Herpes simplex virus and varicella-zoster virus

Anterior uveitis Acute anterior uveitis can be associated with herpetic viral disease. BCSC Section 8, External Disease and Cornea, extensively discusses herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. Anterior uveitis in herpetic viral infections may be associated with corneal involvement (keratouveitis) but also occurs without noticeable keratitis. The inflammation may become chronic.

Chickenpox (varicella), which is caused by the same virus that is responsible for secondary VZV reactivation, may be associated with an acute, mild, nongranulomatous, self-limiting, and bilateral anterior uveitis. Cutaneous vesicles at the tip of the nose (Hutchinson sign) indicate nasociliary nerve involvement and a greater likelihood that the eye will be affected (Fig 11-1). Most patients are asymptomatic; however, monitored prospectively, up to 40% of patients with primary VZV infection may develop anterior uveitis.

Herpes zoster (HZ) is defined as varicella zoster emerging from latency, and herpes zoster ophthalmicus (HZO) is defined as HZ within V1 (ophthalmic division of cranial nerve V). In HZO, the most commonly affected patients are between the ages of 50 and 69, and the eye may or may not be involved. Ophthalmic manifestations of HZO include keratitis, uveitis, conjunctivitis, episcleritis, scleritis, acute retinal necrosis, and cranial nerve palsy. Potential skin manifestations include a painful vesicular eruption within the V1 dermatome. Infection with VZV can be considered in the differential diagnosis of chronic unilateral anterior uveitis, even if the cutaneous component of the condition occurred in the past or was minimal when present. Patients may develop anterior uveitis without ever having had a cutaneous component (varicella-zoster sine herpete).

Patients with intraocular viral infections, particularly with herpes group viruses, may exhibit granulomatous, nongranulomatous, or stellate (fine and fibrillar) keratic precipitates (KPs). If stellate KPs develop, they are often distributed diffusely, as opposed to a regional distribution in the inferior third of the cornea. Diffuse or stellate KPs are not pathognomonic of any particular condition. For example, Fuchs uveitis syndrome (FUS, historically known as Fuchs heterochromic uveitis) may also feature diffuse stellate KPs. Also, notably, patients with herpetic keratouveitis may exhibit diffuse or localized decreased corneal sensation and neurotrophic keratitis.

Ocular hypertension associated with herpetic uveitis may be a helpful diagnostic hallmark. Most other inflammatory syndromes are associated with decreased intraocular pressure (IOP) as a result of ciliary body hyposecretion. However, herpesvirus may cause trabeculitis and thus increase IOP, often to as high as 50–60 mm Hg. In addition, inflammatory cells may contribute to trabecular obstruction and congestion. Cytomegalovirus (CMV)-related anterior uveitis may also present with high IOP (see the section on glaucomatocyclitic crisis in Chapter 8). Other potential findings associated with herpesvirus include hyphema, hypopyon, posterior synechia, KPs, and corneal edema.

Iris atrophy is characteristic of herpetic inflammation and can be present with HSV-, VZV-, or CMV-associated anterior uveitis. The atrophy may be patchy or sectoral (Fig 11-2) and is visualized as transillumination defects upon retroillumination at the slit lamp (Fig 11-3).

Viral retinitis may occur with these entities, particularly in immunocompromised hosts. Vasculitis may occur with HZO, and it may lead to anterior segment ischemia, retinal artery occlusion, and scleritis. Vasculitis in the orbit may cause cranial nerve palsies.

Treatment for viral anterior uveitis includes topical corticosteroids and cycloplegic agents. Topical antiviral drugs are ineffective for intraocular inflammation but may prevent dendritic disease in patients receiving topical steroids. Systemic antiviral drugs such as acyclovir (400–800 mg, 5 times/day), famciclovir (250–500 mg, 3 times/day), or valacyclovir (500 mg to 1 g, 3 times/day) may help treat HSV- or VZV-related intraocular inflammation, with the higher doses used for VZV uveitis. Initiation of oral antiviral therapy at the onset of VZV uveitis is recommended. Patients with herpetic uveitis may require prolonged corticosteroid therapy with very gradual tapering. In fact, some patients with VZV infection require very long-term, albeit extremely low, doses of topical corticosteroids (as infrequent as 1 drop per week) for the condition to remain quiescent. Systemic corticosteroids are sometimes necessary. Long-term, suppressive, low-dose antiviral therapy may be indicated in patients with herpetic uveitis, but controlled studies are lacking. The oral prophylactic dosage for patients with herpes simplex is acyclovir, 400 mg 2 times/day, or valacyclovir, 500 mg/day. For VZV disease, dosage is either acyclovir, 800 mg 2 times/day, or valacyclovir, 1 g/day.

