1) There is one virus, varicella zoster virus (VZV), that causes two diseases: chickenpox (primary infection) and shingles (reactivation). 2) Acyclovir works by incorporating into the VZV DNA during replication, which stops replication. Clinical trials found acyclovir reduces complications of herpes zoster ophthalmicus like keratitis and uveitis. 3) Ocular involvement during herpes zoster ophthalmicus is common and includes inflammation like episcleritis and dendritic keratitis. Acyclovir treatment reduces the incidence but not duration of these complications.

1. Herpes
Zoster
(Ophthal
-micus)
Terminology
There is one virus, VZV, and 2 diseases:
1) Primary Varicella Zoster or chicken pox 2) Herpes Zoster or shingles
From the Immune System’s perspective:
The innate immunity is something you are born with and is somewhat structural including the
skin and general defenses. The acquired immunity develops as the body comes in contact with
infectious agents and includes the humoral immunity (which includes antibodies) and the cell mediated
immunity (which includes T cells). Cytotoxic T cells can directly kill virally infected cells when both T cell
and infected cell are displaying on their surfaces the correct/complementary proteins. In a cell with a
latent virus, no such proteins are displayed, so the virus escapes detection and survives. After primary
infection a subset of T cells, memory T cells, hold the key to a programmed and robust immune
response if and when reactivation of the virus occurs. Vaccines can use a weakened virus to establish a
memory T cell line protective from the full strength wild type virus while bypassing the disease effects of
the primary infection (or a reactivation). Currently the CDC recommends the chickenpox vaccine to all
infants without contraindications. The shingles vaccine, which has more virus in it than the chicken pox
vaccine, is likewise recommended to all adults over 60 years old without contraindications.
Contraindications include gelatin and neomycin allergy and especially immunodeficiency. (Yes, some
who need the protection of the vaccine most are unable get it, because the vaccine requires some level
of host immune response.) Though the details are not understood, with varicella zoster infections,
reactivation occurs once, if ever, in patients with normal functioning T cells.

2. A note on both figures below: 1) HSV K = HSV 1 Keratitis
2) subclinical below dotted line
3) Cell mediated immunity (CMI) (and for VZV
environmental exposure also) is responsible for reducing
viral progeny. The relative inactivity of HZ (one
reactivation in HZ versus multiple reactivationsin HSV)
engendersreduced CMI and a larger peak/greater viral
progenyfor HZ than for HSV K
Viral
Progeny
Primary VZV
Herpes Zoster
Zoster sine herpete
Time
Viral
Progeny
Primary
HSV 1
2⁰ HSV K 2⁰ HSV K 2⁰ HSV K 2⁰
Time
The principle of one reactivation only is the basis for the recommendation to treat with
antivirals for the acute reactivation of the virus only. After reactivation the virus is returned to latency
indefinitely in the immunocompetent patient, and therefore treatment of recurrent herpes zoster
ophthalmicus is approached like an autoimmune condition. No large scale studies have been performed
to further clarify treatment of recurrent herpes zoster ophthalmicus.

3. Herpes
VIRAL
DNA
…there is no 5’
hydroxy group
on Acyclovir
triphosphate
so the DNA
chain
immediately
terminates
(deoxy)Guanosine
Triphosphate is not
incorporated into the
chain because
Acyclovir
triphosphate is used
instead to the virus’
detriment because…
Acyclovir triphosphate also
irreversibly binds and
therefore incapacitates
Viral DNA polymerase so
that it cannot begin work
on a new DNA chain
From the Varicella Zoster Virus’ DNA perspective:
The VZV virus has DNA that it must replicate within a particular human cell in order to survive.
Acyclovir is selective to virally infected human cells. Acyclovir feeds faulty DNA parts to the virus,
thereby stopping VZV replication. In a randomized control trial of 71 patients with acute herpes zoster
ophthalmicus, patients on acyclovir had shorter time to 50% scabbing of skin lesions and lower
incidence of the following outcomes than patients on placebo: stromal keratitis, uveitis, and keratic
precipitates. In a different randomized control trial of 1,141 pts with acute herpes zoster, patients on
valacyclovir reached the following outcome more quickly than patients on acyclovir: time to cessation of
pain. Also in the same study, plasma concentrations of acyclovir from valacyclovir were found to be
about four times higher than plasma concentrations of acyclovir (from acyclovir). First line antiviral
therapy for acute herpes zoster ophthalmicus is 1000g of oral valacyclovir three times a day for seven
days (or 500mg of similarly acting oral famciclovir three times a day for seven days).

