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Epstein-Barr Viral Stromal Keratitis
Epstein-Barr Viral Stromal I
Abstract: We have identified seven patients with clinical and serological features suggestive of Epstein-Barr viral (EBV) stromal keratitis. Four had discrete, sharply demarcated, multifocal, pleomorphic or ring-shaped granular anterior stromal opacities with normal inteNening stroma, seemingly distinct from adenoviral or herpes simplex stromal keratitis. Two had soft, blotchy, pleomorphic, multifocal infiltrates, predominantly involving the peripheral cornea at all depths, and with minimal neovascularization, resembling syphilitic stromal keratitis. One patient had features of both forms of keratitis. Our experience suggests that EBV may be more commonly associated with stromal keratitis than recognized previously. [Key words: Epstein-Barr virus, infectious mononucleosis, stromal keratitis.] Ophthalmology 93:7 46-751 , 1986
Infectious mononucleosis (IM) secondary to EpsteinBarr virus infection is a common disease of adolescents and young adults in the United States. 1 However, keratitis in association with IM has only rarely been reported. We have identified seven patients with clinical and serological features suggestive of Epstein-Barr viral stromal keratitis.
CASE REPORTS Case 1. A 20-year-old white woman developed pain, tearing, conjunctival hyperemia and mucopurulent discharge of the left eye within one week of onset of infectious mononucleosis (IM) documented by positive Monospot test. She was treated with prednisolone acetate 1/8% suspension, one drop topicaliy to the left eye four times daily without significant improvement. Subsequent examination by her ophthalmologist revealed multifocal keratitis and she was treated with a topical sulfanomide preparation. The symptoms of irritation and blurred vision persisted for two months but gradually improved. The patient was first referred for examination nine months after the onset of her symptoms. At that time she complained of only occasional, brief episodes of foreign-body sensation, photophobia and tearing of the left eye. Visual acuity was 20/20-3. The conjunctiva was not inflamed. From the Cullen Eye Institute, Baylor College of Medicine, Houston. Presented at an Annual Meeting of the American Academy of Ophthalmology. Supported by Research to Prevent Blindness, Inc. and the Sid W. Richardson Foundation. Reprint requests to Alice Y. Matoba, MD, Cullen Eye Institute, Baylor College of Medicine, 6501 Fannin, Houston, TX 77030.
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Corneal examination revealed multiple discrete anterior stromal opacities scattered throughout the cornea, associated with areas of epithelial granularity or microepithelial defects (Fig 1). In the superotemporal quadrant the anterior stroma had a diffuse, granular quality and multiple superficial vessels were present. There was no iritis. Epstein-Barr anti-viral capsid antigen (VCA) antibody was positive at 1:40. Complement fixation tests for herpes simplex virus (HSV), adenovirus (ADV), and cytomegalovirus were non-reactive. The patient was treated with artificial tears with complete resolution of symptoms over the following six months. No recurrences have been noted during the subsequent four years. Case 2. An 11-year-old white boy developed watering and blurred vision of the right eye two weeks following a mild flulike illness. He noted no pain, photophobia, or injection of conjunctival vessels. The patient was treated by his ophthalmologist with trifluridine and prednisolone acetate 1% topically to the right eye four times daily with slight improvement. He was referred for consultation four weeks after the onset of blurred vision. Visual acuity of the right eye was 20/40. The conjunctiva was not inflamed. The cornea contained multiple ring-shaped well-demarcated opacities in the deep epithelium and anterior stroma consisting of multiple fine punctate opacities (Fig 2). The intervening zones were fairly clear. The opacities ranged in diameter from .1 mm to 1.5 mm. The posterior two-thirds of the stroma was clear. The left eye was normal. Herpes simplex complement fixation antibody titer was 1:8; adenovirus complement fixation antibody test was nonreactive. Anti-VCA antibody titer was 1:80 and anti-Epstein Barr nuclear antigen (EBNA) antibody titer was 1:8. Trifluridine was discontinued and the patient was placed on a tapering regimen oftopical prednisolone acetate. The patient did not return for follow-up examination. Case 3. A 10-year-old white girl was noted by her ophthalmologist to have multiple, discrete, 1 to 2 mm, mid-stromal
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corneal opacities in the right eye during a routine evaluation (Fig 3). One year prior to that visit the ocular examination had been normal and during the preceding year she had noted no flu-like illness or ocular inflammation. During the following year the patient experienced intermittent foreign body sensation of both eyes. The right eye remained uninflamed, however, and the opacities were noted to decrease in density. One year after the corneal lesions were first noted the right cornea contained multiple, patchy, faint anterior stromal opacities, most concentrated centrally and along the superotemporal periphery. Faint neovascularization was present superiorly and inferiorly, extending about 1.0 mm into the cornea. The anterior chamber was quiet. Herpes simplex virus and adenovirus complement fixation tests were nonreactive. Anti-VCA antibody titer was 1:20. Case 4. A 25-year-old black woman was seen with a ten-day history of irritation and injection of the right eye. During the preceding three days she had noted a mild decrease in visual acuity. She denied any antecedent flu-like illness. Visual acuity was 20/30 in the right eye. There was no preauricular lymphadenopathy. The conjunctiva was mildly hyperemic with a mild follicular reaction of the superior and inferior tarsal conjunctivae. The cornea contained multiple focal anterior stromal infiltrates extending to the mid-stroma (Fig 4). The opacities were irregular in shape and varied in size from less than .5 mm to 2 mm. The intervening stroma was relatively clear. No iritis was noted. Serologic evaluation revealed that VDRL and MHA-TP were non-reactive. Anti-VCA antibody titer was 1:160 and the antiEBNA titer was less than 1:8. The patient was treated with prednisolone acetate 1%, one drop three times daily. Within four days the patient noted improvement of her symptoms and the visual acuity improved to 20/20-2. Corticosteroid therapy was gradually tapered during the next month. There have been no recurrences during the ten-month follow-up period. Case 5. An 11-year-old Latin American girl developed bilateral red eyes and photophobia during the second week of an infectious mononucleosis-like illness. She was initially treated with topical steroids with some improvement but the symptoms returned after discontinuation of the drug. Subsequently she was treated in Mexico with a variety of topical medications without significant response. The patient was referred for examination five months after the onset of her ocular symptoms. She complained of persistent photophobia, irritation, and watery discharge. The visual acuity was 20/20 in the right eye and 20/20-1 in the left. There was no preauricular lymphadenopathy. The conjunctiva was mildly hyperemic in both eyes. Examination of the cornea revealed bilateral3600 intrastromal vascularization and patchy, multifocal infiltrative keratitis involving the corneal stroma diffusely at all depths (Fig 5). The ocular examination was normal otherwise. MHA-TP was nonreactive. Herpes simplex complement fixation antibody test was positive at 1:32. Antibody titer to adenovirus was 1:8. Serologic testing for EBV-specific antibodies revealed that anti-EBNA antibody test was positive at 1:16 while antiVCA antibody was positive at 1:10,240. One month later the anti-EBNA antibody titer had increased to 1:128 while the antiVCA titer had decreased to 1:1280. The patient was treated with prednisolone acetate 1% one drop every two hours in both eyes. Within four days the patient noted improvement of her symptoms. The corneal infiltrates resolved, leaving fine granular opacities in the stroma. Prednisolone acetate was tapered over a period of two months. The patient has had no recurrences during the nine-month followup period.
