Chronic Varicella-Zoster Virus Epithelial Keratitis in Patients with Acquired Immunodeficiency Syndrome

CLINICAL SCIENCES Chronic Varicella-zoster Virus Epithelial Keratitis in Patients With Acquired Immunodeficiency Syndrome

Kenneth C. Chern, MD; Diana Conrad, MBBS, FRACO; Gary N. Holland, MD; Douglas S. Holsclaw, MD; Lee K. Schwartz, MD; Todd P. Margolis, MD, PhD

Objective: To characterize further a chronic epithelial fluorescein and rose bengal. The peripheral and midpe- keratitis caused by varicella-zoster virus infection in pa- ripheral cornea was most commonly affected, and, in 13 tients with acquired immunodeficiency syndrome (AIDS). of the 16 patients, the lesions crossed the limbus. Pain was a prominent feature, occurring in 12 of 16 patients. Methods: Patients with AIDS and chronic epithelial In 9 of 12 patients tested, varicella-zoster virus was iden- keratitis associated with varicella-zoster virus from 3 in- tified by culture, direct fluorescent antibody testing, poly- stitutions were identified. Patient records were reviewed merase chain reaction testing, or a combination of these retrospectively for the following data: medical and demo- studies, with direct fluorescent antibody testing (6 of 8 graphic characteristics, techniques of diagnosis, physical positive results) and polymerase chain reaction testing findings, course, response to treatment, and outcome. (3 of 3 positive results) appearing to be the most sensi- tive. Response to antiviral medication was variable. Results: Sixteen patients were studied. CD4+ T- lymphocyte cell counts were available in 11 patients, with Conclusions: In patients with AIDS, varicella-zoster vi- a median of 0.034 ϫ 109/L (range, 0-0.094 ϫ 109/L ). Two rus may cause a chronic infection of the corneal epithe- patients had no history of a zosteriform rash. In the re- lium. The keratitis is characterized by dendriform le- maining patients, the interval between rash and kerati- sions, prolonged course, and frequently by extreme pain. tis ranged from 0 days to 6 years. In all cases, the kera- It can occur without an associated dermatitis. titis was chronic and characterized by gray, elevated, dendriform epithelial lesions that stained variably with Arch Ophthalmol. 1998;116:1011-1017

1 N 1988, Engstrom and Holland re- RESULTS ported a case of chronic varicella- zoster virus (VZV) keratitis that oc- The clinical and laboratory features of 16 curred in a patient with acquired patients with AIDS and chronic epithe- immunodeficiency syndrome lial keratitis associated with VZV are sum- I(AIDS). The keratitis was characterized by marized in Table 1. dendriform epithelial lesions and underly- All patients were men, ranging in age ing anterior stromal haze. Varicella-zoster from 25 to 65 years (median, 36 years). virus was cultured from corneal scraping, CD4+ T-lymphocyte cell counts were avail- and the keratitis responded to topical acy- able in 11 patients and ranged from 0 to clovir ointment therapy, thus distinguish- 0.094 ϫ 109/L (median, 0.034 ϫ 109/L). ing this form of VZV keratitis from the late There was a history of VZV infection pseudodendrites or mucus plaque keratopa- in 15 of the 16 patients. Fourteen patients thy that has been described as a late com- From The Francis I. Proctor had cutaneous herpes zoster. Eight pa- Foundation and Department of plication of herpes zoster ophthalmicus. We tients had herpes zoster ophthalmicus that Ophthalmology, University of have since examined 16 patients with AIDS began between 1 and 3 months before de- California San Francisco who developed chronic epithelial dendri- velopment of the keratitis. One patient had Medical Center (Drs Chern, form keratitis in which VZV was the likely an episode of herpes zoster ophthalmicus Holsclaw, and Margolis and cause of the keratitis. In many of the pa- 6 years before keratitis. In 1 additional pa- Ms Conrad), the University of tients, the clinical findings resemble those tient, the onset of dendriform keratitis oc- California Los Angeles Ocular described by Engstrom and Holland and dif- curred concurrently with active herpes zos- Inflammatory Disease Center, fer from previous descriptions of the acute ter ophthalmicus. Two patients had thoracic the Jules Stein Eye Institute, and chronic corneal epithelial manifesta- herpes zoster preceding the keratitis by 1 Department of Ophthalmology, University of California Los tions of VZV infection in immune- month and 18 months. One patient had pri- Angeles School of Medicine competent patients. In this report, we fur- mary VZV infection (chickenpox) 8 months (Dr Holland), and the Mount ther describe the chronic dendriform before developing the keratitis. Two pa- Zion Hospital, San Francisco keratitis associated with VZV in patients tients had no history of zosteriform rash. (Dr Schwartz). with AIDS. Two patients, 1 with and 1 without a his-

