Ocular Herpetic Disease

1
RESEARCH PERSPECTIVE
DEBORAH PAVAN-lANgSTON, MD, FACS
CLINICAL PERSPECTIVE
TERRY KIM, MD, AND VICTOR CHANg, MD
HISTORICAL PERSPECTIVE
HERBERT E. KAuFMAN, MD
FACULTY ADVISOR MICHAEl B. RAIZMAN, MD
C A N D E O
Ccn}Scvcv Commucn:os, c
Keeping Medical Education in Sight
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university of Florida, gainesville, Fl, uSA
A Continuing Medical Education Program
Jointly sponsored by the
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Supported by an unrestricted educational grant
from Bausch + lomb, Inc.
2011 Candeo Clinical/Science Communications, llC
CME
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Find complete Continuing Medical Education information on page 2 and the Examination on page 20.
2
STATEMENT OF NEED
Herpes simplex keratitis remains a signifcant
cause of blindness and a leading indication for
corneal transplant.
1
Even relatively moderate
cases can prove extremely painful and lead to
corneal scarring. In patients with latent herpes
simplex type 1 (HSV1), a number of ophthal-
mic procedures and medications are known
to create a predisposition to ocular outbreaks.
Moreover, each recurrence increases the risk of
sight-threatening complications.
2-4
At the same
time, leading experts in herpes keratitis have
noted a significant educational gap among
ophthalmologists in terms of their ability to
proactively identify patients with prior history of
ocular herpesyet this is a critical step toward
maximizing prophylaxis prior to performing
any of the invasive procedures or intense UV
light exposures known to trigger recurrences.
2,3
Another educational gap exists pertaining to the
emerging standard of care that calls for lifelong
prophylaxis for patients who experience two or
more occurrences of herpes keratitis.
5
Pertinent to this use, many patients may fnd a
topical drop preferable to long-term systemic
(oral) medication. In Europe and elsewhere out-
side the United States, ophthalmologists have
long used both oral and topical antiviral agents
to help prevent herpes keratitis in their patients.
6

By contrast, until recently, no topical ocular
antiviral has been available in the United States
with the exception of trifuridine, which many
ophthalmologists avoid because of its toxicity to
the ocular surface.
This has now changed with the recent introduc-
tion of ganciclovir 0.15% gel, FDA approved for
the treatment of herpes keratitis. The availability
of this new agent opens up possibilities for US
ophthalmologists wanting an effective, less
toxic, and more comfortable topical antiviral for
their patients. Moreover, recent clinical studies
suggest that ganciclovir gel is effective in treat-
ing adenovirus and varicella-zoster infections
of the eye.
7-9
These results and their relevance
to clinical practice warrant exploration by US
ophthalmologists.
The proposed enduring material will educate US
ophthalmologists about perioperative and/or
lifelong prophylaxis in patients with a history of
herpes keratitis. It will likewise provide the most
current information on the potential uses and ef-
fcacy of ganciclovir 0.15% ophthalmic gelnot
only in regards to prophylaxis of herpes keratitis,
but also in the treatment of other viral eye infec-
tions. It will draw on research and clinical experi-
ence both within and outside the United States.
Additionally, it will feature the perspectives of
leading experts on the treatment and prevention
of sight-threatening herpetic infections as well as
other viral ocular infections against which topical
ganciclovir has shown effcacy.
REFEREncES
1. Liesegang TJ. Herpes simplex virus epidemi-
ology and ocular importance. Cornea. 2001
Jan;20(1):1-13.
2. Kurbanyan K, colby K. cataract and refractive
surgery in herpetic eye disease. Int Ophthal-
mol Clin. 2010;50(1):13-24.
3. Hassan M, Patel DK, Subrayan V. Primary
herpes virus keratitis after penetrating kerato-
plasty. Ann Ophthalmol. 2009;41(3-4):203-5.
4. Rao A, Tandon R, Sharma n, Sihota R, Gupta
V, Dada T. Herpetic keratitis and keratouveitis
after mitomycin-c use in glaucoma fltering
surgery: a short case series. Eur J Ophthalmol.
2009;19(6):1088-90.
5. Lairson DR, Begley cE, Reynolds TF, Wilhelmus
KR. Prevention of herpes simplex virus eye
disease: a cost-effectiveness analysis. Arch
Ophthalmol. 2003;121(1):108-12.
6. colin J. Ganciclovir ophthalmic gel, 0.15%:
a valuable tool for treating ocular herpes.
Clinical Ophthalmol. 2007;1(4):44153.
7. Kinchington PR, Romanowski EG, Jerold Gor-
don Y, et al. Prospects for adenovirus antivi-
rals. J Antimicrob Chemother. 2005;55:4249.
8. Tabbara KF. Ganciclovir effects in adenoviral
keratoconjunctivitis. Poster B253. Presented
at ARVO 2001. Fort Lauderdale, Florida.
9. Kim SJ, Equi R, Belair ML, Fine HF, Dunn
JP. Long-term preservation of vision in pro-
gressive outer retinal necrosis treated with
combination antiviral drugs and highly active
antiretroviral therapy. Ocul Immunol Infamm.
2007;15(6):425-7.
OFF-lAbEl USE STATEMENT
This work discusses off-label uses of antiinfective
medications.
GENErAl INFOrMATION
This cME program is sponsored by the Uni-
versity of Florida college of Medicine and is
supported by an unrestricted educational grant
from Bausch + Lomb, Inc.
Directions: Select one answer to each question
in the exam (questions 1-10) and in the evalua-
tion (questions 11-16). The University of Florida
college of Medicine designates this activity for a
maximum of 2.0 AMA PRA Category 1 Credits.
There is no fee to participate in this activity. In
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read the report, and then take the posttest. A
score of 80% is required to qualify for cME
credit. Estimated time to complete the activity is
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University of Florida cME Offce
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Gainesville, FL 32610-0233
Or you can take the test online at http://cme.
uf.edu/XXXXXXXX.
DATE OF OrIGINAl rElEASE
January 2011. Approved for a period of 12
months.
AccrEDITATION STATEMENT
This activity has been planned and implemented
in accordance with the Essential Areas and Poli-
cies of the Accreditation council for continuing
Medical Education (AccME) through the joint
sponsorship of the University of Florida col-
lege of Medicine and candeo clinical/Science
communications, LLc. The University of Florida
college of Medicine is accredited by the AccME
to provide continuing medical education for
physicians.
crEDIT DESIGNATION STATEMENT
The University of Florida college of Medicine des-
ignates this educational activity for a maximum
of 2.0 AMA PRA Category 1 Credits. Physicians
should only claim credit commensurate with
the extent of their participation in the activity.
TArGET AUDIENcE
This educational activity is intended for ophthal-
mologists and ophthalmologists in residency or
fellowship training.
lEArNING ObJEcTIVES
As a result of participation in this activity, partici-
pants will be able to:
1. List the agents currently available for the
prevention of herpes keratitis outbreaks as-
sociated with ocular surgery and state the
advantages and disadvantages of each.
2. compare and contrast oral vs topical admin-
istration of antiviral medication for prevention
of ocular HSV1 recurrences.
3. List the factors believed to trigger ocular HSV1
recurrences and state prophylactic options
appropriate to each.
4. Discuss available options for the treatment of
ocular infection with adenovirus and varicella-
zoster virus.
FAcUlTY AND DISclOSUrE STATEMENTS
Victor chang, MD, is a former chief resident
at the cullen Eye Institute, of the Baylor college
of Medicine, and is currently a clinical fellow of
cornea, external disease, and refractive surgery
at the Duke Eye center, in Durham, north
carolina. He states that in the previous twelve
months he has not had a fnancial relationship
with any commercial organization that produces,
markets, re-sells, or distributes health care goods
or services consumed by, or used on patients.
Herbert E. Kaufman, MD, is the emeritus Boyd
professor of ophthalmology, pharmacology, and
experimental therapeutics at the Louisiana State
University Eye center. He states that in the previ-
ous twelve months he has worked as a consultant
for ReSearch Pharmaceutical Services, Inc.
Terry Kim, MD, is a professor of ophthalmology
at the Duke University School of Medicine and
the associate director of corneal and refractive
surgery services at the Duke Eye center, in Dur-
ham, north carolina. He states that in the past
twelve months he has been a consultant to Alcon,
Allergan, Inspire, ISTA, OSI, Ocular Therapeutics,
Pfzer, and PowerVision.
Deborah Pavan-langston, MD, FAcS, is
professor of ophthalmology at Harvard Medical
School, director of clinical virology at Harvards
Massachusetts Eye and Ear Infrmary, and a clini-
cal research consultant at the affliated Schepens
Eye Research Institute. She states that in the pre-
vious twelve months she has not had a fnancial
relationship with any commercial organization
that produces, markets, re-sells, or distributes
health care goods or services consumed by, or
used on patients.
Michael b. raizman, MD (Faculty Advisor),
is a cornea specialist at Ophthalmic consultants
of Boston. He is co-director of the cornea and
cataract service and director of the cornea
fellowship and the uveitis and immunology
service at the new England Eye center. He is
also an associate professor of ophthalmology
at Tufts University School of Medicine, Boston.
He states that in the past twelve months he has
received research support from Alcon and has
been a consultant to Alcon and Bausch + Lomb.
DISclAIMEr
Participants have an implied responsibility to
use the newly acquired information to enhance
patient outcomes and professional development.
The information presented in this activity is not
meant to serve as a guideline for patient care.
Procedures, medications, and other courses of
diagnosis and treatment discussed or suggested
in this activity should not be used by clinicians
without evaluation of their patients conditions
and possible contraindications or dangers in use,
applicable manufacturers product information,
and comparison with recommendations of other
authorities.
cOMMErcIAl SUPPOrTErS
This activity is supported by an educational grant
from Bausch + Lomb, Inc.
Advances in the Management of Ocular Herpetic Disease
3
Ongoing research is revealing the many factors
that lead to the development and progression
of herpetic ocular disease, the leading infec-
tious cause of corneal blindness in the devel-
oped world. These ndings, combined with the
results of clinical trials of antiherpetic therapies,
can guide the clinician in diagnosing, treating,
and in some cases, preventing these sight-threat-
ening infections.
Of the eight herpes viruses that infect humans,
fve cause signifcant ocular disease. They are herpes sim-
plex types I and II (HSV-1 and HSV-2), varicella-zoster
(VZV), cytomegalovirus (CMV), and Epstein-Barr virus
(EBV). Typically, herpetic infection is lifelong, with the
initial infection followed by periods of latency. To date,
research has only partially revealed the complex fac-
tors involved in the reactivation of latent herpes virus.
Ocular diseasewhether associated with primary infec-
tion or secondary reactivationcan take the form of
blepharitis, conjunctivitis, epithelial keratitis, stromal
(or endothelial) keratitis, or uveitis.
HSV keratitis is the most familiar of the ocular
herpetic diseases and the single most common in-
fectious cause of corneal blindness in the developed
world.
1
However, herpes zoster ophthalmicus, or ocular
shingles, appears to be increasing in incidence and per-
haps morbidity, particularly in older patients. Indeed,
herpes zoster can cause more damage to the cornea
than does HSV.
2,3