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Case 6. A 17-year-old Mexican-American male experienced "redness," photophobia and blurred vision, alternating between both eyes for four years. The most recent recurrence had occurred in the left eye four weeks prior to examination. The patient had been treated for two weeks with dexamethasone 0.1% four times daily with improvement of symptoms. Visual acuity was 20/20 in both eyes. The external examination was unremarkable. Examination of the corneas revealed mid- and deep stromal vessels, most marked along the temporal and inferonasal peripheral cornea in the right eye and the superior and inferonasal peripheral cornea in the left (Figs 6, 7). The vessels were associated with multifocal areas of deep stromal opacification. No iritis was present. Serologic evaluation revealed that both MHA-TP and FT AABS were non-reactive. Herpes simplex and adenovirus complement fixation tests were non-reactive. Anti-VCA antibody was present at a titer of 1:80 and anti-EBNA antibody titer was 1:128. The patient was placed on a two-month tapering regimen of topical corticosteroid. Six weeks following discontinuation of topical steroid, the patient returned with complaints of photophobia and burning sensation in the left eye. Examination revealed a patch of nodular scleritis near the limbus at 3 o'clock. The patient did not return for re-evaluation for 11 months. At the time of his follow-up visit he reported a recurrence of inflammation during the previous month that was being treated with fluoromethalone by his ophthalmologist. Visual acuity remained 20/20 in both eyes. Slit-lamp biomicroscopic examination, however, revealed slight extension of the areas of stromal opacification and slight increase in the extent of the stromal vessels. Laboratory testing for collagen-vascular disease, including tests for rheumatoid factor and LE prep, were negative. Case 7. A 9-year-old white boy developed foreign-body sensation and tearing of the left eye one month after infectious mononucleosis. Examination disclosed multifocal subepithelial infiltrates of the left cornea with minimal conjunctival inflammation and no iritis (Fig 8). Visual acuity was 20/20. He was treated with a variety of topical medications including prednisolone acetate 0.5-1.0% with some response. He was referred for consultation eight months after the onset of his symptoms. At that time his visual acuity was still 20/20 in both eyes. The left cornea contained multiple, pleomorphic anterior stromal opacities with a coarse granular configuration. Confluent clusters of the opacities were present adjacent to the nasal and supero-temporallimbal zones, accompanied by superficial vascularization. In several areas, the overlying epithelium had punctate granularity. Herpes simplex virus and adenovirus complement fixation tests were reactive at 1:8 and 1:16, respectively. Anti-VCA antibody was present at a titer of 1:80.
DISCUSSION Epstein-Barr virus is a DNA virus of the herpesvirus genus, which is the most common etiologic agent of infectious mononucleosis. 1•2 Infection with EBV in childhood usually produces few signs or symptoms. However, if primary infection occurs during adolescence or adulthood, the classic picture of IM consisting of fever, sore throat, generalized lymphadenopathy, and enlargement of the spleen and liver develops in 50% of cases. 3 The reported ocular manifestations of IM encompass 747
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Fig 1. Top left, case L Discrete, granular opacities of the anterior corneal stroma. Fig 2. Top right, case 2. Sharply demarcated ring opacities of the anterior corneal stroma. Fig 3. Second row left, case 3. Pleomorphic, discrete granular opacities of the anterior corneal stroma. Fig 4. Second row right, case 4. Multifocal, pleomorphic infiltrates of the anterior and mid-stroma. Fig 5. Third row left, case 5. Patchy, deep, peripheral stromal infiltrative keratitis. Fig 6. Third row right, case 6. Mid- and deep peripheral stromal infiltrative keratitis. Fig 7. Bottom left, case 6. Multifocal midand deep peripheral stromal infiltrative keratitis. Fig 8. Bottom right, case 7 _Patchy, granular peripheral anterior stromal opacities.
