PATHOGENESIS

HSV-1 and HSV-2 are antigenically related. HSV-1 more commonly causes infection above the waist (orofacial and ocular infection) and HSV-2, below the waist (genital infection); but either virus can cause disease in either location. Primary infection with HSV-1 frequently manifests as a nonspecific upper respiratory tract infection and is recognized as HSV less than 5% of the time. In industrialized societies, 40%–80% of adults have serum antibodies to HSV-1, which represents a decline in infection from previous decades, and the age at which individuals undergo serologic conversion is increasing; HSV is now more commonly acquired in adolescence than in childhood. HSV infection is spread by direct contact with infected lesions or their secretions, most commonly as a result of exposure to viruses shed without clinical symptoms. HSV can be transmitted to the neonate during passage through the birth canal of a mother with active genital infection. In the newborn, HSV can cause systemic infection, including encephalitis, or disease confined to the skin and mucous membranes. BCSC Section 6, Pediatric Ophthalmology and Strabismus, discusses neonatal herpes infection in greater detail.

HSV spreads from infected skin and mucosal epithelium via sensory nerve axons to establish latent infection in associated sensory nerve ganglia, most commonly the trigeminal ganglion. Latent infection of the trigeminal ganglion may occur in the absence of recognized primary infection, and reactivation of the virus may follow in any of the 3 branches of cranial nerve V (ophthalmic nerve [V1], maxillary nerve [V2], and mandibular nerve [V3]), despite primary disease in the area of innervation of 1 particular branch. Approximately 0.15% of the US population has a history of external ocular HSV infection, and in approximately one-fifth of these individuals, stromal keratitis, the most common blinding manifestation of infection, develops.

Liesegang TJ. Herpes simplex virus epidemiology and ocular importance. Cornea. 2001;20(1): 1–13.

Pepose JS, Keadle TL, Morrison LA. Ocular herpes simplex: changing epidemiology, emerging disease patterns, and the potential of vaccine prevention and therapy. Am J Ophthalmol. 2006;141(3):547–557.

CLINICAL PRESENTATION

Primary ocular HSV infection typically manifests as a blepharoconjunctivitis. The conjunctival inflammatory response is follicular and accompanied by a palpable preauricular lymph node. Vesicles on the skin (Fig 9-2) or eyelid margin (Fig 9-3) are important for diagnosis. Patients with primary ocular HSV infection can develop epithelial keratitis (Fig 9-4), but stromal keratitis and uveitis are uncommon.

Signs that can help the clinician distinguish acute primary ocular HSV infection from acute primary infection associated with adenovirus include the following:

• vesicles on the skin or eyelid margin or ulcers on the bulbar conjunctiva (HSV)

• dendritic epithelial keratitis (HSV)

• conjunctival membranes or pseudomembranes (adenovirus)

Laterality is not a reliable distinguishing feature. Although adenoviral infections are more commonly bilateral, they can be unilateral, bilateral but asymmetric, or bilateral with delayed involvement of the second eye. Similarly, primary HSV infection may be either unilateral (most common) or bilateral.

Figure 9-2 Skin vesicles of herpes simplex virus (HSV) dermatoblepharitis.

(Courtesy of James Chodosh, MD.)

Figure 9-3 Eyelid margin ulcers characteristic of primary ocular HSV infection after vesicular rupture.

(Courtesy of Cornea Service, Paulista School of Medicine, Federal University of São Paulo.)

Figure 9-4 Fluorescein staining of an eye with primary HSV infection demonstrates characteristic upper eyelid margin ulcers and a coarse dendritic epithelial keratitis.

(Courtesy of James Chodosh, MD.)

LABORATORY EVALUATION

Demonstration of HSV is possible in productive epithelial infection with viral culture or antigen- or DNA-detection methodologies. Results of serologic tests for neutralizing or complement-fixing immunoglobulins may show a rising antibody titer during primary infection, but these tests are of no diagnostic assistance during recurrent episodes. As most adults are latently infected with HSV, serologic testing generally is helpful only when the results are negative.

Laboratory tests are indicated in complicated cases when the clinical diagnosis is uncertain and in all cases of suspected neonatal herpes infection. Vesicles can be opened with a needle, and vesicular fluid cultured. Scrapings from the vesicle base can be tested by cytology or for the presence of HSV antigen. Conjunctival scrapings or impression cytology specimens can be similarly analyzed by culture, antigen detection, or PCR.

