VIDARABINE THERAPY O F C O M P L I C A T E D H E R P E S SIMPLEX KERATITIS D E N I S M. O ' D A Y ,
M.D.
Nashville, Tennessee R O B E R T H. P O I R I E R ,
M.D.
San Antonio, Texas D A N B. J O N E S ,
M.D.
Houston, Texas AND J A M E S H. E L L I O T T ,
M.D.
Nashville, Tennessee
The introduction of idoxuridine (IDU) in 1961 1 provided the first effective meth od of control of herpes simplex viral rep lication in corneal epithelium and permit ted the use of corticosteroids to control inflammation in stromal keratitis. 2 De spite the established value of IDU in herpes simplex epithelial keratitis, the development of an alternative antiviral agent was necessary. IDU is a potentially toxic drug and this toxicity may contrib ute to the morbidity of herpetic keratitis 3 : treatment failures may result from ac quired resistance to the compound. IDU may fail to prevent recurrence of epitheli al keratitis in patients receiving combined therapy with corticosteroids for stromal keratitis and uveitis. Laboratory investi gations and preliminary clinical trials 4 suggested that vidarabine* (adenine arab-
inoside, ara-A) may be effective in cases of herpes simplex keratitis that manifest ed resistance or toxicity to IDU. M A T E R I A L AND M E T H O D S
From the Department of Ophthalmology, Vanderbilt University School of Medicine, Nashville, Ten nessee (Drs. O'Day and Elliott); Division of Oph thalmology, University of Texas Medical School, San Antonio (Dr. Poirier); and the Department of Ophthalmology, Baylor College of Medicine, Hous ton, Texas (Dr. Jones). This study was supported in part by National Eye Institute grants EY-00344 and EY-00055 (Drs. Elliott and O'Day), and by an unre stricted grant from Research to Prevent Blindness, Inc. Reprint requests to Denis M. O'Day, M.D., De partment of Ophthalmology, Vanderbilt University School of Medicine, Nashville, TN 37232. *Parke, Davis & Company provided the vidara bine ointment used in our study.
Patient selection—We chose consec utive, unselected cases among patients referred to the three centers for manage ment of herpes simplex keratitis. The cri teria for admission to the trial were: (1) active herpes simplex epithelial keratitis; and (2) failure of IDU therapy as evi denced by progressive increase in ulcer size during treatment, absence of re sponse by the seventh day of therapy, or IDU toxicity demonstrated by an adverse reaction to current therapy or a history of drug toxicity. Observations and documentation—A complete ocular history and examination were recorded on admission to the study. The diagnosis of active herpes simplex epithelial keratitis was established by slit-lamp examination and staining of the lesions with rose bengal. The area of dendritic ulcération was calculated by assuming the width of the ulcer to be 0.1 mm and measuring the length of the major branches with the variable slit on the Haag-Streit 900 or eyepiece reticule (pattern 30-50-13) on the Zeiss 100/16 slit lamp. This technique was used through out the trial. The area of a geographic (ameboid) ulcer was determined by calcu-
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HERPES SIMPLEX KERATITIS
lating the product of the major length and width. On alternate days, we questioned the patient for symptoms of drug toler ance, examined the anterior segment of the eye, and measured the corneal epithe lial lesions during the first week of thera py and generally at weekly intervals while the patient was receiving treatment. Treatment with vidarabine—Patients were instructed to apply one-half inch of vidarabine 3 % ointment, five times daily, in the lower conjunctival sac. When com plete reepithelialization was achieved, the dose was reduced to twice daily for seven days and then discontinued. Treat ment failed if (1) the area of epithelial keratitis was no smaller by day 7, or (2) complete epithelialization had not oc curred by day 14. In patients receiving topical corticosteroids for stromal keratitis or uveitis, vidarabine was continued, five times dai ly, after reepithelialization had occurred in an attempt to prevent a recurrence of active epithelial keratitis. RESULTS