a wide range of clinical signs affecting both the neuroophthalmologic system and the anterior segment. 4 •5 Reported neurologic manifestations include cranial nerve palsies, papilledema, and optic neuritis. 6 - 9 Disease of the anterior segment attributed to EBV-induced IM include follicular conjunctivitis, uveitis, oculoglandular syndrome, dendritic epithelial keratitis, and stromal keratitis. 4•10- 14 Payrau and Hoel described a young man with clinical and serologic (Paul-Bunnell test) evidence of acute IM who developed both epithelial and stromal keratitisY However, the fact that a piece of foreign matter, possibly vegetable in nature, was discovered to be lodged in the corneal stroma in the area of the infiltrate following amelioration of the inflammation, raises the issue of possible existence of other co-factors contributing to or accounting for the corneal disease. In 1980 Pinnolis and associates described a 16-yearold boy who developed multifocal stromal keratitis in both eyes following discontinuation of systemic corticosteroid therapy that had been prescribed to treat systemic complications following IM. 14 The diagnosis of EBV-associated IM was confirmed by a positive Monospot test and significant titers for EBV-specific antibody. Complement fixation tests for adenovirus, herpes simplex virus and cytomegalovirus were all less than 1:8. Although clinical photographs were not available for their patient, their drawings and description indicate that their subject shared several clinical features with our patient group, including the multifocal nature of the infiltrates, the involvement of all levels of the stroma, and the preservation of relatively good visual acuity. The serologic diagnosis of IM has traditionally depended upon the detection of heterophil antibodies, which are immunoglobulins that emerge during the acute infection and are capable of agglutinating sheep and horse erythrocytes. The identification and localization of specific EBV-induced antigens in infected hosts has allowed the development of more sensitive serologic tests for EBV, including tests that detect IgG antibodies, which remain detectable for life. A variety ofEBV-specific antigens have been identified but the most useful and readily available tests are those for antibodies to viral capsid antigen and Epstein-Barr virus nuclear antigen. Antibodies to VCA and EBNA are measured by immunofluorescent techniques. 15 •16 Susceptible individuals have no antibodies to EBV-associated antigens. 15 Individuals who have experienced infection with EBV in the past manifest moderate IgG antibody titers against VCA and EBNA. 15 Patients with acute IM show elevated levels of antibodies against VCA but antiEBNA antibodies are absent (< 1:2) until several weeks or months after the onset of clinical disease. 15 Both antiVCA and anti-EBNA antibodies remain detectable
throughout life. 15 ' 17 Thus the presence of elevated antiVCA antibodies in association with absent or rising (fourfold increase) anti-EBNA antibodies is diagnostic of recent EBV infection. The presence of detectable (> 1:2) levels of anti-VCA and anti-EBNA antibodies is indicative of previous infection with EBV. EBV-specific antibodies are present in 26 to 82% of college students and military cadets in the United States, while under low socioeconomic conditions, early childhood infections prevail so that 50 to 85% of the children acquire antibodies by age 4. 3•18 •19 •20 The identification of our patient group was based upon the distinctive corneal appearances and the temporal association between serologically documented recent infection with EBV or documentation of prior infection with EB virus in association with nonreactive tests for other etiologic agents of multifocal, non ulcerative stromal keratitis occurring in the absence of persistent conjunctivitis, or specific history such as trigeminal zoster or trauma. The corneal opacities observed in our patients were multifocal and pleomorphic. The anterior stromal lesions had a very distinctive appearance of discrete, granular, circular or ring-shaped opacities ranging in size from .1 to 2 mm. The lesions were distributed over the whole cornea and associated with variable degrees of superficial and deep corneal vascularization. The overlying epithelium was intact or had punctate granularity. The intervening stroma was spared. These lesions differed from the adenoviral infection-associated infiltrates, which are soft, spongiform opacities that generally develop sequential to or in association with punctate epithelial keratitis and follicular conjunctivitis, and tend to be confined to the subepithelial and anterior stromal areas without involvement of the mid-stroma. While herpetic keratitis is well-known to manifest a wide variety of corneal signs, the clinical picture manifested by our patients with anterior stromal involvement was very atypical for herpes simplex virus. In contrast, the blotchy, peripheral full-thickness or deep stromal infiltration observed in the second group of patients resembled syphilitic interstitial keratitis and, when unilateral, herpes simplex stromal keratitis. Patients with this form of keratitis were diagnosed on the basis of the serologic evaluation. One patient (case 7) had granular, pleomorphic anterior stromal opacities which clustered in the peri-limbal region. Although herpes simplex virus and adenovirus could not be eliminated as etiologic agents based upon serologic tests, the patient was included in the series based upon the temporal relationship of the onset of ocular signs to infectious mononucleosis and the distinctive corneal findings, which encompassed features of both types of identified keratitis. We believe that the patients that we have described represent a spectrum of ocular disease in keratitis follow-
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ing EBV infection and illustrate several of its characteristics. Corneal disease can be either unilateral (5 cases) or bilateral (2 cases). Four patients had an antecedent flulike illness compatible with IM and in each of these patients ocular symptoms developed one to four weeks following the onset of the systemic illness. In one patient no 1M-like symptoms occurred but serologic testing revealed that the primary infection with EBV had occurred in the recent past. In two patients the long history of the ocular disease prior to the initial evaluation at our facility led to difficulty in identifying a definite temporal link between IM and the onset of ocular symptoms. Six of the seven patients were symptomatic with complaints of irritation, photophobia, and watering. In most cases mild conjunctival hyperemia and mild blurring of vision were also noted. One patient was relatively asymptomatic and was discovered to have corneal opacities during a routine evaluation. Visual acuity was either normal or only minimally reduced in all cases. Following resolution of disease visual acuity improved to 20/15 to 20/ 20 in all six patients for whom follow-up data were available. Because visual acuity is well-preserved and some patients appear to remain relatively asymptomatic, it is likely that some individuals developing keratitis following IM never come to the attention of ophthalmologists. Four patients treated with topical corticosteroids had rapid favorable response to therapy with improvement of symptoms reported within four days in many cases. In two patients the disease became quiescent without therapy and in one of these patients the corneal opacities were noted to fade appreciably during a one year time period. One of the four patients placed on corticosteroid therapy did not return for follow-up evaluation. Two of the remaining three individuals remained free of active disease after discontinuation of therapy for follow-up periods ranging from 9 months to 4 years. One patient experienced recurrent bouts of keratitis in both eyes. Four years after the onset of corneal inflammation this individual also developed nodular scleritis in one eye. Serologic evaluation for auto-immune disease was negative. The possible mechanisms for the development ofEBVassociated keratitis include immunologic and infectious processes. The prompt response of the disease to topical corticosteroid therapy and the apparent resolution of the inflammation without concomitant anti-viral therapy would tend to support an immunologic basis for the corneal inflammation rather than viral replication. If the process is immunologically mediated the cornea may become involved, either because its native keratocytes share a common antigen with EBV or because EBV antigen becomes located within the tissue. Because EBV persists in its host by causing a chronic, low-grade infection (as opposed to latency) with chronic virus shedding and therefore persistent stimulation of the host immune surveillance system, it would be difficult to explain the unilaterality and the lack of recurrence of inflammation in most individuals if a native cell in the cornea shared a common antigen with EBV, unless that antigen is expressed only transiently. 21 •22 It seems more likely that EB 750
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virus or EBV antigen-bearing cells come to locate in the cornea and subsequently become targets for the immunologic defense mechanisms that control spread of infection.
