Herpes Zoster Ophthalmicus

Natural History, Risk Factors, Clinical Presentation, and Morbidity

Thomas J. Liesegang, MD
Topic: The incidence and morbidity of herpes zoster (HZ) and HZ ophthalmicus (HZO), and the potential impact of varicella vaccine on their epidemiology. Clinical Relevance: Herpes zoster affects 20% to 30% of the population at some point in their lifetime; approximately 10% to 20% of these individuals will have HZO. Methods: The peer-reviewed literature published from 1865 to the present was reviewed. Results: Herpes zoster is the second clinical manifestation of varicella-zoster virus (VZV). The incidence and severity of HZ increase with advancing age. Varicella-zoster virusspecic cell-mediated immunity, which keeps latent VZV in check and is boosted by periodic reexposure to VZV, is an important mechanism in preventing VZV reactivation as zoster. Thus, widespread varicella vaccination may change the epidemiology of HZ. Herpes zoster ophthalmicus occurs when HZ presents in the ophthalmic division of the fth cranial nerve. Ocular involvement occurs in approximately 50% of HZ patients without the use of antiviral therapy. There is a long list of complications from HZ, including those that involve the optic nerve and retina in HZO, but the most frequent and debilitating complication of HZ regardless of dermatomal distribution is postherpetic neuralgia (PHN), a neuropathic pain syndrome that persists or develops after the zoster rash has resolved. The main risk factor for PHN is advancing age; other risk factors include severe acute zoster pain and rash, a painful prodrome, and ocular involvement. Many cases of HZ, HZO, and PHN can be prevented with the zoster vaccine. Conclusion: Vaccination is key to preventing HZ, HZO, and PHN, but strategies for both varicella and HZ vaccines will need to be evaluated and adjusted periodically as changes in the epidemiology of these VZV diseases become more evident. Ophthalmology 2008;115:S3S12 2008 by the American Academy of Ophthalmology.

The varicella-zoster virus (VZV, or human herpes virus type 3) is found in a worldwide geographic distribution and causes 2 distinct viral syndromes. Primary infection presents as varicella (chickenpox), a contagious and usually benign childhood illness occurring in annual spring epidemics among susceptible children in temperate climates. In tropical climates, many young adults have not had primary VZV infection and remain susceptible. Second episodes of varicella are rare.1 Herpes zoster (HZ, or shingles) typically manifests as unilateral pain in a dermatomal distribution accompanied by a vesicular rash. Herpes zoster usually occurs in older adults and results from reactivation of the latent VZV within the sensory spinal or cerebral ganglia. The varicella vaccine and zoster vaccine will alter the course of both VZV diseases, though perhaps in a complex fashion.

Varicella
Varicella is characterized by fever, myalgias, anorexia, headache, sore throat, and an acute infectious exanthema with a vesicular eruption of the skin. Before the varicella vaccine was introduced, chickenpox developed in almost all children, producing an incidence equivalent to the United States birth rate at the time, albeit many cases are mild and unrecognized as chickenpox. Although many parents or children may not remember or may not have recognized their prior varicella in the prevaccination era, 95% of the population has serological evidence of prior VZV infection.1 Varicella is spread through respiratory droplets with an initial viremia followed by viral spread to the skin, the eye, and then the sensory ganglia throughout the body, where it establishes latency. Varicella is easily disseminated to susceptible individuals, with 90% of susceptible household contacts contracting the disease.1 Transplacental transfer of VZV may occur when varicella is acquired by the mother during early pregnancy, placing the fetus at risk for congenital varicella syndrome. This is characterized by microcephaly, extensive skin scars, hypopigmented skin areas, undeveloped limbs, and damage to the autonomic nervous system. Serological
ISSN 0161-6420/08/$see front matter doi:10.1016/j.ophtha.2007.10.009

From the Mayo Clinic College of Medicine, Jacksonville, Florida. STATEMENT OF CONFLICT OF INTEREST: this author has no relevant conicts to report. Correspondence to Thomas J. Liesegang, MD, Professor of Ophthalmology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224. E-mail: tliesegang@mayo.edu.
2008 by the American Academy of Ophthalmology Published by Elsevier Inc.

