Ophthalmology Yanoff Herpes Zoster Ophthalmicus 4.5

1. 180
EPIDEMIOLOGY AND PATHOGENESIS
Herpes zoster (zoster, shingles) is a neurocutaneous disease caused by
the human herpes virus 3, the same virus that causes varicella (chick-
enpox). It is a member of the herpes virus family (Herpesviridae) and
exclusively infects human or simian cells. Varicella zoster virus (VZV)
is the smallest of the alphaherpes viruses and has very stable linear
double-stranded DNA. It has an icosohedral capsid and lipid envelope,
which contains glycoproteins for cell entry.1
Herpes zoster has the highest incidence of any neurologic disease,
affecting approximately 500000 people in the United States yearly. The
lifetime risk is 20–30%, and 50% of those living until 85 years of age
will be affected.2–4
The reported incidence varies from 2.2–3.4 per 1000
individuals per year. Herpes zoster develops more frequently in the
elderly, with an incidence rate of 10 per 1000 per year in people over
80 years. The incidence of zoster in immunosuppressed patients is
substantially higher.5
In temperate climates, primary infection with this virus usually
occurs before the age of 10, manifesting clinically as chickenpox (vari-
cella). The virus then establishes a latent state in the sensory ganglia.
In circumstances of diminished virus-specific and cell-mediated immu-
nity, the virus may reactivate and spread to the corresponding der-
matome along a spinal or cranial nerve (usually the trigeminal nerve)
to generate the characteristic unilateral vesicular exanthem. The
accompanying inflammation of the sensory nerve and skin damage are
purportedly responsible for the acute pain.6,7
Physical trauma and surgery have been correlated with the develop-
ment of zoster.8–11
Other reported triggers include tuberculosis, syphilis,
radiation therapy, and steroids.12
The epidemiology of zoster is ultimately dependent on the transmis-
sion and spread of VZV in a population. The spread of primary varicella
(chickenpox) infection is of primary importance, but latent and reacti-
vated infections also play an important role in maintaining VZV infec-
tions within a population. Latently infected elderly adults and
immunosuppressed patients are important reservoirs of the virus, as
these groups are more likely to experience reactivation. When zoster
does occur, the virus can be transmitted to a seronegative individual
during the vesicular phase of the rash and cause a primary varicella
infection. A zoster exposure with a seropositive, latently infected indi-
vidual may result in a subclinical re-infection and boost humoral and
cellular VZV immunity but is unlikely to cause varicella or herpes
zoster.13
Herpes zoster may also develop in immunologically competent
patients who harbor the latent virus and who are re-exposed to it by
contact with someone who has an active varicella or zoster infection
(primary, spontaneous, or infectious zoster).12,14,15
Ophthalmic Herpes Zoster
The frequency of herpes zoster ophthalmicus (HZO) is second only to
thoracic dermatomal occurrence, with up to 250000 cases occurring
yearly in the United States. Of these, 50–70% suffer visual morbidity
with severity increasing in the 5th–8th decades of life.3,16
The virus
most commonly establishes latency in the trigeminal sensory ganglion
and reactivates in 10–25% of the population.16
The ophthalmic division
of the trigeminal nerve is affected 20 times more frequently than the
maxillary or mandibular divisions.17
Ocular involvement occurs in
more than 70% of patients with zoster of the first (ophthalmic) division
of the trigeminal nerve. VZV more commonly resides in the portions
of the ganglion that supply the upper lid and nasociliary branch of the
trigeminal nerve. Nasociliary branch involvement with skin lesions
located on the inner corner of the eye, tip of the nose, and the root or
side of the nose (Hutchinson’s sign) is much more predictive (50–85%)
of ocular involvement and is strongly prognostic for ocular inflamma-
tion and corneal sensory denervation.12,18
It is important to remember
that the eye may be seriously affected in up to 50% of cases in the
absence of Hutchinson’s sign.19
HZO usually begins with a prodrome of influenza-like illness char-
acterized by fatigue, malaise, nausea and mild fever accompanied by
progressive pain and skin hyperesthesia. A diffuse erythematous or
maculopapular rash then appears over a single dermatome 3–5 days
later. These eruptions progress to form clusters of papules and clear
vesicles, which then evolve through stages of pustulation and crusting.
