Volume 4, Chapter 19 Herpes Simplex Keratitis

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Chapter 19

Herpes Simplex KeratitisDENIS M. O'DAY

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HERPES SIMPLEX VIRUS

HERPES SIMPLEX VIRUS INFECTION

PRIMARY HERPESRECURRENT HERPES SIMPLEX

COMPLICATIONS

REFERENCES

Infection of the cornea with Herpesvirus hominis can present the

ophthalmologist with a number of challenging and difficult problems. Much of

what is known of the virus and its relationship to humans, its natural host, has

been accumulated as a result of intensive research in the fields of virology and

immunology. Gaps in our knowledge still exist and as these gaps narrow, our

principles and methods of treatment will change.

In Western countries, infection with herpesvirus is almost universal. By early

adult life, neutralizing antibodies are present in up to 90% of the population.

Peaks of primary infections occur during infancy and adolescence, but sporadic

cases are seen in the neonatal period and throughout adult life. In the majority,

the primary infection is subclinical or goes undiagnosed. The disease usually runs

a self-limited course but occasionally has a fatal outcome. With healing of the

primary infection, the body is apparently free of disease; however, the virus has

not been eliminated. Instead, having established a foothold, it persists

permanently in an almost perfect symbiotic relationship that is marred by

recurrent disease when the virus is reactivated from its apparent latent state.

Primary ocular herpes usually occurs as an acute follicular conjunctivitis withregional lymphadenitis and usually with vesicular ulcerative blepharitis. Most

patients also have an epithelial keratitis, which persists somewhat longer than

the conjunctivitis. Only rarely is there significant stromal involvement.

Recurrent episodes are a different problem. In these, the cornea is the principal

target tissue. Males are inf ected twice as often as females, and attacks,

although occurring all year, tend to be more frequent in autumn and winter. The

most common form is the morphologically characteristic epithelial keratitis

(dendritic, geographic, or punctate). Initially, there may be no serious sequelae

to infection, but with repeated attacks, stromal keratitis, and associated uveitis

may appear. Alternatively, disciform keratitis or other more heavily infiltrated

stromal keratitis may develop without apparent preceding epithelial herpetickeratitis. When stromal keratitis supervenes, permanent structural damage to

the cornea and to the rest of the eye exacts a heavy toll on vision. It is this

effec t, coupled with chronicity and resistance to treatment, that makes herpes

simplex one of the most important viruses to affect the eye.

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HERPES SIMPLEX VIRUS

MORPHOLOGY

Herpes simplex virus (HSV) is a member of the Herpesviridae family. The virion is

180 nm in diameter. It is composed of four principal components: the core, the

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capsid, the tegument, and the envelope (Fig. 1).

Fig. 1 Schematic morphology of herpes simplex virus.

(Published courtesy of Liesegang TJ: Biology and

molecular aspects of herpes simplex and varicella-

zoster virus infections. Ophthalmology 99: 781, 1992)

Core

The viral core contains double-stranded DNA used for viral replication. The viral

genome has a molecular weight of 100 × 10,1,2 large enough to encode

approximately 70 proteins and 72 genes.3 The viral DNA molecule is arranged as

a double helix composed of two chains of repeating units of deoxyribose and

phosphate, with purine and pyrimidine bases extending sideways from the sugar.

The purine bases are guanine and adenine, whereas the pyrimidine are cytosine

and thymine. The chains are linked together by the pairing of protruding bases

to form the double helix. All the information required for virus replication is

inscribed on the DNA molecule in a code constructed according to the order of

repetition of the four bases. The physical form of the DNA of the virion in thereplicating and latent virus is different. In the virion form of the virus, the DNA is

linear but after infecting a cell it becomes circular. The viral DNA contains

several classes of genes that encode regulatory proteins, structural proteins,

and enzymes that are spread in a highly regulated fashion during the replicative

cycle.4 Latency-associated transcripts (LATs) represent limited transcription of

viral DNA during latency and serve as a marker for latently infected cells.3

Capsid

The viral DNA is enclosed within a protein shell with an icosahedral shape called

a capsid. The capsid is composed of 162 five- or six-sided subunits called

capsomeres.3 In addition to protecting the viral genome, the capsid allows entry

of the viral DNA into the host cell.

Tegument

A region of amorphous protein called the tegument lies between the capsid and

the outer envelope. Tegument proteins, in association with cellular factors, play

a role in inducing transcription of viral proteins5 and modulate host protein

production.3

Outer Envelope

An essential component of the infective particle is the outer envelope. The

envelope is composed of lipoproteins, carbohydrates, and lipids that have been

derived from the host cell and have been modified by the viral protein.3,4

Embedded within the envelope and projecting from the external surface are

glycoprotein subunits called peptomers, which play a role in viral attachment

and penetration into the host cell.2,3

PATHOGENICITY

The virus shows a tropism for human tissues of ectodermal origin. In addition to

the ocular infection and the well-known skin and mucous membrane lesions,

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herpes is responsible for a meningoencephalitis and has been associated withtrigeminal neuralgia. In disseminated infections, it may replicate in liver, adrenal,

and lung parenchyma.

REPLICATIVE CYCLE

HSV is an obligate intracellular parasite. Although it contains the genetic

material necessary to induce its own replication, it does not have the metabolic

machinery necessary for biomolecular synthesis. It enters the host cell and uses

the host cell metabolic pathways, often causing destruction of the host cell.The replicative cycle has three phases: entry, eclipse, and envelopment and

release.

Entry Phase

The host cell and the virus come in contac t and bind by means of spec ific cell

surface glycosaminoglycans, principally heparan sulfate.2,6 Lytic genes are

expressed, and the virus enters the cell fusion of the virion envelope with the

cell's plasma membrane. It then penetrates the host cell cytoplasm in a

pinocytotic vesicle, where the envelope is removed. Enzymatic digestion results

in uncoating of the capsid. The bare viral capsid moves to the host cell nuclear

pore, where it is disassembled and the viral DNA released.

Eclipse Phase

The eclipse phase of the replicative cycle is characterized by intense molecular

activity within the host cell nucleus and loss of recognizable viral morphology.

The viral DNA unwinds and is transcribed by messenger RNA, which in turn

directs viral protein synthesis within the ribosome. Enzymes, structural proteins,

and regulatory proteins are produced. Most of the proteins are returned to the

nucleus. DNA replication and capsid reassembly occur there.

Envelopment and Release

Within 6 hours of entry, fully enveloped particles are detectable in the cells. Thenew viral particle is enclosed by the envelope, which is primarily derived from a

nuclear membrane as it leaves the nucleus and enters the cytoplasm. The

mature infected virus negotiates the cell membrane by a process of reverse

phagocytosis to reach the extra cellular space. The cycle is now complete.7

SEROTYPES

On the basis of site of isolation from the body and cell culture characteristics,

two types of herpes simplex virus can be distinguished. HSV-1 characteristically

produces oral, facial, and ocular lesions. It is responsible for 85% of ocular

isolates. HSV-2 serotype has conventionally been associated with the sexually

transmitted form of the disease. It is responsible for ocular disease in neonatalherpes simplex keratitis but in only minority of adult ocular infections.

Simultaneous keratitis infection with both HSV-1 and HSV-2 has been described

in a patient with acquired immune deficiency syndrome (AIDS).8

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HERPES SIMPLEX VIRUS INFECTION

EPIDEMIOLOGY

Humans are the only natural host of HSV, although experimental infection can be

produced in a variety of animals, including rabbits, mice, and primates. Persons

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infected with the virus constitute the sole reservoir of infection. Humans are

extremely susceptible to infections with Herpesvirus. Given this highly

susceptible host, poor sanitary conditions and overcrowding greatly predispose

to infection. Studies of the presence of neutralizing and complement-fixing

antibody within different socioeconomic groups as an index of infection have

underlined this relationship. In the lower socioeconomic groups in the United

States, 80% of individuals have antibodies. This contrasts with 50% of those

more economically advantaged.9 As standards of living increase, an increase in

the number of susceptible adults can be anticipated, with a subsequent increase

in the incidence of adult primary herpes simplex.

