Systemic viral infections and their retinal and choroidal manifestations

SURVEY OF OPHTHALMOLOGY

MAJOR

VOLUME 37. NUMBER 5. MARCH-APRIL 1993

REVIEW

Systemic Viral Infections Choroidal

Manifestations

SETH

M.D., DAVID J. FORSTER,

L. YOSER,

and Their Retinal and M.D., AND NAR!SING

A. RAO, M.D.

Abstract.

Viruses are one of the most common causes of’infertions involving the posteriw segment of the eye. Such infections can occur either on a congenital or an acquired basis, and may affect primarily the retina or the choroid. Congenital cytomegalovirus (CMV) and rubella infections may result in retinitis. <:MV retinitis is also the most common cause of acquired viral retinitis, primarily because of the acquired immunodefkiency syndrome (AIDS). Other types of viral retinitis, such as those caused by herpes simplex or herpes zoster, can occur in immunoconlprornised or immunocompetent individuals. Ketinitis OI choroiditis caused by viruses such as measles, influenza, Epstein-Barr virus, and Rift Valley tcver vit-us. typically occurs subsequent to an acute ciral systemic illness. ‘[‘he systemic and ocular manifestations, as well as the histopathology, laboratory tests, differential diagnoses. and treatment regimens for each of the individual viruses are discussed in detail. (SUIT Ophthalmol 37:3 13-352, 1993)

Key

words.

simplex retinitis

In the forum

l

l

choroiditis c~tonlcpalovil.Ils AIDS human imlnunodeficienc~ herpes roster Rift Valley f&cl

of infectious

l

l

l

disease,

of the twentieth century saw major the understanding of bacteriology;

the middle

advances into with the ad-

lead

to congenital

abnormalities,

(CMV)

retinitis

rably

progressive

and to appreciate

viral retinopathies,

herpes

condition,

that this inexoleft

untreated,

we have reviewed

the litera-

ture on the commonly responsible DNA and RNA viral agents. Members of the herpesvirus f>imily (CMV, HSV, HZV and EBV) dominate

came studies in virology and the development of antiviral therapy. In utero viral infections were to

l

l

would result in severe visual loss and blindness. Aware of the increasing number of diagnosed

vent of antibiotics, the medical community obtained an invaluable resource in fighting bacterial infections. On the heels of these advances

known

Epstein-Barr virus virus measles -

yet

the discussion

the life-threatening and sight-threatening complications of’ viral infection became increasingly evident with the epidemic of the acquired

of DNA viral infections.

Influenza

A, rubella, rubeola and Rift Valley fever viruses are the focus of RNA viral infections. In this review, we discuss background information, ocular and systemic manifestations, differential diagnosis, laboratory diagnosis, histology, and treatment. Koth congenital and acquired infections are discussed. It is hoped that this review will serve to further enhance the ophthalmologist’s recognition and treatment of the posterior seg-

immune deficiency syndrome (AIDS), with greater numbers of patients on immunosuppressive therapy ti)r organ transplantation, and with widespread use of chemotherapy for various malignancies. RJ the late- 19XOs, most ophthalmologists ~vere able to recognize cytomegalovirus

3 13

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ment manifestations

37 (5) March-April

of virally-mediated

1993

diseases.

I. Cytomegalovirus Cytomegalovirus is an enveloped herpes virus formed by an incosahedral capsid and a doublestranded DNA core. The virus ubiquitously infects the majority of the population at some time in their life, and it has been estimated that at least 80-85% of adults are infected by age 40 (Centers for Disease Control, unpublished). Implicated modes of transmission include: close or intimate contact with individuals shedding the virus in urine, stool, saliva, and other excretions, venereal spread; in utero, natal, or perinatal exposure; and via transfusion of blood products, transplanted organs or breast milk.:j.~3,XA,I4:4,155,4XO CMV infection of immunocompetent individuals usually runs a benign, asymptomatic course; occasionally, however, it is associated with a heterophile-negative mononucleosis syndrome. In both cases, there may be shedding of virus in urine and oral secretions for several months to several years after the acute infection.“‘” Additionally, the virus is capable of establishing a latent infection after primary exposure, with the virus genome persisting in cells even though it is undetectable by conventional culture assays. CMV infection of healthy individuals rarely leads to ocular involvement;‘6~‘“.““.X”‘2”” to our knowledge only two such cases of retinitis have been reported to date.““,“” In contrast, CMV represents a potent opportunistic pathogen in immunocompromised individuals. A. CONGENITAL/PEDIATRIC Congenital centally or

INFECTION

CMV infection can occur transplaby exposure in the birth cana~~14',177.22",?"n Transmission to the fetus occurs in approximately 0.5-25% of all live births.’ While most newborns who shed the virus remain asymptomatic, 5-20% of those who shed virus '4,105,151.?23.24Y,251 will develop symptoms.’ Clinical signs and symptoms are more common in the offspring of women with primary infection than in those whose mothers have recurrent infection. Prospective studies have revealed that 45-91% of pregnant females have serum antibodies to CMV either at conception or at first prenatal visit, which may be protective to the fetus. ‘36 2116.157’17X .187250,254 Overall, 40% of the newborns of mothers who have a primary infection will acquire congenital infections, yet only lo-15% of these will develop clinical manifestations. The classic findings in a symptomatic infant include low birth weight, hepatosplenomegaly, jaundice (due to direct hyperbilirubinemia),

YOSER ET AL petechiae (secondary to thrombocytopenia), microcephaly, intracranial calcifications and ocular findings. ii The reported incidence of retinitis and optic atrophy in congenitally afIlicted infants ranges between 5% and 29%.“‘~1x’~27” In addition, isolated cases of anophthalmia and Peter’s anomaly have been described.8’ Mortality rates among symptomatic infants have been reported to be as high as 30%, and those who survive are at risk for mental retardation, learning disabilities and hearing 1oss.IO5,15I.I67,Z.~I Ten percent of asymptomatic CMV-infected newborns will also eventually develop neurologic and behavioral comp~ications.l05,ljO,l~Y,~~~,~5l

Neonatal CMV infection has not been associated with retinitis, perhaps due to passively acquired maternal immunity, but transfusion of blood from donors with CMV antibody titers greater than 1: 8 can lead to CMV retinitis, as can pediatric AIDS. Congenital and acquired pediatric CMV retinitis has an appearance similar to that seen in immunocompromised adults. The differential diagnosis consists of the TORCH syndrome (TO = toxoplasmosis, R = rubella, C = cytomegalovirus, H = herpes simplex). Serologic tests and cultures from both the mother and neonate can help determine the infectious agent. The treatment of CMV retinitis in neonates and children is not well established. Five case reports have shown beneficial effects of ganciclovir sodium (cytovene, DHPG, etc.) treatment; in two of the five patients the retinitis remained stabilized for at least nine months. As in adults, however, granulocytopenia and thrombocytopenia limit the use of this drug. Furthermore, because of potential longterm carcinogenicity and reproductive toxicity of this drug, it can be recommended only when possible benefits of treatment outweigh the risks.“’ Since virus transmission is easily preventable, the American Public Health Association has published recommendations for women of childbearing age who take care of persons known to have or to be at risk of having CMV infections. In general, these guidelines apply to any woman who is pregnant, and state briefly that good handwashing with soap and water should be performed immediately after exposure to body fluids from any other person (Centers for Disease Control, unpublished). B. ACQUIRED

INFECTION

Acquired CMV infection in the adult is usually the result of an immunocompromised state, e.g., AIDS, lymphoma/leukemia and other malignan-

SYSTEMIC

315

VIRAL INFECTIONS

ties, and chemotherapy used to treat malignancies and to suppress renal or other organ graft rejection. Organs con~n~only infected include the lungs, kidneys, gastrointestinal tract, liver, adrenal glands, salivary glands, pancreas, and central nervous system. Ocular involvement has of renal transplant been reported in l-2% CaSeS,Ti and in 12-46% of AIDS patients.‘“. n4.ll’lil”i.ll’:: Acq,,irect C:MV 1.etinitis wils fi,.st re_ ported by Foerster”!’ in 1959, and until the 1970s there were only scattered case reports. (IMV retinitis has been noted to be the initial presentation of‘disseminated (:MV disease, and in recent puhlications more than 50% of acquired (IMV infections manifested as retinitis alonc.““.““~‘X’” In the early yexs of’ the AIDS epidemic, the median surG\;al of untreated AIDS patients diagnosed with (IMV retinitis was about fbur months fk)m the time of’ initial ophthalmic diagnosis.“‘, Ii,, IXL’. I‘)i.“,,‘i‘2”I Recently, the median survival has been reported as high as eight months trom the time of diagnosis. “’ This increase may stem from earlier diagnosis and treatment of CMV retinitis; the role of antiGral therapy such as AZI‘ in the prolonged surllival is questionable, since most patients are taken off of this medication when they are started on gancicloGr (see below). C. RETINAL

MANIFESTATIONS

Prior to the advent ofAIDS, CMV retinitis was seen almost exclusively in patients with malignancies, organ transplant patients, or patients rec.ei\Gig other immunosuppressive therapy (Fig. 1). .I1 present, the vast majority ot‘cases are AI lX+related. with CMV retinitis being the most common

ocular

infection

in these

patients.x2~‘2”

This retinitis may be unilateral or bilateral; however, unilateral disease often progresses to involve the other eye, presumably via hematogenous spread.“” Spontaneous remission is ~extremely rare. The classic description of (:MV retinitis is one of scattered yellow-white areas of necrotizing retinitis with variable degrees of hemorrhage and mild vitreous inflammation. Indeed, some authors haye described this condition as “cottage cheese Faith catsup” or “pizza pie” retinopathy.“” Initially presenting as small white, granular patches (Fig. 2), these areas continue to enlarge if letiuntreated. Active lesions show white retinal necrosis usually associated with hemorrhage. Often, the retinitis follows a peri~ascular distrihution (Fig. 3). The ad\ancing edge ofthese lesions is visually very sharp and spreads contiguously. FI‘ypically. over several weeks untreated lesions

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Fig. 4. The advancing edges of this CMV retinitis lesion are marked by pronounced vascular sheathing as well as small multifocal white areas in the retina. These findings typically signify activity of the lesion.

Fig. 5. The inferior retina is detached with scarring from CMV retinitis adjacent of detachment (arrows).

in this eye, to the areas

progress to full-thickness necrosis with resultant retinal gliosis and pigment epithelial atrophy. Only one case of an accelerated CMV retinitis, occurring during a one-week period, has been reported.‘“” The pathway of expanding lesions can be predicted by the appearance of venous sheathing or white dots distal to the leading edge, indicative of direct cell-to-cell spread of infection (Fig. 4). Expanding lesions often take on a brushfire border, with the active edge of whitening spreading from the previously infected area. With involvement limited to the peripheral retina, patients either have no subjective complaints, or may complain of floaters. If the retinitis begins in the posterior pole, the patient may notice a visual field deficit. The possible mechanisms for visual loss are direct retinal necrosis by infection, optic nerve involvement, and retinal detachment.“x”,‘“” CMV retinitis may result in either serous or rhegmatogenous retinal detachments (Fig. 5), although the latter are much more common. Rhegmatogenous retinal detachment has been reported in from 13.5-29% of patients with CMV retinitis77’gg’26”and may occur during the active or healed phases of the disease. These detachments are particularly difficult to repair using standard techniques because of the markedly atrophic nature of the previously infected retinal tissue. Most cases, however, can be repaired successfully with the use of silicone oil, which provides a long-acting tamponade to the areas of atrophic retina.58a Optic neuritis caused by CMV has been documented in AIDS patients, and in patients with lymphoma~“,~?,~~.‘6:~The involved optic nerve head is usually swollen and contains focal hemor-

rhages (Fig. 6). Other optic nerve findings have included edema, focal necrosis, atrophy, and hypoplasia.““,l 17,I(iO Regression of CMV retinitis lesions generally requires either initiation of specific antiviral treatment or reduction in dosage of immunosuppressive agents; it rarely occurs spontaneously but has been reported to regress in patients on zidovudine (AZT) alone.““‘““““’ Disappearance of tiny satellite lesions, waning of venous sheathing outside of necrotic areas, cessation of sharp advancing edges, and more grayish appearance all herald the healing stage (Fig. 7). The resultant appearance varies from normal to mottled depigmentation to hyperpigmentation. Calcification may develop in the necrotic and atrophied retina, and the vessels in regressing lesions typically appear sclerotic (Fig. 8). Often, a residual gliotic membrane is present, which acts only as a

Fig. 6. CMV papillitis in a patient with AIDS. Note the primary involvement of the optic nerve head, with spread to the adjacent retina. Visual acuity in this eye was 201200.

SYSTEMIC

VIRAL INFECTIONS

317

/;r,q. 7.

Early resolution phase of <:MV retinitis after initiation of ganciclovir therapy. The white areas of retinitis are becoming granular in appearance, partitularly in the center of the lesion.

Fig. K. I,ona-stantlinl:(:MV retinitis. demonstrating tlensc white ~alrification within the retina as well its occlusion of ttic I-Ctillid vessels in the areas ofprcvious activity.

weak adhesion between the retina and choroid. Persistence of an immunocompromised state may lead to reactivation in spite of therapy (breakthrough retinitis; see below). Such reactivation typically occurs at the edges of previously involved atrophic retina (Fig. 9); it does not occur in areas in which the retina has already been destroyed.

more recently, a form of rapidly progressive outer retinal necrosis described by Forster and colleagues (see below).” Dermatologic manifestations and appropriate cultures and serologic tests may distinguish these entities from CMV retinitis. Unlike CMV retinitis, the ARN syndrome is usually associated with a marked vitritis and is seen in patients with normal immune status. Toxoplasmic retinochoroiditis can simulate CMV retinitis. In toxoplasmic retinitis, the lesions are white with a yellowish tinge, have illdefined margins and are usually associated with an old healed toxoplasma scar of the retinochoroid layer. There are usually prominent inflammatory signs in the vitreous and occasionally in the anterior segment of the eye; inflammatory cell deposits along retinal vessels may be present. Toxoplasma retinitis is usually not associated with systemic disease in immunocompetent incli-

D. CONCOMITANT CONDITIONS

OCULAR

AND SYSTEMIC

Numerous ocular manifestations have been associated with CMV retinitis, including iridocyclitis, punctate keratitis, anterior chamber cell and flare, decreased visual acuity, serous detachment I7.,XL’.!M ” li0.ii.l OR.1 CMV virus retina and uveitis.-, of’ particles have been reported in the aqueous humor and the conjunctiva, though the presence of CMV in the cornea has not been documented.“,““.““’ Cornea1 endothelial changes have been described in eyes with CMV retinitis.‘4’ Autopsy eyes with CMV retinitis occasionally show presence of CMV in the ciliary body and in the vitreous. -1’he most common manifestation of CMV infection in a healthy adult is a heterophile-negative mononucleosis syndrome. In the immunocompromised patient, hepatitis, unexplained fever, pneumonia, neuropathy, carditis, arthritis, meningoencephalitis, and gastrointestinal lesions are commonly found.- ‘6.~X.57.r,ti.“lJn.“sJ.L’7!1 E. DIFFERENTIAL

DIAGNOSIS

‘[‘he difrerential diagnosis of CMV retinitis is long and begins with other viral retinopathies, such as herpes simplex, varicella-zoster, measles, the acute retinal necrosis (ARN) syndrome and,

Fig. 9. Reactivation of a previously latent area of CZMV retinitis. Such reactivation usually occurs along the borders of the atrophic retina, as in this patient.