Patients with deeper involvement of the dermis may develop perma-
nent scars with loss of normal pigmentation. Rarely, herpes zoster may
manifest with ophthalmic symptoms in the absence of cutaneous
eruptions.7,20
CLINICAL MANIFESTATIONS
HZO can affect all ocular and adnexal tissues, and manifests with a
diverse array of signs and symptoms. Ocular or extraocular involve-
ment may occur at the time of the cutaneous eruptions or years later.
The skin of the forehead and upper eyelid is commonly affected and
strictly obeys the midline with involvement of one or more branches of
the ophthalmic division of the trigeminal nerve (Fig. 4-5-1). Zoster
involves the deep dermis, in contrast to herpes simplex, which is lim-
ited to the epidermis. The deep involvement causes numerous lid
complications such as scarring, entropion and ectropion. Conjunctival
findings include hyperemia, petechial hemorrhages, papillary or follicu-
lar reaction and rarely a pseudomembrane. Episcleritis and scleritis are
common and tend to progress towards the limbus causing vasculitis
and sterile corneal infiltrates.21
Corneal pathology tends to results from three pathophysiologic
mechanics: (1) active viral infection; (2) immune-mediated inflamma-
tion; and (3) chronic neurotrophic keratopathy. Active viral infections
tend to affect the epithelium, leading to punctate epithelial keratitis
and pseudodendrites (Fig. 4-5-2). These lesions likely contain live
virus. Pseudodendrites are typically smaller than typical dendrites, and
lack terminal end-bulb formations. An immune-mediated stromal
keratitis can take multiple forms. Nummular keratitis is the earliest
finding of corneal stromal involvement and presents during the second
week of the disease in 25–30% of patients.21
It is characterized by mul-
tiple, fine, granular coin-shaped infiltrates of different diameters in the
anterior stroma and can lead to permanent scarring. Chronic intersti-
tial keratitis can lead to deep corneal neovascularization and lipid
keratopathy. Disciform keratitis is a deep stromal infiltrate that devel-
ops 3–4 months after the acute phase. Examination reveals a central
disc-shaped area of diffuse corneal edema that results from
Gene Kim, Majid Moshirfar 4.5Herpes Zoster Ophthalmicus (HZO)
SECTION 3 External Diseases
PART 4 CORNEA AND OCULAR SURFACE DISEASES
Definition: Infection of varicella (chickenpox) in the ophthalmic
division of the trigeminal dermatome most frequently affecting the
nasociliary branch.
Key features
■ HZO can affect any of the ocular and adnexal tissues.
■ Treatment with antivirals more effectively promotes rash healing
and prevents ocular complications compared to placebo.
Associated features
■ Postherpetic neuralgia

2. HerpesZosterOphthalmicus(HZO)
4.5
181
from HZO is often multifactorial. Early causes are from active trabe-
culitis that resolves with steroids, but chronic inflammation leads to
papillary seclusion, chronic angle-closure glaucoma, and eventually
steroid-response glaucoma.
Posterior segment manifestations of HZO include retinal perivascu-
litis, ischemic optic neuritis, and forms of necrotizing retinopathy.
These complications are rather uncommon but vision-threatening.
Two clinical recognizable forms of retinitis are worth noting: acute reti-
nal necrosis (ARN), which tends to occur in immunocompetent
patients, and progressive outer retinal necrosis (PORN), which occurs
in immunocompromised patients. ARN tends to present with severe
ocular inflammation, while PORN tends to have a more quiet appear-
ance, but a much faster and vision-threatening clinical course.21
External ocular motor palsies frequently occur in acute HZO. They
may affect the third, fourth, and sixth cranial nerves. These complica-
tions are thought to be from vasculitis within the orbital apex and fre-
quently resolve within a year.