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 PATIENTS AND METHODS positive for VZV antigen. Viral cultures were positive for VZV. Herpes simplex virus (HSV) was not detected with either direct fluorescent antibody staining or culture. We retrospectively reviewed the clinical records of 16 pa- Six months after the onset of the epithelial keratitis, tients with AIDS and chronic VZV keratitis at 3 institu- therapy with oral sorivudine, 40 mg/d, was started. Within tions. Patients were included if they had documented AIDS, 10 days, the patient noted marked relief in symptoms and chronic dendriform epithelial keratitis, and either derma- resolution of the epithelial lesions with a faint residual stro- tomal zoster within 6 months or laboratory evidence of VZV mal haze contiguous with the limbus with no intervening in corneal epithelial scrapings. Symptoms and signs at ini- clear zone. On day 17 of therapy with sorivudine, the epi- tial evaluation, treatment, diagnostic tests, course, and out- thelial pseudodendrites in the left eye recurred (Figure 1, come were studied. B). By day 29 of sorivudine therapy, the pain had returned and multiple pseudodendrites were present on the left cor- REPRESENTATIVE CASE REPORTS nea. To control pain, Hess drops (0.5% cocaine and 3% epi- nephrine in a 2% boric acid solution) were administered Patient 2 every 4 to 6 hours with oral narcotics. Neither topical trifluridine, oral acyclovir, topical 10% acetylcysteine, nor A 35-year-old man with AIDS (CD4+ T-lymphocyte cell an increase in the dose of oral sorivudine to 80 mg/d had count, 0.094 ϫ 109/L) developed progressive outer retinal any apparent therapeutic benefit. The patient died 6 weeks necrosis syndrome of the right eye. He was treated with in- later. travenous (IV) acyclovir and then received oral acyclovir. Two months later, he noted a foreign-body sensation in the Patient 4 left eye. Pseudodendrites present on the left cornea per- sisted for the next 5 months, despite therapy with topical A 35-year-old man with AIDS (CD4+ T-lymphocyte cell trifluridine and IV acyclovir. He complained of chronic burn- count, 0.024 ϫ 109/L) developed decreased vision, irrita- ing pain of the left eye that was unaffected by cycloplegia tion, and redness of his right eye. One month before, he or oral amitriptyline hydrochloride, but completely re- had a thoracic rash of unknown cause, but no recent facial lieved by topical proparacaine hydrochloride. He had no dermatitis. history of dermatomal herpes zoster. On examination, the bulbar conjunctiva of the right Examination of the left eye revealed multiple el- eye was congested, most notably temporal to the limbus. evated, gray corneal pseudodendrites that crossed the lim- Multiple, gray, raised dendriform lesions of the corneal epi- bus and stained well with rose bengal, but poorly with fluo- thelium stained poorly with fluorescein but well with rose rescein dye (Figure 1, A). There was no inflammation in bengal. There was a faint haze in the temporal corneal the anterior chamber or vitreous. Combined antiviral therapy stroma, extending from the limbus with no intervening clear (IV acyclovir and either topical trifluridine, topical vid- zone. Corneal sensation was normal except over the re- arabine, or topical acyclovir) was ineffective in resolving gion of corneal stromal haze, where sensation was moder- the signs or symptoms. All antiviral drug therapy was ately decreased. The pseudodendrites were de´brided, and stopped for 2 days, and the corneal lesions were scraped tissue samples sent for laboratory analysis. Giemsa stain- and cultured. Cytological examination revealed multinucle- ing revealed multinucleated giant cells, direct immuno- ated giant cells and direct fluorescent antibody staining was fluorescence test result was negative for HSV antigen, but