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viduals, but in patients with AIDS this retinitis is often associated with CNS toxoplasmosis. In patients with AIDS, toxoplasmic retinochoroiditis may not show satellite lesions or pronounced vitritis, and in these patients this protozoa1 retinitis is usually acquired. Fungal retinitis is another important possibility to be ruled out. Candida retinitis is characterized by single or multiple fluffy, moderately discrete retinal lesions with vitreous extension. The retinal and vitreous lesions may have a slightly yellowish, fuzzy appearance with a dense white center. Vitreous abscess formation at or near the retina may be the predominant feature. Inflammatory precipitates may be observed along retinal vessels. Endogenous Candida ocular infections occur in association with debilitating diseases, steroid or antibiotic treatment, chemoand immunosuppressive therapy, and intravenous drug abuse. Patients who have undergone gastrointestinal surgery are also susceptible. Cryptococcal choroiditis, which is usually associated with meningitis, appears as small and sometimes large, moderately discrete retinal lesions with little to marked inflammation. The retinal whitening and hemorrhage seen with CMV retinitis is not a characteristic of this entity. Syphilis can also cause a picture similar to that of CMV retinitis in patients with AIDS. Acquired syphilis can cause a focal or diffuse retinitis, and patients may be coinfected with both syphilis and CMV. Serology for syphilis usually discloses the diagnosis. Generally, a rapid plasma reagin (RPR) or Venereal Disease Research Lab (VDRL) test is used for screening, while a fluorescent treponemal antigen absorption (FTAABS) or microhemaglutination assay for Trefionemu pallidurn (MHA-TP) test is used as a confirmatory test. While the RPR and VDRL may revert to negative after treatment, the FRTA-ABS and MHA-TP remain positive. Several case reports have described Pneumocystis carinii choroiditis in AIDS patients that consists of numerous slightly elevated, plaque-like, yellowishwhite lesions deep to the retina, predominantly in the posterior pole. ‘50.‘59.5’5These, however, do not involve the retina and are not associated with hemorrhage, and thus should not be confused with CMV retinitis. However, as with syphilis, the two may be present concurrently.2’” Branch or central retinal vein occlusions may resemble CMV retinitis,7” as ’ may radiation retinopathy.““” In addition to consideration of the above differential diagnosis, concurrent choroidal or retinal infections may be present, particularly in patients with AIDS. Frequent superinfection with multiple organisms including CMV has

been documented in AIDS patients, and includes herpes simplex virus, Candida, Toxoplasma, various Mycobacteria species, Pneumocystis car21222, Cryptococcus neoformans and bacteria.48a2’gg.2’5 These multiple infections may be present in the eye or may involve nonocular structures, particularly the central nervous system.

F. DIAGNOSTIC

PROCEDURES

Fluorescein angiography in CMV retinitis usually demonstrates delayed arteriolar filling in involved vessels and increased choroidal transmission through areas of destroyed pigment epithelium with areas of pigment clumping blocking transmission in other areas.‘x6’ Marked vascular leakage will occur in some areas, while other areas may demonstrate a relative hypofluorescence (e.g., in areas of white necrosis).‘” Arteriolar narrowing and scattered microaneurysms may also be seen.RJ With regression, scars will continue to reveal late arteriolar filling and a prolonged circulation time. Electrophysiologic studies in one patient with unilateral disease demonstrated slowing with attenuation of the B-wave amplitude in the affected eye; the EOG was normal. The diagnosis of CMV retinitis is usually made based on the characteristic funduscopic findings; however, on rare occasions, the presence of suspicious, mixed, or atypical findings may necessitate laboratory confirmation. Serologic tests may be useful in neonates or infants to help prove a recent or active infection. The complement fixation (CF) test is the most widely used method for measuring antibodies to CMV. This test does not differentiate between IgG or IgM, the latter of which is indicative of active or recent infection. While this method is 90% sensitive in detecting a seropositive patient, immunofluorescence (IF) and ELISA techniques are more sensitive. However, CF is very specific in that it does not crossreact with other herpesviruses.17”.‘“” One report on a small number of patients after primary infection has revealed CF antibody disappearance, leading to a false negative result.‘@’ Although a fourfold rise in antibody titers from convalescent sera (taken approximately lo-14 days following primary infection) is the classic requirement for diagnosing infection, higher increases enhance the likelihood of determining active CMV infection. Large quantities of IgG can lead to false negative results, as IgG has greater affinity for CMV antigen. This is especially true in infected newborns who passively receive large levels of maternal IgG; false negative results in this popu-

SYSTEMIC

VIRAL INFECTIONS

F!q. 10. L@: CMV-infected retinal pigment epithelial cells, demonstrating characteristic intranuclear inclusions (arrows). Note also that there is a perinuclear halo present in the cells (400 x). Right: Cytomegalic cells with intranuclear inclusions (arrows) are seen in an area of retinal necrosis (320 X ).

lation have been reported to be as high as 20%“” Since IgM does not cross the placenta, IgM in cord blood is indicative of in utero infection. Antibody titers are usually of little significance in adults, since most adults will have positive antibody titers. In atypical cases, a vitreous aqueous sample or a chorioretinal biopsy may be obtained for culture or other diagnostic tests. Recovery of CMV in cultures from any body site helps confirm a diagnosis of infection, but as individuals may shed the virus for months to years after infection, biopsy and culture results need to be interpreted in the context of clinical Cultures taken from the signs and symptoms. throat and urine are the most helpful, although subretinal fluid, vitreous, saliva, breast milk, semen, cervical secretions, and buffy coat preparations of lymphocytes have also yielded positive cultures.‘“’ The cytopathogenic effect (WE) of fibroblast destruction after CMV inoculation may not be evident for 4-6 weeks, yet the CPE from inoculated infant urine is seen in as few as 6 days, indicating this source contains the highest CMV titers (Centers for Ijisease Control, unpublished). New techniques exploiting the antigenicity 01 nucleic acid sequence of CMV are being used to simplify diagnosis. Immunofluorescence and immunoperoxidase staining both employ a readily visible antibody marker that binds to CMV antigen. l‘he commercially available kits for the immunofluorescent stains include disrupted whole virus detection (Abbott Labs, N. Chicago, IL), immediate early antigen detection (Ortho Diag-

nostics, Carpinteria, CA), a 43 kb dalton band from glycine extracted CMV antigen, as well as early and late antigen detection (Dako, Santa Barbara, CA). The nucleic acid hybridization (Diagnostic Hybrids, Inc., Athens, OH) methods include in situ DNA hybridization that utilizes specific labeled DNA sequences (known as DNA probes) that are complementary to DNA sequences found in a particular virus, increasing the rapidity and specificity of diagnosis.’ “‘x The polymerase chain reaction (PCR), which amplifies a DNA sequence,‘“’ has seen limited ophthalmic use to date, but it is a highly sensitive and specific test, and may aid greatly in the diagnosis of infectious retinitis when the clinical picture is unclear.“,’

G. HISTOPATHOLOGY Cytomegalovirus produces diffuse and full thickness retinal necrosis. Typically enlarged CMV-infected cells are between 20 and 30 microns in diameter with basophilic intranuclear inclusions measuring 5-10 microns;7 these pathognomonic inclusions give the characteristic “owl’s eye” appearance (Fig. 10). The intracytoplasmic eosinophilic inclusions measure 0.5-I .O micron.“’ Multinucleated giant cells are also often seen. Usually there is a distinct sharp demarcation between normal retina and CMV-infected retina. Retinal vascular endothelium exhibits swollen endothelial cells and lumen narrowing.g4 An exudative retina1 detachment and retinal pigment epithelial atrophy are also observed. A

320 Fig. II.

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37 (5) March-April

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YOSER ET AL

Section through tlle optic

nerve head, demonstrating necrosis secondary to CMV infection. The ne-

crosis involves primarily the prelaminar nerve (60 x ).

mononuclear cell infiltration within the choroid is often noted subadjacent to areas of retinitis. However, this infiltrate is minimal or absent in patients with AIDS. There may be necrosis of the optic nerve. This is usually confined to the lamina cribrosa,‘“” but can extend to involve postlaminar optic nerve (Fig. 11). Immunohistochemical studies may show the presence of viral antigen in the intranuclear or intracytoplasmic inclusion bodies, and the multinucleated giant cells. Positive staining for the viral antigen is seen in various retinal cells including Miiller cells and retinal pigment epithelial cells. Similar positive findings are also seen with the in situ hybridization method. Electron microscopy may reveal necrotic retinal cells, some containing virus particles similar in size and shape to those from the herpesvirus family. These particles may be seen in the nucleus or cytoplasm of infected cells; if free from cells, they will appear with a double-walled envelope formed as a result of extrusion from the nucleus of infected cells. H. TREATMENT CMV retinitis is an often difficult and frustrating disease to treat. I I l.liO.lX2 II95 .203,2L’I Untreated, there is progressive enlargement of retinal lesions, which eventually results in marked visual loss. Irreversible retinal necrosis ultimately results in loss of vision. With the recent FDA approval of ganciclovir, a synthetic acyclovir derivative, and foscarnet, most ophthalmologists now have more ready access to treatment for both sight- and life-threatening CMV infection. Previously tried pharmacologic treatments have included vidarabine (adenosine arabinoside, ~,5.X:~.l’?0.IX:,.“JH ara-A), 4.HY.X4.lHl~,L’II acyclovir, alpha in-

terferon,‘“.*“‘““” broad spectrum antibiotics, antifungal agents, corticosteroids,““B’“7 and transfer factor,‘“” all of which have proved to be of no benefit. Argon laser photocoagulation to the advancing edge of retinitis has also proven unsuccessful.‘“” Organ transplant patients with immunosuppression often experience regression of the lesion(s) with tapering of the immunosuppressive agent.60~‘H2~” Therapy of sight-threatening CMV retinitis needs to be initiated as soon as possible. However, unilateral, small, peripheral areas of CMV retinitis may be observed without therapy, especially since treatment may require the discontinuation of zidovudine (AZT). 1. Ganciclovir Ganciclovir (DHPG, Cytovene) is a synthetic nucleoside analogue of 2’ deoxyguanosine that inhibits replication of all herpesviruses, both in vivo and in vitro. The antiviral activity of this drug is believed to be the result of inhibition of viral DNA synthesis by competitive inhibition of viral DNA polymerases and direct incorporation into viral DNA, resulting in termination of DNA elongation. Numerous clinical studies have substantiated the effectiveness of ganciclovir (Fig. 7).-“J,:17,69.111.121.1?9,1?6,1?7,192.l9~,~2~ Retinitis recurs in almost all cases after termination of treatment (Fig. 9), substantiating that ganciclovir is viroinstatic. III.I’II.I?7,l~i?,lX.,l9G,~~~~ The recommended duction dose of ganciclovir for patients with normal renal function is 5 mgikg (given intravenously over one hour) every 12 hours for 14-21 days. Following induction therapy, the recommended maintenance dose is 5 mg/kg IV over one hour once per day seven days a week. Patients who experience progression of retinitis on

SYSTEMIC VIRAL INFECTIONS

the maintenance therapy should be reinduced on a twice a day regimen. In addition to monitoring serum creatinine levels and adjusting the dose accordingly if there is evidence of renal impairment, neutrophil counts and platelet counts should be performed every one to two days during twice daily dosing and at least weekly thereafter, as granulocytopenia and thrombocytopenia are the most common side effects of ganciclovir. The medication should be withheld if the absolute neutrophil count Falls below 500 cells/mm”. Other side effects include fever, rash, anemia, and abnormal liver function tests.‘“.“.““.‘!” A relatively high prevalence of rhegmatogenous retinal detachment has been noted in eyes following intravenous ganciclovir therapy.” Treatment may enhance the onset of the involutional stage with resoluGon of active disease, while allowing multiple peripheral breaks to form in areas of healed retinitis. Overall, most studies demonstrate improvement or stabilization of vision and/or ophthahnic findings in ovc‘r 80%’ of patients, with many achieving complete remissiori.““~“‘.‘~‘~‘“‘~ ‘S ‘!“‘..‘L’x Breakthrough retinitis appears to range betweell 30 and 50% ,“‘.“‘.“‘.“” and this can usually be treated successfillly with reinduction doses. (:ombination therapy of intravenous ganciclovir and granulocytc-monocyte colony-stimulating factor (GM-<%I;) and ganciclovir combined with CMV hyperimmune globulin are also being evaluated as possible alternative or “salvage” treatments for patients with CMV retinitis that is refractory to systemic ganciclovir therapy alone or who cannot bc treated with adequate doses of the drug because ofsevere neutropenia. (:oncurrent use of zidovudine (Ketrovir, AX) greatly enhances the risk of granulocytopenia, and in most cases the two drugs cannot be used together. In patients who cannot tolerate both medications, dedoxyinosine (ddi) may be used in p 1ace of ziclovudine. :2lternatively, foscarnet could be used in place of ganciclovir. Probenecid and other drugs that inhibit renal tubular secretion or absorption may reduce the renal clearance of’ Sanciclovil-. Furl hermore. drugs such as pcntamidine isethionate, trirnetlioprini/sulfa and anlphotericin B may inhibit bone marrow activity and spel.rrlatogcnesis. Generalized seiLures have been reported in patients using ganciclovir and imipenem-cilastatin sodium.“‘! Accordingly, when consitlcring use of arty potent antibiotic(s) and/or chemotherapeutic agent, potential benefits must be c;u-efJly weighed against possible risks. I nfravitreal ganciclovir has produced favor-

321 “4 ‘Wd. Il14, I I.i.!!lii able results.- .’ The advantages of this route of administration include eliminating the need for hospitalization and catheter-associated septic risks of IV infusion, precluding the myelosuppressive effect of systemic ganciclovir, enabling the patient to remain on concomitant zidovudine therapy, and generally improving the patient’s quality of life. The disadvantages are that the beneficial systemic effects of ganciclovir against disseminated CMV infection are eliminated, and the injections must be repeated on a regular basis (e.;., twice weekly) because of the short half-life of the drug. Potential complications include retinal detachment, vitreous hemorrhage, and endophthalmitis. These occur relatively infrequently, but endophthalmitis did occur in one patient out of a series of five in one study. I”!’The primary indications for intravitreal therapy include severe granulocytopenia precluding the use of systemic ganciclovir, and vision-threatening lesions of the macula and/or optic nerve, which may progress before systemic therapy begins to take effect (often as long as one week after institution of systemic treatment). Kecently, a pilot study was perfbrmed using an intravitreal device which slowly releases ganciclovir.“‘:“’ This device is surgically implanted through the pars plana. In all eyes, regression of CMV retinitis occurred, and no progression occurred fi)r periods ranging from five to greater than 50 weeks. Complications included transient vitreous hemorrhage, astigmatism and suprachoroidal placement of the implant. ‘This device may be ofbenefit in patients who cannot tolerate systemic ganciclovir or foscarnet, but its disadvantages include lack ofsystemic anti-ChlV therapy as well as a useful lif-espan of about four to live months (after which it would need to be replaced). 2. Foscarnet Another agent, trisodium phosplloIioformate (foscarnet, Foscavir), has recently been approved fill- treatment of CMV retinitis. Foscarnet is a pyrophosphate analogue which exerts its antiviral activity by selective inhibition of all herpesvirus DNA-polymeraes at concentrations that do not affect cellular DNA-polymerases. ““’ This drug is presumed to have some anti-HIV activity as well. In Europe, the United States, and Canada, over 200 AIDS patients with CMV infection have been treated with intravenous foscarnet, with resultant clinical improvement in most cases and total regression in a few. I’~l~.l’rri.Ii:~.L’.l:I.L’liX Preliminary clinical experience with f&car-net in

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HIV-negative immunosuppressed hosts (e.g., bone marrow and renal transplant recipients) has also been encouraging.145 Based on data from three multicenter trials of the AIDS Clinical Trials Group (ACTG 015,092, 093), the recommended induction therapy of foscarnet is 60 mg/kg IV every 8 hours for 2 weeks, followed by maintenance therapy (90 mg/kg daily).“” In a study comparing foscarnet to ganciclovir, foscarnet was found to be as effective as ganciclovir in the treatment of CMV retinitis. However, patients treated with foscarnet had an average life expectancy of 12 months vs. 8 months in patients treated with ganciclovir. This difference did not appear to be the result of different antiviral therapy (i.e., AZT). However, in patients with decreased renal function (creatinine clearance < I.2 ml/min/kg), ganciclovir appears to be the drug of choice.72a*256a To date, myelosuppression has not been reported to be a complication of foscarnet ther130.145,155,173,*25,468 Therefore, most patients apy. may be continued on concurrent therapy with AZT. Earlier studies revealed progression of the lesions and relapse in patients on therapy five days a week. As the five-day-a-week regimen did not cause drug toxicity, daily maintenance therapy is now being recommended. Some of the major drawbacks described when this drug has been used on a compassionate basis for serious CMV infection in immunocompromised patients include a rise in serum creatinine level and development of acute renal failure in a few patients,22 infusion-site thrombophlebitis, decrease in hemoglobin, and increase or decrease of serum calcium.‘2g Other reported side effects include lethargy, irritability, tremor, headache, seizures, and status epilepticus, possibly implying some adverse effect on the central and peripheral nervous systems. Central-line associated bacteremia has been reported, and concurrent use of ciprofloxacin appeared to exacerbate renal failure in one patient.lzg Fetal cardiac arrhythmias have occurred with concomitant use of foscarnet and intravenous pentamidine, most likely from a severe acute drop in serum calcium. Rhegmatogenous retinal detachment does occur in a significant number of patients receiving foscarnet, but no direct causal relationship has been proposed. As with ganciclovir, foscarnet is virostatic; therefore, reactivation occurs when the drug is discontinued. A few case reports have documented regression of CMV retinitis in patients receiving only zidovudine (AZT), but this is rare.46.64,‘o’ The

regimen dose has consisted of 200 mg IV every 4 hours daily for as long as active disease is present, and possibly indefinitely. Zidovudine is a dideoxythymidine compound with antiviral activity specific for human immunodeficiency virus (HIV). The mechanism of therapeutic benefit is hypothetical, but argues against direct anti-CMV action, as at least one patient displayed a high titer of CMV in the urine during zidovudine therapy. As CMV and HIV have been documented to be present simultaneously in a few cases of retinitis 25,2’2~z44’45 hypothetical benefits from zidovudine therapy include: (1) enhancement of cellmediated immunity resulting in suppression of CMV replication and infectivity; (2) suppression of HIV replication, thereby reducing HIV-related enhancement of CMV expression; and (3) suppression of HIV.

