Herpetic keratitis

Clinical background

Herpetic keratitis usually results from infection with herpes simplex virus type 1 (HSV-1) in adults and by HSV-2 in neonates. Occasionally the cause is varicella-zoster virus (VZV), either during primary infection or more commonly, as a site during an outbreak of shingles. The epidemiology of HSV-1 and HSV-2 infection is being changed as a consequence of different patterns of human sexual behavior. Persons are seroconverting to HSV-1 later in life and many are now first exposed to the virus as a genital infection. HSV-2 infection is on the increase and more frequently than before may be the cause of keratitis.

Primary infection, especially with HSV-1, may be subclinical or mild and misdiagnosed. However, it can cause a painful lesion that mainly affects the corneal epithelium, lasting for several days or even weeks, but which eventually resolves without permanent damage to the cornea. This event occurs more quickly if antivirals are administered topically or even systemically. However this ancient disease, first described by the Romans, is never cured since the virus ensconces itself in nerve ganglia where it can persist indefinitely in a dormant state, termed latency. Unfortunately, the virus can reactivate from latency, giving rise to recurrent lesions, which are often those of most clinical consequence. Repeated recurrences may develop into a chronic immunoinflammatory event which can markedly impair vision ( Figure 12.1 ). This later form is called stromal keratitis (SK) and accounts for about 20% of cases. SK is only rarely the consequence of primary infection. The clinical aspects of herpetic keratitis are summarized in Table 12.1 .

Figure 12.1

Human eye showing stromal keratitis.

Table 12.1

Clinical manifestation of ocular herpes and its management

Primary Epithelial keratitis Stromal keratitis Disciform keratitis

  • Symptoms

  • Mild malaise and fever with redness, irritation, and watery discharge from the eye (typically unilateral)

  • Follicular conjunctivitis associated with enlargement of the ipsilateral preauricular lymph node

  • Swollen lid and grouped vesicles or ulcers

  • Similar lesions may be present near mouth

  • Edematous or injected conjunctiva

  • Grittiness, photophobia, blurred vision mostly evident with 2 weeks of infection

  • Management

  • Application of antiviral ointment

  • Debridement of the corneal epithelium vescicles on the lid

  • Appropriate antibiotics or antifungal if secondary bacterial infection is involved

  • Symptoms

  • Painful eye, corneal hypothesis, tearing, and photophobia

  • Ciliary injection

  • Dendritic ulcers on the epithelial surface and epithelial erosion

  • Vesicles or ulcers may develop on the lids, face, mouth, and nose

  • Management

  • Similar to primary herpes

  • Analgesics can be used to relieve pain

  • Discontinue or reduce the dose of steroids in case of steroid-enhanced ulcers

  • Symptoms

  • Painful eye; both inflammatory and reparative events could be visible by slit lamp

  • Cellular infiltration, neovascularization, and scarring

  • Stratified opacities and presence of corneal lamellae

  • Corneal necrosis and ground-glass appearance of the stroma

  • Corneal scarring, facet formation, and perforation

  • Management

  • Steroid therapy to control inflammation (lowest effective dose to be used to minimize the side-effects)

  • Administration of antivirals to reduce the chances of recurrence

  • Steroid dose can be reduced slowly but if inflammation recurs it needs to be increased

  • Symptoms

  • Blurred vision with photophobia, tearing, and mild orbital pain

  • Unlike stromal keratitis, lesions are uniform. Intact epithelium with a central or eccentric zone of edema that surrounds a solid disc of edematous stroma

  • Wessely ring might appear

  • White keratitic precipitates on the endothelial surface

  • Management

  • Similar to stromal keratitis

  • Application of steroid

Overall, herpetic keratitis is the most frequent infectious cause of impaired vision in the developed world, with an estimated 20 000 new cases occurring annually in the USA and an incidence of 20.7 cases per 100 000 patient years ( Box 12.1 ). The disease shows no gender bias and any genetic factors that affect susceptibility are poorly understood. Virus strains could vary in virulence, as has been well documented to occur in studies with animal models. Immunosuppressed patients, including the human neonate, however, are more likely to have severe clinical disease. Prolonged and severe lesions may also occur in patients with acquired immunodeficiency syndrome (AIDS).