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tests can be employed during pregnancy to conrm prior varicella infection and better determine the risks of congenital varicella.1 Varicella may be accompanied by ocular signs, including a mild conjunctivitis and episcleritis. Less frequently, microdendritic keratitis, nummular keratitis, disciform keratitis, mucous plaque keratitis, sclerokeratitis, and iritis may occur.2 In children, wild-type varicella is a common selflimiting disease, usually requiring minimal treatment. However, varicella infection in neonates, adults, and the immunosuppressed can lead to severe complications such as pneumonitis and encephalitis.1 Before the introduction of the varicella vaccine in the U.S., about 12 000 to 13 000 patients were hospitalized, and approximately 100 to 150 previously healthy individuals died each year because of complications from varicella.35 The incidence of varicella diminished 90% after implementation of the varicella vaccine in 1995, and the vaccine has permanently changed the epidemiology of varicella in the U.S.35 6% to 26% of immunocompromised patients; 10% to 50% of these patients also develop visceral involvement (e.g., pneumonitis, meningoencephalitis, hepatitis).14 Five percent to 15% of patients with visceral dissemination of HZ die, despite intravenous acyclovir therapy; most of these deaths are due to pneumonitis. Approximately 40% of otherwise healthy individuals with HZ have elevated leukocyte counts and protein levels in the cerebrospinal uid; VZV has been isolated from the cerebrospinal uid of these patients.15 Herpes zoster presents as an acute, painful, vesicular eruption distributed along a single dermatome and is associated with a prodrome of fever, malaise, headache, and pain in the dermatome. An affective disorder, such as anorexia, lassitude, mood changes, antisocial behavior, severe depression, and insomnia, may accompany HZ for a prolonged time. The rash evolves from an erythematous lesion, with macules, papules, vesicles, pustules, and crusts developing subsequently. New lesion formation in the primary dermatome frequently stops within 3 to 7 days, and in the healthy individual, the affected dermatome often heals within 2 weeks but may not resolve for 4 to 6 weeks. Nearly 50% of older adults with HZ develop complications.6 The accompanying inammation of the sensory nerve and skin damage are responsible for the acute pain, which may be severe and may last for weeks or even months.16 Postherpetic neuralgia (PHN) is the most common lingering complication of HZ. Although the zoster rash is a characteristic feature of HZ, zoster sine herpete is diagnosed in patients who have acute unilateral neuropathic pain or unilateral features of HZ with all attendant complications, including HZ ophthalmicus (HZO), in the absence of a recognizable skin involvement.17 An increase in immunoglobulin-G antibody titers between acute- and convalescent-phase specimens can conrm evidence of the VZV reactivation in the absence of skin involvement.18

Herpes Zoster
Herpes zoster is the second clinical manifestation of VZV infection and occurs only in individuals who have had primary VZV infection (varicella) by either wild-type or vaccine-type VZV. Although HZ is not a reportable disease, it is estimated that 1 million or more cases occur each year in the U.S.6 9 Herpes zoster exhibits no seasonal pattern, conrming that the disease results from the reactivation of latent virus rather than new exposure to VZV. It has been predicted that the incidence of HZ will increase in the coming decades, due to the increasing age of the population and also as a possible consequence of childhood varicella vaccination, as described in more detail below.8,10 DNA studies conrm that HZ is a reappearance of the same specic childhood virus. Varicella-zoster virus, like other herpes viruses, has developed complex control of virus host interactions to ensure continued survival in the human population. It lies largely dormant in the ganglion but may move down the neurons and satellite cells along sensory axons to the skin. Once there, the virus may spread from cell to cell and form lesions that eventually penetrate the epidermis; a viremia accompanies this reaction.1,11 Histopathologic studies of ganglia undergoing this process reveal inammation, necrosis, and disruption of the morphology of neuronal and nonneuronal cells; this process may extend into the anterior horn cells, producing myelitis and decits of motor function.1 Periodic episodes of subclinical reactivation of VZV from the ganglia occur throughout an individuals lifetime, serving as immune boosters that increase the cell-mediated immune response to VZV. Using polymerase chain reaction, the presence of subclinical VZV viremia has been conrmed in 19% of bone marrow transplant recipients who had no clinical signs of HZ. Additional studies suggest that elderly adults have similar episodes of transient asymptomatic VZV viremia.12,13 As further evidence of the viremia that likely occurs in all patients with acute HZ, scattered cutaneous lesions outside the primary dermatome occur in

Risk Factors for Herpes Zoster

The virulence of the specic VZV strain may inuence the extensiveness and efciency of the establishment of latent VZV infection in dorsal root ganglia during varicella, but the host factors are more important in determining whether the individual with a latent infection develops symptomatic VZV reactivation as HZ. The incidence and severity of HZ increase with advancing age, especially in those older than 60 years.6,19 Approximately 20% to 30% of the general population develop HZ at some point in their lifetimes, rising to as many as 50% of individuals living until 8520; an 85-year-old has about a 1% chance of HZ appearing twice.21 In 1965, Hope-Simpson initially proposed that immunity to VZV determines the incidence of HZ,22 and many subsequent studies conrm that specic cell-mediated immunity (CMI) to VZV is the major determinant of the risk and severity of HZ in both elderly patients and patients receiving immunosuppressive therapy.13,2229 Remarkably, HopeSimpson also correctly predicted that both periodic expo-