Fifty-six cases of active herpes simplex epithelial keratitis occurred among 54 pa tients who entered the trial (Table 1). Two patients (T-3, Table 2, V-10, Table 3) re-entered the trial two and five months, respectively, after resolution of epithelial keratitis. Forty-nine cases of keratitis (90%) had not healed after IDU therapy (Table 1) and in five of these, IDU toxicity TABLE 1 HERPES SIMPLEX KERATITIS TREATED WITH VIDARABINE Basis for alternative therapy to IDU
Source Vanderbilt Hospital University of Texas Baylor College of Medicine Totals
Drug Toxicity
Treatment Failure and Drug Toxicity
16
3
7
2
3 2
21
2
44
7
No. of Cases
Treatment Failure
22 11 23 56
0 5
643
was also observed simultaneously. The remaining seven cases received alternate therapy with vidarabine on the basis of previous toxic reaction to IDU. Two types of epithelial keratitis were represented in this series. In Group 1, patients had dendritic or geographic epi thelial keratitis with and without subse quent stromal keratitis or uveitis (Table 2). In Group 2, patients developed active epithelial keratitis during corticosteroid therapy for active stromal keratitis or uve itis (Table 3). Group 1—This group consisted of pa tients with dendritic (23) and geographic (12) ulcers (Table 2). None had received corticosteroids for the current disease be fore entry into the trial. Thirty-two cases (91%) were classified as IDU-treatment failures, the mean duration of therapy being 22 days (range, five to 119 days). The mean area of epithelial ulcération among the 35 cases was 2.6 mm. 2 Twenty-eight cases (80%) achieved complete reepithelialization by day 14 with vidarabine and were classified as treatment successes. The mean healing time in this subgroup was 7.3 days. Five patients (V-5, T-5, B-18, B-19, B-45, Table 2) had persistent epithelial ulcération on day 14 and were classified as treatment failures. Each of these patients continued to receive vidarabine, five times daily, since there had been inactivation of the active epithelial disease and reepitheliali zation was occurring. All cases healed on prolonged therapy, the mean healing time being 21 days (range, 15 to 30 days). Two patients had increased areas of epithelial ulcération after seven days of vidarabine therapy. In one (V-17, Table 2), vidara bine was continued, five times daily, and the ulcer healed by day 26. The other patient (V-3, Table 2) was removed from the trial and represents the only complete failure in Group 1. On entry to the trial 19 of the 35 cases had stromal inflammation underlying the
AMERICAN JOURNAL OF OPHTHALMOLOGY
644
MAY, 1976
TABLE 2 HERPES SIMPLEX KERATITIS TREATED WITH VIDARABINE IN GROUP 1
Case No. V-3 V-4 V-5 V-7 V-8 V-9 V-ll V-12 V-17 V-18 V-20 T-l T-3t T-5 T-6 T-9 T-ll T-13 B-16 B-18 Β-1Θ B-26 B-27 B-28 B-36 B-40 Β-4Ι B-44 B-45 B-46 B-48 B-49 B-51 B-52 B-53
Basis for Alternate Therapy to IDU Failure Failure Failure and toxicity Failure Failure Failure and toxicity Failure Failure Failure Failure Failure and toxicity Failure and toxicity Toxicity Toxicity Failure Failure Failure Failure Failure Failure Failure Failure Failure Toxicity Failure Failure Failure Failure Failure Failure Failure Failure Failure Failure Failure
Duration of IDU Therapy, days
Initial Size, mm 2
Ulcer Type
Stromal Keratitis
Uveitis
Days Vidarabine to Heal Therapy, Ulcer days
10 10 28
0.8 0.5 25.0
Dendritic Geographic Geographic
Present Absent Present
Present Absent Present
Failed 9 30
7 7 10
0.7 0.3 1.6
Dendritic Dendritic Geographic
Absent Absent Absent
Absent Absent Absent
14 13 19 10 56
0.3 0.3 0.3 0.7 0.1
Geographic Dendritic Dendritic Dendritic Geographic
Absent Absent Absent Absent Absent
8
0.5
Dendritic
_* _* 14
0.2 0.4 0.2 0.5 0.2 0.3 12.1 0.5 4.6 3.0 0.3 0.1 0.2 0.7 0.1 0.1 9.Θ 0.3 0.8 1.3 5.7 18.2 0.4
Dendritic Dendritic Dendritic Dendritic Dendritic Dendritic Geographic Dendritic Geographic Geographic Dendritic Dendritic Dendritic Geographic Dendritic Dendritic Geographic Dendritic Dendritic Geographic Dendritic Geographic Dendritic
10 33 23 119 46 32 37 10
-*
14 33 5 10 18 14 13 28 5 20 45
Concomitant Cortico steroid Therapy
Visual Acuity Initial
Final
7 20 30
Yes No No
20/400 20/70 HM
20/400 20/70 20/200
4 5 3
13 14 21
No No Yes
20/60 20/40 CF
20/20 20/40 20/30
Present Absent Absent Absent Absent
11 4 26 7 7
20 17 26 24 48
Yes No No No Yes
20/200 20/40 20/100 20/70 20/400
20/200 20/40 20/40 20/50 20/200
Absent
Absent
10
21
No
20/30
20/20
