Epidemiology
Human herpesviruses ( Table 4.15.1 ) have in common a state called “latency,” where the virus remains dormant in cells and periodically reactivates. Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) have an affinity for the sensory ganglion cells and, therefore, are called neurotrophic viruses . These viruses are ubiquitous, and in most parts of the world, exposure to HSV-1 is almost universal by late adulthood. HSV keratitis (HSVK) is the most common cause of corneal blindness in developed nations. In the United States, the incidence of new cases of HSVK is estimated at 24 000 per year, and the total number of episodes at 58 000 per year with a prevalence over 400 000. HSV-1 infections more commonly occur in the orolabial area and HSV-2 in the genital area.
| Abbreviation | Nomenclature | Disease Caused |
|---|---|---|
| HSV-1 | Herpes simplex type-1 | Oral, ocular, genital herpes, whitlow |
| HSV-2 | Herpes simplex type-2 | Genital, oral, ocular herpes, whitlow |
| VZV | Varicella zoster virus | Chickenpox, herpes zoster (shingles) |
| CMV | Cytomegalovirus | Retinitis, range of systemic diseases |
| EBV | Epstein–Barr virus | Infectious mononucleosis |
| HHV-6 | Human herpesvirus-6 | Exanthem subitum (roseola) |
| HHV-7 | Human herpesvirus-7 | Exanthem subitum (roseola) |
| KSRV | Kaposi’s sarcoma–related virus | Kaposi’s sarcoma |
Herpes Simplex Virus
HSV, a large double-stranded DNA virus, has an icosahedral capsid surrounded by a poorly defined tegument enclosed in a host cell membrane-derived envelope with viral-derived glycoprotein projections ( Fig. 4.15.1 ).
Newly formed virions, which replicate in the cell nucleus, egress by budding from the cell membrane, destroying the cell in the process. Recurrent infections progressively destroy sensory ganglion cells, diminishing corneal sensation, one of the hallmarks of HSVK.
Serum antibody production to HSV infections is inconsistent and only partially protective. The major immune response to HSV is T lymphocyte mediated.
Life Cycle of HSV
Initial HSV infection is usually asymptomatic and occurs by direct contact of mucous membranes with infected secretions rather than by fomites or aerosolization. The virus enters epithelial cells on contact, replicates, enters the sensory nerve endings, and travels in a retrograde fashion to the trigeminal ganglion, where it remains latent ( Fig. 4.15.2 ). The cornea also may be a site of HSV latency and replication. After an initial round of replication in the trigeminal ganglion, the virus travels back down the nerve in an antegrade fashion, causing primary infection in about 6% of patients. It then remains latent until certain triggers cause it to reactivate, replicate, and travel back down the nerve to cause recurrent infection. It is not clear if the initial infection occurs by direct contact of ocular tissues with infected secretions, or if the initial infection occurs in the orolabial area with the virus then spreading to the neurons supplying the eye in the trigeminal ganglion (back-door spread).
Life Cycle of HSV
Initial HSV infection is usually asymptomatic and occurs by direct contact of mucous membranes with infected secretions rather than by fomites or aerosolization. The virus enters epithelial cells on contact, replicates, enters the sensory nerve endings, and travels in a retrograde fashion to the trigeminal ganglion, where it remains latent ( Fig. 4.15.2 ). The cornea also may be a site of HSV latency and replication. After an initial round of replication in the trigeminal ganglion, the virus travels back down the nerve in an antegrade fashion, causing primary infection in about 6% of patients. It then remains latent until certain triggers cause it to reactivate, replicate, and travel back down the nerve to cause recurrent infection. It is not clear if the initial infection occurs by direct contact of ocular tissues with infected secretions, or if the initial infection occurs in the orolabial area with the virus then spreading to the neurons supplying the eye in the trigeminal ganglion (back-door spread).