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sures to persons with varicella and routine asymptomatic periodic release of VZV from the ganglia are important mechanisms in providing a boost to CMI against VZV in individuals and delays the occurrence of HZ for decades.22 Antibody levels to VZV only conrm a prior VZV infection and cannot be used as a marker for susceptibility to HZ, although the presence of antibodies does continue to protect from a recurrence of varicella.11 VZV-specic memory T cells are believed to contain VZV reactivation, thus preventing HZ. Once the T cellspecic immunity is below a certain level, a person is at risk for VZV reactivation as HZ. Substantiating this concept is the fact that repeat episodes of HZ are uncommon among immunocompetent persons, probably because an episode of HZ boosts immunity to VZV and usually prevents further episodes.30 Determining the activity of VZV-specic T-cells is a cumbersome laboratory procedure and cannot be used for clinical testing. Although HZ makes no distinction between sexes and demonstrates no seasonal preference, one study suggested that genetic factors may play a role. Elderly black Americans were one fourth as likely as elderly white Americans to develop HZ, after controlling for age, cancer, and demographic factors.31 Although cancer is no longer considered a risk factor for HZ,32 patients treated with immunosuppressive drugs for malignant diseases or to prevent rejection of bone marrow or organ transplants have a signicantly increased risk for HZ; individuals with human immunodeciency virus (HIV) infection also face a higher risk of HZ.33 In immunocompromised patients, HZ is more likely to be prolonged, to recur, and to result in VZV myelitis (weakness and incontinence) and vasculopathy (changes in mental status, speech disturbances, seizure, and severe motor decit).34 Because the relative risk of HZ is at least 15 times greater in men with HIV than in men without HIV, any young individual with HZ should be queried about risk factors for HIV infection.25 Although almost all HZ in AIDS patients occurs when their CD4 counts fall below 200 cells/mm3, occasionally HZ occurs in individuals with higher CD4 counts.35 Recurrences of HZ occur in up to 25% of patients with AIDS, compared with 4% of nonimmunocompromised patients. Human immunodeciency viruspositive patients who develop HZ may be more likely to progress to AIDS than patients who have not been infected with VZV,35 although it is not specically associated with AIDS mortality.36 In Africa, HZO is especially common and severe for several complex reasons, and in sections of Africa, HZ is a marker for HIV infection.35,37 Herpes zoster is unusual in children under 10, with risk factors including varicella acquired during the rst year of life and VZV infection in utero as a result of maternal varicella during gestation.38 In children over 10, HZ is related to immunosuppression, malignancy, blood disorders, HIV infection, or use of systemic immunosuppressant drugs. One study found that rates of HZ in 10- to 17-yearolds are increasing and correlate with increased exposure to oral corticosteroids.39 The incidence of HZ in children with HIV or cancer or among those infected with HIV in utero may exceed 70%; these patients tend to have more complex courses and persistent disease, and almost half the children infected with HIV may have recurrences of HZ.35 Retinal, cutaneous, and neural complications of VZV in children with HIV may be similar to those found in adults, including strokes and vasculitis. Unlike adults, however, children rarely experience PHN, and overall morbidity from HZ is low in children.35,40