Transmission of HSV-1, which is responsible for the vast majority of facial and

ocular herpetic infections, occurs either from direct contact or via contaminated

secretions. It has been shown that virus particles are shed intermittently or

chronically in tears,11 saliva,12 and respiratory secretions,13 as well as from the

genital tract in the absence of overt disease.

Mechanisms of spread from the portal of entry are not known precisely, but a

viremia appears likely and has been demonstrated in severe conditions on a

number of occasions. The incubation period of HSV-1 is 3 to 9 days.14 The

overwhelming majority of primary infections occur in infancy and adolescence,

but sporadic cases of primary infection occur among susceptible individuals

throughout adult life. The primary infection is subclinical in 85% to 90% of

cases.15 A positive titer of serum-neutralizing antibodies is noted by 1 week

after the primary infection. The titer then diminishes but remains positive

throughout life. Complement-fixing antibody follows a similar pattern but is more

variable during asymptomatic periods. Occasionally, primary HSV-1 is ocular and

causes lid vesicles, ulcerative blepharitis, keratitis, and conjunctivitis.

Infected persons become carriers of the disease by transneuronal spread of the

virus into the neural ganglia. The virus persists there in a quiescent state called

latency that may be interrupted by periods of localized recurrence. A variety of

endogenous and exogenous stimuli, such as strong sunlight, fever, menstruation,

and psychiatric disturbances can serve as triggers of reactivation. In addition,

reactivation in the cornea can be precipitated by local factors, one of which has

been shown to be exposure to excimer laser irradiation during refractive surgery.

Ocular herpetic involvement is less common than systemic infection. Projections

from a prevalence study in the northern United States to the whole country

suggest a total of approximately 20,000 new cases per year and 400,000 with a

diagnosis of ocular herpes simplex.18

Herpes simplex infection is the most common cause of corneal blindness in

developed countries.

An initial episode of HSV-1 epithelial keratitis has a 25% recurrence risk within 2

years. A second episode has a 43% recurrence risk.13 Recurrence occurs in the

eye originally infected in the majority of cases, although involvement is bilateral

in approximately 11% of cases.3

PATHOGENESIS AND LATENCY

The pathogenesis of human herpes simplex ocular infection exhibits two critical

features: complexity and diversity. This is demonstrated in the marked

differences in pathogenesis between primary and recurrent ocular disease. It is

also apparent in the many different forms of ocular disease that result from the

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complex interplay of viral replication, host defense systems, and tissuereparative responses. Further confusion arises for the ophthalmologist in the

management of herpetic eye disease: appropriate therapy for one clinical form

of disease may be absolutely contraindicated in another clinical form.

The natural history of HSV-1 infections in humans is generally characterized by

an initiating childhood infection, which may present as a nonspecific upper

respiratory infection or may be totally asymptomatic. Goodpasture20 in 1929 and

subsequently others21,22 postulated that the virus gained access to the central

nervous system during the primary infection by moving centripetally along

sensory nerves to the sensory ganglia. In 1973, Cook and Stevens24 confirmed

the concept of retrograde axonal transport and latency in ganglia.

The process leading to latency is now understood to occur in three stages:

Entry, Spread and Establishment of latency. Entry defines the time of the

primary infection. Spread is the phase during which the virus moves to the

terminal axons of the sensory neurons and then, by retrograde axonal transport

to the neuronal cell bodies in sensory and autonomic ganglia where there may

be further viral replication. In the final stage, Establishment of latency, lytic

gene expression is suppressed and virions cannot be detected. However, the

viral genome persists in the neuron.

Under the influence of various stimuli, control of latency breaks down and viral

replication begins again in the ganglia with spread to peripheral sites where

replication may also occur.25

The mechanisms by which the virus maintains latency and is ultimately altered

to cause recurrent disease are only partially understood. While in the latent

state, viral gene expression is suppressed almost totally. Viral structural

component and infectious viral particles are not produced, although virus can be

detected by cell culture explantation techniques. However, viral RNA molecules

called LATs3,5,26 are transcribed. The LATs serve as useful markers for latent

HSV infection. LATs may play a role in reactivation.

There is also evidence to suggest that latent infection can occur at ocular sites

such as endothelial cells or keratocytes.27–30 This has raised the question of

whether extraganglionic latency occurs within the cornea. HSV-1 DNA

sequences have been identified in some human corneas that do not have any

history of herpetic eye disease5,27; however, the existence of corneal latency

has not been firmly established. The possibility of corneal latency has important

clinical ramifications for it would allow for viral reactivation and replication within

the cornea without ganglionic HSV reactivation.

Recurrent clinical disease apparently occurs when local host defenses in the eye

are unable to control the virus, or there is a break in the epithelial barrierfunction. It is clear that recurrent clinical disease occurs despite systemic

humoral and cell-mediated immunity against the virus.

Interactions

Strain variations in HSV appear to affect reactivation. Certain strains are

associated with high recurrence rates.31 Genetic differences among strains

appear to affect the clinical manifestations of infection, including the

morphology of an epithelial dendrite. Certain strains are more likely to produce

stromal disease and this has been correlated with the amount of glycoprotein

produced during infection.32,33 The impact of corticosteroids on the course of

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the epithelial infection also appears to be strain related.34 Corticosteroids maylead to an increased duration of herpetic disease by interrupting the immune

system, but it is unlikely that they induce viral reactivation.

The host response to the virus plays a role in the disease process. However, the

importance of individual host differences in determining the course of infection is

unclear. For unknown reasons, herpetic infection does appear to be more

common in patients with atopic disease.15

MANAGEMENT

Treatment of herpes simplex keratitis should be tailored according to the clinical

form of herpetic disease that is present. Purely epithelial herpes simplex keratitis

is typically managed with topical antiviral agents with or without debridement.

The management of stromal and disciform endotheliitis is more complex and

usually involves both antiviral and anti-inflammatory measures. Surgery may be

necessary in more severe forms of this disease. Specific therapy for each of

these entities is discussed in detail in the following sections.

In general, a rational approach to therapy for ocular herpes simplex disease

should include:

1. Minimize permanent ocular damage from each recurrent episode.

2. Avoid iatrogenic disease.

3. Counter the socioeconomic effects of a chronic debilitating disorder.

Such an approach is possible only if the ophthalmologist maintains a clear

perspective of the chronic, recurring, progressive course of this disease. The

nature of herpetic keratitis is such that these aims are often in conflict. The

topical antiviral agents used are inherently toxic and the vigilance needed to

manage the patient carefully for protracted periods of time is demanding, as well

as potentially socially and economically crippling. Only currently established

methods of treatment are included here. Controversial therapies and drugs,

given the experimental stage of development, are not discussed.

Antiviral Measures

MECHANICAL DEBRIDEMENT

At one point, mechanical debridement was the only effective means of treating

epithelial herpes. Even with the advent of antiviral agents, it remains a useful,

safe, and sometimes preferred alternative.35 The removal of virus-replicating

epithelium abolishes the source of infection for other cells and eliminates an

antigenic stimulus to inflammation in the adjacent stroma.

Debridement should be performed at the slit lamp or operating microscope, with

the use of topical anesthesia. Controlled removal of the lesion is best achievedby gentle debridement along the margins of the epithelial ulcer with a tightly

rolled cotton-tipped applicator. With this technique, known as minimal wiping

debridement, the virus-infected cells are removed while healthy epithelium is left

intact.36 Sharp knife blades should not be used because of the risk of creating a

portal of entry into the stroma through damage to underlying Bowman's layer.

Recrudescence of viral replication occasionally occurs and can be treated by

repeat debridement or administration of an antiviral agent. Chemical virucidal

agents, such as phenol 10%, have been advocated to sterilize the freshly

debrided ulcer margins but are unnecessary. Scrubbing the bare surface is

injurious, and iodine is damaging, especially to diseased corneal stroma.

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CHEMOTHERAPY.

Idoxuridine (IDU), the first antiviral drug to become available for topical

ophthalmic use, is a substituted pyrimidine nucleoside that resembles thymidine

(Fig. 2).It is phosphorylated to the nucleotide and incorporated into the DNA of

all cells, where it interferes with DNA interactions.

