Objectives

To understand the etiology of herpes simplex and

herpes zoster
Compare and contrast the treatment for herpetic
ocular disease
Review the complications of herpetic eye disease

LyonsOD@cinci.rr.com

HSV and VZV

Similar characteristics
Linear double stranded DNA surrounded by a
icosahedralshaped capsid
The production of virus particles within the host
cell results in destruction of the host
All herpes viruses can establish latency in the
sensory ganglia
Capable of producing unilateral (rarely bilateral)
ocular disease

Herpes Simplex Virus

HSV-1 infection occurs by direct contact of skin or mucous
membrane with virus-laden lesions or secretions
Occurs most commonly in the mucocutaneous distribution of the
trigeminal nerve
After the primary infection, the virus travels in retrograde fashion from
the infected epithelial cells to nearby sensory nerve endings and is
transported along the nerve axon to the cell body located in the
trigeminal ganglion, entering into a latent state.

Interneuronal spread of HSV within the ganglion allows

patients to develop subsequent ocular disease without ever
having had primary ocular HSV infection

Herpes Simplex Keratitis

Ocular Manifestations of HSV

Blepharitis
Conjunctivitis
Scleritis
Keratitis
Iridocyclitis
Retinitis

United States: 20,000 new cases annually

28,000 reactivations annually

United States: Roughly 500,000 people with the disease

Recurrence Rates of ocular HSV (Liesegang et al. 1989)

122 patients over 33 years

Mean age of initial onset = 37.4 years
36% after 5 years
63% after 20 years
After a second episode, 70-80% had another recurrence within 10 years

Infectious Epithelial Keratitis

Classification of HSV Keratitis

I. Infectious Epithelial Keratitis
II. Stromal Keratitis
III. Endotheliitis

IEK
1. Cornea vesicles
2. Dendritic ulcer
3. Geographic ulcer
4. Marginal ulcer

Different viral strands may produce different pattern

of ocular disease with variability of recurrence
(Wander et al, 1980)

Infectious Epithelial Keratitis

Infectious Epithelial Keratitis

Cornea Vesicles
Cystic lesion of the epithelium
Contains live virus
No epithelial defect

Negative staining early

Late staining

Precedes dendritic ulcer

Very rarely seen due to early presentation

Dendritic Ulcer
Branching linear ulceration
Dendron Greek for tree

Contain live virus

Swollen epithelial borders
Staining centrally

Infectious Epithelial Keratitis

Infectious Epithelial Keratitis

Geographic Ulcer
Enlarged dendritic ulcer
Scalloped borders
Contains live virus

Marginal Ulcer
Also referred to as Limbitis (IEK near limbus)
Active virus with moderate inflammatory reaction
Due to proximity to limbus

Easily confused with Staph Marginal Ulcer

Course:

Begins as a peripheral ulcer

Stromal infiltrate rapidly develops
Peripheral corneal neovascularization
Dilated limbal vessels
Antibiotic therapy fails

Stromal Keratitis
Stromal Keratitis
1. Interstitial (Immune Stromal) Keratitis
2. Necrotizing Stromal Keratitis

Interstitial Keratitis
Etiology
Immune reaction to retained viral antigen

Clinical Findings:

Stromal haze / infiltration

Intact epithelium
Immune ring
Keratic precipitates
Previous stromal scars

Stromal Keratitis

Stromal Keratitis

Interstitial Keratitis

Necrotizing Stromal Keratitis

Clinical Course

Etiology

Often chronic and recurrent

May occur weeks or months after IEK
May occur w/o prior hx of IEK (~2%)
Persistent inflammation may lead to:

Rare manifestation of HSV

Viral invasion of stromal with severe inflammatory reaction
Dense stromal infiltrate with overlying epithelial defect
Thinning and perforation

Scarring
Thinning
Neovascularization
Lipid depositation
Loss / distortion of vision

Endotheliitis
Endotheliitis
Clinical Findings:

Keratic precipitates
Overlying stromal & epithelial edema
Iritis
Trabeculitis with increased IOP

This is often the primary presentation

Types
1. Disciform
2. Linear
3. Diffuse

Disciform
Most common primary presentation of endotheliitis
Central or paracentral disc-shaped area of edema
KPs corresponding to edema

Endotheliitis

Endotheliitis
Linear

Diffuse
Diffuse keratic precipitates
Diffuse stromal and epithelial edema
Retrocorneal plaque

Varicella Zoster Virus

Progressive line of keratic precipitates

Stromal edema follows leading edge of KPs
Difficult to manage requires aggressive treatment

Varicella Zoster Virus

During the viremic phase, VZV gains access to epidermal

VZV is a human pathogen that infects approximately

98% of the adult population in the United States.
Typically during childhood as varicella (chickenpox)

Transmission is through respiratory secretions or

from direct contact with cutaneous lesions
Varicella much more contagious than zoster

cells, causing the typical varicella rash.

