Ocular disease associated with Epstein-Barr virus infection

SURVEY OF OPHTHALMOLOGY VOLUME 35-NUMBER 2-SEPTEMBER-OCTOBER 1990

REVIEW I N MEDICINE,

ALAN SUGAR, EDITOR

Ocular Disease Associated With Epstein-Barr Virus Infection ALICE Y. MATOBA, M .D.

Cullen Eye Institute, Baylor College of Medicine, and Ophthalmology Service, Houston Veterans Administration Medical Center, Houston, Texas

Abstract. Epstein-Barr virus (EBV) is a ubiquitous DNA virus of the herpesvirus genus with a high prevalence rate for antibody (about 90%) in the adult population . It is the most common causative agent of infectious mononucleosis syndrome . During recent years an increasing number of ocular disease entities have been reported to be linked to EBV infection . These entities include oculoglandular syndrome, conjunctivitis, dry eye, keratitis, uveitis, choroiditis, retinitis, papillitis and ophthalmoplegia . While EBV-specific serologic tests can now document recent and past primary infection with EBV and also identify patients manifesting atypical immunologic reactions to EBV, the lack of an animal model, the absence of clear-cut response to therapy and the paucity of documentation by culture render the pathogenesis uncertain or the association questionable in many of these cases . (Sum Ophthalmol 35 :145-150, 1990) dry eye syndrome • Epstein-Barr virus Key words . choroiditis infectious mononucleosis • keratitis • ophthalmoplegia • papillitis or optic neuritis Parinaud's syndrome • retinitis

The Epstein-Barr virus (EBV), a DNA virus of the herpesvirus genus, was first discovered in 1964 .' In 1968 its association with infectious mononucleosis syndrome was reported 15 's4 and in 1973 its etiologic role was clearly established ." The EBV is now known to be the most common causative agent of infectious mononucleosis . The EBV has also been linked to endemic Burkitt's lymphoma," nasopharyngeal carcinoma" and thymic carcinoma ." Recently an association with rheumatoid arthritis' and Sjogren's syndrome" •40 has been suggested . Primary infection with EBV leads to a virus carrier state that persists for life . Cells susceptible to EBV infection include B-lymphocytes," for which the virus exhibits marked tropism, oropharyngeal epithelial cells49 and salivary gland duct cells ." Oropharyngeal epithelial cells permit viral replication in vitro ;" this observation is compatible with the finding that random screening of oropharyngeal

secretions of seropositive individuals reveal detectable virus in 15-60% of subjects ."" B-cell infection with EBV is largely nonproductive, but "spontaneous transformation" of B-cell lines to lymphoblastoid lines permitting EBV genome replication has been observed in cultures ." The diagnosis of IM is based upon the presence of clinical, hematologic and serologic findings . 3119 .30 Clinical features include the classical triad of fever, sore throat and lymphadenopathy with frequent enlargement of the spleen and liver (Table 1) . Prodromal symptoms include chills, sweats, anorexia, malaise, headache, arthralgia and myalgia . The hematologic picture consists of a relative and absolute lymphocytosis in 70% of patients, peaking during the second or third week, and a mild relative and absolute neutropenia .3"9 Mild thrombocytopenia may be seen in 50% of patients .' Usually at least 30% of the lymphocytes are atypical, but the range is 145



1 46

MATOBA

Surv Ophthalmol 35 (2) September-October 1990 TABLE I Infectious Mononucleosis: Clinical Diagnosis 3 Signs/Symptoms

Duration

Onset

Pharyngitis

Presentation

10-14 days

Fever Lymphadenopathy

Presentation Presentation

10-14 days

Generalized fatigue Splenomegaly

Presentation Maximal in second week of illness

2-3 weeks Resolves over next 7-10 days

0-90% . Primary infection with EBV leads to antibody formation directed against viral capsid antigen (VCA), early antigen (EA), and membrane antigen (MA), followed weeks or months later by a serologic response to Epstein-Barr nuclear antigen (NA) ." Primary infection is also accompanied by a wide range of 1gM antibodies with reactivity against "nonrelevant" antigens as well as autoantigens . 79 It is not clear whether this phenomenon is purely a manifestation of the EBV's ability to act as a polyclonal B-cell activator or whether EBV-infected cells express new antigens that were previously not exposed . Cellular responses to primary EBV infection is characterized by the appearance of atypical lymphocytes that are T lymphocytes." "Atypical" Tcells are primarily of the cytotoxic/suppressor (T8+) phenotype manifesting virus-specificity as TABLE 2 EBV-Specific Antibodies. Laboratory Diagnosis 192 ' Mean Titer