Primary HSV Infection
Primary HSV ocular infection most commonly manifests as blepharoconjunctivitis (often with conjunctival ulceration) that heals without scarring ( Fig. 4.15.3 ). The associated follicular conjunctivitis is often mistaken for adenoviral conjunctivitis ( Fig. 4.15.4 ); up to a third of unilateral follicular conjunctivitis may be culture-positive for HSV. Other features include lid vesicles and conjunctival dendrites. Keratitis is rare, occurring in only 3%–5% of cases, although severe bilateral disease can occur in atopic or immunocompromised patients.
Recurrent HSV Infections
Multiple factors are thought to trigger recurrence, including fever, menses, sunlight, irradiation, and emotional stress. Anecdotal reports have also implicated prostaglandin analogues, immunosuppression, and refractive surgery. Recurrent disease, estimated to occur in 27% of patients at 1 year and over 60% at 20 years, commonly causes keratitis (HSVK), although it can affect all parts of the eye. The risk of a subsequent recurrent infection increases with the number of recurrences to 83% at 20 years after one or more recurrences.
HSVK is broadly classified into epithelial and stromal/endothelial keratitis. This classification not only is anatomical but also is important for understanding the pathophysiology of HSVK and for planning treatment.
Epithelial Keratitis
Caused by actively replicating virus on the corneal surface, this usually starts as epithelial vesicles, punctate keratitis, or opaque plaques that coalesce and break down centrally. Initial episodes present with foreign body sensation, but subsequent episodes usually are painless because of corneal hypoesthesia. However, the associated inflammation may cause significant photophobia. It includes the conditions discussed below.
Dendritic Ulcer
This classic herpetic lesion consists of a linear, dichotomously branching lesion with terminal bulbs ( Fig. 4.15.5 ). The borders consist of acantholytic, infected cells and are slightly raised, grayish, and stain with Rose Bengal stain. The central epithelial defect stains with fluorescein. The underlying stroma may have minimal inflammation. On resolution, a dendrite-shaped scar, called ghost dendrite , may remain in the superficial stroma.
Geographical Ulcer
Patients who are immunocompromised, on topical corticosteroids, or have long-standing, untreated ulcers can develop very large epithelial defects. However, dichotomous branching and terminal bulbs are often seen at the periphery and the staining is similar to dendritic keratitis.
Marginal Keratitis
These lesions located near the limbus can resemble staphylococcal catarrhal ulcers. An epithelial defect and lack of corneal sensation can aid in diagnosis. Significant stromal inflammation can occur because of the proximity to limbal blood vessels. More resistant to treatment, they frequently become trophic ulcers.
Metaherpetic (Trophic) Ulcer
This is not associated with live virus and results from inability of the epithelium to heal ( Fig. 4.15.6 ). It is called a trophic ulcer if it arises de novo or a metaherpetic ulcer if it follows a dendrite or geographical ulcer, although the terms are used interchangeably. The causes are multifactorial and include toxicity from antiviral medications, unrecognized trauma, lack of neural-derived growth factors, poor tear surfacing, and underlying, low-grade stromal inflammation. Neurotrophic ulcers start as roughened epithelium that breaks down to produce an epithelial defect with smooth margins. The borders are grayish, elevated, and consist of multiple layers of epithelium. In contrast to geographical ulcers, Rose Bengal stains the unhealthy epithelial cells attempting to migrate across the base of the ulcer while fluorescein leaks between these poorly adherent cells into the stroma and stains the periphery—so-called “reverse staining” (see Fig. 4.15.6 ).
Stromal/Endothelial Keratitis
Usually an immune-mediated response to nonreplicating viral particles, stromal keratitis can affect all layers of the cornea and may even involve the trabecular meshwork and iris. It is classified based on the predominant site and type of involvement.
Endotheliitis
This is the most common form, and it manifests as overlying stromal edema from endothelial dysfunction. Long-standing stromal edema leads to permanent scarring and decreased vision.
Localized Endotheliitis
This appears as a disc-shaped area of corneal edema called disciform keratitis ( Fig. 4.15.7 ). Minimal stromal inflammation occurs without epithelial involvement, although microcystic edema and bullae may develop later in some cases. Focal keratic precipitates underlying the edema are highly suggestive but may be difficult to visualize. Sharp demarcation between involved and uninvolved stroma distinguishes this from other causes of stromal edema.