The virus then enters sensory
nerves in mucocutaneous sites
and travels through retrograde
axonal transport to the sensory
dorsal root ganglia adjacent to
the spinal cord
Establishes permanent latency in
neuronal cell bodies

Information from the CDC website, updated May 15, 2008

Herpes Zoster (Shingles)

Annual incidence: 3.2-4.2 / 1,000
Not a reportable condition

More than 1,00,000 new cases annually in US

Age is significant risk factor
Those >60 years and older: 10 / 1,000
Immunocompromised even higher

Herpes Zoster (Shingles)

1 of 3 persons will develop zoster
Caused by the reactivation of the latent VZV in
the sensory ganglion.
Typically begins with 1-4 days of prodromal
symptoms of headache, photophobia, and malaise,
with fever being less common.
Abnormal skin sensations and pain of varying
severity radiate through the affected dermatome.

Herpes Zoster (Shingles)

Possible Causes:

Fever
Ultraviolet Light Exposure
Cold Wind
Systemic Illness
Surgery
Menstruation
Emotional Stress
Local Trauma
Immunosuppression

Herpes Zoster (Shingles)

Viral release from the sensory nerve endings
forms a rash that is initially erythematous and
maculopapular, but progresses to form
coalescing clusters of clear vesicles
containing high concentrations of VZV
HZ is typically unilateral and does not cross
the mid-line, erupting in 1-3 adjacent
dermatomes.
In general, thoracic, cervical, and ophthalmic
involvement are most common

Herpes Zoster Ophthalmicus

First described by Hutchinson in 1865
Involves the reactivation of VZV in the
trigeminal ganglia with ophthalmic
involvement
Accounts for 10%-25% of zoster episodes
Nasociliary branch of the ophthalmic nerve
innervates the skin of the eyelids, conjunctiva,
sclera, cornea, iris, choroid, and the tip of the nose

Herpes Zoster Ophthalmicus

Hutchinsons sign
Presence of vesicles at the side of the tip of the nose
Indicator of nasociliary involvement
Associated with a 50-76% chance of ocular complications
The risk lowers to 34% without nasociliary involvement

Herpes Zoster Ophthalmicus

Herpetic Complications

Signs
External
Lid edema and vesicles
Conjunctival hyperemia
Episcleritis and scleritis

Cornea

Punctate epithelial keratitis

Pseudodendrites
Anterior stromal infiltrates
Keratouveitis

Uveitis

Iridocyclitis
Dendritic Epitheliopathy
Neurotrophic Keratopathy
Corneal Scarring
Iris Atrophy

Specific to HSV

Herpetic Complications
Iridocyclitis
Clinical Situations
Concomitant with keratitis
Subsequent to keratitis
Without history of keratitis
Tougher to confirm herpes etiology

Clinical Findings

Stellate keratic precipitates

Mild to moderate anterior chamber reaction
Chronic, recurrent course
Iris atrophy

Herpetic Complications
Dendritic Epitheliopathy

Healing epithelium following dendritic ulcer

Negative staining gives dendritic appearance
Pseudodendrite: No active virus
May persist for weeks to months
Made worse by toxic agents
Antivirals, antibiotics, etc.

Treat by:
Discontinuing toxic agents!

Herpetic Complications
Neurotrophic Keratopathy
Etiology
Neither immune nor infectious
Impaired corneal innervation combined with decreased
tear secretion
Inflammation
Toxicity from medication

Clinical appearance
Punctate epithelial erosions
Neurotrophic ulcer
Dendritic epitheliopathy

Herpetic Complications
Management of Corneal Scarring
Observation
Rigid Contact Lenses
Penetrating keratoplasty
Success rate has improved with oral antivirals
Complications
Recurrence
Increase rate of rejection
Poor wound healing

Herpetic Complications
Neurotrophic Keratopathy
Treatment:

Punctal occlusion / cauterization

Autologous blood serum ophthalmic drops
Tarsorrhaphy
Conjunctival flap
Scleral lens

Herpetic Complications
Iris Atrophy
Exclusive to HSV
Results in iris transillumination defects,
creating increased glare sensitivity
Painted iris lenses
Implantable prosthetic iris implants available,
although not FDA approved at this time

Topical Antiviral

Treatment of HSV

Treatment of IEK **Dendrite present**

1.
2.
3.

Topical Antiviral
Oral Antiviral
Corticosteroid

Active vs. Immune?

or both?

Topical Antiviral
NEW Treatment

Zirgan (ganciclovir gel) Sirion Therapeutics

FDA approved September 2009

Acquired by B&L June 2010
1 gtt 5x per day until dendrite heals, then TID for 7 days
Better tolerated and effective then trifluridine

Viroptic (1% trifluridine):

1 gtt Q2H W.A. x 10-14 days

Vidarabine ointment 3%:

Applied 5x per day

Especially in children
Less potent and more toxic than trifluridine

Acyclovir ointment

Not commercially available in USA

Better control against some resistant strands

Topical Antiviral
Treatment of IEK **Dendrite present**
Treat at maximum dose for 5-7 days, then taper to
minimize epithelial toxicity
Treat for 10-14 days
Exceptions
Immunocompromised
Resistant strain (very rare)

