Chapter 162 – Herpes and Other Viral Infections
P. KUMAR RAO
Varicella-Zoster and Herpes Simplex Virus–Induced Acute Retinal Necrosis
Progressive Outer Retinal Necrosis
• A necrotizing retinitis caused by infection with VZV or HSV in an immunocompetent host.
• Severe uveitis or vitritis.
• Retinal vasculitis.
• Retinal necrosis.
• Keratic precipitates.
• Retinal detachment.
• A necrotizing retinitis caused by infection with VZV of HSV in an immunocompromised host.
• Multifocal lesions.
• Outer retinal involvement.
• Minimal or no vasculitis and vitritis.
• Rapid progression.
• Poor prognosis.
• Other viruses
– Epstein-Barr virus
– Human T-cell lymphotropic virus type I
– Influenza A virus
– Measles virus
– Rubella virus
VARICELLA-ZOSTER AND HERPES SIMPLEX VIRUS
Both varicella-zoster (VZV) and herpes simplex viruses (HSV) can cause devastating intraocular inflammation.
In general, transmission is thought to occur through exposure to a person with an actively shedding viral lesion. Most cases of retinal disease are believed to be reactions of previously acquired infection. Along with VZV, two types of HSV (HSV1 and HSV2) can
Figure 162-1 Progressive outer retinal necrosis—early.
cause acute retinal necrosis (ARN). This retinal necrosis is seen in otherwise healthy individuals of both sexes and any age but may occur in immunocompromised persons. Necrotizing herpetic retinopathies represent a spectrum of disease, which may range from ARN to progressive outer retinal necrosis (PORN).
Both VZV and HSV can affect a variety of ocular tissues and result in manifestations such as blepharitis, conjunctivitis, scleritis, keratitis, anterior uveitis, glaucoma, vitritis, and retinitis. Maternal transmission to a developing fetus can cause serious systemic and ocular disease. Congenital VZV or HSV retinitis may appear as a pigmentary retinopathy in babies born to mothers known to have varicella-zoster or congenital herpes simplex infection during pregnancy.
The most common clinical manifestation of VZV or HSV retinitis has been called the acute retinal necrosis syndrome. Typically, it presents with a severe uveitis, retinal vasculitis, and retinal necrosis in presumably immunocompetent patients. In the early phase, there may be keratic precipitates and vitritis ( Fig. 162-1 ). The retinitis typically begins in the periphery and results in rapid confluence over a week to 10 days and can be associated with an occlusive vasculitis and papillitis. Retinal detachment typically occurs several weeks later. The retinitis may develop in the contralateral eye in over one third of patients. Usually VZV or HSV1 causes ARN in patients older than 25 years, whereas HSV2 causes ARN in younger patients. This viral infection can also present as a variant of retinal vasculitis with a frosted branch angiitis-like picture.
In the immunocompromised patient, the clinical appearance of zoster or simplex retinitis may be similar to that of ARN or may follow a pattern called progressive outer retinal necrosis. PORN differs from ARN in that it may begin in the posterior pole or the periphery and is commonly multifocal ( Fig. 162-2 ). It may not be associated with vasculitis, and vitritis may be minimal
Figure 162-2 Progressive outer retinal necrosis—late.
Figure 162-3 Acute retinal necrosis.
( Fig. 162-3 ). In general, the rate of progression is rapid. Treatment of PORN is difficult and visual prognosis is poor.
The diagnosis of ARN is based mainly on its clinical features. Diagnostic dilemmas occur in unusual cases. In these cases, confirmation of the diagnosis is possible through viral culture, detection of antiviral antibodies, and, more recently, polymerase chain reaction (PCR) analysis for viral DNA from ocular samples.
The differential diagnosis of ARN includes cytomegalovirus (CMV) retinitis, aspergillosis of the eye, and lymphoma. However, patients with ARN tend to demonstrate more vitritis than those with CMV infection, and the eye tends to be more red or painful than in patients with lymphoma. Aspergillosis is mainly seen in patients with granulocytopenia.
Histopathologically, ARN demonstrates full-thickness retinal necrosis with arteritis. The areas of necrotic retina are demarcated sharply from areas of normal retina. The necrotic retina may contain intranuclear inclusions. Electron microscopic studies may demonstrate viral particles.
