regeneration lines, and frank neurotrophic ulcers characterize neurotrophic keratopathy. These ulcers can be distinguished from herpetic epithelial keratitis by a relative absence of rose bengal staining. Neurotrophic ulcers are typically round or oval and located in the central or inferior cornea. Corneal epithelium at the edges of a neurotrophic ulcer may appear to roll under itself and typically has a gray, elevated appearance. Liberal use of nonpreserved lubricating drops, gels, and ointments combined with punctal occlusion are the mainstays of therapy. To prevent progressive stromal thinning and perforation, tarsorrhaphy is indicated for neurotrophic ulcers that fail to respond to conservative therapy. On occasion, active or resolving interstitial stromal keratitis due to HSV is associated with a chronic epithelial defect that does not stain with rose bengal. This so-called metaherpetic ulcer probably results from neurotrophic mechanisms or a devitalized corneal stroma.
Severe or long-standing disciform keratitis can result in persistent bullous keratopathy. Stromal inflammation in general, whether interstitial or necrotizing, commonly leads to permanent corneal scarring and irregular astigmatism. Both scarring and astigmatism may improve with time in some patients. Fitting with a gas-permeable contact lens usually improves vision beyond that achieved with spectacle refraction. In patients with deep corneal stromal vascularization due to prior necrotizing herpetic inflammation, secondary lipid keratopathy may further impair the vision. Topical corticosteroids may suppress new vessel growth and halt additional lipid deposition.
Herpetic Eye Disease Study Group. A controlled trial of oral acyclovir for iridocyclitis caused by herpes simplex virus. Arch Ophthalmol. 1996;114(9):1065–1072.
Surgical treatment
Penetrating keratoplasty (PK) is indicated in selected patients with visually significant stromal scarring and astigmatism not correctable by spectacle or contact lens. Oral antiviral therapy may improve graft survival by reducing the risk of HSV recurrence and allow more liberal use of topical corticosteroids. Oral antiviral agents are not toxic to the corneal epithelium and are therefore generally preferable to topical antivirals in patients after PK. The prognosis for successful optical PK approaches 80% in eyes without signs of active inflammation for at least 6 months prior to surgery. Tectonic PK is indicated in impending or frank corneal perforation due to necrotizing or neurotrophic ulcers. Stromal inflammation and ulceration may develop and graft failure may occur in inflamed herpetic eyes undergoing tectonic PK. Therefore, small descemetoceles and perforations in inflamed eyes may best be treated by applying therapeutic tissue adhesive and a bandage contact lens and delaying PK until inflammation can be controlled. Amniotic membrane transplantation or conjunctival flaps may also be used for persistent epithelial defects with and without corneal thinning. Keratoprostheses or anterior lamellar keratoplasty may have an important role because of the risk of rejection and recurrence in HSV corneal disease.
Varicella-Zoster Virus Dermatoblepharitis, Conjunctivitis, and Keratitis
PATHOGENESIS As with other herpesviruses, VZV causes a primary infection (varicella, or chickenpox) and subsequent latency, occasionally followed later by recurrent disease (zoster, or shingles). Primary VZV infection occurs upon direct contact with VZV skin lesions or respiratory secretions via airborne droplets and is highly contagious for naive individuals. VZV infection is usually a selflimited infection of childhood rarely associated with long-term sequelae. However, infection of adults or immunosuppressed individuals can be fatal. In children, VZV infection manifests with fever, malaise, and a vesicular dermatitis that lasts 7–10 days. Except for eyelid vesicles and follicular conjunctivitis, ocular involvement is uncommon during primary infection. As with HSV, VZV latency occurs in neural ganglia and, in approximately 20% of infected individuals, reactivates later. Of all
cases with zoster, 15% involve the ophthalmic division of CN V (trigeminal). VZV infection, whether primary or recurrent, can usually be distinguished from HSV infection through a careful history and examination. Distinguishing features of each infection are listed in Table 4-7.
Table 4-7
CLINICAL PRESENTATION The rash of chickenpox begins as macules and progresses to papules, vesicles, and then pustules that dry, crust over, and may leave individual scars. Ocular involvement may include follicular conjunctivitis, occasionally associated with a vesicular lesion on the bulbar conjunctiva or eyelid margins. Punctate or dendritic epithelial keratitis is uncommon. Although subepithelial infiltrates, microdendritic keratitis, stromal keratitis, disciform keratitis, uveitis, and elevated IOP are rare, recurrent varicella keratouveitis may cause significant morbidity in some patients.
LABORATORY EVALUATION Laboratory confirmation of acute or recurrent VZV infection is possible by immunodiagnostic methods, viral culture, and PCR. Serologic testing is used primarily to identify varicella-naive adults who might benefit from prophylactic vaccination. As with HSV, scrapings from a vesicle base can be tested by cytology, PCR, or culture, or for the presence of VZV antigen. Conjunctival scrapings or corneal impression cytology specimens can be similarly analyzed by culture, antigen detection, or PCR.
MANAGEMENT Because infected individuals shed the virus in respiratory secretions before the onset of the characteristic rash, avoiding infected persons is not always possible. Vaccination against varicella is recommended for anyone older than 12 months without a history of chickenpox or with a negative serology. The severity of signs and symptoms may be reduced in clinically ill patients by the administration of oral acyclovir. Significant keratitis or uveitis can be treated with topical corticosteroids.