Absent Present Present Present Absent Present Present Present Present Present Present Absent Absent Present Present Present Present Absent Present Present Present Present Absent
Absent Absent Absent Present Absent Present Present Absent Present Absent Absent Absent Absent Present Absent Present Present Absent Present Absent Absent Present Absent
14 21 7 3 5 7 14 15 18 3 7 7 5 7 2 2 19 7 6 7 12 10 7
21 65 35 20 10 21 28 52 25 58 13 7 12 14 14 239 72 14 14 13 19 17 14
No No No No No No No No No Yes No No No No No Yes Yes No No Yes No No No
20/20 20/200 HM 20/30 20/40 20/50 20/400 20/70 20/40 HM 8/20 20/30 20/20 20/80 20/50 20/30 20/400 20/60 20/70 20/20 20/60 20/100 20/60
20/20 20/200 15/400 20/20 20/20 20/20 20/200 20/40 20/50 20/50 20/40 20/30 20/30 20/50 20/20 20/50 20/100 20/50 20/25 20/20 20/30 20/25 20/25
*History of toxic reaction to IDU; not administered for this episode. fRe-entry of Case T-l.
epithelial keratitis. Fourteen resolved without additional anti-inflammatory therapy. Of the remaining five, four (B-26, B-44, B-45, B-49, Table 2) resolved after topical corticosteroid administration ini tiated after epithelial healing with contin uation of vidarabine therapy. Three other patients (V-9, V - l l , V-30, Table 2) devel oped stromal keratitis during the study and required topical corticosteroid thera py for inactivation of inflammation. There was no recurrence of active epithe lial keratitis among these seven patients receiving combined vidarabine and corti costeroid therapy. Group 2—Twenty-one cases (Table 3) entered the trial with active epithelial keratitis complicating stromal keratitis and uveitis. Thirteen (62%) had geo
graphic ulcération. Seventeen had devel oped epithelial keratitis during combined IDU and corticosteroid therapy or had failed to heal following the addition of IDU. The mean duration of treatment with IDU in this subgroup was 59 days (range, six to 420 days). The mean area of ulcération among the 21 cases was 7.2 mm. 2 Eleven cases (52%) achieved complete reepithelialization by day 14 and were classified as treatment successes. All of these patients continued to receive topical corticosteroid therapy for control of stro mal inflammation during the period of reepithelialization. The mean healing rate was 6.6 days. Two patients (V-14, V-23) were re moved from the trial as treatment failures
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HERPES SIMPLEX KERATITIS
645
TABLE 3 HERPES SIMPLEX KERATITIS TREATED WITH VIDARABINE IN GROUP 2
Case No. V-l V-2 V-6
v-iot V-13 V-14 V-16 V-19 V-21 V-22 V-23 T-2 T-8 T-10 T-12 B-3 B-9 B-23 B-25 B-29 B-31
Basis for Alternate Therapy to IDU
Duration of IDU Therapy, days
Initial Size, mm 2
Ulcer Type
Stromal Keratitis
Uveitis
4.5
Geographic
Present
Present
Days Vidarabine to Heal Therapy, Ulcer days 2
HM
HM
358
Yes
20/400
30 266 244 7 234 51
Yes Yes Yes Yes Yes Yes
20/200 HM 20/400 CF 20/60 CF
3 21 Failed 33 20 5 5
130 56 14 101 47 93 20
Yes Yes Yes Yes Yes Yes Yes
20/70 20/200 20/70 20/200 20/70 HM 20/40
20/200 20/200 20/70 20/25 20/15 20/40 20/20
21 12 21 7 3 14
28 75 28 73 66 86
No Yes No Yes Yes Yes
20/40 20/40 20/50 N.D.t 20/400 15/400
20/30 20/40 20/70 N.D.t 2/200 20/200
-*
18
Geographic
Present
Present
48
Failure Toxicity Toxicity Failure Failure Failure and toxicity Failure Failure Failure Failure Failure Failure Failure and toxicity Failure Failure Failure Failure Failure Toxicity
28
180 42
3.9 60.0 0.5 1.8 2.0 0.6
Geographic Geographic Dendritic Geographic Geographic Dendritic
Present Present Present Present Present Present
Present Present Absent Present Present Present
21 5 4 Failed 47 14
420 7 10 14 8 7 10
0.4 0.7 0.5 24.8 0.3 18.0 0.3
Geographic Dendritic Dendritic Geographic Dendritic Geographic Dendritic
Present Absent Present Present Present Present Present
Present Present Present Present Absent Present Present
88 6 28 28 32
0.5 1.9 6.7 3.2 0.3 2.0
Dendritic Geographic Geographic Geographic Dendritic Geographic
Present Present Present Present Absent Present
Present Absent Present Absent Absent Absent
-*
Final
CFat 6 ft 20/400 HM 20/400 CF 20/80 CF
31
-* _* 14
Visual Acuity Initial
Yes
Failure and toxicity Toxicity
134
Concomitant Corticosteroid Therapy
*History of toxic reaction to IDU; not administered for this episode. tRe-entry of Case V-l. tVisual acuity not determined: 9-month-old infant.
