Humans are the only known natural hosts for VZV. As with the other herpesviruses, such as herpes simplex virus (HSV), cytomegalovirus (CMV), and Epstein-Barr virus, VZV can persist in a latent form. Nearly everyone with an initial VZV infection (varicella) recovers, but can harbor the latent virus in the trigeminal ganglion or in one of the sensory ganglia of the spinal cord. Although the majority of patients who have had varicella experience no further problems, approximately 20% will develop herpes zoster later in life, as a result of either reactivation of or reexposure to the VZV virus.^2–6

EPIDEMIOLOGY

Virtually all who live in a populous society eventually contract varicella, usually before 9 years of age.^2,7,8 Transmission of the disease occurs less readily in uncrowded areas of the world, and infection occurs more often later in life in those areas.^2,7,8

VZV present in respiratory secretions or cutaneous lesions can transmit varicella.⁹ The virus usually enters the host by way of the respiratory mucosa. After an incubation period of 10 to 21 days, during which time the virus replicates in regional lymph nodes, a systemic viremia ensues.^2,7,8,9

The high prevalence of varicella has been reduced as a result of the development of a safe and effective vaccine (Varivax®), now approved for general use.^10,11 The Varivax® vaccine is obtained from live attenuated viruses of the Oka strain of VZV.^10,11 Immunization begins in childhood and booster injections are needed. The vaccine has been shown to be immunogenic and clinically effective in both healthy and immunocompromised children.¹² Routine varicella vaccination programs for healthy children would result in significant savings in medical and work-loss costs.¹³ Herpes zoster may still occur after immunization, caused by reactivation of either the vaccine strain or a wild-type strain; however, herpes zoster appears to occur less frequently in patients who have received the vaccine than in patients who have had natural varicella.^11,14,15

SYSTEMIC MANIFESTATIONS AND THERAPY

The main clinical manifestations of varicella are fever, malaise, and a mucocutaneous exanthem, all of which develop at the time of, or shortly after, the viremia. The cutaneous rash begins with macular and papular lesions, which evolve into vesicles before crusting. Although the varicella skin eruption is generalized, the lesions are more numerous on the face and trunk (Fig. 1) than on the extremities, creating a so-called centripetal rash. Mucosal vesicles occur but are less common than cutaneous lesions. New “crops” of macules, papules, and vesicles appear on the skin and evolve over the course of a few days, so lesions in different stages of maturity are typically present at any given time. The vesicles rupture and become encrusted approximately 1 week after their initial appearance, at which time the patient is no longer contagious. In the absence of secondary bacterial infection, cutaneous scarring in varicella is unusual.^8,16

Recovery from varicella is generally rapid and uneventful, occurring 1 to 2 weeks after onset of clinical disease. The immunocompetent patient is able to eliminate the viremia quickly by means of humoral antibodies, while cellular (lymphocyte-mediated) immunity controls intracellular virus. Nevertheless, some virus can enter sensory ganglia and may remain permanently dormant.¹⁷ Subsequent reactivation of the latent virus produces the quite different clinical picture of herpes zoster, presumably because the host is partially immune. Reactivation of the virus can occur idiopathically or in association with a decline in the patient's immune status, reexposure to the virus, or surgical or other traumatic insults to the sensory nerves whose ganglia contain latent virus.^2,5–7

Varicella is often more severe in infants and adults than in children, even in those at the extremes of age who seem otherwise healthy. The disease can be fatal in infants, probably because their immune systems are immature. Adults are especially susceptible to varicella pneumonitis.^3,18 Immunocompromised patients at any age can develop widespread and sometimes fatal involvement of the viscera, vascular system, and central nervous system.^2,3,19

Varicella is usually a benign disease that requires only symptomatic therapy with analgesics, antipyretics, antipruritics, and general hygienic measures. Aspirin should be avoided because its use is thought to be associated with an increased risk of postvaricella Reye's syndrome.

Zoster immune globulin (containing antibodies against VZV) can prevent or ameliorate varicella in immunodeficient patients who have been exposed to the virus but who have not yet developed the disease.^2,3 In addition to passive immunization, vaccination with the recently approved live attenuated varicella vaccine (Varivax®) may help to decrease the occurrence and severity of varicella in these patients. Immunocompromised patients with chronic varicella or varicella pneumonitis have been helped by the administration of intravenous vidarabine.²⁰ Kunitomi and colleagues²¹ found that intravenous vidarabine and intravenous acyclovir were equally effective in treating immunocompromised children with varicella, whereas Balfour and co-workers²² and Shepp and co-workers²³ found intravenous acyclovir to be significantly more effective than intravenous vidarabine in this situation, with minimal side effects.²⁴

OCULAR MANIFESTATIONS AND THERAPY

Ocular manifestations of varicella infection include epibulbar conjunctival or limbal corneal “pocks” (round, focal accumulations of inflammatory cells, lymphocytes and neutrophils), punctate keratitis, nonherpetic dendriform keratitis, nummular keratitis, disciform keratitis or keratouveitis (Fig. 2).^7,25–32 Rarely, varicella has been associated with gangrene of the eyelids, interstitial keratitis, progressive corneal ulceration (“melting”), extraocular muscle palsies, internal ophthalmoplegia, cataract, uveitis, retinopathy, or optic neuritis.^{26,28,33–40} Infants born with varicella (congenital varicella syndrome) can manifest microphthalmos, chorioretinitis, cataracts, microcephaly, deafness, and cardiac anomalies.^28,41

Epibulbar pocks occur most often during active systemic varicella and are suspected to harbor live virus. Pocks can also develop weeks or months after the systemic disease, at which time they probably represent a sterile, phlyctenule-like, cell-mediated immunologic reaction to retained viral antigen (but not the live virus). In either case, the pocks persist for 1 to 2 weeks and then resolve spontaneously. These conjunctival lesions are visually insignificant, but corneal pocks can leave scarring and vascularization. Varicella pocks are can be treated empirically with a topical antiviral agent such as trifluridine or simply observed. Pocks that develop later respond to short-term pulsed topical corticosteroid therapy.

Punctate or dendritic epithelial keratitis can rarely occur during active varicella infection and is thought to be caused by proliferation of VZV in the corneal epithelium. Varicella keratitis closely resembles herpes simplex keratitis, including the presence of dendriform lesions and decreased corneal sensation,²⁹ although varicella dendrites, similar to those of herpes zoster, consist of heaped up (rather than ulcerated as in herpes simplex) epithelium and are less responsive to topical antiviral therapy. The varicella dendrites can be removed by mechanical debridement using a sterile cotton-tipped applicator.

Varicella disciform keratitis (keratouveitis) resembles the disciform keratitis of herpes simplex and herpes zoster, but it generally lasts for a shorter time (2 to 5 months for varicella versus 5 to 10 months for herpes simplex disciform keratitis or more than 1 year for herpes zoster disciform keratitis).^7,32 Varicella disciform keratitis is the mildest of the viral disciform keratitides and leads to less corneal scarring.^7,32 Viral disciform keratitis is caused by sterile, immunologic reactions to viral antigen that has been retained in the corneal stroma, following prior replication of live virus in the corneal epithelium.⁴² Varicella disciform keratitis can be treated with topical corticosteroids, but such therapy poses steroid-related risks such as secondary infection, corneal melting, glaucoma, cataract, and prolongation of the disease. If possible, avoid topical steroids and allow the disciform keratitis to run its natural course with supportive therapy such as topical antibiotics and cycloplegics, lubricants, hypertonic agents.

Late, and presumably immunologic, manifestations of varicella, such as chorioretinitis and optic neuritis, may be treated with systemic corticosteroids. This strategy should be avoided during the early stages of systemic varicella because widespread viral dissemination can occur.⁶

Varicella keratitis, unlike herpes simplex keratitis, tends not to recur. Childhood varicella infection can recur later in life as herpes zoster.