Viral Capsid Antigen (V ( A) IgM IgG Nuclear Antigen (EBNA or NA) Early Antigen (FA) Diffuse (EA-D) Restricted (EA-R)

Tonsillar enlargement, pharyngeal edema, palatal petechiae, secondary streptococcal infection may be seen Up to 90%n of patients ; 48-50 degrees C 80-90%0 of patients ; symmetrical posterior cervical involvement most common ; also anterior cervical and submandibular; axillary and inguinal less common 50% of patients

10-15% of patients ; jaundice in 5%

Hepatomegaly

Antibody

Comments

Acute Infection

160 >160

Long Past Primary Infection

Nondetectable >40

<1 ;2*

>40

>40** <10

<10 <10***

*Rises weeks to several months following acute infection . "Observed in over 80% of patients. ***May persist at higher titers in some healthy patients for up to 104 months .

well as more broad-ranging effects .' Recently atypical immunological responses with persistence of serologic profiles suggestive of early primary EBV infection have been noted in patients with persistent infectious mononucleosis-like illness, characterized by chronic debilitating fatigue, 51 '52 sore-throat and lymphadenopathy . Prolonged elevation of antibodies to EBV antigens expressed in productively infected cells (VCA, EA) with low titers of NA antibodies and persistence of suppressor T-cell activity have been documented in some of these patients .' However, at a recent meeting of a working group at the Centers for Disease Control a critical review of viral seroepidemiology revealed a questionable association between this clinical syndrome and EBV . LO The syndrome has been renamed the "chronic fatigue syndrome" to reflect the uncertain association with EBV and its possible heterogeneous nature .

Serologic Diagnosis The serologic diagnosis of EBV infection has depended in the past upon the detection of heterophil antibodies that agglutinate sheep and horse erythrocytes and lyre ox red blood cells in the presence of complement ." Heterophil antibodies, which are of the IgM class, usually achieve peak levels between the second and third week of illness and remain detectable for up to one year ." They are present in 90% of adults with primary EBV infection ." The Monospot test is a rapid slide agglutination test that is fairly specific for EBV infection, with a low frequency of false positive results (<3%) . 19 However, patients with atypical clinical features and patients suspected of infection in the distant past are better evaluated with EBV-specific serologic tests . EBVspecific studies are also useful in evaluating hetero-

EPSTEIN-BARR VIRUS

14i

phil negative patients with IM to distinguish those cases from IM due to other agents such as cytomegalovirus . EBV-specific serologic tests include measurements of antibody levels against VCA, NA and EA (Table 2) . Patients with recently acquired infectious mononucleosis manifest elevated IgM and IgG antibodies to VCA and EA, but NA antibodies are absent until several weeks or months after the onset of clinical disease . The presence of elevated VCA 1gM or lgG antibodies in association with rising (fourfold increase) NA antibodies is diagnostic of recent EBV infection ." Although IgM components become nondetectable, both VCA and NA IgG antibodies remain detectable throughout life . FA antibody is defined as restricted (EA-R) or diffuse (EA-D), based upon their distribution within the host cell . EA-D antibody is present at the time of acute illness but EA-R antibody may not be detectable for several weeks or months . In most cases components decrease to nondetectable levels within six months to three years following the acute illness, but rarely persistence of EA in asymptomatic patients has been reported to Iasi as long as 104 months following infectious mononucleosis ."