Diffuse and Linear Endotheliitis
These are rare and usually accompanied by trabeculitis and elevated intraocular pressure. Pseudo-guttae and Descemet’s folds may cause confusion with Fuchs’ dystrophy. Linear keratic precipitates can resemble allograft rejection.
Necrotizing Keratitis
The significantly greater inflammation is thought to be a reaction to live viral particles in the corneal stroma ( Fig. 4.15.8 ). It is most commonly seen in patients with multiple recurrences, especially with HSV-2. Difficult to distinguish from other causes of microbial keratitis without a high index of suspicion, it may cause corneal melting and perforation. Frequently, it is associated with uveitis and trabeculitis that may lead to recalcitrant glaucoma.
Immune Stromal Keratitis
This manifests as focal, multifocal, or diffuse stromal opacities or an immune ring ( Fig. 4.15.9 ). It often is accompanied by stromal edema and a mild anterior chamber reaction. The epithelium and endothelium are relatively spared. It also is called interstitial keratitis (IK) and can lead to deep stromal vascularization. HSV is now the most common cause of IK, especially unilateral, in the United States. Unlike syphilitic IK, HSV neovascularization is usually unilateral, sectoral, at multiple levels within the stroma, and leads up to a stromal scar.
Lipid Keratopathy
Newly formed or inflamed vessels are permeable to lipid because of the action of vascular endothelial growth factor. Once exuded, the lipid collects within keratocytes and intercellular matrix and is the major cause of vision loss requiring corneal transplantation in patients with HSV.
Keratouveitis
Uveitis is usually granulomatous with large “mutton fat” keratic precipitates on the endothelium ( Fig. 4.15.10 ). Although often immune mediated, sectoral iritis with a plasmoid aqueous is caused by release of live virus from the sympathetic nerves. It can lead to significant morbidity from synechiae, iris atrophy, cataracts, and glaucoma. Unilateral uveitis with high intraocular pressure often is caused by HSV.
Miscellaneous Syndromes
Herpes has been implicated in various chronic, unilateral diseases of the iris and trabecular meshwork. HSV DNA has been isolated by polymerase chain reaction (PCR) from the endothelium of corneas with iridocorneal endothelial (ICE) syndrome and from the aqueous humor of patients with Posner–Schlossman syndrome and Fuchs’ heterochromic iridocyclitis.
Epithelial Keratitis
Caused by actively replicating virus on the corneal surface, this usually starts as epithelial vesicles, punctate keratitis, or opaque plaques that coalesce and break down centrally. Initial episodes present with foreign body sensation, but subsequent episodes usually are painless because of corneal hypoesthesia. However, the associated inflammation may cause significant photophobia. It includes the conditions discussed below.
Dendritic Ulcer
This classic herpetic lesion consists of a linear, dichotomously branching lesion with terminal bulbs ( Fig. 4.15.5 ). The borders consist of acantholytic, infected cells and are slightly raised, grayish, and stain with Rose Bengal stain. The central epithelial defect stains with fluorescein. The underlying stroma may have minimal inflammation. On resolution, a dendrite-shaped scar, called ghost dendrite , may remain in the superficial stroma.
Geographical Ulcer
Patients who are immunocompromised, on topical corticosteroids, or have long-standing, untreated ulcers can develop very large epithelial defects. However, dichotomous branching and terminal bulbs are often seen at the periphery and the staining is similar to dendritic keratitis.
Marginal Keratitis
These lesions located near the limbus can resemble staphylococcal catarrhal ulcers. An epithelial defect and lack of corneal sensation can aid in diagnosis. Significant stromal inflammation can occur because of the proximity to limbal blood vessels. More resistant to treatment, they frequently become trophic ulcers.