tory of dermatomal herpes zoster, had progressive outer responding to the epithelial lesions. One patient had mild retinal necrosis syndrome 3 and 8 weeks before develop- stromal haze and corneal edema. An additional patient ing the dendriform keratitis. developed subepithelial infiltrates. The corneal epithelial lesions were usually mul- In 12 of the 16 patients, pain was an important man- tiple, elevated, gray dendriform in pattern and most com- agement issue. Corneal pain was variably described as a monly seen in the corneal periphery and midperiphery foreign-body sensation, reminiscent of a paper cut, or se- (Figure 3). The number and distribution of lesions vere burning. For the 7 patients in whom the effect of changed with time. In 13 of the 16 patients, the corneal topical anesthetics on the pain was documented, the an- epithelial lesions were observed to cross the limbus on esthetic provided relief in all cases. The pain was diffi- at least 1 examination. The lesions stained variably with cult to control in 3 patients, who required systemic nar- fluorescein (Figure 4) and rose bengal, but, in most pa- cotics (2 patients), chronic topical anesthetic drops (3 tients, staining with rose bengal was more prominent. patients), and retrobulbar alcohol (1 patient). There was variable loss of corneal sensation in 8 pa- Varicella-zoster virus was identified in the corneal tients; 2 patients had normal corneal sensation. The kera- epithelium of 9 patients by 1 or more of the following titis was chronic in all 16 patients, persisting for 5 weeks techniques: direct fluorescent antibody staining for VZV to 14 months from initial examination to resolution or antigen (6 patients); viral culture of VZV (2 patients); unavailability for follow-up. and polymerase chain reaction amplification of VZV DNA In 10 patients, there was an associated stromal kera- (3 patients). A Giemsa stain of the epithelial scraping also titis. Eight of these patients had a faint stromal haze con- demonstrated multinucleated giant cells in 3 of these 9 tiguous with the limbus without an intervening lucent patients. All 6 clinical samples that had positive results area and best visualized with retroillumination. In all pa- for VZV antigen by direct fluorescent antibody staining tients, the stromal haze was present in the quadrant cor- had negative results by direct fluorescent antibody stain-

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 positive for VZV antigen, and viral cultures were negative were gray, elevated, and stained poorly with fluorescein but for both VZV and HSV. extremely well with rose bengal (Figure 2, A). There was The patient was treated with oral acyclovir, 800 mg 5 no loss of corneal sensation. The pseudodendrites were de´- times daily, and topical trifluridine every 3 hours. After 9 brided, and tissue samples were sent for viral culture and days of therapy, his symptoms had improved markedly and immunofluorescence, both of which were negative for VZV the corneal pseudodendrites had resolved; however, the cor- and HSV. Despite treatment with acyclovir and trifluri- neal stromal haze had worsened, and there was now a mild dine, the pain and pseudodendrites slowly worsened. anterior chamber inflammatory reaction. With the addi- Cycloplegia, topical 0.1% diclofenac sodium, systemic tion of topical 1% prednisolone acetate, the corneal haze amitriptyline, topical 1% prednisolone acetate, and topi- promptly cleared. The trifluridine was discontinued, and cal 3% acyclovir ointment failed to relieve the pain or have the patient remained asymptomatic while receiving the oral any apparent effect on the pseudodendrites. The pain be- acyclovir and topical corticosteroid drops for the next 7 came excruciating, and the patient began having suicidal weeks. He discontinued the acyclovir for financial rea- ideation. sons, and the pseudodendrites recurred 7 days later. Acy- The patient was admitted to the hospital for IV acyclovir and trifluridine drops were restarted, and, within 2 clovir therapy, 800 mg every 8 hours, with moderate, but weeks, the pseudodendrites had disappeared. The patient incomplete resolution of his corneal disease after 2 weeks remained free of active corneal lesions for the next month of therapy (Figure 2, B). Treatment was changed to IV fos- and was then unavailable for follow-up. carnet sodium, 3.7 g every 8 hours, with dramatic resolution of the pain and pseudodendrites (Figure 2, C). After Patient 6 17 days of therapy, however, the foscarnet was discontinued because of unexplained fevers, elevated liver function A 38-year-old man with AIDS (CD4+ T-lymphocyte cell test results, and granulocytopenia. Oral acyclovir, 800 mg count, Ͻ0.020 ϫ 109/L) came in with acute onset of right 5 times daily, was resumed, but within 3 weeks the pseu- herpes zoster ophthalmicus and was admitted for IV acy- dodendrites had returned much more extensively than be- clovir therapy. Ophthalmologic examination of the right fore (Figure 2, D). Recombinant human interferon alfa-2a eye revealed vesicular lesions around the eyelids, conjunc- was administered topically 4 times daily, but without im- tival injection and chemosis, punctate defects of the cor- provement in signs or symptoms. All therapy was stopped neal epithelium, and small corneal pseudodendrites. Topi- for 24 hours, and the pseudodendrites were scraped for labo- cal trifluridine was added to the therapy. Within 5 days, ratory examination. Direct immunofluorescent antibody all the skin lesions had crusted over and the pseudoden- staining of the tissue was positive for VZV antigen and nega- drites had cleared. Antiviral therapy was discontinued tive for HSV antigen. Giemsa staining of the tissue re- shortly thereafter. During the next 2 months, the patient vealed multinucleated giant cells. The patient’s pain be- had 2 recurrences of corneal pseudodendrites. Each epi- came worse after debridement, and within 1 week the sode promptly resolved following therapy with oral acy- pseudodendrites had returned. Topical 10% acetylcyste- clovir and topical trifluridine. ine and oral sorivudine, 40 mg/d, had no obvious effect on He returned 4 months later with severe right eye pain signs or symptoms of the persistent keratitis. Pain control and pseudodendrites over the superior third of the cor- was achieved with systemic morphine sulfate and topical nea. The pseudodendrites crossed the limbus and ex- Hess drops until the patient died 14 months after the ini- tended onto the bulbar conjunctiva. The pseudodendrites tial onset of the pseudodendrites.