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II. Herpes

Simplex

Virus

Herpes simplex viruses (HSV) consist of a linear double-stranded DNA with molecule weights ranging from 80 to 150 million, packaged within an icosahedral capsid.226” The outer covering of the virus is a lipid-containing membrane (envelope) which is acquired as the DNA-containing capsid buds through the host inner nuclear membrane. The genome structure of this DNA virus is unusual in that two unique nucleotide sequences are flanked by inverted repeated sequences. Variability between HSV-1 strains results from either variability in the number of repeated sequences in the genome, or from base substitutions which may change an amino acid, or add or delete a restriction endonuclease cleavage site.2”a For practical purposes, HSV isolates obtained from two individuals can be differentiated by restriction enzyme patterns, unless the isolates are from epidemiologically related sources, such as sexual partners, mother-infant pairs, or common source outbreaks4’ Originally, neutralization tests determined the presence of two antigenic types (HSV-1 and HSV-2) of the herpes simplex virus, which has been isolated from multiple visceral and mucocutaneous sites. Both viral subtypes can cause genital and oral-facial infections, and these infections are clinically indistinguishable. However, the frequency of future reactivations of infection appears to be influenced by the anatomic site and virus type. Genital HSV-2 infection is more likely to reactivate and recur than genital HSV-1 infection; conversely, recurrence of oral-labial HSV- 1 infections are more common than those of HSV2.4’ However, in one study of individuals coinfected with HSV- 1 and HSV-2, recurrences were

SYSTEMIC VIRAL 1NFECTIONS more common with HSV-2 regardless of the site (oral-facial vs. genital).‘““” HSV infection of certain cells, neurons in particular, does not always result in virus replication and cell death. Kather, the virus may be maintained in a latent state, with repression of the viral genome, that is compatible with survival and normal cell activity. Subsequent reactivation of the viral genome can occur, resulting in virus replication and, in SOIWZcases, redevelopment of herpetic lesions. Whereas infectious virus is rarely recovered from sensory or autonomic nervous system ganglia dissected from cadavers, such neural cells in organ culture do produce infectious virions known to harbor HSV that are capable of infecting susceptible cells.4’ HSV infections are found worldwide. In many western industrialized countries, the age-specific prevalence rates of HSV-1 infection appear to be decreasing, while those of HSV-2 are increasing. The incubation period of infection ranges from 1 to 26 days (median 6 to X days). The efficiency of transmission is likely to be greater during symptomatic versus asymptomatic periods ofvirus excretion.” Primary infection with HSV occurs in a susceptible host with no HSV antibodies. Type 1 HSV is generally the agent responsible for initial infections in children and for the majority of herpetit eye disease in all age groups.“” However, type 2 HSV has been recovered, albeit rarely, from eyes of both adults and neonates with ocu.?!4,ov~.‘)x”.px:I lar disease., ‘,‘i ” I,,:i.1,%l.,!ll Overall, it is estimated that fewer than 1% of persons infected with HSV develop overt ocular disease, and involvement is usually unilateral.“‘” Furthermore, neonates and children are at much greater risk of’ ocular infection than are adults, except for those adults who are immunocompromised. While conjunctivitis and keratitis are the predominant ocular manifestations of HSV infection, chorioretinitis and chorioretinal scarring occui~ in some neonates.lH4

ofinfection

A. CONGENITAL 1. Systemic

INFECTION

Manifestations

In most reported series, 70% of neonatal HSV cases are due to HSV-2 infection, almost all of which result from contact with infected genital secretions at the time of delivery. Neonatal HSVI infections are usually acquired postnatally through contact with immediate family members who have symptomatic or asymptomatic oral-labial HSV-1 infection, or from nosocomial transmission.” The clinical and ophthalmologic manifestations ofthese two antigenic types of HSV are

323 similar. A wide spectrum exists in the systemic and ocular manifestations of neonatal herpes simplex infection. Typical dermatologic findings consist of red macules that rapidly progress to vesicular eruptions with erythematous bases and an overlying yellow-golden crust. Predominantly, these lesions are found on the eyelids, the per&al area and the trunk. Encephalitis is a common and frequently fatal complication of HSV infection, usually presenting with an acute onset of fever, lethargy, and focal neurologic symptoms, particularly seizures, due to temporal lobe involvement. Prenatal encephalitis can cause congenital malformations such as microcephaly and intracranial calcifications.“.” Other manifestations include esophagitis, pharyngitis, rhinitis, pneumonitis, hepatitis, hepatosplenomegaly, thrombocytopenia, lymphadenopathy, necrotizing enteritis, adrenal necrosis, and glomerulonephritis.” 2. Ocular

Manifestations

Ocular manifestations of neonatal HSV indevelop usually 2-14 days after fections and occur in approximately onebirth, 4T.“1”.‘H”.‘X4 sixth of infected newborns, according to a review article of almost 300 cases.la4 Few of these infants had isolated ocular involvement. The most common ocular finding is conjunctivitis, which, unlike that in the adult, reveals an absence of follicles, at least until the infant is 4-6 weeks of age.‘” Keratitis is the next most reported finding, predisease with diffuse as nonspecific senting fluorescein staining of the epithelium as geographic ulceration of a large area of epithelial defect, or with a classic dendritic pattern. The third most frequent finding is chorioretinitis or chorioretinal scarring, at times presenting as an acute necrotizing retinitis.“‘” Other rnanifestations include cataracts, optic atrophy, optic neuritis, iritis, and microphthalmia. In many instances, the keratitis makes ophthalmoscopy difficult to perform in the neonate. When examination is possible, retinal findings may include whitish-yellow, punctate lesions in both the macula and posterior pole, perivascular sheathing, perivascular hemorrhage, vitreous inflammation, atrophic and noninflamed scars with variable border pigmentation, cicatricial fibrous bands with possible optic disc and retinal traction, normal or atrophic optic disc, retinal pigment epithelium atrophy and vascular tortuosity. Rarely, exudative retinitis and necrosis are seen. 1l1:~.1”2,I_1H,Itir,.L’O~.:!lY.‘LL’1 A recent report discussed the ocular findings

1993

YOSER ET AL

in 32 children with virologically verified HSV infection who were examined one to 15 years after the time of infection.6’” A much higher incidence of ocular involvement (40%) was found in this study than in previous studies. One child had cataracts, two had cornea1 scars, seven had optic atrophy, and nine had chorioretinal scars. The higher incidence of chorioretinal scars in this long-term study may indicate a long latency of the virus in the retinal tissues.

uals.““,” Other ocular manifestations are similar to those seen in neonates, with the most common being keratitis that is heralded by acute onset of pain, blurry vision, chemosis, conjunctivitis, and characteristic dendritic lesions of the cornea. Early funduscopic examination of patients with HSV retinitis will likely reveal perivenous sheathing, flame-shaped hemorrhages, arteriolar narrowing and tortuosity, and retinal edema. In some instances, fine vitreous opacities and yellowish exudative plaques in the macula and posterior pole are present. With appropriate treatment, the exudates and hemorrhages may regress, leaving scars with focal areas of hyperpigmentation. On the other hand, progression of the disease can occur, leading to papilledema, arterial occlusion, and retinal pigment epithelial and choroidal atrophy. Papilledema and subsequent optic atrophy as late findings typically occur as a result of increased intracranial pressure associated with a meningoencephalitis. Retinal tears, multifocal hemorrhages, retinal and preretinal neovascularization, exudative retinal detachment, and areas of full-thickness necrosis may also appear as late manifestations. Some patients with retinal necrosis may present with all the features typical of the acute retinal necrosis (ARN) syndrome. 14.174,197,20”.835.262,27~

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3. Differential Diagnosis The differential diagnosis of HSV retinitis generally consists of rubella, toxoplasmosis, cytomegalovirus, and syphilis (TORCH syndrome). Varicella, tuberculosis and histoplasmosis rarely occur in the newborn.“’ Other possibilities include degenerative diseases and drug-related etiologies. Because maternal IgM antibodies do not cross the placental barrier, the presence in the neonate of IgM antibodies to HSV is diagnostic. of in utero infection. B. ACQUIRED

INFECTION

1. Systemic Manifestations HSV infection in children and adults is similar to that in neonates. Vesicular eruptions are common and can occur on any mucocutaneous surface. Herpetic whitlow, an HSV infection of the finger, is commonly associated with fever, lymphadenitis, and epitrochlear and axillary lymphadenopathy. HSV esophagitis often presents with odynophagia, dysphagia, and substantial weight loss. HSV pneumonitis is uncommon except in severely immunosuppressed patients, and usually progresses to a focal necrotizing form. Other relatively uncommon complications include hepatitis, disseminated intravascular idiopathic coagulation, thrombocytopenia, monoarticular arthritis, adrenal necrosis, glomerulonephritis, pancreatitis and necrotizing enterocolitis. HSV encephalitis, which is the most commonly identified form of acute, sporadic viral encephalitis in the United States, is often fatal and presents with fever, headache, stiff neck and focal neurologic signs, including seizures, aphasias and focal motor and sensory deficits. A number of cases have been associated with retinitis. 14.96,1:~:,.174.197.20~,~~~,~fi~ 2. Ocular Manifestations While most cases of HSV retinitis have occurred in healthy individuals, it is likely that an increasing number of cases may occur in AIDS patients and other immunosuppressed individ-

3. Differential Diagnosis HZV and CMV retinitis most closely mimic this disease, although funduscopic examination usually reveals more extensive intraocular inflammation with HSV retinitis when compared to Cultures and serologic tests CMV infections.“’ are therefore necessary to differentiate the viral cause of retinitis. Another likely diagnosis is the acute retinal necrosis (ARN) syndrome, usually caused by HZV, which differs in clinical presentation from HSV retinitis by the common occurrence of severe vitritis and a high incidence of rhegmatogenous retinal detachment. In addition to herpes zoster, herpes simplex and CMV have both been implicated as etiologies of acute retinal necrosis.44.fi7.‘00~‘66However, the majority of ARN cases caused by HSV are seen in children or young adults. The ARN syndrome was recently reviewed in an excellent report by Duker and Blumenkranz.“xh A further diagnostic possibility is Behget’s syndrome, which is a multisystem disorder characterized by recurrent oral and genital aphthous ulcers and severe uveitis that may lead to blindness. Its incidence ranges from 1: 1000 in Japan to 1: 500,000 in North America While the etiology and pathoand Europe.“’

325

SYSTEMIC VIRAL INFECTIONS genesis remain obscure, it is believed to be an autoimmune disorder. Common ocular findings include iritis, posterior uveitis, retinal vessel occlusion and optic neuritis. The course of Behcet’s retinitis is commonly slowly progressive and is often characterized by exacerbations of increased activity.““,“X C. DIAGNOSTIC

PROCEDURES

Fluorescein angiography in patients with HSV retinitis often reveals diffuse retinal edema with areas of nonperfusion, scattered deep and superficial hemorrhages, arteriolar, capillary and venous leakage and occlusion, hyperfluorescence with blurred margins from acute lesions, increased transmission of the choriocapillaris, denoting areas of pigment epithelial atrophy, and leakage from the optic nerve. Serial studies over a period of time may reveal resolution of areas of leakage and hvperfluorescent acute lesions. loKI!Ix.!!(I~.“ix Acute and convalescent serum can be useful in documenting seroconversion during primary HSV-I or HSV-2 infection. However, only 5%, of patients with recurrent mucocutaneous HSV infection show a fourfold or greater rise in antiHSV antibodies between acute and convalescent sera. Serologic assays are best used to identify persons with past infection.” Laboratory confirmation of HSV infection is best performed by isolation of virus in tissue culture. HSV causes a characteristic cytopathic effect in a variety of cell culture systems; most specimens infected with the virus are identified within 48-96 hours after inoculation. Immunofluorescent assays using monoclonal antibodies and DNA hydridization procedures or other methods are used for detecting HSV from extraocular, genital and oral-labial lesions, as well as from cervical and salivary secretions. Restriction endonuclease analysis of viral DNA can be used to differentiate between HSV-I and HSV-2.” An increase in cerebral spinal fluid and serum antibodies to HSV does occur with most cases of HSV encephalitis; however, these antibody rises rarely OCCUI-prior to 20 days into the illness. Due to the high diagnostic yield and low complication rate. brain biopsy is felt by many to be the most expeditious method to diagnose HSV encephalitis, particularly if typical frontal and temporal lobe lesions are evident on computerized tomography. Some advocate chorioretinal biopsy as a consideration in progressive bilateral sightthreatening inflammation of unknown cause; this procedure has been reported to be without

significant postoperative complications.““.‘““,“” Such chorioretinal tissues are processed for SUCcessful morphologic identification of viral particles, culture of the virus and immunohistochemistry for detection of viral antigens. D. HISTOPATHOLOGY Histologic examination of HSV-infected retina generally reveals acute and chronic inflammation, possibly with hemorrhagic full-thickness necrosis of the retina and retinal pigment epithelium, fibrinoid necrosis and occlusion of retinal arteries and veins, and exudative detachment. “‘i,‘7’~i”ll’Acute and chronic optic nerve inflammation with associated demyelination, choroidal and scleral lymphocytic infiltration, and multinucleated giant cells are also common findings. Intranuclear inclusions are occasionally visible within retinal cells; these inclusions are basophilic F eu 1gen-positive (Cvwdry type A) containing viral DNA. These are similar in appearance to the inclusions seen with CMV (Fig. 10). Electron microscopy readily confirms the presence of virus particles measuring approximately 100 nm in nuclear debris with cytvplasmic vacuoles of macrophages in the optic nerve and retina, in free nuclear debris in the subretinal space, in the nuclear region of dying cells and in many retinal pigment epithelial cells.“9.“” Isolated particles with envelopes, seen in areas of cellular debris, are evidence of ongoing cellular parasitization.‘7’ Immunofluvrescent assays using monoclonal antibodies have detected herpes simplex antigens in all layers of the retina. Monoclonal antibodies can also determine which type of HSV infection is present. The avidin biotin complex (ABC) immunoperoxidase technique is a more recent and apparently equally effective method of localizing HSV antigens.‘“‘,“” In situ DNA hybridization method utilizing the viral genome segments is also found to be a highly sensitive method of detecting the viral genome. E. TREATMENT Therapy for HSV retinitis has centered on two antiviral agents, acyclovir and vidarabine (adenosine arabinoside). For neonatal HSV infection, systemic acyclovir and vidarabine are both effective; the dose for each is 30 mg/kg per day. Recommended adult doses of intravenous vidarabine are 15 mgikg per day over 12 hours, and intravenous acyclovir, given as a 5.0-7.5 mg/kg infusion over one hour at S-hour intervals for 10 days to 4 weeks.” However, in patients with HSV encephalitis, acyclovir is more efficacious than

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vidarabine, and is associated with a lower mortality. The major side effect associated with intravenous acyclovir is transient renal insufficiency, which can usually be avoided by keeping the patient well-hydrated. Dry rash and gastrointestinal intolerance occur rarely. Systemic vidarabine tends to produce more hematopoietic and hepatic toxicity than does acyclovir. Use of simultaneous or separate therapy with systemic corticosteroids is problematic and without documented beneficial eflects. Other experimental agents without documented success in treating HSV retinitis include 5’iodo-2’-deoxyuridine (IDU), interferon, cytarabine, pooled transfer factor and polyriboinosinic acid-polyribocytidylic acid (Poly IC), which is an interferon inducer.5”‘27 IDU was formerly used systematically to treat HSV encephalitis, but because of associated toxicity and lack of demonstrated efficacy, it is now primarily used topically along with topical vidarabine for HSV keratitis and mucocutaneous lesions.“:’ Early diagnosis and urgent administration of appropriate antiviral chemotherapy decreases the likelihood of ocular morbidity although recurrent infection is common among immunocompromised individuals despite therapy.