Herpes Zoster Ophthalmicus

Herpes zoster ophthalmicus is dened as HZ involvement of the ophthalmic division of the fth cranial nerve. The ophthalmic division further divides into the nasociliary, frontal, and lacrimal branches, of which the frontal nerve is most commonly involved with HZO.41 The nasociliary nerve innervates the anterior and posterior ethmoidal sinuses, skin of both eyelids and the tip of the nose, conjunctiva, sclera, cornea, iris, and choroid. Hutchinsons sign is dened as skin lesions at the tip, side, or root of the nose and is a strong predictor of ocular inammation and corneal denervation in HZO, especially if both branches of the nasociliary nerve are involved.42,43 Herpes zoster ophthalmicus accounts for approximately 10% to 20% of cases of HZ, and therefore, every individual has about a 1% risk of developing HZO during his or her lifetime, if they live long enough.44 Most cases of HZO have a prodromal period before skin eruptions that may include fever, malaise, headache, and pain in the eye. Ocular involvement occurs overall in about 50% of patients with HZO (before the antiviral era), but it is not always correlated with age, sex, or severity of the skin rash.45,46 The pathophysiology of the diffuse and severe ocular complications of HZO includes components of virus infection, inammatory and immune reactions, vascular and neural inammation, and tissue scarring. As a consequence of these neuropathogenic and vasculopathic processes, it is not surprising that the benet of antiviral agents is limited in patients with HZO. The disease may manifest with acute, chronic, or relapsing components, depending on the mechanisms involved. Chronic disease can persist in 30% of patients with HZO, increasing to 70% in patients older than 80 years, even in this era of antiviral agents.45 A prominent cause of persistent or chronic disease is vasculitis, perivasculitis, neuritis, and perineuritis; in fact, the neurologic damage begins before the characteristic dermatomal rash appears. The acute neuralgia that occurs in the initial phase of HZO is signicant, as is the pain of PHN, a major complication of HZO. Postherpetic neuralgia can be problematic to treat and may require prolonged management. Current pain management options are often inadequate, despite the recommended use of antiviral therapy soon after the onset of the zoster rash.6 Herpes zoster ophthalmicus has a severe visual prognosis in Africa, related to the high prevalence of HIV and several other complex factors.47 There is a long list of potential complications associated with HZO, beginning with the skin and anterior segment of the eye but potentially involving the optic nerve, retina, and CNS. It is not clear why some individuals have no or minimal complications and others develop a range of com-

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plications; it may be related to virulence of the infection, the host immune response, or both. The skin rash of HZO evolves through the same stages as the disease elsewhere, with erythema, macules, papules, and vesicles. Periorbital edema and ptosis may be prominent. In most patients, new skin lesions continue to appear for 3 to 5 days; the rash then evolves through stages of possible pustulation and crusting. Zoster involves the deep dermis in contrast to herpes simplex, which is limited to the epidermis. As the inammation resolves, there may be residual ptosis, lid scarring, deep scalp pitting, entropion, ectropion, loss of normal pigmentation, and lid necrosis (sloughing). Although HZO is characterized by this typical rash, a minority of patients have only ophthalmic symptoms and demonstrate zoster non herpete,48,49 emphasizing that the risk of ophthalmic complications may not be related to the severity of the skin rash. The surface of the globe may demonstrate an episcleritis or deeper involvement with scleritis in the early stages of the disease that may become persistent or appear in a delayed fashion. The scleritis may progress toward the limbus, manifesting as a limbal vasculitis and sclerokeratitis with a later patchy scleral atrophy. The inltrative perivasculitis and perineuritis may result in a painful posterior scleritis. Conjunctival ndings include hyperemia, petechial hemorrhages, papillary or follicular reaction, and, rarely, a pseudomembrane.50 There are multiple corneal complications of HZO that tend to occur in a temporal course related to the virus, inammatory and immune reactions, and vasculopathy and neuropathy.51 Punctate epithelial keratitis and pseudodendrites are early and transient ndings. Studies suggest that VZV DNA can persist on the corneal surface for as long as 1 month after acute HZO.52 Moreover, the duration of the viral DNA shedding varies and depends on age, possibly related to the host immune response. A nummular anterior stromal keratitis can develop, which usually resolves but may become chronic. All the corneal inammatory conditions in HZO can give rise to lipid keratopathy and facet formation. Keratouveitis/endotheliitis presents with localized stromal edema, keratic precipitates, and cell and are, and may represent direct viral infection of the endothelium or an immune reaction. Unilateral anterior uveitis in association with a specic vascular occlusive sectoral iris atrophy and no evidence of prior or concurrent epithelial or stromal keratitis is a common presentation for herpetic uveitis.49 The release of viral antigens in the iris and ciliary body initiates a mild uveitis often accompanied by temporary elevation of the intraocular pressure that may become chronic. A disciform stromal keratitis may represent a VZV infection of the endothelium or may be related to a zoster immune reaction. It resolves within a few months but may become chronic with edema and lipid keratopathy. Corneal mucus plaques or delayed pseudodendrites occur several months or years after HZO, usually in a quiescent eye. They are variable in size, migratory, and transitory around the cornea. Some reports have demonstrated the presence of VZV antigen on the ocular surface, which may respond to antiviral therapy.5355 Interstitial keratitis results from any long-term HZ corneal inammation condition and usually results in extensive corneal vascularization that subsequently leads to lipid deposition, scarring, and possible perforation. The nerve damage inherent to HZO results in a neurotrophic keratopathy with diminished corneal sensation and subsequent loss of corneal epithelial integrity and tear dysfunction. The neurotrophic keratopathy may occur abruptly months after HZO with diffuse epitheliopathy and chronic surface problems. Subsequent calcareous plaque formation may develop. Corneal edema can be transient but usually represents the chronic end stage of cornea endothelial destruction by VZV or the related inammation.50 Exposure keratopathy is associated with cicatricial eyelid changes leading to corneal desiccation and may be additive to several other corneal complications of HZO, especially the impaired corneal sensation and associated inadequate tear production. External ocular motor palsies with diplopia are frequent in acute HZO if diligently evaluated but are usually transient.56 There can be involvement of the third, fourth, or sixth cranial nerves. Such involvement may be related to vasculitis within the orbital apex (orbital apex syndrome) or to brain stem dysfunction.57 Uncommon posterior segment complications of HZO include retinal perivasculitis, ischemic optic neuritis, and forms of necrotizing retinopathy. Acute optic neuritis may lead to a permanent loss of vision.34,58 Necrotizing herpetic retinopathy is a continuous spectrum of posterior segment inammation induced by several herpes viruses, most commonly VZV. Its 2 most recognizable clinical patterns are acute retinal necrosis and progressive outer retinal necrosis. Usually, the former occurs in healthy persons and HIV patients with only mild immune dysfunction and higher CD4 counts, whereas the latter usually develops in those who are severely immunosuppressed. Common neurological complications of HZO include acute neuralgia and PHN; rare complications include a delayed contralateral hemiplegia,34 encephalitis, and myelitis. The combination of evidence that demonstrates more prolonged activity of the VZV on the surface of the eye as well as within the CNS implies that antiviral treatment regimens may need to be more prolonged, especially in the elderly and in immunosuppressed patients.