Intravenous acyclovir is given at 1500?mg/m2 every 8 hours for about 7 days. Because fellow eye involvement may occur within the following few weeks, intravenous acyclovir is usually followed by 4 to 6 weeks of oral acyclovir at 2–4?g/day. Occlusive vasculopathy and optic neuropathy have been treated with aspirin and corticosteroids. As retinal detachment may be the most devastating cause of vision loss in these patients, prophylactic laser demarcation has been administered posterior to the advancing border of retinitis. Repair of ARN-associated retinal detachments may be achieved by using vitrectomy, endolaser, and silicone oil techniques. Treatments for PORN include the use of intravenous Acyclovir, and some patients have been treated with intravenous and intravitreal administration of foscarnet and ganciclovir.
COURSE AND OUTCOME
Visual recovery depends upon the extent of retinal involvement. In addition, the presence of vascular occlusion and optic neuropathy may limit the overall visual outcome. Immunosuppressed patients have the worst visual outcomes.
The Epstein-Barr virus (EBV) is double-stranded DNA virus. It is transmitted through exchange of saliva or blood transfusions. By adulthood, most people have acquired an infection with the virus. EBV is the causative agent of infectious mononucleosis, and it is also associated with Burkitt’s lymphoma and other B-cell malignancies seen in immunosuppressed patients. Various ocular manifestations related to EBV occur primarily in association with infectious mononucleosis.
The ocular manifestations of EBV infection are varied. Ocular motor nerve palsy, abducens nerve palsy, and optic neuritis have been attributed to EBV infections. Anterior segment manifestations have included conjunctivitis, iritis, mucosa-associated lymphoid tissue (MALT)–related lymphomas, conjunctival Burkitt’s lymphoma, iritis, and Parinaud’s oculoglandular syndrome. Posterior segment involvement may include multifocal choroiditis characterized by punched-out areas of pigment epithelial changes and vitritis ( Table 162-1 ).
The diagnostic entities that may mimic EBV chorioretinitis include presumed ocular histoplasmosis syndrome (POHS), recurrent multifocal choroiditis, multiple evanescent white dot syndrome (MEWDS), acute retinal pigment epitheliitis, and birdshot choroidopathy.
DIAGNOSIS AND ANCILLARY TESTING
Immunoglobulin M (IgM) and IgG antibodies in the serum can be detected and followed. In addition, EBV-related antigen can be quantified in the serum. PCR techniques to detect viral DNA
TABLE 162-1 — POSTERIOR SEGMENT FINDINGS IN EBV, HTLV-1, INFLUENZA A, MEASLES, AND RUBELLA VIRAL INFECTIONS
Retinal Pigment Epithelium Changes
Optic Nerve Changes
Gray-white granular deposits
Shiny dots at termination of capillaries
Darkened macular area
Small retinal hemorrhages
Stellate macular lesions
White retinal infiltrates
in ocular fluids have been successful. In situ hybridization techniques applied to biopsy specimens from the eye have also demonstrated the presence of EBV.
In general, EBV-related chorioretinitis appears to be fairly self-limiting, but for severe cases acyclovir therapy may be of some value. In general, because the EBV-related disease appears to be fairly self-limited, little documentation exists regarding its most effective therapy.
HUMAN T-CELL LYMPHOTROPIC VIRUS TYPE I
Perinatal infection with human T-cell lymphotropic virus type 1 (HTLV-1) is considered a risk factor for adult T-cell leukemia and of a degenerative neurological disorder known as tropical spastic paraparesis. This viral infection can cause intermediate uveitis.
In certain populations, infection with HTLV-1 is considered endemic, such as in areas of southwest Japan. In one study, 0.79% of people tested were seropositive for the HTLV antigens. The Tax protein of HTLV-1 is oncogenic and binds to transcription factors. The interaction of HTLV-1–disregulated cells with various kinds of normal lymphocytes and vascular endothelial cells may determine the type of HTLV-1–associated disease manifestation. 
Ocular manifestations include vitritis and uveitis/vasculitis.  A vasculitis composed of gray-white granular deposits scattered on the retinal veins and arteries may be characteristic of HTLV-1–associated retinal disease. Other manifestations include T-cell conjunctival and intraocular lymphomas, interstitial keratitis, Sjögren’s syndrome, optic neuritis, and retinal choroidal degeneration similar to retinitis pigmentosa.
DIAGNOSIS AND ANCILLARY TESTING
Tests for viral DNA, including PCR techniques, have proved the presence of the HTLV-1 virus. Serum antibodies against the HTLV-1 proteins have also been used to make the diagnosis of systemic HTLV-1 infection.
The differential diagnosis of HTLV-1–associated uveitis includes those uveitic conditions caused by multiple sclerosis, syphilis, sarcoidosis, and Behçet’s disease.
