction, in contrast to adenoviral keratoconjunctivitis. High magnification reveals each opacity to be a cluster of multiple smaller
pinpoint opacities (Fig 7-15). A characteristic feature is the waxing and waning appearance of individual epithelial opacities, which change in location and number over time. The greatest density of these lesions typically appears in the central cornea. The raised punctate epithelial lesions themselves stain faintly with fluorescein and rose bengal.
Figure 7-15 A, Thygeson superficial punctate keratitis. B, At higher magnification, each lesion is seen to consist of raised, granular lesions.
No conjunctival inflammatory reaction is noted during exacerbations, but occasionally patients have mild bulbar conjunctival injection. In rare cases, a mild subepithelial opacity may develop under the epithelial lesion—more commonly in patients who have received topical antiviral therapy. The important facet of this condition is that the patient’s symptoms may far exceed the apparent signs; frequently, patients report severe photophobia and foreign-body sensation in the setting of only a few central epithelial lesions.
MANAGEMENT Supportive therapy with artificial tears is often adequate in mild cases. Treatment alternatives for persistently symptomatic cases include low-dose topical corticosteroids and bandage soft contact lenses. Antiviral therapy is not the standard of care at this time, as there are no firm data to associate this condition with an active replicative viral infection.
If a topical corticosteroid is prescribed, only a very mild preparation is needed (eg, fluorometholone 0.1%). Because the lesions are quite responsive to corticosteroids, treatment will hasten their resolution, but they frequently recur in the same or different locations on the cornea after the topical corticosteroids are stopped. Overall, the use of corticosteroids should be minimized in these cases and monitored closely. Topical cyclosporine 0.05% or tacrolimus ophthalmic suspension 0.1% given 2–4 times daily is also effective in causing regression of the lesions. Higher concentrations of cyclosporine (1%) or tacrolimus can also be tried. Although there is little to suggest that this treatment is superior to corticosteroid therapy, it is preferred over corticosteroid use because of the higher safety profile.
Connell PP, O’Reilly J, Coughlan S, Collum LM, Power WJ. The role of common viral ocular pathogens in Thygeson’s superficial punctate keratitis. Br J Ophthalmol. 2007;91(8):1038–1041.
Tatlipinar S, Akpek EK. Topical ciclosporin in the treatment of ocular surface disorders. Br J Ophthalmol. 2005;89(10):1363– 1367.
Interstitial Keratitis Associated With Infectious Diseases
PATHOGENESIS Interstitial keratitis (IK) is a nonsuppurative inflammation of the corneal stroma that features cellular infiltration and usually vascularization without primary involvement of the
epithelium or endothelium. Most cases result from a type IV hypersensitivity response to infectious microorganisms or other antigens in the corneal stroma. The topographic distribution (diffuse versus focal or multifocal) and depth of the stromal infiltration, in addition to associated systemic signs, are helpful in determining the cause of IK.
Congenital syphilis was the first infection to be linked with IK. Herpes simplex virus, which accounts for most cases of stromal keratitis, and varicella-zoster virus keratitis are discussed earlier in this volume. Many other microorganisms are much rarer causes of IK; these include
Mycobacterium tuberculosis Mycobacterium leprae
Borrelia burgdorferi (Lyme disease) measles virus
Epstein-Barr virus (infectious mononucleosis) Chlamydia trachomatis (lymphogranuloma venereum)
Leishmania spp
Onchocerca volvulus (onchocerciasis)
Syphilitic interstitial keratitis
CLINICAL PRESENTATION Syphilitic eye disease is discussed further in BCSC Section 6, Pediatric Ophthalmology and Strabismus, and Section 9, Intraocular Inflammation and Uveitis. Systemic aspects of syphilis are discussed in BCSC Section 1, Update on General Medicine.
Keratitis may be caused by either congenital or acquired syphilis, although most cases are associated with congenital syphilis. Manifestations of congenital syphilis that occur early in life (within the first 2 years) are infectious. However, IK is an example of a later, immune-mediated manifestation of congenital syphilis. Affected children typically show no evidence of corneal disease in their first years; stromal keratitis lasting for several weeks develops late in the first decade of life (or even later). These patients may also have other nonocular signs of congenital syphilis:
dental deformities: notched (Hutchinson) incisors and mulberry molars
bone and cartilage abnormalities: saddle nose, palatal perforation, saber shins, and frontal bossing
cranial nerve VIII (vestibulocochlear) deafness rhagades (circumoral radiating scars) cognitive impairment
Congenital syphilitic keratitis is bilateral in 80% of cases, although both eyes may not be affected simultaneously or to the same degree. Initial symptoms are pain, tearing, photophobia, and perilimbal injection. The inflammation may last for weeks if left untreated. Sectoral superior stromal inflammation and keratic precipitates are typically seen early. As the disease progresses, deep stromal neovascularization develops. Eventually, the inflammation spreads centrally, and corneal opacification and edema may develop (Fig 7-16). In some cases, the deep corneal vascularization becomes so intense that the cornea appears pink—hence the term salmon patch. Sequelae of stromal keratitis include corneal scarring, corneal thinning, and ghost vessels in the deep layers of the stroma. Vision may be reduced because of irregular astigmatism and stromal opacification.
Figure 7-16 Active syphilitic interstitial keratitis with salmon patch.
Stromal keratitis develops only rarely in acquired (as opposed to congenital) syphilis and, if it does, is unilateral in 60% of cases. The ocular findings are similar to those seen in congenital syphilitic keratitis. In general, uveitis and retinitis are much more common manifestations of acquired syphilis than keratitis.
LABORATORY EVALUATION AND MANAGEMENT The diagnosis can be confirmed serologically with the rapid plasma reagin (RPR) test and a treponeme-specific antibody test (fluorescent treponemal antibody absorption test [FTA-ABS] or microhemagglutination assay for Treponema pallidum [MHA-TP]). During the acute phase, ocular inflammation should be treated with cycloplegic agents and topical corticosteroids to limit stromal inflammation and late scarring. The corneal disease can be suppressed effectively with topical corticosteroids; however, even if left untreated, the disease typically burns out after several weeks, although it can lead to severe corneal opacification before doing so. Systemic syphilis (or neuroretinal manifestations) should be treated with penicillin or an appropriate alternative antibiotic according to the protocol appropriate for either congenital or acquired syphilis. The necessity of lumbar puncture in syphilitic IK is uncertain. See BCSC Section 9, Intraocular Inflammation and Uveitis, for a more in-depth discussion of noncorneal syphilitic disease.
Reactive Arthritis
Reactive arthritis (formerly called Reiter syndrome) is a systemic disorder characterized by the classic triad of ocular (conjunctivitis/episcleritis, iridocyclitis, or keratitis), urethral, and joint inflammation. The joint inflammation is often highly asymmetric and involves a few joints (oligoarticular). These manifestations can appear simultaneously or separately, in any sequence. Less common manifestations include keratoderma blennorrhagicum (a scaling skin eruption), balanitis, aphthous stomatitis, fever, lymphadenopathy, pneumonitis, pericarditis, and myocarditis. Attacks are self-limited, lasting from 2 to several months, but they may recur periodically over the course of several years.
PATHOGENESIS Reactive arthritis may occur after dysentery due to gram-negative bacteria (most frequently Salmonella, Shigella, and Yersinia) or after nongonococcal urethritis caused by C trachomatis. More than 75% of patients with reactive arthritis are HLA-B27–positive. See BCSC Section 9, Intraocular Inflammation and Uveitis, for discussion of HLA-B27–related diseases and