Postherpetic Morbidity
The most frequent debilitating and perhaps refractory complication of HZ is PHN, a neuropathic pain syndrome that persists or develops after the dermatomal rash has healed.59 61 Postherpetic neuralgia has a variety of denitions in the literature, including pain persisting from 1 month after rash onset, pain persisting after rash resolution, pain at 3 to 6 months after the acute episode, pain persisting 1 year after the acute episode, and pain differing from acute pain.62,63 The pain has variable manifestations, including allodynia (supercial hypersensitive burning pain), deep aching pain, sharp intermittent pain, or lancinating pain. Patients run the entire gamut of pain levels. There is a

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correlation of PHN with the severity of the rash, presence of ocular involvement, decline in corneal sensation, and presence of early severe neuralgia.19,64 Antiviral therapy reduces the severity and duration of HZ skin involvement but does not prevent the development of PHN.65 Although the adverse impact of acute pain in HZ is relatively modest when averaged across all patients, it is considerably greater in those patients who suffer from more severe and longer-lasting pain.66 It does appear to be more common, severe, widespread, and recalcitrant as patient age increases in the elderly.60,67 69 Postherpetic neuralgia occurs in 36.6% of patients over age 60 and in 47.5% of those over 70.67 Several studies have proposed a greater risk of chronic protracted pain in patients with HZO compared with HZ elsewhere, but this relation has not been found consistently.45,70 The pain and discomfort associated with HZ can be prolonged and disabling, diminishing the patients quality of life and ability to function to a degree comparable to diseases such as congestive heart failure, myocardial infarction, type 2 diabetes mellitus, and major depression.71 The greater pain burden of PHN, as assessed by the product of pain intensity and duration, is associated with poor physical functioning, increased emotional distress, decreased social functioning, depression, and psychological impairment.66,72 Postherpetic neuralgia is the primary cause of intractable debilitating pain in elderly patients and is the leading cause of suicide in patients over 70 with chronic pain.73 The intensity of acute pain during the initial phase of HZ seems to be a predictor of the severity of PHN, which suggests that the nerve damage signied by intense acute pain may cause long-lasting damage to the nervous system.19,74 Studies have conrmed that, during an episode of zoster, VZV damages both the peripheral nervous system and CNS.74 Patients who develop PHN have greater damage and loss of peripheral nerve bers than patients who have HZ but who do not develop PHN. These acute effects may lead to abnormal pain responses in the CNS. The Shingles Trial of Oral Medications to Prevent Postherpetic Neuralgia is now underway to determine if aggressive treatment of the acute pain might decrease the incidence and severity of PHN.61,75 Although the live, attenuated varicella vaccine was developed in Japan in 1974, it took over 20 years before it was approved for use in the U.S. (in 1995) because of a continuing controversy regarding infant varicella vaccination that revolves around the costs of vaccination and revaccination, the long-term efcacy of vaccination, whether the vaccine could lead to an increase in adult varicella disease, and whether it could lead to an increase in the incidence of HZ.77 Due to concerns of a potential increase in the incidence of HZ after varicella vaccination, some countries have not implemented or have abandoned varicella vaccination programs. After 1 decade of use, there is no evidence that the pediatric varicella vaccination program is increasing varicella disease rates in older children and adults, the ones at greater risk of severe disease. The vaccines effectiveness does decrease over time, and consequently, chickenpox in a previously immunized person (breakthrough varicella) is now relatively common.4,78 Approximately 3% of children and 30% of adults who were previously vaccinated will have a breakthrough infection, and a number of outbreaks or epidemics of chickenpox have been reported in daycare centers and schools where more than 75% of children had been vaccinated. Breakthrough cases of varicella are generally very mild, with an atypical rash characterized by sparse lesions that are primarily papular or papulovesicular, as opposed to vesicular; this atypical presentation makes it difcult to diagnose isolated cases clinically. Children with breakthrough varicella can still transmit the virus to unimmunized children, although transmission is less frequent than from wild-type varicella.4 Consequently, the routine