Box 12.1

A typical case of stromal keratitis

  • Herpetic keratitis is the commonest infectious cause of blindness in the USA

  • Usual cause is herpes simplex virus (HSV)-1 or HSV-2 and, more rarely, varicella-zoster virus

  • Virus remains dormant (latent) after infection

Primary and recurrent HSV-induced keratitis can be confused with abrasions as well as with infectious causes of keratitis by bacterial, chlamydial, parasitic, and fungal agents. Additionally, recurrent herpetic lesions need to be distinguished from graft rejection following keratoplasty and with zoster caused by VZV. Accurate diagnosis can be made by demonstrating HSV in the corneal tissue samples or ocular secretions by cell culture, immunofluorescence staining, or by detecting the viral genome by polymerase chain reaction. The appropriate response to therapy may also provide a clue. Serological diagnosis is unreliable except to confirm a primary infection since the majority of the population are seropositive, as will be all of those who experience recurrent lesions.

The acute and epithelial forms of herpetic keratitis respond to treatment with several types of antiviral drugs which are usually given topically. The most commonly administered drugs are various nucleoside analogs, such as vidarabin, trifluorothymidine, aciclovir, ganciclovir, and cidofovir. Chronic forms of keratitis such as disciform and SK may not respond to antivirals since replicating virus may no longer be present in the cornea in later stages of disease. Treatment focuses on the use of anti-inflammatory drugs, particularly steroids. Typically treatment starts with a high dose given daily, tapering off to a very low dose that may be continued for weeks or even months. There is a place for future therapies aimed at essential steps in the pathogenesis of the disease, which modern research is revealing. Some of these are listed in Table 12.2 , along with the event they target.

Table 12.2

Potential future approaches to control herpetic keratitis

Target Approach
Inflammation Anti-inflammatory molecules such as COX-1 and -2 inhibitors
Blocking critical cytokines and chemokines
Ciclosporin A
Targeting angiogenic factors and their receptors VEGF: anti-VEGF antibody and siRNA
Inhibiting metalloproteinase with siRNA or TIMP-1
Immunomodulation Changing the balance from Th1 to Th2
Affecting T-cell activation: CTLA4 Ig, anti-BB
Adoptive transfer of regulatory T cells
Nonmitogenic anti-CD3 antibody
Anti-CD200 Fc
Sequestering T cells in lymph nodes using FTY720
Inducing regulatory T cells by administration of rapamycin, FTY720, retinoic acid, and blocking histone deacetylase
Tissue-repairing therapy Application of FGF

COX-1, cyclooxygenase-1; VEGF, vascular endothelial growth factor; TIMP-1, tissue inhibitor of metalloproteinase 1; CTLA4, cytotoxic T-lymphocyte antigen 4; Ig, immunoglobulin; FGF, fibroblast growth factor.

Conceptually, the best way to deal with herpetic keratitis is to develop effective prophylactic, or better still, therapeutic vaccines. The mission to develop such vaccines has been vigorously pursued but so far with no real success. Currently, the target HSV-induced diseases are genital infections caused mainly by HSV-2, since these are far more common than ocular problems. If success is achieved in the HSV-2 vaccine field, this could help reduce the incidence of neonatal ocular herpes. As mentioned, the most serious consequence of ocular HSV in adults results from recurrences and these often have an immunopathological component. Conceivably, therapeutic vaccines could make matters worse rather than better – an issue that will need to be examined carefully.


Herpes simplex virus infection of the eye has two major consequences: firstly, direct lysis, the fate of all cells in which the virus completes a replication cycle. The second effect is the induction of an inflammatory reaction that itself may lead to tissue damage. The latter can ultimately become chronic, mainly because components of the virus become targets for an immunopathological reaction.

The commonest causes of pathologic lesions with HSV ocular infection are the lytic effects of viral replication ( Box 12.2 ). Such lesions may be confined to the corneal epithelium or additionally affect the nearby tissues such as the conjunctiva, uveal tract, corneal endothelium, and even the retina, as occurs most often in HSV-2-infected neonates. The lytic cells are shed, giving rise to ulcers, and an inflammatory reaction occurs. Frequently the ulcers are irregular in outline and are described as dendritic. Figure 12.2 shows such an ulcer in a recently infected rabbit. Lytic infection of the corneal endothelium usually results in edema, swelling of the stroma, and perhaps entrance of viral antigen into this tissue. This form of keratitis is called disciform keratitis. The viral antigens that enter the stroma react with antibody and may form ring-shaped opacities called Wessely rings. Immune complexes can also fix complement, resulting in a necrotizing lesion which may represent one form of SK in humans as well as in the rabbit model.

Box 12.2

General features

  • Acute herpetic keratitis is mainly caused by herpes simplex virus (HSV)-1, but changing sexual behavior is making HSV-2 a more common cause

  • Neonatal keratitis is usually caused by HSV-2 infection of seronegative infants

  • Acute infections respond well to antiviral therapy

  • Control of chronic lesions requires anti-inflammatory drugs

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Aug 26, 2019 | Posted by in OPHTHALMOLOGY | Comments Off on Herpetic keratitis

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