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Herpetic Simplex Immune Stromal Keratitis: Case Report, Review and Treatment
By:
Previous candidate. Actual case report submission
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Abstract
Purpose. To present a case study and discussion on the management of Herpes Simplex Virus
Immune Stromal Keratitis.
Case Report. A 57-year-old white female presented to the office complaining of a painful red
eye. She was treated with topical Pred Forte (1% prednisolone acetate), which alleviated the
acute symptoms, but after years of recurrences, found that oral Zovriax (acyclovir),was the
most effective treatment to prevent outbreaks and decrease scarring.
Conclusions. HSV Immune Stromal keratitis is an immune- mediated process, and is best
treated with topical corticosteroids, with oral antiviral prophylaxis. The most important
findings of HEDS were that use of topical corticosteroids shortened the course of HSV stromal
keratitis, and prophylactic treatment with oral acyclovir decreased the risk of recurrent HSV
ocular infection by 41%, which was evident in this case.
Key Words: Immune Stromal Keratitis, Acyclovir, Herpes Keratitis
Introduction
The word herpes is derived from the Greek word meaning “to crawl,” because of the
serpiginous nature of herpetic lesions.1 They are ubiquitous human pathogens capable of
causing both asymptomatic infection and active disease in a wide variety of end organs. Herpes
viruses affecting humans include herpes simplex virus types 1 and 2 (HSV-1, HSV-2), varicella
zoster virus (VZV), cytomegalovirus, and Epstein- Barr virus.1,2 These double- stranded DNA
viruses have a viral derived capsid enclosed in a host cell–derived envelope with viral- derived
glycoprotein projections. Although HSV-1 usually involves the oropharynx and HSV-2 usually
involves the genital area, both types can infect either location. Typically, ocular disease is
caused by type 1 rather than type 2, with the exception of herpetic keratitis in neonates, in
which 75% is caused by HSV-2.3
Primary infection can be either asymptomatic or active and is followed by a latent state of
nonreplication characteristic of herpesviruses.4 HSV is capable of causing severe primary
disease in children and neonates and has been known to cause a variety of ocular diseases in
addition to oral-facial infections, encephalitis, meningitis, myelitis, erythema multiforme,
hepatitis, and disseminated infection resulting in death.4 More common infections include
recurrent herpes labialis caused by HSV-1, which occurs in 20–45% of the world population, and
herpes genitalis caused by HSV-2, which causes an estimated 100 000 new cases each year in
the United States, with an increasing seroprevalence, estimated at 21.9% in the last NHANES
(National Health and Nutrition Evaluation Survey).5 A longitudinal study by Liesegang et al.
extrapolated data to an estimated 20 000 new cases of ocular HSV in the United States per year
and between 40 000 – 60 000 episodes annually.1,6 HSV infection remains a serious public
health problem associated with significant morbidity and mortality.
Case Report
Initial Visit 7/26/10 - Nancy H, a 57-year-old white female presented complaining of a painful
left eye that was extremely sensitive to light. Her ocular history was remarkable for an
“infection” about a year earlier in that same eye, that needed prescription eye drops to clear it
up. Her medical history was significant for menopause. Her family history was remarkable for
glaucoma (father and 8 of his siblings). Her medications include Premarin (conjugated
estrogen), and she reported no known medical allergies.
Best corrected visual acuity was 20/20 OD, OS. Pupils, extraocular muscles and confrontation
fields were intact. The right anterior segment was clear. The left conjunctiva showed 1+
injection. The left cornea showed a focal area of stromal infiltration inferior to the visual axis
surrounded by stromal cell and edema. There was no evidence of an epithelial break, and the
cornea did not stain with fluorescein. There appeared to be some scarring on the cornea,
perhaps from the previous event. There were no keratic precipitates on the endothelium. The
anterior chamber had Trace-1+ cell. She was dilated with 1% tropicamide and the posterior
segment showed no signs of inflammation OU, with cup to disc ratios at .3 /.3 OD, OS. Corneal
sensitivity testing was reduced on the left eye using waxed dental floss. Tonometry by
applanation was 16mmHg OU using Fluress.
NH was diagnosed with HSV Immune Stromal Keratitis OS. Treatment prescribed consisted of
topical Pred Forte (1% prednisolone acetate) every two hours, and oral Zovirax (acyclovir)
400mg BID to prevent epithelial breakthrough and to start preventative treatment. She was
scheduled to return to the office in 2-3 days.
7/29/2010 – NH followed up stating things felt better and that she was not as sensitive to light,
and overall feeling much much better.
Best corrected visual acuity was 20/20 OD, OS. The right anterior segment was clear. The left
conjunctiva showed trace injection. The left cornea showed reduced stromal infiltration
inferior to the visual axis and much less stromal cell and edema. There was no evidence of an
epithelial break, and the cornea did not stain with fluorescein. There was definite evidence of
previous scarring on the cornea. There were no keratic precipitates on the endothelium. The
anterior chamber had no cell. She was dilated with 1% tropicamide and the posterior segment
showed no signs of inflammation OU, with cup to disc ratios at .3 /.3 OD, OS. Tonometry by
applanation was 17mmHg OS using Fluress.
NH was diagnosed with Resolving HSV Immune Stromal Keratitis OS. Treatment prescribed
consisted of tapering topical Pred Forte (1% prednisolone acetate) every four hours for an
additional 4 days (for 1 week total), then QID x 1 week, TID x 1 week, BID x 1 week, QD x 1 week
and QOD x 1 week and stop. She was continued on oral Zovirax (acyclovir) 400mg BID as
preventative. She was scheduled to return to the office in 3-4 weeks.