Topical Antiviral
Topical Antiviral
Treatment of IEK **Dendrite present**
If topical antiviral is used for > 14d and a
dendritic appearance is still present:

Rethink diagnosis
Dendritic epitheliopathy
Neurotrophic keratopathy

Treatment of HZO
Topical acyclovir may be effective, but not
commercially available in US
Some vidarabine success in recurrent strands
New success with off-label use of Zirgan
(ganciclovir gel)

Oral Antiviral
Herpetic Eye Disease Study
Oral antiviral is effective in treatment and prophylaxis of HSK

Interstitial Keratitis with concurrent topical steroid use

Endotheliitis (especially linear)
Iridocyclitis
Recurrent Disease

Oral Antiviral in HSV

Acyclovir (Zovirax)
Active: 200-400 mg 5x/day
Suppression: 400-800 mg BID

Valacyclovir (Valtrex)
Prodrug of acyclovir
Active: 1000-3000 mg QD
Suppression: 500-1000 mg QD

Famciclovir (Famvir)
Active: 250 mg TID
Suppression: 125-250 mg BID

Oral Antiviral

Oral Antiviral in HZO

Prophylactic Indications

Ideally within 72 hours

Acyclovir (Zovirax)
800mg 5x/d for 7-10 days (HSV was Acyclovir 200mg 5x/d)

Post-PK patients
Monocular patients
Recurrent Disease

Valacyclovir (Valtrex)
1000mg TID for 7 days (HSV was 1000mg QD)

Famciclovir (Famvir)
500mg TID x 7 days (HSV was 250 mg TID)

Note: With HZO, often the duration of the oral antiviral is extended
weeks to months

Topical Steroids in HSV

Advantages
Effective tx for corneal and intraocular inflammation
Reduces corneal scarring and neovascularization
Reduces intraocular complications of inflammation

Topical Steroids in HSV

Disadvantages
Enhancement of viral replication
Slows collagen synthesis with subsequent corneal
thinning
Secondary infections
Cataract
Glaucoma
Induction of steroid dependant inflammation by
allowing the build up of viral antigens

Topical Steroids in HSV

Topical Steroids in HSV

Indications
Marginal keratitis, interstitial keratitis, endotheliitis, iritis
Severe or chronic inflammation, decrease in vision

Topical Steroids
Flare dose
Chronic inflammation requires chronic steroids
Most patients have a critical level of steroids that prevents
inflammation
Goal is to stay above flare dose for several months before
any attempt to taper

Avoid use in
Active epithelial disease or ulceration
Mild inflammation

Avoid abrupt discontinuation

Dosage dependant on level of inflammation

Most Common Management Error:

Under treatment with topical steroids

Topical Steroids in HZO

Avoid use in minimal to mild inflammation
Corticosteroids are thought to create an antiinflammatory dependency, resulting in prolonged
treatment and recurrences

If uveitis is worsening or severe, start with small

dosages of topical drops and taper quickly as
disease improves

Postherpetic Neuralgia
Persistent dermatome pain after resolution of the rash
10%-18% of HZO patients
Caused by axonal and cell body degeneration, atrophy
of the spinal cord dorsal horn, scarring of the dorsal
root ganglion, and loss of epidermal innervation
Neuronal damage might be caused by ongoing viral
replication

PHN can last for weeks or months and occasionally

persists for many years

Postherpetic Neuralgia
Treatment

Rapid administration of antiviral (within 72 hours)

Analgesics
Corticosteroids
Nerve blocks
Cimetidine
Tricyclic antidepressants
Famvir?

HZO Treatment
Systemic corticosteroids
Studies indicate that receiving adjacent therapy
along with oral antivirals significantly accelerates
the cutaneous healing rate and acute pain
No beneficial effect on PHN

Zoster Vaccine
Drop in immunity to VZV may occur due to:
Immunosuppressive conditions
Immunosuppressive therapy
Loss of Exogenous Boosts in Immunity
Healthy adults who have had chicken pox get new bursts of immunity
when exposed to their children with chicken pox = exogenous immunity
With the advent of varicella vaccine, it is postulated that the incidence
and perhaps severity of shingles will increase and occur at younger
ages

Zoster Vaccine
Zoster Vaccine
Shingles Prevention Study
In 1999, a double-blind randomized, placebo-controlled trial
was started which included 38,546 patients over the age of 60
who had had varicella in the past.
Identical strain as used in the varicella vaccines (Varivax, Proquad) with
14-times the potency
Half given vaccine and other half given placebo
Study was completed in 2005

Vaccine reduced the chance of developing shingles by 51.3%

In those that developed shingles, also reduced PNH and the severity of
the outbreak

ZOSTAVAX (Merck)
Zoster vaccine is recommended for all persons aged
>60 years who have no contraindications, including
persons who report a previous episode of zoster or
who have chronic medical conditions
Single 0.65 mL subcutaneous dose
Zoster vaccination is not indicated to treat acute
zoster, to prevent persons with acute zoster from
developing PHN, or to treat ongoing PHN
No booster recommendations at this time
7,500 zoster-free patients followed for 10 years