on days 7 and 14, respectively, because of an increase in the area of epithelial ulcér ation. Eight patients had persistent epi thelial ulcération after two weeks of vi darabine therapy and were classified as treatment failures. Vidarabine therapy was continued, five times daily, in these eight cases. Five of these patients (V-2, V-6, V-16, T-2, T-8, Table 3) had inactive herpes simplex epithelial disease before or after day 14 (Table 4), and had epitheli al defects due to other mechanisms. In the remaining three cases (V-22, V-3, V-23, Table 3), there was progressive daily healing although active epithelial disease was still present at day 14. In this group of eight patients, complete reepithelialization occurred in 21 to 48 days (mean, 29 days). Nineteen patients (95%) in Group 2 had active stromal keratitis and one patient had severe iritis at entry to the trial. One developed stromal and uveal inflamma tion during the trial. All were receiving topical corticosteroids and with two ex
ceptions this was continued throughout the trial. The stromal keratitis in these two patients was resolved on vidarabine alone after termination of corticosteroid therapy. In 16 of the remaining 19, com bined vidarabine and corticosteroid ther apy led to inactivation of corneal and uveal inflammation before or after epithe lial healing. Of the two failures removed from the study, one patient (V-23, Table 3) had resolution of epithelial and stromal keratitis following debridement. The case of the other patient (V-14, Table 3) pro gressed to descemetocele formation. Ac tive herpes simplex epithelial keratitis did not recur in 19 patients receiving com bined vidarabine and corticosteroid ther apy. Results of frequent biomicroscopic ex amination and rose bengal staining reaf firmed our concept that reepithelialization of herpes simplex epithelial keratitis progresses in two stages during effective antiviral therapy 5 : Stage 1. Progression from an active to
646
AMERICAN JOURNAL OF OPHTHALMOLOGY
inactive viral ulcer—The first observable development was the disappearance of the heaped-up, opaque cells at the ulcer margins. This loss of diseased epithelial cells frequently gave the impression of an adverse enlargement of the area of ulcéra tion. The margins of intact epithelium be came flat and smooth, and lost their coarse, punctate staining with rose bengal. Dendritiform lesions lost their characteristic ragged appearance and geo graphic ulcers became round. Rose ben gal pooled in the area of deepithelialization and stained the remaining abnormal epithelial cells in the base of the ulcer. This response was generally accompa nied by a decrease in the fine, cellular infiltrate within the underlying anterior stroma. The epithelial defect was indis tinguishable from an indolent or trophic epithelial defect and could be classified as an "inactive" epithelial ulcer (Figs. 1 and 2). Stage 2. Complete reepithelialization —This stage was characterized by pro gressive growth of the smooth margin of new epithelial cells. Border cells ap peared normal without rose bengal stain ing. There were fine, irregular lines of punctate epithelial granularity at the final junction of reepithelialization. This line occasionally simulated active herpes sim-
Fig. 1 (O'Day and associates). Case B-45. Large geographic ulcer stained with rose bengal before therapy with vidarabine.