• A controlled trial of oral acyclovir for iridocyclitis caused by herpes simplex virus. The Herpetic Eye Disease Study Group. Arch Ophthalmol. 1996;114(9):1065–1072.

• Liesegang TJ. Herpes zoster ophthalmicus natural history, risk factors, clinical presentation, and morbidity. Ophthalmology. 2008;115(2 Suppl):S3–12

• Siverio Júnior CD, Imai Y, Cunningham ET Jr. Diagnosis and management of herpetic anterior uveitis. Int Ophthalmol Clin. 2002;42(1):43–48.

• Tran KD, Falcone MM, Choi DS, et al. Epidemiology of herpes zoster ophthalmicus: recurrence and chronicity. Ophthalmology. 2016;123(7):1469–1475.

• van der Lelij A, Ooijman FM, Kijlstra A, Rothova A. Anterior uveitis with sectoral iris atrophy in the absence of keratitis: a distinct clinical entity among herpetic eye diseases. Ophthalmology. 2000;107(6):1164–1170.

Acute retinal necrosis, progressive outer retinal necrosis, and nonnecrotizing herpetic retinitis The necrotizing retinopathies include acute retinal necrosis (ARN), CMV retinitis, and progressive outer retinal necrosis (PORN). Retinal lesions of presumed herpetic etiology that are not consistent with ARN, CMV retinitis, or PORN are grouped under the umbrella designation nonnecrotizing herpetic retinopathy.

Acute retinal necrosis may occur in healthy adults or children, but may also occur in immunocompromised patients, including patients with HIV. Acute, fulminant disease may arise without a systemic prodrome, often months or years after primary infection or following cutaneous or systemic herpetic infection such as chickenpox, herpes zoster, or herpetic encephalitis. Patients may have a history of recurrent cutaneous herpetic outbreaks. The prevalence is nearly equal between the sexes, with the majority of cases clustering in patients between the fifth and seventh decades of life. The American Uveitis Society has established criteria for the diagnosis of ARN solely on the basis of clinical findings and disease progression, independent of viral etiology or host immune status (Table 11-1).

Patients with ARN usually present with acute unilateral loss of vision, photophobia, floaters, and pain. Fellow eye involvement occurs in approximately 36% of cases, usually within 6 weeks of disease onset, but sometimes months or years later. Panuveitis develops, beginning with significant anterior segment inflammation, Keratic precipitates, posterior synechiae, and elevated IOP, together with heavy vitreous cellular infiltration and often-times vitreous haze. Within 2 weeks, the classic triad of occlusive retinal arteriolitis, vitritis, and a multifocal yellow-white peripheral retinitis evolves. Early on, the peripheral retinal lesions may be discontinuous and have scalloped edges that appear to arise in the outer retina. Within days the lesions coalesce to form a confluent 360° creamy retinitis that progresses in a posterior direction, leaving full-thickness retinal necrosis, arteriolitis, phlebitis, and occasional retinal hemorrhage in its wake (Fig 11-4). Widespread necrosis of the peripheral and midzonal retina, multiple posterior retinal breaks, and proliferative vitreoretinopathy may lead to combined tractional–rhegmatogenous retinal detachments in 75% of patients (Figs 11-5, 11-6). Optic nerve swelling and a relative afferent pupillary defect may develop.

Table 11-1 American Uveitis Society Criteria for Diagnosis of Acute Retinal Necrosis

In most cases, the diagnosis is made clinically. The differential includes CMV retinitis, atypical toxoplasmic retinochoroiditis, syphilis, lymphoma, leukemia, and autoimmune retinitis with retinal vasculitis such as that of Behçet disease. Acute retinal necrosis may also be present in association with concurrent or antecedent herpetic encephalitis (HSV-1 or -2).