MANAGEMENT

Primary ocular HSV infection is a self-limited condition. Oral antiviral therapy speeds resolution of signs and symptoms. Table 9-5 summarizes the antiviral agents that are effective against ocular HSV infections. For discussion about their use, see the respective clinical syndromes below.

PATHOGENESIS

Recurrent HSV infection is caused by reactivation of the virus in a latently infected sensory ganglion, transport of the virus down the nerve axon to sensory nerve endings, and subsequent infection of ocular surface epithelia. HSV latency locally, in the cornea, as a cause of recurrent disease remains a controversial concept.

Table 9-5 Antiviral Agents in External/Corneal Infections With Herpes Simplex Virus

The concept of environmental factors (psychological stress, systemic infection, sunlight exposure, menstrual cycle, and contact lens wear) acting as triggers for the recurrence of HSV ocular disease was not confirmed by the Herpetic Eye Disease Study (HEDS), despite reports of UV light–induced reactivation of herpes labialis and keratitis. HSV keratitis recurs more frequently in patients with HIV infection, but the severity of the keratitis is equal to that occurring in immunocompetent persons.

Herpetic Eye Disease Study Group. Psychological stress and other potential triggers for recurrences of herpes simplex virus eye infections. Arch Ophthalmol. 2000;118(12): 1617–1625.

CLINICAL PRESENTATION

Recurrent HSV infection can affect almost any ocular tissue, including the eyelid, conjunctiva, cornea, iris, uveal tract, trabecular meshwork, retina, and optic nerve, and it is typically unilateral, with only 3% of patients demonstrating bilateral disease (see Table 9-7). The presence of bilateral disease should raise the possibility of immune dysfunction (eg, atopic dermatitis).

CLINICAL PRESENTATION

Patients with epithelial keratitis report foreign-body sensation, light sensitivity, redness, and blurred vision. HSV infection of human corneal epithelium manifests as areas of punctate epithelial keratitis (Fig 9-5) that may coalesce into 1 or more arborizing dendritic epithelial ulcers whose branches have terminal bulbs. The cytopathic swollen corneal epithelium at the edge of a herpetic ulcer stains with rose bengal (Fig 9-6) or lissamine green because of loss of cell membrane glycoproteins and subsequent lack of mucin binding by the cells. The bed of the ulcer stains with fluorescein (Fig 9-7) because of loss of cellular integrity and absence of intercellular tight junctions. Areas of dendritic keratitis may coalesce further, enlarging into a more expansive geographic epithelial ulcer (Fig 9-8; see also Fig 9-7), particularly when topical corticosteroids are used.

Figure 9-5 A, Punctate epithelial keratitis (arrows); the lesion was culture-positive for HSV. B, Note the atypical raised edges and depressed center.

(Courtesy of Woodford S. Van Meter, MD.)

Figure 9-6 Rose bengal staining of herpetic epithelial keratitis outlines a typical dendrite.

(Courtesy of James Chodosh, MD.)

Figure 9-7 Combined fluorescein and rose bengal staining of geographic HSV keratitis.

(Courtesy of Cornea Service, Paulista School of Medicine, Federal University of São Paulo.)

Patients with HSV epithelial keratitis exhibit a ciliary flush and mild conjunctival injection. Mild stromal edema and subepithelial white blood cell infiltration may occur beneath the epithelial keratitis. Following resolution of dendritic epithelial keratitis, non-suppurative subepithelial infiltration and scarring may be seen just beneath the area of prior epithelial ulceration, resulting in a ghost image, or ghost dendrite (Fig 9-9), which reflects the position and shape of the prior epithelial involvement.

Focal or diffuse reduction in corneal sensation occurs following HSV epithelial keratitis. The distribution of corneal hypoesthesia is related to the extent, duration, severity, and number of recurrences of herpetic keratitis. See Chapter 4 for a more detailed description of neurotrophic keratopathy.

Figure 9-8 Herpetic geographic epithelial keratitis.

(Reprinted with permission from Chodosh J. Viral keratitis. In: Parrish RK, ed. The University of Miami Bascom Palmer Eye Institute Atlas of Ophthalmology. Boston: Current Medicine; 1999.)

Figure 9-9 Residual stromal inflammation following dendritic epithelial keratitis may leave the impression of a ghost image of the dendrite.