REFERENCES 1. Henle G, Henle W, Diehl V. Relation of Burkitt's tumor-associated Herpes-type virus to infectious mononucleosis. Proc Natl Acad Sci USA 1968; 59:94-101. 2. Henle W, Henle G. Epstein-Barr virus and infectious mononucleosis. N Engl J Med 1973; 288:263-4. 3. Niederman JC, Evans AS, Subrahmanyan L, McCollum RW. Prevalence, incidence and persistence of EB virus antibody in young adults. N Engl J Med 1970; 282:361-5. 4. Tanner OR. Ocular manifestations of infectious mononucleosis. Arch Ophthalmol 1954; 51 :229-41 . 5. Matoba A Y, McCulley JP. Epstein-Barr virus and its ocular manifestations. In: Darrell RW, ed. Viral Diseases of the Eye. Philadelphia: Lea & Febiger, 1985; 112-7. 6. Nellhaus G. Isolated oculomotor nerve palsy in infectious mononucleosis; a report of an unusual case and review of the literature. Neurology 1966; 16:221-4. 7. Slavick HE, Shapiro RA. Fisher's syndrome associated with EpsteinBarr virus. Arch Neurol1981; 38:134-5. 8. Piel JJ, Thelander HE, Shaw BB. Infectious mononucleosis of the central nervous system with bilateral papilledema. J Pediatr 1950; 37: 661-5. 9. Karpe G, Wising P. Retinal changes with acute reduction of vision as initial symptoms of infectious mononucleosis. Acta Ophthalmol1948; 26:19-24. 10. Wechsler HF, Rosenblum AH, Sill CT. Infectious mononucleosis: Report of an epidemic in an army post. Ann Intern Med 1946; 25:236-65. 11. Meisler OM, Bosworth DE, Krachmer JH. Ocular infectious mononucleosis manifested as Parinaud's oculoglandular syndrome. Am J Ophthalmol 1981; 92:722-6. 12. Wilhelmus KR. Ocular involvement in infectious mononucleosis. Am J Ophthalmol1981; 91:117-8. 13. Payrau P, Hoel J. Mononucleose infectieuse et keratite. Bull Soc Ophtalmol Fr 1958; 381-4. 14. Pinnolis M, McCulley JP, Urman JD. Nummular keratitis associated with infectious mononucleosis. Am J Ophthalmol1980; 89:791-4. 15. Henle W, Henle G. Serodiagnosis of infectious mononucleosis. Resident Staff Physician 1981; 27(1 ):37 -43. 16. Henle W, Henle G, Horwitz CA. Epstein-Barr virus specific diagnostic tests in infectious mononucleosis. Hum Pathol1974; 5:551-65. 17. Rickinson AB, Yao QY, Wallace LE. The Epstein-Barr virus as a model of virus-host interactions. Br Med Bull1985; 41:75-9. 18. Henle G, Henle W. Observations on childhood infections with the Epstein-Barr virus. J Infect Dis 1970; 121 :303-10. 19. Henle G, Henle W. Immunofluorescence, interference, and complement fixation techniques in the detection of the herpes-type virus in Burkitt tumor cell lines. Cancer Res 1967; 27:2442-6. 20. Evans AS, Niederman JC, Cenabre LC, et al. A prospective evaluation of heterophile and Epstein-Barr virus-specific lgM antibody tests in clinical and subclinical infectious mononucleosis: specificity and sensitivity of the tests and persistence of antibody. J Infect Dis 1975; 132:546-54. 21. Epstein MA, Achong BG. Pathogenesis of infectious mononucleosis. Lancet 1977; 2:1270-3. 22. Tosato G, Blaese RM. Epstein-Barr virus infection and immunoregulation in man. Adv lmmunol1985; 37:99-149.
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Discussion
by
Chandler R. Dawson, MD The authors present the provocative hypothesis that manifest and inapparent infections with Epstein-Barr virus cause two forms of keratitis: (l) a multifocal anterior stromal keratitis with superficial peripheral vascularization; and (2) a deep stromal patchy multifocal lesion with midstromal vascularization. Epstein-Barr virus was originally isolated in London from a iymphoma specimen obtained by Dr. Denis Burkitt (for whom this tumor is named) in Uganda. Subsequently the virus was shown to cause persistent infections of lymphocytes and, like other human herpesviruses, it causes chronic persistent infections. Epstein-Barr virus causes 56% of infectious mononucleosis. In Africa, however, the virus is the etiological agent of Burkitt's lymphoma. The first group of four cases and case 7 all had discrete lesions of the superficial corneal stroma and two had superficial vascularization. Only one case had a clear-cut relationship to a proven episode of infectious mononucleosis. Among the syndromes that should be considered in the differential diagnosis of such cases are: 1. Epidemic keratoconjunctivitis: this adenovirus syndrome is rarely associated with corneal vascularization and is unlikely when tests for adenovirus complement fixing antibody are negative. 2. Keratoconjunctivitis caused by sexually transmitted strains of Chlamydia trachoma! is can cause subepithelial stromal opacities and superficial vascularization; follicular conjunctivitis was not a prominent feature in these cases, however. 3. Thygeson's superficial punctate keratitis causes granular epithelial lesions that can be recurrent and remittent; it only leads to focal stromal opacities when treated with antivirals. 4. Focal epithelial lesions with herpes simplex virus can be followed by focal anterior stromal opacities often associated
From the Francis I. Proctor Foundation, University of California, San Francisco.
with superficial vessels; the negative CF titers for HSV in cases 1 and 3 rule this out but herpes remains a possibility in cases 2 and 4. 5. Sterile infiltrates with contact lenses. In summary, this first group of cases is indeed consistent with a distinct form of keratitis caused by Epstein-Barr virus. This association, however, cannot yet be stated with certainty, except in case 1. In the second group of cases, the relationship of the disease to EB virus infection is even less suggestive. These individual patients with multifocal midstromal patches of corneal inflammation with vascularization all had evidence of EB virus infection in the past but also had complicating factors. Case 5 had an antibody to herpes simplex, so herpes simplex keratitis cannot be ruled out in this case. In case 6, there had been recurrent episodes of ocular inflammation and these presented both as stromal keratitis and as nodular scleritis. In this second group of cases, the entities to be included in the differential diagnosis include: Syphilitic interstitial keratitis, which is ruled out by a negative serology in cases 5 and 6; Dimmer's nummular keratitis, a syndrome that is not usually associated with neovascularization; Stromal keratitis caused by herpes simplex virus, which cannot be ruled out in case 5; Herpes zoster or varicella infection (unlikely in the absence of skin infections); and Cogan's interstitial keratitis with tinnitus and deafness. Thus, the association with Epstein-Barr virus infection seems even less certain in this group of cases. The authors have presented a challenging hypothesis about the possible role of Epstein-Barr virus infections of the cornea. They have certainly examined the grounds for confirming this disease link by including serological tests to rule out the common causes of confusion: Herpes simplex virus, adenovirus, and syphilis. Ideally, the disease association could be established with even more certainty by demonstrating recent infection during the first few weeks of the corneal disease by demonstrating rising titers (fourfold) or IgM antibody to VCA (fourfold), early antibody, and on absence of late EBNA antibody. This dynamic group will be able to contribute significantly to unravelling this problem in the future.