III. Varicella/Herpes Zoster Virus Varicella-zoster virus (VZV) causes two distinct clinical entities: varicella, or chickenpox, and herpes zoster, or shingles. Chickenpox is usually a benign, albeit highly communicable, illness primarily of childhood, that is characterized by an exanthematous, vesicular rash. With reactivation of latent VZV in sensory (dorsal root) ganglionic neurons, most common after age 50, the disease presents as a dermatomal, vesicular rash, in most cases associated with severe pain. In children, the course of herpes zoster is short, with less pain and motor disturbances. Varicella-zoster virus is a member of the herpesvirus family, and consists of a lipid envelope surrounding an icosahedral nucleocapsid with a central double-stranded DNA core. Only the enveloped virions are infectious.272 The incubation period of chickenpox ranges between 10 and 20 days; patients are infectious approximately 48 hours prior to the onset of the vesicular rash, during the period of vesicle formation (which usually lasts 4-5 days) and until all vesicles are crusted. The onset of shingles is heralded by dermatomal pain that may precede lesions by 48 to 72 hours, followed by erythematous maculopapular rash that rapidly evolves to vesicles. The total duration of disease is generally

YOSER ET AL between 7 and 10 days; long as 2-4 weeks before ma1.‘7’ Similar to other virus family, VZV is also retinitis. A. CONGENITAL

however, it may take as the skin returns to normembers of the herpesimplicated in producing

INFECTION

Congenital varicella infection is rare, but is associated with a mortality rate as high as 30% when maternal disease develops within five days before delivery or 48 hours post-partum.‘7’ Because the newborn does not receive protective transplacental antibodies and has an immature immune system, illness may be exaggerated. Clinical manifestations of congenital infection include atrophic limbs, cicatricial skin lesions, cerebral atrophy, seizures, low birth weight for gestational age, neuropathic bladder, bulbar palsy, hemiparesis, developmental delay and learning difficulties. Ocular manifestations include microphthalmos, cataract and Horner’s syndrome, with chorioretinitis and chorioretinal scars.28,‘5s In the few cases of congenital VZV reported, funduscopic exam has revealed small or large discrete chorioretinal scars consisting of white, elevated, gliotic centers, each surrounded by an irregular ring of black pigment. The optic disc may appear elevated and structurally full or atrophied, with tortuous retinal vessels nearby. Remaining areas of the ftmdus generally appear normal, with frequent sparing of the macula and retinal vessels. The chorioretinitis is typically described as being unilateral.‘““5’ As with other congenital herpesvirus infections, the differential diagnosis consists largely of the TORCH syndrome. B. ACQUIRED

INFECTION

Clinically, varicella/herpes zoster retinitis presents in association with the hallmark maculopapular and vesicular skin lesions of chickenpox or herpes zoster ophthalmicus. Recent studies suggest that VZV is a major cause of the acute retinal necrosis (ARN) syndrome, which is found in otherwise healthy individuals.2”,3’,44~49Patients who are immunocompromised due to leukemia/ lymphoma, chemotherapy, or AIDS appear to be at greater risk of acquiring this infection.‘7*3’B’28 C. RETINAL

MANIFESTATIONS

Presenting signs and symptoms may include blurred vision, decreased visual acuity, headache, eye pain and foreign body sensation, ocular inflammation and concurrent herpes zoster ophthalmicus. 17~3’,‘28While one author has reported a macular lesion and papillitis, with com-

SYSTEMIC VIRAL INFECTIONS

retinal necrosis from herpes zosFig. 12. Peripheral ter infection (A). Rapidly progressive outer retinal necrosis in an HIV-positive patient, (B) right eye, (C) left eye. Note the primary involvement of the outer retina, ahsencc of vascular involvement, and clear media, which distinguish this entity from the acute retinal necrosis (ARN) syndrome (see Fig. 13). Retinal necrosis and atrophy in herpes zoster infection (D, x 400). Electron microscopic examination of the retina revealed viral particles (E, x 104,000).

plete recovery in three weeks,“” more reports exudative chorioretinitis scribe a focal,

deor

Recently, two patients

Forster

and

associatesi’

who had a rapidly

described

progressive

form

necrotizing retinitis, usually peripheral (Fig. 12A), with possible macular extension, occasional hemorrhages, multiple small retinal tears pe-

of retinitis characterized by necrosis of the outer retina (Fig. 12B and C). Both patients had a preceding zoster dermatitis, and evidence of a her-

ripherally, atrophic scarring, central retinal vein occlusion,

petit process was obtained by electron microscopy as well as polymerase chain reaction of retinal biopsies. Both patients showed primary involvement of the outer retina, sparing of the retina1 vasculature, absence of vitritis, development of rhegmatogenous retinal detachment

ritis and optic atrophy, detachments,“l.“X.17”.1”4

unilateral taneously

sheathed vessels, vitritis, optic neu-

retinal edema and retinal These findings may be

or bilateral, and the retinitis may sponregress in occasional cases.

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and poor response to acyclovir. This may represent an atypical zoster infection of the retina in immunocompromised patients. D. CONCOMITANT

OCULAR FINDINGS

The eyelid and lid margins are common sites for the vesicular lesions of chickenpox. Herpes zoster affects the ophthalmic branch (Vl) of the trigeminal nerve in up to 56% of reported cases, and is second only to thoracic zoster in respect to area of involvement. Almost all cases of zoster ophthalmicus are unilateral and associated with tender preauricular or submandibular lymphadenopathy. lg4 The occurrence of conjunctivitis and keratitis from this virus reflects nasociliary nerve involvement.g” The conjunctivitis is usually mild and nonspecific, and the keratitis may be dendritic and similar to that seen with herpes simplex infection. Other common manifestations include cornea1 anesthesia, uveitis, and glaucoma secondary to inflammation. Rarely reported findings include pseudoptosis, proptosis, with extraocular muscle palsy, internal ophthalmoplegia manifested as a dilated, fixed, or poorly reactive pupil, anterior segment ischemia with necrosis, sometimes leading to phthisis bulbi, extrusion of the eyeball, and scleritis.‘“‘,‘!i’ E. CONCOMITANT

SYSTEMIC

DISEASE

The hallmark vesicular lesions of chickenpox appear on the face and trunk in successive crops over a 24 day period, are small and have an erythematous base. Younger children tend to have fewer vesicles than do older individuals. Those who are immunocompromised, particularly with leukemia, often have numerous lesions with a hemorrhagic base, which can take three times as long to heal. Bacterial superinfection of the skin is the most common infectious complication of VZV. The most common extracutaneous manifestation in children is acute cerebellar ataxia, which is relatively benign and rarely requires hospitalization. More serious central nervous system complications include aseptic meningitis, encephalitis, transverse myelitis, and Reye’s syndrome. The most serious complication of chickenpox is varicella pneumonitis, but other rare complications include myocarditis, nephritis, acute glomerulonephritis, arthritis, bleeding diatheses and hepatitis. Chickenpox, and its sequelae, is usually a more severe disease in the adult, but rarely fatal even in immunosuppressed patients.279 The most debilitating complication of herpes zoster, in both immunocompetent and immunosuppressed hosts, is pain associated with acute neuritis and postherpetic

YOSER ET AL neuralgia. F. DIAGNOSTIC

PROCEDURES

Due to the paucity of VZV retinitis cases, and to the relative ease with which the diagnosis is made in most cases, fluorescein angiography, electrophysiology and ultrasound data are lacking. Retinal vasculitis and papillitis were confirmed by fluorescein angiographylg4 in one patient with VZV retinitis. In another patient with congenital varicella, electroretinograms and pattern-reversal visual-evoked potentials were attenuated and degraded. In still another patient, computerized tomography revealed unilateral atrophy and porencephaly of the parieto-occipital region.‘“’ Ultrasonography of the orbit may reveal slight shortening of the anteroposterior diameter, and, when funduscopic examination is not possible, may also reveal retinal detachment and chorioretinal scarring.4’,7g~‘54 Unequivocal confirmation of diagnosis is possible only through the isolation of VZV in susceptible tissue culture cell lines, or by the demonstration of seroconversion or a fourfold or greater rise in antibody titer when comparing acute and convalescent sera. A rapid diagnosis can be achieved by cytology of smears of the scraped base of a vesicular lesion, which may disclose multinucleated giant cells. The most frequently employed serologic tools for assessing host infectivity are immunofluorescent detection of antibodies to VZV membrane antigens, the fluorescent antibody to membrane antigen (FAMA) test, immune adherence hemagglutination or enzyme-linked immunosorbent assay (ELISA). The FAMA and ELISA tests appear to be the most sensitive assays. G. HISTOPATHOLOGY As VZV retinitis rarely necessitates chorioretinal biopsy or enucleation, tissue for histologic examination is not usually obtained. In congenital varicella, the retina is likely to appear immature and poorly differentiated with coloboma and gliosis present. Optic nerve hypoplasia would also be likely to occur. Specimens obtained from patients with acquired zoster retinitis reveal full-thickness or partial thickness (Fig. 12D) necrotizing retinitis, retinal arteritis, and mononuclear inflammatory cell infiltration. Areas of necrosis are sharply demarcated, and intact cells with eosinophilic intranuclear and intracytoplasmic inclusions (confirmed by electron microscopy to be hexagonal nucleocapsids surrounding an electron dense core) are present in the inner nuclear retinal layer.“‘,7” Retinal pig-

SYSTEMIC VIRAL INFECTIONS

329

globulin (VZIG) should be considered for immunosuppressed individuals and those previously uninfected who have had prolonged exposure to or close contact with persons known to be infected with VZV.

IV. Acute Retinal Necrosis

r/g. 13. Peripheral areas of white necrosis in a patient with the acute retinal necrosis (AKN) syndrome. Note also the pronounced vascular involvement (occlrlsion) which is typical of the AKN syndrome hut is not a feature of the rapidly progressive outer retinal necrosis shown in Fig. IL’.

rnent epithelial cells occasionally contain eosinophilic intranuclear inclusion bodies, and thrombosis and endothelial cell necrosis are seen in areas of hemorrhagic retinitis. Viral inclusions are not seen in areas in which the endothelium is intact.” “I

While electron microscopy may reveal the presence of herpesvirus particles (Fig. 12E), immunohistochemical techniques are needed to identify VZV antigens in retinal tissue. Staining with monoclonal antibody has been successful. This antibody detects the major gp98igp62 varicella zoster glycoprotein complex.!” H. TREATMENT

Intravenous acyclovir and vidarabine are the mainstay of therapy in patients with VZV retinitis. The recommended dose of acyclovir is 1500 mgim” every eight hours for seven days. For vidarabine the recommended dose is 10 mg/kg per day in a 12 haul- infusion for five days, both in normal and immunocompromised hosts. Intravenous courses ofacyclovir are often followed by 7-14 days of oral acyclovir as the retinitis regresses~“14.“4271’ Laser photocoagulation is not successful in limiting the spread of the retinitis, but may prevent the spread of retinal detachment posteriol-ly.“7,‘“,i”.‘~~ Interferons have not proved eff ective in treatment of VZV retinitis. While systemic corticosteroids are of questionable benefit in this type of retinitis, topical corticosteroids and acyclovir are beneficial in the treatment ofcorneal and conjunctival infections, as well as in zoster ophthalmicus.“’ immune Prophylaxis with varicella-zoster

Syndrome

The acute retinal necrosis (ARN) syndrome is a relatively newly described, visually devastating disorder.“j4 Since it has been recently reviewed in an excellent report by Duker and Blumenit only briefly here. kranz,“gh we will mention ARN has typically been described in otherwise healthy adults of either sex and any age,‘x”.s”4 but recent reports have described it in immunocompromised patients as well, including patients with AIDS.I”,:“,7!‘.“” In the vast majority of the patients the retinal necrosis syndrome appears to be caused by herpes zoster. However, herpes i~~.15R.l~~l~.L"~i.‘_"~l1.'_,1i.* has been implicated as a simplex causative agent. Clinically, the syndrome may be insidious in onset, with the initial presentation ofa mild anterior uveitis accompanied by blurred vision; in other instances, severe ocular pain may be present. Examination of patients during the early stage of this syndrome may reveal evidence of posterior and anterior uveitis, keratic precipitates, vitreous cells and clouding of the ocular media. The retinitis is often seen first in the peripheral fundus but within a matter of days to weeks, may progress to dramatic whitening of the peripheral retina and retinal pigment epithelium in multifocal and coalescent patches (Fig. 13). Vasculitis involving both arteries and veins is a prominent feature, usually with associated areas of hemorrhage and vascular occlusion. With evolution of necrotizing retinitis, there may be an increase in vitreous turbidity associated with vitreous organization and development of retinal traction. Acute swelling of the optic nerve head and macular edema are often present during the active phase of the disease. If the second eye becomes involved, the clinical course is similar. The subsequent course is one of resolution of the retinal lesions with regression of the retinal whitening, followed by mild pigmentary scarring of the retina with sharp demarcation between normal and affected areas. Regression begins at the outer margin of the lesions and moves centrally; this may be quite rapid, taking only 2-3 weeks. A late sequela is the development of vitreoretinal traction due to organization of the vitreous. This traction leads to retinal tears, retinal detachment, and rhegmatogenous detachment

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in approximately 75% of the ARN syndrome reported cases.‘6*3’,67 Most cases of ARN are diagnosed based on the clinical appearance of the retinitis combined with a moderate to severe vitritis. Serologic investigations should probably be obtained in these patients, even though the sensitivity and specificity of such tests in ARN are unknown. IgG and IgM antibodies to HSV-1 and 2, VZV, and CMV should be obtained. A positive IgM titer is strong evidence of a recent infection, but a positive IgG titer merely indicates an infection with that particular virus at some time in the past. Convalescent titers may be obtained 4-6 weeks after the acute stage; a fourfold increase in titer is likewise suggestive of a recent infection, but is not beneficial in identifying the causative organism during the acute stage when therapy must be initiated. In cases where the diagnosis is unclear, diagnostic vitrectomy and/or retinal biopsy may be indicated.“,” This may allow the demonstration of virus particles by electron microscopy within the retinal tissue and necrosis of the retina.44.‘“” Cultures of biopsy specimens are only rarely positive, but a negative culture in no way rules out the possibility of a viral etiology. It has been demonstrated that cultures may be negative even in the presence of numerous viral inclusions on electron microscopy.7g Specific viral agents may only be identified using immunohistochemical stains or in situ hybridization. Both of these techniques can be performed relatively quickly (in l-2 days) using formalin-fixed tissue.” Previous studies have demonstrated herpesvirus antigens on vitreous cells,‘“’ intraocular herpesvirus antibody synthesis,‘~“~‘66~‘20~z66 circulating immune complex formation,‘@ and isolation of varicella zoster virus from an enucleated eye using tissue culture and immunocytologic techniques,45 lending support to the argument that these viral agents are causative organisms in ARN. While controlled randomized prospective studies have not been conducted, most authorities agree that acyclovir (1500 mg/m’/day in 3 divided doses) should be used for 7-2 1 days, and be followed by oral acyclovir 400 mg five times per days for 4-6 weeks. In one study, treatment led to regression of the retinal lesions after an average of 3.9 days, with no progression of existing lesions and no development of new lesions.‘” Treatment did not ameliorate vitritis, or prevent retinal detachment or involvement of the contralateral eye; however, no ocular or systemic complications occurred. Oral administration of acyclovir at 400 mg five times a day results in

YOSER ET AL aqueous levels above the ED,, for herpes viruses, but higher intraocular levels are achieved with intravenous administration; therefore this route is preferred in the initial stages of the disease. Corticosteroids in the treatment of ARN remains controversial. While they may be effective in treating the severe vitritis which often accompanies ARN, they have permissive effects on herpesviruses and thus should be used judiciously, generally after treatment with acyclovir has begun. Cytotoxic agents such as chlorambucil are contraindicated because of their immunosuppressive effects.“x The natural history of classic ARN syndrome indicates a generally poor prognosis in untreated eyes, with only 28% obtaining a final vision better than 201200, because of rhegmatogenous retinal detachment, optic nerve dysfunction or macular pathology. The use of microsurgical techniques, including prophylactic vitrectomy, scleral buckling, intravitreal silicone injection and demarcating laser photocoagulation, leads to a high percentage of retinas being anatomically attached, although multiple procedures are commonly required.‘“*” Despite the fact that the vitritis is particularly responsive to high dose corticosteroids, it is often followed by severe vitreous organization, membrane formation and vitreoretinal traction,‘” and the prevention of retinal detachment remains the major obstacle to successful treatment of this disorder.