Epidemiology Studies published in the 1970s reported that EBV-specific antibodies are present in 26-82% of college students and military cadets in the United

Fig. 1 . Subepithelial infiltrates resembling adenoviral infection-associated keratitis in a patient with recent primary E:RV infection ; complement fixation testing for adenovirus was negative

ophthalmoplegia,s' =;ss' impaired accommodation, 54 and facial nerve palsy .' Retinitis was also reported ." External and anterior segment disease reported in patients with documentation of infection by EBV-specific tests include oculoglandular syndrome, dry eye syndrome, conjunctivitis and keratitis . In 1981 Meisler and coauthors described an eleven-year-old boy with Parinaud's syndrome manifested as inflamed nodular mass formation on the superior tarsal conjunctiva with cervical and preauricular lymphadenopathy .s' The serologic

States . In low socioeconomic conditions, early childhood infection prevails, and 50-85% of the children acquired antibodies by age four . 10,17,95 A recent study of 40 normal individuals detected EBV-specific antibodies in 65% of tear and 87 .5% of serum samples .'

Ocular Manifestations The reported ocular manifestations of systemic E:B V infection involve all segments of the eye . Cases reported prior to the availability of EBV-specific serologic tests were documented by hemagglutination tests and the presence of clinical signs compatible with infectious mononucleosis . Infectious agents other than EBV, including cytomegalovirus and Toxoplasmosis gondii, are capable of producing infectious mononucleosis syndrome, and since differential absorption, which renders the hemagglutination tests more specific was not always performed, these early reports must be critically reviewed . Anterior segment disease reported prior to the availability of virus-specific tests include conjunctivitis," dacryoadenitis, s episcleritis, n keratitis ss and iritis . s s Reported neurologic complications documented only by clinical signs or hemagglutination tests include papilledema, 47• 5 s optic neuritis, Y4

Fig . 2 . Multifocal, granular, discrete, anterior and midstromal opacities in a 20-year-old woman who developed ocular irritation one week following the onset of infectious mononucleosis ; the symptoms improved over two months but the lesions were still present at nine months . Complement fixation tests for herpes simplex virus and adenovirus were non-reactive . (Courtesy of Dan B . Jones .)



148

Surv Ophthalmol 35 (2) September-October 1990

profile was consistent with recent EBV infection . Pflugfelder and associates have reported cases of primary Sjogren's syndrome, which developed immediately after infectious mononucleosis." Subsequently, Pflugfelder and coworkers evaluated patients with aqueous tear deficiency for serologic evidence of EBV infection ." A multivariate analysis of the data showed a significant correlation between severe aqueous tear deficiency and elevated EBV EA titers suggesting that EBV infection may be a risk factor for development of aqueous tear deficiency . Conjunctival inflammation has been reported in association with keratitis, with the description ranging from mild hyperemia to mild follicular reaction of the superior and inferior tarsal conjunctiva 2 8 In 1981 Wilhelmus reported the observation of multiple, diffusely scattered small, dendritic lesions in the cornea of a 16-year-old girl with acute infectious mononucleosis ." Epstein-Barr virus was cultured from the tears and corneal scrapings . Stromal keratitis associated with EBV infection has been reported to involve all layers of the stroma . We have observed two patients with serologic evidence of EBV infection with nondetectable antibody levels for adenovirus who developed corneal subepithelial infiltration resembling adenoviral keratitis 29 (Fig. 1) . One patient, a 29-year-old black woman, had no history of conjunctivitis, while the second patient, a 30-year-old white woman, developed steroid-dependent recurrent subepithelial infiltration lasting for two years following a bout of follicular conjunctivitis. Neither patient could recall an antecedent flu-like illness . In 1980, Pinnolis and associates" described a young boy who developed multiple coin-shaped lesions throughout the corneal stroma following infectious mononucleosis ." More recently we reported seven patients with EBV-associated stromal keratitis2 8 All patients had serologically documented recent primary EBV infection or documentation of prior EBV infection in conjunction with negative serologic tests for other etiologic agents of stromal keratitis . Two forms of EBV-associated keratitis were observed : 1) multiple, granular, well-defined, circular or ring-shaped opacities scattered throughout the anterior and mid-stroma (Fig . 2) ; and 2) multifocal, nonsuppurative keratitis involving the full-thickness or deep layers of the peripheral cornea and associated with various degrees of vascularization (Fig . 3) . In 1987 Wong and coauthors described peripheral keratitis with corneal stromal edema overlying "confluent, geographic patches of white precipitates" in a patient who manifested persistent laboratory and clinical signs of infectious mononucleosis ." Reported ocular disease involving the posterior