CMV is most associated with severe retinitis in
immunocompromised individuals. But recent reports
suggest it is a more common cause of corneal endotheli-
itis and iritis in the immunocompetent population than
previously realized.
4,5
Finally, the Epstein-Barr virus is
associated with a range of ocular complications, from
relatively inconsequential conjunctivitis to keratitis,
uveitis, or optic neuritis.
6,7
Despite the prevalence of herpetic ocular disease
and its ability to cause signifcant morbidity, many clini-
cians lack awareness of these infections and the latency
and reactivation factors that can trigger recurrence and
progression. A deeper understanding of this family of
viruses can guide differential diagnosis, prevention,
and management of both active infection and associ-
PART ONE: The Research Perspective
Advances in the Management
of ocular herpetic disease
ated infammatory damage. It can also help the clini-
cian protect the silently infected patient who may be
at elevated risk of ocular disease triggered by a variety
of stress-related factors and ophthalmic procedures.
HErPES SIMPlEX
HSV is globally endemic. Historical references ex-
tend at least as far back as Hippocrates, whose descrip-
tion of spreading skin lesions gave us the Latinized herpes
from the Greek herpion, to crawl.
8
Humans are the only
natural reservoir of HSV. HSV-1 is most associated with
lesions in the facial area; HSV-2 with genital outbreaks.
Initial infection typically results from direct or
indirect contact with lesions or the salivary droplets
(HSV-1) or genital secretions (HSV-2) of a virus-shedding
carrier.
9
Common iatrogenic sources include the physi-
cians unwashed hands and contaminated tonometer
heads. HSV remains viable for up to 2 hours on a dry
tonometer head, up to 8 hours if the instrument is
Deborah Pavan-langston, MD, FAcS
FIguRE 1
Herpes simplex type I and Herpes zoster both establish
latency in the ganglion of the trigeminal nerve, which
innervates the eye, periorbital area, forehead, and lips.
(Image: Grays Anatomy.)
4
moist. Dry wiping and ophthalmic solutions such as
anesthetics have little antiviral effect, but swabbing
with 70% isopropyl alcohol is fully viricidal.
10

Following initial infection, HSV-1 establishes
lifelong latency in the trigeminal ganglion near the
ventral area of the brain stem (Figure 1).
11
On reactiva-
tion, virus travels back down the trigeminal nerve, most
commonly to the site of original infection (typically the
lips), but with diversions possible to other trigeminally
innervated tissues, including the eye.
12

cHANGING EPIDEMIOlOGY
HSV-1 was once almost universally acquired in
infancy and still appears to be so in developing nations.
But epidemiological studies suggest that primary acqui-
sition of HSV-1 is becoming progressively delayed in
industrialized countries. German researchers identify-
ing HSV-1 in the trigeminal ganglia of cadavers found
it in just 18% of those under 20 years of age, but more
than 90% of those age 60 or older.
13
Other studies have
documented an epidemic increase in HSV-2, with ap-
proximately one in four Americans over age 30 geni-
tally infected and a corresponding rise in potentially
blinding neonatal infections.
14,15
Epidemiological studies in Minnesota suggest
that approximately 500,000 Americans have developed
ocular HSV disease, with about 20,000 new cases and
28,000 recurrences diagnosed each year.
16
Breakdown of
the Minnesota data suggests that approximately 72% of
ocular simplex disease involves the corneal epithelium;
41%, the lid or conjunctiva; 12%, the corneal stroma;
and 9%, the iris and associated uveal tract.
A recent retrospective study at the Cullen Eye
Institute documented recurrence rates in children simi-
lar to those in adults, though with higher risk of bilat-
eral involvement (26%).
17
The transmission of HSV by
corneal transplant is a dreaded cause of primary graft
failure.
18,19

rEAcTIVATION AND OcUlAr INVOlVEMENT
Most ocular herpetic infections stem from reacti-
vation of latent virus, with or without associated cold
sores around the mouth or nose. Though latent in-
fection is near ubiquitous in the adult population, less
than a third of immunocompetent adults experience
clinical disease, and a still smaller subset is prone to
frequent recurrence. HSV-1 strains clearly vary in their
predisposition to breaking latency.
20
Studies have like-
wise revealed human gene variations that predispose
individuals to recurrences.
21,22

In addition, research has identifed a variety of
reactivation triggers including hormonal fuctuations,
immune suppression, systemic illness, stress, lack of
sleep, shoulder stiffness, physical fatigue, and local tis-
sue damage, including subclinical cell damage caused
by exposure to ultraviolet light.
23,24
As noted in a study
by Shimomura, many patients report that psychologi-
cal stress is a signifcant predictor of recurrence.
24
The
Herpes Eye Disease Study (HEDS) failed to corroborate
this association and attributed it to recall bias.
25

Of particular importance to ophthalmology is
the realization that intense light exposure can trigger
herpetic ocular disease and may partially explain its
postoperative incidence after LASIK and PRK proce-
dures.
23,26,27
The local trauma of invasive procedures
such as cataract removal and lamellar keratoplasty
likewise carry the risk of this complication.
23,28
Risk ap-
pears to be highest for patients who have previously
experienced ocular herpes. However, patients without
such a history can also present with this complication
following ophthalmic surgery, and a patient history of
frequent labial or nasal herpes may indicate a general
predisposition to reactivation.
Ocular steroids themselves do not appear to trig-
ger reactivation of the herpes virus, but if reactivation
CORE CONCEPTS
Most adults harbor latent herpes simplex and
zoster in the trigeminal ganglia. Reactivated
viruses can follow innervation paths to cause sight-
threatening ocular disease.
Patients vary in their predisposition to HSV
reactivation. common triggers include systemic
illness, local trauma (eg, ocular surgery), and
UV light, including strong sunlight and laser
procedures.
Initial HSV ocular disease tends to be limited to
superfcial dendritic keratitis, while subsequent
recurrences can trigger sight-threatening stromal
infammation.
Research confrms a role for topical antiherpetic
drugs for treating HSV epithelial keratitis. Oral
antiherpetics are used for both the treatment of
stromal disease and the prevention of recurrent
ocular disease.
The incidence of herpes zoster disease is increasing
in the adult population; individual susceptibility
increases with age due to waning cellular
immunity.
The eye is the second most common site of
zoster disease, which may be even more sight-
threatening than HSV infection.
Though rare, cMV anterior segment disease in
the immunocompetent is more common than
previously thought.
Symptomatic EBV infection (mononucleosis) can
include a range of ocular manifestations, from
conjunctivitis to keratitis.
AdvAnces in the MAnAgeMent of oculAr herpetic diseAse pArt one: the reseArch perspective
5
occurs in the presence of steroids, an unusually aggres-
sive disease can result.
29,30
PrIMArY VS rEcUrrENT DISEASE
HSV can cause a wide array of ocular disease (Table
1). As mentioned, most ocular disease involves reacti-
vation of latent HSV. But primary ocular infections are
not uncommon. Typically they involve rapidly spread-
ing viral dendrites or geographic ulcers in the corneal
epithelium because there is no antibody in the tear
flm to contain the virus. More distinctively, there is
no associated immune reaction to cloud the stroma or
deeper ocular tissues.
By contrast, recurrent infection can unfold against
the background of a hypersensitive immune response.
In many cases, the secondary disease remains confned
to the epithelium in the form of infectious dendrites
or geographic ulcers. In other cases, however, the im-
mune reaction causes stromal edema, with invasion by
lymphocytes, macrophages, and other white cells. This
stromal immune reaction and its frequently associated
corneal scarring pose the greatest lasting threat to vision.
Studies suggest that 10% of patients with epi-
thelial keratitis will go on to experience stromal dis-
ease within a year, and patients with a history of mul-
tiple recurrences remain at increased risk for future
recurrences.
1,31
TrEATMENT ADVANcEMENTS
By the 1980s, trifuridine had become the pre-
ferred topical treatment of infectious epithelial HSV
keratitis in the United States, surpassing older antivirals
such as idoxuridine and vidarabine.
32,33
The mecha-
nism of action of all three drugs was a mild to moder-
ately toxic, non-specifc targeting of viral and cellular
enzymes and DNA in infected and non-infected cells
alike, with clinician and patient preference favoring
trifuridine for its drop formulation and equal to supe-
rior therapeutic effectiveness.
33-35