V. Epstein-Barr

Virus

The Epstein-Barr virus (EBV) contains a double-stranded DNA core surrounded by an icosahedral nucleocapsid and complex envelope and is morphologically indistinguishable from other herpesviruses. It is a B lymphotrophic virus ubiquitously found worldwide. There is no convincing evidence that strain differences among EBV isolates account for the wide range of clinical conditions associated with EBV infection. EBV is transmitted primarily in saliva, although it can be transmitted by blood transfusions. Primary EBV infection tends to occur at an earlier age among lower socioeconomic groups and in In industrialized coundeveloping countries. tries, approximately 50% of individuals have had a primary EBV infection by adolescence, either clinically unapparent or mild and nonspecific. A second wave of seroconversions to EBV occurs with the onset of social activity associated with adolescence and young adulthood. Primary EBV infection among this age group accounts for most cases of infectious mononucleosis (IM), with peak incidence between 14 and 16 years for

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SYSTEMIC VIRAL INFECTIONS girls and 16 and 18 years for boys. By adulthood, most individuals are EBV-seropositive.““7 EBV is shed from the oropharynx for up to 1X months following infection; thereafter, even in the absence of clinical illness, it continues to be shed intermittently by all seropositive individuals. While EBV can be isolated from oropharyngeal washings of 15-25% of healthy seropositive individuals on any given day, immunosuppressed individuals shed the virus more frequently. Asymptomatic shedding of EBV by healthy individuals accounts for most of the spread to uninfected members of the population. While transmitted by saliva, the initial site of replication is the oropharynx. B lymphocytes support a productive infection by EBV and are the only cells known to have surface receptors for the virus. After the infection subsides, the virus can be isolated from a small number of B lymphocytes of EBV-seropositive individuals and may also be found within nasopharyngeal epithelial cells.“” During the primary immune response to EBV, global cellular immune hyporesponsiveness is readily demonstrable. l‘his resolves after resolution of the illness, but reactivation of EBV is facilitatecl by conditions that interfere with the cellular immune response. The cellular hyporesponsiveness associated with EBV reactivation is generally less intense and of shorter duration than that associated with CMV, but may also contribute to morbidity in immunocompromised individuals.“” A. SYSTEMIC MANIFESTATIONS ‘l-he role of EBV as the etiologic agent of infectious mononucleosis (IM) was established in 1973.” ‘After an incubation period of 4-8 weeks, prodromal symptoms of malaise, anorexia, and chills frequently precede by several days the onset of fever, pharyngitis, and lymphadenopathy. Most patients also complain of headache and malaise and, less frequently, of abdominal pain. Fever is present in SOY%of patients with IM, may reach 39-40X, and is generally higher in the late afternoon. The pharyngitis is usually diffuse, with an exudate observed in one-third of the cases. Posterior and/or anterior cervical adenopathy is present in 90% of patients with IM. Other possible findings include periorbital edema, mild hepatic tenderness, hepatomegaly, splenomegaly, and a macular, petechial, scarlatiform, urticarial or erythema multiforme-like rash. Administration of ampicillin results in a pruritic, maculopapular eruption in 90-100%) of the patients.“‘” Most reports of‘ocular manifestations of

EBV are in association with IM. EBV infection is also associated with Burkitt’s lymphoma, more so in the African population than the American population. EBV has also been found in anaplastic nasopharyngeal carcinoma, which is a common neoplasm in southeast China. EBV nucleic acid sequences are detectable in up to half of the B-cell malignancies encountered in immunosuppressed individuals.“” B. OCULAR

MANIFESTATIONS

Conjunctivitis is the most commonly reported ocular manifestation of IM. -I‘he conjunctivitis is usually follicular, appears early in the course of the disease, may be unilateral, and is mild and self-limited. l’he keratitis associated with IM is epithelial and rarely stromal. Infrequent complications of IM include iritis, uveitis, episcleritis, dacryoadenitis, cranial nerve palsies and l’arinaud’s oculoglandular syndrome.“” Overall, few case reports exist of EBV chorioretinitis. Indeed, the majority of cases described in the literature are from at least 30 years ago. The earliest report of ophthahnoscopic findings in IM was that of Clemens”’ in 1907, who noted “optic neuritis” or “hyperemia of the discs,” with no more detailed description. He also noted an abnormal leukocytosis in the blood cell count.“’ Karpe and Wising I”’ in 1948, were the first to attribute retinitis to IM. Their account described a patlent with acute loss of vision due to severe retinal edema. Later, optic nerve swelling and papillitis developed, and eventually macular edema appeared, associated with a large, dense central scotoma. The lesion later regressed, leaving extensive pigmentary changes in the macula. In the 195Os, several case reports noted an association between bilateral papilloretinal edema, retinal hemorrhages, optic neuritis, optic nerve edema, swelling or hyperemia with IM.“‘.‘‘-““‘,““” In the past few years, some case reports have again associated posterior segment clisease with EBV infection. Kaymond et al”” reported a case of punctate outer retinitis in a patient with acute EBV infection and IM. They described retinal pigment epithelial pigment clumping and depigmentation near the macula, gray-white deep retinal lesions with indistinct borders in the peripheral retina, and cells in the vitreous. ‘I‘iedeman”” reported a syndrome of multifocal choroiditis, pigment epithelial disturbance, and inflammatory cells in the vitreous in patients with serologic evidence of EBV infection. These patients were generally healthy and had no history of a clinical episode of IM. Ophthalmoscopic findings included active lesions appearing as gray to yellow

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Fig. 14.

Patient with presumed Epstein-Barr virus (EBV)-related choroiditis, demonstrating peripheral punched-out lesions similar to those seen in the presumed ocular histoplasmosis syndrome (POHS).

Fig. 15.

infiltrates in the periphery and posterior pole, while older inactive lesions appeared as punched-out areas of pigment epithelial scarring, similar to those seen in ocular histoplasmosis (Fig. 14). Other findings included localized accumulations of subretinal fluid around some active lesions, pigment epithelial metaplasia or fibrosis bridging some lesions, macular disciform scars, and a peripapillary neovascular membrane (Fig. 15). The role of EBV in this syndrome is unknown, as no attempts at virus isolation were made. Also, a recent study failed to demonstrate evidence of chronic EBV infection in patients with multifocal choroiditis and panuveitis.‘46”

tients in Tiedeman’s report. Another consideration in the differential

C. DIFFERENTIAL

DIAGNOSIS

The differential diagnosis in patients with multifocal choroiditis includes the presumed ocular histoplasmosis syndrome (POHS), which is apparently caused by infection with the fungus Histoplasma capsdatum, and which is confined to individuals who have lived for some time in areas endemic for histoplasmosis. About 88% of affected patients display cutaneous hypersensitivity to histoplasmin; chest and abdominal x-rays show calcified scars in the lungs and spleen. The clinical triad of this syndrome consists of punchedout, discrete chorioretinal scars observed frequently only outside the vascular arcades, with occasional pigment dots, peripapillary atrophy, and a macular subretinal neovascular membrane; a disciform macular scar may also be present. There may be an association with human leukocyte antigens HLA-B7 and HLA-DRwe.‘“” However, patients with POHS do not have inflammatory cells in the vitreous, as did the pa-

Same patient as in Fig. 14, showing subretinal neovascular membrane in the fovea, with subretinal exudation and hemorrhage. There is a surrounding serous detachment of the retina as well (arrows).

diag-

nosis is recurrent multifocal choroiditis, or multifocal choroiditis and panuveitis.‘“,“x,‘x” This is a syndrome which is usually bilateral, with a predilection for females in their 20s and 30s. It is characterized by multiple discrete lesions in the posterior pole at the level of the retinal pigment epithelium and choriocapillaris, with cells in the vitreous cavity and/or anterior chamber. There may be associated disc edema, and frequently the eyes develop macular subretinal neovascularization or progressive subretinal fibrosis. In some instances, the condition responds well to corticosteroid treatment, but patients may experience multiple recurrences. There may be a preceding viral or flu-like illness, but no specific systemic abnormality has been found to be associated with this entity. The multiple evanescent white dot syndrome (MEWDS) is another entity which must be considered.‘“” It, too, affects mostly females in the second through fourth decades of life, but is usually unilateral. There are numerous small white dots in the posterior pole at the level of the RPE or deep retina, associated with an acute unilateral loss of vision. The lesions resolve over a period of several weeks with return of vision to near normal. Acute retinal pigment epitheliitis is an uncommon condition which affects young to middleaged patients.“” It may be unilateral or bilateral and results in an acute loss of vision. The lesions appear as multiple dark round spots surrounded by lighter haloes, and are present in the posterior pole at the level of the RPE. Often the loss of

vision is out of proportion

to the funduscopic

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SYSTEMIC VIRAL INFECTIONS appearance. The vision gradually returns to normal over two to three months. Birdshot retinochoroidopathy (vitiliginous chorioretinitis)“” occurs in older individuals, usually females in the fifth to seventh decades of life. It is characterized by multiple cream-colored spots in the midperiphery at the level of the KPE or choroid. and is associated with a gradual rather than an acute loss of vision. There is usually an associated vitritis, and cystoid macular edema may also develop. The HLA-A29 haplotype is present in 807% of patients with this disease.‘nn The disease tends to be slowly progressive with multiple recurrences and a relatively poor response to corticosteroids.

D. DIAGNOSTIC

PROCEDURES

Due to the paucity ofcase reports of EBV choroiditis, little infijrmation is available regarding typical fluorescein angiograms and electrophysiology of this disease. Fluorescein angiographic descriptions include findings of peripapillary or macular choroidal neo\,ascularization early and late hyperfluorescence, multiple small punchedout pigment epithelial lesions, and macular lesions with bridging areas of subretinal fibrosis and pigment clumping.“x~“” Heterophil antibodies are demonstrated in 5W? of children and in 90-95(X of adults and adolescents with IM. Monospot tests may be slightly more sensitive than are heterophil antibodies. Of patients with IM, 10-l 5%: may be heterophil-negative if tested during the first weeks of’ illness, so clinical suspicion may warrant repeat testing in the second or third week of illness. Heterophil antibodies decline in titer after resolution of the acute illness, but may be detectable for nine months.“” A relative and absolute lymphocytosis is present in 75%Nofcases of IM and usually peaks in the second or third week of illness. The atypical lymphocytes, which are primarily activated T lymphocytes, are larger than mature lymphocytes and often contain eccentrically placed lobulated nuclei with nucleoi, and vacuolated cytoplasm with rolled up edges. Mild neutropenia, thrombocytopenia. polyclonal increase in immunoglobulins of the IgM, IgG, and IgA classes, and hepatocellular enzyme elevations may be seen.2’ii Antibodies to several EBV-specific antigens arise during primary IKBV infection. IgM antibodies to the viral capsid antigen (VCA) are diagnostic of a primary EHV infection; IgG antibodies to VGA also appear at clinical presentation of IM, and titers are f-ollowed as a

marker for prior or current infection. The IgM antibodies persist for l-2 months; IgG antibodies are lifelong. Approximately TO%, of patients with IM make antibodies to diffuse early antigens (EA-1)) that peak :3-4 weeks after the onset of illness and usually disappear after recovery. The presence of these antibodies correlates with more severe disease, and are also tound in nasopharyngeal carcinoma. Kestricted early antigens (EA-K) are present in high titer in African Burkitt’s lymphoma, and may be useful as an indicator of reactivation of EBV in immunosuppressed patients. Antibodies to Epstein-Barr nuclear antigens (EBNA) appear at 6-X weeks in virtually all patients with IM and subsequently persist for life. The presence of IgM anti-VCA antibodies and seroconversion to EBNA is diagnostic of‘s primary EBV infection. Patients with defects in cellular immunity may fail to make antibodies to EBNA.‘,” E. PATHOLOGY

AND PATHOGENESIS

EBV infection has both direct and indirect eE fects on the cellular and humor-al immune responses. Within 1X-24 hours after entry of EBV into B lymphocytes by means of the C3d receptor, EBNA are detectable within the nucleus of the infected cell. Expression of EBN.4 corresponds to the acquisition of the transformed 01 immortalized phenotype. EBV-infected B lymphocytes also express lymphocyte-determined membrane antigens (LYDMA), which serve as the target for the cellular immune response to the viral infection. Immortalized B lymphocytes can be propagated continuously in vitro and are polyclonally stimulated by EBV to produce immunoglobulin. A minority of EBV-infected B lymphocytes enter the lytic cycle and produce EBV antigens that are detected during viral replication. The early antigen complex consists of tlifhlse (EA-D) antigens that are detectable in both the cytoplasm and the nucleus ofcells in the lytic cycle, and restricted (LA-K) antigens demonstrable only in the cytoplasm. After the appearance of viral capsid antigens (V(:A), the host cell dies and whole virions are released that can infect and transform additional B lymphocytes.‘” An ef‘f‘ective immune response to EBV involves humoral and cellular components. Neutralizing antibodies that inactivate cell-free virus and antibodies to VCA and EBNA appear during primary infection in all patients; antibodies to EA-D appear in most. The cellular immune response is largely responsible for controlling B-cell proliferation and polyclonal irnmunoglobulin produc-

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tion triggered by EBV, and is composed primarily of T lymphocytes. As the illness progresses, memory T lymphocytes capable of limiting proliferation of autologous EBV-infected B lymphocytes are demonstrable and persist for life. Latent EBV remains in a small proportion of B lymphocytes, and perhaps also in epithelial cells in the oropharynx.9”7 EBV infection rarely leads to blinding disease. Indeed, in the absence of subretinal neovascularization, the disease course appears to terminate in resolution of the choroiditis with return to normal visual acuity. Because of this, there is little data as to the histopathology of EBV choroiditis. From autopsy data on patients who died from IM, one might expect to see perivascular infiltration of both normal and atypical lymphocytes, mild to moderate edema of the retina and optic nerve, lymphocytic infiltration of the optic nerve, and mild hemorrhage without evidence of necrosis.‘58 Immunofluorescent techniques and in situ DNA hybridization would likely result in areas of positive staining and localization of the viral nucleic acid in EBV-infected tissue. F. TREATMENT Overall, EBV choroiditis appears to be as selflimiting as IM, and thus little documentation exists as to effective therapy. Reasonable therapeutic considerations for slowly resolving EBV retinitis would include acyclovir or alpha interferon, both of which are active inhibitors of EBV replication in vitro. Alpha interferon has antiviral activity and decreases shedding of EBV. Corticosteroids are likely to be of limited benefit.