Fig. 2 Chemical structures of A thymidine, B

Idoxuridine, C vidarabine, and D acyclovir.

Disadvantages include poor corneal penetration,37 lack of select ivity for virus-

infected cells, and toxicity. In the majority of patients, the earliest signs of

toxicity are recognizable after 2 weeks of therapy. These include punctatekeratoplasty, burning, injection, irritation, lacrimation, hypersensitivity, and

punctal stenosis (Table 1).

TABLE 1. IDU Toxicity*

Region Signs

Fine punctate keratopathy

Cornea Corneal filaments Retardation of epithelial healing

Indolent ulceration

Superficial vascularization (late)

Superficial stromal opacificat ion

Conjunctiva Chemosis

Congestion

Perilimbal edema

Perilimbal filaments Punctate staining with rose bengal

Follicles in lower tarsus

Lid margin Punctal edema → occlusion (may be irreversible)

Edema of orifices of meibomian glands

Lids Ptosis

*Other currently available antiviral agents exhibit similar toxicities, although

trifluridine is less toxic than IDU or vidarabine; contact allergy to each of these

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drugs is also possible.

IDU, idoxuridine.

Vidarabine, first synthesized in the early 1960s, is a purine nucleoside analogue

with in vitro activity against Herpesvirus and certain other DNA viruses. Cellular

enzymes convert vidarabine to the triphosphate form, which acts as a

competitive inhibitor of DNA polymerase. Corneal penetration is poor but better

than that of IDU. Because vidarabine does not selectively inhibit virally inducedenzymes, there is potential for cellular toxicity. It is probably less toxic than

IDU. Vidarabine is available as a 3% ophthalmic ointment, and the usual dose is

five times per day. Collaborative studies have indicated that vidarabine is

effec tive in the therapy of epithelial herpetic disease.38 As with IDU, resistant

strains exist, but cross-resistance has not been observed. Hypertrophic

epithelial changes similar to those seen with IDU occur, and some

hypersensitivity reactions have been reported.

Trifluridine, a thymidine analogue that inhibits thymidylate synthetase, is

incorporated in both viral and cellular DNA. It is semi selective, interfering with

viral metabolism in preference to normal cellular metabolism, and is thus less

toxic than IDU. Trifluridine is 10 times more soluble in water than IDU and isavailable as a 1% drop. Studies have shown the healing time for active epithelial

ulcers to be better than that with IDU and comparable to that with

vidarabine.12 When used in higher doses for prolonged periods of time, toxicity

does develop, producing changes similar to those seen with IDU, although not as

severe.

Acyc lovir is an acyclic analogue of guanosine and is the prototype of the

generation of specific antiviral drugs that are activated by a viral thymidine

kinase to become potent inhibitors of viral DNA polymerase. The selectivity of

acyclovir for virus-infected cells is approximately 200 times that for normal cells.

Its antiviral spectrum is limited to the herpes group and excludes vaccinia,

adenovirus, and RNA viruses.39 Acyclovir is available in the United States in oraland intravenous forms, and as a topical dermatologic ointment. Topical 3%

acyclovir ointment for ophthalmic use (not commercially available in United

States) can penetrate the cornea to reach the anterior chamber.40,41 It has

been shown to be effective in the treatment of HSV epithelial keratitis.40,41

Oral acyclovir in a dosage of 400 mg five times per day results in therapeutic

levels in the aqueous42 and tear fluid.43,44

In a recent analysis of 97 randomized treatment trials for herpes simplex

epithelial keratitis comparing the efficacy of topical or oral antiviral agents with

or without debridement, Wilhelmus45

concluded that vidarabine, trifluridine andacyclovir are effective and nearly equivalent. In contrast to treatment with

idoxuridine, treatment with vidarabine, trifluridine or acyclovir resulted in a

significantly greater proportion healing in one week. The combination of a

nucleoside and debridement seemed to hasten healing.45

Valcyclovir is the L-valyl ester prodrug of acyclovir with enhanced bioavailability

and significantly greater plasma concentrations of acyclovir than can be

achieved with oral acyclovir.46 Although there are reports of animal studies, no

case series or controlled trials have been published.

Anti-inflammatory Measures

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Administration of topical corticosteroid is contraindicated in the treatment of

herpes simplex epithelial keratitis. In the management of HSV stromal and

disciform endotheliitis, topical corticosteroid therapy combined with prophylactic

antiviral cover is a typical form of treatment. Controversial aspects of

corticosteroid therapy is discussed in detail below.

It is logical to limit inflammatory response in the cornea, because this is largely

responsible for the destructive effects of herpetic infections. This inflammation

has an immunologic basis and might therefore be combated by systemic and

local immunosuppressive measures. For herpetic disease, the disadvantages andthe dangers of systemic immunosuppressive therapy make its use undesirable.

Corticosteroids can modify the immune response in a number of ways. Applied

locally in the cornea, their effect seems to be chiefly on the efferent arc,

possibly inhibiting chemotaxis and degranulation of polymorphonuclear

leukocytes. Although they also inhibit local antibody production to some degree,

their influence on the afferent arc and central responses is probably less

important. Corticosteroids appear to have more effect on hypersensitivity

reactions mediated by humoral antibody than by cell-mediated immunity,

although their action in controlling corneal allograft reactions suggests that they

may block such reactions by causing destruction of sensitized lymphocytes.

Steroids are associated with a number of complications that tend to diminish

their effectiveness and at times prohibit their use:

1. Enhancement of viral replication. Steroids clearly foster Herpesvirus

replication in the corneal epithelium once this has been initiated. For this

reason they must never be used in the treatment of epithelial herpes. The

demonstration of replicating virus in corneal stroma and deeper ocular

tissues by electron microscopy suggests that steroids may also enhance

virus replication in these tissues. There is as yet no conclusive evidence

of this, and experiments in animals have yielded conflicting results.47

Nevertheless, in the absence of an antiviral agent that can effectively

penetrate the corneal stroma, the possibility of enhancement of virusreplication must cause concern.

2. Secondary infection. The immunosuppressive effects of steroids may allow

bacteria and fungi to proliferate in the absence of spec ific therapy.

3. Elevat ion of intraocular pressure. Prolonged administration produces an

elevation in intraocular pressure in some patients. In our experience, the

latent period before the pressure begins to rise can be quite variable and

may be prolonged. The effects of an unrecognized pressure elevation in an

already diseased eye are devastating.

4. Cataract formation. Posterior subcapsular cataracts that may progress to

complete lens opacities have been associated with systemic steroids.

However, prolonged local administration is also a risk factor for cataract.

5. In the presence of an inflammatory stimulus such as residual herpessimplex antigen, a rebound in the inflammatory response almost invariably

follows the cessation or too rapid reduction in the topical steroid therapy.

As a consequence of the removal of steroid, immature leucocytes

proliferate and produce antibody in large amounts. Antibody complexes

with antigen and the resulting inflammatory cascade leads to invasion of

the cornea by a new wave of polymorphonuclear leucocytes. This

inflammatory rebound may lead to rapid deepening of corneal ulceration

and perforation. Clinically, the exacerbation in corneal inflammation may be

mistaken for deteriorating underlying disease.48

It is clear that steroids are dangerous preparations in inexperienced hands

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because they introduce new hazards to an already complex and difficultsituation. Nevertheless, they are the only effective anti-inflammatory agent

available. It is mandatory that the clinician be constantly aware of these

hazards. The haphazard administration of steroids in poorly monitored patients

contributes significantly to the disastrous sequelae of this disease.

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PRIMARY HERPES

CLINICAL MANIFESTATIONS

Primary ocular herpes is predominantly a disease of infants and young adults,

but it c an occur sporadically at all ages. Neonatal infect ion is caused by HSV-2

in approximately 80% of cases. The scant emphasis that primary herpetic

infection has received in the literature is regrettable in view of its importance as

a cause of follicular conjunctivitis or keratoconjunctivitis.11 These conditions

remain largely unrecognized, therefore, affected patients may be exposed

unwittingly to the hazards of corticosteroid administration.