EPIDEMIOLOGY

The term herpes zoster derives from the Greek words herpein, meaning “to creep or to spread,” and zoster, which means “a girdle, sword, belt, or zone,” applied because of the belt-like dermatomal distribution of the disease. When there is involvement of the ophthalmic branch of the trigeminal nerve, the term herpes zoster ophthalmicus (HZO) is used. In 1818, Mahlis reported that the cutaneous eruption of herpes zoster followed the distribution of nerves, but it remained for Hutchinson in 1865 to describe HZO in detail and to report on several cases.^43,44

Herpes zoster causes approximately 1% of all skin disease, and most commonly affects the dermatomal distributions of the thoracic (56%) and trigeminal nerves (15%).⁴⁵ In aggregate, the thoracic dermatomes are the most common areas involved in herpes zoster, but the trigeminal nerve is the single most common dermatomal site. Herpes zoster is four to five times more common in patients who have been immunocompromised by malignancy or immunosuppressive therapy than in those who have not, however, most patients with herpes zoster have no underlying systemic disease.⁴⁶ A retrospective study of 1000 patients with HZO found that only 12 patients (1.2%) presented either with a malignancy or in an immunocompromised state. No new examples of malignancy or immunosuppression were found in follow-up evaluations.⁴⁷ For 15 years, Ragozzino and co-workers⁴⁸ followed prospectively 590 patients with herpes zoster who did not have underlying malignancy. They found that: (1) 9.3% had trigeminal nerve involvement; (2) there was an equal incidence of herpes zoster between male and female patients; (3) there was a relatively low incidence of malignancy (1.1% per year, which is similar to the normal population); and (4) the average annual incidence rate was 1.3 per 1000 person–years. HZO does not appear to be more prevalent in a particular race or gender, but it does seem to have a predilection for elderly patients, who are also more likely to develop other systemic complications from the disease.

Herpes zoster nearly always occurs in patients who have had previous exposure to VZV (chickenpox). Two theories have been proposed to explain the adult form of VZV infection, namely the latency theory and the theory of altered immunity with reinfection.

The latency theory states that after an initial VZV infection the virus remains latent in one or more dorsal root ganglia.^3,17 Later in life and as a function of T-cell alterations, varicella reappears from the nerve root ganglion as herpes zoster, in a specific dermatomal area and not in a diffuse cutaneous distribution.^3,17,48 This so-called secondary (or symptomatic) zoster occurs in patients in whom the host-parasite relationship to latent VZV has been altered by age, trauma, systemic disease, surgery, or iatrogenic immunosuppression.¹⁶ There is a decrease in VZV-neutralizing antibody preceding this event.^7,49,15

Herpes zoster may also develop in immunocompetent 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 (so-called primary, spontaneous, or infectious zoster).^16,50,51 This is the theory of altered immunity with reinfection, but it is not known whether reactivation or fresh exogenous infection by VZV is the cause.^16,51,52

Age is the most common predisposing factor to herpes zoster, probably as a result of alterations in T cells and a decrease in neutralizing VZV antibody associated with senescence, allowing reactivation of latent virus.¹⁶ Herpes zoster occurs most commonly in the fifth to seventh decades of life; however, some patients with zoster are younger, have a history of recent exposure to someone with active varicella or zoster, and have not had serious predisposing underlying systemic disease.^7,8

PATHOGENESIS AND HISTOPATHOLOGY

After primary VZV infection, the virus becomes latent within one or more sensory nerve root ganglia and later reactivates in association with age, immunocompromised state or trauma to the involved ganglion.^7,17,52 Other presumed triggers include tuberculosis, syphilis, radiation therapy, and systemic corticosteroid use.¹⁶ Viral proliferation in the nerve root ganglion causes inflammation and tissue destruction.

Some of the ophthalmic sequelae of zoster are the result of chronic inflammation and ischemia secondary to vasculitis.⁵³ The inflammatory reaction can be granulomatous or diffusely lymphocytic.^53–55 Granulomatous intracranial arteritis is a specific complication of HZO.^53–55

Inflammatory sequelae may also be caused by direct viral infection. VZV has been identified in sensory neural ganglia and has been recovered from the skin and corneal surface during the early stages of zoster.^53,55,56 The duration of VZV DNA detection on the ocular surface from rash onset varies from 2 to 34 days.⁵⁷ Live intraocular VZV has been recovered in a case of acute retinal necrosis syndrome reported by Culbertson and co-workers.⁵⁸ Herpes zoster–like particles have been found in the retina and in the iris as well.^59,60

CLINICAL CHARACTERISTICS

Dermatomal Considerations

The first (ophthalmic) division of the trigeminal nerve is most frequently involved in HZO, 20 times more often than the second (maxillary) or third (mandibular) divisions.¹⁶ The predilection of VZV for the ophthalmic division may result from trauma (leading to virus reactivation) or because the localization of herpes simplex virus in the portions of the ganglion that supply the maxillary and mandibular branches has an interference effect against later-acquired VZV.¹⁶ HSV preferentially resides in those portions of the ganglion that supply the upper and lower lid, whereas VZV more commonly resides in the portion that supplies the upper lid and nasociliary branch of the trigeminal nerve—usually a sign of dissemination in an immunocompromised host. The diagnosis of HZO is applied if the area of distribution of the ophthalmic division of the trigeminal nerve is involved, even if the globe itself is not inflamed.⁷

The ophthalmic division of the trigeminal nerve has three parts: the frontal nerve, the lacrimal nerve, and the nasociliary nerve (Fig. 3). The supraorbital and supratrochlear branches of the frontal nerve supply the upper lid and forehead and are most often involved in HZO. The nasociliary nerve provides sensory innervation to the cornea, ciliary body, iris, and conjunctiva. Its terminal branch is the anterior ethmoidal nerve, which innervates the sides of the tip of the nose (alae nasae) via the external nasal nerve.

Hutchinson⁴³ was the first to observe that ocular involvement is much more common in herpes zoster patients who had VZV involvement of the nasociliary branch of the trigeminal nerve. The classic Hutchinson's sign of cutaneous VZV involvement on the alae nasae, that is, the side of the tip of the nose (and not just the tip of the nose), is evidence of nasociliary nerve involvement. Ocular sequelae occur in 50% to 85% of such cases.¹⁶ It is important to remember, however, that the eye may be seriously affected in half of all cases, even if Hutchinson's sign is absent (Fig. 4). Thus, Hutchinson's sign is not entirely reliable as a predictor of ocular involvement; however, if present, ocular inflammation is more likely to occur.

HZO begins with a prodrome of severe burning or lancinating pain, dysesthesia or hyperesthesia over the affected dermatome, mild fever, nausea, and malaise (Fig. 5). The preeruptive pain may be insidious. At this stage, the cerebrospinal fluid shows a mild lymphocytic pleocytosis. A cutaneous eruption usually appears over one dermatomal area 3 to 5 days after the onset of pain (Figs. 6 and 7). The erythema and swelling may be mistaken for an insect bite or cellulitis. Initially, the HZO eruption is erythematous and maculopapular, but soon becomes vesiculopapular, ulcerative, and eventually cicatrizing. Material in the vesiculopapular eruption is at first clear, but becomes yellow-brown and purulent as the vesicles erupt and crust. Because VZV involves the dermis, cutaneous scarring, sloughing, and subsequent exposure and superinfection can occur (Figs. 8 and 9). Herpes zoster without cutaneous eruption, called zoster sine herpete or zoster sine eruptione, has been observed. Schwab⁶¹ reported 16 patients with zoster sine herpete, in whom an anterior uveitis or iridocyclitis was present without ipsilateral skin lesions; in 9 of these 16 cases there was a documented rise and fall in VZV titers.