MATOBA

Peripheral, deep stromal, recurrent infiltrative keratitis in a 17-year-old patient with elevated antibody titers to VCA and NA . An extensive evaluation for causes of stromal keratitis was otherwise negative . (Courtesy of Dan B . Jones .) Fig. 3 .

segment in patients with evidence of EBV infection includes uveitis in two patients with clinical and serologic signs of "chronic" EBV infection ." These patients had persistently elevated antibodies to EA or persistently elevated IgM antibody to VCA . The acute choroidal lesions were described as "gray to yellow infiltrates," ranging in size from 50 to 500 µn while the older inactive lesions appeared as "punched out areas of pigment epithelial scarring ." Associated vitreous inflammation was noted in all patients . Recently retinitis has been reported in association with acute EBV infection . 29 .48 One patient, a seven-year-old boy had multiple gray white macular lesions 50-75 µm in diameter with mild vitritis, 4s while fluffy white retinitis in the posterior pole with marked vitritis and optic nerve edema was noted in ." Both patients however had a 17-year-old patient serologic evidence of previous infection with Toxoplasma gondii; therefore, the association between EBV infection and retinitis remains uncertain . Reported neurologic complications include Fisher's syndrome, a syndrome of acute ophthalmoplegia, ataxia and areflexia . 50

Treatment Treatment of infectious mononucleosis is largely supportive since the disease is usually self-limited . Limitation of activity is recommended during the acute illness . If splenomegaly is present the patient should avoid contact sports and heavy lifting .' Systemic acyclovir has been shown to inhibit EBV replication in immunocompetent patients with infectious mononucleosis;' ," however, viral replication resumed after cessation of therapy and the observed clinical improvement was undramatic . Sys-

EPSTEIN-BARR VIRUS temic acyclovir is not recommended for the routine treatment of infectious mononucleosis . The treatment of EBV-associated ocular disease is not well established due to the small number of documented cases . The patient with oculoglandular syndrome had no recurrence of the tarsal conjunctival lesions following excisional biopsy ." The regional lymphadenopathy resolved without systemic therapy . The patient with epithelial keratitis had resolution of the lesions after two days of therapy with topical acyclovir .' 6 To my knowledge, only one case of epithelial keratitis has been documented to date ; therefore it is not possible to estimate the natural course of the keratitis nor to judge whether topical therapy is warranted . The treatment of stromal keratitis should depend upon the amount of inflammation present . If the inflammation is very mild or absent, as often is the case in the anterior stromal form of the keratopathy, artificial tears or no treatment is appropriate . If active inflammation is noted topical prednisolone acetate or phosphate 1% one drop QID or every 2 hours is recommended . Concurrent topical antiviral therapy is not necessary if other potential etiologic agents such as herpes simplex has been excluded . Other systemic infections such as Ittes should be considered and excluded in the deep stromal infiltrative form of the keratitis . The panuveitis, choroiditis and papillitis in patients with "chronic" EBV infection can be complicated by macular edema and cataract formation .'" Therapy with corticosteroid and acyclovir (both given systemically and topically) appeared to be of some benefit ; however, neither appeared to reliably induce longterm remission of the inflammation . Neurologic disease should be managed in cooperation with a neurologist . Acyclovir [9-(2-hydroxyethoxy-methyl)guanine] is a synthetic acyclic nucleoside compound with potent inhibitory activity against herpes simplex virus types 1 and 2 and less activity against other members of the herpesvirus genus including varicella zoster virus, Epstein-Barr virus and cytomegalovirus . 45 Acyclovir has been documented to inhibit productive replication of EBV DNA in vitro, but has little effect on nonreplicating EBV genomes .R Recent clinical trials have demonstrated that IV acyclovir can inhibit replication of EBV in oropharyngeal cells . -''" However, acyclovir has no effect on EB V-induced transformation of B lymphocytes nor does it inhibit ERV genome replication in tronpermissively infected cells . Clinical benefit is limited in immunocompetent patients with acute infectious mononucleosis . In immunosuppressed organ allograft recipients with EBV reactivation-associated lymphoproliferative disorders, systemic acyclovir

149 has been reported to be of some benefit ." Ocular formulations of acyclovir are not commercially available at this time . Subconjunctival injection of acyclovir solution has been reported to produce high drug levels in the aqueous of rabbits '46 but ocular penetration of topically applied acyclovir in rabbits has been variable ." ," The role of acyclovir in the treatment of EBV-associated ocular disease is not clear, since the mechanisms of disease production are not well understood .