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Abstract: We have identified seven patients with clinical and serological features suggestive of Epstein-Barr viral (EBV) stromal keratitis. Four had discrete, sharply demarcated, multifocal, pleomorphic or ring-shaped granular anterior stromal opacities with normal inteNening stroma, seemingly distinct from adenoviral or herpes simplex stromal keratitis. Two had soft, blotchy, pleomorphic, multifocal infiltrates, predominantly involving the peripheral cornea at all depths, and with minimal neovascularization, resembling syphilitic stromal keratitis. One patient had features of both forms of keratitis. Our experience suggests that EBV may be more commonly associated with stromal keratitis than recognized previously. [Key words: Epstein-Barr virus, infectious mononucleosis, stromal keratitis.] Ophthalmology 93:7 46-751 , 1986
Infectious mononucleosis (IM) secondary to EpsteinBarr virus infection is a common disease of adolescents and young adults in the United States. 1 However, keratitis in association with IM has only rarely been reported. We have identified seven patients with clinical and serological features suggestive of Epstein-Barr viral stromal keratitis.
CASE REPORTS Case 1. A 20-year-old white woman developed pain, tearing, conjunctival hyperemia and mucopurulent discharge of the left eye within one week of onset of infectious mononucleosis (IM) documented by positive Monospot test. She was treated with prednisolone acetate 1/8% suspension, one drop topicaliy to the left eye four times daily without significant improvement. Subsequent examination by her ophthalmologist revealed multifocal keratitis and she was treated with a topical sulfanomide preparation. The symptoms of irritation and blurred vision persisted for two months but gradually improved. The patient was first referred for examination nine months after the onset of her symptoms. At that time she complained of only occasional, brief episodes of foreign-body sensation, photophobia and tearing of the left eye. Visual acuity was 20/20-3. The conjunctiva was not inflamed. From the Cullen Eye Institute, Baylor College of Medicine, Houston. Presented at an Annual Meeting of the American Academy of Ophthalmology. Supported by Research to Prevent Blindness, Inc. and the Sid W. Richardson Foundation. Reprint requests to Alice Y. Matoba, MD, Cullen Eye Institute, Baylor College of Medicine, 6501 Fannin, Houston, TX 77030.
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Corneal examination revealed multiple discrete anterior stromal opacities scattered throughout the cornea, associated with areas of epithelial granularity or microepithelial defects (Fig 1). In the superotemporal quadrant the anterior stroma had a diffuse, granular quality and multiple superficial vessels were present. There was no iritis. Epstein-Barr anti-viral capsid antigen (VCA) antibody was positive at 1:40. Complement fixation tests for herpes simplex virus (HSV), adenovirus (ADV), and cytomegalovirus were non-reactive. The patient was treated with artificial tears with complete resolution of symptoms over the following six months. No recurrences have been noted during the subsequent four years. Case 2. An 11-year-old white boy developed watering and blurred vision of the right eye two weeks following a mild flulike illness. He noted no pain, photophobia, or injection of conjunctival vessels. The patient was treated by his ophthalmologist with trifluridine and prednisolone acetate 1% topically to the right eye four times daily with slight improvement. He was referred for consultation four weeks after the onset of blurred vision. Visual acuity of the right eye was 20/40. The conjunctiva was not inflamed. The cornea contained multiple ring-shaped well-demarcated opacities in the deep epithelium and anterior stroma consisting of multiple fine punctate opacities (Fig 2). The intervening zones were fairly clear. The opacities ranged in diameter from .1 mm to 1.5 mm. The posterior two-thirds of the stroma was clear. The left eye was normal. Herpes simplex complement fixation antibody titer was 1:8; adenovirus complement fixation antibody test was nonreactive. Anti-VCA antibody titer was 1:80 and anti-Epstein Barr nuclear antigen (EBNA) antibody titer was 1:8. Trifluridine was discontinued and the patient was placed on a tapering regimen oftopical prednisolone acetate. The patient did not return for follow-up examination. Case 3. A 10-year-old white girl was noted by her ophthalmologist to have multiple, discrete, 1 to 2 mm, mid-stromal
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corneal opacities in the right eye during a routine evaluation (Fig 3). One year prior to that visit the ocular examination had been normal and during the preceding year she had noted no flu-like illness or ocular inflammation. During the following year the patient experienced intermittent foreign body sensation of both eyes. The right eye remained uninflamed, however, and the opacities were noted to decrease in density. One year after the corneal lesions were first noted the right cornea contained multiple, patchy, faint anterior stromal opacities, most concentrated centrally and along the superotemporal periphery. Faint neovascularization was present superiorly and inferiorly, extending about 1.0 mm into the cornea. The anterior chamber was quiet. Herpes simplex virus and adenovirus complement fixation tests were nonreactive. Anti-VCA antibody titer was 1:20. Case 4. A 25-year-old black woman was seen with a ten-day history of irritation and injection of the right eye. During the preceding three days she had noted a mild decrease in visual acuity. She denied any antecedent flu-like illness. Visual acuity was 20/30 in the right eye. There was no preauricular lymphadenopathy. The conjunctiva was mildly hyperemic with a mild follicular reaction of the superior and inferior tarsal conjunctivae. The cornea contained multiple focal anterior stromal infiltrates extending to the mid-stroma (Fig 4). The opacities were irregular in shape and varied in size from less than .5 mm to 2 mm. The intervening stroma was relatively clear. No iritis was noted. Serologic evaluation revealed that VDRL and MHA-TP were non-reactive. Anti-VCA antibody titer was 1:160 and the antiEBNA titer was less than 1:8. The patient was treated with prednisolone acetate 1%, one drop three times daily. Within four days the patient noted improvement of her symptoms and the visual acuity improved to 20/20-2. Corticosteroid therapy was gradually tapered during the next month. There have been no recurrences during the ten-month follow-up period. Case 5. An 11-year-old Latin American girl developed bilateral red eyes and photophobia during the second week of an infectious mononucleosis-like illness. She was initially treated with topical steroids with some improvement but the symptoms returned after discontinuation of the drug. Subsequently she was treated in Mexico with a variety of topical medications without significant response. The patient was referred for examination five months after the onset of her ocular symptoms. She complained of persistent photophobia, irritation, and watery discharge. The visual acuity was 20/20 in the right eye and 20/20-1 in the left. There was no preauricular lymphadenopathy. The conjunctiva was mildly hyperemic in both eyes. Examination of the cornea revealed bilateral3600 intrastromal vascularization and patchy, multifocal infiltrative keratitis involving the corneal stroma diffusely at all depths (Fig 5). The ocular examination was normal otherwise. MHA-TP was nonreactive. Herpes simplex complement fixation antibody test was positive at 1:32. Antibody titer to adenovirus was 1:8. Serologic testing for EBV-specific antibodies revealed that anti-EBNA antibody test was positive at 1:16 while antiVCA antibody was positive at 1:10,240. One month later the anti-EBNA antibody titer had increased to 1:128 while the antiVCA titer had decreased to 1:1280. The patient was treated with prednisolone acetate 1% one drop every two hours in both eyes. Within four days the patient noted improvement of her symptoms. The corneal infiltrates resolved, leaving fine granular opacities in the stroma. Prednisolone acetate was tapered over a period of two months. The patient has had no recurrences during the nine-month followup period.