When she returned all inflammation was resolved, and she was continued on oral Zovirax
400mg BID to prevent additional flare ups that could create more scarring and loss of vision.
She was educated on the potential triggers and told to follow up immediately if she
experienced any difficulties.
5/9/2011 - NH followed up for a routine exam stating things had been feeling fine and that it
was almost a year, and would really like to get off the oral medication.
Best corrected visual acuity was 20/20 OD, OS. The right anterior segment was clear. The left
conjunctiva was clear. There was definite evidence of stromal scarring on the cornea inferior to
the visual axis. There were no keratic precipitates on the endothelium. She was dilated with
1% tropicamide and the posterior segment was clear OU, with cup to disc ratios at .3 /.3 OD,
OS. Tonometry by applanation was 18mmHg OU using Fluress.
NH was diagnosed with a History of HSV Immune Stromal Keratitis OS (quiescent at this visit).
Ongoing treatment was discussed at length, and NH made a strong case for discontinuing oral
treatment (i.e., she was stopping regardless). She was educated on the potential triggers and
told to follow up immediately if she experienced any difficulties and told to follow up for
routine care.
6/24/2011 – Approximately two months of discontinuing the oral Zovirax, NH returned to the
office complaining of a painful left eye that was extremely sensitive to light.
Best corrected visual acuity was 20/20 OD, OS. Pupils, extraocular muscles and confrontation
fields were intact. The right anterior segment was clear. The left conjunctiva showed 1+
injection. The left cornea showed a focal area of stromal infiltration inferior to the visual axis,
but just superior to the previous bout, surrounded by stromal cell and edema. There was no
evidence of an epithelial break, and the cornea did not stain with fluorescein. There was also
evidence of neovascularization inferior to the scarring. There were no keratic precipitates on
the endothelium. The anterior chamber had Trace cell. She was dilated with 1% tropicamide
and the posterior segment showed no signs of inflammation OU, with cup to disc ratios at .3 /.3
OD, OS. Tonometry by applanation was 16mmHg OU using Fluress.
NH was diagnosed with Recurrent HSV Immune Stromal Keratitis OS. Treatment prescribed
consisted of topical Pred Forte (1% prednisolone acetate) every two hours, and she was
restarted on oral Zovirax (acyclovir) 400mg BID to prevent epithelial breakthrough, and to restart preventative treatment. She was scheduled to return to the office in 2-3 days.
When she returned, the HSV Immune Stromal Keratitis was responding nicely to treatment.
The Pred Forte (1% prednisolone acetate) was then tapered to QID x 1 week, TID x 1 week, BID
x 1 week, QD x 1 week and QOD x 1 week and stop. The oral Zovirax (acyclovir) 400mg BID was
continued to prevent additional flare ups that could create more scarring and loss of vision.
She was scheduled to return to the office in 3-4 weeks.
2/20/2012 - Approximately eight months later, NH returned to the office complaining of a
painful left eye that was sensitive to light. She reported that she had not been terribly
compliant with the oral Zovirax lately. She also reported that she had already started the Pred
Forte that morning, and had been using it every two hours OS.
Best corrected visual acuity was 20/20 OD, OS. Pupils, extraocular muscles and confrontation
fields were intact. The right anterior segment was clear. The left conjunctiva showed 1+
injection. The left cornea showed a focal area of stromal infiltration inferior to the visual axis,
but again superior to the previous bouts, surrounded by stromal cell and edema. There was no
evidence of an epithelial break, and the cornea did not stain with fluorescein. There was also
distinct evidence of previous scarring and neovascularization (see picture below). There were
no keratic precipitates on the endothelium. The anterior chamber had Trace cell. She was
dilated with 1% tropicamide and the posterior segment showed no signs of inflammation OU,
with cup to disc ratios at .3 /.3 OD, OS. Tonometry by applanation was 17mmHg OU using
Fluress.
NH was diagnosed with Recurrent HSV Immune Stromal Keratitis OS. Treatment prescribed
consisted of topical Pred Forte (1% prednisolone acetate) every two hours, and she was
instructed to make sure she used the oral Zovirax (acyclovir) 400mg BID, not only to prevent
epithelial breakthrough, but to prevent additional flare ups that could create more scarring and
loss of vision. She was scheduled to return to the office in 2-3 days.
When she returned, the HSV Immune Stromal Keratitis was responding nicely to treatment.
The Pred Forte (1% prednisolone acetate) was then tapered to QID x 1 week, TID x 1 week, BID
x 1 week, QD x 1 week and QOD x 1 week and stop. The oral Zovirax (acyclovir) 400mg BID was
continued as a preventative therapy. She was scheduled to return to the office in 3-4 weeks.
1/28/2014 – NH followed up for a routine exam stating things had been feeling fine and that it
was almost two years since she had a flare up. She had been very compliant with the oral
Zovirax and was taking 400mg BID as prescribed.
Best corrected visual acuity was 20/20 OD, OS. The right anterior segment was clear. The left
conjunctiva was clear. There was definite evidence of stromal scarring and neovascularization
on the cornea inferior to the visual axis. There were no keratic precipitates on the
endothelium. She was dilated with 1% tropicamide and the posterior segment was clear OU,
with cup to disc ratios at .3 /.3 OD, OS. Tonometry by applanation was 18mmHg OU using
Fluress.
NH was diagnosed with a History of HSV Immune Stromal Keratitis OS (quiescent at this visit).