Although this section is principally concerned with the keratitis that often

follows primary follicular conjunctivitis, it would be unrealistic to consider it as

an entity distinct from the primary syndrome. Symptoms of infection appear 2 to12 days after contact with an infected individual (although not necessarily one

with an active lesion). In contrast to the recurrent form of the disease, there is

mild malaise and fever, indicating a constitutional illness. Conjunctival injection,

irritability and watery discharge are typically unilateral and rarely severe. The

patient or parents, whose chief concern may be the skin lesions adjacent to the

eye, may not even mention the ocular disease.

The follicular conjunctivitis of primary herpes is associated with a regional

adenitis. Typically, the ipsilateral preauricular lymph node is slightly enlarged and

a little tender. Swollen lids and a primary skin lesion are often readily apparent

(Figs. 3 and 4), but on occasion only a careful search will reveal the single or

grouped vesicles of c rusted ulcers (Figs. 5 and 6) hidden among the lashes or inthe intermarginal strip. Similar lesions may be located elsewhere on the face or

at the mucocutaneous junction of the mouth, in the nose, or on the trunk, and

they may be easily missed unless a specific search is made. In nearly one fourth

of cases, no cutaneous lesions are present.35 The conjunctiva is injected and

edematous. Follicles develop, especially in the fornices, and extend to the tarsal

areas (Fig. 7);they rarely occur at the limbus. Small subconjunctival

ecchymoses are not uncommon and phylectenule-like lesions may develop on

the globe (Fig. 8).

Fig. 3 Child with primary ocular herpes. (Courtesy of Dr. S.

Darougar)

Fig. 4 Primary herpetic blepharoconjunctivitis in an adult.

Fig. 5 Herpetic ulcer on lid margin in a patient with primary

herpes. (Courtesy of Dr. S. Darougar)

Fig. 6 Umbilicated primary herpetic lesions at the inner canthal area. (Courtesy

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of Dr. S. Darougar)

Fig. 7 Acute follicular conjunctivitis in primary

herpetic infection: A Upper tarsus, B Upper

fornix, C Lower fornix. (Courtesy of Dr. S.

Darougar)

Fig. 8 Chemosis and ecchymosis of bulbar conjunctiva.

(Courtesy of Dr. S. Darougar)

Within 2 weeks, approximately half of these patients develop corneal lesions

associated with only relatively minor symptoms: a little grittiness, photophobia,

and blurring of vision. Initially these lesions are epithelial and present a variety

of appearances.

A fine punctate epithelial keratitis, consisting of tiny white flecks in the

superficial layers that stain poorly with fluorescein and variably with rose bengal,

may be present. These are transient spots, only rarely progressing to larger

lesions. As the flecks desquamate, fluorescein stains the flecks more intensively

during the healing stages.

A coarse punctate epithelial keratitis presenting a variety of shapes (circles,

ovals, irregular elongated areas, and stellate figures) may appear. Any of these

lesions may progress to macroscopic dendritic figures. They consist of slightlyraised, closed clusters of opaque epithelial cells, those in the periphery often

being the most regularly arranged. These swollen white cells stain well with rose

bengal but poorly with fluorescein. Typical herpetic intranuclear inclusions can

be demonstrated in these cells (Fig. 9).Initially, there is no stromal reaction, but

within 2 to 3 weeks, and sooner if the lesions are peripheral (and regardless of

epithelial healing), subepithelial infiltrates appear.35

Fig. 9 Corneal epithelial cells stained in vivo with rose bengal

in a child with coarse punctate corneal epithelial lesions of

primary Herpesvirus infection. The cells were subsequently

removed and counterstained with hematoxylin. Many stained

cells are swollen and show eosinophilic intranuclear inclusions

with margination of chromatin.

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

The diagnosis can be made on clinical grounds alone in patients with typical

cutaneous lid lesions or typical herpetic corneal lesions. In the absence of such

lesions (approximately one fourth of all patients with primary herpetic

conjunctivitis), laboratory investigations are essential for diagnosis. The

differential diagnosis includes:

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1. Keratitis with lid lesions: zoster, chickenpox, molluscum contagiosum, and

ulcerative blepharitis with keratitis caused by staphylococcal infection.

2. Keratitis without lid lesions: vaccinia, adenoviral infections (types 3, 7,

and 8 and 19), chlamydial infections, herpes zoster and Epstein-Barr

keratitis.

LABORATORY INVESTIGATIONS

In most cases, laboratory confirmation of the clinical diagnosis is unnecessary.

In the remainder, an attempt should be made to isolate the virus from untreatedactive lesions in skin and cornea and from the conjunctiva. Positive cultures may

take from 2 to 5 days to develop.

Typical viral multinucleate giant cells may be demonstrated in Giemsa-stained

scrapings of the base of cutaneous lesions on the lid. These are also seen in

varicella or zoster.

The appearance of neutralizing and complement-fixing antibodies a week after

the onset, followed by a rising titer for the next few weeks, is useful

confirmatory evidence. The cytology of cornea and conjunctival scrapings is

useful in conjunction with antibody levels but is not diagnostic.

MANAGEMENT

Therapy must be directed toward the elimination of virus from the cornea and

adjacent skin lesions. It is essential that lid vesicles and ulcers be treated

concurrently with the corneal disease because they are a potent source of virus

that, being continually shed, can reinfect the c ornea and vastly prolong the

keratitis.

Trifluridine is instilled into the conjunctival sac fives times per day. An antiviral

ointment (acyclovir) can be applied to the eyelid and adjacent skin lesions.

Topical corticosteroids are contraindicated.

Systemic administration of acyclovir is recommended for neonatal infectionsbecause of the enhanced risk of systemic disease as a result of viral

dissemination. In this age group, administration of eye drops can be difficult.

The addition of systemic therapy has the added benefit of ensuring adequate

therapeutic concentrations in the eye. In older children and adults with a

primary infection, systemic therapy is usually unnecessary.

Since the advent of topical antiviral agents, debridement of the corneal

epithelium is seldom performed but it remains an effective method of healing the

corneal lesions. Solitary vesicles on the lids may be removed by general

debridement with a cotton-tipped applicator moistened with phenol.

A cycloplegic may be prescribed when indicated to relieve photophobia or ciliary

spasm. The use of Atropine should be avoided because of the risk of

hypersensitivity. Scopolamine hydrobromide 0.25% twice daily or cyclopentolate

hydrochloride 1% to 2% three times daily is usually effective. Patching is

undesirable. However, wearing sunglasses may give symptomatic relief.

A return visit is advisable within 2 to 3 days in all but the mildest infections.

Thereafter, patients can be seen weekly, provided recovery is uneventful. The

administration of an antiviral agent must be continued until corneal and lid

lesions are healed. Hospitalization is rarely necessary, except in patients with

severe bilateral and secondary infections.

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VIRAL ISOLATION.

Cornea.

Gently swab the surfaces of the lesion with a dry, sterile, cotton-tipped

applicator. Place the applicator in a viral transport medium for later inoculation

into tissue culture. If cell lines of the culture are not immediately available, the

specimen can be frozen at -4°C.

Conjunctiva.

Gently swab (or preferably scrape) the conjunctiva in a similar manner.

Lid lesions.

Unroof ulcers and vesicles with a fine needle tip prior to taking the specimen

with a cotton-tipped applicator.

CYTOLOGY.

Gently scrape the opaque cells of the corneal lesion onto a glass slide, using a

platinum spatula, Beaver blade, or Bard-Parker knife. This is best done under

magnificat ion, preferably at the slit lamp. Stain with Giemsa.

ANTIBODY TITERS.

On initial presentation, blood is drawn for neutralizing antibody titers. Two to 3

weeks later, another sample is assayed to determine whether the titer has risen.

BACTERIAL CULTURES.

Cultures of the eyelid lesions and conjunctival sac are desirable. They should be

accompanied by direct smear if bacterial infection is suspected.