5. From the perspective of the disease:
VZV’s selectivity shapes the characteristic features of herpes zoster. VZV is selective to sensory neurons,
and so it can cause (focal) pain as well as other sensations spontaneously. (The pain can be
accompanied by other constitutional symptoms as well). VZV is latent in a single ganglia with a limited
distribution, and so it can, but does not have to, cause a dermatome bound blistering scarring rash.
Reactivation – Herpes Zoster/Shingles
A group of vesicles that vary in size. (In contrast: Vesicles
of herpes simplex are of uniform size.)
VZV is also selective to autonomic ganglia, like the ciliary ganglion, so it can cause a tonic pupil. VZV is
selective for T cells, and after entry into the bloodstream can affect distant sites and in a few cause life-
threatening complications. VZV’s selectivity is based on the envelope proteins on the outside of the
virus merging with proteins on the surface of axon terminals or the membranes of other specific cell
types. VZV’s DNA is then carried to the nucleus. VZV can then be either actively replicated (causing
epidemic disease) or made latent (a prelude to nonepidemic disease). Sensory neurons have their nuclei
in the dorsal root and cerebral ganglia, and so chicken pox and herpes zoster predominantly occur in the
trunk and head. All sensory ganglia potentially harbor VZV after primary infection, but reactivation
usually occurs in just one ganglia or a few adjacent ganglia. The trigeminal ganglia is a cerebral ganglion
and its first branch, whose distribution includes the forehead and nose skin to the midline, upper eyelid
and globe, is of the three branches, the branch most often affected by herpes zoster. When the tip,
side, or root of the nose is involved (Hutchison’s Sign) there is potential ocular disease. Ocular
involvement is not correlated with age, sex, or severity of the skin rash. Involvement of any part of the
first branch of the trigeminal is called herpes zoster ophthalmicus.

6. In, Oral Acyclovir in the Treatment of Acute Herpes Zoster Ophthalmicus Cobo et al 1986, a
randomized control trial of 71 patients with acute herpes zoster ophthalmicus, the following was noted:
Acyclovir dose of 600mg five times a day for ten days was used. After ten days ocular
complications were treated without specific protocols. Prelesion pain preceded the onset of
diagnostic skin lesions of HZO in 62% of the entire study group. In none of the 71 patients did the lid
margin irregularity or presence of trichiasis or distichiasis necessitate corrective surgery.
Conjunctival inflammation was a common nonspecific sign which was present principally at the time
of entry and appeared to correlate with lid margin vesicular involvement. Neurotrophic keratopathy
as evidenced by corneal erosion or sterile stromal ulceration, occurred in 5 patients, one acyclovir-
treated and four placebo-treated. Neurotrophic keratopathy was variable in its time of first
appearance (5 to 154 days after entry into the trial) and had a duration of 10 to 278 days. In all
cases it was associated with a profound decrease in measured corneal sensation.
Pavan-Langston 2008: Studies by Hung et al and Collum et al on the concentrations of acyclovir
in the tear film and aqueous humor in patients on 400 mg (peroral 5 times daily) showed levels
of 0.64 umol/l (range, 0.16 –1.45) and 3.26 umol/l (range, 1.10 –5.39), respectively, 4 hours
after the last oral dose. The mean effective dose of herpes simplex virus 1 (HSV-1) reducing
viral plaque count in tissue culture by 50% ranges from 0.1 to 1.6 umol/l, indicating that the tear
film and aqueous levels achieved were well in excess of those needed to eliminate the virus. In
comparison to those for HSV, the inhibitory doses for VZV are much higher, at 3 to 4 umol/l,
resulting in the need for 4-fold higher drug dosing, as noted above, and less leeway in terms of
resistance. To inhibit most strains of VZV, oral dosing of 800 mg 5 times a day is needed to
yield peak and trough serum levels of 6.9 umol/l and 0.96 umol/l
Equally important, there is also a significant reduction in the incidence and severity of acute
dendritiform keratopathy; incidence, but not severity, of corneal stromal immune
keratitis; and incidence of late-onset ocular inflammatory disease (e.g., episcleritis, scleritis,
iritis). Dosing and time to treatment are key factors in treatment success. When adequate
treatment of acyclovir was given (800 mg 5 times a day for at least 7 days starting within 3 days
after rash eruption), complications occurred in only 4% (2/48) of patients; patients with
no treatment or with inadequate treatment had a greater frequency of severe ocular
complications: 21% (34/164) and 25% (5/20), respectively.

7. Anterior segment ocular inflammatory sequelae of HZO were the
most common and protracted ocular complications encountered.
It is in this group that a beneficial prophylactic effect of acyclovir
was most dramatically demonstrated.

8. After randomization episcleritis was at entry in a higher proportion of the placebo-treated group
(thereby confounding further analysis). Episcleritis lasted less than a month in 70% of cases and
persisted beyond three months in 15%. Other sclera inflammatory disorders were infrequent.
Dendriform keratopathy was likewise present in a high proportion of patients at entry (24%). Here a
significant beneficial prophylactic effect with respect to incidence was obtained from acyclovir but
the mean duration of the lesion was comparable: 4.9 days in acyclovir-treated patients versus 5.5
days in placebo-treated patients. Stromal keratitis, occurring in 41% of all study patients, was
significantly reduced in the acyclovir treatment group. The severity of stromal keratitis and corneal
scarring or vascularization consequent to stromal keratitis was not affected by antiviral therapy.
Duration of stromal keratitis, likewise was not affected by acyclovir treatment. While the majority
of patients with stromal keratitis responded in 30 days, eight patients (2 acyclovir, 6 placebo)
experienced this complication beyond 3 months.