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Case 6. A 17-year-old Mexican-American male experienced "redness," photophobia and blurred vision, alternating between both eyes for four years. The most recent recurrence had occurred in the left eye four weeks prior to examination. The patient had been treated for two weeks with dexamethasone 0.1% four times daily with improvement of symptoms. Visual acuity was 20/20 in both eyes. The external examination was unremarkable. Examination of the corneas revealed mid- and deep stromal vessels, most marked along the temporal and inferonasal peripheral cornea in the right eye and the superior and inferonasal peripheral cornea in the left (Figs 6, 7). The vessels were associated with multifocal areas of deep stromal opacification. No iritis was present. Serologic evaluation revealed that both MHA-TP and FT AABS were non-reactive. Herpes simplex and adenovirus complement fixation tests were non-reactive. Anti-VCA antibody was present at a titer of 1:80 and anti-EBNA antibody titer was 1:128. The patient was placed on a two-month tapering regimen of topical corticosteroid. Six weeks following discontinuation of topical steroid, the patient returned with complaints of photophobia and burning sensation in the left eye. Examination revealed a patch of nodular scleritis near the limbus at 3 o'clock. The patient did not return for re-evaluation for 11 months. At the time of his follow-up visit he reported a recurrence of inflammation during the previous month that was being treated with fluoromethalone by his ophthalmologist. Visual acuity remained 20/20 in both eyes. Slit-lamp biomicroscopic examination, however, revealed slight extension of the areas of stromal opacification and slight increase in the extent of the stromal vessels. Laboratory testing for collagen-vascular disease, including tests for rheumatoid factor and LE prep, were negative. Case 7. A 9-year-old white boy developed foreign-body sensation and tearing of the left eye one month after infectious mononucleosis. Examination disclosed multifocal subepithelial infiltrates of the left cornea with minimal conjunctival inflammation and no iritis (Fig 8). Visual acuity was 20/20. He was treated with a variety of topical medications including prednisolone acetate 0.5-1.0% with some response. He was referred for consultation eight months after the onset of his symptoms. At that time his visual acuity was still 20/20 in both eyes. The left cornea contained multiple, pleomorphic anterior stromal opacities with a coarse granular configuration. Confluent clusters of the opacities were present adjacent to the nasal and supero-temporallimbal zones, accompanied by superficial vascularization. In several areas, the overlying epithelium had punctate granularity. Herpes simplex virus and adenovirus complement fixation tests were reactive at 1:8 and 1:16, respectively. Anti-VCA antibody was present at a titer of 1:80.
DISCUSSION Epstein-Barr virus is a DNA virus of the herpesvirus genus, which is the most common etiologic agent of infectious mononucleosis. 1•2 Infection with EBV in childhood usually produces few signs or symptoms. However, if primary infection occurs during adolescence or adulthood, the classic picture of IM consisting of fever, sore throat, generalized lymphadenopathy, and enlargement of the spleen and liver develops in 50% of cases. 3 The reported ocular manifestations of IM encompass 747
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Fig 1. Top left, case L Discrete, granular opacities of the anterior corneal stroma. Fig 2. Top right, case 2. Sharply demarcated ring opacities of the anterior corneal stroma. Fig 3. Second row left, case 3. Pleomorphic, discrete granular opacities of the anterior corneal stroma. Fig 4. Second row right, case 4. Multifocal, pleomorphic infiltrates of the anterior and mid-stroma. Fig 5. Third row left, case 5. Patchy, deep, peripheral stromal infiltrative keratitis. Fig 6. Third row right, case 6. Mid- and deep peripheral stromal infiltrative keratitis. Fig 7. Bottom left, case 6. Multifocal midand deep peripheral stromal infiltrative keratitis. Fig 8. Bottom right, case 7 _Patchy, granular peripheral anterior stromal opacities.