That widespread preference has changed with
the FDA approval of topical ganciclovir ophthalmic
gel 0.15%, owing to ganciclovirs therapeutic effcacy
and low toxicity, which relate to its specifc targeting
of viral DNA in infected cells.
36
In Europe, acyclovir 3%
ointment is an additional option, with studies showing
equal effcacy to ganciclovir gel but lower patient toler-
anceowing largely to ointment-associated blurring.
37
By the late 1980s, research had demonstrated
the superiority and ease of oral antiviral drugs for the
treatment of infectious herpetic keratitis and the inhi-
bition of recurrent HSV infectious disease. This proved
particularly important when topical steroids were being
used to treat stromal disease, scleritis, episcleritis, and
iritis. Today, available oral antiherpetic drugs include
acyclovir, valacyclovir, and famciclovir, all of which
demonstrate low toxicity to uninfected cells as they
Table 1 Classifcation of ocular HSV disease
I. Primary Infection
A. neonatal
B. Primary (children, adults)
II. Recurrent Infection
A. Blepharitis
B. conjunctivitis, scleritis
c. Dendritic or geographic epithelial keratitis
D. Sterile corneal neurotrophic ulceration
E. Stromal keratitis (primarily immune)
F. Endotheliitis/trabeculitis (primarily immune)
G. Iridocyclitis (primarily immune)
are specifcally activated by HSV- and HZV-induced en-
zymes such as thymidine kinase and DNA polymerase.
38

The frst and most extensively studied oral anti-
viral is acyclovir.
39-41
No large controlled studies have
compared acyclovir with newer drug analogs such as
valacyclovir or famciclovir, but these newer drugs offer
clear advantages for case management. Studies show,
for example, that valacyclovir has fve times acyclovirs
bioavailability and that famciclovir has a longer intra-
cellular half-life than acyclovir.
42,43
(See also, Table 2:
FDA-approved antiviral agents for ocular disease.)
HEDS confrmed the value of combining oral
antiherpetic therapy with topical corticosteroids in
treating HSV stromal disease and iritis.
44
The study
employed a 10-week, tapered regimen of topical corti-
costeroid. Compared to placebo, treatment produced
more rapid resolution and a lower likelihood of disease
progression. More recent research suggests that cyclo-
sporine may be useful in controlling herpetic infam-
mation without the steroid-associated risk of elevating
intraocular pressure.
45

PrEVENTION
When it comes to preventing the recurrence of
ocular herpetic disease, our best guidance comes from
ongoing HEDS trials and the recent Minnesota study
on incidence, recurrence, and outcome of HSV eye
disease.
16,44
Some of the most recent HEDS fndings
include the ability of oral acyclovir to reduce the re-
currence rate of all types of ocular HSV (19% recur-
rence over 1 year with acyclovir vs 32% with placebo).
Importantly, acyclovir maintenance therapy halved the
annual recurrence rate of vision-threatening stromal
disease (14% with acyclovir vs 28% with placebo).
46

When used for long-term antiviral prophylaxis, both
acyclovir and valacyclovir have been shown to decrease
the risk of recurrent conjunctivitis, epithelial keratitis,
stromal keratitis, and blepharitis, and to signifcantly in-
hibit recurrent HSV in post-operative, HSV-penetrating
keratoplasty.
16,32,47-49
6
In addition, a number of animal studies and
uncontrolled patient series suggest that perioperative
prophylaxis with oral acyclovir or valacyclovir can sig-
nifcantly reduce the incidence of laser-induced HSV
reactivation.
26,50,51
There is great interest in developing a vaccine
able to prevent either primary infection or recurrent
disease. But to date, neither passive nor active immu-
nization has produced signifcant protection in animal
models.
14,52,53
HErPES ZOSTEr OPHTHAlMIcUS (HZO)
Herpes zoster, or shingles, is caused by reactiva-
tion of the varicella virus that causes chickenpox. When
this reactivation involves latent virus in the trigeminal
ganglion, the result can be herpes zoster ophthalmicus
(HZO). Approximately 20% of the worlds population
suffers from herpes zoster at least once in a lifetime,
and 10% to 20% of these people experience ophthal-
mic involvement.
54
Indeed, the eye is the second most
common disease site, second only to the torso. Adding
to the insult, cadaver studies show that trigeminal co-in-
fection with herpes simplex and varicella is common.
55
Two factors are expected to signifcantly increase
Table 2 FDA-approved antiviral agents for ocular disease
The ideal antiherpetic agent interrupts viral replication at a critical step without affecting the hosts cellular metabolism.
These targeted steps include viral adsorption, penetration, uncoating, viral genome transcription, synthesis of viral
proteins, and viral release. cell attachment and penetration require interaction between viral structures and cellular
membranes. Uncoating is typically accomplished by cellular enzymes and infuenced by viral proteins. Viral transcription
likewise is performed by the cell but under the infuence of virus-specifc proteins. Key proteins include virus-specifc
thymidine kinase and DnA polymerase. Herpes viruses acquire host-derived nuclear membranes before migration to
the cell surface for release. current antiherpetic therapy and research focuses on these functions, targeting components
such as enzymes that are more specifc to the herpes virus than to the infected cell.
Antiherpetic agents Mechanisms of action Target viruses
Trifuridine
(pyrimidine nucleoside)
non-specifcally inhibits viral and
cellular thymidylate synthetase
blocking DnA thymidine uptake
HSV-1, HSV-2
Acyclovir
(acyclic pyrimidine
nucleoside)
Preferential substrate for viral
thymidine kinase other enzymes
AcV-tri-PO4 viral DnA chain
termination. Poor GI uptake
HSV-1, HSV-2, VZV, EBV cMV
Valacyclovir
(1-valine ester of acyclovir)
Same as acyclovir. Enhanced GI uptake HSV-2, HSV-1 VZV, EBV HHV 68, cMV
Famciclovir
(acyclic guanine derivative)
Same as acyclovir HSV-1, HSV-2, VZV, EBV
Ganciclovir
(acyclic purine nucleoside)
competes with deoxyguanosine for
incorporation into viral DnA and DnA
chain growth
cMV, HSV-1, HSV-2, VZV, EBV
Abbreviations: cMV, cytomegalovirus; EBV, Epstein-Barr virus; HHV, human herpesvirus; HSV, herpes simplex virus; VZV, varicella-zoster virus.
(Adapted from Pavan-Langston D, John T. Ocular Antivirals. In: Albert D, Miller J, eds. Principles and Practice of Ophthalmology, 3
rd
ed., Philadelphia:
Saunders;2008:215-22.)
zosters incidence in the coming years. The frst is the
demographic aging of the U.S. populationvaricella
activation being strongly associated with the waning
of cell-mediated immunity in old age.
54

The second is the introduction of the chickenpox
vaccine to the early childhood immunization schedule.
While of huge beneft to our children and future genera-
tions, this has removed the immunological booster
that exposure to actively infected children historically
provided parents and other adults. A recent Australian
study found herpes zoster rates in adults age 40 and
older have been increasing 2% to 6% a year since the
2005 introduction of childhood varicella immuniza-
tion in that country.
56

The good news is that an effective zoster vaccine is
now available for adults.
57
It has been shown to decrease
both the incidence of zoster and the severity of post-her-
petic pain by 50% to 60%.
58
However, the vaccines FDA-
approval (and associated insurance coverage) remains
limited to persons age 60 and older. This is unfortunate,
as those in their 40s and 50s are likewise at elevated risk.
Indeed, herpes zoster can manifest at any age, though in-
cidence rises dramatically after age 60. Beyond age, risk
factors include Caucasian ethnicity, female gender, ge-
7
netic susceptibility, immune suppression, local trauma,
and possibly psychological stress and depression.
59,60
OcUlAr MOrbIDITY
HZOs high ocular complication rate may render
it even more vision threatening than HSV (Table 3). Its
potential complications include dermatomal vesicular
rash and severe pain, viral shedding, acute dendritiform
or geographic corneal ulcers, anesthetic neurotrophic
ulcers (which may perforate), corneal stromal immune
keratitis, scleritis, episcleritis, iritis, and recurrent ocu-
lar infammatory disease, such as episcleritis, scleritis,
iritis, or corneal ulceration.
32,61
On occasion a patient
may have dermatomal pain and/or iritis associated with
zoster sine herpete, or reactivated VZV without the
classic rash or keratitis.
62