ing for HSV antigen. Both clinical samples that were posi- herpes zoster while receiving IV acyclovir. In vitro an- tive for VZV by culture had negative results for HSV. All tiviral drug testing of this isolate revealed resistance to samples that had positive results for VZV DNA by poly- acyclovir. Patient 5 developed recurrent dendriform kera- merase chain reaction techniques had negative results for titis while taking oral acyclovir. Patient 6 developed re- HSV and cytomegalovirus DNA. In 7 patients, the diag- current pseudodendrites that failed to respond to oral acy- nosis was made clinically on the basis of a recent VZV clovir or sorivudine. This patient’s keratitis responded dermatitis (within 3 months) and the findings of the char- partially to IV acyclovir and fully to foscarnet. Patient 10 acteristic keratitis, as described above. Herpes simplex had recurrence of dendriform lesions when famciclovir virus was an unlikely cause of keratitis in these patients was discontinued. The lesions cleared completely with given the elevated and atypical appearance of the epi- IV foscarnet. Patient 11 developed pseudodendrites while thelial lesions, which lacked terminal bulbs and were not receiving maintenance IV foscarnet therapy for cyto- associated with ulceration. Furthermore, viral cultures megalovirus retinitis and had only a partial response to of the corneal epithelium performed for 3 of the 7 eyes oral acyclovir. Patient 13 developed pseudodendrites that were negative for HSV. failed to respond to acyclovir or foscarnet. All 16 patients required prolonged courses of multiple antiviral medications for control of the keratitis. In COMMENT 6 patients, the keratitis recurred when antiviral medications were discontinued. Seven patients had clinical fea- We present a retrospective review of 16 patients with AIDS tures suggestive of drug resistance. Patient 2 failed to re- and low CD4+ T-lymphocyte cell counts who developed spond to IV acyclovir, topical acyclovir, vidarabine, and an unusual form of chronic epithelial keratitis, charac- trifluridine. Furthermore, he had only a transient re- terized by dendriform corneal lesions, pain, and vari- sponse to oral sorivudine. Patient 3 developed thoracic able clinical response to antiviral medications.

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Figure 1. Multiple elevated dendriform corneal epithelial lesions in patient 2 (A) highlighted by rose bengal staining. Both viral culture and direct fluorescent antibody staining were positive for varicella-zoster virus. Recurrent dendriform lesions (B) present while patient receiving oral sorivudine therapy.

A B

C D Figure 2. Pseudodendrites on the right superior cornea and limbus in patient 6 (A) 4 months after an episode of herpes zoster ophthalmicus. Partial resolution of the lesions (B) was achieved with intravenous acyclovir sodium therapy. Complete disappearance (C) of the epithelial lesions achieved with treatment using intravenous foscarnet sodium. Fulminant recurrence of the pseudodendrites (D) 3 weeks following discontinuation of foscarnet treatment.

