Slit lamp photo demonstrating classic epithelial dendrites in our patient after fluorescein staining.

Jeffrey D. Welder, MD, Anna S. Kitzmann, MD,Michael D. Wagoner, MD,

PhD
Dec. 31, 2012

Welder et al (2012). Herpes Simplex Keratitis. Available at:

http://webeye.ophth.uiowa.edu/eyeforum/cases/160-HSV.htm Accessed on: 20 Agustus 2015

Figure 2 (A and B). Early stromal inflammation in HSV keratitis from a similar case

HSV keratitis is the most common corneal infection in the United States.[2] It is
the number one cause of corneal and infectious blindness and a leading
indication for corneal transplantation

Table 1. Manifestations of herpetic keratitis

Live virus
Epithelium

Dendrite, geographic

Stroma

Necrotizing keratitis

Immune reaction

"Meta-herpetic"
Epithelial defect

Immune keratitis

Microbial and nonmicrobial ulcerative

keratitis

Endotheliu

Disciform keratitis

m
Anterior

Keratouveitis

Keratouveitis

chamber

HSV epithelial keratitis invariably involves active viral proliferation.[1-4]

The classic epithelial dendrite is the most common presentation of
epithelial disease (Figure 1). It represents areas of epithelial breakdown
due to cell destruction by proliferating virus and is best demonstrated
after fluorescein staining under cobalt blue lighting. Adjacent epithelium
stains with rose bengal in a "terminal bulb" configuration and represents
intact, virally-infected epithelium. In immunocompetent individuals the
herpetic epithelial disease is self-limited and will resolve, even in the
absence of pharmacologic intervention. Faint anterior stromal opacities
corresponding to the dendritic epithelial defect (often referred to as
"footprints") may persist for some time and should not be mistaken for
active stromal disease. In atopic or immunocompromised patients, or eyes
with localized immunosuppression (e.g. topical corticosteroid use), the
dendritic epithelial defects may continue to grow and coalesce to form
characteristic geographic epithelial defects.

HSV stromal keratitis is associated with the highest and most severe
morbidity of any ocular herpetic disease.[1-4] Although this condition
frequently follows previous HSV epithelial keratitis, it can be the initial
presentation of ocular herpetic disease. The vast majority of cases are an
immune stromal keratitis (ISK), which involves the antibody-complement
cascade against retained viral antigens in the stroma. The quintessential
manifestation is a mid-to-deep stromal infiltrate that is associated with an

intact epithelium and minimal stromal necrosis and thinning (Figure 3).
However, the initial presentation may be multiple areas of diffuse stromal
haze (such as that in our case presentation) that is often dismissed by
clinicians as "chronic stromal scarring." Chronic ISK may be associated
with progressive mid-to-deep stromal vascularization, with or without
associated lipid keratopathy and permanent corneal scarring (Figure 4).
Necrotizing interstitial keratitis (NIK) is a rare manifestation that is
believed to be associated with live viral proliferation within the stroma. It
presents with an epithelial defect, dense stromal infiltration, and
progressive necrosis that often results in corneal perforation. It is often
difficult to differentiate from culture-negative bacterial or fungal
superinfection. Neither ISK nor NIK is self-limited and failure to provide
appropriate pharmaceutical intervention will result in progressive corneal
scarring and visual impairment.

HSV disciform (endothelial) keratitis is a cell-mediated immune reaction to

corneal endothelial tissue that presents with diffuse stromal edema.[1-4]
In approximately half of cases, there is no prior history of HSV epithelial
keratitis. Accordingly, acute-onset, unilateral corneal edema should be
considered to be due to herpetic eye disease unless proven otherwise.
Clinical findings include corneal stromal edema that is almost invariably
confined to the central cornea (Figure 5). In advanced cases, microcystic
epithelial edema may be present as well. Although keratic precipitates are
often present, they may be difficult to see due to the corneal edema. The
condition responds remarkably well to treatment with topical
corticosteroids with restoration of endothelial function and resolution of
corneal edema. In neglected cases, permanent endothelial cell injury and
corneal decompensation may occur.

HSV keratouveitis may occur as a separate entity or in association with

herpetic epithelial, stromal, or endothelial disease.[1-4] It may be
granulomatous or non-granulomatous and may, in some cases, be
associated with live virus (Figure 6). Acute trabeculitis may result in an
acute rise in IOP. The presence of keratouveitis mandates a thorough
funduscopic examination to exclude concomitant acute retinal necrosis.