In particular, research suggests more corneal nerve
damage with zoster disease than with simplex, result-
ing in a greater frequency of anesthetic corneas and ex-
tensive scarring.
61
Chief among zosters other sequelae
is post-herpetic neuralgia emanating from local and
central nervous system damage. It can range in sever-
ity from mild and transient to enduring and intractable
pain in the area of the affected dermatome.
54,63
Recent
research suggests that post-herpetic neuralgia affects
10% to 20% of herpes zoster patients over age 50 and
up to 30% of those over age 80.
64

Research has demonstrated that prompt, high-
dose treatment with oral antivirals can signifcantly
reduce the incidence, severity, and sequelae of HZO.
32,58
Unfortunately, ineffective and inadequate treatment is
common given the tendency of nonspecialists to mis-
take zosters pseudodendritic presentation for the less
treatment-resistant herpes simplex. (See The Clinical
Perspective for differential diagnosis and treatment.)
Zosters high complication rate has inspired a
number of studies comparing the effcacy of treatment
with high-dose acyclovir, valacyclovir, or famciclovir.
Though a number of early studies showed equiva-
lence, several recent clinical trials have demonstrated
the superiority of valacyclovir and famciclovir in re-
ducing the incidence of post-herpetic neuralgia.
63-66

Valacyclovir and famciclovir also lend themselves to
greater patient compliance at the high dosages needed
to manage zoster. Topical ophthalmic antivirals such as
ganciclovir gel may be a helpful adjunct to treatment
when dendritic outbreaks prove resistant to oral drugs.
Studies show topical corticosteroids to be use-
ful in managing associated stromal immune disease
and endotheliitissuppression of which is crucial for
preserving corneal clarity.

Importantly, steroids do not
appear to exacerbate HZO.
32
cYTOMEGAlOVIrUS
CMV silently infects an estimated 50% to 80%
of adults in the United States.
67
Initial infection typi-
cally goes unnoticed, although the virus can produce a
glandular-fever syndrome. Unlike herpes simplex and
zoster, cytomegalovirus does not persist in neurogan-
glia, but establishes latency in white blood cells such
as T lymphocytes and monocytes.
CMVs most common ocular manifestation is
chorioretinitis in the immunocompromised patient.
68

Prior to antiretroviral therapy, up to 45% of AIDS pa-
tients developed blinding CMV infections. Intravenous
ganciclovir often proved effective, though effcacy
plummeted in severely immunocompromised patients.
Fortunately, effective antiretroviral therapy (HAART)
has dramatically reduced the toll of AIDS, including
this ocular complication.
69
Recently, it has become clear that corneal and iris
CMV infection is more common in immunocompetent
patients than previously thought. These infections can
mimic herpes simplex or zoster stromal disease.
68,70
The
key difference is that CMV keratitis involves the deepest
layers of the cornea (endotheliitis), while ocular sim-
plex and zoster tend to involve superfcial and middle
stroma.
70
Holland and others have reported transmis-
sion of CMV by corneal transplantation.
71
Diagnosis of this endotheliitis requires tapping
the anterior chamber for evidence of cytomegalovi-
rus DNAa procedure currently restricted to major
medical centers. CMV does not respond to acyclovir
but is responsive to topical and systemic ganciclovir.
Observation periods are long, ranging up to 14 months.
Table 3
Herpes zoster: incidence of
corneal complications*
Finding Incidence
Punctate epithelial keratitis 51%
Pseudodendrites (acute) 50%
Anterior stromal infltrates 41%
Keratouveitis, endotheliitis 34%
neurotrophic keratitis 25%
Delayed mucous plaques
(pseudodendrites)
13%
Exposure keratitis 11%
Disciform keratitis 10%
Serpiginous ulceration 7%
Scleral keratitis 1%
Delayed limbal vasculitis <1%
*Adapted from Leisegang T. corneal complications from herpes zoster
ophthalmicus. Ophthalmology. 1985;92:316-24.
8
EPSTEIN-bArr VIrUS
The Epstein-Barr virus (EBV) is likewise globally
endemic, infecting up to 95% of the worlds population.
Like cytomegalovirus, EBV establishes lifelong latency
in white blood cells.
72

Infection in early childhood tends to be asymp-
tomatic. In adolescence and adulthood, it can cause
infectious mononucleosis. The ocular manifestations
of overt mononucleosis can include conjunctivitis,
scleritis, and dendritic epithelial keratitis, stromal ker-
atitis, and iritis.
73,74
In the absence of mononucleosis,
Epstein-Barr ocular disease is rare and associated with
relatively low-grade infammation and minor scarring
of the anterior cornea.
Deborah Pavan-Langston, MD, FACS, is professor of ophthal-
mology at Harvard Medical School, director of clinical virology
at Harvards Massachusetts Eye and Ear Infrmary, and a clini-
cal research consultant at the affliated Schepens Eye Research
Institute. She states that in the previous twelve months she has
not had a fnancial relationship with any commercial organiza-
tion that produces, markets, re-sells, or distributes health care
goods or services consumed by, or used on patients.
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10
The human herpes viruses include several that can
produce severe ocular disease, herpes simplex and
varicella-zoster being chief among them. recent
therapeutic advances have enhanced our ability to
treat and prevent herpetic ocular disease. but optimal
use of these agents still depends on the clinicians
ability to distinguish both the type of herpes virus
involved and the nature of the ocular manifestation.
As corneal specialists we see an average of fve
to ten cases of ocular herpetic disease each month,
and ophthalmologists with more diversifed practices
likely see fewer cases. Nonetheless, ocular herpespar-
ticularly disease due to herpes simplex virus (HSV)
is rightly infamous as the leading cause of infectious
corneal blindness in the developed world, and many
of the cases we see involve scarring extensive enough
to warrant corneal transplantation.
Prompt diagnosis and appropriate treatment are
vital to preventing such outcomes. The good news is
that treatment options have expanded and improved
in recent years. The Herpetic Eye Disease Study (HEDS)
demonstrated that oral acyclovir can reduce the recur-
rence of ocular herpes simplex, and last year brought
the US introduction of ganciclovir gel, our frst new
topical drug for herpetic eye disease since the advent
of trifuridine in the 1970s. Ganciclovir gel is a particu-
larly welcome addition, as it requires less frequent dos-
ing and lacks trifuridines potential for ocular toxicity.
PART TWO: The Clinical Perspective
Terry Kim, MD, and Victor chang, MD
But diagnosis and differentiation of herpetic
infections remain challenging. The pseudodendrites
of herpes zoster, for example, can resemble the den-
drites of herpes simplex on cursory examination. And
a patient presenting with diffuse or multifocal stromal
infammation may be actively infected with HSV, vari-
cella-zoster virus, or rarely cytomegalovirus (CMV) or
Epstein-Barr virus (EBV) (Table 1). As treatment regi-
mens differ for these herpes viruses, proper diagnosis
is crucial. In the following pages, we will review ad-
vances in the diagnosis and treatment of herpetic eye
infections and the damaging stromal infammation
they can leave behind.
HErPES SIMPlEX
Primary HSV infection begins with the virus enter-
ing compromised skin or mucous membrane. Many pri-
mary infections remain subclinical. Others cause local-
ized vesicular eruption, with or without accompanying
fever. After initial infection of trigeminally innervated
tissues, HSV type 1 migrates up the trigeminal nerve
to establish latency in its ganglion. (HSV-2 generally
establishes latency in the ganglion of the sacral nerve.)
Following reactivation, HSV travels back down
the axon to cause an eruption of new lesions. Most
often, the reactivated disease involves the original in-
fection site. But HSV-1 can travel down any of the tri-
geminal nerves facial pathways, including those leading
to the eye. Around 90% of patients who develop HSV
Table 1 The human herpes viruses and ocular disease
Name Ocular disease Other manifestations
Herpes simplex virus-1
Blepharitis, conjunctivitis, keratitis,
anterior uveitis, retinal necrosis
Oral (fever blisters), encephalitis
Herpes simplex virus-2
Genital/anal lesions, severe neonatal infections,
meningitis
Varicella-zoster virus
chickenpox (primary infection), shingles
(reactivation)
Epstein-Barr virus Epithelial and stromal keratitis
Infectious mononucleosis (primary infection),
lymphoma, nasopharyngeal carcinoma
cytomegalovirus Epithelial and stromal keratitis, retinitis
Disseminated infections in the
immunocompromised patient
11
keratitis recover with 20/40 acuity or better. But 3% to
5% are left with 20/100 or worse.
1
In recent decades, an epidemic increase in genital
herpetic infections has made HSV-2 a major cause of
neonatal ocular herpes. Moreover, this strain appears
to be more associated with acute retinal necrosis syn-
drome than is HSV-1.
1
Presentation
The great majority (~90%) of ocular herpes simplex
infections present unilaterally. Indeed, bilateral presen-
tation suggests an immunocompromised state. We can
classify herpes infections by their presentation (Figure 1):
Eyelid/Conjunctiva
HSV dermatoblepharitis can result from either
primary infection or reactivation of latent virus. The
skin lesions appear as vesicular eruptions of the eyelid
or lid margin, occasionally accompanied by lymphatic
swelling and pain (Figure 2). The lesions typically heal
without scarring, but in some cases dermatoblepharitis
can progress to conjunctivitis and keratitis.
CORE CONCEPTS
Herpetic eye disease remains the leading cause
of infectious corneal blindness in the developed
world.
Five types of herpes viruses can cause ocular
disease, and differentiating between them can be
key to appropriate treatment.
The HEDS trials settled many of the controversies
surrounding the treatment of ocular herpes
simplex.
Since the HEDS trials, treatment advances for
ocular HSV have included more effective oral
antiviral medications (valacyclovir and famciclovir)
and a less toxic, more patient-friendly topical drug
(ganciclovir ophthalmic gel).
FIguRE 2
HSV dermatoblepharitis. (courtesy Wills Eye Hospital.)
HSV conjunctivitis can produce a follicular re-
action indistinguishable from mild forms of adenovi-
rus conjunctivitis. However, unlike adenovirus, HSV
conjunctivitis rarely forms pseudomembranes. The
presence of dendrites on the conjunctiva can help
confrm this diagnosis. With recurrence, conjunctivi-
tis may occur without eyelid or corneal involvement;
therefore HSV should be included in the differential
diagnosis when patients present with follicular con-
junctivitis alone.
Epithelial Keratitis
HSV epithelial keratitis may initially manifest as
corneal vesicles. These small, raised, clear vesicles rep-
resent the corollary to the vesicular lesions that can
develop on skin and mucous membranes. Fluorescein
aids visualization by pooling around the raised epi-
thelial vesicles.
As the vesicular lesions of HSV progress, they co-
alesce to form the classic herpes dendritic ulcer with its
branching shape and terminal bulbs. The raised edges
of the dendritic lesion are comprised of swollen epithe-
lial cells containing live virus (Figure 3). In differentiat-
ing herpes simplex from varicella-zoster keratitis, keep
in mind that zoster lesions appear as tapering lines
of heaped up epithelium without central ulceration
(Figure 4). Fluorescein and vital dyes (eg, rose bengal
PRIMARY INFECTION
DERMATOBLEPHARITIS
STROMAL
KERATITIS:
Immune
Stromal
Necrotizing
ENDOTHELIITIS:
Disciform
Diffuse
Linear
EPITHELIAL
KERATITIS:
Vesicular
Dendritic
Geographic
Marginal
IRIDOCYCLITIS
POSTERIOR
UVEITIS
CONJUNCTIVITIS
LATENCY
FIguRE 1
clinical forms of ocular herpes.
AdvAnces in the MAnAgeMent of oculAr herpetic diseAse pArt two: the clinicAl perspective
12
Findings range from mild epithelial irregularity to mac-
roulceration. The latter may be confused with an HSV
geographic ulcer; but unlike the amoeboid shape of a
geographic ulcer, neurotrophic ulcers appear oval or
round. These ulcers may be associated with stromal thin-
ning and scarring. Since the fndings of neurotrophic
keratopathy may be mistaken for active viral activity,
the clinician may inadvertently prolong the course of
topical antiviral agents, resulting in delayed healing if
the antiviral agent has associated epithelial toxicity.
Stromal Keratitis
Although HSV epithelial and endothelial disease
may result in stromal infammation, primary HSV stro-
mal keratitis can be divided into immune stromal (or
interstitial) and necrotizing types. Immune stromal
keratitis results from an antigen-antibody response and
appears as unifocal or multifocal stromal haze with or
without neovascularization. After the infammation
subsides, stromal scarring may be severe enough to
necessitate corneal transplantation. Non-HSV causes
for immune stromal keratitis include varicella-zoster,
EBV, syphilis, Acanthamoeba, mumps, Lyme disease,
sarcoidosis, and Cogan syndrome.
Necrotizing stromal keratitis is a rare manifesta-
tion of HSV that appears as a dense area of suppura-
tive stromal infammation and is associated with an
epithelial defect. This entity is diffcult to distinguish
from bacterial or fungal keratitis and hence poses a
therapeutic challenge that may require Gram staining
and cultures for defnitive diagnosis. Fortifed antimi-
crobial agents may be warranted until Gram stain and
cultures prove negative.
Endotheliitis
HSV endotheliitis is thought to be an immuno-
logically mediated manifestation of ocular herpes. This
entity presents as keratic precipitates associated with
varying degrees of stromal edema and uveitis. Based
or lissamine green) can be useful in distinguishing HSV
dendrites. Since the HSV ulcers represent true epithe-
lial defects, fuorescein stains the base of each lesion,
and vital dyes will stain the epithelial cells comprising
the raised edge. Clinicians should be mindful that rose
bengal inhibits viral replication and, so, can decrease
the yield of virus culture and possibly inhibit detec-
tion by PCR.
2,3