In cases of diagnostic uncertainty, classically intraocular antibody production was assayed from an aqueous humor sample, and a Goldmann-Witmer (GW) coefficient calculated. Polymerase chain reaction (PCR) testing of aqueous or vitreous specimens has largely supplanted viral culture, intraocular antibody titers, and serology. For presumed ARN, aqueous sampling is usually sufficient. Quantitative PCR may add information with respect to viral load, disease activity, and response to therapy.

Studies using PCR-based assays suggest that the most common cause of ARN is VZV infection, followed by infections with HSV-1, HSV-2, and, in rare cases, CMV. Patients with ARN caused by HSV-1 or VZV infection tend to be older (mean age, 40 years), whereas those with ARN due to HSV-2 infection tend to be younger (below age 25 years). There is a higher risk of encephalitis and meningitis among patients with ARN caused by HSV-1 infection than by VZV infection. In rare cases in which PCR results are negative but the clinical suspicion for necrotizing herpetic retinitis is high, endoretinal biopsy may be diagnostic.

Timely diagnosis and prompt initiation of antiviral therapy are essential, given the rapidity of disease progression, the frequency of retinal detachment, and the guarded visual prognosis. Intravenous acyclovir, 10 mg/kg every 8 hours for 10–14 days, is effective against HSV and VZV. Reversible elevations in levels of serum creatinine and liver enzymes may occur; in the presence of frank renal insufficiency, the dosage will need to be reduced. After 24–48 hours of antiviral therapy, systemic corticosteroids (prednisone, 1 mg/kg/day) are introduced to treat active inflammation and are subsequently tapered over several weeks. Aspirin and other anticoagulants have been used to treat an associated hypercoagulable state and prevent vascular occlusions, but the results have been inconclusive. Following intravenous antiviral induction for VZV infection, treatment with acyclovir at 800 mg orally 5 times daily, valacyclovir at 1 g orally 3 times daily, or famciclovir at 500 mg orally 3 times daily should be continued for 3 months. For ARN associated with HSV-1 infection, the follow-on oral dose is one-half of that for VZV. Extended antiviral therapy may reduce the incidence of contralateral disease or bilateral ARN by 80% over 1 year.

Oral valacyclovir at doses of up to 2 g 3 times daily has been used successfully as an alternative to intravenous acyclovir as induction therapy. In addition, intravitreal ganciclovir (2.0 mg/0.05 or 0.1 mL) and foscarnet (1.2–2.4 mg/0.1 mL) have been used to achieve a rapid induction in combination with both intravenous and oral antivirals as first-line therapy or for disease that fails to respond to systemic acyclovir (see Chapter 12). High-dose systemic oral therapy, alone or in combination with intravitreal antiviral drugs, has not been demonstrated as superior to the classic intravenous approach. Given the short intravitreal half-life of these drugs, injections may need to be repeated twice weekly until the retinitis is controlled. Effective treatment inhibits the development of new lesions and promotes lesion regression over 4 days.

Retinal detachment may occur within weeks to months of disease onset. The use of prophylactic barrier laser photocoagulation, applied to the areas of healthy retina at the posterior border of the necrotic lesions once the view permits, is controversial and employed by some practitioners. If detachment occurs, vitrectomy techniques are preferred over standard scleral buckling. Optic nerve atrophy may be visually limiting even with a favorable retinal anatomic outcome.

Progressive outer retinal necrosis is a morphologic variant of acute necrotizing herpetic retinitis, occurring in those who are profoundly immunosuppressed, most often in advanced AIDS (CD4⁺ T lymphocytes ≤50 cells/μL). The most common cause of PORN is VZV infection; HSV has also been isolated. As with ARN, the retinitis begins as patchy areas of outer retinal whitening that coalesce rapidly. In contrast to ARN, the posterior pole may be involved early in the disease course, significant vitreous cell and haze are typically absent, and the retinal vasculature is minimally involved, at least initially (Fig 11-7). Patients with PORN and HIV infection or AIDS frequently have a history of cutaneous zoster (67%) and eventually incur bilateral involvement (71%); they also have a similarly high rate (70%) of retinal detachment as in ARN. The visual prognosis is poor; in the largest series reported to date, 67% of patients had a final visual acuity of no light perception. Although PORN is often resistant to treatment with intravenous acyclovir alone, successful management has been reported with combination systemic and intraocular therapy using foscarnet and ganciclovir. Long-term suppressive antiviral therapy is required in patients with HIV/AIDS who are not able to achieve immune reconstitution through combination antiretroviral treatment. See also BCSC Section 12, Retina and Vitreous, for additional discussion of viral retinitis.