VI. Influenza A Virus Influenza A is one type of influenza virus that commonly causes an acute respiratory illness. The genome of influenza A virus consists of eight single-stranded segments of viral RNA, that code for the structural and nonstructural proteins. Overall, the virion is an irregularly shaped sphere, 80-120 nm in diameter, and contains a lipid envelope from which hemagglutinin (H) and neuraminidase (N) glycoproteins project. The hemagglutinin serves as the site at which virus binds to cell receptors, while the neuraminidase degrades the receptor and probably plays a role in release of virus from infected cells after replication has taken place. Antibodies directed against the H antigen are the major determinants of immunity against influenza virus, while antineuraminindase antibodies limit virus spread. The virus also contains the matrix protein (M), whose function is incompletely understood, the

YOSER ET AL nucleoprotein (NP) with which the viral genome is associated, and polymerase protein (P), which is essential for transcription and synthesis ofviral RNA.‘” Influenza outbreaks occur every year, although the extent and severity vary widely. The most extensive and severe outbreaks are caused by influenza A, because of the propensity of the H and N antigens to periodically undergo antigenie mutation. Major antigenic variations (“antigenic shifts”) occur from reassortment of genome segments between virus strains, while minor variations (“antigenic drifts”) likely arise from point mutations. The epidemics begin abruptly, reach a peak over a 2-3-week period, generally last for 2-3 months, and often subside almost as rapidly as they began. A major determinant of the extent and severity of an outbreak is the elevel of immunity present in the population at risk.55 A. SYSTEMIC

MANIFESTATIONS

The initial event in influenza is infection of the respiratory epithelium with influenza virus, which is acquired from respiratory secretions of acutely infected individuals. The respiratory illness is usually accompanied by the abrupt onset of headache, fever, chills, malaise, myalgia, cough, and sore throat; however, a wide spectrum of clinical presentations may occur. The patient may also experience pain and burning of the eyes, as well as photophobia. In uncomplicated cases, the acute illness generally resolves over 2-5 days, and most patients have largely recovered in one week.5” The most common complication of influenza is pneumonia, which may be viral, secondary bacterial, or both. Reye’s syndrome is a serious complication, more common with influenza B than influenza A infection. Other complications include myositis, rhabdomyolysis, myocarditis, pericarditis, encephalitis, transverse myelitis, and Guillain-Barre syndrome. In elderly and other high risk individuals, deterioration of underlying cardiovascular, pulmonary, and renal function may lead to irreversible changes and death.“’ B. OCULAR MANIFESTATIONS Few published case reports describe influenza A retinopathy, but macular edema, macular lesions consisting of shiny vesicular dots at the termination of a capillary, absent fovea1 reflexes, darkening of the macular area, optic neuritis with and without exudate, small hemorrhages and sclerotic vasculature have been described.

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SYSTEMIC VIRAL INFECTIONS All these changes appear to be reversible;‘4”,‘“” however, post-influenza1 retinal pigmentary degeneration can be a complication. The lack of thorough ophthalmoscopic examinations during influenza outbreaks, and the benign nature of the disease in most patients, accounts for the paucity of case reports and detailed retinal findings. Other ocular complications include iridocyclitis, interstitial keratitis, marginal cornea1 ulcers, and dacryoadenitis.““’

is usually accomplished in tissue culture or, less commonly, in the chick embryo amniotic cavity within 48-72 hours after inoculation. Viral antigens may be detected somewhat earlier by use of indirect immunofluorescence techniques in tissue culture, or directly in exfoliated nasopharyngeal cells obtained by washings.“” Immunohistochemical and histopathologic reports of influenza A retinopathy have not been described.

C. DIFFERENTIAL

The course of influenza A infection is usually uncomplicated, as is likely to be the case with influenza A retinopathy. While no proven therapy exists to resolve influenza retinopathy, amantadine hydrochloride, which is active against only influenza A viruses, reduces the duration of systemic and respiratory symptoms by at least 50%. The dose of amantadine is 200 mg orally per day beginning within 48 hours of the onset of illness, and continuing for 3-5 days or up to 48 hours after illness has resolved. The dose is reduced in individuals with renal insufflciency. Kimantidine, an experimental analogue of amantadine, appears to be equally effective and to have fewer side effects. Kibavirin, a nucleoside analogue with activity against a variety has been reported effective of viral agents, against influenza A infection when administered as an aerosol, not orally.“” In addition to amantadine prophylaxis, inactivated influenza vaccination is highly recommended for those with chronic cardiovascular and pulmonary disorders, nursing home residents, medical personnel in contact with highrisk patients, healthy individuals over 65 years of age, individuals with chronic metabolic disease, and immunocompromised patients. Vaccination should be administered early in the autumn before influenza outbreaks occur, and should be administered annually to maintain immunity against the most current strains.”

DIAGNOSIS

The differential diagnosis of influenza A retinopathy includes the Vogt-Koyanagi-Harada (VKH) syndrome or uveomeningitic syndrome, which is a systemic disorder involving the eyes, meninges, ears, and skin. It is most prevalent in Japanese and Latin Americans, particularly Brazilians, and in American Indians, occurring most commonly between their second and fourth decades of life. Classically, the anterior segment findings include a granulomatous intraocular inflammatory disease with mutton fat keratic precipitates, anterior chamber reaction, and Koeppe or Busacca nodules. Posterior segment findings include early optic nerve edema, retinal edema, vitreous inflammation, exudative (nonrhegmatogenous) retinal detachment, peripheral retinal yellow-white, well circumscribed retinal lesions, and depigmentation of the choroid and retinal pigment epithelium leading to a “sunset ow” of the fundus. Extraocular findings ing’ clude hearing loss, headache, orbital pain, stiff neck, vertigo, pleocytosis on lumbar puncture, vitiligo, poliosis, and alopecia. The diagnosis is made by the constellation of clinical signs and symptoms; no confirmatory diagnostic test is available.“” However, fluorescein angiography and standardized echography7’ have been found to be helpful. Other viral infections should be included in the differential of influenza A retinopathy; serologic testing is most helpful in differentiating the responsible organism. D. LABORATORY

DIAGNOSIS

Serologic methods for diagnosis require comparison ofantibody titers in sera obtained during the acute illness with those obtained lo-14 days after the onset of illness, and are useful primarily in retrospect. A fourfold or greater rise in titer as detected by hemagglutination inhibition, complement fixation, or ELISA techniques is diagnostic of acute infection. Isolation of virus from throat swabs, nasopharyngeal washes or sputum

E. TREATMENT

VII.

Measles Virus

The measles virus is composed of a central core of KNA with a helically arranged protein coat surrounded by a lipoprotein envelope with small, spikelike structures. The virus is 120-200 nm in diameter and is classified as a paramyxovirus. Measles, or rubeola, is an acute febrile eruption. This has been one of the most common diseases of civilization. The virus is transmitted by transfer of nasopharyngeal secretions, either directly or in airborne droplets, to the respiratory mucous membranes or conjunctivae of sus-

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ceptible individuals. Persons infected with the virus may transmit the disease from five days after exposure until five days after skin lesions have appeared. The virus is highly contagious, with secondary attack rates among susceptible household contacts usually exceeding 90%. Measles is typically a disease of childhood, yet in the United States there has been a distinct shift in age-specific infection rates, with recent outbreaks most commonly occurring among teenagers and young adults. This is probably because of inadequate immunity among individuals vaccinated early in life. Infants under six months of age are uncommonly affected, presumably because of maternal antibody acquired by transplacental transmission.“”

idiopathic neuroretinitis may cause macular star formation similar to that described in measles retinopathy.

A. CONGENITAL

37 (5) March-April

INFECTION

1. Systemic Manifestations It has been known since the seventeenth century that measles can be transmitted from a pregnant woman to her fetus. Prenatal transmission in the first trimester of pregnancy causes abortion in about 20% of cases, and infection later in gestation often results in premature birth. Malformations attributable to maternal measles include cardiopathy, cataract, pyloric stenosis, genu valgum, dacryostenosis, deafness, mongolism, vertebral anomalies, cleft lip and cleft palate, rudimentary ear and pigmentary retinopathy.“’ 2. Retinal Manifestations The rare case reports of retinal pigmentary disturbance following maternal measles describe patients with normal visual acuity, but with ophthalmoscopic findings that include: optic nerve head drusen; a diffuse, fine, scattered retinal pigmentary pattern bilaterally with equal involvement of the posterior pole and periphery; pigment accumulation in the macula; normal or attenuated vessels; macular star formation and retinal edema. Constricted visual fields may be present; photopic and scotopic ERG responses are usually normal. These findings are similar to those found in acquired rubeola retinopathY.‘0’,‘7’ 3. Differential Diagnosis Among the clinical entities that mimic measles retinopathy are congenital rubella, TORCH syndrome, and atypical retinitis pigmentosa.‘2’,‘7’ Influenza virus also has been found to produce pigmentary retinopathy following maternal infection during the third, fourth, and sixth months of pregnancy.‘7’ Other considerations include syphilis and cytomegalovirus. Leber’s

B. ACQUIRED

INFECTION

1. Systemic Manifestations The time from exposure to the development of the first symptoms of measles infection is usually 9-l 1 days, and from exposure to the appearance of rash is about two weeks. The initial manifestations of the disease are malaise, irritability, fever, conjunctivitis with excessive lacrimation, eyelid edema, photophobia, moderately severe hacking cough, and nasal discharge. Koplik’s spots small, red, irregular epithelial necrotic lesions with blue-white centers - appear on the oral mucosa and occasionally on the conjunctiva or intestinal mucosa l-2 days before onset of the rash. The red maculopapular rash of measles erupts first on the forehead, spreads downward over the face, neck and trunk, and appears on the feet by the third day. The lesions in each area persist for about three days and disappear in the same order as they apeared, resulting in total rash duration of six days. As the maculopapules fade, a brownish discoloration and fine desquamation may occur. In adults the duration of fever may be longer, the rash more prominent, and the incidence of complications higher.“’ Measles is usually a benign self-limited disease, but may be associated with a number of complicating illnesses. Subacute sclerosing panencephalitis (SSPE) is a late complication of measles and other viruses of the paramyxovirus group. In the United States, its incidence is about one per million, the male to female ratio is about 4: 1, and the disease is more common in rural areas. The mean age of onset is about seven years. The patient may present with visual problems, behavior disorders, and memory impairment, followed by myoclonus and deterioration to spastic quadriparesis and dementia. Decerebrate rigidity and coma usually develop, leading to fatality within 5-l 2 months. Although a few documented cases of SSPE have occurred following immunization with the measles vaccine, the overwhelming majority of cases are in unvaccinated children. The clinical diagnosis is confirmed by the typical EEG changes, namely the presence of paroxysmal bursts of high voltage discharge occurring simultaneously with the myoclonus.‘Y~70~“0~Y’ 2. Ocular Manifestations The most common ocular manifestations of measles are keratitis and conjunctivitis. The ker-

SYSTEMIC VIRAL INFECTIONS

atitis appears within a few days ofthe outbreak of the skin rash and may last for up to three months; this classically presents as punctate epithelial erosions visible only with slit-lamp examinations. The conjunctivitis associated with measles is mild and nonspecific in nature. Both the keratitis and conjunctivitis are normally selflimited and resolve without sequelae.‘t” Dilated pupils with a poorly reactive pupillary light reflex may also be present. Measles retinopathy is more common with acquired than with congenital measles. In one compiled study of 2702 children in schools for the blind, both entities accounted for 0.9%.!’ The retinopathy may be associated with encephalitis and subacute sclerosing panencephalitis (SSPE), but is often seen in otherwise uncomplicated caSeS,2:“’ During the acute stage of the illness, the fundus reveals attentuate vessels, especially arterioles, and diffuse retinal edema. Additional findings include optic disc swelling with blurred margins, small retinal hemorrhages, and an exudative, stellate, macular, lesion. Irregular, flat, depigmcnted areas ma!. also be present. As the symptoms of measles resolve, and as visual acuity improves, a secondary pigment retinopathy with a “salt and pepper” or a “bone corpuscle” pigment pattern frequent]!, appears in association with retinal pigment eplthelial (RPE) alteration. While the retinal and optic disc edema subsides, the arterioles are likely to remain mildly attenuated with or without perivascular sheathing. The stellate exudate in the macula usually resolves, in some instances to be replaced with macular pigment stippling or punctate, exudative dots,~.‘:‘,“‘,,~:“’ Ophthalmoscopic findings that may be associated with subacute sclerosing panencephalitis (SSPE) include papilledema, optic atrophy, temporal optic disc pallor, macular edema, macular pigment epithelial abnormalities, small hemorretinochoroiditis, gliotic retinal scar, rhages, whitish retinal infiltrates, internal limiting membrane contracture, serous macular detachment, areas of retinal depigmentation, drusen, and preretinal opacities. Neither satellite lesions nor vascular sheathing have been noted..‘!‘,“““‘I”

3. Differential

Diagnosis

Included in the dif‘ferential diagnosis of measles retinopathy is central serous retinopathy. This idiopathic entity occurs typically in healthy young adults (most commonly men) between the

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ages of 20 and 40, often following emotional stress. Symptoms are those of metamorphopsia, scotoma, and micropsia. The area of involvement is usually the macula and there is often fluid present beneath it. The detached neural retina is poorly demarcated from normal retina. Often white spots are seen in the detached area. A localized detachment of the neural retina may be associated with a focal detachment of the RPE. Fluorescein angiography of this condition reveals an early focal area of hyperfluorescence, which enters the sub-RPE space and then spreads slowly into the large sub-neuroretinal showing “smoke stack” and space, classically “umbrella” configurations. In the late phases, the fluorescein fills the subneuroretinal space incompletely, so the boundaries of the detachment show fllzzy, poorly demarcated borders.“’ Other viral retinopathies may simulate measles retinopathy, but usually can be ruled out by serologic testing. Other entities in the differential diagnosis include Vogt-Koyanagi-Harada’s disease, discussed in the section on influenza A retinochoroiditis, disretinitis, toxoplasmic cussed in the CMV retinitis section and retinitis pigmentosa. C. DIAGNOSTIC

PROCEDURES

In the acute phase of the disease, fluorescein angiography is likely to reveal diffuse leakage secondary to the widespread retinal edema presence, Once the acute disease resolves, fluorescein angiography reveals a generalized increased transmission of background choroidal fluorescence due to widespread pigment epithelial disThe posterior pole shows a fine turbance. granular pigment pattern (salt and pepper pigmentation) with perivascular bone corpuscle pigment. The macula typically shows ciense pigmentation with a surrounding halo of pigment rarefaction. Late stage angiograms show stabilization of the appearance.““’ In SSPE, fluorescein angiographic findings will likely include capillary occlusion involving the vessels surrounding the macula, focal defects in the retinal pigment epitheliurn without evidence of choroidal exudates, and cystic areas of’ hyperfluorescence.“~“‘~““.“’ If pigmentary changes are present, these will probably be visible on angiography; in most cases, staining ceases after 36 to 60 minutes. Electroretinography is typically extinguished in the actue phase of measles retinopathy, the tirne at which visual acuity is reduced to light perception or no light perception. As the acute

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illness resolves and vision improves, the ERG may show return of activity.7”Z”6 One case report described abnormal photopic, scotopic, and flicker fusion responses in a cone-rod pattern with the rod-mediated b-wave amplitude greater than the photopic waveform. The ERG amplitudes were less than half normal size.‘” Subsequent visual field testing after the acute phase of illness often reveals severe constriction with central vision of 5 to 10 degrees at best remaining in each eye. There may be ring scotomas and small peripheral islands of vision.8,7”.‘36 Similar findings can be found associated with SSPE.4g,Y’ Complement fixation, enzyme immunoassay, immunofluorescent, and hemagglutination inhibition tests are available for serologic confirmation of measles. Measles antigen can often be detected quickly by fluorescent antibody staining of infected respiratory or urinary epithelial cells. The measles virus can be isolated by inoculation of sputum, nasal secretions, or urine onto appropriate cultures. Leukopenia is frequent in the prodromal phase of measles, and the appearance of leukocytes suggests bacterial superinfection or another complication. Spinal fluid protein of patients with encephalomyelitis and SSPE can be elevated, and lymphocytes may also be present. The spinal fluid pressure is usually normal, but high titers of measles antibodies and an increase in gamma globulins are often found in the CSF.2’6

of neurons, most conspicuously in the ganglion cell and inner nuclear layers. Occasional large masses of multinucleated syncytial giant cells containing numerous intranuclear eosinophilic inclusions surrounded by marginated nuclear chromatin are also observed in areas of retinal thinning. The optic nerve will likely show swelling with possible obliteration of the physiologic cup. Moderate infiltration of lymphocytes, gliosis, cellularity of the nerve fiber bundles, and scattered gliotic intranuclear inclusions can be observed in the optic nerve. Scattered focal hemorrhages may also be present. Similar findings are present in brain biopsy, including areas of demyelination, perivascular cufftng of mononuclear cells, and cortical necrosis.4Y~7”~“0~g’ Immunofluorescent techniques have shown that the infected retinal cells are positive for measles antigen in cases of SSPE and measles retinopathy.‘“,‘“” Electron microscopic studies have revealed the inclusions to be composed of filamentous microtubular structures of the paramyxovirus nucleocapsid.“’