administration of a second dose of the varicella vaccine is now recommended for all children. A primary infection with either the wild-type or the vaccine-type VZV results in seeding into the ganglion during the viremia or through sensory nerves from the skin lesions. Periodic exposure to persons with varicella and routine periodic release of VZV from the ganglia are both important in providing a boost to CMI against VZV in individuals. Studies before introduction of the varicella vaccine demonstrated that adults who live with children or who come into contact with them through their work have a lower risk of developing shingles than adults who have infrequent contact with children.79,80 With fewer children currently having wild-type varicella, the lower incidence of periodic exogenous exposures to wild-type varicella is expected to lead to an increasing HZ incidence rate among individuals under 50, who were previously not at much risk for HZ due to their often boosted and sufcient levels of VZV-specic cellular immunity (Figs 1, 2).81 In elderly individuals, the decreased exposure, combined with natural decline in CMI to VZV, is expected further to increase the risk of HZ in this age group in future years.4 Because skin lesions develop in response to varicella vaccination in only 5% to 7% of patients, the vaccines may develop a lower degree of ganglion population by the varicella vaccine virus; thus, the frequency of zoster is anticipated and has been found in the early years after introduction of the varicella vaccine to be lower among vaccinees than among persons who have had chickenpox.

Varicella-Zoster Virus Vaccines and Effect on Herpes Zoster

Before the varicella vaccine was introduced, almost every child in the U.S. developed chickenpox. Varicella vaccine coverage has increased steadily, reaching 67.8% nationally in 2000 among 19- to 35-month-olds.76 Since introduction of this recommended childhood vaccine, hospitalizations due to varicella have declined by 88% and ambulatory visits by 59%.3,5,76 Hospitalizations and ambulatory visits declined in all age groups, with the greatest declines among infants younger than 1 year. Total estimated direct medical expenditures for varicella hospitalizations and ambulatory visits declined by 74%, from an average of $84.9 million in 1994 to 1995 to $22.1 million in 2002.

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Figure 1. Effect of varicella vaccine on incidence of herpes zoster in various age groups in the years after vaccination. It is thought that periodic exogenous exposures to varicella help adults, especially those under age 50 years who have more exposure to children and maintain their immunity against varicella-zoster virus, helping to prevent herpes zoster (HZ). However, with the advent of the varicella vaccine, these adults will have far fewer, if any, exposures to exogenous zoster, and the incidence of HZ in those under 50 is expected to rise. Modied with permission from Goldman GS. Cost-benet analysis of universal varicella vaccination in the US taking into account the closely related herpes-zoster epidemiology. Vaccine 2005;23:3349 55.

There is concern then that varicella disease may be ameliorated in the population at the expense of causing later onset of HZ in the elderly, which would then put patients at higher risk for more severe complications such as PHN. The gradual disappearance of wild-type varicella as more children receive the varicella vaccine means that adults will not be receiving natural immunity boosts from reexposure to VZV through exposure to children infected with varicella. The zoster vaccine is anticipated to become a substitute for this boosting effect (discussed by Gelb in this supplement) (Fig 3). Ironically, the more effective the varicella vaccine is in reducing varicella, the more imperative is the need for an effective zoster vaccine as a means of boosting VZV-specic cell immune responses. This zoster vaccine intervention, presently approved only for

adults over 60 years, may fail to ameliorate the potential increased burden of HZ disease among adults under 50 (i.e., parents), who, in the prelicensure era, received considerably more exogenous exposures (boosts) than did elderly persons.82 As the generation of vaccinated children replaces those with a history of wild-type varicella, increasing HZ incidence will not be an immediate issue, but it may become an issue in a few decades. Therefore, health ofcials need to devise a costeffective universal varicella vaccination program in coordination with a zoster booster vaccine intervention strategy that exceeds the level of natural boosting that occurred when wildtype varicella circulated in the community.81 Most analyses of the cost-effectiveness of the varicella vaccine were modeled on the assumption that varicella vacci-