Nonnecrotizing herpetic retinitis (nonnecrotizing posterior uveitis) may occur in patients with herpetic infections, including acute retinochoroiditis with diffuse hemorrhages following acute VZV infection in children and chronic choroiditis or retinal vasculitis in adults. Patients may be immune competent or immune compromised. In a study using PCR-based assays and local antibody analysis of aqueous fluid samples for herpesviruses, a viral etiology was confirmed in 13% of cases deemed “idiopathic posterior uveitis.” Inflammation is typically bilateral, and the disorder may present with uveitic macular edema, as a birdshot uveitis–like chorioretinopathy, or as an occlusive bilateral retinitis. The disease is initially resistant to conventional therapy with systemic corticosteroids and/or immunomodulatory therapy (IMT), but favorable response is achieved when patients are switched to systemic antiviral medication.

• Aizman A, Johnson MW, Elner SG. Treatment of acute retinal necrosis syndrome with oral antiviral medications. Ophthalmology. 2007;114(2):307–312.

• Chau Tran TH, Cassoux N, Bodaghi B, Lehoang P. Successful treatment with combination of systemic antiviral drugs and intravitreal ganciclovir injections in the management of severe necrotizing herpetic retinitis. Ocul Immunol Inflamm. 2003;11(2):141–144.

• Engstrom RE Jr, Holland GN, Margolis TP, et al. The progressive outer retinal necrosis syndrome. A variant of necrotizing herpetic retinopathy in patients with AIDS. Ophthalmology. 1994;101(9):1488–1502.

• Goldstein DA, Pyatetsky D. Necrotizing herpetic retinopathies. Focal Points: Clinical Modules for Ophthalmologists. San Francisco, CA: American Academy of Ophthalmology: 2008, module 10.

• Wensing B, de Groot-Mijnes JD, Rothova A. Necrotizing and nonnecrotizing variants of herpetic uveitis with posterior segment involvement. Arch Ophthalmol. 2011;129(4): 403–408.

Cytomegalovirus

Cytomegalovirus is a double-stranded DNA virus in the Herpesviridae family. It is the most common cause of congenital viral infection and causes clinically relevant disease in neonates. It also causes illness in immunocompromised children and adults (leukemia, lymphoma, or HIV/AIDS), transplant recipients, and patients with conditions requiring systemic IMT. CMV retinitis is the most common ophthalmic manifestation of both congenital CMV infection and CMV as an opportunistic coinfection in patients with HIV/AIDS. The clinical appearance is similar regardless of clinical context, with 3 distinct variants:

• a classic or fulminant retinitis with large areas of retinal hemorrhage against a background of whitened, edematous, or necrotic retina. The retinitis typically appears in the posterior pole, near the vascular arcades, in the distribution of the nerve fiber layer, and associated with blood vessels (Fig 11-8)

• a granular or indolent form found more often in the retinal periphery, characterized by little or no hemorrhage, edema, or vascular sheathing. Active retinitis may progress from the borders of the lesion (Fig 11-9)

• a perivascular form often described as a variant of “frosted-branch” angiitis, an undifferentiated retinal perivasculitis initially described in immunocompetent children (Fig 11-10)

The diagnosis of congenital CMV disease is suggested by the clinical presentation; positive serum antibodies or PCR testing of urine, saliva, or intraocular fluids; and systemic findings. Serum antibody testing may be useful 5–24 months after the loss of maternal antibodies transferred after pregnancy. Congenital CMV retinitis is usually associated with other systemic manifestations of disseminated infection, including fever, thrombocytopenia, anemia, pneumonitis, and hepatosplenomegaly; the reported prevalence in children with congenital CMV infection is between 11% and 22%.

