Herpes zoster ophthalmicus (HZO) is seen in 10% to 25% of the approximately 1 million new cases occurring annually in the United States.1,2 Corneal complications of HZO include both acute and chronic infectious and immune keratitis. The epithelial pseudodendritic lesions can be seen in the acute stages or months to years later.3 These ulcerations harbor viral DNA and warrant antiviral treatment to prevent further corneal damage.4–6
Despite there being an increased understanding of the condition, there is no consensus regarding the treatment of these late corneal lesions in HZO.4,5 Earlier, topical antiviral, trifluridine (TFT) 1% ophthalmic solution (Viroptic), had been used for these lesions with variable success.5 But ocular toxicity limits its use.7 Recently, topical ganciclovir 0.15% ophthalmic gel (Zirgan; Bausch & Lomb, Rochester, NY) has become available in the United States for treatment of herpetic disease. Although very effective for Herpes simplex virus keratitis,8 we also report the successful use of topical ganciclovir gel in pseudodendritic Herpes zoster keratitis as well.
MATERIALS AND METHODS
This is a retrospective, interventional case series of 4 patients with a history of HZO (2 weeks–13 months) who presented to the Cornea and Refractive Surgery Service at the Massachusetts Eye and Ear Infirmary between 2011 and 2013, approved by the institutional review board. All the patients had pseudodendritic epithelial corneal lesions and were currently on or had recently received oral antiviral therapy (valacyclovir). Their history was noted carefully, and the examination included best-corrected visual acuity (BCVA), intraocular pressures (IOP), slit-lamp examination (SLE) with fluorescein and rose bengal ocular surface staining, central corneal sensation (CCS) measured by the Cochet–Bonnet esthesiometer (Luneau Ophthalmologie, Chartres, France), and fundus examination.
The case series has been summarized in Table 1.
A 61-year-old white female presented with a 2-week history of a first episode of blurry vision of the right eye (OD) associated with severe intermittent pain, and a cutaneous rash on the right side of her forehead. On day 1 of the rash, she was started on oral (PO) valacyclovir (Valtrex, GlaxoSmithKline) 1 g tid by an outside physician. The BCVA was 20/40 OD and 20/25 OS (left eye). Corneal sensation was decreased OD (4.5/6.0) and normal OS (6.0/6.0). The SLE revealed a small epithelial defect. Valacyclovir was maintained, and topical antibiotic was added prophylactically.
At the 1-week follow-up, vision was unchanged, and SLE OD showed new staining corneal pseudodendrites, and 2 to 3 + stromal edema with Descemet folds. The PO antiviral was stopped and topical ganciclovir 0.15% gel (Zirgan; Bausch &Lomb), 5 times a day, was started. After 1 week of topical treatment, the BCVA OD improved (20/30). The SLE revealed healing pseudodendrites and epithelial defects, with only trace punctate keratopathy. The ganciclovir gel was tapered to bid and stopped in 2 weeks. The patient remained stable over 9 months with a BCVA of 20/20 OU; CCS OD improved (5.0/6.0).
A 77-year-old white male presented with pain and numbness on the right side of his forehead. Ocular history included open angle glaucoma, cataracts OU, and postherpetic neuralgia after an acute HZO with rash and keratouveitis OD 13 months previously. At the time of presentation, he had been on 1 g of valacyclovir PO qd for the past 6 months, topical prednisolone 1% qid, and antiglaucoma medications (brimonidine and timolol). The BCVA OD and OS, respectively, was 20/60 and 20/25; the IOP was 28 and 16 mm Hg in OD and OS; and the CCS was 1.0/6.0 in OD and 6.0/6.0 in OS. Examination of OD showed the presence of corneal pseudodendrites (Fig. 1A), whereas OS was normal on SLE. The failed oral antiviral was stopped, and topical ganciclovir 0.15% gel 5 times a day and prednisolone 1% qd were started; the latter was to treat the increase in pressure secondary to suspected trabeculitis.
At 1 week, the patient had improved symptomatically; the BCVA was stable at 20/60 OD and 20/25 OS, respectively. SLE OD showed the complete resolution of the pseudodendrites. The ganciclovir gel was discontinued, and slow steroid taper was started. At 4 months, the patient had no complaints, and the OD was stable with 20/80 BCVA, CCS1.0/6.0, IOP of 18 mm Hg, and no sign of epithelial or stromal disease (Fig. 1B). The decrease in the vision was felt to have been caused by the worsening of a cataract.