Metaherpetic manifestations of HSV keratitis include neurotrophic

keratopathy and microbial (i.e. bacterial and fungal) superinfections.
Neurotrophic keratopathy is a non-healing, non-infectious epithelial defect
in a patient with HSV keratitis caused by decreased corneal innervation,
decreased production of tears, or topical medication toxicity (including
steroids and topical antivirals). Unlike geographic ulceration, neurotrophic
keratopathy is characterized by smooth borders and a central,
interpalpebral location. Complications include thinning, perforation,
scarring, and neovascularization.

Figure 3. Classic immune stromal keratitis with mid-deep stromal infiltration and intact epithelium

Figure 5. Disciform HSV keratitis with central corneal edema, keratic precipitates and microcystic
edema

Figure 4 (A,B,C). HSV stromal keratitis with resultant stromal vascularization (A &B) and lipid keratopathy (C)

Figure 6 (A and B). HSV Keratouveitis with hypopyon

Table 2. Recommended management of herpetic keratitis

Recommended Management

Epithelial

Stromal

Endothelial

Anterior

Acyclovir 400 mg PO 5 times daily x 21 daysOR

Valacyclovir 500 mg PO 3 times daily x 21 days

Consider debridement

Try to avoid topical anti-viral therapy

Long-term oral anti-viral prophylaxis x 1 year if recurrent

Appropriate steroid therapy followed by slow taper

Consider antiviral coverage commensurate with steroid therapy

Long-term oral antiviral prophylaxis (1 year to indefinite)

Appropriate steroid therapy followed by slow taper

Consider antiviral coverage commensurate with steroid therapy

Long-term oral antiviral prophylaxis (1 year to indefinite)

Appropriate steroid therapy followed by slow taper

Strongly consider full dose oral antiviral therapy

Long-term oral antiviral prophylaxis (1 year to indefinite)

chamber

William B. Potter, O.D.

An Overview of Ocular Herpetic Disease

MAY 2010
http://www.reviewofoptometry.com/continuing_education/tabviewtest/lessonid/1067
45/

Herpes simplex is the leading cause of infectious corneal blindness in the United States. 4 In its epithelial
form, dendritic keratitis is the most common presentation to the primary care optometrist. Confusion of
these lesions with pseudodendrites is a common problem that can best be solved by remembering the
two key features of the classic dendritic lesion: True dendritic lesions show arborization and terminal end
bulbs.
Secondarily, the clinician can be tipped to the possibility of prior herpes infection if there exists
unexplained corneal scarring, corneal hypoesthesia or iris atrophy. Pseudodendrites can be caused by
contact lenses and their solutions, trauma, dry eye, and other infections

Prognosis
HSV keratitis is the most frequent cause of corneal blindness in the United States and is a leading indication for
corneal transplantation. It is also the most common cause of infectious blindness in the Western world.
The prognosis in HSV keratitis is generally favorable with aggressive treatment. Even with proper therapy,
however, corneal scarring can occur. If the scarring develops centrally, visual acuity can be lost.

Stromal keratitis
Significant anterior chamber inflammation may accompany stromal keratitis. Permanent stromal scarring may
lead to profound visual loss. In addition, all stromal keratitis types may develop uveitis, trabeculitis, and
secondary glaucoma.

Herpes Simplex Keratitis

Author: Jim C Wang

http://emedicine.medscape.com/article/1194268-overview#a7

After the primary infection, HSV typically becomes quiescent or latent in the
trigeminal ganglion.
Recurrent ocular HSV-1 infection and inflammation may eventually cause corneal
scarring, thinning, neovascularization, and stromal keratitis.

Initial Infection

Herpes simplex virus is typically spread by direct contact, most often from virus shed into
saliva or genital secretions.
Herpes simplex virus can be acquired following contact with an active oro-labial lesion.
Asymptomatic individuals regularly shed HSV in their saliva, 34 and therefore, HSV can also
be acquired by contact with virus-laden saliva of asymptomatic patients. 34 While
symptomatic patients shed more HSV viral DNA than asymptomatic patients, the
asymptomatic patients are likely the more common source of transmission since there are
many more of them.14
At the time of initial acquisition of HSV-1, active viral replication in mucosa or skin spreads
through neurons to dorsal root ganglia, or in the face, the trigeminal ganglia. Some patients
may experience symptoms during this initial acute infection but most patients do not. In fact,
nearly two-thirds of all primary HSV infections are either unrecognized or
asymptomatic.35 The first presentation of ocular HSV (which may or may not represent
primary infection by the virus) was elucidated in a study at Moorfields Hospital in
London.24 Between 1973 and 1980, 108 adult patients with primary ocular HSV were
studied. This study found that 84% of patients had moderate to severe conjunctivitis, 38%
had moderate to severe blepharitis, 35% had a concomitant upper respiratory infection, and
31% had generalized symptoms. Only 15% of these patients had dendritic ulcers and 2%
had disciform keratitis.24 Twenty (19%) of these patients had bilateral disease. 24