However, CMV retinitis has been reported to occur later in life among children with no discernible lesions ophthalmoscopically and no evidence of systemic disease reactivation. This pattern suggests that even asymptomatic children with evidence of congenital CMV infection should be monitored at regular intervals for potential ocular involvement later into childhood. Resolution of the retinitis leaves both pigmented and atrophic lesions, with retinal detachment occurring in up to one-third of these children. Optic atrophy and cataract formation are not uncommon sequelae.

The diagnosis of CMV retinitis in patients with HIV/AIDS or undergoing IMT is essentially clinical. Early CMV retinitis may present as a small, white retinal infiltrate and look like a cotton-wool spot. Patients may have coincidental HIV-associated retinopathy (dot-blot hemorrhages, cotton-wool spots), and early CMV retinitis is distinguished by its inevitable progression without treatment. In patients with atypical lesions or whose disease is not responding to therapy, early treatment and close follow-up are important. Polymerase chain reaction testing of aqueous or vitreous may help differentiate CMV from necrotizing retinitis secondary to HSV1/2 or VZV and from toxoplasmic retinochoroiditis. Toxoplasmosis may masquerade as a viral retinitis.

Prior to modern antiretroviral therapy, an estimated 30% of patients with HIV/AIDS, usually with CD4⁺ T lymphocyte counts ≤50 cells/μL, experienced CMV retinitis. Secondary to breaks in areas of peripheral retinal necrosis, rhegmatogenous retinal detachments occurred at a rate of approximately 33% per eye per year. Modern antiretroviral regimens have reduced the incidence of CMV retinitis and its associated complications, such as retinal detachment, by 80%. This decrease has stabilized, and new cases of CMV retinitis can occur in patients where combination antiretroviral treatment fails or in those who abandon treatment or experience immune reconstitution but do not develop CMV-specific immunity.

Cytomegalovirus reaches the eye hematogenously, with passage of the virus across the blood–ocular barrier, infection of retinal vascular endothelial cells, and cell-to-cell transmission of the virus within the retina. The histologic features of both congenital and acquired disease include a primary, full-thickness, coagulative necrotizing retinitis and secondary diffuse choroiditis. Infected retinal cells show pathognomonic cytomegalic changes consisting of large eosinophilic intranuclear inclusions and small basophilic cytoplasmic inclusions. Viral inclusions may also be present in the retinal pigment epithelium (RPE) and vascular endothelium.

Management of CMV retinitis requires antiretroviral regimens and anti-CMV therapy. Anti-CMV therapy is particularly important, since CMV retinitis signifies a twofold-increased mortality risk in patients with a CD4⁺ T-cell count below 100 cells/μL (an effect not observed with counts ≥100 cells/μL). Resistant CMV infection is further associated with increased mortality in patients with HIV/AIDS and CMV retinitis. Options for systemic coverage include high-dose induction with either intravenous ganciclovir (5 mg/kg twice daily) or foscarnet (90 mg/kg twice daily) for 2 weeks followed by low-dose daily maintenance therapy or oral valganciclovir (900 mg twice daily) for 3 weeks followed by maintenance therapy (900 mg/day).

Intravitreal injection of ganciclovir or foscarnet effectively treats intraocular disease and is a useful alternative in patients who cannot tolerate intravenous therapy because of myelotoxicity. However, intravitreal therapy alone leaves extraocular systemic CMV and the fellow eye untreated. Combination treatment with oral valganciclovir may ameliorate this limitation. This combination is also useful for vision-threatening, posteriorly located retinitis. In patients with CMV retinitis who are on antiretroviral regimens and experience sustained immune recovery (CD4⁺ T lymphocytes ≥100 cells/μL for 3–6 months), systemic anti-CMV maintenance therapy may be safely discontinued. Antiretroviral therapy–naive patients may require only 6 months of anti-CMV therapy with good immune reconstitution, whereas antiretroviral therapy–experienced patients may require long-term maintenance therapy. Despite immune recovery, patients with a history of CMV retinitis who discontinue maintenance anti-CMV therapy remain at risk for recurrence and should be monitored at 3-month intervals.

Patients with immune recovery may, months or years later, develop intermediate uveitis in the absence of CMV reactivation. Rather, the reconstituted immune system reacts to residual CMV antigens within the eye. Cystoid macular edema may develop. Topical, periocular, and oral steroids are utilized. Initial aggressive anti-CMV therapy initiated at the same time as antiretroviral treatment may ultimately decrease the incidence of immune recovery uveitis.