Summary The reported ocular manifestations of systemic EBV infection are varied and encompass all segments of the eye . Although the granular form of the stromal keratitis is quite distinctive in appearance, most of the reported conditions are less distinctive and are compatible with other etiologic agents . Therefore, ERV infection should be considered in the differential diagnosis of any atypical ocular inflammatory process . The documentation of the association of EBV with ocular disease in the cases reviewed has depended for the most part upon serologic evidence of recent or past EBV infection coupled with negative tests for other potential etiologic agents . Since EBV has not been cultured from any lesions except the corneal microdendrites reported by Wilhelmus' 6 nor have any of the lesions been reproduced by exposure to the virus, the association of many of the ocular abnormalities with EBV remain less than certain . Nevertheless, the serologic abnormalities and in some cases the temporal relation to primary EBV infection are intriguing . The role of this ubiquitous virus in ocular disease remains to be fully delineated .

References 1.

Alspaugh MA, Jensen PC, Rabin H, et a] ; Lymphocytes transformed by Epstein-Barr virus . Induction of nuclear antigen reactive with antibody in rheumatoid arthritis . J Exp Med 147: 1018-1027, 1987

2.

Andersson J, Skoldenberg B, Ernberg 1, et al : Acyclovir treatment in primary Epstein-Barr virus infection . .Scand J Infect Dis Suppl 47:107-115, 1985

3. 4.

Benson CA, Kessler HA : Update : Epstein-Barr virus-related disease . Comprehensive 7lterapv 14 :58-64, 1988 Bernstein TC, Wolfe HG : Involvement of the nervous system in infectious mononucleosis. Ann Ins Med 33 :11201138, 1950

5.

Bo yscziewicz LK, Haworth SJ, Cohen J, et al : Epstein-Barr virus-specific immune detects in patients with persistent symptoms following infectious mononucleosis . Q J Med

6.

Colby 851, Shaw J E, Elion GB, et al : Eflect ofacyclovir 19-(2hydro-xyethoxymethyl)guaninel on Epstein-Barr virus DNA replication . J Virvt 34 :560-568, 1980 Coyle PK, Sihony PA: Viral antibodies in normal tears. Invest

58(226):111-121, 1986

7.

Ophthalznol Vis Sci 29 :1552-1558, 1988 Davie JC, Ceballos R, Little SC : Infectious mononucleosis with fatal neuronitis . Arch Neural 9 :265-272 . 1963 9 . Epstein MA, Achong BG, Barr YM : Virus particles in cultured lymphoblasts from Burkitt's lymphoma . Lancet , :7028.