The intraocular inflammation may respond to corticosteroid therapy. 
COURSE AND OUTCOME
A single episode of uveitis with resolution over a few weeks occurs in the majority of patients. Only a few patients suffer poor visual outcomes from either steroid-induced cataracts or a retinal choroidal degeneration.
INFLUENZA A VIRUS
The influenza A virus is a single-stranded RNA virus that commonly causes acute respiratory illnesses. The ability of the virus to undergo reassortment of genomic segments between virus strains allows antigenic shifts in the lipid envelope of the virus. This allows new outbreaks every year.
The infection is acquired from secretions of the respiratory tract from acutely infected individuals. The virus first infects the respiratory epithelium and respiratory illness ensues, accompanied by headache, fever, chills, malaise, myalgia, cough, and sore throat. The acute illness usually resolves over the following 2 to 3 days, and most patients largely recover in 1 week’s time.
Ocular complications of influenza infection include iridocyclitis, interstitial keratitis, and dacryoadenitis. Posterior segment manifestations include macular edema, macular lesions consisting of shiny dots at the termination of a capillary, absent foveal reflexes, darkening of the macular area, optic neuritis, and small retinal hemorrhages (see Table 162-1 ). These changes appear reversible.
DIAGNOSIS AND ANCILLARY TESTING
Serological methods to confirm the diagnosis exist but require comparison of antibody titers obtained during the acute illness
with those obtained several weeks after the onset of the illness. Virus can be isolated from throat swabs or nasopharyngeal washes and grown in tissue culture. Viral antigens may be detected by the use of indirect immunofluorescent techniques on exfoliated nasopharyngeal cells.
Influenza A retinopathy may appear similar to Vogt-Koyanagi-Harada (VKH) syndrome or other viral infections.
Inactivated influenza vaccination is recommended for patients with chronic cardiovascular or pulmonary disorders, nursing home patients, medical personnel in contact with high-risk patients, or people with chronic metabolic disease as well as immunocompromised individuals. There have been case reports of optic neuropathy and corneal graft rejection after influenza vaccination.  These complications were treated successfully with steroids.
COURSE AND OUTCOME
Fortunately, influenza viral infection usually resolves without any sequelae. The posterior segment manifestations of influenza A infection appear to be reversible and leave minimal visual effects.
The measles virus is another RNA virus classified as a paramyxovirus. Infection with the virus is usually self-limited but can be associated with subacute sclerosing panencephalitis (SSPE).
The virus is transferred by nasopharyngeal secretions to the respiratory tract or conjunctiva of susceptible patients. The virus is highly contagious and is typically contracted in childhood. Congenital infections can occur. Prenatal transmission in the first trimester may cause abortion; infection later may result in premature birth or malformations such as cardiomyopathy, cataract, deafness, and pigmentary retinopathy.
The ocular manifestations of congenital infection include cataract and pigmentary retinopathy. The most common ocular manifestations of acquired infection are a self-limited keratitis or conjunctivitis. Retinopathy can occur with acquired measles infections. During the acute stages of retinal involvement, the fundus vessels may appear attenuated. There may be diffuse retinal edema associated with optic disc swelling, small hemorrhages, and stellate macular lesions. Irregular, flat, depigmented areas may also appear with some decline in vision. As the retinopathy resolves, a secondary pigment retinopathy with a salt-and-pepper appearance may occur (see Table 162-1 ). Retinal findings associated with SSPE include macular edema, pigment epithelial abnormalities, choroiditis, whitish retinal infiltrates, serous macular detachments, areas of retinal depigmentation, and optic neuritis.   
DIAGNOSIS AND ANCILLARY TESTING
Fluorescein angiography may demonstrate a diffuse leakage associated with retinal edema or increased transmission of choroidal fluorescence related to the pigment epithelial disease. There may be vascular occlusions, retinal pigment epithelial disturbances,
Figure 162-4 Rubella retinopathy. Classic salt-and-pepper appearance of the fundus is seen in this case of congenital rubella retinopathy. (Courtesy of George S. Novalis, MD.)
and cystic areas of hyperfluorescence. Serological tests for measles virus include compliment fixation, enzyme immunoassay, immunofluorescence, and the hemagglutination inhibition test. In addition, PCR techniques may be used for detecting viral RNA.
The differential diagnosis of measles retinopathy includes central serous chorioretinopathy, VKH disease, influenza A retinitis, toxoplasmic retinal choroiditis, and retinitis pigmentosa.