Edema and vesicular cutaneous eruption of the lower eyelid in HZO do not necessarily indicate involvement of the maxillary division of the trigeminal nerve but may just represent local sequela of frontal nerve involvement. The infratrochlear branch of the nasociliary nerve supplies the medial aspect of the lower lid and conjunctiva. Therefore, VZV vesicles can erupt along the medial aspect of the lower lid margin as a result of involvement of the ophthalmic division of the nerve. Similarly, contralateral eyelid edema is not usually a sign of dissemination, but a local consequence of intense inflammation and swelling on the involved side (see Fig. 7).

The cutaneous eruption of herpes zoster usually follows classic dermatomal patterns, but vesicular eruption may occur several millimeters outside a particular dermatomal distribution and still not signify dissemination.⁷ True herpes zoster dissemination is defined by involvement of two or more noncontiguous dermatomes. Multiple crops of vesicles in more than one noncontiguous dermatome are almost always a sign of an immunocompromised state, and the patient should be appropriately evaluated (see “Systemic Work-Up” section).

Ocular Involvement

A convenient categorization is to define the ophthalmic manifestations of HZO anatomically. All ocular and adnexal tissues can be affected by herpes zoster inflammation (Table 1). HZO can cause blepharitis, canaliculitis, conjunctivitis, dacryoadenitis, keratitis, keratouveitis, iridocyclitis, vitritis, retinitis, acute retinal necrosis, retinal vasculitis, choroiditis, inflammatory glaucoma, optic neuritis, meningeal encephalitis, inflammatory extraocular muscle palsies, anterior segment ischemia, episcleritis, scleritis, postherpetic neuralgia (PHN), and cephalalgia. Secondary cataract can result from uveitis or prolonged topical or systemic corticosteroid therapy. Ocular sequelae can occur immediately, a few weeks later, or seemingly idiopathically months to years after the cutaneous eruption. It is imperative for the clinician to ask about a prior history of herpes zoster or “shingles” in any patient with chronic inflammatory eye disease.

TABLE 1. Ocular Involvement in Herpes Zoster Ophthalmicus

LIDS AND LASHES.

During the active vesiculoulcerative cutaneous disease, VZV can usually be cultured from skin lesions (see “Laboratory Evaluation” section). Zoster dermal involvement can cause cutaneous sloughing and secondary infection, usually from Staphylococcus aureus or Streptococcus species.¹⁶ The pain and hyperesthesia of the eyelid skin may be so intense during the first 3 to 5 days of cutaneous eruption that it may be impossible to examine the conjunctiva, cornea, or internal eye (see Fig. 7). Eyelid involvement can be lead to permanent scar formation, cicatricial ectropion or entropion, trichiasis, eyelash whitening (poliosis), eyelash loss (madarosis), or even frank loss of eyelid tissue. Chronic contracted eyelid scars may occur. Zoster scarring of the lacrimal punctum can cause punctal stenosis and epiphora.

The skin vesicles and ulcerations are virologically sterile after 5 to 7 days and heal within 2 or 3 weeks. Occasionally these lesions require several months to heal totally as a result of secondary bacterial infection or an allergic contact dermatitis caused by topical medication.⁷

Dysesthesia, hyperesthesia, and pain are common throughout the distribution of the cutaneous eruption, especially in the elderly. PHN may be mild, moderate, severe, or occasionally incapacitating (see “Neurologic Involvement” section).

Hemorrhagic complications may occur, especially in patients who have underlying hematopoietic diseases (e.g., thrombocytopenia, anemia) (see Fig. 7) in association with the cutaneous crisis. Subdural, subarachnoid, and intracranial hematomas have been described in herpes zoster patients taking anticoagulant medications concurrent with the onset of the herpes zoster skin eruption.²⁶

CONJUNCTIVA.

Herpes zoster conjunctivitis can manifest as papillary, pseudomembranous, membranous, or follicular. Transitory nonulcerative vesicles, hemorrhages, and conjunctival cicatrization may occur.¹⁶ Conjunctival cytology reveals mostly a mononuclear and lymphocytic infiltration, but polymorphonuclear leukocytes can be found in severe cicatrizing membranous forms of the disease, even in the absence of microbial superinfection. After the occurrence of pseudomembranous, membranous, or vesicular types of conjunctivitis, chronic scarring and symblepharon formation can occasionally ensue.¹⁶

CORNEA.

Herpes zoster corneal disease is insidious in onset, protean in manifestation, and potentially visually devastating, even if promptly and appropriately managed. Herpes zoster keratitis manifests in six basic clinical forms: (1) an acute or chronic epithelial keratitis; (2) nummular (coin-shaped) stromal keratitis; (3) disciform keratitis; (4) limbal vascular (fascicular) keratitis; (5) serpiginous ulceration; and (6) neurotrophic keratitis, with or without corneal perforation.

Acute Epithelial Keratitis.

This coarse, punctate keratitis usually occurs 5 to 10 days after onset of the dermatomal eruption. It is characterized by multiple fine, raised intraepithelial lesions located paracentrally or at the limbus.⁶¹ There may be a subjacent anterior stromal infiltrate with a ground-glass appearance. These initially coarse, punctate lesions sometimes coalesce into elevated, snake-like, dendriform epithelial lesions, which are called pseudodendrites to distinguish them from the true dendrites of herpes simplex keratitis (Fig. 10).^16,62–65

Herpes Simplex Keratitis.

The dendrite is a true ulceration with terminal end-bulb formations and represents active viral replication. Corneal sensation is usually decreased. Because epithelial herpes simplex represents active viral replication, the edges of these lesions stain vividly with rose bengal dye and the ulcer base with fluorescein dye. Debridement causes ulceration of the epithelium, and steroids are contraindicated because they enhance the growth of these lesions

Herpes Zoster Keratitis.

Pseudodendrites are typically smaller and snake-like, and they do not have terminal end-bulb formations. Debridement of these lesions causes less damage to the epithelium. Corneal sensation is variable, being either normal or profoundly decreased. These lesions stain only mildly with fluorescein and variably with rose bengal dye. Steroids have little or no effect on these lesions.⁶⁴

Pseudodendriform herpes zoster keratitis lesions are transient and usually resolve within 2 weeks after the cutaneous eruption. Viral particles were isolated in one study by Pavan-Langston and McCulley⁵⁴ but were not identified in another study by Piebenga and Laibson.⁶³ VZV DNA has been recovered from the ocular surface at various time periods after the cutaneous eruption.⁵⁶ In evaluating these studies, it is apparent that the timing of retrieval of live virus is critical.

Chronic Epithelial Keratitis.

Chronic epithelial keratitis was described by Piebenga and Laibson⁶³ as a chronic form of herpes zoster keratitis characterized by epithelial mucous plaques that can appear from 1 week to as late as 1 year (typically 3 to 4 months) after the cutaneous eruption. This occurs in approximately 8% of patients with HZO.⁶⁴ Corneal mucous plaques may be seen in isolation or in association with limbal hyperemia and iridocyclitis (Fig. 11A). In areas of mucous-plaque formation, the cornea appears edematous and desquamated (Fig. 11B). These pleomorphic plaques tend to wander over the surface of the cornea.⁶¹ The chronic coarse mucous plaques of herpes zoster are elevated and associated with diffuse anterior stromal haze.⁶⁵ These lesions demonstrate poor fluorescein staining but vivid staining with rose bengal dye.⁵⁰ Debridement of these plaques is not associated with any damage to the underlying epithelium, and steroids have little or no effect.⁶¹ Delayed corneal mucous plaques are typically culture-negative and result from immune, neurotrophic, or abnormal epithelial phenomena.^65,68,69 Soft contact lenses, lubrication, steroids, acetylcysteine, and antivirals have been therapeutically inconsistent.^{55,62,64,67,68,69} Pavan-Langston and colleagues⁶⁶ found VZV DNA by polymerase chain reaction (PCR) assay in some cases of delayed herpes zoster mucous plaques and pseudodendrites, suggesting an infectious association. Chern and co-workers⁶⁷ described a chronic form of dendritic herpes zoster epithelial keratitis in acquired immune deficiency syndrome (AIDS).