Ongoing treatment was discussed at length. The oral Zovirax (acyclovir) 400mg BID was
continued to prevent additional flare ups that could create more scarring and loss of vision.
She was educated on the potential triggers and told to follow up immediately if she
experienced any difficulties and told to follow up for routine care.
Summary of treatment:
Visits
7/26/10
Treat
ment
Plan:
HSV Immune
Stromal
Keratitis flare
up
HSV Immune
Stromal
Keratitis
Resolving
Pred Forte
Q2H OS
Pred Forte
Taper QID OS
x 1 week,
reducing by
drop a week
Started
Zovirax
400mg BID PO
– Antiviral
coverage
during steroid
tx and begin
preventative
7/29/10
Cont Zovirax
400mg BID PO
– long term
preventative
5/9/11
6/24/11
H/O HSV
Immune
Stromal
Keratitis
Quiescent
HSV Immune
Stromal
Keratitis flare
up (2 mo off
Zovirax)
Zovirax.
Almost year w
no flares. Pt
would like to
D/C, so
stopped
Pred Forte Q2H
OS
Re-Started
Zovirax 400mg
BID PO –
Antiviral
coverage
during steroid
tx and restart
preventative
Visits
2/20/12
Treat
ment
Plan:
HSV Immune
Stromal
Keratitis flare
up (reports
noncompliance
with Zovirax)
Pred Forte
Q2H OS
Edu on need
for Continued
Zovirax
400mg BID PO
– Antiviral
coverage
during steroid
tx and
preventative
1/28/14
H/O HSV
Immune
Stromal
Keratitis
(Quiescent)
Continue
Zovirax.
Almost two
year w no
flares. Pt
reports good
compliance
with meds
Discussion
Life Cycle
Humans are the only natural reservoir of HSV despite experimental models using other hosts. 2
Close personal contact is thought to be necessary for the spread of HSV because of the physical
instability of the virus and the fact that the major portals of entry are the mucous membranes
and external skin. Initial end-organ infection can be asymptomatic and unrecognized, and is
followed by latency in sensory ganglia. In fact, primary infection manifests clinically in only 1–
6% of people infected with the virus.1,2 The oral route can provide access to the trigeminal
ganglion and subsequently the eye.2 Because many patients with HSV infection do not have
definitive contact with a source, it has been suggested that asymptomatic shedding of virus is
an important source of transmission.2 In addition, clinical appearance of an infection may
represent earlier primary infection at a different end organ. Therefore, what appears to be a
primary ocular infection may indeed be an attack in a new end organ within a previously
infected host. The time between contact and disease is typically between 3 and 9 days.
After peripheral entry into the host and primary infection with viral replication within an end
organ, HSV travels in a retrograde fashion to various ganglia including the trigeminal, cervical,
and sympathetic gangliae, and possibly the brain stem.2 Here it resides during the lifespan of
the host. This process usually begins within 1 to 2 days of the primary infection and may take
several weeks to complete.2 Despite an early immune response by the host, ganglionic infection
occurs rapidly and does not require virus replication. Once ganglionic presence has been
established, active replication in neurons and surrounding cells leads to cell death. It has been
suggested that virus replication within the trigeminal ganglion is of paramount importance for
viral spread to sites other than the inoculation site. Regardless, latency can be established and
is thought to represent the presence of the viral genome within the neuronal cells. 7 The cornea
itself has also been found to host latent HSV virus, with potential for reactivation.
Primary HSV Infection - Primary HSV ocular infection is frequently missed and rarely affects the
cornea. The most common pattern of infection is blepharoconjunctivitis that heals without
scarring. The associated follicular conjunctivitis is often mistaken for adenoviral conjunctivitis.
However, unilateral, nonepidemic follicular conjunctivitis should always make one suspect HSV,
as studies have shown at least 25% of such cases to be culture- positive for HSV.1 In rare
instances, especially in patients with severe eczema or other immunocompromised states, this
usually innocuous infection can become life threatening.
Recurrent HSV Infection - Once the primary infection resolves, the virus becomes latent and
remains in this state until certain triggers, such as fever, sunlight exposure, stress, and menses,
cause it to reactivate, multiply, and travel back down the nerve to cause recurrent infection. It
is uncertain whether ocular recurrences are caused by virus that initially infected ocular tissues
or by “back-door spread,” via the trigeminal ganglion, from an initial oral infection.2 HSV utilizes
cellular enzymes for replication and the cell dies when it is released from the cell. The loss of
ganglion cells with recurrent infections leads to decreased corneal sensation, one of the
hallmarks of HSK. Recurrent HSV infection most frequently involves the cornea, although all
parts of the eye can be affected concurrently or independently. HSV can cause retinitis,
trabeculitis, uveitis, and optic neuritis.
Classification
From a diagnostic and therapeutic perspective, HSV keratitis is one of the most challenging
entities to diagnose. A variety of clinical manifestations of not only infectious keratitis, but also
immunologic disease can affect all levels of the cornea. Corneal disease includes infectious
epithelial keratitis, neurotrophic keratopathy, immune stromal (interstitial) keratitis, necrotizing
stromal keratitis, and endotheliitis.2 Understanding the anatomic basis for this classification
may give a clearer picture of the pathophysiology and treatment of the disease.