Postherpetic Neuralgia
Pain that continues following rash healing has been termed posther-
petic neuralgia (PHN). Pain in HZO has three phases: (1) acute pain –
first 30 days after rash onset; (2) subacute herpetic neuralgia – between
30 and 120 days; and (3) PHN when greater than 120 days.22,23
Postherpetic neuralgia can occur in any patient with HZO; however,
it is not usually seen in patients less than 50 years of age, and its fre-
quency increases until age 70. It afflicts about one-half of all herpes
zoster patients older than 70 and appears to be more severe in older
patients.12
The pain may occasionally be so extreme and persistent that
patients may consider suicide.12
Risk factors for PHN include greater
acute pain severity,23,24
greater rash severity,25,26
and the presence of a
painful prodrome preceding the rash.27
Additional independent risk fac-
tors for the development of PHN include older age and female sex.22
HERPES ZOSTER OPHTHALMICUS IN ACQUIRED
IMMUNE DEFICIENCY SYNDROME (AIDS)
HZO is an important early clinical marker for AIDS, especially in high-
risk younger patients.28–30
These patients have a higher incidence,
greater severity, and prolonged course of corneal and uveitic involve-
ment, as well as PHN compared with immunocompetent patients with
HZO.31
All young patients with HZO should be tested for HIV. Patients
with HZO and HIV should be treated with intravenous acyclovir.32
Progressive outer retinal necrosis (PORN), a distinct form of necrotiz-
ing herpetic retinopathy, is reported with increasing frequency in AIDS
patients. PORN is characterized by multifocal, deep retinal lesions that
rapidly progress to confluence with minimal or no intraocular inflam-
mation, an absence of vascular inflammation, and perivenular clearing
of retinal opacification.19
Following cytomegalovirus retinopathy, PORN
is the second most frequent opportunistic retinal infection in patients
with AIDS in North America.33
DIAGNOSIS
The diagnosis of herpes zoster disease is generally based on clinical
findings, although in recent decades the clinical manifestations and
spread of VZV have shifted, largely due to the high prevalence of HIV
and otherwise immunocompromised patients. This may confound
clinical impressions, e.g., HSV lesions may show a zosteriform spread
and be difficult to differentiate from shingles. Differential diagnosis
includes eczema herpeticatum, eczema vaccinatum, impetigo contagio-
sum, enterovirus-associated exanthema, contact dermatitis, drug erup-
tions, and insect bites.
Direct detection of the virus and indirect serological detection of
specific antibodies may be used to boost diagnostic acumen. Specimens
(cutaneous vesicular scraping or conjunctival swab) must be trans-
ported to the laboratory as quickly as possible under low temperature
conditions (4°C).33
Cytologic examination of cutaneous vesicular scrapings reveals mul-
tiple eosinophilic intranuclear inclusions (Lipschutz bodies) and multi-
nucleated giant cells (Tzanck preparation). Electron microscopy (EM)
may be used to directly detect VZV; however, the morphology is identical
for all herpesviridae, so immune EM techniques using specific
peroxidase-labeled monoclonal antibodies against specific virus anti-
gens are necessary to distinguish VZV from other herpes viruses.34
endotheliitis and anterior chamber inflammation. Perilimbal vasculitis
results from immune-complex deposition and can lead to sterile,
peripheral, anterior cornea stromal infiltrates.
Active zoster infections travel through branches of the ophthalmic
division of cranial nerve.5
Each reactivation damages the corneal nerves
causing progressive neurotrophic cornea. Late-stage HZO gives the
picture of chronic epitheliopathy with filamentary keratitis and anterior
stromal scars from a compromised ocular surface. The risk of second-
ary bacterial infection is very high in this setting.19
HZO can cause either a nongranulomatous or granulomatous iri-
docyclitis (anterior uveitis) with keratic precipitates. It often has a
chronic and recurrent course necessitating topic cortical steroids for
control. Specific signs include elevated intraocular pressure from
trabeculitis and sectorial, vaso-occlusive iris atrophy. The glaucoma
Fig. 4-5-1 Herpes zoster ophthalmicus involving the V1 distribution.
Fig. 4-5-2 Peripheral corneal epithelial pseudodendrites in a patient with a history
of herpes zoster ophthalmicus. (From Hu AY, et al. Late varicella-zoster virus dendriform keratitis in
patients with histories of herpes zoster ophthalmicus. Am J Ophthalmol 2010;149:214–220 e3.)

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182
CORNEAANDOCULARSURFACEDISEASES
effective than tricyclic antidepressants against treating allodynia,
another subtype of neuralgia.46
Capsaicin cream (0.025%) is effective
when applied to the involved skin 3–4 times daily, although 2 weeks of
treatment are often required for pain relief.47
PHN may be severe,
intractable, and permanent, with some patients requiring psychiatric
and pain clinic care, and occasionally trigeminal rhizotomy or stellate
ganglion block.48
The use of systemic steroids in the treatment of PHN remains con-
troversial. Recent studies have found no benefit of oral prednisolone
compared with placebo in preventing PHN.49
Prednisolone-treated
patients did have more pain relief initially; however, at 6 months there
was no difference between the two groups.