Nummular Keratitis.

Superficial, nummular anterior stromal opacities may be found beneath areas of prior acute epithelial keratitis. Nummular keratitis appears as granular infiltrates that are located in the anterior stroma.^62,65 These lesions are usually evanescent but can lead to nebulous scarring (Fig. 12).

Disciform Keratitis.

Disciform keratitis may develop weeks to months after the original cutaneous eruption and often recurs in the vicinity of an area of previous acute epithelial keratitis. Rarely, it occurs spontaneously, with no clinical evidence of previous epithelial disease. A central, well-defined, disc-shaped area of diffuse stromal edema without vascularization is usually seen. If left untreated, disciform edema runs a chronic course, producing scarring, occasional lipid deposition, and neovascularization (Fig. 13). Herpes zoster disciform keratitis cannot be distinguished from disciform keratitis secondary to herpes simplex virus or other viral diseases. Steroids have some beneficial effect.

Limbal Vascular (Fascicular) Keratitis.

Limbal vascular (fascicular) keratitis may occur early or late in relation to the cutaneous eruption. Limbal-vessel ingrowth and stromal edema are seen. Episcleral or scleral inflammation is often noted adjacent to the limbal involvement (sclerokeratitis). Limbal vascular keratitis is thought to represent an immune-complex vasculitis, resulting in corneal edema, vascularization, and in some cases, the eventual deposition of lipid and subsequent scarring (Fig. 14).

Serpiginous Ulceration.

Large geographic ulcers may form, and the entire epithelium may slough.⁷⁰ This form of chronic serpiginous ulceration mimics HSV infection, in which trophic ulceration without secondary pannus or vascularization leads to corneal melting.

Neurotrophic Keratitis.

One of the most ominous corneal manifestations of HZO is neurotrophic keratitis; this can occur because corneal sensation is often chronically and profoundly decreased or absent. An inferior, horizontally oval, epithelial defect with rolled-under edges is characteristic. These indolent ulcers do not readily epithelialize and may lead to trophic corneal ulceration, corneal melting, descemetocele formation, and ultimately corneal perforation. Limbal corneal vascularization (pannus) to fill the epithelial defect is a reparative process and should be encouraged (Fig. 15).⁷⁰ The resulting scar is usually in the inferior pupillary axis and is preferable to corneal melting. Careful, long-term follow-up for this insidious corneal complication is mandatory. Other corneal findings in HZO include epithelial inclusion cysts⁶⁹ and peripheral corneal ulceration.⁷¹

IRIS AND UVEA.

HZO can cause either a nongranulomatous or granulomatous iridocyclitis (anterior uveitis) with extensive keratic precipitates and posterior synechiae.⁶⁹ The iridocyclitis tends to be chronic and recurrent and may require long-term, carefully titrated topical corticosteroids for control. Anterior uveal involvement can occur independent of corneal disease and is heralded by blurred vision, intense photophobia, ciliary injection, edema of the iris, hyperemia, miosis, and inflammatory anterior chamber cells and protein flare.⁶² A severe “plastic” iridocyclitis, with hypopyon, hyphema, and intractable secondary glaucoma, can be observed (Fig. 16). As a result of chronic iridocyclitis, corneal edema secondary to endothelial damage and sectoral iris atrophy can occur.⁶² Endothelial cell loss is especially common with herpes zoster keratouveitis, even with normal intraocular pressure.^64,65 Histopathologically, herpes zoster iritis is an ischemic, occlusive vasculitis. The typical sector iris atrophy that accompanies HZO is the result of focal ischemic necrosis (Fig. 17).⁷⁰ In contrast, herpes simplex iritis is primarily a lymphocytic infiltration without ischemia, and causes a more diffuse iris atrophy.^16,72,73

Ciliary-process ischemia can cause hypotonia, cyclitic-membrane formation, and ultimately atrophy and phthisis bulbi.

LENS.

HZO can cause cataracts either secondary to the acute anterior uveitis or as a result of the attendant need for topical or systemic corticosteroids. The cataracts of HZO are typically posterior subcapsular in location.

ANTERIOR CHAMBER ANGLE AND GLAUCOMA.

Glaucoma can occur in HZO as a result of several mechanisms: (1) plugging of the trabecular mesh-work because of the presence of cellular debris, iris pigment, or hyphema; (2) pupillary-block glaucoma secondary to posterior synechiae, with resultant iris bombé; (3) peripheral anterior synechiae; or (4) chronic open-angle glaucoma long after the acute infection is resolved, presumably because of damage to the trabecular meshwork.⁶²

VITREOUS.

Vitreous opacities, vitritis, and vitreous hemorrhage have all been seen in HZO.¹⁶

RETINA

Retinal hemorrhages, retinal thrombophlebitis, branch or central retinal artery occlusion, retinal arteritis and necrotizing retinopathy, necrotizing retinitis, exudative or rhegmatogenous retinal detachment, and ischemic perivasculitis have been described in HZO.^72–75 In addition, neuroretinitis with papillitis and macular edema can be seen.⁷⁶

Acute retinal necrosis (ARN) is a clinical syndrome with the following characteristics: anterior chamber reaction, occlusive arteritis and phlebitis of the retina and choroid, a necrotizing peripheral circumferential retinitis, and vitritis.⁷⁷ Anterior segment inflammation and late retinal detachment are prominent sequelae of this disease. ARN results from viral infection caused by human herpes viruses, which includes herpes simplex virus types 1 and 2, cytomegalovirus, and VZV. Of these, varicella zoster virus is thought to account for the majority of cases of ARN.^58,59 ARN is an infrequent complication of HZO.^58,78–80

Ganatra et al.⁶⁰ used PCR to identify both VZV and HSV type I as causative in ARN in patients over 25 years of age, whereas they found HSV type II caused ARN in patients younger than 25 years old. Most investigators now accept that immunosuppression is a condition compatible with ARN. In fact, there is evidence that there may be an immunogenetic predisposition to the development of ARN, with an apparent association with the HLA-DQw7 antigen.⁷⁷

A newer clinical entity known as the progressive outer retinal necrosis (PORN) has been recognized as a unique and devastating VZV retinopathy associated with AIDS (Fig 18; also see section below on herpes zoster in AIDS)⁸⁷.

PUPIL.

Involvement of the sympathetic nervous system can result in Horner's syndrome, which involves pupillary miosis, ptosis, and anhidrosis of the involved side. A pseudo-Argyll-Robertson or a tonic (Adie's) pupil, secondary to herpes zoster ciliary ganglionitis, can also occur.¹⁶

OPTIC NERVE.

Herpes zoster optic neuritis can appearing as an isolated finding, in association with macular edema in neuroretinitis, as a retrobulbar neuritis, or as an ischemic optic neuropathy.⁷⁶ A finding of herpes zoster optic neuritis does not necessarily indicate central nervous system involvement by herpes zoster because local transmission of the virus within the orbit can occur from the fifth to the second cranial nerve.^50,72 Optic neuritis associated with cerebrospinal fluid pleocytosis and increased protein, however, indicates meningeal involvement.¹⁶

EXTRAOCULAR MUSCLES.