HSV Epithelial Disease
These forms of keratitis are usually caused by actively replicating virus. The most commonly
recognized clinical manifestations of infectious epithelial keratitis are the dendritic and
geographic ulcers. Corneal vesicles and marginal keratitis are less common and may go
unrecognized as active infections. Most patients with infectious epithelial keratitis complain of
photophobia, pain, and a thin, watery discharge; those with central lesions also may present
with decreased vision.
Corneal Vesicles are the earliest epithelial lesions of reactivated HSV. They are small vesicles in
the epithelium, which have been described as punctate epithelial keratopathy (PEK). Careful
examination of these lesions demonstrates minute, raised, clear vesicles that correspond to the
vesicular eruptions seen in the skin or mucous membranes elsewhere in the body. These
lesions are important to recognize. Typically, within 24 hours, the vesicles coalesce to form the
typical dendritic and geographic ulcers, unless immunocompromised , then they could
remain.1,2,4
Dendritic ulcer is the most common and classic herpetic corneal lesion that is caused by
replicating virus. These lesions are linear and dichotomously branching, with each branch
terminating with a bulb. The borders of the lesion are slightly raised and grayish and consist of
HSV- infected cells that stain with rose bengal (RB) dye. These HSV- infected cells have
undergone balloon degeneration. In contrast, the center of the lesion is devoid of cells and
stains with fluorescein. This lesion represents a true ulcer in that it extends through the
basement membrane. This clinical feature is important to recognize because it aids in
differentiating a true dendritic ulcer from the many other branching lesions of the corneal
epithelium.1,2,4 The underlying stroma has minimal inflammation. After dendritic epithelial
keratitis resolves, a dendritic scar, called a ghost dendrite, may remain in the superficial stroma.
Geographic ulcer is similar to a dendritic ulcer, and is also caused by replicating virus, but has a
much larger epithelial defect. As it progresses, the ulcer loses its dendritic shape and takes on a
form that often resembles the shape of a country—hence the term geographic. Like a dendritic
ulcer, it is a true ulcer in that it is an epithelial lesion that extends through the basement
membrane. This presentation usually occurs in persons with compromised immunity, especially
patients taking topical corticosteroids. It can also occur in individuals who have untreated, long
standing originally dendritic ulcers, in which case it can be hard to distinguish from a trophic
ulcer. The dichotomous branching and terminal bulbs of the geographic ulcer, which are seen
peripherally, however, often distinguish it from a trophic ulcer.
Marginal keratitis lesions are located near the limbus and can resemble staphylococcal
catarrhal ulcers. They tend to have more underlying stromal inflammation and tend to be more
resistant to treatment. Also, they are more likely to become a trophic ulcer. These lesions result
from active viral disease like that of the dendritic ulcer. However, the proximity of this lesion to
the limbus, with its accompanying blood vessels, accounts for the unique clinical features. The
epithelial lesion is quickly infiltrated with white blood cells from the nearby limbal blood
vessels. The resultant lesion typically seen on presentation has an anterior stromal infiltrate
underlying the ulcer and adjacent limbal injection. Careful inspection may show a dendritic
ulcer overlying the stromal infiltrate. Marginal ulcers are typically more symptomatic than
those with central dendritic ulcers, because of the intense inflammation associated with the
marginal lesion.1,2,4
Neurotrophic or metaherpetic ulcers are the only form of epithelial ulceration that does not
have any live virus. The ulcer is called trophic if it arises de novo and metaherpetic if it follows a
dendritic or geographic ulcer, although the terms are frequently used interchangeably.1,2
Patients who have had infectious epithelial keratitis are at risk to develop neurotrophic
keratopathy. This clinical entity is unique because it is neither immune nor infectious. Rather, it
arises from impaired corneal innervation in combination with decreased tear secretion. The
keratopathy may be exacerbated by chronic use of topical medications, especially antivirals.
Although neurotrophic ulcers are difficult to differentiate from geographic ulcers, they can be
distinguished by their smooth, gray, elevated borders that do not stain with RB. The RB dye
stains the unhealthy epithelial cells attempting to migrate across the base of the ulcer, whereas
fluorescein leaks through these poorly adherent cells into the stroma and stains the periphery
so called reverse staining.1,2,4
HSV Stromal Disease
This form of keratitis is usually an immune- mediated response to nonreplicating viral particles,
but more severe forms may be caused by live virus. Although stromal disease accounts for
approximately 2% of initial episodes of ocular HSV disease, it accounts for 20–48% of recurrent
ocular HSV disease. The clinical course of immune stromal keratitis is chronic, recurrent
inflammation that can persist for years. Patients may experience constant low-grade
inflammation with mild fluctuations in severity. Other patients may have periods of complete
resolution of inflammation with intermittent flare-ups of severe inflammation. Long-term
topical corticosteroids may be required to suppress the inflammatory reaction of immune
stromal keratitis. Some patients are exquisitely sensitive to mild reductions in topical
corticosteroid. Untreated or undertreated inflammation can lead to stromal scarring, thinning,
persistent neovascularization, lipid deposition, and severe loss of vision.1,2,4
The corneal stroma may be affected in HSV disease through a variety of mechanisms, either
primarily or secondarily. Primary manifestations occur in two varieties, necrotizing and
immune mediated. Necrotizing stromal keratitis occurs from direct viral invasion of the stroma,
whereas immune stromal keratitis is the result of an immune reaction within the stroma.
Secondary involvement may occur as a sequela to infectious epithelial keratitis, neurotrophic
keratopathy, or endotheliitis.1,2,4,8 When stromal involvement occurs secondarily to infectious
epithelial keratitis, neurotrophic keratopathy, or endotheliitis, the source of inflammation is in
the epithelium or endothelium, and treatment must be focused toward the proper origin of
inflammation if stromal injury is to be minimized.