MAY, 1976
Fig. 2 (O'Day and associates). Case B-45. After five days of treatment with vidarabine, ulcer as sumed appearance of an inactive or trophic lesion.
plex epithelial keratitis but was readily distinguished by biomicroscopic exami nation and rose bengal staining (Fig. 3). These two stages of healing were most evident in patients with geographic epi thelial keratitis complicated by stromal keratitis (Group 2). Because we recog nized these patterns, we successfully pro longed vidarabine therapy in both groups and combined therapy with corticosteroids. We did not observe reactivation compatible with viral replication in any of our cases. Representative examples of two-staged healing are summarized in Table 4. No patient developed a toxic or allergic reaction to vidarabine. One noted mild, transient, stinging discomfort immediate-
Fig. 3 (O'Day and associates). Case B-45. After 19 days of treatment with vidarabine, the ulcer is healed, apart from punctate stain with rose bengal.
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HERPES SIMPLEX KERATITIS TABLE 4
TWO-STAGE HEALING O F HERPES SIMPLEX EPITHELIAL ULCERATION
Case No.
Initial Size of Ulcer, mm2
V-2 V-6 V-16 T-2 T-8 B-45
18.0 3.9 2.0 24.8 0.3 9.6
Ulcer Type
Days From Vidarabine Therapy to Inactive Ulcer
Size of Inactive Ulcer, mm2
Additional Days to Complete Healing
Geographic Geographic Geographic Geographic Dendritic Geographic
10 7 21 21 14 5
10.5 2.0 0.8 4.7 0.2 3.8
38 14 26 12 7 14
ly after application of the ointment which did not require termination of therapy. Nine patients have now received vidara bine for more than three months (93 to 358 days) without adverse reaction. DISCUSSION
Epithelial ulcération due to active her pes simplex viral replication in epithelial cells occurs in two major sequences. It may develop as the initial disease process with little or no stromal inflammation, or it may arise intercurrently in an eye in which active stromal keratitis is the major therapeutic problem. In the first situation, represented by the patients in Group 1, the therapeutic failure of IDU from resis tance or toxicity is a serious matter. The morbidity of the disease is prolonged and the delay in reepithelialization increases the likelihood of anterior stromal scarring with impaired visual acuity. This situa tion requires an alternate form of therapy effective against active epithelial keratitis. Although mechanical debridement may be used successfully in this instance, our results show that vidarabine is an effec tive, nontoxic, convenient form of thera py. This alternate antiviral compound avoids the difficulties of debridement in younger patients and eliminates the re quirement of patching and daily reexamination. The development of active epithelial keratitis in patients with stromal inflam mation is a more severe problem. Control
647
of the stromal keratitis by corticosteroid therapy is initially compromised, thereby threatening the preservation of structural integrity of the cornea and useful vision. Healing of the epithelial ulcer is crucial to the inactivation of stromal inflamma tion but the management is complicated if there is manifest IDU resistance or toxicity. Debridement is unwise in the presence of large ameboid ulcers or active stromal disease. Without an effective anti viral agent, corticosteroid therapy for the stromal disease must be administered cautiously and may have to be abandoned in an attempt to reestablish epithelial continuity. The greatest impact of a sec ond effective antiviral agent will be in such cases of herpetic keratouveitis with intercurrent epithelial disease. When designing a multicentered trial of vidarabine in herpes simplex epithelial keratitis, of which this series was a part, the collaborators established a limit of 14 days for reepithelialization as a measure of successful antiviral therapy. Our docu mentation of two-staged healing of epi thelial ulcération emphasises the necessi ty for considering the multiple factors which may influence epithelial regenera tion, of which viral replication in epithe lial cells is only one. Vidarabine therapy is directed toward inhibition of viral rep lication alone and may not influence other determinants of epithelial healing. As demonstrated in this series, an ulcer can lose the morphologic characteristics asso ciated with active viral replication with out necessarily progressing to healing. In Stage 1 of this process, the ulcer loses the dendritiform edges and heaped-up opaque balloon cells along the ulcer mar gin characteristic of active viral replica tion and assumes the appearance of an indolent epithelial ulcer. In Stage 2, the ulcer heals without regressing to the ac tive stage, a process that may require extension of therapy for several weeks. The geographic ulcer in Case V-2 (Tables