9. Anterior uveitis: the incidence for the entire study group was 44%. Acyclovir not only provides a
beneficial prophylactic effect with respect to anterior uveitis, but the maximum severity scores of
this event indicate more severe disease in placebo-treated patients. As with stromal keratitis,
duration of this complication of HZO is not significantly ameliorated by acyclovir. Keratic
precipitates, a clinical indicator of anterior uveitis, are significantly reduced in incidence by acyclovir
treatment.
Iris atrophy was observed in 7% of all study patients. It was not observed before three months
follow-up and presented at a mean time of 206 days after entry into the trial. Four of five patients
in whom it occurred also experienced anterior uveitis. No patient developed secondary cataract,

10. vitritis, retinitis, optic neuritis, extraocular muscle palsies, or contralateral hemiparesis during the
period of observation. No significant differences in intraocular pressure were observed between
acyclovir and placebo treated patients. Four patients followed beyond three months had HZO-
related reduction in visual acuity to 20/100 or worse (5.6%). The one acyclovir treated patient in
this group developed corneal scarring as a consequence of stromal keratitis and anterior uveitis.
Three other patients, placebo-treated, developed visual loss due to posterior scleritis (two
patients) and neurotrophic corneal ulceration (one patient). Pain persisted beyond three months
in 41% of acyclovir treated and 35% of placebo treated patients with post herpetic neuralgia.

11. HZ KERATITIS Frequency
(%)
Usual
onset
TREATMENT (REVIEW OF CASE STUDIES)
Acute HZO (1 week):
oral antiviral (Famvir or Valtrex) + topical steroid +
topical antibiotic
Late HZO (> 1 week):
topical steroid + topical antibiotic
Among respondents who chose to treat with topical
corticosteroids, the most common choice of
corticosteroid and dose was 1% prednisolone acetate 4
times a day (55 of 97, 57%),
punctate epithelial keratitis 50 2 days keratoconjunctivitis was established. A 7-day course of
oral acyclovir (800 mg/day) along with topical
prednisolone acetate 1% and moxifloxacin
early pseudodendrites – stain
with rose Bengal not
fluorescein, tapered ends,
raised not ulcerated
50 4-6day Generally self-limited and treated with lubrication with
artificial tears or ointment. May respond to topical
antiviral agents (e.g. vidaribine ointment or ganciclovir
gel,) especially if the pt is immunocompromised.
anterior stromal infiltrates 40 10days Topical steroid
keratouveitis/endotheliitis 34 7 days Topical steroid and nonprostaglandin antiglaucoma drop
serpiginous ulceration 7 1 mo Antibiotic, late topical steroid
sclerokeratitis 1 1 mo Topical steroid and Oral NSAID for scleritis
Corneal mucous plaques 13 2-3mos Full dose oral antivirals or topical vidaribine or TFT may or
may not succeed.
Disciform keratitis 10 3-4mos Topical steroid
neurotrophic keratopathy (and
persistent epithelial defects can
lead to perforation)
25 2 mos Lubrication, antibiotic, surgical
exposure keratopathy 11 2-3mos Lubrication, antibiotic, surgical
Interstitial keratitis/lipid
keratopathy
15 1-2 yrs 1-month course of prednisolone acetate,
1%, starting at 4 times per day
Permanent corneal edema 5 1-2yrs Topical steroid, surgical

12. Herpes Zoster Complications include:
1. Ramsay Hunt Syndrome– 7th
CN, facial muscle weakness, loss of taste in anterior 2/3rds of tongue
and vesicles in the external auditory canal or pinna.
2. Acute Retinal Necrosis – potentially blinding condition which can occur due to VZV, HSV, or CMV in
otherwise normal patients. May begin with anterior uveitis, and progress to include retinal arteritis,
perivascular sheathing, necrotizing retinitis (peripheral retinal whitening which progresses over several
days, active retinitis lasting 4 to 6 weeks during which an exudative RD may occur), vitritis,
rhegmatogenous RD (75%), NVD/NVE.
3. Progressive Outer Retinal Necrosis – reported in HIV patients—multifocal, patchy choroidal and deep
posterior retinal opacification that may initially be parafoveal. There is an absence of vitreous or
anterior chamber reaction or signs of active vasculitis. Progresses rapidly from the posterior pole to
involve the entire retina.

13. After Reactivation stabilizes:
Post Herpetic Neuralgia
Plot of duration of any pain from start of herpes zoster
among patients in two age groups.
Other important points:
The development of Zoster in healthy young adults should raise suspicion of HIV
Whether it occurs early or late in the pregnancy, Herpes Zoster appears to have no
deleterious effects on either the mother or the infant.
References
Albert and Jacobiec, Pavan-Langston, Krachmer’s Cornea, Sundmacher’s Color Atlas of Herpetic
Eye Disease, Rapuano’s Wills Eye Cornea, Habif’s Clinical Dermatology, Zajac and Harrington at
UAB