a wide range of clinical signs affecting both the neuroophthalmologic system and the anterior segment. 4 •5 Reported neurologic manifestations include cranial nerve palsies, papilledema, and optic neuritis. 6 - 9 Disease of the anterior segment attributed to EBV-induced IM include follicular conjunctivitis, uveitis, oculoglandular syndrome, dendritic epithelial keratitis, and stromal keratitis. 4•10- 14 Payrau and Hoel described a young man with clinical and serologic (Paul-Bunnell test) evidence of acute IM who developed both epithelial and stromal keratitisY However, the fact that a piece of foreign matter, possibly vegetable in nature, was discovered to be lodged in the corneal stroma in the area of the infiltrate following amelioration of the inflammation, raises the issue of possible existence of other co-factors contributing to or accounting for the corneal disease. In 1980 Pinnolis and associates described a 16-yearold boy who developed multifocal stromal keratitis in both eyes following discontinuation of systemic corticosteroid therapy that had been prescribed to treat systemic complications following IM. 14 The diagnosis of EBV-associated IM was confirmed by a positive Monospot test and significant titers for EBV-specific antibody. Complement fixation tests for adenovirus, herpes simplex virus and cytomegalovirus were all less than 1:8. Although clinical photographs were not available for their patient, their drawings and description indicate that their subject shared several clinical features with our patient group, including the multifocal nature of the infiltrates, the involvement of all levels of the stroma, and the preservation of relatively good visual acuity. The serologic diagnosis of IM has traditionally depended upon the detection of heterophil antibodies, which are immunoglobulins that emerge during the acute infection and are capable of agglutinating sheep and horse erythrocytes. The identification and localization of specific EBV-induced antigens in infected hosts has allowed the development of more sensitive serologic tests for EBV, including tests that detect IgG antibodies, which remain detectable for life. A variety ofEBV-specific antigens have been identified but the most useful and readily available tests are those for antibodies to viral capsid antigen and Epstein-Barr virus nuclear antigen. Antibodies to VCA and EBNA are measured by immunofluorescent techniques. 15 •16 Susceptible individuals have no antibodies to EBV-associated antigens. 15 Individuals who have experienced infection with EBV in the past manifest moderate IgG antibody titers against VCA and EBNA. 15 Patients with acute IM show elevated levels of antibodies against VCA but antiEBNA antibodies are absent (< 1:2) until several weeks or months after the onset of clinical disease. 15 Both antiVCA and anti-EBNA antibodies remain detectable
throughout life. 15 ' 17 Thus the presence of elevated antiVCA antibodies in association with absent or rising (fourfold increase) anti-EBNA antibodies is diagnostic of recent EBV infection. The presence of detectable (> 1:2) levels of anti-VCA and anti-EBNA antibodies is indicative of previous infection with EBV. EBV-specific antibodies are present in 26 to 82% of college students and military cadets in the United States, while under low socioeconomic conditions, early childhood infections prevail so that 50 to 85% of the children acquire antibodies by age 4. 3•18 •19 •20 The identification of our patient group was based upon the distinctive corneal appearances and the temporal association between serologically documented recent infection with EBV or documentation of prior infection with EB virus in association with nonreactive tests for other etiologic agents of multifocal, non ulcerative stromal keratitis occurring in the absence of persistent conjunctivitis, or specific history such as trigeminal zoster or trauma. The corneal opacities observed in our patients were multifocal and pleomorphic. The anterior stromal lesions had a very distinctive appearance of discrete, granular, circular or ring-shaped opacities ranging in size from .1 to 2 mm. The lesions were distributed over the whole cornea and associated with variable degrees of superficial and deep corneal vascularization. The overlying epithelium was intact or had punctate granularity. The intervening stroma was spared. These lesions differed from the adenoviral infection-associated infiltrates, which are soft, spongiform opacities that generally develop sequential to or in association with punctate epithelial keratitis and follicular conjunctivitis, and tend to be confined to the subepithelial and anterior stromal areas without involvement of the mid-stroma. While herpetic keratitis is well-known to manifest a wide variety of corneal signs, the clinical picture manifested by our patients with anterior stromal involvement was very atypical for herpes simplex virus. In contrast, the blotchy, peripheral full-thickness or deep stromal infiltration observed in the second group of patients resembled syphilitic interstitial keratitis and, when unilateral, herpes simplex stromal keratitis. Patients with this form of keratitis were diagnosed on the basis of the serologic evaluation. One patient (case 7) had granular, pleomorphic anterior stromal opacities which clustered in the peri-limbal region. Although herpes simplex virus and adenovirus could not be eliminated as etiologic agents based upon serologic tests, the patient was included in the series based upon the temporal relationship of the onset of ocular signs to infectious mononucleosis and the distinctive corneal findings, which encompassed features of both types of identified keratitis. We believe that the patients that we have described represent a spectrum of ocular disease in keratitis follow-
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ing EBV infection and illustrate several of its characteristics. Corneal disease can be either unilateral (5 cases) or bilateral (2 cases). Four patients had an antecedent flulike illness compatible with IM and in each of these patients ocular symptoms developed one to four weeks following the onset of the systemic illness. In one patient no 1M-like symptoms occurred but serologic testing revealed that the primary infection with EBV had occurred in the recent past. In two patients the long history of the ocular disease prior to the initial evaluation at our facility led to difficulty in identifying a definite temporal link between IM and the onset of ocular symptoms. Six of the seven patients were symptomatic with complaints of irritation, photophobia, and watering. In most cases mild conjunctival hyperemia and mild blurring of vision were also noted. One patient was relatively asymptomatic and was discovered to have corneal opacities during a routine evaluation. Visual acuity was either normal or only minimally reduced in all cases. Following resolution of disease visual acuity improved to 20/15 to 20/ 20 in all six patients for whom follow-up data were available. Because visual acuity is well-preserved and some patients appear to remain relatively asymptomatic, it is likely that some individuals developing keratitis following IM never come to the attention of ophthalmologists. Four patients treated with topical corticosteroids had rapid favorable response to therapy with improvement of symptoms reported within four days in many cases. In two patients the disease became quiescent without therapy and in one of these patients the corneal opacities were noted to fade appreciably during a one year time period. One of the four patients placed on corticosteroid therapy did not return for follow-up evaluation. Two of the remaining three individuals remained free of active disease after discontinuation of therapy for follow-up periods ranging from 9 months to 4 years. One patient experienced recurrent bouts of keratitis in both eyes. Four years after the onset of corneal inflammation this individual also developed nodular scleritis in one eye. Serologic evaluation for auto-immune disease was negative. The possible mechanisms for the development ofEBVassociated keratitis include immunologic and infectious processes. The prompt response of the disease to topical corticosteroid therapy and the apparent resolution of the inflammation without concomitant anti-viral therapy would tend to support an immunologic basis for the corneal inflammation rather than viral replication. If the process is immunologically mediated the cornea may become involved, either because its native keratocytes share a common antigen with EBV or because EBV antigen becomes located within the tissue. Because EBV persists in its host by causing a chronic, low-grade infection (as opposed to latency) with chronic virus shedding and therefore persistent stimulation of the host immune surveillance system, it would be difficult to explain the unilaterality and the lack of recurrence of inflammation in most individuals if a native cell in the cornea shared a common antigen with EBV, unless that antigen is expressed only transiently. 21 •22 It seems more likely that EB 750
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virus or EBV antigen-bearing cells come to locate in the cornea and subsequently become targets for the immunologic defense mechanisms that control spread of infection.