Necrotizing stromal keratitis is a rare manifestation of HSV that is thought to result from direct
viral invasion of the corneal stroma. The clinical findings are necrosis, ulceration, and dense
infiltration of the stroma with an overlying epithelial defect. The combination of replicating
virus and severe host inflammatory response leads to destructive intrastromal inflammation
that is often refractory to treatment with high-dose anti-inflammatory and antiviral
medications. The severe inflammation may lead to thinning and perforation within a short
period of time. The clinical findings of necrotizing stromal keratitis may resemble those of
infectious keratitis secondary to microbial invasion.1,2,4 Therefore, bacterial and fungal
pathogens must be considered when treating for necrotizing stromal keratitis. The use of
topical corticosteroids without antiviral coverage has been implicated as a possible risk factor.
Immune stromal keratitis on the other hand is a common chronic recurrent manifestation of
HSV, occurring in 20% of patients with ocular HSV.1.2.4 Additional studies have reported the
incidences of stromal disease of 21% within 2 years and 26% - 48% within 7 years of infectious
epithelial keratitis.2,9,10 The inflammation is thought to be due to retained viral antigen within
the stroma. This antigen triggers an antigen-antibody-complement (AAC) cascade that results in
intrastromal inflammation.1.2.4 Molecular mimicry has been linked with activation of T-cellmediated autoimmune responses in murine models.
Stromal infiltration is the most common finding in recurrent immune stromal keratitis and can
present as punctate stromal opacities that most likely represent AAC immune complexes. The
overlying epithelium is almost always intact except in the situation of combined infectious
epithelial keratitis and immune stromal keratitis. In the acute phase, these opacities may be
accompanied by haze that is indicative of inflammatory cellular infiltrate of the stroma. The
haze and punctate lesions may become permanent opacities. The pattern of stromal
inflammation may be focal, multifocal, or diffuse.1,2,4 Stromal infiltration is often accompanied
by anterior chamber inflammation, ciliary flush, and significant discomfort. Stromal edema also
can accompany this reaction. The edema most likely results from the consequences of stromal
inflammation rather than endothelial dysfunction. Severe inflammation can lead to dense
infiltration with subsequent scarring and profound visual loss. Vision loss from HSV immune
stromal keratitis is the main reason that 3% of all penetrating keratoplasties have been
performed in the United States in recent years.
A specific form of stromal infiltration secondary to HSV is the immune ring. This ring is also
thought to be an AAC precipitate similar to a Wessely ring. It can form an incomplete or
complete ring and can be singular or multiple.2 It is most commonly found in the mid stroma of
the central or paracentral cornea.
Another finding of immune stromal keratitis is stromal neovascularization.1,2
Neovascularization may occur at any level of the cornea. In some cases of severe inflammation,
there can be rapid neovascularization with multiple fronds of new vessels associated with
intense infiltration. This rapid neovascularization can range from sectoral, with a single frond of
vessels, to complete, involving all quadrants of the cornea. Neovascularization also can progress
in a subacute or chronic fashion in response to persistent, low-grade stromal inflammation. The
neovascularization in these less acute cases tends to be sectoral rather than circumferential.
Aggressive treatment of inflammation can result in complete resolution of the blood vessels.
Ghost vessels, which represent empty vessel channels within the stroma, can occur if the
inflammation and neovascularization is long-standing before it is quieted. If ghost vessels are
present, there is typically significant accompanying stromal scarring and thinning because of
the chronicity of the inflammation. Lipid keratopathy can follow stromal neovascularization
and can lead to further scarring and loss of vision. A more serious sequela of stromal
neovascularization is permanent neovascularization of the cornea, which will decrease the
success rate of penetrating keratoplasty because of increased risk of rejection
Immune stromal keratitis may present days to years after an episode of infectious epithelial
keratitis. In some cases, there may be no history of a dendritic ulcer; in other cases, the first
documented ulcer may actually occur after an episode of immune stromal keratitis. In cases
where there is no antecedent dendritic ulcer, the diagnosis of HSV immune stromal keratitis
usually is made presumptively.
HSV Endothelial Disease
Disciform edema or a disciform keratitis reaction, is not a reaction of the stroma and should not
be classified or treated as a stromal keratitis.2 Careful observation of the patient with disciform
edema reveals that this process is an inflammatory reaction of the endothelium, with only
secondary stromal and epithelial edema. This distinction between stromal and endothelial
inflammation is important because the prognosis and clinical course are different, and visual
outcome depends on proper recognition and treatment of the endothelium as the primary site
of inflammation.
HSV endotheliitis can be classified based on the distribution of the KP and the configuration of
the overlying stromal and epithelial edema. The three forms of HSV endotheliitis are disciform,
diffuse, and linear.2,8
Disciform endotheliitis is most common presentation of endotheliitis. Patients present with
photophobia and mild to moderate ocular discomfort. Limbal injection is usually seen, as these
patients have an accompanying iritis. Visual acuity may range from normal to severely reduced,
depending on the location and severity of the stromal edema. The most striking finding of
disciform endotheliitis on slit lamp examination is a round or disc-shaped area of stromal
edema.2,8 This edema may be in the central or paracentral cornea. The edema usually spans the
entire stromal thickness, resulting in the usual ground-glass appearance seen with corneal
edema from other entities of endothelial decompensation. Typically, in disciform endotheliitis,
the edema is within a strikingly focal pattern with a definite demarcation between involved and
uninvolved cornea. In the acute setting, the stroma is void of infiltrate and neovascularization.