Ophthalmoplegia is a well-known complication of HZO, various studies have showin a rate of 11% to 31%.⁸¹ Marsh and colleagues⁸¹ found extraocular motor palsies in 31% of 77 consecutive patients with HZO; however, only 28% of these patients were symptomatic.⁸¹ A highly significant association was observed between the occurrence of oculomotor palsies and the clinical severity of the herpes zoster infection, as well as the presence of iritis and iris atrophy.⁸¹ Typically, the third cranial nerve is involved, usually within the first 2 weeks of the initial cutaneous eruptions. The fourth and sixth cranial nerves can also be involved, either in isolation or with third-nerve paresis. Most cases of herpes zoster extraocular muscle palsies resolve within 1 year.⁸¹ Contralateral or bilateral involvement occurs in approximately 12% of these patients ⁸¹

ORBIT.

HZO orbital myositis resulting proptosis and extraocular muscle palsies has been described.⁸² HZO can produce ptosis from a secondary Horner's syndrome. Kattah and Kennerdell⁸³ reported on two patients with orbital apex syndrome (optic neuropathy with complete ophthalmoplegia and anesthesia), associated with meningoencephalitis. A patient with HZO with proptosis, optic neuropathy, and restriction of abduction and up-gaze showed marked enlargement of the inferior and medial rectus muscles on computed tomography (CT) scanning, which resolved with systemic corticosteroid therapy (Fig. 19A and 19B).⁸⁴ Orbital myositis is a cause of HZO-associated ophthalmoplegia, an entity most often attributed to primary or secondary cranial nerve VZV involvement.

Neurologic Involvement

One of the most dreaded complications of HZO is PHN and cephalgia. The Scandinavian word for herpes zoster, helvedesild (“hellfire”) is descriptive of this intense, incapacitating neuralgia and cephalgia.¹⁶ By definition, zoster pain is divided into acute pain (so-called zoster-associated pain or ZAP), and chronic PHN. ZAP is pain occurring any time within the first 4 weeks of the initial cutaneous crisis. In contradistinction, PHN is pain that begins after the fourth week of HZO. PHN can occur in any patient with HZO; however, it is not usually seen in patients younger than 50 years of age, and its frequency and severity increase with age. PHN affects approximately one-half of all patients with herpes zoster who are older than 70. In some instances, the pain may be so extreme and persistent that the patient is driven to consider suicide.¹⁶ Children in whom HZO develops, usually secondary to immunosuppressive disease, do not have much PHN and in fact, may have a paradoxical sensation of numbness in the involved dermatome (so-called anesthesia dolorosa).^7,16 Contralateral hemiplegia, facial palsies, and cerebral angiitis also have been described.⁸⁵ These neurologic sequelae occur months after the original episode, and their association with HZO may be overlooked.

Zoster pseudotemporal arteritis has also been reported.⁵⁵ Intense pain in the temporal area can occur in the preeruptive phase of HZO and can be mistaken for temporal arteritis. We have seen three elderly patients who presented with intense unilateral temporal area pain, in whom ipsilateral HZO subsequently developed. Biopsy of the temporal artery was performed in each case and showed evidence of granulomatous arteritis without breaks in the tunica intima. Therefore, in addition to the possibility of temporal arteritis, the differential diagnosis of periorbital pain out of proportion to clinical findings should include the preeruptive phase of HZO.

HERPES ZOSTER OPHTHALMICUS IN AIDS

HZO is an important early clinical marker for AIDS, especially in young patients in high-risk groups.^86–91 In a prospective study, Sandor and associates⁸⁵ followed 54 patients with HZO for a 2-year period. Of the 23 patients younger than 45 years of age, 14 were at high risk for contracting human immunodeficiency virus (HIV), and 3 of these patients subsequently were diagnosed with AIDS. Kestelyn and co-workers⁹¹ examined 19 young Africans who presented with HZO and found that they were all HIV positive. These patients had a higher proportion of keratitis, uveitis, and PHN compared with immunocompetent patients with HZO. Therefore, a physician who finds HZO in a young person should be alerted to the strong possibility of coexistent HIV infection.

A more prolonged and severe disease course may characterize HZO in AIDS. Recurrence of HZO may be more frequent than in immunocompetent patients, in whom recurrence is very uncommon.⁹² Successful treatment with intravenous acyclovir has been reported in numerous cases, and this has become the recommended treatment for patients at high risk for acquiring HIV.⁸⁹ Because cessation of treatment may result in subsequent recurrence, repeated and prolonged treatment may be required.

ARN is a retinopathy not unique to patients with AIDS but is more commonly seen in that population. The causative agent in ARN is usually a herpes virus, either VZV, HSV type I or II, or CMV.⁵⁹ In contrast, PORN syndrome is a distinct form of acyclovir-resistant necrotizing herpetic retinopathy seen in patients with AIDS.⁸⁷ VZV is considered the most likely etiology in most cases.^92,93 PORN is characterized by multifocal, deep retinal lesions that progress rapidly to confluence, minimal or no intraocular inflammation, absence of vascular inflammation, and perivenular clearing of retinal opacification (Fig. 20). It is an extremely rapid and visually devastating form of retinal necrosis. After CMV retinopathy, PORN is the second most frequent opportunistic retinal infection in patients with AIDS in North America.⁸⁷ In a retrospective study of 38 patients with PORN, Engstrom and colleagues⁸⁷ reported that 67% had a history of cutaneous herpes zoster and 41% had HZO. VZV retinopathy in patients with AIDS may present a particularly difficult therapeutic challenge with regard to recurrence and resistance.

LABORATORY EVALUATION

VZV can be isolated from cutaneous vesicles at the time of acute dermatologic crisis. The collected material should be placed in viral transport medium for immediate shipment to the virology laboratory.⁵⁰ The virus can be propagated in embryonic lung tissue culture. Cells may also be examined by fluorescent antibody techniques.⁵⁰ There are several serologic tests that can also detect herpes zoster, including complement-fixation and neutralizing antibodies. Antibody titers rise for 2 weeks after infection and then fall to a lower level, where they may remain for many years. Because many VZV antigens are shared by HSV, there may be false-positives with herpes simplex serologies.

Cytology of cutaneous vesicular scrapings with Papanicolaou's stain displays multiple eosinophilic intranuclear inclusions, the so-called Lipschütz type II bodies (Fig. 21). In addition, multinucleated giant cells identical to those of herpes simplex virus infection can be seen. Although the inclusions cannot be seen with either Giemsa or Gram's stain, the giant cells are readily visible with Giemsa stain (Tzanck preparation).⁵⁰ The spherical icosahedral proteinaceous coat (capsid) of the VZV can be seen with electron microscopy, although it is impossible to distinguish VZV from other members of the herpesvirus group unless it is previously tagged with specific peroxidase-labeled antibody.⁵⁰

SYSTEMIC WORK-UP

A careful history should elucidate identifiable factors predisposing the patient to HZO, such as childhood varicella, older age, stress, trauma, radiation, surgery (especially on the trigeminal nerve), heavy-metal poisoning, pharmacologic immunosuppression,⁷ or systemic disease. Predisposing systemic diseases include leukemia, lymphoma (especially Hodgkin's disease), other malignant neoplastic diseases, tuberculosis, syphilis, and (congenital or acquired immunodeficiency syndromes.^6,7,51,92,93

Patients with HZO who have cutaneous dissemination, immune compromise, or a history of chronic illness should undergo a general medical examination.⁹⁴ In HZO patients who are otherwise healthy, medical examination is usually not necessary, although screening tests such as liver function studies, chest x-ray film, and complete blood count occasionally reveal an underlying chronic illness.

The epidemiologic data (see “Epidemiology” section earlier in this chapter) support the notion that medical work-ups to detect underlying immunosuppression or malignancy in patients with HZO are usually not contributory. Nevertheless, it is usually prudent to have an internist or dermatologist follow a patient with HZO, both to confirm the usual absence of underlying disease and to assist in the medical management of HZO, which may require the use of systemic corticosteroids or other immunosuppressive agents (see “Management Strategies” section). If a patient with HZO has no previous history of varicella and no recent exposure to the virus, the possibility of underlying systemic disease should be considered and the patient medically evaluated. In a young patient with HZO, HIV should be suspected, especially if any of the usual risk factors are present. An appropriate history should be obtained, and testing for HIV should be considered if it is at all suspected.