A 64-year-old white female with a history of HZO OS 4 months previously presented with redness OS. The initial HZO rash had involved all 3 trigeminal branches, and the patient was treated with 1 g of oral valacyclovir tid and topical steroids. At the current visit, the patient was not on oral antivirals. The BCVA was 20/20 OD and 20/60 OS, with an IOP of 19 mm Hg OU. The CCS was totally absent OS (0.0/6.0) but normal (6.0/6.0) OD. SLE OS showed corneal epithelial pseudodendrites and recurrent uveitis with moderate anterior chamber cells. The patient was started on topical ganciclovir gel 0.15% 5 times a day, prednisolone 1% tid, and prophylactic antibiotics.
On the 1-week follow-up, the patient reported symptomatic improvement. The BCVA OS improved to 20/40, and the corneal epithelial lesions were resolved. The frequency of ganciclovir and steroid was reduced and stopped after 2 months. Over the ensuing 10 months, the patient did not develop any pseudodendrites, maintained stable vision (BCVA OS: 20/50), IOP 13 mm Hg, but total corneal anesthesia persisted (0.0). The slight worsening of vision was felt to have occurred because of anterior stromal haze.
A 51-year-old white diabetic male with a 6-month history of HZO OS and glaucoma presented with blurred vision OS. An outside physician had recently prescribed 1 g of oral valacyclovir tid for 10 days and topical prednisolone 1% qid to treat recurrent HZO. The valacyclovir treatment had been completed 2 days before presentation. The BCVA was 20/20 OD, 20/25 OS, and IOP was in the low teens OU. SLE revealed punctate keratopathy and pseudodendrites nasally (Fig. 1C). Corneal sensation was decreased (1.0 out of 6.0). Topical ganciclovir 0.15% gel 5 times a day, topical steroid taper, and antibiotic were started.
At 1 week, the BCVA was 20/20 and 20/20-1 OD/OS, respectively. Healing pseudodendrites were noted on SLE, and the treatment was maintained. By 3 weeks, the symptoms were markedly improved with 20/20 BCVA OU. SLE revealed mild punctate superficial stain, no pseudodendrites but central stromal haze. Ganciclovir gel was tapered to bid, and prednisolone was changed to rimexolone 1% bid. After 2 months, the patient was asymptomatic with only trace epithelial staining and mild stromal haze. Ganciclovir gel was discontinued, and rimexolone slow taper was prescribed. Subsequent 3- and 6-month examination OS showed BCVA 20/20, no corneal epithelial lesions, faint stromal haze, and sustained decreased sensation (1.0/6.0) (Fig. 1D).
At 9 months, however, the patient developed recurrent HZO ocular involvement OS characterized by conjunctival redness and pain. Examination revealed a BCVA down to 20/30, increased IOP (33 mm Hg), aqueous flare with keratic precipitates, but no active corneal lesions. To treat this keratouveitis/trabeculitis episode, the patient was started on famciclovir (Famvir, Novartis) 500 mg orally bid, topical cyclopentolate bid, prednisolone 1% qid, and timolol 0.5% increased to bid.
After 1 week, the BCVA OS was 20/25, IOP 16 mm Hg, and the anterior chamber was quiet. SLE, however, showed corneal pseudodendritic lesions OS, this time temporally (Fig. 1E). Topical ganciclovir 0.15% gel 5 times a day was promptly started. Famciclovir was maintained for 2 more days, thus completing a 10-day course. All corneal lesions had healed after 1 week of this added topical treatment. Ganciclovir was then decreased to bid and discontinued 2 weeks thereafter. Steroid drops were tapered over 1 month. Three months after the former episode, the patient had a normal BCVA (20/20) and an IOP of 14/16 mm Hg OD/OS. CCS OS was 5.0, and SLE showed a faint subepithelial haze centrally, but no pseudodendritic or other active disease (Fig. 1F).
We present 4 HZO-affected patients with a total of 5 episodes of pseudodendritic keratitis despite current or recent systemic antiviral therapy. We treated the lesions using topical ganciclovir gel with resultant rapid healing.