In all cases of disciform endotheliitis, KP are present.2,8 The KP underlie the distribution of
stromal edema and are not found in the nonedematous areas. It is sometimes difficult to see
the KP because of the severity of the stromal edema. In these cases, it is useful to view the
endothelium obliquely to detect the KP. Often, as the stromal edema resolves, the hidden KP
become visible because the KP tend to resolve at a slower rate than the edema. An iritis may
accompany disciform endotheliitis, but can be difficult to detect through the edematous
cornea. In addition, elevated intraocular pressure, which may be severe, is often present. The
increased pressure may be due either to inflammatory cells blocking aqueous outflow or to a
primary trabeculitis. An episode of disciform endotheliitis may occur months to years after a
documented episode of infectious epithelial keratitis. Often, there will not be a documented
history of HSV disease, and a careful examination looking for footprints of HSV is helpful in
making the proper diagnosis.
Diffuse endotheliitis is a rare presentation of HSV keratitis. These patients experience pain,
photophobia, injection, and decreased vision. They typically have scattered KP over the entire
cornea with overlying diffuse stromal edema. A mild to moderate iritis is usually present,
although it may be difficult to detect because of the corneal edema. Epithelial edema is present
in cases of significant stromal edema. In severe cases, a dense, retrocorneal plaque of
inflammatory cells accompanied by hypopyon may be seen. Diffuse endotheliitis represents an
immune reaction targeted against the corneal endothelium. Failure to control the inflammation
leads to scarring, neovascularization, persistent edema, and loss of vision.2,8
Linear endotheliitis is the rarest form and appears clinically as a line of KP on the corneal
endothelium that progresses centrally from the limbus. It is accompanied by peripheral stromal
and epithelial edema between the KP and the limbus. The line of KP can be sectoral or, in some
cases, circumferential. It may have a distinct linear pattern as it moves centrally, but in some
cases it may have a more serpiginous appearance. There is usually a well-demarcated line
between the area of edematous and nonedematous cornea, with the KP located at the leading
edge of the edema. The major complaints are pain, photophobia, and injection. Linear
endotheliitis is quite difficult to treat. Failure to recognize and properly treat this condition
leads to corneal decompensation.2,8
Diagnosis
Although the diagnosis of primary and recurrent ocular HSV infection relies on a thorough
ophthalmic examination, viral culture can help make a definitive diagnosis. This requires early
culturing (usually within several days of the onset) and may require up to 1 week of incubation.
Laboratory tests are of no use in stromal keratitis. The following tests can be useful in
challenging cases of epithelial keratitis:2,11




Corneal Sensitivity – using either an esthesiometer or waxed dental floss
Herpes Culture - The virus, once grown, can be typed to HSV-1 or HSV-2.
Fluorescent Antibody (FAB) Testing - The corneal swab can be smeared on a slide, or
impression cytology using a nitrocellulose membrane can be performed.
DNA Amplification - This test does not require a high number of viral particles, but it is
more expensive.


Tzanck Smear - Papanicolaou or Giemsa stains of corneal smears are examined for the
presence of multinucleated giant cells and intranuclear eosinophilic inclusion bodies.
Serum Antibody Testing - The presence of anti-HSV IgM in a child may indicate active
infection. However, false negatives are common and positive titers in adults merely
indicate past infection, which is nearly universal.
Management
Herpetic Eye Disease Study12
The Herpetic Eye Disease Study (HEDS) was originally organized to evaluate oral acyclovir for
herpetic stromal keratitis. Eight eye centers throughout the United States joined together to
prospectively test whether acyclovir was effective in the management of stromal HSV. Five
randomized double-masked placebo-controlled multicenter clinical trials have studied specific
treatment protocols for the management of ocular HSV disease. Trial design in each of the
HEDS has included well-defined inclusion criteria, standardized treatment protocols, careful
monitoring of patient compliance during the study, and precise outcome measures.
Herpetic Eye Disease Study: a controlled trial of oral acyclovir for herpes simplex
This study was designed to evaluate the efficacy of oral acyclovir in treating stromal keratitis
caused by HSV in patients receiving concomitant topical corticosteroids and trifluridine. The
stromal keratitis included disciform disease, which is non-necrotizing keratitis and necrotizing
stromal keratitis. The authors reported on 104 patients randomized to receive a 10-week
course of either oral acyclovir (400 mg 5 times daily, n = 51) or placebo (n= 53). All patients also
received a standard regimen of topical prednisone phosphate and trifluridine. Ophthalmologic
examinations were performed for 6 months after entry into the trial. The results showed that
the median time to treatment failure (defined as worsening or no improvement of stromal
keratitis or an adverse event) was 84 days for the acyclovir group and 62 days for the placebo
group. By 16 weeks, 75% in the acyclovir group and 74% in the placebo group had failed
treatment. By that time, the keratitis had resolved with trial medications, and there was no
subsequent worsening in 18% in the acyclovir group and 19% in the placebo group. None of
these results were statistically significant. Visual acuity improved over 6 months in significantly
more patients in the acyclovir group than in the placebo group. The study concluded that there
was no clinically significant beneficial effect of oral acyclovir in treating HSV stromal keratitis in
patients receiving concomitant topical corticosteroids and trifluridine in regard to time to
treatment failure, proportion of patients who failed treatment, proportion of patients whose
keratitis resolved, time to resolution, or 6-month best-corrected visual acuity.