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D. HISTOPATHOLOGY Retinal tissue is rarely obtained from uncomplicated measles cases; however, as SSPE and encephalomyelitis are frequently fatal, autopsy specimens have been examined. Histologically, focal retinal necrosis with invasion of pigmentladen macrophages is seen. Inflammatory cells are likely to be absent. The retinal pigment epithelium may show patchy loss of pigment, but the choroid will likely appear normal.‘“4 In SSPE the pathology consists of retinitis of the neural retina and pigment epithelium, with choroidal involvement limited to the choriocapillaris. Retinal folds and detachment, and rupture of the internal limiting membrane may be present. The macular region may reveal marked atrophy and thinning of the retina, with areas of gliosis and a preretinal inflammatory membrane. The rod and cone layer shows focal areas of degeneration, as does the RPE, with large clumps of pigment granules attached to the degenerated segments. Intranuclear inclusions (Cowdry type A) can be observed in glial cells as well as in all three layers

E. TREATMENT, PROGNOSIS

COMPLICATIONS,

No therapy is indicated for uncomplicated measles. Measles can be prevented by the prophylactic administration of 0.25 ml/kg gamma globulin within live days of exposure, although this is of no value once symptoms are evident. Passive immunization should be considered for any susceptible person exposed to the disease, but is especially important for children under three years of age, for pregnant women, for patients with tuberculosis, and for those with impaired immune mechanism. Active immunity can be induced by the use of live, attenuated measles virus without spread to contacts of vaccinated individuals. The attenuated vaccine is associated with few local or systemic reactions, and it induces antibody formation in more than 95% of susceptible individuals inoculated at age 15 months or older. Vaccination results in protection for at least 15 years, but the total duration of immunity is not known.“” In cases of retinopathy following measles, a guarded longterm prognosis should be given. With the onset of acute blindness l-2 weeks following the appearance of the measles rash, generally resolving in subsequent weeks to months with return of useful vision, the visual fields usually remain constricted to less than 15 degrees and the ERG does not regain full activity. No documented therapy for measles retinopathy has been reported, although corticosteroid use

SYSTEMIC VIRAL INFECTIONS should be considered. A secondary pigmentary retinopathy often remains in a “bone corpuscle” or “salt and pepper” pattern.“’ As mentioned earlier, an encephalomyelitis may develop as a complication of measles, separate from the entity of SSPE, with a 10%) mortality. Pigmented paravenous retinochoroidal atrophy is a degenerative pattern characterized by paravenous atrophy of the RPE and bone spicule pigment deposition along the course of veins. The cause is unknown and the course of the degeneration is initially unpredictable, with both progressive and nonprogressive cases reported. This nonspecific degenerative pattern can appear as a complication of measles retinopathy.”

VIII.

Rubella

Virus

The rubella virion is a somewhat spheroidal RNA virus of the togavirus family that measures 60-70 nm in diameter. ‘This viral agent was first recovered in 1962 in cell cultures inoculated with nasopharyngeal secretions of infected persons. Rubella, also known as “(ierman measles,” is usually a benign febrile exanthem. This entity is not as contagious as measles nor is its immunity as widespread. Before the routine introduction of vaccine in 1969, epidemics occurred at 6-9 year intervals, but this cycle is no longer seen. In lCHi4, more than I .X million cases of rubella were reported in the United States; in 1984, only 745 cases were reported. Kuhella was once most common among children 5-9 years of age, but with the advent of immunization programs directed at preschoolers, a greater proportion of cases is older schoolchildren now reported among (15-19 years) and young adults (20-24 years). Estimates of susceptibility to rubella among unimmunized women of childbearing age range from 1O-25% .-“1i The rubella virus likely induces infection by instillation in the nasopharynx. Virus is present in blood, throat washings, and occasionally feces for several days before the exanthem appears. It can be detected in blood for 1-2 days and in throat washings for as long as seven days before appearance of rash, and may continue to be detected fi)r as long as two weeks after rash onset.” A. CONGENITAL

INFECTION

1. Systemic Manifestations (:ongenital rubella results from transplacental transmission of virus to the fetus from an infected mother, usually during the first trimester of pregnancy. This may subsequently lead to seriOKS chronic fetal infection and malformations. Serologically identified , asymptomatic maternal

339

rubella can also result in severe fetal disease. The congenital rubella syndrome consists of: heart malformations (patent ductus arteriosus, interventricular septal defect, or pulmonic stenosis), eye lesions, cornea1 clouding, cataracts, chorioand microphthalmia; microcephaly; retinitis, mental retardations; and deafness. In the 1984 thrombocytopenic purpuAmerican epidemic, r-a, hepatosplenomegaly, intrauterine growth retardation, interstitial pneumonia, myocarditis 01 myocardial necrosis, and metaphyseal bone lesions were commonly encountered manifestations of congenital rubella.“’ 2. Ocular Manifestations Retinopathy is the most common ocular complication of congenital rubella, but the exact incidence is uncertain because dense cataracts sometimes prevent visualization of the retina. The manifestation of retinopathy may not be apparent until the patient’s first ophthalmologic exam, as this condition frequently permits normal visual fields, visual acuity, and electrophysiologic studies. Gregg”’ in 1942 and Swan and colleagues”” in 1943 were the first to document retinopathy in infants and children whose mothers had rubella in the first trimester of pregnancy. Since that time, the retinopathy of congenital rubella has been described as a pigment disturbance most often involving the posterior pole of the eye and most marked in the macular region. It may occur in one or both eyes and has been variously described as consisting of small, black, irregular masses varying in size, fine to gross pigmentary stippling with colloid changes and waxy disc, coarse mottling of the macula, and measly or The changes. I”,, - i..~,.ii.!l-l.l,‘l.,!l~~,~~~~.~.i~.~~i blotchy terms “salt and pepper retinitis” and “moth-eaten changes” are frequently used. A fovea1 reflex may be absent. Typically the optic nerve head and retinal vessels appear normal, although optic atrophy may be present if there is an associated glaucoma. I”,, - 7.3,.!,-1.I-l!l.,!l:i.i’tli.~.~i.~Xi Subretinal neovascularization and hemorrhage may develop, with the neovascularization occurring particularly in the macula. The macula neovascularization may later develop into a disciform scar or cicatricial mass, li.5l.i?.lO:\.W~ Cataract is the second most common ocular problem associated with congenital rubella, affecting almost 15% of patients. The pearly nuclear cataract can be unilateral or bilateral and is frequently associated with microphthalmia. If the hmduscopic red reflex is viewed through an ophthalmoscope held several inches from the di-

1993

YOSER ET AL

lated eye, a dark central shadow is detected. In most cases, early extraction is recommended for any visually significant cataract in order to prevent the development of sensory-deprivational amblyopia. Microphthalmia is reported in lo-20% of infants with congenital rubella, and is associated with cataracts, optic nerve abnormalities, and glaucoma.‘““,“” Glaucoma is found in 10% of patients and may be associated with microphthalmos with small corneas, buphthalmos, or enlargement of the globe, with enlarged or hazy cornea due to corneal edema. Less commonly reported eye abnormalities include iris atrophy and iritis. Pendular nystagmus and strabismus develop as a consequence of visual deterioration secondary to the various ocular abnormalities.‘““.“”

before the rash, are most impressive during the early eruptive phase, and may persist several days after the rash has disappeared. Splenomegaly or generalized lymphadenopathy may occur, but the postauricular and suboccipital nodes are most strikingly involved. Young women may especially experience arthralgias and slight joint swellings. Purpura with or without thrombocytopenia may occur and may be associated with hemorrhage. Testicular pain is also occasionally reported in young adults.“7

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3. Differential

37 (5) March-April

Diagnosis

The TORCH syndrome forms the bulk of the differential diagnosis for congenital rubella retinitis. The chorioretinitis of congenital syphilis is of the salt and pepper variety and is most accentuated in the periphery, although the entire fundus may be involved. The presence of positive serologies and associated stigmata typical of congenital syphilis differentiate this entity.“‘” Viral infections such as varicella-zoster, CMV, HSV, mumps, roseola, and vaccinoencephalitis should be considered and ruled out by appropriate serological tests. Manifestations of most of these viral infections, as well as those of toxoplasmosis, have been discussed in other sections. Other possibilities include nephropathic cystinosis and radiation in the first trimester. B. ACQUIRED 1. Systemic

INFECTION

Manifestations

The time for exposure to the appearance of the rash of rubella is 15-2 1 days, although a prodromal illness may precede the exanthem by l-7 days. The prodrome consists of malaise, headache, fever, mild conjunctivitis, and lymphadenopathy. In children, the rash may be the first manifestation of disease, and respiratory symptoms are mild or absent. Small, red lesions (Forchheimer’s spots) occasionally can be seen on the soft palate, but these are not pathognomanic of the disease.‘17 The rash begins on the face and forehead and spreads downward to the trunk and extremities. The small maculopapular lesions are usually discrete and of lighter hue than those of measles, but they may coalesce to form a diffuse erythema suggestive of scarlet fever. The rash may last for l-5 days. Enlarged, tender lymph nodes appear

2. Ocular

Manifestations

The ocular manifestations of rubella in children and in adults tend to be mild and self-limited. Conjunctivitis is the most common finding, being seen in 70% of patients. It is characterized by mild hyperemia and sometimes by follicular development. Epithelial keratitis is reported in 7.6% of patients and consists of punctate epithelial opacities of the central cornea that resolve without sequelae in 2-7 days. Deep cornea1 stroma1 involvement or ititis does not occur.““.‘?” Few case reports exist to date of acquired rubella retinitis. Two such reports have described ophthalmoscopic findings of acute onset of disseminated chorioretinitis with several large areas of bullous retinal detachment with underlying pigment epithelial detachment involving the entire posterior pole, preretinal white cells in the vitreous with a small gliotic lesion, RPE depigmentation, dark-gray atrophic posterior pole lesions, mild anterior uveitis, normal retinal vessels and optic nerve head, and absence of hemorrhage. The bullous detachments seem to spontaneously resolve, but with some atrophic areas remaining in the RPE. The visual acuity returns to normal as well.H7~‘“X 3. Differential

Diagnosis

The differential diagnosis of acquired rubella retinitis consists of the entities to be considered when congenital rubella is diagnosed in childhood or young adulthood. Syphilis tops the list, and again serologic studies can help confirm this diagnosis. Retinitis pigmentosa and associated systemic disorders are characterized by a bone corpuscle type of pigmentation most marked in the peripheral retina. Arteries are markedly narrowed and the disc is waxy yellow. Night-blindness, constriction of the visual fields, extinction of the electroretinogram, and dark adaptation are present.“‘” Leber’s amaurosis is a congenital form of retinitis pigmentosa in which, within a few months of life, the infant is found to have poor vision. The fundus examination may ap-

SYSTEMIC

VIRAL INFECTIONS

pear normal at a very early age, but with time pigmentary deposits or various generalized ret< inal changes, including bull’s eye maculopathy will develop. -rhese inf:mts are often highly hyperopic and have a searching nystagmus; the nvstagmus is often present at birth, but, if not, will invariably clevelop by two years of age. The electroretinogram will likely be severely attenuated and the visual fields constricted.” Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is another possibility and has been described in the differential diagnosis of EI3V chorioretinitis. l‘his disorder is invariably unilateral, characteristically occurs between the ages of20 and 50 years, and consists of’ the acute onset of multiple pale lesions at the level of‘ the RPE and rapid loss of central vision. The tilndus changes consist of multifocal yellowwhite lesions at the level of the posterior pole RPE. I‘hese lesions are usually round and discrt’tr. with the more peripheral lesions tencling to be oval or linear anct with the long axis oriented radially. Occasionally patients have a single central lesion rather than multiple lesions. New lesions are identified fi)r up to three weeks after the initial symptoms. Spontaneous resolution of tlica lesions generally follows within 2-3 weeks, leaving discrete pigment epithelial scars. Visual aalit), t~sually returns to normal.“’ .Acutr. retinal pigment epitheliitis is a rare disease first described in 1972 in young adults who de\reloped Irletamor-phol)sia and sudden visual loss that varied from minimal to the level of W/l 00, either r~nilatcrally or bilaterally. Patients demonstrate normal anterior segments, but small discrete cluster-s of small brown and grayish 5por.s (usually 2 -4 spots per cluster) are seen deep in the involved macula. Sometimes the spots arc SUI-I-ouncted hy il small yellow or white halo. Fluorescein angiography reveals small, central, nontransrnitting spots surrounded by a halo of increased transmission of choroidal fluorescen(‘~ through the KPE. Electroretinograph?, and visual evoked responses are normal. Lesions evolve OVC’I-a li-12-week period to a darkened, diminished prominence with a return of‘< entral visual acuity in most cases. l‘he exact nature of this entity remains uncertain.“‘.“‘” Vogt-lic,~;lnagi-H~l.~cla’s syndrome, previously disc r~ssed in the differential diagnosis ofinfluenza :I retinitis, completes the differential diagnosis of rubella retinitis. C. DIAGNOSTIC

PROCEDURES

Early fluorescein angiography is apt to show transmission and blockage of choroid fluores-

341 cence from pigmentary clumping. It will also show subretinal neovascularization, if present. Small RPE window defects in the macula are often seen. The arteriovenous phase ofclye transit usually outlines the extent of RPE disturbance and may reveal early staining of a macular cicatrix. Late phase fluorescein study often clemonstrates no leakage or pooling of dye from the retinal vessels, but hyperfluorescence may be present in the area of scar tissue, pigment mottling, macular disciform scar or cicatricial mass, or in areas with subretinal neovascularization. The late phase may also reveal blockage of the background fluorescence by punctate hemorrhages beneath the sensory retina. Fluorescein angiography may also confirm the infrequent ocIi.,iI.i?.Xi.II1X.I!~:~.L'l~i.i'X', currence of RPE detachment. The ERC; is usually normal in rubella retinitis, ,i..~l.7i.H7.11~S.I~‘I.I’ri.L’-lli.i’Xi but may be diminished. A definitive ctiagnosis of rubella can be made only by virus isolation and identification, or by changes in antibody titers. Rubella hernagglutination-inhibiting antibodies may be present by the second day of rash, and increase in quantity over the next 10-21 days. Other serologic tests used ti)r diagnosis or determination ot‘immunity include complement fixation ((IF), enzymelinked immunosorbent assay (ELISA), fluorescence immunoassay (FIA), ratlioirri~rii~noassay (KIA), and a variety of IgM-specific antibody tests. Some rapid, economic, semiquantitative screening tests to determine immunity include latex agglutination, passive hemagglutination (PHA), and single radial hemolysis. Antibodies detected by ELISA, FIA, and RIA tend to parallel the hemagglutination-inhibiting antibodies, while CF antibody lags behind the others by Z5--7days and often does not disappear until I-2 years after infection. The PHA antibody first appears 14-21 days after onset of the rash, but persists thereafter. Fl?le presence of IgM-specific antibodies suggests recent rubella infection within the past two months; however, these antibodies have heen known to persist for as tong as one year. Patients with congenital rubella may lose hemagglutination-inhibiting antihodies at age three or four years. Therefore, a negative serologic test in a child over three years does not exclude the possibility of congenital rubella. IgM-specilic antibodies are often found early in the first year of life in infants with congenital rubella, but virus isolation is the most reliable way to confirm the diagnosis.“’ D. HISTOPATHOLOGY ‘I‘he histologic

description

of rubella

retinitis

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1993

generally results from autopsies following neonatal deaths, and therefore does not include changes that might require years to develop. In addition, the neonatal macula is not fully developed. Pathologic observations do describe an irregular, depigmented degeneration of the RPE, most frequently and most markedly present at the posterior pole. Some dispersion of pigment with phagocytosis beneath the retina is noted on occasion with cells devoid of pigment intermingled with cells containing excessive pigment. Bruch’s membrane appears unaltered. The absence of choroidal inflammation has been stressed, with a paucity of vessels of large dimension. The choriocapillaris usually appears normal. 17,rr1.“‘1,2x5 While the literature does not contain electron microscopic studies of such tissue, virions of the togavirus family measuring 60-70 nm would likely be present. E. TREATMENT, PROGNOSIS

COMPLICATIONS,

No specific therapy is indicted for either the congenital or acquired forms of rubella retinitis, as this disease only rarely produces progressive funduscopic changes, and generally results in normal visual acuity, visual fields, and electrophysiologic studies.“““’ Topical or oral corticosteroids appeared to have been beneficial in the two case reports of adult rubella retinitis.H’.‘“X Laser photocoagulation of subretinal neovascularization is often difficult when the new vessels are near the fovea. Ii..?1.ir,.l!~:~.L’-lli Bullous detachment associated with rubella retinitis appears to spontaneously resolve with corticosteroid therapy. Encephalomyelitis following acquired rubella is much less common than following measles. Later complications of congenital rubella infection include an apparent higher risk of developing diabetes mellitus. In addition, there are reports of patients with congenital rubella who develop a progressive, subacute panencephalitis with onset in the second decade of life; this is characterized by intellectual deterioration, ataxia, seizures, and spasticity.“7 Because of the potential risk of these complications, ophthalmoscopic examination with adequate pupillary dilation should be performed on all newborns whose mothers had rubella or have a history of rubella exposure in the first trimester of pregnancy. Furthermore, it is desirable to ascertain the immune status of every woman, either before conception or as early in the pregnancy as possible, by history of previous immunization or by serologic testing. If antibodies are present before

YOSER ET AL or within 10 days after exposure, the patient is considered immune, and the risk of fetal damage is virtually nil. If antibodies are not detectable after exposure, acute and convalescent antibody titers should be determined simultaneously on sera obtained 2-4 weeks apart, depending on how long after exposure the acute sample was drawn. Administration of gamma globulin to exposed persons can preclude/prevent clinical disease, but seroconversion and transmission of the disease from mother to fetus may still occur.“’ Active immunization with live attenuated rubella vaccines has been practiced in the United States since 1969, especially among young children. The aim has been to decrease the frequency of the infection in the population and to decrease the chance that susceptible pregnant women will be exposed. There has been increasing enthusiasm of serologic screening of pubertal females with no history of immunization, followed by selective immunization of those who are seronegative. The vaccine induces detectable antibodies in about 95% of recipients. Rubella vaccine must never be given to pregnant women or those who may become pregnant within three months of immunization due to the theoretical risk of vaccine virus-induced fetal damage. In addition, vaccine is contraindicated in patients who have immunodeflciency diseases or who are taking immunosuppressive drugs.