Chronic and recurrent epithelial lesions have been reported to occur in 4% to 13% of HZO-affected patients.9–11 Typically pseudodendritic in shape without terminal bulbs, these lesions have been variously called delayed Herpes zoster pseudodendrites, dendritic plaques, or late Varicella Zoster Virus dendritiform keratitis.5,6,9,12 Yawn et al13 reported a nonocular Herpes zoster recurrence rate of 2.0%, 3.6%, and 6.2% at 2, 4, and 8 years, 87% of which were immunocompetent. In contrast to nonocular recurrences, only limited data in the form of a few case reports and series are available for the recurrence of HZO.14 In a series of 20 patients with these delayed corneal lesions, a cumulative recurrence rate of 45.6% per 100 person-years of follow-up was identified.6 Ghaznawi et al15 reported that delayed pseudodendrites occurred more frequently (36%) in patients who had an initial HZO onset at a younger age (<60 years) compared with development after 60 years of age (16.7%). As with systemic recurrences, the corneal lesions can also occur in both immunocompromised and immunocompetent states.4–6
The finding of viral DNA in these lesions using polymerase chain reaction has established the underlying pathogenesis and role of antiviral therapy.6,16 However, there is no consensus regarding the management; ophthalmologists often use different antivirals in varying combinations, dosages, and duration.5,16,17 This is illustrated in a recent practice pattern survey. Over 85% of cornea specialists reported treating recurrent, chronic HZO in the prior year. Although a majority (63%) chose to treat with a combination of oral antivirals and topical steroids, 24% used steroids alone. There was also no standardization of the duration of the treatment: 37% prescribed oral antivirals for 7 to 14 days, 15% for over a year, whereas 15% used them as long as the patient was on topical steroids.11 The oral antiviral regimen used in recurrences is similar to acute HZO.18 Hu et al5 have reported the use of TFT alone or in combination with oral acyclovir in acute HZO, but it does not relate to late epithelial pseudodendrites after such therapy. They have also noted recurrence after treatment. In their study, 3 of 10 HZO pseudodendritic recurrences were observed while patients were on oral antivirals. Six of the remaining 7 patients had been treated with antivirals at some point between first noted lesions and the first recurrence.
In our experience, gancioclovir gel seems to be more effective in eradicating corneal HZO infectious lesions. Ganciclovir is a topical antiviral drug long available in Europe and the Far East. Ganciclovir 0.15% ophthalmic gel has been approved by the Food and Drug Administration for “acute herpetic keratitis” in the United States in 2009.19 Ganciclovir a nucleoside analog is activated by phosphorylation in infected cells and is incorporated into the replicating viral DNA strand thus inhibiting replication.20 The required concentration to inhibit 50% of the viral activity per in vitro studies is 1.45 ± 0.57 μM for Varicella Zoster Virus.21 The drug concentration in tears ranges from 0.92 to 6.86 μg/mL after 12 hours of q3 hourly administration of 0.15% gel,22 that is, 2 to 18 times more than what is required. As a small lipophilic molecule, it has prolonged corneal contact, is retained in the aqueous for 4 hours, and has low systemic absorption.23,24 All these properties allow an easy to use and effective topical preparation of the drug.
Ganciclovir gel is now being widely used to treat acute herpes simplex virus keratitis.8,23 The recommended regimen is 0.15% gel 5 times a day in the affected eye until the corneal lesions heal and then tid for 7 days. Few side effects have been reported, including blurred vision (60%), eye irritation (20%), punctate keratitis (5%), and conjunctival hyperemia (5%).25 Recently, cytomegalovirus (CMV) glaucomatous keratouveitis was successfully treated with ganciclovir gel 5 times a day until it was resolved and then tapered to bid with no toxicity despite daily therapy for over 2 years.26
TFT is the other topical antiviral used for herpetic eye diseases in the United States. However, severe ocular toxicity, allergic reaction to the preservative thimersol, and low corneal penetration limit its use.7,27 Ganciclovir acts only on infected cells and thus has low toxicity and better efficacy.20
In brief, topical ganciclovir gel used 5 times a day initially until corneal lesions resolve and then tid or bid for 1 week to 2 months, depending on disease activity, is successful in treating persistent or recurrent pseudodendrites in HZO.
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