Herpetic Eye Disease Study: a controlled trial of topical corticosteroids for herpes
simplex stromal keratitis
The efficacy of topical corticosteroids in treating herpes simplex stromal keratitis was evaluated
in this study. One hundred six patients with active herpes simplex stromal keratitis who had
not received any corticosteroids for at least 10 days before the study were enrolled. Patients
were assigned to the placebo group (n = 49) or the steroid group (topical prednisolone
phosphate; n =57). Both regimens were tapered over 10 weeks, and both groups received
topical trifluridine. Ophthalmic examinations were performed for 6 months after entry into the
trial. Compared with placebo, corticosteroid therapy reduced the risk of persistent or
progressive stromal keratouveitis by 68%. The steroid-treated group had a significantly
shorter time to resolution of stromal keratitis. Postponing steroid treatment during careful
observation for a few weeks delayed resolution of stromal keratitis but had no adverse effect
on the visual outcome at 6 months. The incidence of recurrent herpes was not affected by
topical steroid use. It was concluded that topical steroid treatment was significantly better than
placebo in reducing persistence or progression of stromal inflammation and in shortening the
duration of HSV stromal keratitis.
Herpetic Eye Disease Study: a controlled trial of oral acyclovir for iridocyclitis caused
by herpes simplex virus
This study was designed to evaluate the benefit of adding oral acyclovir to a regimen of topical
prednisolone phosphate and trifluridine for the treatment of iridocyclitis caused by HSV.
Patients were randomly assigned to receive a 10-week course of either acyclovir 400 mg, 5
times daily, or oral placebo in conjunction with topical trifluridine and a topical corticosteroid.
Follow-up examinations were done for 26 weeks after enrollment. The trial was stopped
because of slow recruitment after only 50 of the originally planned 104 patients were enrolled
in more than 4 years. Treatment failure was defined as persistence or worsening of ocular
inflammation, withdrawal of medication because of toxicity, or request by the patient to
withdraw from the trial for any reason. Treatment failure occurred in 50% of the 22 patients in
the acyclovir-treated group and in 68% of the 28 patients in the placebo group. The treatment
effect noted seemed slightly greater when only the patients with a persistence or worsening of
ocular HSV were considered as treatment failures. The possible benefit of acyclovir became
apparent after 3 weeks of follow-up. While the number of patients studied was too small to
achieve statistically conclusive results, the results suggested a benefit of oral acyclovir in the
treatment of HSV iridocyclitis.
Herpetic Eye Disease Study: a controlled trial of oral acyclovir for the prevention of
stromal keratitis or iritis in patients with herpes simplex virus epithelial keratitis
The efficacy of oral acyclovir in preventing stromal keratitis or iritis in patients with epithelial
keratitis caused by HSV was tested in 287 patients. These patients were randomly assigned to
receive a 3-week course of oral acyclovir, 400 mg 5 times a day (n = 153), or placebo (n = 134) in
addition to topical trifluridine for their epithelial disease. Patients were assessed for a 12month follow-up period. Stromal keratitis or iritis developed in 11% of the acyclovir group and
in 10% of the placebo group. The development of stromal keratitis or iritis was more frequent
in patients with a history of HSV stromal keratitis or iritis than in those without such a history
(23% vs 9%). The study concluded that for patients with HSV epithelial keratitis treated with
topical trifluridine, no apparent benefit of a 3-week course of oral acyclovir in preventing HSV
stromal keratitis or iritis was seen during the subsequent year.
Herpetic Eye Disease Study: acyclovir for the prevention of recurrent herpes simplex
virus eye disease
This study was designed to evaluate the efficacy of oral acyclovir as a prophylaxis for the
prevention of recurrent ocular HSV disease. Seven hundred three patients with a history of
ocular HSV disease within the preceding year were randomly assigned to receive 400 mg of
acyclovir (n = 357) or placebo (n = 346) orally twice daily. The study outcomes were the rates of
development of ocular or nonocular HSV disease during a 12-month treatment period and a 6month observation period. The cumulative probability of a recurrence of any type of ocular HSV
disease during the 12-month treatment period was 19% in the acyclovir group and 32% in the
placebo group. In the subset of patients with a history of stromal keratitis, the cumulative
probability of recurrent stromal keratitis was 14% in the acyclovir group and 28% in the placebo
group. The cumulative probability of a recurrence of nonocular (primarily orofacial) HSV disease
was also lower in the acyclovir group than in the placebo group (19% vs 36%). There was no
rebound in the rate of HSV disease in the 6 months after acyclovir treatment was stopped. The
study concluded that long-term oral prophylaxis is effective in reducing the rate of recurrent
ocular HSV disease and orofacial HSV disease, and is most important for the subset of patients
with a previous history of HSV stromal keratitis.
Medical Management
Treatment of HSV epithelial keratitis differs dramatically from that of HSV immune mediated
stromal keratitis.
HSV Epithelial Keratitis
Epithelial keratitis often resolves spontaneously; however, the aim of treatment is to minimize
scarring and stromal inflammation. The infected cells are poorly adherent, and a gentle wiping
debridement with a cotton tipped applicator removes nearly all infected cells without damaging
normal epithelium. Debridement results in much faster resolution and consequently less
scarring. Debridement should be performed prior to initiating drug therapy.2,11 Topical antivirals
are the drugs of choice for acute epithelial disease. Topical Viroptic (1% trifluridine) can be used
every 2 hours until the ulcer heals, followed by every 4 hours for an additional week.