MANAGEMENT STRATEGIES

General Considerations

The multitude of therapeutic strategies for HZO underscores the lack of any one successful prophylactic or curative treatment for this disease.

Human leukocytic interferon, intravenous vidarabine, and cytarabine have been shown to accelerate healing of cutaneous vesicles in HZO and to lessen visceral complications in immunocompromised patients if they are treated within the first 3 days of onset of the cutaneous eruption.⁷ However, the data on the efficacy of these agents have been mixed, principally because of drug toxicity or systemic immunocompromise. Cytarabine can actually enhance the dissemination of VZV because of its immune-suppressing properties.⁹⁵

ACYCLOVIR.

Acyclovir (acycloguanosine, Zovirax®) has in vitro and in vivo efficacy against VZV. Balfour and co-workers²² and Bean and associates⁹⁸ documented improvement in the cutaneous eruption and acceleration of VZV virus clearance from vesicles in immunocompromised patients with herpes zoster. Compared with placebo, intravenous acyclovir also reduced PHN-associated pain. In the initial, prospective, longitudinal, randomized, double-blind, placebo-controlled trial using oral acyclovir, Cobo and co-workers^80,96 prospectively evaluated 71 immunocompetent patients with HZO, who presented within 7 days of onset of characteristic skin eruptions. They found that a 10-day course of treatment with 600 mg of oral acyclovir, 5 times per day, significantly reduced the incidence and severity of the most common complications of HZO, including dendritic keratopathy, stromal keratitis, and uveitis. The drug is well tolerated, significantly decreases cutaneous herpes zoster dissemination, and accelerates clearance of VZV virus from vesicles. It also reduces the pain, especially if initiated within 72 hours of the cutaneous eruption. The current standard suprathreshold dosage of acyclovir is 800 mg, 5 times per day for 10 days (not the original 600-mg dosage in the study by Cobo and associates). This higher dosing is based on acceptable tolerance, adequate MICs-minimum inhibitory concentration and drug pharmacokinetics.⁹⁹ For immunocompromised hosts acyclovir should be administered intravenously at 30 g/kg per day.¹⁰⁰

NEWER ANTIVIRAL DRUGS.

A number of promising newer and more effective antiviral agents are now available.¹⁰⁰ These drugs have been developed with improved activity against VZV, as well as more favorable pharmacokinetic properties. They include famciclovir, valacyclovir, and sorivudine. The precise role of each of these in the treatment of HZO has yet to be elucidated by comparative trials.

Famciclovir™ (Famvir™) is the diacetyl ester prodrug of penciclovir. It is hepatically deesterified to pencyclovir after oral administration.¹⁰² After oral administration, famciclovir has a much higher bioavailability (77%) than acyclovir (18%). The recommended oral dosage is 750 mg of famciclovir, 3 times per day for 7 days; This dosing schedule (fewer doses per day for a fewer number of days than with acyclovir) creates better compliance. A recent randomized, double-blind, placebo-controlled, multicenter trial demonstrated that famciclovir was well tolerated and safe.¹⁰² Significantly, patients who took famciclovir had faster resolution of PHN (by approximately twofold) than placebo recipients.

Valaciclovir (Valtrex™) is the L-valine ester prodrug of acyclovir.^100,103 The bioavailability after oral adminis-tration is also high (80%) compared to acyclovir (18%). Valaciclovir is converted to acyclovir by hepatic first-pass metabolism.^100,103 The dosage is 1000 mg three times per day for 7 days. This is a simpler dosing regimen with a similar mechanism of action as acyclovir in the treatment of HZO and the prevention of its sequelae.

Sorivudine (5-bromo-vinyl-arabinosyluracil) is one of two new potent uracil derivatives that are active against VZV.^100,104 The other is BW882C87, a nucleoside analogue that is approximately seven times as potent as acyclovir, with a bioavailability of 21% to 25%.¹⁰³ Sorivudine's mechanism of action is the inhibition of DNA polymerase.^100,104 The dosage of sorivudine is 40 mg once daily for 7 days.¹⁰⁴ Sorivudine 40 mg per day is equivalent to 800 mg of acyclovir 5 times per day. A recent report has shown sorivudine to be effective in the treatment of an AIDS patient who had PORN syndrome, presumably caused by VZV.¹⁰⁶ Sorivudine is inactive against HSV, and is toxic if taken in combination with 5-fluorouracil.¹⁰⁰ Sorivudine is not available in the United States.

Foscarnate (trisodium phosphonoformate) is an inorganic phosphate analogue.¹⁰⁰ The mechanism of antiviral action of foscarnate is a reversible inhibition of virus-induced RNA and DNA polymerases.¹⁰⁰ Foscarnate does not require phosphoryation to be active, and is thus an option for acyclovir-resistant strains of VZV, and is available only in intravenous and intravitreal forms.⁹⁹

Other antivirals used for acyclovir-resistant VZV strains include ganciclovir, cidofovir, and lubocavir.^100,101

Herpes Zoster Ophthalmicus: Treatment and Management

Dividing the treatment of HZO into the management of acute herpes zoster dermal eruption, corneal sequelae, other ocular involvement, and PHN provides a framework for the clinician when attempting to manage this protean disease.

ACUTE HERPES ZOSTER DERMAL ERUPTION.

Local treatment of cutaneous zoster is mostly palliative. Topical idoxuridine 40% in dimethyl sulfoxide (DMSO) has some benefit, but is not approved for use in the United States.¹⁰⁷ The astringent Domboro's (Burow's) solution (acetic acid/aluminum acetate), cool compresses, and mechanical cleansing of the involved skin are helpful. Topical antibiotic ointment may inhibit scarring and decrease the possibility of bacterial superinfection. Sensitizing antibiotics with neomycin should not be used. Topical corticosteroid ointment should be avoided, at least during the initial few days after the acute dermatologic crisis, during which active replicating virus is present in the epidermis and dermis.⁵⁰ Drying preparations should also be eschewed, because they may prolong healing, produce confluence and necrosis of lesions, and enhance cicatrization and immobilization of the upper eyelid, resulting in exposure.¹⁰⁰ The use of 5% acyclovir ointment topically on the zoster skin rash may have some value. However, the usual natural history of the acute dermatologic eruption in HZO is vesiculation and crusting with eventual scarring, regardless of the use of any of the above strategies.

CORNEAL SEQUELAE.

The punctate and pseudodendritic forms of herpes zoster epithelial keratitis can represent active viral replication in the corneal epithelium.^56,57 Whether this live VZV is at the terminal corneal nerve ending or deposited on the corneal surface from the lid margin or conjunctiva is debated.^64,65

The antivirals idoxuridine, vidarabine, and trifluridine have in vitro activity against VZV, but little or no in vivo effect. Theoretically, these agents might be of benefit during the first few days of HZO by inhibiting viral replication in the epithelium and reducing the residual amount of viral antigen.⁷ However, because the MICs for VZV are so high, these drugs are of no clinical value for the treatment of HZO keratitis. The apparent simultaneous occurrence of herpes simplex and herpes zoster may actually represent herpes zoster pseudodendrites, rather than simultaneous infection with herpes simplex. Therefore, the management of HZO keratitis is not favorably influenced by the use of first-generation antivirals.

Second-generation antiviral agents such as acyclovir do have in vivo efficacy against VZV, and intravenous acyclovir has been shown to be of value in the management of herpes zoster keratitis. Oral acyclovir in HZO keratitis also has shown efficacy.^80,96 McGill and Chapman^109,110 have successfully used topical ophthalmic acyclovir in HZO keratitis and keratouveitis, however, topical ophthalmic acyclovir is not available for corneal use in the United States. Maudgal and associates^111,112 and DeClerq¹¹³ used topical or oral 5-2-bromovinyl-2'-deoxyuridine (BVDU) in the management of HZO keratitis. No placebo-controlled studies of BVDU have been performed to date. BVDU is not available in the United States.