Laboratory evidence implicates VZV as the cause of tomegalovirus can also cause chronic dendriform kera- this disorder. Direct fluorescent antibody staining and titis. We did not consider cytomegalovirus to be a likely polymerase chain reaction testing confirmed the pres- cause of the keratitis in our patients for several reasons. ence of VZV in 8 patients. In 2 of 9 patients in whom First, many of the patients had a recent history of VZV viral cultures of corneal epithelial scrapings were taken, dermatitis. Second, in 9 of 12 patients, direct fluores- VZV was isolated. Our inability to detect VZV in the recent antibody staining, polymerase chain reaction test- maining 7 patients by culture is not unusual, since VZV ing, or viral culture confirmed the presence of VZV in is highly cell associated and is difficult to culture, espe- the corneal epithelium. Third, many of our patients re- cially with the extremely small samples procured from sponded to topical acyclovir, a drug with little activity corneal scrapings. A recent report2 of keratitis caused by against cytomegalovirus. Finally, although we did not spe- cytomegalovirus in a patient with AIDS showed that cy- cifically culture for cytomegalovirus in our epithelial

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Table 1. Clinical and Laboratory Characteristics of Patients With Chronic Varicella-zoster Virus (VZV) Epithelial Keratitis*

Viral Identification Techniques CD4+ T- Patient Lymphocyte Cytologic DFA Results of No./ Count, Affected Previous Examination Staining Culture PCR for Duration of Age, y ؋109/L Eye VZV Infection Findings for VZV for VZV VZV DNA Keratitis Treatment: Outcome 1/53 0 OD Right V2 zoster ND ND ND ND 3 mo Oral acyclovir, trifluridine: resolved 7 wk before, PORN syndrome OS 3 wk before 2/35 0.094 OS PORN syndrome Multinucleated Positive Positive ND 6 mo Acyclovir: unresponsive OS 8 wk before giant cells Trifluridine: unresponsive Vidarabine: unresponsive Sorivudine: transient response† 3/28 0.050 OD Thoracic VZV ND Positive Negative ND 6 mo Oral acyclovir: resolved, 1 mo before recurrence when discontinued‡ 4/35 0.024 OD Primary zoster Multinucleated Positive Negative ND 9 wk Oral acyclovir, trifluridine: resolved, infection giant cells recurrence when discontinued (chickenpox) 8 mo before 5/35 0.050 OD V1, V2 zoster ND ND ND ND 7 wk Oral and topical acyclovir: unresponsive 4 wk before Trifluridine: unresponsive Interferon alfa-2a: unresponsive IV acyclovir: partial response 6/38 0.025 OD V1 zoster Multinucleated Positive Negative ND 14 mo Oral acyclovir, trifluridine: resolved, 6 wk before giant cells recurrence when discontinued Sorivudine: unresponsive Interferon alfa-2a: unresponsive IV acyclovir: partial response Foscarnet: resolved 7/33 NA OU Thoracic zoster ND ND Positive ND 5 wk Oral acyclovir: resolved 18 mo before 8/41 NA OS V1 zoster ND Positive Negative ND 3 mo Oral acyclovir, trifluridine: resolved 12 wk before 9/36 0.076 OD V1 zoster ND ND Negative ND 5 mo Vidarabine ointment, 5 mo before IV foscarnet: lost to follow-up 10/39 NA OD V1 zoster ND ND Negative ND 4 mo Acyclovir ointment: unresponsive 4 mo before Trifluridine: unresponsive Famciclovir: resolved, recurrence when discontinued IV foscarnet: resolved 11/43 0 OS V1 zoster ND Positive ND Positive 3 mo Foscarnet: unresponsive 6 y before Oral acyclovir: partial response 12/65 0.080 OS None ND Negative ND Positive 12 mo Oral acyclovir, trifluridine: resolved, recurrence when discontinued 13/29 NA OS V1 zoster ND Negative Negative ND 7 mo IV acyclovir, foscarnet, 12 wk before Trifluridine: partial response§ 14/38 NA OD V1 zoster ND ND ND ND 8 mo Oral acyclovir: resolved, 12 wk before recurrence when discontinued 15/34 0.034 OD V1 zoster ND ND ND Positive 3 mo Oral acyclovir: unresponsive 12 wk before Trifluridine: unresponsive Vidarabine: unresponsive Acyclovir ointment: resolved 16/25 0.012 OD V1 zoster at initial ND ND ND ND 3 mo Oral and topical acyclovir: resolved examination

*DFA indicates direct fluorescent antibody; PCR, polymerase chain reaction; V1, distribution of the first division of the fifth cranial nerve; V2, distribution of the second division of the fifth cranial nerve; NA, data not available; ND, test not done; PORN, progressive outer retinal necrosis; and IV, intravenous. †This patient required narcotics for pain control. ‡This patient developed acyclovir-resistant thoracic zoster. §This patient required retrobulbar alcohol for pain.