NATURAL COURSE AND VARIATIONS IN CLINICAL PRESENTATION

The epithelial lesions tend to heal, but additional crops may appear if active

herpes persists untreated on the lids. The superficial stromal infiltrates may

persist for several weeks before gradually resolving. Healing may be

accompanied by superficial scarring in these sites. Occasionally, these stromal

lesions progress to a frank disciform keratitis indistinguishable from the type

usually associated with recurrent herpes.

Primary herpes uncommonly presents as a bilateral ocular disease, except in

atopic individuals, who tend to have a more florid form of disease.49 In rare

instances, the course of primary infection is severe: widespread herpetic

infection in the face and trunk, often pustular and accompanied by a severe

systemic illness, may supervene and is characteristic of Kaposi's varicelliformeruption. Encephalitis and hepatitis occur rarely but can be lethal, especially in

infants.

COMPLICATIONS

Secondary bacterial infection occasionally supervenes. The appropriate

antibiotic, the selection of which is made from the results of culture and

sensitivity testing, best treats it locally. Severe cellulitis of the lids may require

systemic antibiotics. Prophylactic antibiotics are unnecessary and may confuse

the clinical picture. In atopic individuals, management can be difficult, because

topical antivirals may not be tolerated. Careful debridement of the lesions is an

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alternative in these situations.

Permanent damage to the cornea is uncommon. Most of the opacification in the

stroma seen during active infection is probably caused by temporary edema

rather than scarring. Should stromal keratitis develop, it is treated in

accordance with the principles of management of recurrent disease (discussed

later). Transient superficial stromal infiltrates do not require treatment.

PROGNOSIS

Most primary infections respond rapidly to antiviral therapy with little or no

sequelae and no loss of vision. Occasionally, the development of antiviral

toxicity necessitates cessation of the drug therapy. Complications occur mainly

in undiagnosed or ineffectively treated cases.

Back to Top

RECURRENT HERPES SIMPLEX

Recurrent HSV infection occurs as a result of reactivation of the virus in latently

infected ganglia. Recurrent ocular HSV infection is thought to be caused by

reactivation of the virus in the trigeminal ganglion. The virus travels down the

nerve axon to the sensory nerve endings, where it is transferred to corneal

epithelial cells and keratocytes. If favorable conditions exist in the epithelium,viral replication and cell lysis ensue, producing clinical disease. HSV-specific

nucleic acid sequences have been detected, and HSV has been organ-cultured

from corneal buttons excised from patients with chronic stromal keratitis. These

patients had no active disease at the time that penetrating keratoplasty was

performed. These data suggest that the human cornea may also be a site of

latency and a potential source of recurring clinical ocular disease.50

There are several different types of recurrent ocular HSV infection, including

dendritic and geographic epithelial keratitis, interstitial and necrotizing stromal

keratitis, disciform endotheliitis, and uveitis.

EPITHELIAL KERATITIS

Pathology

In the corneal epithelium, normal epithelial cells are interspersed with balloon

cells (cytoplasmic vacuolation with marginated chromatin). These balloon cells

stain intensely with rose bengal in vivo and contain replicating virus. Syncytial

multinucleate giant cells and occasionally epithelial cells with intranuclear

eosinophilic inclusions are also seen. The leukocytes that are present are

predominantly mononuclear. During a recurrent episode, the inflammatory cell

type in the conjunctiva is also predominantly mononuclear with some admixture

of polymorphonuclear leukocytes. Only occasionally are giant cells and inclusions

seen. By contrast, in the initial stages of a primary infection, the predominantcell is the polymorphonuclear leukocyte. Only after several weeks does the

mononuclear cell dominate the picture.

Initially, the epithelium is swollen along the margins of the dendritic ulcer

because of intercellular and intracellular edema. The previously described

general cytologic pattern is present and there are necrotic cells in the ulcer

bed. These changes gradually progress to complete epithelial loss in some areas

and the accumulation of inflammatory cells and debris. In the geographic type of

ulcer, the changes are similar but more extensive.

In the early stages, the lesion is confined to the epithelium. However, with time

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the process spreads to involve the anterior stroma. Bowman's layer and the

immediately adjacent stroma become edematous, necrotic in places, and

infiltrated by a variable number of inflammatory cells, predominantly

polymorphonuclear leukocytes.

Purely epithelial lesions heal rapidly and with little scarring; however, with

stromal involvement superficial scarring occurs. Some degree of faceting is

inevitable when there has been loss of corneal substance.

Clinical Manifestations

Patients with epithelial keratitis caused by HSV may be asymptomatic or may

experience mild to severe foreign-body sensation, photophobia, redness, and

blurred vision. After a number of episodes, the symptoms of foreign-body

sensation are commonly muted by cornea hypoesthesia. Recurrent HSV epithelial

keratitis typically has a classic dendritic (dichotomously branching) shape. The

pathogenesis of the branching ulceration has not been elucidated. It may simply

be a function of viral linear spread by contiguous cell-to-cell movement.

Initially, a plaque of opaque cells appears on the epithelial surface. Although

usually dendritic, the shape may be coarsely punctate or stellate. Within a few

days, the center of the plaque desquamates to form a linear, branching ulcer

(Fig. 10) barely 0.1 mm wide with overhanging margins of swollen opaque cells(Fig. 11). The dendritic figure may be single or multiple; it can extend across the

entire cornea but is usually considerably smaller (Fig. 12). At the ends of the

branches terminal bulbs are typically seen. The cells lining the edge of the ulcer

are laden with virus and stain brilliantly with rose bengal. Fluorescein stains the

ulcer bed and seeps beneath the adjacent cells (Fig. 13). Several days after the

appearance of the dendritic ulcer, infiltrate appears in the immediately subjacent

stroma. It usually remains superficial and localized. In addition to these changes,

scattered punctate epithelial erosions are common and evidence of past attacks

in the form of superficial scars and superficial vascularization may be present

(see Fig. 10). Although dendritic keratitis can occur at any location on the

cornea, recurrences tend to affect the same areas noted in previous attacks.

Initially, corneal hypoesthesia is focal, so a great proportion of the cornea

appears unaffected. With repeated episodes, the loss of corneal sensation

becomes more profound. Ulcerations can occasionally occur within 2 mm of the

limbus. These lesions may not exhibit the typical features of a dendritic ulcer

and may be mistaken for staphylococcal marginal keratitis. They tend to be

more resistant to antiviral therapy than more centrally located herpetic

infections.

Fig. 10 Linear dendritic ulcer stained with rose bengal.

Fig. 11 Macrophotograph of portion of a dendritic ulcer by

retroillumination. Note opaque heaped-up cells along the ulcer

margin. (Magnification × 10) (Courtesy of Mr. N. Brown)

Fig. 12 Extensive dendritic ulcer, stained with rose bengal,

running around the margin of the corneal graft.

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Fig. 13 Geographic ulcer stained with rose bengal and fluorescein. Rose bengal

especially stains cells lining the ulcer margin. Note the greenish

tinge in the central area of the ulcer and the green halo

around the ulcer margin. This effect is caused by fluorescein

seeping into bare stroma and under ulcer margins.

The disease process is usually confined to the cornea. However, ciliary injection

can be quite intense and frequently appears out of proportion to the symptoms.

Slight flare with an occasional cell is indicative of a mild uveal reaction, but

keratic precipitates (KP) are uncommon. Concurrently with the corneal lesions,vesicles or ulcers can develop on the lids, face, mucocutaneous junction of the

mouth, and nose or elsewhere.

Diagnosis and Differential Diagnosis

The true dendritic ulcer is pathognomonic and requires no laboratory

confirmation. In cases in which there is doubt, viral isolation should be

attempted. The differential diagnosis is extensive (Table 2).

