deteriorating vision, severe pain, or even (occasionally) perforation of the globe. Scleritis during the acute episode of herpes zoster ophthalmicus is easily associated with VZV infection. However, because scleritis often occurs months after the onset of the VZV infection, herpes zoster scleritis is sometimes difÞcult to diagnose. A careful past history review and meticulous facial and ocular examination are essential for early diagnosis of herpes zoster scleritis. Subsequent aggressive and prolonged treatment may halt the progression of the scleral destruction.

Epidemiology

Herpes zoster may occur in any age group, but is most common in individuals over age 60. That the aging process enhances the risk of developing herpes zoster infection can be judged from the fact that herpes zoster has an incidence of three cases per 1,000 population per year for ages 20Ð49 years, and of ten cases per 1,000 population per year for ages 80Ð89 years [158]. Immunosuppressed patients, such as patients with acquired immune deÞciency syndrome, organ transplantation, neoplasia, or blood dyscrasia, are also at great risk for developing herpes zoster infection [159].

Pathogenesis

Varicella (chickenpox) and herpes zoster are different clinical conditions caused by the same virus. Primary infection with VZV results in chickenpox. In the USA, over 90% of adults have serologic evidence of previous infection by VZV and most of them have VZV in a latent state [160]. About 20% of these adults may have a reactivation of VZV occurring as herpes zoster [161].

Ocular herpes zoster is thought to represent a reactivation of latent VZV left in the trigeminal ganglion following a previous attack of chickenpox; [162] this involves a partial immune response after Þrst exposure to the virus: the immune system is not capable of effectively eliminating the virus but is capable of producing immunopathology. There is no convincing evidence that herpes zoster can occur after contact with exogenous VZV from a patient suffering active chickenpox

or zoster. Herpes zoster most commonly involves the thoracic nerves; however, the trigeminal nerve is involved in 9Ð16% of patients [163Ð166]. Of the three divisions of the trigeminal nerve (ophthalmic, maxillary, and mandibular), the Þrst or ophthalmic is the most frequently affected.

The ophthalmic division of the trigeminal nerve has three branches, the frontal, the lacrimal, and the nasociliary. The frontal branch, supplying the upper lid, forehead, and superior conjunctiva, is the most commonly involved. The lacrimal branch supplies the lacrimal gland, the conjunctiva, and the skin of the temporal angle of the eye. The nasociliary branch is the sensory nerve that supplies the eyeball. This branch divides into the infratrochlear and the nasal nerves. The infratrochlear nerve goes to the lacrimal sac, conjunctiva, skin of both lids, and root of the nose. The nasal nerve goes to the most critical structures: the sclera, cornea, uveal tract, and the tip of the nose. Because VZV most commonly affects all three branches of the ophthalmic division, ocular involvement in herpes zoster may lead to devastating ocular pathology.

Skin papules, pustules, or vesicles, conjunctival or episcleral vesicles, and corneal dendritic ulcers are caused by direct invasion of the virus. Scleritis, sometimes episcleritis, keratitis, trabeculitis, and anterior uveitis are most commonly caused by immune-mediated reactions triggered by the virus; [167] recurrences are independent of the presence of the virus.

Clinical Features

Herpes zoster is a disease characterized by an intense painful, vesicular eruption involving the skin or mucous membrane in the distribution of a single sensory nerve. Although the incubation period after reactivation of endogenous virus is not known, the incubation period after contact with exogenous virus ranges from a few days to 2 weeks [168]. Headache, malaise, fever, and chills may precede the skin eruption by 4 or 5 days; neuralgia may precede the skin eruption by 2 or 3 days. The skin eruptions begin as papules, which rapidly become vesicles and pustules; vesicles subside within 2 weeks, often leaving permanent scars, variable degrees of hypoesthe-

sia, or severe post-zoster neuralgia [169]. Eye lesions occur in about 50% of these cases [170]. Rarely, the ocular manifestations may appear without the skin eruption; a careful search for subtle papules, pustules, or vesicles in scalp or serial VZV blood titers may contribute greatly to the diagnosis.

Ocular involvement in VZV infection often includes conjunctivitis, episcleritis, scleritis, keratitis, uveitis, and glaucoma; scarred lid retraction, paralytic ptosis, retinitis, acute retinal necrosis, disk edema, pupil abnormalities, and extraocular nerve palsies also may occur [170, 171]. Hypopyon, hemorrhage into the anterior chamber and phthisis bulbi may result from herpes zoster vasculitis and ischemia (anterior segment necrosis).

Postherpetic neuralgia may be deÞned as pain in the involved dermatome persisting for more than 2 months following the onset of zoster dermatitis. It is more common in patients over 60 years of age (about 50% of these). It may be the result of herpes zoster vasculitis and neuritis.