Metaherpetic (Trophic) Ulcer
This is not associated with live virus and results from inability of the epithelium to heal ( Fig. 4.15.6 ). It is called a trophic ulcer if it arises de novo or a metaherpetic ulcer if it follows a dendrite or geographical ulcer, although the terms are used interchangeably. The causes are multifactorial and include toxicity from antiviral medications, unrecognized trauma, lack of neural-derived growth factors, poor tear surfacing, and underlying, low-grade stromal inflammation. Neurotrophic ulcers start as roughened epithelium that breaks down to produce an epithelial defect with smooth margins. The borders are grayish, elevated, and consist of multiple layers of epithelium. In contrast to geographical ulcers, Rose Bengal stains the unhealthy epithelial cells attempting to migrate across the base of the ulcer while fluorescein leaks between these poorly adherent cells into the stroma and stains the periphery—so-called “reverse staining” (see Fig. 4.15.6 ).
Dendritic Ulcer
This classic herpetic lesion consists of a linear, dichotomously branching lesion with terminal bulbs ( Fig. 4.15.5 ). The borders consist of acantholytic, infected cells and are slightly raised, grayish, and stain with Rose Bengal stain. The central epithelial defect stains with fluorescein. The underlying stroma may have minimal inflammation. On resolution, a dendrite-shaped scar, called ghost dendrite , may remain in the superficial stroma.
Marginal Keratitis
These lesions located near the limbus can resemble staphylococcal catarrhal ulcers. An epithelial defect and lack of corneal sensation can aid in diagnosis. Significant stromal inflammation can occur because of the proximity to limbal blood vessels. More resistant to treatment, they frequently become trophic ulcers.
Metaherpetic (Trophic) Ulcer
This is not associated with live virus and results from inability of the epithelium to heal ( Fig. 4.15.6 ). It is called a trophic ulcer if it arises de novo or a metaherpetic ulcer if it follows a dendrite or geographical ulcer, although the terms are used interchangeably. The causes are multifactorial and include toxicity from antiviral medications, unrecognized trauma, lack of neural-derived growth factors, poor tear surfacing, and underlying, low-grade stromal inflammation. Neurotrophic ulcers start as roughened epithelium that breaks down to produce an epithelial defect with smooth margins. The borders are grayish, elevated, and consist of multiple layers of epithelium. In contrast to geographical ulcers, Rose Bengal stains the unhealthy epithelial cells attempting to migrate across the base of the ulcer while fluorescein leaks between these poorly adherent cells into the stroma and stains the periphery—so-called “reverse staining” (see Fig. 4.15.6 ).
Stromal/Endothelial Keratitis
Usually an immune-mediated response to nonreplicating viral particles, stromal keratitis can affect all layers of the cornea and may even involve the trabecular meshwork and iris. It is classified based on the predominant site and type of involvement.
Endotheliitis
This is the most common form, and it manifests as overlying stromal edema from endothelial dysfunction. Long-standing stromal edema leads to permanent scarring and decreased vision.
Localized Endotheliitis
This appears as a disc-shaped area of corneal edema called disciform keratitis ( Fig. 4.15.7 ). Minimal stromal inflammation occurs without epithelial involvement, although microcystic edema and bullae may develop later in some cases. Focal keratic precipitates underlying the edema are highly suggestive but may be difficult to visualize. Sharp demarcation between involved and uninvolved stroma distinguishes this from other causes of stromal edema.
Diffuse and Linear Endotheliitis
These are rare and usually accompanied by trabeculitis and elevated intraocular pressure. Pseudo-guttae and Descemet’s folds may cause confusion with Fuchs’ dystrophy. Linear keratic precipitates can resemble allograft rejection.
Necrotizing Keratitis
The significantly greater inflammation is thought to be a reaction to live viral particles in the corneal stroma ( Fig. 4.15.8 ). It is most commonly seen in patients with multiple recurrences, especially with HSV-2. Difficult to distinguish from other causes of microbial keratitis without a high index of suspicion, it may cause corneal melting and perforation. Frequently, it is associated with uveitis and trabeculitis that may lead to recalcitrant glaucoma.