TABLE 2. Differential Diagnosis of Dendritic Keratitis

Herpes zoster dendritic keratitis

Mucous plaques in herpes zoster ophthalmicus

Acanthamoeba keratitis

Contact lens keratopathy

Antiviral toxicity

Healing ruptured bleb

Recurrent erosion syndromeEpstein Barr keratitis

Tyrosinemia type 11 (rare)

Vaccinia keratitis

Laboratory Investigation

In cases in which the diagnosis is in doubt, an attempt can be made to recover

the virus from untreated corneal lesions. However, viral culture is expensive. It

lacks some specificity because Herpesvirus can be recovered from the tear filmin the absence of corneal epithelial disease. Examination of corneal scrapings

may reveal typical cytology. Herpetic antigen can be detected in corneal

scrapings by use of a fluorescein antibody staining technique. The polymerase

chain reaction can also be used to identify herpetic nucleic acid. It is both

sensitive and specific for Herpesvirus.

Conjunctival smears are not diagnostic, showing a nonspecific inflammatory

response that is predominantly mononuclear in some cases but largely

polymorphonuclear in others. Serum-neutralizing antibody titers are elevated but

do not rise further during the recurrent episodes, whereas rising titers of

complement-fixing antibody are sometimes found.

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with rose bengal typical of a dendritic or geographic herpetic ulcer. Evidence is

lacking of viral replication in the epithelium in such indolent, so-called

metaherpetic ulcers. However, the electron microscopic picture of Herpesvirus

replication may occasionally be demonstrated in indolent ulcers deep in the

stroma (Figs. 15 and 16). Often, there is considerable stromal edema or infiltrate

associated with these ulcers, or the ulcer may represent breakdown over a

previously scarred area. Indolent ulcers are more common in stromal

keratouveitis and will be discussed in more detail below.

Fig. 14 Indolent herpetic ulcer. This type of ulcer tends to becircular with smooth, rolled margins that stain poorly, if at all,

with rose bengal (see Fig. 15). Electron microscopy revealed

Herpesvirus particles in keratocytes at all depths under this

ulcer.

Fig. 15 Indolent herpetic ulcer in the same patient as in Fig.

14. Rose bengal stains the base but not the epithelium at the

edge of ulcer.

Fig. 16 Dendritic-ameboid ulcer stained with rose bengal. Dendritic

shape is still discernible, but ulcer has widened considerably.

Antiviral toxicity is probably the most frequent immediate complication of

recurrent epithelial herpes and it may occur as soon as 10 days after initiation

of therapy. Because this is often the period when healing is occurring, the

appearance of new staining can give rise to considerable confusion. It is

sometimes impossible to be sure whether the signs represent recrudescence of

the infection or the onset of toxicity. This dilemma may be resolved only in

retrospect. When there is doubt, cessation of antiviral therapy is often

necessary. Resolution of antiviral toxicity is extremely slow and may take weeks.

Toxic effects of the current topical antiviral agents51 are similar, although

trifluridine seems to be the least toxic of the three.

Herpetic stromal keratitis is a serious complication. It develops in approximately

3% of dendritic ulcers. Steroids are frequently needed for its control. The

subsequent section deals with this in detail. Management of bacterial infection

in these patients should always be based on the results of isolate recovery.

Natural Course and Variations of Clinical Presentation

Untreated, the dendritic ulcer may spontaneously heal, but it usually persists

and may insidiously arborize to previously uninvolved epithelium. Segments of

the lesion may broaden, or large areas of epithelium may desquamate so the

ulcer assumes a geographic configuration (see Figs. 13 and Figs. 16, 17, and18). This is particularly likely to happen when steroids have been administered.

The margins are similar in appearance to a dendrite and contain actively

replicating virus (see Figs. 16 and 17). With persistence of the ulcer, especially

if it enlarges, stromal involvement becomes more marked and the uveitic

reaction may become more intense. Eventually the stromal keratouveitis may

dominate the clinical picture (see Fig. 15).

Fig. 17 Macrophotograph of the margin of a geographic ulcer. Note the ragged

appearance and the opaque swollen cells lining the ulcer margin. (Magnification

× 10) (Courtesy of Mr. N. Brown)

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Fig. 18 Typical ameboid ulcer stained with fluorescein. Dye stains

whole ulcerated area. (Fig. 18, courtesy of Mr. A.J. Bron)

Healing is accompanied by a variable degree of scarring, dependent on the

severity of stromal infiltration. Portions of the ulcer may persist for a

considerable time as opaque, slightly elevated nodes that stain with rose

bengal. It is uncertain whether these represent sites of continuing viral

replication.

With recurrences of epithelial keratitis, superficial vascularization is not

uncommon. Corneal hypoesthesia in initial episodes may be slight and only a

portion of the cornea may be affected. However, with repeated attacks it

becomes a feature of the disease.52

Occasionally an apparent abortive form of herpes develops. Small epithelial

mounds appear that stain with rose bengal. Herpesvirus can be cultured from

these lesions. They may persist for a considerable time before fading or

transforming into the typical dendritic ulcer.

Prognosis

Most cases heal with remarkably little scarring. Unfortunately, with repeated

attacks there is an inevitable accumulation of superficial scarring with the

formation of corneal facets. Vision may be markedly affected. In some

instances, and especially with steroid-worsened ulcers, healing is excessively

prolonged and in others there is gradual transition to a stromal keratitis.

Occasionally, the ulcer will heal partially and then worsen while treated with

antiviral therapy. This probably indicates the emergence of a resistant strain of

herpes18 or inadequate administration of the drug.

In children, dendritic keratitis is usually associated with a good visual outcome.

However, in a subset with geographic ulcers the outlook is less optimistic. Vision

tends to be worse with more scarring, a higher degree of astigmatism and more

recurrences. In this group, an aggressive approach is necessary including the

use of oral acyclovir, prompt treatment of stromal keratitis should it develop and

close monitoring for the onset of amblyopia.53

STROMAL KERATITIS

Pathology

The corneal stroma is the site of an inflammatory reaction that is irregularly

distributed, is of varying intensity and is accompanied by an anterior uveitis.

Epithelial keratitis, as previously described, is variably present. In addition, there

may be a more generalized epithelial edema in which the epithelium may be

separated from Bowman's layer by the edema fluid (Fig. 19).The corneal lamellae

may be necrotic in places, and inflammatory cells, predominantly

polymorphonuclear leukocytes, diffusely and focally infiltrate the stroma. The

process may involve the cornea at all levels from Bowman's layer to Descemet's

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membrane. The endothelium may be edematous or infiltrated by inflammatory

cells and, especially beneath the stromal lesion, may be replaced by a

coagulated film of fibrin and inflammatory cells. Keratic precipitates are

prominent. The aqueous contains fibrin and inflammatory cells (neutrophils,

lymphocytes, macrophages, and plasma cells). These cells frequently infiltrate

the angle and the trabecular bands are thickened and appear edematous, so the

term trabeculitis appears justified. Involvement of the iris is variable, but it is

frequently infiltrated by lymphocytes and plasma cells and thickened by edema.

The anterior ciliary body shows a similar involvement. Posterior synechiae and

anterior lens changes are common, frequently in association with a fibrovascularmembrane extending across the pupil.

Fig. 19 Gross epithelial edema with bullae, resulting from

severe endothelial decompensation, in an eye that had

previously been the site of a severe herpetic uveitis. As

edema resolved, endothelium was seen to be studded with

numerous secondary guttatae.

When ulceration occurs, Bowman's layer and superficial lamellae are replaced by

debris and inflammatory cells. The ulcer may deepen, form a descemetocele

(Fig. 20), and ultimately perforate. If this is the case, the immediately adjacent

stroma is necrotic, edematous, and densely infiltrated by acute and chronicinflammatory cells.

Fig. 20 Descemetocele in an eye with severe stromal keratitis.

Epithelium has been stained with rose bengal.

Repair is accompanied by scarring and vascular ingrowth (Fig. 21), but foci of

active inflammation may persist for a considerable period. The endothelium has a

remarkable propensity for recovery but may be replaced by shrunken keratic

precipitates.54

Fig. 21 Herpes simplex interstitial keratitis. Active inflammation

has resolved, leaving stromal scarring, thinning, and stromal

vascularization.

HSV is associated with several classes of antigens, including soluble diffusible

antigens that are released from an infected cell when it is lysed, antigens fixed

to the surface of the infected cells, and insoluble large structural proteins that

are capsid components. Any of these c lasses of antigens can probably react

with antibody, complement, or sensitized cells and initiate the immune response.