Trifluridine is effective in the treatment of epithelial keratitis, but can cause significant
epithelial toxicity. It also contains thimerosal as a preservative and has a highly acidic pH that
adds to its toxicity. Another option is topical Zirgan gel (0.15% ganciclovir), used 5 times a day
until the ulcer heals, then 3 times a day for an additional week.13 Both are effective at
eliminating the ulcer and should result in complete resolution. Oral acyclovir may be another
option for both pediatric and allergic patients. A good rule of thumb is that epithelial disease
that is adequately treated but persists beyond 2 or 3 weeks is either metaherpetic
(noninfectious), caused by virus that is resistant to the antiviral agent, or due to drug toxicity.
HSV Stromal and Endothelial Keratitis
The mainstay of treatment is topical corticosteroids. Corticosteroids suppress inflammation by
interfering with the normal immunologic response to various stimuli. Interference with
lymphocyte function, migration, and the release of cellular digestive enzymes are all part of the
mechanism of action seen clinically.2,11 The use of these agents in the setting of HSV ocular
disease presents a challenge requiring both knowledge and experience. The use of antivirals is
essential in the elimination of virions in the setting of active infection. However, the benefit of
these agents when the disease has an immunologic component is controversial. Although HEDS
did not show any statistically significant difference in visual outcome with the use of
corticosteroids, they do accelerate resolution of HSV ocular infection. Simultaneous oral
antiviral prophylaxis decreases the risk of HSV reactivation at the ganglion level. Topical
corticosteroids used for the treatment of HSV stromal keratitis and uveitis are always given
under antiviral cover. Typically, 1% prednisolone acetate or 0.1% dexamethasone is used. The
dosing frequency should be based on the severity of the inflammation. On resolution of the
inflammation, the steroids need to be tapered gradually to prevent rebound inflammation.
Another option for treating immune mediated stromal disease is topical cyclosporine. 14
Cyclosporine is an immunomodulator that inhibits activation of T cells. Understanding that the
pathological mechanism of immune mediated stromal HSV is not active viral infection, but viral
antigens initiating a T-lymphocytic destruction of the stroma, helps predict the potential
success of cyclosporine. Clinical studies have documented that cyclosporine after topical
application accumulates at the ocular surface and cornea reaching concentrations that are
sufficient for immunomodulation.15 It has also been used as an alternative treatment to topical
steroids in the treatment of the inflammatory response in progressive corneal melting.
Although no long term studies have been performed, several case reports showing the efficacy
of topical cyclosporine A in prevention of immune mediated herpes stromal disease have been
published.14 The typical regimen is two times daily of topical 0.05% cyclosporine A (Restasis,
Allergan, Irvine, CA) for as long as needed to prevent reactivation.
Neurotrophic Keratitis
The basic principle of therapy for this disease is to rapidly heal the epithelial defect. Methods to
accomplish this include stopping use of toxic medications, performing punctal occlusion,
instilling tear film supplements, fitting a bandage contact lens, amniotic membrane,
tarsorrhaphy, and, if there is significant underlying inflammation, cautiously using topical
corticosteroids while watching carefully for corneal melts.2,11
Prophylaxis and Medications
Oral antivirals are typically used as systemic prophylaxis against reactivation of HSV at the
ganglion level. Topical medications are toxic with prolonged usage and are usually reserved for
acute epithelial disease. Prophylaxis is useful in patients who have multiple recurrences (two or
more in one year); those who have scarring close to the visual axis; those who are using topical
corticosteroids for stromal disease; and those who are systemically immunocompromised. For
prophylaxis of HSV infection, acyclovir is most commonly used at a dosage of 400 mg twice
daily.9,11 All the current antivirals used in the treatment of ocular HSV, are nucleoside
analogues that inhibit viral replication by competitively inhibiting viral DNA polymerase.
Systemic antivirals are used primarily for prophylaxis of recurrent disease or as an antiviral
cover during corticosteroid therapy for stromal keratitis. The three main systemic antivirals for
the treatment of HSK are acyclovir, valacyclovir, and famciclovir. They have a high therapeutic
index but resistance is an issue, especially in immunocompromised patients. Unfortunately
there is cross- resistance among these three agents.9,11,16
Long-Term Complications
Unfortunately, resolution of HSK does not protect the eye from future complications. Recurrent
disease is the major cause of the morbidity associated with HSK. Each recurrent episode causes
increased inflammation and scarring and further decreased corneal sensation. In addition, the
risk of stromal disease increases with multiple recurrences of HSV epithelial keratitis.
Even when HSK is treated promptly, scarring is common and can cause significant morbidity. A
recurrent episode usually occurs adjacent to the site of a previous episode—thus the visual axis
is invariably involved eventually. Corneal hypesthesia is a sensitive sign of previous HSK.
The lack of innervation causes poor tear production and decreased release of growth factors in
response to injury, leading to persistent epithelial defects and neurotrophic ulcers that may
melt and perforate.2
Conclusion
Dendritic and geographic epithelial ulcers are caused by live virus and are best treated with
topical antiviral medications. Stromal keratitis is an immune- mediated process and is best
treated with topical corticosteroids, with oral antiviral prophylaxis. Neurotrophic ulcers are
neither infectious nor immune- mediated and are treated with measures to promote epithelial
healing. The most important findings of HEDS were that use of topical corticosteroids shortened
the course of HSV stromal keratitis, and prophylactic treatment with oral acyclovir decreased
the risk of recurrent HSV ocular infection by 41%, which was evident in this case.
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