(Reprinted with permission from Chodosh J. Viral keratitis. In: Parrish RK, ed. The University of Miami Bascom Palmer Eye Institute Atlas of Ophthalmology. Boston: Current Medicine; 1999.)

Dendritiform epithelial lesions may develop in various settings, including

• VZV (see the discussion later in the chapter)

• adenovirus (uncommon)

• EBV (rare)

• epithelial regeneration line

• neurotrophic keratopathy (postherpetic, diabetes mellitus)

• soft contact lens wear (due to solutions containing thimerosal)

• topical medication use (antivirals, beta-blockers)

• Acanthamoeba epithelial keratitis

• epithelial deposits (eg, iron lines, Fabry disease, tyrosinemia type II, systemic drug use)

LABORATORY EVALUATION

A specific clinical diagnosis of HSV as the cause of dendritic keratitis can usually be made based on the presence of characteristic clinical features. Multinucleated giant cells (nonspecific) and intranuclear inclusions (more specific of herpesviruses) may be seen on corneal scrapings. Tissue culture, antigen detection techniques (ELISA), and PCR may be helpful in establishing the diagnosis in atypical cases.

MANAGEMENT

Most cases of HSV epithelial keratitis resolve spontaneously, and there is no clinical evidence to suggest that antiviral therapy influences the subsequent development of stromal keratitis or recurrent epithelial disease. However, treatment shortens the clinical course and might conceivably reduce the magnitude of any associated herpetic neuropathy, subepithelial scarring, or the potential risk of immune-mediated diseases of the cornea. Antiviral therapy can be used alone or in combination with epithelial debridement. Trifluridine 1% solution 8 times daily is efficacious for both dendritic and geographic epithelial keratitis. Ganciclovir 0.15% gel seems to have similar efficacy to topical acyclovir but is less toxic to the ocular surface than is trifluridine. Acyclovir 3% ophthalmic ointment has been reported to be as effective as and less toxic than trifluridine and vidarabine, but the ophthalmic form is not available in the United States at this time except through specialty compounding pharmacies. Treatment of the disease with topical antivirals generally should be discontinued within 10–14 days to avoid unnecessary toxicity to the ocular surface. Gentle epithelial debridement with a dry cotton-tipped applicator or cellulose sponge speeds resolution and may be helpful as adjunctive therapy in drug-resistant HSV keratitis.

Oral acyclovir has been reported to be as effective as topical antivirals for the treatment of epithelial keratitis and does not cause ocular toxicity. For this reason, oral therapy is preferred by an increasing number of physicians. Valacyclovir, a prodrug of acyclovir, is just as effective for ocular HSV disease but can cause thrombotic thrombocytopenic purpura/ hemolytic uremic syndrome in severely immunocompromised patients such as those with AIDS; thus, it must be used with caution if the patient’s liver function is compromised or the immune status is unknown. Alternative systemic antiviral drugs are listed in Table 9-5.

As previously noted, topical corticosteroids are contraindicated in the presence of active herpetic epithelial keratitis; patients with this disease who are using systemic corticosteroids for other indications should be treated aggressively with systemic antiviral therapy.

CLINICAL PRESENTATION

Herpetic stromal keratitis can be nonnecrotizing (interstitial or disciform) or necrotizing, and different forms may present simultaneously. Herpetic interstitial keratitis presents as unifocal or multifocal interstitial haze or whitening of the stroma in the absence of epithelial ulceration (Fig 9-10). Mild stromal edema may accompany the haze, but epithelial edema is not typical. In the absence of significant extracorneal inflammatory signs such as conjunctival injection or anterior chamber cells, it may be difficult to identify active disease in an area of previous scarring and thinning. Long-standing or recurrent HSV interstitial keratitis may be associated with corneal vascularization. The differential diagnosis of herpetic interstitial keratitis includes

Figure 9-10 Herpetic interstitial keratitis (nonnecrotizing).

(Reprinted with permission from Chodosh J. Viral keratitis. In: Parrish RK, ed. The University of Miami Bascom Palmer Eye Institute Atlas of Ophthalmology. Boston: Current Medicine; 1999.)