Although viral particles have been demonstrated by electron microscopy within

the corneal stroma in cases of stromal herpes simplex keratitis55–57 (Figs. 22

and 23), attempts to isolate infected virions in tissue culture have been

successful in only a minority of cases. In most cases of stromal herpes simplex

keratitis, the clinical disease appears to be predominantly the result of an

immunopathologic process, which is a response to viral antigen rather than an

active infectious process caused by replicating virus. Immunocytochemical

studies of cornea tissue obtained from patients with herpes simplex stromal

keratitis at the time of penetrating keratoplasty have shown the stromal

infiltrate to be composed largely of macrophages and lymphocytes.58

Controversy exists as to whether cytotoxic or helper T cells play the major role

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in herpetic keratitis.58

Fig. 22 Electron micrograph of deep corneal

stroma. Numerous Herpesvirus particles can be

seen lying in and around two degenerate cells

(probably keratocytes) between stromal

lamellae. (Magnification × 16,000) (Courtesy of

Dr. R. Tripathi).

Fig. 23 Electron micrograph of keratocyte. This

degenerating cell is filled with Herpesvirus

particles. Some of these have typical

morphology (arrow). Note the number of

incomplete forms, empty capsids and great

variability in size (arrow). (Magnification ×

100,000) (Courtesy of Dr. R. Tripathi).

However, it is thought that some cases of herpes simplex stromal keratitis may

be caused by a combination of active viral replication and the immune

response.1 Specifically, some cases of necrotizing stromal herpes simplex

keratitis may be the result of this dual etiology.

Clinical Manifestations and Variation in Clinical Presentation

The clinical manifestations of stromal involvement with HSV are protean.

Patients exhibiting stromal keratouveitis commonly have a history of previousattacks of epithelial herpes. The stroma may have been involved to some degree

in these episodes, but the emphasis for the most part remains directed toward

the epithelial keratitis. Then, insidiously over a few episodes, but at times quite

suddenly, the pattern changes so that stromal disease becomes the dominant

feature. Occasionally, this time scale is shortened, and in extreme instances,

the transition is completed in the initial attack. Some patients will develop

stromal keratouveitis, having had an epithelial herpes in the past, or will

experience their first dendritic ulcer subsequently; in others, stromal

keratouveitis will follow an episode of dendritic keratitis. It is important to realize

that regardless of preceding events, the onset of stromal disease is a serious

portent because it marks a new stage in the disease; deeper ocular structures

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are involved, vision is seriously threatened and morbidity is significantly

increased.

Apart from a complaint of blurred vision, the signs and symptoms are

nonspecific. The eye feels uncomfortable and tears excessively. The pain

experienced varies considerably from patient to patient. These signs and

symptoms are extremely variable and can be difficult to interpret, especially

when viewed against a background of previous structural damage, secondary

glaucoma, and endothelial dysfunction. Evidence of coexisting inflammatory and

reparative processes can be recognized by slit lamp examination. Cornealedema, infiltration, vascularization, ulceration, endothelial inflammation, and

uveitis can all occur to varying degrees in herpes simplex stromal disease. At

times, the degree of cellular infiltration and edema will indicate that infiltration is

the dominant process and, at other times, scarring and neovascularization are

more apparent.

Several common response patterns can be distinguished clinically, which can aid

in making the diagnosis and guiding treatment. These include chronic interstitial

keratitis and necrotizing stromal keratitis.

INTERSTITIAL KERATITIS.

When the predominant clinical findings include stromal infiltration accompaniedby an intact epithelium, the term interstitial keratitis is appropriately used. The

infiltration can present as single or multiple patches of infiltrate and edema and

involve the entire stromal thickness or discrete lamellae. The infiltration tends to

run a chronic, indolent course that persists for many months. Superficial and

deep stromal vessels often accompany the infiltrate and can occur early or late

in the disease course. The infiltrates may resemble those seen in infection with

other viruses, bacteria, fungi, or acanthamoeba but tend to be more indolent

and with an intact epithelium. This form of stromal inflammation is thought to

represent antigen-antibody-complement-mediated immune disease.59 Resolution

of the inflammation often leads to the formation of a dense, white vascularized

scar (see Fig. 21).

When the stroma is edematous, it exhibits a ground-glass appearance and is

thickened. Edema commonly encompasses the infiltrate and, at times, is the

main feature of the disease and it is also an essential component of the stromal

inflammatory reaction. It may result in endothelial dysfunction secondary to

uveitis.

Limbal vasculitis and immune (Wessely) rings in the anterior stroma are two

other clinical manifestations of presumed immune stromal disease.60–62 The

Wessely ring is a partial or complete ring of infiltrate in the stroma, surrounding

the main stromal lesion and separated from it by a relatively clear zone of

cornea. It presumably results from the inflammatory reaction to a ring or arcprecipitate of antigen-antibody complexes. Limbal vasculitis presents as an

edematous, hyperemic reaction. Although usually focal, more than one quadrant

may be involved. These vessels will often invade the cornea while associated

with stromal interstitial keratitis.

In the epithelium, a fine superficial edema, occupying a variable surface area

over the active stromal lesion, is common and is related to endothelial

dysfunction. At times the epithelium is grossly edematous, with recurrent bullae

appearing and sometimes breaking down to form indolent ulcers that have to be

distinguished from active epithelial viral disease. Punctate erosions that stain

well with rose bengal and fluorescein are frequently seen.

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The endothelial layer of the cornea is involved in all but the most superficial

lesions. Fine, white keratic precipitates may be scattered over the surface or

crops of discrete white precipitate may appear (Fig. 24). Some of these lesions

become pigmented. It is not unusual for large endothelial plaques to develop in

relation to the active stromal lesion (Fig. 25). Secondary guttae are quite

common but usually reversible.

Fig. 24 Typical keratic precipitates in an eye with a disciform

keratitis caused by herpes.

Fig. 25 Large endothelial plaque behind disciform keratitis.

Anterior uveitis is invariably present although it may be difficult or impossible to

assess because of the corneal opacification. In severity it varies from the

presence of an occasional cell and minimal flare to the development of

hypopyon. Posterior synechiae and rubeosis iridis frequently complicate severe

cases. The intraocular pressure may be elevated in the acute stage as a resultof an associated trabeculitis.

Vascularization can occur at any stage of the disease process. Vessels

penetrate the stroma from the limbus at all levels to invade the active stromal

lesion. They are often cuffed by fine granular infiltrates while active but, as the

inflammatory process subsides, they lose the cuff of cells and may eventually

become almost bloodless. The first signs of a recrudescence of inflammation may

be the reactivation of these vessels.

During the acute stages of the inflammatory reaction, scarring may not be

obvious, but as the signs of inflammation subside, it becomes more apparent. In

the early stages the discrete white opacification may easily be mistaken for

infiltrate. Once significant scarring has occurred, the clarity of the cornea is

permanently impaired (see Fig. 20).

Loss of corneal substance, ranging from minor faceting to gross thinning or even

perforation, is of variable occurrence. It often relates to preceding dense

infiltration and is most frequently seen in the rebound phenomenon following

withdrawal of topical steroid therapy for stromal herpetic keratitis with dense

infiltration (Fig. 26).

Fig. 26 Perforation of the cornea at the site of dense

infiltration in severe herpetic keratitis.

During the later stages of healing as the inflammation subsides, hard white or

sometimes yellowish lipid deposits, either crumbly dots or fine crystals, may

appear. Usually these are seen within vascularized opacities and may be

progressive. In some patients, they are associated with demonstrable

abnormalities of lipoprotein metabolism. These deposits are not an indication for

continuing energetic steroid therapy. It is important to differentiate them from

dense inflammatory infiltrates, with which they are sometimes confused.

NECROTIZING STROMAL KERATITIS.