An HSV geographic ulcer can develop when the
ulcerated base of a dendritic lesion widens, as com-
monly occurs under the infuence of topical cortico-
steroids. The geographic lesion takes on an amoeboid
shape with raised edges, which likewise stain with vital
dyes (Figure 5).
HSV epithelial disease can also present as a mar-
ginal ulcer. This type of epithelial defect is often as-
sociated with stromal infltration by white blood cells
supplied by limbal blood vessels. Typically, there is no
intervening zone of clear cornea between the infltrate
and limbus, as may be seen with staphylococcal mar-
ginal keratitis.
HSV epithelial disease may lead to permanently de-
creased corneal sensation and neurotrophic keratopathy.
FIguRE 5
HSV geographic epithelial keratitis. (courtesy Wills Eye
Hospital.)
FIguRE 4
HZOs pseudodendrites appear as lines of heaped
epithelium without central ulceration. (courtesy Joseph
Halabis, OD.)
FIguRE 3
HSV dendritic epithelial keratitis. (courtesy Joseph
Halabis, OD.)
13
on the distribution of keratic precipitates and overly-
ing stromal edema, HSV endotheliitis can be divided
into three clinical formsdisciform, diffuse, and linear.
Disciform endotheliitis is associated with stromal edema
in a round confguration (Figure 6). Diffuse endotheliitis
manifests as scattered keratic precipitates with diffuse
stromal edema. With linear endotheliitis, the keratic
precipitates are arranged in a straight or wavy line with
overlying stromal edema.
Iridocyclitis
HSV iridocyclitis may occur alone or secondary
to corneal disease. Findings include anterior cham-
ber infammation with fne keratic precipitates. Often,
the uveitis is accompanied by trabeculiitis and ocular
hypertension.
Treatment
In the mid-1990s, treatment of ocular herpes sim-
plex advanced signifcantly with the results from HEDS,
a series of prospective, randomized, double-masked and
placebo-controlled multi-center trials. Indeed, HEDS
helped resolve many of the controversies that had
clouded the treatment of ocular HSV disease (Table 2).
4-7
While HEDS addressed the use of oral acyclovir and
topical trifuridine, our treatment options have since ex-
panded with the introduction of additional oral therapies
(valacyclovir and famciclovir) and a new topical medi-
cation (ganciclovir ophthalmic gel 0.15%). Valacyclovir
has fve times acyclovirs bioavailability, and famciclo-
vir has a longer intracellular half-life than acyclovir.
8,9
The recent FDA-approval of ganciclovir ophthal-
mic gel provides us a new topical antiherpetic agent
with several attractive attributes compared to older topi-
cal antiviral formulations such as trifuridine. Before the
introduction of topical ganciclovir, trifuridines ocular
surface toxicity had already prompted many ophthal-
mologists to switch to oral antiherpetic medications to
treat epithelial keratitis. Since ganciclovir mainly tar-
gets viral DNA (trifuridine, vidarabine, and idoxuridine
target both cellular and viral DNA), we should expect
selective killing of viral-infected cells and sparing of nor-
mal, non-infected cells with this newer agent, thereby
lessening treatment-associated toxicity to the epithe-
lium. We anticipate that the availability of ganciclovir
gel will see many clinicians switching back to topical
treatment from oral medications to avoid unnecessary
systemic drug exposure and the potential for side effects
such as the renal toxicities that, on rare occasion, have
been associated with oral antiherpetic agents.
In our clinical experience, patients fnd ganciclo-
virs ophthalmic gel preparation particularly comfort-
able on the eye and convenient in its dosing. Application
compliance is improved with ganciclovirs less-frequent
dosing (5 times daily vs 9 times daily with trifuridine).
In addition, patients can store ganciclovir gel at room
temperature versus the refrigeration that was recom-
mended with trifuridine. An additional advantage in-
cludes the use of a low concentration of benzalkonium
chloride 0.075%, as opposed to the outdated and more
toxic thimerosal 0.001%, which preserves trifuridine.
The gel formulation also extends contact time
with the ocular surface, which should enhance pen-
etration and bioavailability as well as prove benefcial
for patients who tend to dilute topical ophthalmic
medications with excess tearing or crying, as often
seen with children.
Incorporating all these advances, we have devel-
oped a set treatment plan based on the clinical presenta-
tion of ocular HSV. (See box Treatment of Ocular HSV.)
Table 2
Treatment guidance from the
Herpetic (Herpes Simplex) Eye
Disease Study (HEDS)
1
Topical corticosteroids are safe and effective in
the treatment of stromal keratitis when used
concomitantly with prophylactic oral acyclovir
or topical trifuridine.
2
Prophylaxis with oral acyclovir reduces the
recurrence of ocular HSV
3
The addition of oral acyclovir to treatment
with topical trifuridine and corticosteroid
may improve treatment of HSV iridocyclitis
(nonstatistically signifcant trend).
4
The addition of oral acyclovir to topical
trifuridine and corticosteroid treatment shows
no beneft in treating HSV immune stromal
keratitis.
5
The addition of oral acyclovir to topical
trifuridine and corticosteroid treatment of
HSV epithelial disease fails to reduce the
likelihood of subsequent stromal keratitis or
iridocyclitis.
nOTE: The HEDS trials employed acyclovir as the oral antiherpetic
medication and trifuridine as the topical antiherpetic agent. newer
options include valacyclovir and famciclovir as oral antiviral agents
and ganciclovir ophthalmic gel for topical application.
FIguRE 6
HSV disciform endotheliitis. (courtesy Wills Eye Hospital.)
14
Prophylaxis
We recommend long-term, possibly lifelong, pro-
phylaxis for patients with a history of severe stromal
keratitis as well as those who experience more than
one episode of epithelial keratitis per year. Lifelong
prophylaxis is likewise warranted for patients receiving
corneal transplants for vision loss related to herpetic
scarring. Either oral acyclovir (400 mg twice daily) or
valacyclovir (500 mg once daily) are suitable options
so long as the patient maintains good renal function.
We recommend against elective laser procedures
in patients who have a history of ocular herpetic disease,
particularly if there is evidence of corneal scarring. This
recommendation stems from clear evidence that stressors
such as ocular trauma and exposure to strong UV light
can trigger HSV reactivation.
10-12
For the patient with a
history of recurrent fever blisters or other forms of facial
herpes, we recommend 1 week of prophylaxis with oral
acyclovir or valacyclovir prior to refractive procedures.
When patients with a history of ocular herpes
require glaucoma laser surgery, cataract removal, or
other invasive ocular procedures, we recommend pro-
phylaxis with oral acyclovir or valacyclovir for at least
1 week prior to surgery and for 1 to 6 months postop-
eratively, depending on the frequency and severity of
past herpes outbreaks.
HErPES ZOSTEr OPHTHAlMIcUS (HZO)
The varicella-zoster virus that causes chickenpox
can, like HSV, establish lifelong latency in the trigeminal
ganglion. When this virus reactivates in later life, it is
referred to as herpes zoster, or shingles. Shingles can
affect any area of the body, and the eye is second only
to the trunk as the most common site of involvement.
Presentation
HZO is frequently misdiagnosed as the more
treatable HSV. The distinguishing characteristics of
herpes zoster epithelial keratitis include an elevated
ridge of epithelium that is neither as coarse nor as
thick as that associated with HSV. HZO keratitis also
lacks HSVs characteristic terminal bulbs. Instead HZOs
pseudodendrites have tapered ends and tend to be more
infltrative and branching in a Medusa-like pattern. In
addition, the base of the HZO pseudodendrite is not ul-
cerated and so does not stain with fuorescein (Figure 4).
Like herpes simplex, zoster tends to present uni-
laterally. However, the zoster virus often affects an
entire sensory dermatome, respecting the midline of
the face (Figure 7). In addition, look for a recent his-
tory of fu-like symptoms. Low grade fever and malaise
are often present up to a week before vesicle eruption.
Like herpes simplex, HZO can manifest as blepharo-
conjunctivitis, epithelial keratitis, stromal keratitis,
endotheliitis, or iritis.
Treatment and Prophylaxis
Ideally, treatment with oral antiviral agents
should be initiated within 72 hours of the frst ap-
pearance of skin lesions. Moreover, HZO demands sig-
nifcantly higher dosages (800 mg of acyclovir 5 times
daily for 7 to 10 days or 1 gm of valacyclovir 3 times
daily for the same duration).
The discomfort of HZO blepharoconjunctivitis
can be eased with cool compresses and lubrication
(refrigerated artifcial tears). An antibiotic ointment
can be added to help prevent bacterial superinfection.
Antiviral agents are not typically needed for HZO
epithelial keratitis due to the feeting duration of the re-
activated virus. Post-infection infammation can produce
stromal keratitis, keratouveitis, and iritis, which warrant
treatment with topical steroids. Typically we treat with
prednisolone acetate or difuprednate (the latter at half
the dosing frequency of prednisolone acetate). Initial
FIguRE 7
Zoster eruptions often involve an entire sensory
dermatome of the face, producing a line of multiple
vesicles that usually respects the midline. (courtesy
Wills Eye Hospital.)
TREATMENT OF OCulAR HSV
HSV dermatoblepharitis: Oral acyclovir
(400mg 5 times daily for 5 days) or valacyclovir
(500 mg 3 times daily for 5 days).
Epithelial keratitis: Ganciclovir ophthalmic gel
0.15% (1 drop 5 times daily until the herpetic ulcer
heals, which is typically within 1 week, followed by
1 drop 3 times daily for another 7 days) and/or oral
acyclovir or valacyclovir (at above dosages).
Stromal keratitis: Topical prednisolone
acetate 1% administered 8 times daily or topical
difuprednate 0.05% administered 4 times daily,
gradually tapering to 1 drop daily over 2 to 3
months, depending on clinical responsewhile
continuing either oral or topical antiviral coverage.
Endotheliitis and Iridocyclitis: Topical steroids
based on the severity of infammation, along with
oral antiviral coverage as above. Add topical
intraocular pressure-lowering medications as needed.
15
application can be as frequent as eight times daily with
prednisolone acetate or four times daily with difupred-
nate, with gradual tapering based on the persistence and
severity of infammation. Continued prophylaxis with
oral or topical antiherpetic medication is not necessary.
As mentioned, the incidence of herpes zoster ap-
pears to be rising in the general population, particularly
among those over 40 years of age.
13
Fortunately, we now
have a zoster vaccine available, though its current FDA
approval covers only those age 60 or older. Given HZOs
high morbidity, it behooves us as ophthalmologists to
both encourage our older patients to avail themselves
of this vaccine and work with primary care physicians
to increase the awareness of its importance.
cYTOMEGAlOVIrUS AND EPSTEINbArr VIrUS
Even as corneal specialists, we rarely see com-
plications related to infection with CMV or EBV, two
other ubiquitous members of the herpes virus family.
Childhood infection with either virus typically goes
unnoticed, but can cause the fu-like malaise syndrome
known as mononucleosisseen most frequently in
teenagers and young adults.
During such a period of active infection, Epstein-
Barr can produce a wide range of anterior segment and
neuroophthalmic fndings. The former can include fol-
licular conjunctivitis, scleritis, subconjunctival hemor-
rhage, iridocyclitis, dendritic epithelial keratitis, and
stromal keratitis. On rare occasions conjunctival biopsy
reveals malignant lymphoma. Neuroophthalmic disease
can include papilledema, optic neuritis, and cranial
nerve palsies. We generally treat EBV anterior segment
disease with topical steroids, sometimes coupled with
systemic immunosuppressants. Malignant disease should
be treated with surgical removal and chemotherapy.
Immune suppression can reactivate latent CMV
infection and produce ocular manifestations such as cho-
rioretinitis. Before the advent of antiretroviral therapy,
ophthalmologists saw many AIDS patients develop this
potentially blinding complication. More recently, studies
have revealed that ocular CMV disease, though rare in
the immunocompetent population, is more common
than previously thought.
14
The ophthalmologist should
remain aware that active CMV infection can mimic HSV
or zoster disease, but can be distinguished by its associa-
tion with infammation that progresses to the deepest
layers of the cornea (versus the surface). Diagnosis may
require vitreous tapping for evidence of cytomegalovirus
DNA. Active CMV chorioretinitis warrants treatment
with intravenous ganciclovir (2-5 mg/kg IV every 8 hours
for two weeks if tolerated without hemosuppression),
followed by weekly intravitreal injections (400 g.)
15