Figure 2. Effect of varicella vaccine on the incidence of herpes zoster (HZ) over the next several decades. Varicella vaccine may increase the incidence of HZ in the next 50 years, but in the long term it may decrease the incidence of HZ, because vaccine-type varicella results in fewer skin lesions, reducing the likelihood that varicella-zoster virus will take up residency in the dorsal root ganglion and reemerge to cause HZ. Modied with permission from Goldman GS. Cost-benet analysis of universal varicella vaccination in the US taking into account the closely related herpes-zoster epidemiology. Vaccine 2005;23:3349 55.

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Figure 3. Herpes zoster is directly related to the levels of cell-mediated immunity to varicella-zoster virus (VZV). Both exogenous varicella and herpes zoster (HZ) boost immunity to VZV, reducing the likelihood that an immunocompetent individual will develop HZ. The zoster vaccine performs a similar function, signicantly reducing the likelihood that a vaccinated individual will develop HZ. It is not known how long natural, HZ-induced, or vaccine-induced boosts to immunity against VZV last. Modied from Hope-Simpson R. The nature of herpes zoster: a long-term study and a new hypothesis. Proc R Soc Med 1965;58:9 20 and Arvin A. Aging, immunity, and the varicella-zoster virus. N Engl J Med 2005;352:2266 7, with permission from the latter.

nation would have no adverse effect on the epidemiology of the closely related disease HZ; this assumption, however, seems incorrect.8,81,83,84 Several articles have modeled the possible changes in HZ epidemiology as a result of the varicella vaccine and predict that the more effective the varicella vaccination is at preventing varicella, the larger the increase will be in HZ incidence as vaccinees get older.8,81,83,84 Some of these authors predict an increase in the incidence of zoster and an increase in overall cost from VZV disease over the next 5 to 40 years (Fig 4); however, this increase may be temporary, because the risk of reactivation of the vaccine virus is much lower than the risk of reactivation of the wild-type virus.

Eventually, the vaccine-type virus may replace all wild-type viruses, leading to a progressive decline in the risk of HZ.81,85 However, Goldman estimates that universal varicella vaccination will result in an additional 14.6 million (42%) cases of HZ among adults younger than 50 years during a 50-year time span, at a substantial medical cost burden.81 Despite the theory presented in these models, no increase in HZ prevalence has yet been found since administration of the varicella vaccine began in 1995, whereas the incidence of varicella has declined dramatically in morbidity and mortality.77 A double-blind placebo-controlled vaccine trial is underway to assess whether varicella immunization of children affects the incidence of HZ

Figure 4. Varicella-zoster virus health care costs. Varicella vaccination is expected to result in decreased health care costs. However, if varicella vaccination increases the incidence of herpes zoster among younger adults, health care costs instead of savings may actually be incurred over the next several decades. Modied with permission from Goldman GS. Cost-benet analysis of universal varicella vaccination in the US taking into account the closely related herpes-zoster epidemiology. Vaccine 2005;23:3349 55.