samples, we did not detect cytomegalovirus DNA by poly- sions that occur several days following a rash and are ac- merase chain reaction in any of the 3 patients tested. companied by catarrhal conjunctivitis. These early den- The corneal epithelial lesions described in this study driform lesions are self-limited with resolution within 6 have features that distinguish them from both acute and days, found most frequently in the corneal periphery, and chronic forms of VZV keratitis that have been described associated with loss of corneal sensation. Varicella- previously (Table 2). The acute epithelial dendriform zoster virus can be cultured from these lesions, but only lesions of VZV in immune-competent patients have been within the first 48 to 72 hours after onset of cutaneous described3-5 as small, fine, elevated intraepithelial le- eruption. Superficial stromal infiltration can be seen with

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Figure 3. Unstained, gray corneal epithelial lesions in patient 1. Figure 4. Corneal epithelial lesions in patient 12, which, unlike a dendrite caused by herpes simplex virus, are elevated without epithelial ulceration and lack terminal bulbs (fluorescein stain).

Table 2. Comparison of Epithelial Dendritic Lesions Associated With Varicella-zoster Virus

Chronic Infectious Lesion Feature Acute Dendrite Lesion* Late Pseudodendrite Lesion† in Patients With AIDS‡ Average age at keratitis onset 60-69 y 60-69 y 35 y Interval between zosteriform 2-3 d 2 wk-2 y 0-6 y§ rash and corneal lesions Appearance of dendritic lesion Small, fine, elevated stellate Coarse, gray, elevated plaques Multiple, gray, elevated, intraepithelial lesions with blunted ends epithelial lesions Location Peripheral Central or midperipheral Midperipheral and peripheral, crossing limbus Corneal sensation Decreased Decreased in 33% of patients Variable Epithelial staining Poorly with rose bengal and fluorescein Good with rose bengal Variable with rose bengal Stromal keratitis None Diffuse haze Sectoral haze Recoverable virus Yes࿣ No Yes Duration Ն1wk 1-8wk 5wkto14mo Responds to antiviral medications Yes No Yes

*Data from Marsh et al.3 †Data from Marsh and Cooper.6 ‡AIDS indicates acquired immunodeficiency syndrome. §In some cases of varicella-zoster virus, there is no history of rash. ࿣In acute dendrite lesions, virus is recoverable within the first 24 to 48 hours.

resolution of the dendrites. Although our patients had sions tend not to respond to antiviral medications. The clini- replicating virus, their lesions differed from those of acute cal appearance of the dendriform lesions in our patients VZV in several ways. First, unlike the small, fine lesions resembled in some ways that of mucus plaques; however, that we have seen and have been described by Marsh et in contrast to the late lesions described by Marsh and Coo- al3 and others,4,5 most of the lesions described herein were per6 and others,5,7 the epithelial lesions in our patients thick and discontinuous with blunt ends, bearing little crossed the limbus, were associated with pain, and, in many resemblance to the Medusa-like lesions described by Pa- cases, had either recoverable virus or VZV antigen. In ad- van-Langston and McCulley.4 Second, in 13 of the 16 af- dition, the epithelial lesions in many of our patients re- fected eyes, the lesions crossed the corneal limbus. Third, sponded to antiviral medications, then worsened or re- the lesions in our patients were chronic, persisting for curred when the antiviral medications were discontinued. weeks to months, and, in many cases, first appeared Mucolytics had no discernible effect on the epithelial le- months after a zosteriform rash. sions in our patients. The dendriform lesions described Chronic epithelial pseudodendrites, or mucus plaques, herein may therefore more closely resemble those de- as described by Marsh and Cooper6 and others5,7 can oc- scribed by Piebenga and Laibson7 and more recently by Pa- cur from 7 days to 2 years following herpes zoster oph- van-Langston et al.8 In that study,8 these lesions had a posi- thalmicus. These transitory plaques are gray, elevated, lin- tive result for VZV DNA by polymerase chain reaction ear or branching, and stain well with rose bengal and poorly testing and responded variably to topical antiviral medi- with fluorescein. Abnormal accumulation of mucus, pos- cations. To date, however, in patients without AIDS, we sibly a consequence of poor tear film quality, has been pos- have been unable to amplify by polymerase chain reaction tulated to be the mechanism for the formation of these techniques VZV DNA from chronic mucus plaques that re- plaques, which frequently respond to topical mucolytics. semble lesions described by Marsh and Cooper.6 Varicella-zoster virus has not been cultured from these le- A key feature of the epithelial lesions reported herein sions, and VZV antigen has not been detected. These le- was their chronicity. Other VZV infections in patients with