REFERENCES 1. Henle G, Henle W, Diehl V. Relation of Burkitt's tumor-associated Herpes-type virus to infectious mononucleosis. Proc Natl Acad Sci USA 1968; 59:94-101. 2. Henle W, Henle G. Epstein-Barr virus and infectious mononucleosis. N Engl J Med 1973; 288:263-4. 3. Niederman JC, Evans AS, Subrahmanyan L, McCollum RW. Prevalence, incidence and persistence of EB virus antibody in young adults. N Engl J Med 1970; 282:361-5. 4. Tanner OR. Ocular manifestations of infectious mononucleosis. Arch Ophthalmol 1954; 51 :229-41 . 5. Matoba A Y, McCulley JP. Epstein-Barr virus and its ocular manifestations. In: Darrell RW, ed. Viral Diseases of the Eye. Philadelphia: Lea & Febiger, 1985; 112-7. 6. Nellhaus G. Isolated oculomotor nerve palsy in infectious mononucleosis; a report of an unusual case and review of the literature. Neurology 1966; 16:221-4. 7. Slavick HE, Shapiro RA. Fisher's syndrome associated with EpsteinBarr virus. Arch Neurol1981; 38:134-5. 8. Piel JJ, Thelander HE, Shaw BB. Infectious mononucleosis of the central nervous system with bilateral papilledema. J Pediatr 1950; 37: 661-5. 9. Karpe G, Wising P. Retinal changes with acute reduction of vision as initial symptoms of infectious mononucleosis. Acta Ophthalmol1948; 26:19-24. 10. Wechsler HF, Rosenblum AH, Sill CT. Infectious mononucleosis: Report of an epidemic in an army post. Ann Intern Med 1946; 25:236-65. 11. Meisler OM, Bosworth DE, Krachmer JH. Ocular infectious mononucleosis manifested as Parinaud's oculoglandular syndrome. Am J Ophthalmol 1981; 92:722-6. 12. Wilhelmus KR. Ocular involvement in infectious mononucleosis. Am J Ophthalmol1981; 91:117-8. 13. Payrau P, Hoel J. Mononucleose infectieuse et keratite. Bull Soc Ophtalmol Fr 1958; 381-4. 14. Pinnolis M, McCulley JP, Urman JD. Nummular keratitis associated with infectious mononucleosis. Am J Ophthalmol1980; 89:791-4. 15. Henle W, Henle G. Serodiagnosis of infectious mononucleosis. Resident Staff Physician 1981; 27(1 ):37 -43. 16. Henle W, Henle G, Horwitz CA. Epstein-Barr virus specific diagnostic tests in infectious mononucleosis. Hum Pathol1974; 5:551-65. 17. Rickinson AB, Yao QY, Wallace LE. The Epstein-Barr virus as a model of virus-host interactions. Br Med Bull1985; 41:75-9. 18. Henle G, Henle W. Observations on childhood infections with the Epstein-Barr virus. J Infect Dis 1970; 121 :303-10. 19. Henle G, Henle W. Immunofluorescence, interference, and complement fixation techniques in the detection of the herpes-type virus in Burkitt tumor cell lines. Cancer Res 1967; 27:2442-6. 20. Evans AS, Niederman JC, Cenabre LC, et al. A prospective evaluation of heterophile and Epstein-Barr virus-specific lgM antibody tests in clinical and subclinical infectious mononucleosis: specificity and sensitivity of the tests and persistence of antibody. J Infect Dis 1975; 132:546-54. 21. Epstein MA, Achong BG. Pathogenesis of infectious mononucleosis. Lancet 1977; 2:1270-3. 22. Tosato G, Blaese RM. Epstein-Barr virus infection and immunoregulation in man. Adv lmmunol1985; 37:99-149.
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Discussion
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Chandler R. Dawson, MD The authors present the provocative hypothesis that manifest and inapparent infections with Epstein-Barr virus cause two forms of keratitis: (l) a multifocal anterior stromal keratitis with superficial peripheral vascularization; and (2) a deep stromal patchy multifocal lesion with midstromal vascularization. Epstein-Barr virus was originally isolated in London from a iymphoma specimen obtained by Dr. Denis Burkitt (for whom this tumor is named) in Uganda. Subsequently the virus was shown to cause persistent infections of lymphocytes and, like other human herpesviruses, it causes chronic persistent infections. Epstein-Barr virus causes 56% of infectious mononucleosis. In Africa, however, the virus is the etiological agent of Burkitt's lymphoma. The first group of four cases and case 7 all had discrete lesions of the superficial corneal stroma and two had superficial vascularization. Only one case had a clear-cut relationship to a proven episode of infectious mononucleosis. Among the syndromes that should be considered in the differential diagnosis of such cases are: 1. Epidemic keratoconjunctivitis: this adenovirus syndrome is rarely associated with corneal vascularization and is unlikely when tests for adenovirus complement fixing antibody are negative. 2. Keratoconjunctivitis caused by sexually transmitted strains of Chlamydia trachoma! is can cause subepithelial stromal opacities and superficial vascularization; follicular conjunctivitis was not a prominent feature in these cases, however. 3. Thygeson's superficial punctate keratitis causes granular epithelial lesions that can be recurrent and remittent; it only leads to focal stromal opacities when treated with antivirals. 4. Focal epithelial lesions with herpes simplex virus can be followed by focal anterior stromal opacities often associated
From the Francis I. Proctor Foundation, University of California, San Francisco.
with superficial vessels; the negative CF titers for HSV in cases 1 and 3 rule this out but herpes remains a possibility in cases 2 and 4. 5. Sterile infiltrates with contact lenses. In summary, this first group of cases is indeed consistent with a distinct form of keratitis caused by Epstein-Barr virus. This association, however, cannot yet be stated with certainty, except in case 1. In the second group of cases, the relationship of the disease to EB virus infection is even less suggestive. These individual patients with multifocal midstromal patches of corneal inflammation with vascularization all had evidence of EB virus infection in the past but also had complicating factors. Case 5 had an antibody to herpes simplex, so herpes simplex keratitis cannot be ruled out in this case. In case 6, there had been recurrent episodes of ocular inflammation and these presented both as stromal keratitis and as nodular scleritis. In this second group of cases, the entities to be included in the differential diagnosis include: Syphilitic interstitial keratitis, which is ruled out by a negative serology in cases 5 and 6; Dimmer's nummular keratitis, a syndrome that is not usually associated with neovascularization; Stromal keratitis caused by herpes simplex virus, which cannot be ruled out in case 5; Herpes zoster or varicella infection (unlikely in the absence of skin infections); and Cogan's interstitial keratitis with tinnitus and deafness. Thus, the association with Epstein-Barr virus infection seems even less certain in this group of cases. The authors have presented a challenging hypothesis about the possible role of Epstein-Barr virus infections of the cornea. They have certainly examined the grounds for confirming this disease link by including serological tests to rule out the common causes of confusion: Herpes simplex virus, adenovirus, and syphilis. Ideally, the disease association could be established with even more certainty by demonstrating recent infection during the first few weeks of the corneal disease by demonstrating rising titers (fourfold) or IgM antibody to VCA (fourfold), early antibody, and on absence of late EBNA antibody. This dynamic group will be able to contribute significantly to unravelling this problem in the future.
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