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Necrotizing stromal keratitis is manifested clinically as a dense yellow-white

infiltration within the corneal stroma. The predominant clinical pattern is stromal

infiltration and necrosis (Fig. 27). This more complicated manifestation of herpes

simplex keratitis usually occurs in corneas that have had recurrent episodes of

herpetic eye disease. Thus, it may follow chronic or recurrent epithelial disease,

disciform keratitis, superficial stromal disease, or recurrent disease of any type.

In a prospective study of 152 patients with either dendritic or geographic

epithelial keratitis, Wilhelmus and coworkers63 noted that one-fourth of their

patients developed subsequent stromal inflammation. Of these, 37% presented

with necrotizing inflammation as the predominant pattern.

Fig. 27 Herpes simplex necrotizing stromal keratitis. A dense

yellow-white infiltrate occurs in the stroma with breakdown of

the overlying epithelium.

In mild cases, infiltrates can be localized, but in more severe cases a stromal

abscess (Fig. 28) may develop, consisting of necrotic, cheesy-white infiltrate

that may occupy the entire cornea thickness. The overlying epithelium often

breaks down over the stromal infiltrate. This can be followed by the appearance

of edema, ulceration, and stromal neovascularization. Ring infiltrates (Wesselyring) may occasionally be seen surrounding the stromal infiltrate (an antigen-

antibody-complement–mediated event), calling forth an influx of

polymorphonuclear leukocytes. Uveitis is nearly always present and may be

severe, with retro corneal membrane, hypopyon, synechiae formation,

secondary glaucoma and secondary cataract. Stromal perforation or super

infection with fungi or bacteria can occur (see Fig. 26).

Fig. 28 Large irregular stromal abscess underlying a large ameboid

ulcer, with a small hypopyon. Superficial and deep vascularization

is developing.

The frequent documentation of viral particles or antigen in herpes simplex

necrotizing stromal keratitis supports the belief that this form of keratitis is a

direct viral infection of the stroma with a subsequent host immune

response.1,55,62,64 Holbach and colleagues65 found that 91% of keratectomy

specimens from patients with ulcerative necrotizing keratitis displayed HSV

antigens, compared to only 11% of keratectomy specimens from patients with

nonulcerative, nonnecrotizing, or disciform keratitis. These antigens were

located primarily in stromal keratocytes and the extracellular stroma.

It is clear that there is a tremendous variation in the appearance of the cornea,

but if each case is approached with appreciation for these features, activity of

the disease can be assessed in a way that has meaning both clinically andpathologically. Thus, a stromal keratitis that is superficial and free of new

vessels is still relatively mild, whereas involvement of a full-thickness cornea,

associated with a significant uveitis and neovascularization, indicates severe

disease.

Diagnosis and Differential Diagnosis

The diagnosis must be made on clinical grounds alone. In most cases there is

little problem, but occasionally the diagnosis can be in doubt. Because the

presentation of HSV stromal disease can be so variable, many other conditions

can result in similar clinical presentations and must be considered in the

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differential diagnosis. A history of recurrent disease and prior herpes simplex

epithelial keratitis can be helpful, but a history of herpetic epithelial keratitis is

not absolute evidence that the subsequent stromal keratitis is herpetic in origin.

The laterality of HSV stromal keratitis may also be important in establishing a

clinical diagnosis because bilateral disease occurs rarely.66 Many potential

causes of stromal inflammation will have associated systemic disease that offers

clues to the etiology and helps differentiate it from HSV, such as herpes zoster

ophthalmicus, Cogan's interstitial keratitis, Epstein-Barr virus, and mumps. A

history of previous corneal trauma or contact lens wear, particularly associated

with disruption of corneal epithelium, should make one more suspicious of bacterial, fungal, or acanthamoeba infection. Although HSV keratitis can present

predominantly in a perilimbal location, confinement of the stromal inflammatory

process to the peripheral cornea should alert the examiner to associated eyelid

disease (staphylococcal keratitis), adjacent scleral inflammation, or possible

collagen vascular disease.

Laboratory Investigations

The thrust of the investigation should be most appropriately directed to a

consideration of possible differential diagnoses. Stromal herpetic eye disease is

best diagnosed from the patient's history and the clinical appearance of the

cornea.

If the epithelium is involved in a patient with stromal disease, cytologic

examination may reveal multinucleated giant cells (Giemsa stain) and

intranuclear and eosinophilic inclusions that are infrequent in adults

(Papanicolaou stain). These tests are easy to perform but are relatively

insensitive. Viral isolation in human cell culture is unavailable to many and is

expensive. A variety of immunologic tests can be used to detect viral antigen in

tissue specimens. These include immunofluorescent staining, immunoperoxidase

staining, immunofiltra-tion techniques, enzyme-linked immunosorbent assay

(ELISA), and DNA probes. The most sensitive test readily available commercially

is the Herpchek, a simple kit based on the ELISA system.67,68

Management

Treatment of HSV stromal keratitis is considerably more controversial than

treatment of HSV epithelial disease. Mechanisms involved in the pathogenesis of

HSV stromal keratitis are complex and incompletely understood. Both virus and

host immune factors appear to be important in the development and progression

of HSV stromal keratitis.58 The goal of management of HSV stromal keratitis is

to guide the patient through each episode while minimizing ocular damage,

reducing morbidity, and reducing the side effects of treatment.

In general, the most frequently used therapy for management of HSV stromal

keratitis currently includes the judicious use of topical steroids with prophylacticantiviral cover. The dosing and frequency of both steroid and antiviral cover are

debatable. The Herpetic Eye Disease Study (HEDS) was designed in an effort to

resolve these controversies, reach consensus on the management of herpes

simplex stromal disease, and establish therapeutic guidelines for antiviral and

anti-inflammatory agents.69,70 The series of double-blinded, placebo-controlled,

multicentered clinical trials included studies designed to compare (1) the

efficacy of topical corticosteroid, (2) the efficacy of oral acyclovir combined

with topical steroid for the treatment of herpes simplex stromal keratitis and

iridocyclitis, (3) the efficacy of oral acyclovir in the prevention of stromal

keratitis or iridocyclitis in patients with HSV epithelial disease, and (4) the

efficacy of acyclovir in the prevention of recurrent HSV ocular disease.

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TOPICAL CORTICOSTEROID THERAPY.

Corticosteroids will suppress an immune response, resulting in reduced corneal

edema, inflammation, infiltrat ion and neovascularization. Therefore, many believe

they are indicated in the treatment of HSV stromal keratitis (with antiviral

cover) to reverse the inflammatory response, minimize permanent structural

alteration, and improve corneal clarity.71,72 Others caution that topical

corticosteroids may prolong the course of the disease and increase the severity

of the stromal keratitis.73,74 Although steroids do not experimentally induce

recurrent herpetic epithelial keratitis,75 they can predispose to an increased

susceptibility to recurrent infection76 and can exacerbate active viral infection.

Corticosteroids can also predispose to secondary complications, including

microbial super infection, stromal melting, secondary glaucoma and cataract

formation. Once corticosteroids are begun, it is often difficult to discontinue

them and a marked rebound inflammatory response can ensue when withdrawal

is too abrupt. Nevertheless, in the HEDS controlled trial of topical corticosteroid,

given concomitantly with trifluridine, for herpes simplex stromal keratitis, the

topical steroid was significantly better than placebo in reducing the persistence

or progression of stromal inflammation. The regimen also significantly shortened

the duration of the keratitis.77

The introduction of corticosteroids in the management of HSV stromal keratitis is

influenced by the need to control the inflammatory process and to provide

symptomatic relief to the patient. Effective and safe administration of steroids

requires close observation in reliable patients. The dosage of steroid requires

some judgment and several options of corticosteroid administration are

available.78 The use of the lowest effective dose seems prudent because the

goal of therapy is to produce a clinically recognizable reduction in inflammation

while minimizing undesirable side effects. An antiviral agent (trifluridine) should

be administered concurrently to reduce the chance of recurrence of live virus in

the epithelium. Cycloplegics, lubricants, and dark glasses can provide

symptomatic relief.

ANTIVIRAL THERAPY.

Neither idoxuridine79 nor vidarabine37 is clinically effective top

Volume 4, Chapter 19 Herpes Simplex Keratitis

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