Histological specimens from uncomplicated measles cases are rare, but specimens have been documented in patients who have suffered from SSPE. Histologically, there may be areas of focal retinal necrosis with invasion of pigment-laden macrophages. The retinal pigment epithelium may show patchy areas of loss, but the choroid may appear normal. Intranuclear inclusions can be seen in the nuclear layers of the retina. 
No treatment is necessary for uncomplicated measles infections. Measles retinopathy may result in the onset of acute blindness a few weeks following the measles rash and in general resolving over the following months. No therapy for measles-related retinopathy exists.
The ophthalmic manifestations of rubella virus are similar to those of measles virus infections, and both can be seen in congenital and acquired forms. The congenital rubella retinitis may present as a salt-and-pepper fundus appearance ( Fig. 162-4 ). Acquired rubella begins with a classical rash and malaise. Ophthalmic manifestations include conjunctivitis, keratitis, and iritis. A retinitis may appear and can be associated with exudative detachments of the retina and retinal pigment epithelium. 
Multiple viruses can cause intraocular inflammation. Many of them can cause decreased vision and can have devastating long-term
effects. Ocular manifestations of other viral infections are being discovered. New diagnostic techniques such as PCR may allow testing for the presence of a viral cause for some of the idiopathic intraocular inflammations.
1. Ganatra JB, Chandler D, Santos C, et al. Viral causes of acute retinal necrosis syndrome. Am J Ophthalmol. 2000;129:166–72.
2. Markomichelakis NN, Barampouti F, Zafirakis P, et al. Retinal vasculitis with frosted branch angiitis-like response due to herpes simplex virus type 2. Retina. 1999;19:455–7.
3. Madhavan HN, Priya K, Anand AR, Therese KL. Detection of herpes simplex virus (HSV) genome using polymerase chain reaction (PCR) in clinical samples comparison of PCR with standard laboratory methods for the detection of HSV. J Clin Virol. 1999;14:145–51.
4. Demols PF, Cochaux PM, Velu T, Caspers-Velu L. Chorioretinal post-transplant lymphoproliferative disorder induced by the Epstein-Barr virus. Br J Ophthalmol. 2001;85:93–5.
5. Goto K, Sato K, Kurita M, et al. The seroprevalence of HTLV-1 in patients with ocular diseases, pregnant woman and healthy volunteers in the Kanto district, central Japan. Scand J Infect Dis. 1997;29:219–21.
6. Uchiyama T. Human T cell leukemia virus type I (HTLV-I) and human diseases. Annu Rev Immunol. 1997;15:15–37.
7. Mochizuki M, Ono A, Ikeda E, et al. HTLV-I uveitis. J Acquir Immune Defic Syndr. 1996;13(Suppl):s50–6.
8. Ishioka M, Goto K, Nakamuara S, et al. Prevalence of HTLV-1-associated uveitis in the Kanto Plain, Japan. Graefes Arch Clin Exp Ophthalmol. 1995;233:476–8.
9. Mathur SP. Macular lesion after influenza. Br J Ophthalmol. 1958;40:702.
10. Ray CL, Dreizin IJ. Bilateral optic neuropathy associated with influenza vaccination. J Neuroophthalmol. 1996;16:182–4.
11. Solomon A, Frucht-Pery J. Bilateral simultaneous corneal graft rejection after influenza vaccination. Am J Ophthalmol. 1996;121:708–9.
12. Foxman SG, Heckenlively JR, Sinclair SH. Rubeola retinopathy and pigmented paravenous retinochoroidal atrophy. Am J Ophthalmol. 1985;99:605–6.
13. De Laey JJ, Hanssens M, Colette P. Subacute sclerosing panencephalitis: fundus changes and histopathologic correlations. Doc Ophthalmol. 1983;56:11–21.
14. Totan Y, Cekic O. Bilateral retrobulbar neuritis following measles in an adult. Eye. 1999;13:383–4.
15. Park DW, Boldt HC, Massicotte SJ, et al. Subacute sclerosing panencephalitis manifesting as a viral retinitis: clinical and histopathologic findings. Am J Ophthalmol. 1997;123:533–42.
16. Tomoda A, Miike T, Miyagawa S, et al. Subacute sclerosing panencephalitis and chorioretinitis. Brain Dev. 1997;19:55–7.
17. Gerstle C, Zinn KM. Rubella-associated retinitis in an adult: report of a case. Mt Sinai J Med. 1976;43:303–8.
18. Hayashi M, Yoshimura N, Kondo T. Acute rubella retinal pigment epitheliitis in an adult. Am J Ophthalmol. 1982;93:285–8.