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later in life. The challenge for the future remains in predicting how the resulting substantial reduction in circulation of VZV will affect immunity among both varicella vaccinees and unvaccinated persons in relation to HZ. Vaccination strategies for both varicella and zoster vaccines will likely need to be evaluated and adjusted periodically as the changes in epidemiology of both VZV diseases become more evident in the U.S. Even more complex is the effect of international travel and immigration to the U.S., which brings the potential for both wild-type and vaccinetype VZV continuing to circulate in the population. Because of the aging of the population and the fact that the zoster vaccine has not been recommended for administration to those under 60 (placing this age group at higher risk than previously), and due to the demonstrated lack of adherence by older individuals to any vaccination program, for zoster vaccination to reduce the incidence of HZ appreciably below current levels, adherence of patients to adult vaccination recommendations must be improved.10
6. Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005;352:2271 84. 7. Brisson M, Edmunds WJ, Law B, et al. Epidemiology of varicella zoster virus infection in Canada and the United Kingdom. Epidemiol Infect 2001;127:30514. 8. Brisson M, Edmunds WJ, Gay NJ. Varicella vaccination: impact of vaccine efcacy on the epidemiology of VZV. J Med Virol 2003;70(suppl 1):S317. 9. Insinga RP, Itzler RF, Pellissier JM, et al. The incidence of herpes zoster in a United States administrative database. J Gen Intern Med 2005;20:748 53. 10. Schuette MC, Hethcote HW. Modelling the effects of varicella vaccination programs on the incidence of chickenpox and shingles. Bull Math Biol 1999;61:1031 64. 11. Arvin A. Aging, immunity, and the varicella-zoster virus. N Engl J Med 2005;352:2266 7. 12. Devlin ME, Gilden DH, Mahalingam R, et al. Peripheral blood mononuclear cells of the elderly contain varicella-zoster virus DNA. J Infect Dis 1992;165:619 22. 13. Wilson A, Sharp M, Koropchak CM, et al. Subclinical varicella-zoster virus viremia, herpes zoster, and T lymphocyte immunity to varicella-zoster viral antigens after bone marrow transplantation. J Infect Dis 1992;165:119 26. 14. Gnann JW, Whitley RJ. Natural history and treatment of varicella-zoster in high-risk populations. J Hosp Infect 1991; 18(suppl A):31729. 15. Gold E. Serologic and virus-isolation studies of patients with varicella or herpes-zoster infection. N Engl J Med 1966;274: 1815. 16. Haanpaa M, Dastidar P, Weinberg A, et al. CSF and MRI ndings in patients with acute herpes zoster. Neurology 1998; 51:140511. 17. Lewis GW. Zoster sine herpete. Br Med J 1958;2:418 21. 18. Gilden DH, Dueland AN, Devlin ME, et al. Varicella-zoster virus reactivation without rash. J Infect Dis 1992;166(suppl 1):S30 4. 19. Nagasako EM, Johnson RW, Grifn DR, Dworkin RH. Rash severity in herpes zoster: correlates and relationship to postherpetic neuralgia. J Am Acad Dermatol 2002;46:834 9. 20. Chapman RS, Cross KW, Fleming DM. The incidence of shingles and its implications for vaccination policy. Vaccine 2003;21:25417. 21. Cooper M. The epidemiology of herpes zoster. Eye 1987;1: 41321. 22. Hope-Simpson R. The nature of herpes zoster: a long-term study and a new hypothesis. Proc R Soc Med 1965;58:9 20. 23. Miller AE. Selective decline in cellular immune response to varicella-zoster in the elderly. Neurology 1980;30:5827. 24. Galil K, Choo PW, Donahue JG, Platt R. The sequelae of herpes zoster. Arch Intern Med 1997;157:1209 13. 25. Buchbinder SP, Katz MH, Hessol NA, et al. Herpes zoster and human immunodeciency virus infection. J Infect Dis 1992; 166:1153 6. 26. Burke BL, Steele RW, Beard OW, et al. Immune responses to varicella-zoster in the aged. Arch Intern Med 1982;142:2913. 27. Levin MJ, Murray M, Rotbart HA, et al. Immune response of elderly individuals to a live attenuated varicella vaccine. J Infect Dis 1992;166:2539. 28. Gershon AA, Steinberg SP. Cellular and humoral immune responses to varicella-zoster virus in immunocompromised patients during and after varicella-zoster infections. Infect Immun 1979;25:170 4. 29. Hayward AR, Herberger M. Lymphocyte responses to varicella zoster virus in the elderly. J Clin Immunol 1987;7:174 8. 30. Oxman MN. Immunization to reduce the frequency and se-

Conclusion
Herpes zoster is the second clinical manifestation of VZV. The incidence and severity of HZ increase with advancing age. Varicella-zoster virusspecic CMI, which keeps latent VZV in check and is boosted by periodic reexposure to VZV, is an important mechanism in preventing VZV reactivation as zoster. Herpes zoster ophthalmicus occurs when HZ presents in the ophthalmic division of the fth cranial nerve. Without the use of antiviral therapy, approximately 50% of HZ patients develop ocular involvement. There is a long list of complications from HZ, including those that involve the optic nerve and retina in HZO, but the most frequent and debilitating complication of HZ regardless of dermatomal distribution is PHN, a neuropathic pain syndrome that persists or develops after the zoster rash has resolved. The main risk factor for PHN is advancing age; other risk factors include severity of acute zoster pain and rash, a painful prodrome, and ocular involvement. Vaccination strategies for both varicella and HZ will need to be evaluated and adjusted periodically as changes in the epidemiology of these VZV diseases become more evident.

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