cONclUSION
As described in this article, the family of human
herpes viruses incorporates a diverse group of viruses that
can produce a variety of ocular manifestations. Obtaining
a good clinical history and knowing the distinguish-
ing signs are crucial in identifying the exact entity and
initiating the appropriate therapy for optimal results.
Terry Kim, MD, is a professor of ophthalmology at the Duke
University School of Medicine, and the associate director of
corneal and refractive surgery services at the Duke Eye Center,
likewise in Durham, North Carolina. He states that in the past
twelve months he has been a consultant to Alcon, Allergan,
Inspire, ISTA, OSI, Ocular Therapeutics, Pfzer, and PowerVision.
Victor Chang, MD, is a former chief resident at the Cullen Eye
Institute, of the Baylor College of Medicine, and is currently a
clinical fellow of cornea, external disease, and refractive surgery
at the Duke Eye Center, in Durham, North Carolina. He states
that in the previous twelve months he has not had a fnancial
relationship with any commercial organization that produces,
markets, re-sells, or distributes health care goods or services con-
sumed by, or used on patients.
REFERENCES
1. Liesegang TJ. A community study of ocular herpes simplex. Curr
Eye Res. 1991;10(Suppl):111-5.
2. Chodosh J, Banks MC, Stroop WG. Rose bengal inhibits herpes
simplex virus replication in vero and human corneal epithelial
cells in vitro. Invest Ophthalmol Vis Sci. 1992;33(8):2520-7.
3. Seitzman GD, Cevallos V, Margolis TP. Rose bengal and lissamine
green inhibit detection of herpes simplex virus by PCR. Am J
Ophthalmol. 2006;141(4):756-8.
4. Wilhelmus KR, Gee L, Hauck WW, et al. Herpetic Eye Disease Study. A
controlled trial of topical corticosteroids for herpes simplex stromal
keratitis. Ophthalmology. 1994;101(12):1883-95;discussion 1895-6.
5. Oral acyclovir for herpes simplex virus eye disease: effect on pre-
vention of epithelial keratitis and stromal keratitis. Herpetic Eye
Disease Study Group. Arch Ophthalmol. 2000;118(8):1030-6.
6. A controlled trial of oral acyclovir for the prevention of stromal
keratitis or iritis in patients with herpes simplex virus epithelial
keratitis. The Epithelial Keratitis Trial. The Herpetic Eye Disease
Study Group. Arch Ophthalmol. 1997;115(6):703-12.
7. Barron BA, Gee L, Hauck WW, et al. Herpetic Eye Disease Study.
A controlled trial of oral acyclovir for herpes simplex stromal
keratitis. Ophthalmology. 1994;101(12):1871-82.
8. Weller S, Blum M, Smiley M. Phase I pharmacokinetics of the
acyclovir prodrug, valacyclovir. Antivir Res. 1993;20(suppl 1):144.
9. Perry CM, Wagstaff AJ. Famciclovir. A review of its pharmacologi-
cal properties and therapeutic effcacy in herpes virus infections.
Drugs. 1995;50:396-415.
10. Asbell PA. Valacyclovir for the prevention of recurrent herpes
simplex virus eye disease after excimer laser photokeratectomy.
Tr Am Ophth Soc. 2000;98:285-303.
11. Levy J, Lapid-Gortzak R, Klemperer I, et al. Herpes simplex vi-
rus keratitis after laser in situ keratomileusis. J Refract Surg. 2005
Jul-Aug;21(4):400-2.
12. Beyer CF, Arens MQ, Hill JM, et al. Penetrating keratoplasty in
rabbits induces latent HSV-1 reactivation when corticosteroids
are used. Curr Eye Res. 1989;8:1323-9.
13. Jardine A, Conaty SJ, Vally H. Herpes zoster in Australia: evidence
of increase in incidence in adults attributable to varicella immu-
nization? Epidemiol Infect. 2010 Aug;23:1-8.
14. Van Boxtel LA, van der Lelij A, van der Meer J, Los LI.
Cytomegalovirus as a cause of anterior uveitis in immunocom-
petent patients. Ophthalmology. 2007 Jul;114(7):1358-62.
15. Hodge WG, Lalonde RG, Sampalis J, et al. Once-weekly intra-
ocular injections of ganciclovir for maintenance therapy of cy-
tomegalovirus retinitis: clinical and ocular outcome. J Infect Dis.
1996;174(2):393-6.
16
The ophthalmologist who developed the worlds
rst effective antivirals reects on a half century
of advances in the treatment and prevention of
herpetic ocular infections.
When I was a first-year resident at the
Massachusetts Eye and Ear Infrmary in the 1950s,
there were no treatments for viral diseases, unless you
counted chicken soup. We managed ocular herpes by
simply scraping off eroded surface tissue and applying
iodinea painful and diffcult procedure that was far
from effective. In some of the most severe cases, we
would cover the entire ocular surface with periocular
tissue, a procedure that relieved the excruciating pain
but left the patient blind.
I will always remember one patient in particu-
lara lovely woman with two children. I watched her
go blind because we had nothing to stop her ocular
herpes. In a sense, it drove me crazy. At least it drove
me into the laboratory before and after my resident
rounds each day.
Hundreds of laboratories were working on anti-
viral therapies at the time. But I believed that virtually
all of them were on the wrong path. They were trying
to starve the herpes virus by blocking production of the
nucleic acids that it needed to reproduce. But I believed
that the virus would simply rob cells of the nucleic acids
it needed to replicategiven the extremely high affn-
ity that viral DNA polymerase had for these building
blocks. The end result would be dead cells, not less virus.
I believed that the only way to stop a herpes virus
was to block its DNA polymerase. The frst drug I used
was iododeoxyuridine, or IDU (Figure 1).
1
This nucleic
acid analog had been developed as a potential cancer
drug. It did not prove terribly successful in treating can-
cer, but it showed high affnity for DNA polymerase. In
effect, it tricked the herpes virus into taking it up and,
so, committing suicide.
It was the frst effective antiviral and revolution-
ized the feld. First, it demonstrated that one could treat
viral diseasea huge question at the time, seeing that
viruses essentially made themselves part of the cell.
Second, it showed that a specifc class of drugs, the
substituted nucleotides, offered a way to block viral
DNA polymerase.
PART THREE: The Historical Perspective
Herbert E. Kaufman, MD
Limiting IDUs effectiveness against ocular herpes
was the drugs lack of solubility. It had to be adminis-
tered every 2 hours around the clock. At least we had
something; but I believed we could do better. I began
working with trifuridine (Figure 2).
THE TrIFlUrIDINE STOrY
Like IDU before it, trifuridine was an anticancer
drug. The connection is a logical one because viruses,
like cancer cells, depend on the mass assembly of nucleic
acids to fuel their rapid reproduction.
Trifuridine proved to be a tremendously effec-
tive ocular antiviral. In controlled studies, 97% of all
herpetic keratitis infections treated with trifuridine
healed within 2 weeks.
2
Without treatment, less than
half of infections resolved this quickly.
Nonetheless I got laughed out of the park when
it came to the price tagover $600 a gram. Fortunately,
a German company learned how to make trifuridine
for just $25 a gram. By the early 1970s, trifuridine
was in wide usethe drug of choice for the treatment
of ocular herpes until the introduction of ganciclovir
ophthalmic gel.
The problem with trifuridine was that its action
was not selective. It inhibits not only virus reproduc-
tion, but also cellular DNA synthesis. As such, it can
interfere with wound healing. Associated complications
are rare, but can be serious when infection produces
large corneal ulcers that require signifcant cell division
to heal. Other rare but serious side effects include al-
lergic reaction and the occlusion of lacrimal drainage.
16
N
N
O
O
I
CH
2
OH
O
OH
FIguRE 1
Iododeoxyuridine.
FIguRE 2
Trifuridine.
CH
2
OH N
N
O
O
O
OH
F
3
C
17
cOrTIcOSTErOID cONTrOVErSY
Another huge but controversial advance came
with corticosteroids. Blocking virus multiplication
stopped the development of herpetic ulcers on the cor-
neal surface. But it became clear that topical antivirals
did little if anything to stop damage deeper within the
eye. This deeper damage, we realized, did not stem di-
rectly from viral activity, but from the immune systems
hypersensitive reaction to viral antigens. Moreover, it
was the enduring damage from this infammation that
most threatened a patients sight.
Immune suppression would
seem to be the answer. But it had
long been known that corticoste-
roids fueled active herpetic infec-
tions. So one can imagine the re-
action I received when I proposed
that we could use corticosteroids to
limit stromal damage if we simulta-
neously used an antiviral to prevent
the associated fare ups. I had good
results with this approach in rabbit
studies.
1
But it took a lot of cour-
age to try it in patientscourage
inspired by a terrible disease that
caused horrifc pain and blindness.
The simultaneous suppres-
sion of both infection and infam-
mation is now standard in the treat-
ment of many viral and bacterial
diseases that trigger destructive im-
mune reactions. But at the time it was a radical idea
and one being proposed by a mere resident! Clinical
studies would prove us right.
3
But it would take the
results of the frst Herpes Eye Disease Study (HEDS) to
lay doubts to rest.
4
THE ADVENT OF AcYclOVIr
Gertrude Elion gave us the next great advance in
herpetic therapy with her development of acyclovir.
Like IDU and trifuridine, acyclovir must be activated
by thymidine kinase before it can stop DNA synthe-
sis. Both cells and viruses make this enzymeeach in
a slightly different version. Elions breakthrough came
with a slight alteration in the sugar groups on her sub-
stituted nucleoside that rendered it selective. Viral DNA
polymerase readily activated acyclovir, but the pickier
cellular enzyme ignored it.
This difference in selectivity makes perfect sense
when one considers that if our cells make errors in DNA
metabolism, the result can be disastrous. But with a vi-
rus, the goal is to multiply as fast as possible, mistakes
be damned. Elion took advantage of this discrimina-
tion to target the virus without harming the patient.
In doing so, she gave us the frst systemic antiviral.
5
Still, doubts persisted about the ability of a sys-
temic drug to treat corneal herpes. As for topical use,
acyclovirs poor solubility meant that ophthalmic prepa-
rations had to be in the form of a thick ointment that
interfered with vision. This lack of patient friendliness
may explain why acyclovir ointment was never brought
to the U.S. market.
Meanwhile, we were keenly interested in whether
long-term use of oral acyclovir could prevent the re-
currence of ocular herpes. Answering this question was
one of the goals of the HEDS study.
6
Oral acyclovir (400
mg two times a day) reduced the
risk of recurrence by about 40%.
For the frst time, we knew we had
a way to reduce the reactivation
of a viral disease. Additionally we
found that when one stopped oral
acyclovir, there was no rebound ef-
fect. The overall risk of recurrence
returns to what it was before treat-
ment (around 25% over two years).
We had hoped that acyclo-
vir would reduce the tendency of
ocular herpes simplex to progress
from surface infection to deeper
stromal disease with each occur-
rence. But HEDS showed no beneft
in this regard.
More recent work in rab-
bits, by Jim Hill and my group at
Louisiana State University, suggests
that at much higher doses, the re-
lated drug valacyclovir may in fact reduce both the re-
currence and the severity of stromal disease and iritis.
7