Herpes zoster ophthalmicus
PATHOGENESIS Following primary infection, VZV establishes latency in sensory neural ganglia. Zoster (shingles) represents endogenous reactivation of latent virus in people with a waning level of immunity to infection. Most patients are in their sixth to ninth decades of life, and the majority are healthy, with no specific predisposing factors. However, zoster is more common in patients on immunosuppressive therapy; in those with a systemic malignancy, a debilitating disease, or HIV infection; and after major surgery, trauma, or radiation. However, herpes zoster in otherwise healthy children has been described in the literature.
CLINICAL PRESENTATION Zoster manifests as a painful vesicular dermatitis typically localized to a single dermatome on the thorax or face. Patients may complain initially of fever and malaise, and warmth, redness, and increased sensation in the affected dermatome. The most commonly affected dermatomes are on the thorax (T3 through L3) and those supplied by CN V. The ophthalmic division of the trigeminal nerve is affected more often than the maxillary and mandibular branches, and its
involvement is referred to as herpes zoster ophthalmicus (HZO) (Fig 4-12). A maculopapular rash, followed by vesicles and then pustules, is characteristic. Zoster dermatitis may result in large scabs that resolve slowly and leave significant scarring. Neurotrophic keratopathy and sectoral iris atrophy are characteristic. Inflammation of almost any ocular tissue can occur and recur in HZO.
Figure 4-12 Herpes zoster ophthalmicus (HZO). (Courtesy of Vincent P. deLuise, MD.)
Zoster dermatitis is accompanied by pain and dysesthesia. The pain usually decreases as lesions resolve; however, neuralgia in the affected dermatome can continue for months to years. The severity of pain ranges from mild to incapacitating. Ocular involvement occurs in more than 70% of patients with zoster of the first division of CN V and may appear in association with any branch, including the nasociliary, frontal, or lacrimal branches. Ophthalmic complications also may occur with zoster of the second (maxillary) division of CN V. In immunosuppressed patients, zoster may involve more than 1 branch of the trigeminal nerve at the same time, can chronically reactivate, and may be multiply recurrent. See BCSC Section 2, Fundamentals and Principles of Ophthalmology, for discussion of the innervation of the eye and face.
Eyelid vesicular eruption can lead to secondary bacterial infection, eyelid scarring, marginal notching, loss of cilia, trichiasis, and cicatricial entropion or ectropion. Scarring and occlusion of the lacrimal puncta or canaliculi may occur. Episcleritis or scleritis associated with zoster may be nodular, zonal, or diffuse.
Both punctate and dendritic epithelial keratitis caused by viral replication in corneal epithelium are common manifestations of ophthalmic zoster. Herpes zoster pseudodendrites, distinguished from the true dendrites of HSV, form branching or “medusa-like” lesions, are superficial, lack central ulceration, stain minimally with fluorescein and rose bengal, and have blunt rather than bulbous ends. Dendrites may persist and remain chronically culture-positive for VZV in patients with AIDS. Elevated dendritiform mucous plaques may occur weeks to months after resolution of the skin lesions. Diminished corneal sensation develops in up to 50% of patients. Nummular corneal infiltrates are said to be characteristic of zoster stromal keratitis (Fig 4-13), but the interstitial keratitis, disciform keratitis, and anterior uveitis with increased IOP in HZO are clinically indistinguishable from those caused by HSV infection. Chronic corneal stromal inflammation can lead to corneal vascularization, lipid keratopathy (Fig 4-14), and corneal opacity. Corneal anesthesia may be profound, and neurotrophic keratopathy due to HZO can be extremely difficult to manage.
Figure 4-13 Nummular keratitis of HZO. (Courtesy of Rhea L. Siatkowski, MD.)
Figure 4-14 Lipid keratopathy following HZO. (Reprinted with permission from Chodosh J. Viral keratitis. In: Parrish RK, ed. The University of Miami Bascom Palmer Eye Institute Atlas of Ophthalmology. Boston: Current Medicine; 1999.)
Focal choroiditis, occlusive retinal vasculitis, and retinal detachment have been reported. Ipsilateral acute retinal necrosis (ARN) temporally associated with HZO is uncommon.
Orbital or central nervous system (CNS) involvement as a result of an occlusive arteritis may lead to eyelid ptosis, orbital edema, and proptosis. Papillitis or retrobulbar optic neuritis may also develop. Cranial nerve palsies, when meticulously investigated, have been reported to occur in up to one-third of cases of HZO, with CN III (oculomotor) most commonly affected. Cranial nerve involvement may occur within the orbit or the cavernous sinus. Systemic dissemination is unusual in immunocompetent patients but can occur in up to 25% of those who are immunocompromised.
MANAGEMENT Oral antiviral therapy for HZO was found in randomized clinical trials to reduce viral shedding from vesicular skin lesions, reduce the chance of systemic dissemination of the virus, and decrease the incidence and severity of the most common ocular complications. Oral antiviral therapy may reduce the duration if not the incidence of postherpetic neuralgia if begun within 72 hours of the onset of symptoms. There are also reports to suggest that initiating antiviral therapy after 72 hours, especially in the presence of new vesicles, is beneficial. Amitriptyline has also been reported to decrease the duration of postherpetic neuralgia if given early on and continued until pain symptoms remit.