Among immunocompetent adults, CMV infection may produce a chronic or recurrent unilateral anterior uveitis associated with ocular hypertension, corneal edema, and variable degrees of sectoral iris atrophy. Positive PCR testing of aqueous fluid for CMV DNA combined with negative testing for HSV and VZV is diagnostic. Treatment options for CMV anterior uveitis include systemic anti-CMV treatment (usually valganciclovir), topical ganciclovir gel 0.15%, and intravitreal ganciclovir injections. Relapses are common after discontinuation of therapy.

• Chee SP, Bascal K, Jap A, Se-Thoe SY, Cheng CL, Tan BH. Clinical features of cytomegalovirus anterior uveitis in immunocompetent patients. Am J Ophthalmol. 2008;145(5):834–840.

• Jabs DA, Holbrook JT, Van Natta ML, et al; Studies of Ocular Complications of AIDS Research Group. Risk factors for mortality in patients with AIDS in the era of highly active antiretroviral therapy. Ophthalmology. 2005;112(5):771–779.

• Jabs DA, Martin BK, Forman MS; Cytomegalovirus Retinitis and Viral Resistance Research Group. Mortality associated with resistant cytomegalovirus among patients with cytomegalovirus retinitis and AIDS. Ophthalmology. 2010;117(1):128–132.

• Kedhar SR, Jabs DA. Cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Herpes. 2007;14(3):66–71.

• Kempen JH, Min YI, Freeman WR, et al; Studies of Ocular Complications of AIDS Research Group. Risk of immune recovery uveitis in patients with AIDS and cytomegalovirus retinitis. Ophthalmology. 2006;113(4);684–694.

Epstein-Barr virus

Epstein-Barr virus (EBV) is a ubiquitous double-stranded DNA virus with a complex capsid and envelope; it belongs to the subfamily Gammaherpesvirinae. EBV is commonly associated with infectious mononucleosis (IM) and has been implicated in the pathogenesis of Burkitt lymphoma (especially among African children), nasopharyngeal carcinoma, Hodgkin disease, and Sjögren syndrome. EBV has a tropism for B lymphocytes, the only cells known to have surface receptors for the virus.

Ocular manifestations may arise either as a consequence of congenital EBV infection or, more commonly, during primary infection in the context of IM. Cataract may occur with congenital EBV infection. In contrast, a mild, self-limiting follicular conjunctivitis is most common with acquired IM. Other, less frequently reported anterior ocular manifestations of acquired IM include epithelial or stromal keratitis; episcleritis; bilateral, granulomatous anterior uveitis; dacryoadenitis; and, less frequently, cranial nerve palsies and Parinaud oculoglandular syndrome.

A variety of posterior segment manifestations have been reported in association with EBV infection, including isolated optic disc edema and optic neuritis, macular edema, retinal hemorrhages, retinitis (Fig 11-11), punctate outer retinitis, choroiditis, multifocal choroiditis and panuveitis (MCP), pars planitis and vitritis, progressive subretinal fibrosis, uveitis, and secondary choroidal neovascularization (CNV). Acute retinal necrosis has also been reported. Epstein-Barr virus is rarely a cause of these findings in the absence of proper systemic context (eg, recent IM). Antibody testing against a variety of EBV-specific capsid antigens is rarely useful given the very high seroprevalence of EBV (90%) in the adult population; PCR assay from intraocular fluid can be helpful.

Most EBV-associated ocular disease is self-limiting. The presence of anterior uveitis may necessitate topical corticosteroids and cycloplegia. Systemic corticosteroids can treat posterior segment inflammation. Systemic antiviral therapy for EBV infection may be considered for the management of necrotizing retinitis/ARN.

• Matoba AY. Ocular disease associated with Epstein-Barr virus infection. Surv Ophthalmol. 1990;35(2):145–150.

• Peponis VG, Chatziralli IP, Parikakis EA, Chaira N, Katzakis MC, Mitropoulos PG. Bilateral multifocal chorioretinitis and optic neuritis due to Epstein-Barr virus: a case report. Case Rep Ophthalmol. 2012;3(3):327–332.

Excerpted from BCSC 2020-2021 series: Section 9 - Uveitis and Ocular Inflammation. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.