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 human immunodeficiency virus (HIV) have shown this tients, we have found the chronic, dendriform epithelial propensity to chronicity. Chronic forms of herpes zos- lesions to have recoverable virus. Host immunosuppres- ter dermatitis resulting in hyperkeratotic verrucous lesion and viral pathogenicity may play a role in the de- sions have been recognized.9-11 These lesions are thought velopment and persistence of these lesions. to be caused by ongoing viral replication, possibly modi- fied by drug resistance,12 or be a limited form of lytic in- 13 Accepted for publication May 4, 1998. fection. It is likely that the same mechanisms contrib- Supported, in part, by Research to Prevent Blindness ute to the chronic nature of the disease in our patients. Inc (New York, NY) Lew Wasserman Merit Award (Drs Hol- Five of the 16 patients described herein developed land and Margolis), the Ralph and Sophie Heintz Labora- keratitis without a preceding history of facial herpes zos- tory Fund, San Francisco, Calif (Dr Margolis), the Heed Oph- ter dermatitis, although 2 patients had prior thoracic her- thalmic Foundation, Chicago, Ill (Dr Chern), and by grant pes zoster and 1 patient had primary systemic herpes zos- EY02162 from the National Eye Institute, National Insti- ter. The development of VZV disease without skin 14-16 tutes of Health, Bethesda, Md (Dr Margolis). eruption has been termed zoster sine herpete. Varicella- Reprints: Todd P. Margolis, MD, PhD, Francis I. zoster virus ocular disease without skin manifestations Proctor Foundation, Box 0944, University of California has been described in both immunosuppressed and im- 17 San Francisco Medical Center, San Francisco, CA 94143- munocompetent patients, including VZV iritis, kerati- 0944 (e-mail: [email protected]). tis,18 and VZV necrotizing retinitis.19,20 The cases that pre- sented sine herpete in this series suggest that it is important to consider VZV in the differential diagnosis REFERENCES of chronic dendriform keratitis in patients with HIV disease even in the absence of skin lesions. 1. Engstrom RE, Holland GN. Chronic herpes zoster virus keratitis associated with Pain was a prominent feature of the disease in 12 of the acquired immunodeficiency syndrome. Am J Ophthalmol. 1988;105: 556-558. the 16 patients. Since the pain was rapidly relieved by 2. Wilhelmus KR, Font RL, Lehmann RP, Cernoch PL. Cytomegalovirus keratitis in topical anesthesia, but not by tricyclic antidepressants, acquired immunodeficiency syndrome. Arch Ophthalmol. 1996;114:869-872. 3. Marsh RJ, Fraunfelder FT, McGill JI. Herpetic corneal epithelial disease. Arch Oph- it was unlikely to be postherpetic neuralgia. The sever- thalmol. 1976;94:1899-1902. ity of the pain is exemplified by the 2 patients in whom 4. Pavan-Langston D, McCulley JP. Herpes zoster dendritic keratitis. Arch Oph- systemic narcotics and chronic topical anesthetic drops thalmol. 1973;89:25-29. 5. Liesegang TJ. Corneal complications from herpes zoster ophthalmicus. Oph- were required for relief. An additional patient required thalmology. 1985;92:316-324. a retrobulbar injection of alcohol to control the pain. All 6. Marsh RJ, Cooper M. Ophthalmic zoster: mucous plaque keratitis. Br J Ophthal- 4 patients without pain had preceding herpes zoster der- mol. 1987;71:725-728. 7. Piebenga LW, Laibson PR. Dendritic lesions in herpes zoster ophthalmicus. Arch matitis in the distribution of the first division of the tri- Ophthalmol. 1973;90:268-270. geminal nerve and loss of corneal sensation. 8. Pavan-Langston D, Yamamoto S, Dunkel EC. Delayed herpes zoster pseudodendrites: polymerase chain reaction detection of viral DNA and a role for antiviral Treatment of the keratitis was difficult. Based on our therapy. Arch Ophthalmol. 1995;113:1381-1385. experience, we would recommend initial treatment with 9. Vaughan Jones SA, McGibbon DH, Bradbeer CS. Chronic verrucous varicella- oral or topical acyclovir or trifluridine. In the event of zoster infection in a patient with AIDS. Clin Exp Dermatol. 