Topical corticosteroids are of little benefit in the treatment of acute epithelial herpes zoster keratitis. In the past, corticosteroids were considered deleterious in HZO because of the possibility of superinfection or dissemination, but more recent evidence shows that herpes zoster pseudodendrites can respond to topical steroids.^56,57,63 Because most cases of herpes zoster epithelial keratitis usually have a self-limited and visually asymptomatic course even without treatment, the most appropriate management strategy is to use ocular lubrication with nonpreserved artificial tears and possible debridement and to avoid topical antivirals and steroids.⁷

Topical steroids do have a place in the management of the components of zoster corneal disease associated that are inflammatory in etiology, namely, sclerokeratitis, keratouveitis, interstitial keratitis as well as immune-related sequelae such as anterior stromal infiltrates, disciform keratitis, and delayed corneal mucous plaques.⁶⁵ Herpes zoster interstitial keratitis is probably an antigen-antibody-complement-mediated reaction, whereas disciform keratitis is a manifestation of delayed hypersensitivity.⁶⁵ The use of topical steroids in these settings diminishes inflammation and vascularization, but the patient must be evaluated frequently and carefully because of the rapidity of changes in herpes zoster keratitis and because of the potential for corneal melting. Patients should be forewarned of the potential for chronic topical corticosteroid treatment, even at low, seemingly homeopathic doses, with the potential for side effects such as cataract or elevated intraocular pressure. Steroids should not be used in cases of exposure or neurotrophic keratitis because of the possibility of keratolysis.⁶⁵

Indolent epithelial defects associated with neurotrophic keratitis (Fig. 22) that are unresponsive to nonpreserved artificial tears, bland ointments, pressure patching, or therapeutic soft contact lenses should be considered for lateral, central, or total tarsorrhaphy, bridge or full Gundersen conjunctival flap, or amniotic membrane transplantation. A lateral or central tarsorrhaphy is one of the simplest and most effective means of reducing the sight-threatening sequelae of HZO neurotrophic keratitis (Fig. 23). Waring and Ekins¹¹⁴ have delineated the various factors that can cause corneal perforation in HZO (Fig. 24) and underscored the prophylactic benefit of early, large tarsorrhaphy to prevent initial epithelial erosion and subsequent corneal melting and perforation.¹¹⁵

Therapeutic soft contact lenses may be a reasonable short-term strategy in herpes zoster neurotrophic keratitis, but they must be used with caution and with frequent follow-up to guard against lens spoilage, microbial superinfection, and hypoxic iridocyclitis.

The development of cicatricial entropion or ectropion with subsequent trichiasis further exacerbates the corneal surface.¹¹⁵ Timely repair of ectropion or entropion from HZO protects the corneal epithelium and makes subsequent tarsorrhaphy easier to perform. Superior lid cicatrization can make subsequent tarsorrhaphy in HZO quite difficult to perform, resulting in immediate retraction or breakage of the tarsal scar. When there is severe cicatricial ectropion, a simple tarsorrhaphy (performed by scraping the superior and inferior tarsal plates and placing 6-0 silk sutures on bolsters) may not be effective in closing the lids permanently; in these cases a tongue-in-groove tarsorrhaphy or Hughes-type procedure may be required.

If less than 1.0 mm in diameter, impending or actual corneal perforation can be managed with 2-butyl-cyanoacrylate (Histacryl™) adhesive and a thick therapeutic soft contact lens (e.g., Bausch & Lomb piano T, or Wessley-Jensen CSI) (Figs. 25 and 26). Larger perforations can be managed acutely with scleral grafting or corneal patch grafting. These grafts should in turn be covered with conjunctiva to prevent the initial melting process from destroying the scleral or corneal graft (Figs. 27 and 28). Steroid therapy should be tapered and then stopped, and cycloplegics added. Some patients with herpes zoster keratitis end up with vascularized, lipid-containing scars and may have some residual return of corneal sensation. In this particular subset of patients, corneal transplantation can be considered (Figs. 29 and 30). Tanure and associates¹¹⁷ presented positive follow-up data on patients who had keratoplasty for VZV keratopathy. Simultaneous lateral tarsorraphy was helpful in these patients. In patients with HZO keratitis who have profound corneal anesthesia, however, corneal transplantation could lead to a greater risk of corneal wound dehiscence, healing problems, and graft rejection, and is not recommended.¹¹⁷

OTHER OCULAR INVOLVEMENT.

The use of topical cycloplegics is quite helpful in decreasing the ciliary spasm associated with herpes zoster inflammatory disease and in breaking posterior synechiae. For many patients with HZO, cycloplegia is the only form of treatment necessary for ocular comfort.

Focal corneal infiltrates, stromal edema, stromal keratitis, and disciform keratitis may be treated with topical corticosteroids (the equivalent of prednisolone acetate 12.5% four times per day). Pulsing steroids is sometimes preferable to chronic treatment to decrease the associated complications of steroid therapy. Again, steroids should be reserved for patients who have intact epithelium with herpes zoster disciform keratitis, endotheliitis, or keratouveitis.

Glaucoma in HZO is typically secondary to plugging of the trabecular meshwork as a consequence of inflammatory anterior chamber reactivation, or it may result from peripheral anterior synechiae formation. The use of topical β-blockers and carbonic anhydrase inhibitors (e.g., timolol-dorzolamide combination) and α-adrenergic medications (e.g., brimonidine) along with topical corticosteroids usually results in a significant reduction in intraocular pressure. Herpes zoster vitritis, vitreous hemorrhage, or vitreous debris is usually secondary to severe inflammation and may respond to topical, periocular, or systemic steroids.

HZO retinitis, HZO optic neuritis, HZO chorioretinitis, and the ARN syndrome are most appropriately treated with a combination of systemic steroids and intravenous acyclovir.⁷⁷ PORN syndrome (acyclovir-resistant VZV retinopathy in AIDS) management requires the intravenous administration of various combinations of antivirals, including foscarnet, ganciclovir, and vidarabine.^93,100 Another strategy for PORN syndrome is the intravitreal injection of ganciclovir and foscarnet.¹⁰¹ VZV retinopathy in patients with AIDS requires long-term suppressive antiviral therapy to prevent recurrences.

POSTHERPETIC NEURALGIA.

Most therapeutic strategies for PHN have been of only modest value. These include analgesics, with or without narcotics; the tricyclic antidepressants chlorprothixene, desipramine, nortriptyline and amitriptyline; and the neurotonic agents carbamazepine and phenytoin. The tricyclic antidepressants should be used in low doses in the elderly to avoid anticholinergic effects and drowsiness.