Findings of a meta-analysis reveal that famciclovir and valacyclovir
significantly reduce the duration but not incidence of PHN. Steroids
have no effect on PHN. Amitriptyline for 90 days reduced the incidence
of pain at 6 months. Finally, a single trial of percutaneous electrical
nerve stimulation (PENS) in 50 patients suggested a decrease in pain
incidence at 3 and 6 months when compared with famciclovir.50
PREVENTION
The varicella vaccine is available in two formulations which are both
given subcutaneously: Varivax (Merck) and Zostavax (Merck). The
former prevents primary varicella infections in infants while the latter
prevents reactivation of zoster in adults. Both utilize live attenuated
virus. The main differences between the two vaccines are their dosing
and concentration. Zostavax is only administrated once and has 14
times the concentration of Varivax, which needs to be given twice.51
The Shingles Prevention Study (SPS) showed that the vaccine reduced
the incidence of HZO by 49% and reduced the severity of the illness in
those that did have a reactivation of the virus.52
The vaccine was gener-
ally safe and well tolerated with the rate of adverse events being 1.4%
and no difference in the vaccine versus placebo group. The most com-
mon adverse effect was pain and erythema at the injection site. The
vaccinated group, however, did have a higher rate of serious adverse
events. A couple of case reports in the literature report exacerbation of
chronic HZO and also of new onset retinitis in immunocompromised
patients within the first 6 weeks following vaccination.51,53
Currently, the Centers for Disease Control and Prevention (CDC)
and Advisory Committee on Immunization Practices (ACIP) recom-
mend that the zoster vaccine be administrated to adults aged 60 and
above for the prevention of herpes zoster, including those who have
already had a case of zoster.
KEY REFERENCES
Arvin AM. The varicella-zoster virus. In: Watson CPN, Gershon AA, editors. Herpes zoster and
post herpetic neuralgia. 2nd ed. Pain research and clinical management, vol. 11. New York:
Elsevier Science BV; 2001. p. 25–39.
Balfour Jr HH, Bean B, Laskin OL, et al. Acyclovir halts progression of herpes zoster in
immunocompromised patients. N Engl J Med 1983;308:1448.
Brinsson M, Edmunds WJ, Law B, et al. Epidemiology of varicella zoster virus infection in Canada
and the United Kingdom. Epidemiol Infect 2001;127:305–14.
Choo PW, Galil K, Donahue JG, et al. Risk factors for postherpetic neuralgia. Arch Intern Med
1997;157:1217–24.
Colin J, Pristant O, Beatrice C, et al. Comparison of the efficacy and safety of valaciclovir and
acyclovir for the treatment of herpes zoster ophthalmicus. Ophthalmology 2000;107:
1507–11.
Gelb LD. Preventing herpes zoster through vaccination. Ophthalmology 2008; 115(2 Suppl):
S35–8.
Liesegang TJ. Herpes zoster ophthalmicus natural history, risk factors, clinical presentation,
and morbidity. Ophthalmology 2008;115(2 Suppl):S3–12.
Mahalingam R, Wellish M, Lederer D, et al. Quantitation of latent varicella-zoster virus DNA in
human trigeminal ganglia by polymerase chain reaction. J Virol 1993;67:2381–4.
Pavan-Langston D. Herpes zoster antivirals and pain management. Ophthalmology 2008;
115(2 Suppl):S13–20.
Sellitti TP, Huang AJ, Schiffman J, et al. Association of herpes zoster ophthalmicus with acquired
immunodeficiency syndrome and acute retinal necrosis. Am J Ophthalmol 1993;116:297.
Wolff MH, Schunemann S, Rahaus M, et al. Diagnosis of varicella-zoster virus associated diseases
with special emphasis on infections in the immunocompromised host. In: Wolff MH,
Schunemann S, Schimdt A, editors. Varicella-zoster virus: molecular biology, pathogenesis
and clinical aspects. Contributions to Microbiology, vol. 3. Basle: Karger; 1999. p. 150–7.
Zaal MJW, Volker-Dieben HJ, D’Amaro J. Prognostic value of Hutchinson’s sign in acute herpes
zoster ophthalmicus. Graefes Arch Clin Exp Ophthalmol 2003;241:187–91.