• VZV keratitis

• Acanthamoeba keratitis

• syphilis

• EBV keratitis

• mumps keratitis

• Lyme disease

• sarcoidosis

• Cogan syndrome

• atopic keratitis

• vernal keratitis

Herpetic disciform keratitis is a primary endotheliitis, which presents as corneal stromal and epithelial edema in a round or oval distribution, associated with keratic precipitates underlying the zone of edema (Fig 9-11). Iridocyclitis can be associated, and the disciform keratitis may be confused with uveitis with secondary corneal endothelial decompensation. However, in disciform keratitis, disc-shaped stromal edema and keratic precipitates appear out of proportion to the degree of anterior chamber reaction. Disciform keratitis due to HSV and that due to VZV are clinically indistinguishable.

Necrotizing herpetic keratitis appears as suppurative corneal inflammation (Fig 9-12). It may be severe, progress rapidly, and appear clinically indistinguishable from fulminant bacterial or fungal keratitis. Overlying epithelial ulceration is common, but the epithelial defect may occur somewhat eccentric to the infiltrate, and the edges of the epithelial ulcer do not stain with rose bengal dye. Corneal stromal vascularization is common. The differential diagnosis for necrotizing herpetic keratitis includes microbial keratitis due to bacteria, fungi, or acanthamoebae; retained foreign body; and topical anesthetic abuse.

Figure 9-11 Herpetic disciform keratitis (nonnecrotizing).

(Reprinted with permission from Chodosh J. Viral keratitis. In: Parrish RK, ed. The University of Miami Bascom Palmer Eye Institute Atlas of Ophthalmology. Boston: Current Medicine; 1999.)

Figure 9-12 Necrotizing herpetic stromal keratitis.

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Kip KE, Cohen F, Cole SR, et al; Herpetic Eye Disease Study Group. Recall bias in a prospective cohort study of acute time-varying exposures: example from the Herpetic Eye Disease Study. J Clin Epidemiol. 2001;54(5):482–487.

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MANAGEMENT

Many past controversies regarding the optimal management of HSV stromal keratitis have been resolved by the landmark HEDS (Table 9-6). Most important, HEDS findings showed that topical corticosteroids given with a prophylactic antiviral reduce persistence or progression of stromal inflammation and shorten the duration of HSV stromal keratitis; in addition, long-term suppressive oral acyclovir therapy reduces the rate of recurrent HSV keratitis and helps preserve vision. Lifelong antiviral prophylaxis is recommended for patients with multiple recurrences of HSV stromal keratitis.

The experimental protocol applied by HEDS investigators for patients with herpetic stromal keratitis is a useful starting point for a treatment algorithm. Visually significant herpetic interstitial keratitis is treated initially with prednisolone 1% drops every 2 hours, accompanied by a prophylactic antiviral drug, either topical trifluridine 4 times daily or an oral agent such as acyclovir 400 mg twice daily or valacyclovir 500 mg once a day. The prednisolone drops are tapered every 1–2 weeks depending on the degree of clinical improvement. The antiviral is given to prevent severe epithelial keratitis should the patient shed HSV while using corticosteroid drops, and it is generally continued until the patient has completely stopped the corticosteroids or is using less than 1 drop of prednisolone 1% per day. The corticosteroid should be tapered to the lowest possible dosage that controls the patient’s inflammation.

Currently available topical antiviral medications are not absorbed by the cornea through an intact epithelium, but orally administered acyclovir penetrates an intact cornea and anterior chamber. In this context, anecdotal evidence suggests that oral acyclovir might benefit the deep corneal inflammation of disciform keratitis. The HEDS showed no additional benefit when acyclovir was added to trifluridine and prednisolone for the treatment of herpetic stromal keratitis, but disciform keratitis was not analyzed as a separate group. Some cornea specialists routinely substitute oral acyclovir for topical trifluridine in treating disciform keratitis.

Necrotizing stromal keratitis is probably the least common but most destructive form of herpetic keratitis. The diagnosis is frequently one of exclusion following negative cultures for fungal and bacterial pathogens, but it is suggested by a history of facial, conjunctival, and/or corneal HSV infection. The toxicity of topical antiviral agents may be undesirable in patients with necrotizing inflammation and can confuse the clinical picture. Therefore, an oral antiviral such as acyclovir is preferred. Fortunately, necrotizing herpetic keratitis seems to be very sensitive to topical corticosteroids, and twice-a-day dosing may be sufficient to control inflammation in many patients.