Valacyclovir has the advantage of being much more
bioavailable than acyclovir, which is poorly absorbed
through the gut. By contrast, valacyclovir passes read-
ily into the bloodstream, where it is metabolized into
acyclovir.
GANcIclOVIr
The recent US introduction of ganciclovir oph-
thalmic gel generated great excitement. But in intra-
venous or ocular implant form, this member of the
acyclovir family had already carved out a distinguished
place in ophthalmology. Indeed, it is effective against
some viruses that do not respond to acyclovirinclud-
ing cytomegalovirus, which can cause vision-destroying
infections in the immunocompromised.
Ganciclovirs systemic toxicity contraindicates
long-term oral or intravenous use. But its greater solu-
bility lent itself to the patient-friendly ophthalmic gel
formulation that has been widely used in Europe for
over 15 years. European studies have demonstrated it
to be as effective as acyclovir ointment in treating den-
dritic herpes keratitis, with signifcantly higher patient
tolerability.
8,9
It has never gone head to head with tri-
17
In 1963, Herbert Kaufmans
antiherpetic breakthroughs put him
on the cover of Medical World News.
AdvAnces in the MAnAgeMent of oculAr herpetic diseAse pArt three: the historicAl perspective
18
furidine, but appears to be at least as effective.
In addition, I fnd it exciting that while acyclo-
vir ointment has never demonstrated effcacy against
adenovirus conjunctivitis, there is early evidence that
ganciclovir gel can reduce the duration of these com-
mon infections and perhaps even mitigate potentially
serious sequelae.
10
Given its relative lack of toxicity, ganciclovir
ophthalmic gel should now be the standard of care
in the topical treatment of herpes keratitis. Yet there
may still be a place for trifuridine. In our laboratory,
we have found that ganciclovir and trifuridine can
act synergistically against the herpes simplex virus.
11