1994;19:327-329. 10. Hoppenjans WB, Bibler MR, Orme RL, Solinger AM. Prolonged cutaneous her- treatment failure, alternative antiviral drugs, such as oral pes zoster in acquired immunodeficiency syndrome. Arch Dermatol. 1990;126: famciclovir, should be used. For thymidine kinase– 1048-1050. deficient strains of VZV, foscarnet or cidofovir, which do 11. LeBoit PE, Limova M, Yen TS, et al. Chronic verrucous varicella-zoster virus infection in patients with the acquired immunodeficiency syndrome (AIDS): his- not depend on thymidine kinase for activation, should tologic and molecular biologic findings. Am J Dermatopathol. 1992;14:1-7. be considered. Although others21 have reported that topi- 12. Jacobson MA, Berger TG, Fikrig S, et al. Acyclovir-resistant varicella zoster virus infection after chronic oral acyclovir therapy in patients with the acquired cal interferon alfa-2a may modify the severity of VZV in immunodeficiency syndrome (AIDS). Ann Intern Med. 1990;112:187-191. immunosuppressed patients, we found this treatment to 13. Nikkels AF, Rentier B, Pierard GE. Chronic varicella-zoster virus skin lesions in have minimal effect in the 2 patients treated. As with other patients with human immunodeficiency virus are related to decreased expres- + sion of gE and gB. J Infect Dis. 1997;176:261-264. viral infections in patients with AIDS and low CD4 T- 14. Lewis G. Zoster sine herpete. BMJ. 1958;2:418-421. lymphocyte cell counts, antiviral treatment is likely to 15. Snoeck R, Gerard M, Sadzot-Delvaux C, et al. Meningoradiculoneuritis due to be prolonged. In view of the recent success of Pavan- acyclovir-resistant varicella zoster virus in an acquired immune deficiency syn- 8 drome patient. J Med Virol. 1994;42:338-347. Langston et al in using vidarabine for the treatment of 16. Gilden DH, Dueland AN, Devlin ME, Mahalingam R, Cohrs R. Varicella-zoster vi- 2 cases of late pseudodendrites, this drug should be con- rus reactivation without rash. J Infect Dis. 1992;166(suppl 1):S30-S34. 17. Schwab IR. Herpes zoster sine herpete. Ophthalmology. 1997;104:1421-1425. sidered. 18. Silverstein BE, Chandler D, Neger R, Margolis TP. Disciform keratitis: a case of Varicella-zoster keratitis in HIV-infected patients herpes zoster sine herpete. Am J Ophthalmol. 1997;123:254-255. should be differentiated from HSV keratitis, which has also 19. Margolis TP, Lowder CY, Holland GN, et al. Varicella-zoster virus retinitis in pa- 22,23 tients with the acquired immunodeficiency syndrome. Am J Ophthalmol. 1991; been described in this population. Perhaps more im- 112:119-131. portantly, this disease must be differentiated from dry eye 20. Stavrou P, Mitchell SM, Fox JD, Hope-Ross MW, Murray PI. Detection of varicella- and exposure keratopathy, both of which are seen with high zoster virus DNA in ocular samples from patients with uveitis but no cutaneous + eruption. Eye. 1994;8:684-687. frequency in patients with AIDS who have low CD4 T- 21. Winston DJ, Eron LJ, Ho M, et al. Recombinant interferon alpha-2a for treat- lymphocyte cell counts. We have found the use of rose ben- ment of herpes zoster in immunosuppressed patients with cancer. Am J Med. 1988;85:147-151. gal to be valuable in helping to differentiate these entities. 22. Young TL, Robin JB, Holland GN, et al. Herpes simplex keratitis in patients with In summary, we believe that there may be forms of acquired immune deficiency syndrome. Ophthalmology. 1989;96:1476-1479. epithelial dendriform lesions associated with VZV that 23. Hodge WG, Margolis TP. Herpes simplex virus keratitis among patients who are positive or negative for human immunodeficiency virus: an epidemiologic study. are distinct from the classic acute dendrites and late pseu- Ophthalmology. 1997;104:120-124. dodendrites described by Marsh and Cooper.24 In our pa- 24. Marsh RJ, Cooper M. Ophthalmic herpes zoster. Eye. 1993;7:350-370.

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