150

Sure Ophthalmol 35 (2) September-October 1990

703, 1964 10 . Evans AS, Niederman JC, Cenabre LC, et al : A prospective evaluation of heterophile and Epstein-Barr virus-specific IgM antibody tests in clinical and subclinical infections mononucleosis : specificity and sensitivity of the tests and persistence of antibody . ] Infect Dis 132:546-554, 1975 11 . Carzelli C, Taub FE, Scharff JE, et al : Epstein-Barr virustransformed lymphocytes produce monoclonal antibodies that react with antigens in multiple organs .] Virol 52 :722725, 1984 12 . Gerber P, Nonoyama M, Lucas S, et al : Oral secretion of Epstein-Barr virus by healthy subjects and patients with infectious mononucleosis . Lancet ii:988-989, 1972 13 . Grose C, Henle W, Henle G, Feorino PM : Primary EpsteinBarr virus infections in acute neurologic diseases . New Eng] Med 292 :392-395, 1975 14. Hanto DW, Gajl-Peczalska KJ, Frizzera G, ct al : EpsteinBarr virus (EBV) induced polyclonal and monoclonal B-cell lymphoproliferative diseases occurring after renal transplantation. Ann Surg 198 :356-368, 1983 15 . Henlc G, Henle W, Diehl V : Relation of Burkitts tumorassociated Herpes-type virus to infectious mononucleosis . Proc Nail Acad Sri USA 59:94-101, 1968 16. Henle G, Henle W : Epstein-Barr virus-specific IgA serum antibodies as an outstanding feature of nasopharyngeal carcinoma . Ird ] Cancer 17:1-7, 1976 17, Henle W, Henle G : Observations on childhood infections with the Epstein-Barr virus .] Infect Dis 121 :303-310, 1970 18. Henle W, Henle G : Epstein-Barr virus and infectious mononucleosis. New Eng] Med 288:263-264, 1973 19. Henle W, Henle C : Serodiagnosis of infectious mononucleosis . Resident Staff Physician 27:37-43, 1981 20. Holmes GP, Kaplan JE, Gantz NM, et al : Chronic fatigue syndrome : a working case definition . Ann hit Med 108:'387389, 1988 21 . Horwitz CA, Henle W, Henle G, et al : Long-term serologic follow-up of patients for Epstein-Barr virus after recovery from infectious mononucleosis . ] Infect Dis 151 :1150-1153, 1985 22 . Jones BR, Howie JB, Wilson RP : Ocular aspects of an epidemic of infectious mononucleosis . Prac Univ Otago Med Sch 30:1-4, 1952 23 . Karpe G, Wising P : Retinal changes with acute reduction of vision as initial symptoms of infectious mononucleosis . Arta Ophthalmol 26:19-24, 1948 24 . Kelly SP, Rosenthal AR, Nicholson KG, et al : Retinochoroiditis in acute Epstein-Barr virus infection . Br] Ophthalmol 73 :1002-1003, 1989 25 . Lenoir GM : Role of the virus, chromosomal translocations and cellular oncogenes in the etiology of Burkitt's lymphoma, in Epstein MA, Achong BG (eds) : The Epstein-Burr firm: Recent Advances. New York, John Wiley and Sons, 1986, pp 184-207 26 . Leyvraz S, Henle W, Chahinian AP, et al : Association of Epstein-Barr virus with thymic carcinoma . N Engl ] Med 312 : 1296-1299, 1985 27 . Librach IM : Ocular symptoms in glandular fever . Br ] Ophthalmol40:619-621, 1956 28 . Mamba AY, Wilhelmus KR, Jones DB : Epstein-Barr viral stromal keratitis . Ophthalmology 93:746-751, 1986 29 . Matoba AY, Jones DB : Corneal subepithelial infiltrates associated with systemic Epstein-Barr viral infection . Ophthalmology 94:1669-1671, 1987 30 . Mauer AM : Mononucleosis and lymphocytosis, in Stein JH (ed) : Internal Medicine . Boston, Little Brown, 1987, pp 1086-1090 31 . Meister DM, Bosworth DE, Krachmer JH : Ocular infectious mononucleosis manifested as Parinand's oculoglandular syndrome . Am] Ophthalmol 92:722-726, 1981 32. Miller C, Niederman JC, Andrews L : Prolonged oropharyngeal excretion of Epstein-Barr virus following infectious mononucleosis . N Engl ] Med 288:229-232, 1973 33 . Nelhaus G : Isolated oculomotor nerve palsy in infectious mononucleosis . Neurology 16 :221-224, 1966