We do not yet know how important this synergy will
prove in treating herpetic infections, but we are eager
to explore the potential.
FUTUrE DIrEcTIONS
As a professor emeritus, I am eager to see oth-
ers build upon my work. In particular, we need ways
to truly treat herpetic stromal disease and iritis. Yes,
corticosteroids can suppress the infammation while a
18
concurrent antiviral prevents complications. But often
these treatments must be maintained for months and
even then cannot be said to cure the disease so much
as contain the bodys hypersensitivity reaction to the
virus while the infection runs its course. The key to ef-
fective treatment, I believe, will come from drugs that
inhibit virus multiplication more powerfully.
In addition, we need ways to not just reduce the
frequency of herpetic recurrences but stop them. This
may come with greater understanding of how and why
the latent herpes virus reactivates. We likewise need
more effective treatments against other herpes viruses
such as zoster, which can cause such terrible ocular
damage. Clearly, we are only beginning to understand
these often devastating viral infections. Much work
remains to be done.
Herbert Kaufman, MD, is the emeritus Boyd professor of oph-
thalmology, pharmacology, and experimental therapeutics at the
Louisiana State University Eye Center. He states that in the previ-
ous twelve months he has worked as a consultant for ReSearch
Pharmaceutical Services, Inc.
REFERENCES
1. Kaufman HE, Maloney ED. IDU and hydrocortisone in experimen-
tal herpes simplex keratitis. Arch Ophthalmol. 1962 Sep;68:396-8.
2. Wellings PC, Awdry PN, Bors FH, et al. Clinical evaluation of
trifuorothymidine in the treatment of herpes simplex corneal
ulcers. Am J Ophthalmol. 1972 Jun;73(6):932-42.
3. Kaufman HE, Martola El, Dohlman CH. Herpes simplex treat-
ment with IDU and corticosteroids. Arch Ophthalmol. 1963
Apr;69:468-72.
4. Wilhelmus KR, Gee L, Hauck WW, Herpetic Eye Disease Study:
A controlled trial of topical corticosteroids for herpes simplex
stromal keratitis. Ophthalmology. 1994;101:1883-96.
5. Elion GB. Mechanism of action and selectivity of acyclovir.Am
J Med.1982;73:7-13.
6. Herpetic Eye Disease Study Group. Oral acyclovir for herpes sim-
plex virus eye disease: effect on prevention of epithelial keratitis
and stromal keratitis. Arch Ophthalmol.2000 Aug;118(8):1030-6.
7. Kumar M, Kaufman HE, Clement C, et al. Effect of high versus
low oral doses of valacyclovir on herpes simplex virus-1 DNA
shedding into tears of latently infected rabbits. Invest Ophthalmol
Vis Sci. 2010 Sep;51(9):4703-6.
8. Hoh HB, Hurley C, Claoue C, et al.Randomised trial of ganci-
clovir and acyclovir in the treatment of herpes simplex dendritic
keratitis: a multicentre study.Br J Ophthalmol.1996;80:140-3.
9. Colin J, Hoh HB, Easty DL, et al. Ganciclovir ophthalmic gel
(Virgan 0.15%) in the treatment of herpes simplex keratitis. Cornea.
1997;16:3939.
10. Tabbara KF. Ganciclovir effects in adenoviral keratoconjunctivitis.
Poster B253. Presented at ARVO 2001. Fort Lauderdale, Florida.
11. Hobden JA, Kumar M, Kaufman HE, et al. In vitro synergism of tri-
fuorothymidine and ganciclovir against HSV- 1. Invest Ophthalmol
Vis Sci. 2010 Sep 22. [Epub ahead of print]
AdvAnces in the MAnAgeMent of oculAr herpetic diseAse pArt three: the historicAl perspective
19
Once you have read this newsletter, you may take the cME Examination
on the following page. Please fll out the Examination Answer Sheet,
photocopy it or cut it out, and MAIL it to:
UnIVERSITY OF FLORIDA cOLLEGE OF MEDIcInE
OFFIcE OF cOnTInUInG MEDIcAL EDUcATIOn
PO BOX 100233
GAInESVILLE, FL 32610-0233
Or fax the completed form to: 352-733-0007
You can also take the test online at http://cme.uf.edu/XXXXXXXXXX
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This CME program is sponsored by the University of Florida College of Medicine and supported by an unrestricted educational grant from Bausch + Lomb, Inc.
Directions: Select the one best answer to each question in the Exam (Questions 1-10) and in the Evaluation (Questions 11-16) below by circling one letter
for each answer. Participants must score at least 80% on the questions and complete the entire Evaluation section on the form below. The University of Florida
College of Medicine designates this activity for a maximum of 2.0 AMA PRA Category 1 Credits. There is no fee to participate in this activity. You can take the
test online at http://cme.uf.edu/XXXXXXXXXXX.
eXamination answer sheet advances in the management of ocular herpetic Disease
1. HSV remains viable on a moist
tonometer head for:
A. Up to 2 hours.
B. Up to 8 hours.
C. Up to 24 hours.
D. Up to 48 hours.
2. Breakdown of Liesegangs Minnesota
data suggests that approximately
what percentage of ocular simplex
disease involves the corneal stroma?
A. 75%
B. 41%
C. 12%
D. 1%
3. Of the approximately 20% of the
worlds population who develop
herpes zoster, what percentage
experience ocular involvement?
A. 2% to 5%
B. 10% to 20%
C. 45% to 50%
D. 70% to 80%
4. How is ocular CMV disease generally
treated?
A. Intravenous ganciclovir.
B. Topical ganciclovir.
C. Topical corticosteroids.
D. All of the above.
5. Which of the following is/are known
triggers for ocular herpetic disease?
A. Local trauma and systemic
disease.
B. Systemic and local immune
suppression.
C. Laser refractive procedures and
cataract surgery.
D. All of the above.
6. CMV and EBV are estimated to infect
what percentages of American
adults, respectively?
A. up to 2% and 5%
B. up to 22% and 55%
C. up to 80% and 95%
D. up to 98% and 100%
7. How does treatment of herpes zoster
ophthalmicus difer from that of
ocular herpes simplex?
A. Zoster warrants higher doses of
oral antiherpetic agents.
B. Zoster responds to lower doses of
oral antiherpetic agents.
C. Topical corticosteroids should be
avoided with zoster.
D. Zoster warrants aggressive
debridement.
8. Approximately what percentage of
patients recover from HSV keratitis
with 20/100 visual acuity or worse?
A. 90%
B. 30% to 40%
C. 3% to 5%
D. 1%
9. Approximately what percentage
of ocular herpes simplex infections
present unilaterally?
A. 100%
B. 90%
C. 70%
D. Less than 50%
10. Which of the following is diagnostic
of herpes zoster keratitis but not
simplex keratitis?
A. A branching ulcer.
B. Unilateral presentation.
C. Ulcerated base that stains with
fuorescein.
D. Non-ulcerated base that does not
stain with fuorescein.
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This CME program is sponsored by the University of Florida
and Candeo Clinical/Science Communications, LLC, and
supported by an unrestricted educational grant from
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Ofce, PO Box 100233, Gainesville, FL 32610-0233. Di-
rections: Select the one best answer for each question
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entire Evaluation (Questions 11-16) to receive CME credit.
ANSWERS:
evaluation:
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changes in your practice? Yes No
14. If yes, please describe: __________________________
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