Sklar and co-workers¹¹⁸ performed a randomized, placebo-controlled, double-blind trial of intramuscular adenosine monophosphate (AMP) for PHN and found that herpes zoster skin ulcers healed faster and virus shedding was reduced compared with placebo. AMP, a naturally occurring antiviral agent, is converted intracellularly to adenosine and is then taken up by the actively replicating VZV. After a 4-week trial, 88% of the AMP-treated patients were free of pain as opposed to only 43% in the placebo group. In the placebo group, patients who still had pain after 4 weeks were then given AMP treatment, and all of these patients recovered within 3 weeks after initiation.¹¹⁸

Cimetidine has been used successfully in PHN management in an uncontrolled trial.¹¹⁹ However, a controlled study reported no significant benefit from cimetidine over placebo.¹²⁰ Cimetidine prevents itching, redness, swelling, and neuronal irritation. In addition, cimetidine is an H₂ receptor antagonist, and thymus-dependent suppressor T lymphocytes have H₂ histamine receptors on their surface.¹¹⁹ Cimetidine may therefore work by attaching to the H₂ receptor and serving as an immune-modulating agent, thereby enhancing the immune response by preferentially blocking H₂ receptor sites on suppressor T cells and favorably modulating helper T-cell activity.¹²⁰

Substance P is one of the principal mediators of pain impulses from the peripheral nervous system to the central nervous system.¹²¹ Capsaicin (trans-8-methyl-N-vanillyl-6-nonemaide, Zostrix™) is a vanilyl alkaloid extract of the plant Solanaceae family Capsicum (a genus that also includes the red, chili, and jalapeno peppers). Capsaicin depletes and prevents the reaccumulation of substance P from small peripheral sensory neurons. Capsaicin is available in a 0.025% cream, and has been found to be effective in some patients with PHN. The reported failures with capsaicin are attributed to inadequate usage. When used appropriately, capsaicin can cause improvement in up to 75% of patients.^121,122 Capsaicin cream needs to be applied three to four times per day and may require several weeks before pain relief occurs.¹²¹ The main side effect of capsaicin application is stinging. If no improvement in neuralgia is noted after 6 weeks, it is unlikely that further usage will be effective.

Topical forehead administration of a eutectic mixture of local anesthetics (EMLA) patch, which is a 5% cream made of lidocaine 2.5% and procaine 2.5%, can be an effective strategy for mild PHN.¹⁰⁰

The anticonvulsant gabapentin (1-aminoethyl cyclohexaneacetic acid, Neurontin™) has been used successfully in the management of PHN.¹²³ Gabapentin is structurally similar to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), but it does not act by mimicking GABA. The precise mechanism action of gabapentin in the management of PHN is unknown. Gabapentin is begun at 100 mg orally at bedtime, for several days. Side effects include somnolence, dizziness, and ataxia.¹²³ The dosage can be increased as tolerated to 300 mg orally three times daily and higher, up to a maximum dosing of 3600 mg per day.¹²³

Despite favorable reports on the use of single categories of medication in the management of PHN—the antivirals acyclovir or famcyclovir or valacyclovir or oral corticosteroids—there are few controlled studies comparing the relative benefits of one, all, or combinations of these medications. A large prospective, placebo-controlled trial would have to be initiated, and considering the pleomorphic nature of PHN in HZO, it would be difficult to compare patients and outcomes.¹²⁴ In the original placebo-controlled study of oral acyclovir in the management of acute HZO, Cobo and associates^80,96 concluded that the drug had no effect on the incidence, severity, or duration of PHN. A more recent study by McGill and White,¹²⁵ however, showed a significant decrease in the occurrence of PHN with oral acyclovir versus placebo. The role of systemic corticosteroids in the treatment of PHN is moot. Scheie⁴⁵ initially reported on the successful use of oral corticosteroids in treating PHN and in reducing the severity of keratiti, uveitis, and glaucoma, without dissemination of herpes zoster. Epstein¹²⁶ reported favorable responses to subcutaneous triamcinolone in HZO patients with PHN. The initial caution expressed by Merselis and co-workers¹²⁷ on the possibility of HZO dissemination with oral corticosteroid use is tempered by the fact that 11 of their 17 patients had preexisting immunologic compromise, including lymphoma, Hodgkin's disease, or leukemia. Of the 6 otherwise immunocompetent patients, only 2 actually received steroids and neither had dissemination of disease.¹²⁷ A more recent prospective, double-blind study showed no difference between oral prednisolone and placebo in the occurrence of PHN.¹²⁸ Two large, controlled clinical trials examined the role of acyclovir with or without oral prednisone in the management of PHN.^129,130 In both of these studies, there was a statistically significant reduction in ZAP (the acute pain in the first 4 weeks after the zoster cutaneous eruption), and in the rate of healing of vesicles, but no effect on the incidence or duration of PHN.^129,130

If oral corticosteroids are to be used in acute HZO, wait a few days before instituting them, to allow humoral immunity to arise and to let the oral antiviral (acyclovir or famcyclovir or valacyclovir) kill circulating VZV. An oral corticosteroid such as prednisone can then be initiated and tapered during a period of two weeks. The use of oral corticosteroids without concomitant antiviral therapy is not recommended.⁴ Oral corticosteroids should not be used in high-risk patients such as those with diabetes or those with gastritis.⁴

Olson and Ivy¹³¹ successfully treated 27 patients with PHN refractory to medical management with sympathetic (stellate ganglion) block. There is evidence that the early use of stellate ganglion block may increase the rate of relief from PHN.¹³² Other strategies for PHN include transcutaneous electrical nerve stimulation, acupuncture, psychotherapy, hypnosis, biofeedback, and in extreme cases, trigeminal rhizotomy. It is strongly recommended that a neurologist or anesthesiologist specializing in pain management closely follow HZO patients with PHN.

1. Begin oral valacyclovir, 1000 mg three times per day for 7 days, or oral famcyclovir, 750 mg, three times per day for 7 days, or oral acyclovir, 800 mg five times daily for 10 days. In immunocompromised patients, give intravenous acyclovir for 7 days at 10 mg/kg every 8 hours for adults (30 mg/kg per day), or 500 mg/m² every 8 hours for children less than 12 years of age.
   
2. After a few days on this regimen, for patients without immunosuppression, gastritis, or diabetes, oral prednisone 60 mg per day, an oral H₂ blocker and a rapid taper could be considered in the presence of acute neuralgia or severe cutaneous eruption.
   
3. Use topical corticosteroids only to address those specific aspects of HZO that have inflammatory etiology, such as episcleritis, scleritis, disciform keratitis, limbal fasciculitis, iridocyclitis, and only as a function of the morphology and severity of the anterior segment inflammation. Topical corticosteroid therapy is withheld in zoster epithelial keratitis, as it is usually ineffective.
   
4. Provide long-term ocular lubrication, using nonpreserved artificial tears four to six times per day, and a bland ophthalmic lubricant ointment at bedtime.
   
5. Use a cycloplegic such as cyclogyl 1%, four times per day, for zoster iridocyclitis, uveitis, vitritis, keratitis or scleritis.
   
6. Apply a topical antibiotic ointment, such as erythromycin or polymyxin B-bacitracin, to the forehead and affected lid areas twice daily to protect against bacterial superinfection. Avoid neomycin-containing antibiotic ointments.
   
7. Follow the patient with HZO often for the first several months after the initial cutaneous eruption in order to check for the development of PHN, the need for analgesics or antidepressants, the possibility of keratitis, a decrease in corneal sensation, the presence of uveitis, or other ocular sequelae.
   
8. After the initial few weeks of following a patient with HZO, especially if the patient enjoys good vision with no ocular sequelae, there can be a decrease of follow-up visits. Since neurotrophic keratitis can develop abruptly, careful follow-up is recommended for at least 1 year after the onset of HZO. In addition, other intraocular or extraocular inflammation, such as episcleritis and scleritis, can occur idiopathically months to years after the original bout of herpes zoster. Therefore a “middle game” strategy is advised, of bimonthly visits for the first 6 months, trimonthly visits for the next 6 months, and then yearly visits to identify exposure changes, cicatricial ectropion or entropion, to measure corneal sensation, and promptly identify the development of neurotrophic keratitis and to assess for PHN.
   
9. If PHN develops, begin gabapentin in low doses (100 mg at bedtime) and increase as tolerated. A referral to a neurologist or anesthesiologist specializing in pain management is advised to coordinate this and other strategies.
   
10. In the event of neurotrophic corneal ulceration, rapidly taper any topical corticosteroids, increase nonpreserved tears, and plan for prompt lateral tarsorrhaphy, or a Gundersen or bridge conjunctival flap or amniotic membrane transplant.
    

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