VZV-DNA can be directly obtained via anterior chamber paracentesis or
vitreous tap and analyzed using real-time PCR.35
Fluorescent antibody
techniques, cytospin direct immunofluorescence staining, and rapid
direct immunofluorescence assays (SimulFluor direct fluorescent anti-
body) are additional methods for detecting VZV virus.36
Serologic testing to detect herpes zoster antibodies is of limited use
as cross-reactivation between VZV and HSV can occur. Following
zoster, a booster of IgG is detected for 2 weeks after infection, which
then falls to lower levels, where it may remain for years.37
MANAGEMENT
HZO is treated with oral antivirals: acyclovir, famciclovir, or valacyclo-
vir. Acyclovir (800 mg, five times daily) for 7–10 days, which reduces
viral shedding and the chance of systemic dissemination of the virus as
well as the incidence and severity of ocular complications, particularly
if used within 72 hours of onset of symptoms.38,39
Acyclovir can also
shorten the duration of pain if taken within the first 3 days of onset of
symptoms.40,41
Intravenous acyclovir is recommended in immunocom-
promised patients.38
Famciclovir is a prodrug of penciclovir and has a much higher bioa-
vailability (77%) than acyclovir (18%). The recommended dosage is
500 mg three times daily for 7 days, which has been shown to be well
tolerated and safe with similar efficacy to acyclovir 800 mg five times
daily.42
Valacyclovir is the L-valine ester of acyclovir and has higher bioavail-
ability (80%) than acyclovir (18%). The usual dosage is 1000 mg three
times daily. It has similar activity to acyclovir in the prevention of the
sequelae of herpes zoster. Valacyclovir has been shown to be as effective
as acyclovir in preventing ocular complications of HZO, including con-
junctivitis, superficial and stromal keratitis, and pain. This compara-
tive analysis also showed that tolerability of the two drugs was similar,
but the dosing schedule of valacyclovir was simpler.43
Valacyclovir has
been shown to significantly accelerate the resolution of pain when com-
pared with acyclovir.44
Comparisons between valacyclovir and famciclo-
vir treatment in HZO have not shown a statistically significant
difference in resolution of pain or rash.45
Management of Ocular Manifestation
Palliative therapy, including Burow’s solution, cool compresses,
mechanical cleansing of the involved skin, and topical antibiotic oint-
ment without steroid, are helpful in treating skin lesions.
Oral acyclovir has been shown to be effective for the punctate, pseu-
dodendritic, and delayed corneal mucous plaque forms of herpes zoster
epithelial keratitis.40,41
Debridement may also be helpful.
Neurotrophic keratitis or the epithelial defects associated with her-
pes zoster keratitis may be treated with nonpreserved artificial tears,
eye ointments, punctal occlusion, pressure patching, or therapeutic soft
contact lenses. If these measures are unsuccessful then tarsorrhaphy,
conjunctival flap, or autologous conjunctival transplantation should be
considered.
Topical steroids are useful in the management of sclerokeratitis,
keratouveitis, interstitial keratitis, anterior stromal infiltrates, and
disciform keratitis.21
Steroids should not be used in cases of exposure
or neurotrophic keratitis because of the possibility of keratolysis.21
Topical cycloplegics prevent ciliary spasm associated with herpes zoster
inflammatory disease. Aqueous suppressants and topical corticoster-
oids should be used to treat HZO glaucoma. Herpes zoster vitritis,
vitreous hemorrhage, or vitreous debris is usually secondary to severe
inflammation and may respond to topical, periocular, or systemic
steroids. Herpes zoster infections affecting the cranial nerves are best
treated with a combination of systemic steroids and intravenous acy-
clovir. Retinitis (acute retinal necrosis syndrome and progressive outer
retinal necrosis) is best treated with a combination of intravitreal injec-
tion and oral valacyclovir.
Postherpetic Neuralgia
Postherpetic neuralgia may be treated with analgesics, tricyclic antide-
pressants (nortriptyline, amitriptyline, desipramine, clomipramine),
and anticonvulsants (carbamazepine and phenytoin), often in combina-
tion. Newer medications, e.g., gabapentin and pregabalin, are more
Access the complete reference list online at

4. HerpesZosterOphthalmicus(HZO)
4.5
182.e1
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