MATOBA

34. Niederman IC, McCollum RW, Henle G, et al : Infectious mononucleosis : clinical manifestations in relation to EB virus antibodies. ]AMA 203 :205-209, 1968 3 .5. Niederman JC, Evans AS, Subrahmanyan L, et al : Prevalence, incidence and persistence of EB virus antibody in young adults . N Engl ] Med 282 :361-365, 1970 36 . Nilsson K, Klein G, Henle W, Henle G : The establishment of lymphoblastoid cell lines from adult and from foetal human lymphoid tissue and its dependence on EBV . 1nt f Cancer 8:443-450, 1971 37. Pagano JS, Sixties, JW, Lin JC : Acyclovir and Epstein-Barr virus infection . ] Antimirrob Chemother 12/8 :113-121, 1983 38 . Payrau P, U66 3 : Mononucleose intectieuse et keratite . Bull .Soc Ophlalmol Fr 5-6 :381-384, 1958 39 . Pflugfelder SC, Roussel'1], Culbertson WW : Primary Sjogren's syndrome after infectious mononucleosis.]AMNA 25 7_1049--1050, 11987 40 . Pfugfelder SC, Tseng SCG, Pepose JS, et al : Epstein-Barr virus infection and immunologic dysfunction in patients with aqueous tear deficiency . Ophthalmology 97 :313-323, 1990 41 . Pinnolis M, McCulley JP, Urman JD : Nutnmular keratitis associated with infectious mononucleosis . Am ] Ophthalmol 89:791-794, 1980 42 . Poirier RH, Kingham JD, de Miranda P, et al : Intraocular antiviral penetration . Arch Ophthalmol 100:1964-1967, 1982 43 . Raymond LA, Wilson CA, Linnemann Jr CC, et al : Punctate outer retinitis in acute Epstein-Barr virus infection . Am] Ophthalmol 104 :424-426, 1987 44 . Reinhertz El, O'Brien C, Rosenthal P, Schlossman SF : The cellular basis for viral-induced immunodeficiency : analysis by monoclonal antibodies .] Immunol 125 :1269-1274, 1980 45 . Rosenberry KR, Bryan CK, Soln CA : Acvclovir : evaluation of a new antiviral agent . Clin Pharm 1 :399-406, 1982 46. Schulman J, Peyman GA, Fiscella R, et al : Intraocular acyclovir levels after suhconjunctival and topical administration . Br] Ophthalmol 70:138-140, 1986 47 . Shaw EB : Infectious mononucleosis of the central nervous system with bilateral papilledema . ] Pedwtr 37 :661-665, 1950 48 . Sheldon PJ, Papamichail M, Hemsted EH, Holborow EJ : Tltyntic origin of atypical lymphoid cells in infectious mononucleosis . Lancet i:1153-1155, 1973 49 . Sixby JW, Nedrud JG, Raab-'Iraub N, et al : Epstein-Barr virus replication in oropharyngeal epithelial cells . N Engl] ,Wed 310:1225-1230, 1984 50 . Slavick HE, Shapiro RA : Fisher's syndrome associated with Epstein-Barr virus . Arch Neurol 38:134-135, 1981 51 . Straus SE, Tosato G, Armstrong G, et al : Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection . Ann Int Med 102 .7-16, 1985 52 . Straus SF .: The chronic mononucleosis syndrome . ] Infect Des 157:405-412, 1988 53 . Tanner OR : Ocular manifestations of infectious mononucleosis . Arch Ophthalmol 51 :229-241, 1952 54 . Thal LS, Phillips SR, Stark L : Paralysis of accommodation in infectious mononucleosis . Am ] Oplom Physiol Optics 54 :1926, 1977 55 . Tiedeman JS : Epstein-Barr viral antibodies in multifocal choroiditis and panuveitis . Am ] Ophthalmol 103 :659-663, 1987 56 . Wilhelmus KR: Ocular involvement in infectious mononucleosis . Am] Ophthalmol 89 :117-118, 1981 57 . Wolf H, Hairs M, Wilmes E : Persistence of Epstein-Barr virus in the parotid gland .] Virol51 :795-798, 1984 58 . Wong K W, D'Mnico DJ, Hedges TR, et al : Ocular involvement associated with chronic Epstein-Barr virus disease . Arch Ophthalmol 105 :788-792, 1987 59 . Yao QY, Rickinson AB, Epstein MA : A re-examination of the Epstein-Barr virus carrier state in healthy seropositive individuals . Int ] Gower 35 :35-40, 1985 Reprint address : Alice Y . Matoba, M .D ., Cullen Eve Institute, NC-200, 6501 Fannin Street, Houston, TX 77030 .