IX.

Rift Valley Fever Retinitis

Rift Valley fever (RVF) is an arthropod-borne viral disease principally of livestock, sheep, goats, cattle, and camels that is widespread throughout eastern Africa and South Africa.“2,?““.?“‘,‘“7,~i~ It is caused by an RNA virus with a diameter of 94-100 nm that belongs to the Bunyavirus family. The virus has been found in several species of mosquitoes, which likely act as the vector. While antibodies to Rift Valley fever have been found in wild field rats in Uganda, the reservoir is unknown. Although humans presumably can be infected by arthropods, many infections occur as a result of handling infected animal tissues. In addition, laboratory-acquired infections have been common, suggesting a respiratory route of transmission.““” A. SYSTEMIC MANIFESTATIONS Rift Valley fever usually presents as an acute influenza-like illness with an incubation period of 3-6 days. The onset is abrupt, with malaise, chills, rigors, diarrhea, vomiting, retroorbital pain, severe headache, and generalized aching and backache. The temperature rises rapidly to

SYSTEMIC

10 l-l 04°F. Later symptoms include anorexia, loss of taste, epigastric pain, and photophobia. Findings on examination are usually unremarkable except for flushing of the face and conjunctival injection. The temperature curve is often saddleback in type, with an initial elevation lasting 2-Y days, followed by a remission and second febrile period. Convalescence is typically rapid. Prior to the outbreak in Egypt, Rift Valley fever was a benign illness with almost no fatalities. In Egypt, approximately 1% of patients developed severe complications.“” B. OCULAR

343

VIRAL INFECTIONS

MANIFESTATIONS

The first reported ophthalmoscopic abnormalities leading to a loss of central vision were reported during the 195 1 epizootic; subsequently 10 cases of Rift Valley fever retinitis, most with macular changes, were reported by the end of the 1977 Egyptian epitlemic.“‘,“” Ophthalmoscopic evaluation usually reveal white, cotton wool exudates in the macula or paramacular region, hemorrhages both peripherally and in the macula, vascular occlusions and sheathing, retinal and macular edema, and pale optic discs. Optic atrophy, vitreous hemorrhage, irregular reticular alterations in the RPE, areas of infarction, retinal detachment, and epiretinal macular fibrosis may also develop.. The retinitis may occur unilaterally or bilaterally.“‘,“” Concomitant ocular findings with RVF retinitis may include markedly decreased visual acuity, retrobulbar pain, conjunctivitis, normal intraocular pressure, photophobia, aqueous flare and fine keratic precipitates. The conjunctivitis may be purulent and the anterior segment generally appears normal. Vitreous haze and uveitis occurs in less than one-third of these patie*lts,‘~.~~~

patches, flame-shaped hemorrhages, Roth spots, exudates, uveitis, and vitreous opacities. Q fever is another acute rickettsial disease caused by Coxielln burnetii and characterized by sudden onset of fever, malaise, headache, weakness, anorexia, and interstitial pneumonitis. In the United States, a number of tick species are naturally infected; inhalation of rickettsia-laden tick feces, which can contaminate cowhide, has caused a number of human infections. Complications are rare, but include retinitis, hepatitis, hepatic granulomas, and endocarditis. Scrub typhus, caused by Rickettsia tsutszlgamushi, is characterized by a’primary lesion at the site of the bite of an infected mite. This disease is limited to eastern and southeastern Asia, India, northern Australia, and the adjacent islands. Ocular findings in scrub typhus fever include retinal and venous engorgement, hemorrhages, exudates, perivasculitis, venous thrombosis, peripapillary chorioretinitis, optic nerve edema, vitreous opacities, and uveitis. History of tick bite and subsequent complement-fixing antibody titers to these suspected agents aid in their diagnosis.“’ A final consideration in this differential is Lyme disease. This is a tick-transmittecl spirochetal illness of Borrelia burgdorfer-i that begins as a characteristic enlarging skin lesion (erythema chronicurn migrans) accompanied by “flu-like” or “meningitis-like” symptoms that may progress to frank meningitis, cranial or peripheral neuritis, carditis, migratory musculoskeletal pain and arthritis. Lyme disease is seen worldwide. Ocular abnormalities associated with Lyme disease include conjunctivitis, keratitis, iritis, iridocyclitis, vitritis, intermediate uveitis simulating pars planitis, retinal vascultitis, and optic disc edema. 1,“nO.l D. DIAGNOSTIC

C. DIFFERENTIAL

DIAGNOSIS

‘l-he differential diagnosis of RVF retinitis includes such viral entities as measles, rubella, and influenza, which were discussed in earlier sections. Serologic evaluation should help eliminate these possibilities. Rickettsial infections may also resemble RVF retinitis. The principal retinal lesions in Rickettsial infections appear to be vascular in nature and include periphlebitis, central retinal vein occlusion and branch retinal vein occlusion, central retinal artery occlusion, and retinal vasculitis. Several reports of retinal involvement in Rocky Mountain spotted fever have described vasculitis, retinal and optic disc edema, retinal vein engorgemcnt, arterial occlusions, cotton wool

PROCEDURES

Fluorescein angiography in patients with Rift Valley fever retinitis reveals delayed filling of the arterioles and venules in the arteriovenous phase, with alterations in the RYE in the peripheral retina and macula and small retinal hemorrhages. The late venous phase reveals decompensation of the outer blood-retinal barrier with fluorescein leakage in the macular and paramacular areas. Arteriolar and branch retinal vein occlusions may be present, as well as macular exudates. Follow-up angiography months after initial symptoms may reveal window defects in the area of paramacular scars, residual delay in peripapillary choroidal filling, residual sheathed vessels, and a general absence of macular vesse,s,X!2~’

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1993

The electroretinogram during the acute illness may be unrecordable, but may eventually improve. Visual-evoked cortical potentials may also be unrecordable or minimally recordable. The electro-oculogram may also appear flat, with no increase upon light adaptation, and the visual fields may be highly constricted.52 On resolution of the disease, there may be marked improvement in these electrophysiologic parameters. A characteristic finding is an initial normal total leukocyte count followed by leukopenia, with a decrease in neutrophils and an associated increase in band forms. The diagnosis is made by isolating the virus from blood which has been inoculated into tissue culture cells or by intracerebral inoculation of suckling mice.‘“” Neutralizing antibodies have been demonstrated as early as four days after onset of disease. Comparing acute and convalescent serum samples helps confirm recent infection by this virus; a fourfold or greater rise in hemagglutination-inhibition (HI) and complement fixation (CF) antibody titers to RVF virus is considered diagnostic. Liver function tests may be slightly abnormal, and lactic acid dehydrogenase and gamma globulin levels may be greater than the normal range. Lumbar puncture frequently reveals pleocytosis, predominantly lymphocytes, and elevated protein levels with normal glucose levels. In patients who develop severe bleeding, marked anemia 267 and thrombocytopenia result. 5".?54,242 No histopathologic studies of ocular tissue from patients with RVF retinitis have been reported in the literature. Extrapolation from postmortem examinations of patients who died from complications of RVF would suggest the presence of focal areas of retinal necrosis and RPE degeneration with round cell inflammatory infiltration and perivascular cuffing. Hemorrhage may be present in certain areas.s(i7 E. TREATMENT, PROGNOSIS

YOSER ET AL evolved, and consisted of generalized hemorrhages and icterus; deaths from massive hepatic necrosis occurred 7-l 0 days after onset of illness. The fatality rate in severely ill patients may exceed 50%. Visual loss, including loss of light perception, occurred 2-7 days after onset of fever, and one-half of patients had some permanent loss of visual acuity."','"",?~""7

X. Human

Immunodeficiency Type 1 (HIV-l)

Virus

The human immunodeficiency virus type 1 (HIV-l) is a retrovirus that consists of an electron-dense core surrounding a single-stranded RNA genome, all of which is enveloped by a cell membrane. The sine qua non of a retrovirus is the DNA polymerase, known as reverse transcriptase, that is complexed to the RNA in the viral core and catalyzes the transcription of the RNA genome into a DNA form (the provirus). The DNA form usually migrates from the cytoplasm to the nucleus, and then, after assuming a double-stranded circular form, integrates into the host cell DNA, where it may remain for the lifetime of the cell. HIV is the etiologic agent of AIDS. The pathogenesis of this syndrome relates to HIV-l infection of the CD,+ inducer/helper subset of lymphocytes, leading to premature cell death and predisposition to overwhelming opportunistic infections and certain malignancies.” HIV-infected cells have been found in the blood, semen, vaginal secretions, breast milk, lymph nodes, brain, spinal cord, and peripheral nerves.lWl’ In addition to isolation from tears, conjunctival epithelium, iris, and cornea, HIV has recently been isolated from all layers of the retina and retinal vascular endotheli“t,L’I”,‘?~-I.‘L~.‘1 as well as from vitreous humor.“‘8 urn, In some cases, concurrent CMV retinitis has been present. All documentations are from adult autopsy specimens.

COMPLICATIONS,

There is no specific treatment for Rift Valley fever, although consideration could be given to using corticosteroids, antibiotics, and antiviral agents. An inactivated vaccine and a live mitigated vaccine have been prepared and are recommended for individuals living in endemic areas. In the Egyptian epizootic of 1977, approximately 1% of the patients developed severe complications, such as encephalitis and hemorrhagic manifestations, in addition to retinopathy. Encephalitis appeared as the acute infection waned, and left serious residua in some survivors. Hemorrhagic manifestations appeared as the disease

A. OCULAR AND SYSTEMIC FINDINGS Retinal microvascular changes are the most common ocular manifestations of HIV infection, occurring in up to 71% of AIDS patients.‘“” These are characterized by cotton wool spots and intraretinal hemorrhages (Fig. 16). Histopathologic examination and immunohistochemical analysis have failed to demonstrate the presence of CMV or other viruses in these lesions,““‘“” although concurrent CMV retinitis is frequently seen.?“.9.15The exact role of HIV in the development of the retinal changes remains undetermined but the underlying mechanism is most likely a microvasculopathy.

SYSTEMIC

t“/g. 16.

VIRAL INFECTIONS

HIV rctinopathy,

tion (/y/O. and intraretinal

demonstrating hemorrhage

345

multiple cotton-wool

The remainder ofthe ophthalmic examination is likely to be unremarkable. Other systemic manifestations typically found in patients with AIDS include multiple infections, such as Pneumoc:ysti.su~mz~ pneumonia, tuberculosis, gonorrhea, syphilis, Mycobuc~terium u-i~i~~~m-i?lt~ucrllnll~e bacteremia, cryptococcemia, Candidemia, and Kaposi’s sarcoma, chronic diarrhea, encephalopathy, hepatitis, polyarthropathy, adrenalitis, carcerebral abscesses, and lymdiomyopathy, pt101na.

B. LABORATORY

spots, predominantly

in a pcrivascular

distribu-

(rig/L/).

DIAGNOSIS

Serologic confirmation of HIV-1 infection is made by enzyme-linked immunosorbent assays (ELISA) for antibodies to the ~‘24 antigen, which is the most antigenic gene product of HIV. The sensitivity and specificity of the ELISA tests currently marketed in the IJnited States is >99.0%. Western blot (WB) analysis, which established the specificity of the immunologic reaction between the antibodies and the virus-encoded proteins, can confirm the ELISA findings. Serologic testing for antibodies to gp160 should also include antibodies to gp41 and gp120, the cleaved products of this precursor membrane glycoprotein.‘)“” .$ decrease in the lymphocyte T-helper to T-suppressor ratio should heighten suspicion of HIV infection. Present technologic advances include in situ hybridization testing for HIV nucleic acid sequences and the polymerase chain reaction (P(:R).“‘,“” Indirect immunofluorescence assays (IFA) and immunohistochemical methods are used extensively to locate HIV-I antigen in infected cells. “’ In some cases where CMV retinitis was concurrent with HIV retinitis, dual immunofluorescence or immunohistochemica1 methods for HIV- 1 and CMV antigens appeared in many

of the same cells and separately in adjacent cells. HIV-l antigens were localized within the cytoplasm of cells in all layers of the retina and also within retinal vascular endothelial cells, where CMV inclusions are rarely found.‘)‘L’.L”-l.“’ Overall, it appears that the interactions between HIV1 and CMV are bidirectional. One in vitro study has demonstrated that coinfection by these viruses in a given cell population enhances both HIV-l replication and productive CMV infection,‘~~.“” Further correlation with clinical and pathologic progression as well as with disease severity will be important to assess the mechanism of this dual infection. C. HISTOPATHOLOGY In eyes found to be infected with HIV-l alone, HIV antigens were detected in areas of normal appearing retina in the absence of necrosis, surrounding cellular infiltrate, or evidence of CMV infection.“” Electron microscopic studies from nonocular tissues reveal the viruses to be buds of the cell membrane. The viruses are C type particles (130 nm) with double membrane envelopes and electron dense laminar crescent or semicircular cores. An intermediate, less electron-dense layer lies in between the envelope and core. In extracellular mature virions, the core appears as a barshaped nucleoid structure, circular and eccentrically located in cross-section.“” D. TREATMENT Antiviral agents that inhibit reverse transcriptase activity of the HIV retrovirus are most likely to be beneficial in the treatment ofAIDS. Zidovudine (AZT) is one such example. Foscarnet, which is used to treat CMV retinitis, also appears to have some effect in halting HIV replication.

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Recently, dideoxyinosine (ddi) has been approved for use in AIDS patients. Clinical trials of a number of other drugs with activity against HIV in a variety of cell lines have begun; these include C-didehydrodideoxyguanosine (carbovir), dideoxycytidine (ddC), dideoxyadenosine (ddA), azidouridine (AZdU or CS-87), dideoxydidehydrothymidine (D4T), and castanospermine.‘“7,‘“x AZdU and D4T are both nucleoside analogues distinct from AZT, and castanospermine is a natural product isolated from the Australian chestnut tree that blocks the maturation process of viral glycoprotein.‘“x Immune mediator therapy with interleukin-2 and the inferons may also be of some benefit. Any concurrent retinal infections should be treated appropriately.‘O7

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Outline I. II. III. IV. VI. VII. VIII. IX. X.

Cytomegalovirus Herpes simplex virus Varicelltiherpes zoster virus Acute retinal necrosis syndrome Influenza A virus Measles virus Rubella virus Rift Valley fever retinitis Human immunodeficiency virus type

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