While it is true that HSV-1 tends to be responsible for most orofacial infections and HSV-2 is
responsible for most genital herpes infections, HSV-1 and HSV-2 are found in equal
numbers in the trigeminal and sacral ganglia at autopsy.36 Therefore, local host factors are
likely responsible for the predilection of HSV-1 infection for the facial area and HSV-2 for the
genital area. The frequency of HSV-2 infections of the orofacial and ocular areas is not well

defined. However, HSV-1 disease tends to recur more readily in the orofacial area and less
in the genital area after primary infection from either site. 30, 37-39

Viral Reactivation and Shedding

1. Transmission
Herpes simplex virus is typically infectious during the 510 days it takes to heal skin lesions
as well as during asymptomatic shedding in saliva. 34 In 2005, Kaufman et al used a
quantitative PCR technique to detect HSV-1 DNA in the tears and saliva of 50 asymptomatic
HSV-infected patients. Samples were taken twice daily for 30 days, yielding 2,806
samples.34 The results showed that 33.5% of all samples (941/2,806) contained HSV-1 DNA
and 98% of subjects (49/50) shed HSV-1 DNA from their tears or saliva at least once over
the 30-day sampling period. Forty-six (92%) subjects excreted HSV-1 DNA in their tears at
some time during the study. Only 37 out of 50 (74%) subjects were IgG positive for HSV-1,
suggesting that seronegative individuals might still harbor HSV in the trigeminal and/or
dorsal root ganglia.
2. Clinical Recurrences
The critical relationship between latency, reactivation, and recurrence has been studied for
years, but remains largely elusive. In one hypothesis, both a high number of latent virus
copies and the number of latently infected neurons may promote reactivation by
overwhelming the cellular mechanisms that silence virus transcription. 40 Recurrence of HSV
epithelial keratitis may correlate to trigeminal ganglia reactivation, but the relationship
between HSV reactivation in the trigeminal ganglia with recurrences of HSV stromal or
endothelial keratitis is not known.
Virus reactivation and shedding in the orofacial area can lead to clinically evident infection
of the skin (vesicular dermatitis), ocular surface (conjunctivitis and epithelial keratitis), or
asymptomatic shedding only. Compared to primary ocular herpetic disease, which primarily
manifests as blepharitis, conjunctivitis, and less commonly HSV keratitis (17%), recurrent
disease can manifest as either adnexal infection or HSV keratitis. 18, 24, 25 Most recurrences in
the HEDS prevention trial manifested in the cornea (37% epithelial and 46% stromal) as
opposed to the eyelid and adnexa, but patients entering the study were selected for a
history of HSV keratitis.25 Recurrent episodes of HSV keratitis account for most of the
morbidity associated with ocular HSV. For example, HSV stromal keratitis recurrence, an
immunopathologic process, can lead to stromal scarring, neovascularization, endothelial
dysfunction, and vision loss.

ATOPY
The term atopy designates a group of patients with a personal or family history of one or
more of the following diseases: hay fever, asthma, and atopic eczema. 69 Atopic patients
have altered reactivity to common environmental antigens that do not cause clinical
reactions in most people. Atopy is characterized by the persistence or aberrant activation of
TH2 lymphocytes leading to the generation of cytokines that stimulate B-lymphocyte
synthesis of IgE antibody and the production of eosinophils. 70There is a relative imbalance
of Th1 and Th2 T-cell immune response in atopic individuals. As a result, atopic patients
exhibit altered cell-mediated immunity and are particularly susceptible to HSV infections,
including HSV keratitis.28, 66, 71-74 In a large retrospective case control study in California,
individuals with severe atopic disease had between 2.0 and 4.8-fold greater odds of
developing ocular HSV than those without atopy.