Scleritis

The reported incidence of scleritis in herpes zoster ophthalmicus ranges from 0.68 to 8% [7, 13, 80, 172Ð174]. Although scleritis may occur during the acute disease (about 10Ð15 days after the onset of skin lesions), it most commonly appears months or years after an episode of herpes zoster ophthalmicus [175], sometimes triggered by ocular surgery. Zoster scleritis is of immune etiology and, although it may be diffuse or nodular, it often is necrotizing, with painful, persistent, circumscribed nodules with translucent centers, and risk of perforation or staphyloma formation [176Ð179]. It requires aggressive and prolonged therapy or even adjunctive procedures, such as scleral homografting to maintain the integrity of the globe. Scleritis may take months to resolve and often leaves extensive scleral thinning. Recurrences, sometimes occurring not at the same site as the previous attack of scleritis, may be frequent, even after many years. Zoster scleritis may be accompanied by stromal keratitis, either immune disciform or white necrotic interstitial keratitis, which may progress

to sclerosing keratitis or even to peripheral ulcerative keratitis. It also may be associated with anterior uveitis, which may cause a sectorial iris atrophy and/or trabeculitis, which in turn may cause glaucoma. Decreased corneal sensation in the affected area and sectorial iris atrophy are helpful indicators for the diagnosis of herpes zoster ophthalmicus.

In our prior series of 172 patients with scleritis [13], two patients had scleritis secondary to herpes zoster infection (1.16%). The Þrst patient was an 85-year-old white female who developed necrotizing scleritis and sclerosing keratitis near the superior limbus in her right eye. Visual acuity at presentation was at the count Þngers level in the right eye and corneal sensation was markedly decreased. Six months prior to the onset of scleritis she had had an episode of herpes zoster ophthalmicus with skin lesions and dendritic keratitis, which was treated with oral acyclovir and oral steroids. She had also had an uncomplicated extraocular cataract extraction with implantation of an intraocular lens 9 months prior to the onset of scleritis. An extensive laboratory investigation revealed only circulating immune complexes. A diagnosis of herpes zoster necrotizing scleritis with marked scleral destruction and uveal show associated with peripheral ulcerative keratitis was made (Fig. 7.8), treatment with oral prednisone was initiated, and scleral debridement and homografting were performed (Fig. 7.9). Pathological examination of the sclera showed chronic granulomatous inßammation with multinucleated giant cells and epithelioid cells, and inßammatory microangiopathy. Immunohistochemical studies with anti-VZV antibodies did not detect VZV antigen. The patient could not tolerate oral prednisone and oral acyclovir, and she developed progressive melting of the scleral graft and peripheral ulcerative keratitis (Fig. 7.10). Institution of oral methotrexate initially reduced scleral and corneal inßammation but, after 3 weeks, progressively destructive inßammatory activity again increased. Extensive scleral and corneal melting, and hemorrhage into the anterior chamber with a profound Þbrin-type reaction, indicated anterior segment necrosis. Enucleation was performed by her local ophthalmologist and we did not obtain the pathology report. VZV infection in

Fig. 7.8 Necrotizing scleritis in a patient with herpes zoster ophthalmicus. Note the intense degree of inßammation and the associated scleral necrosis with uveal show. Also note the area of peripheral ulcerative keratitis at the far edge of the superior corneal periphery

Fig. 7.9 Same patient as in Fig. 7.8, following quieting of the active inßammatory process through treatment with systemic prednisone and acyclovir and scleral grafting

Fig. 7.10 Same patient as in Figs. 7.8 and 7.9: Necrotizing scleritis and peripheral ulcerative keratitis have recurred following discontinuation of the oral prednisone and acyclovir, which had been used to achieve quiescence prior to grafting

this elderly patient triggered an immune-mediated necrotizing scleritis with peripheral ulcerative keratitis, presumably through deposition of circulating immune complexes in the area previously traumatized by ocular surgery. Cyclophosphamide might have been more effective than was methotrexate.

The second patient was a 75-year-old male who developed necrotizing scleritis with uveal prolapse and peripheral ulcerative keratitis at 12 oÕclock in his left eye 6 years after a herpes zoster ophthalmicus infection and 9 months after an extracapsular cataract extraction. The patient had developed recurrent anterior uveitis, glaucoma, and cataract 3 months after the onset of acute VZV infection and had undergone extracapsular cataract extraction 5 years after the onset of anterior uveitis. Therapy for destructive sclerocorneal process included oral cyclophosphamide, oral acyclovir, and scleral homografting. Pathological examination of the resected necrotic tissue revealed granulomas and inßammatory microangiopathy. Immunohistochemical studies did not detect VZV antigen. The scleral graft and peripheral cornea remained stable without further melting. Necrotizing scleritis and peripheral ulcerative keratitis developed as a result of a VZV-induced immune-mediated reaction in the area traumatized by ocular surgery.

Episcleritis

Simple or nodular episcleritis, often accompanied by vesicles in conjunctiva and episclera, or dendrites in cornea, may appear before or early in the course of the skin eruption. Episcleritis in this case is the result of direct viral invasion and usually resolves in 3 or 4 weeks without sequelae [17]. Immune-mediated episcleritis may develop between 10 and 15 days after the onset of skin lesions.

In our series of 94 patients with episcleritis, 1 patient had episcleritis associated with herpes zoster ophthalmicus infection (1.06%). The patient developed simple episcleritis and dendritic keratitis 2 days after the onset of skin vesicles. Skin and ocular lesions recovered without sequelae with oral acyclovir and there were no recurrences.