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AMERICAN JOURNAL OF OPHTHALMOLOGY
3 and 4) was indistinguished from a tro phic or inactive ulcer on day 10 of vidarabine therapy and achieved complete reepithelialization 38 days after additional therapy. By the conventional criteria of the study, this type of case would be classified as a treatment failure. A more realistic end point for judging the efficacy of vidarabine and other antiviral agents would be the stage of inactivation of viral replication in the epithelium. Although virologie confirmation is not feasible, the same clinical features used to identify cases of inclusion in this and previous studies of antiviral agents apply and seem adequate. Reference to this stage as the end point reduces the realistic incidence of drug failure. The availability of vidara bine as an effective nontoxic alternate agent diminishes the requirement for pre cise distinction of the transition from Stage 1 to Stage 2 healing by the inexperi enced clinician and facilitates prolonga tion of therapy during final healing. Vidarabine therapy successfully inacti vated the stromal inflammation in Group 2 cases despite active epithelial disease. There are three potential mechanisms by which vidarabine may contribute to ef fective management of active stromal keratitis. 1. Inhibition of viral replication in the epithelium, thereby permitting the judi cious use of corticosteroids and enhanc ing the prospects for resolution of stromal keratitis or uveitis. 2. Direct antiviral activity in the stroma and anterior uvea by vidarabine or its hypoxanthine derivative. 6 One of us (R.H.P.) 7 established that the hypoxanthine deriva tive, not vidarabine, penetrates into the anterior chamber in small amounts in the presence of intact epithelium after appli cation of 3 % vidarabine ointment. 3. Reestablishment of the intact corneal epithelium as a contribution to the resolution of the stromal inflammation. 8 The results of this study do not permit
MAY, 1976
conclusions regarding the relative signifi cance of these potential mechanisms. Resolution of stromal keratitis in 23 of 27 cases (Groups 1 and 2) by combined vidarabine and corticosteroid therapy supports the efficacy of this approach in treating complicated herpes simplex kera titis. This study substantiates that vidara bine 3 % ointment is an effective alternate form of therapy in herpes simplex epithe lial keratitis and should enhance the pros pects of treating successfully complicated and refractory cases of stromal keratitis and uveitis. SUMMARY
Patients with active herpetic epithelial keratitis who had toxic reactions or were resistant to idoxuridine received vidara bine. Only one of 35 cases of herpetic epithelial keratitis without stromal dis ease failed to heal. Of 21 patients with active epithelial keratitis complicating stromal keratitis or uveitis, 11 had com plete reepithelialization by day 14. Two patients were removed from the trial as treatment failures. The remaining cases healed in 21 to 48 days. In most instances the stromal keratitis was inactivated when the epithelial ulcer healed. In our patients treated with vidarabine, healing of herpes simplex epithelial ulcers was biphasic: Stage 1, progression from an active to an inactive viral ulcer, and Stage 2, complete reepithelialization. REFERENCES 1. Kaufman, H. E., Nesburn, A. B., and Malone, E. D.: IDU therapy of herpes simplex. Arch. Ophthalmol. 67:583, 1961. 2. Aronson, S. B., and Moore, T. E., Jr.: Cortico steroid therapy in central stromal keratitis. Am. J. Ophthalmol. 67:873, 1969. 3. O'Day, D. M., and Jones, B. R.: Herpes simplex keratitis. In Clinical Ophthalmology. New York, Harper & Row, in press. 4. Pavan-Langston, D., and Dohlman, C. H.: A double-blind clinical study of adenine arabinoside therapy of viral keratoconjunctivitis. Am. J. Oph thalmol. 74:81, 1972. 5. O'Day, D. M., Jones, B. R., Poirier, R., Pilley,
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S., Chisholm, I., Steele, A., and Rice, N. S. C : Proflavine photodynamic viral inactivation in her pes simplex keratitis. Am. J. Ophthalmol. 79:941, 1975. 6. Pavan-Langston, D., Dohlman, C. H., Geary, P., and Sulzewski, D.: Intraocular penetration of ara-A and IDU. Therapeutic implication of clinical herpetic uveitis. Trans. Am. Acad. Ophthalmol. Otolaryngol. 77:455, 1973.
649
7. Poirier, R. H., Kinkel, A. W., Ellison, A. C , and Lewis, R.: Intraocular penetration of topical 3 % adenine arabinoside. In Pavan-Langston, D., Bu chanan, R. A., and Alford, C. A. Jr.: Adenine Arabin oside: An Antiviral Agent. New York, Raven Press, 1975, p p . 307-312. 8. Aronson, S. B., Moore, T. E., and O'Day, D. M.: Effects of structural alterations on anterior ocular inflammation. Am. J. Ophthalmol. 70:886, 1970.
O P H T H A L M I C MINIATURE
The Visionary Moon The visionary moon is rising bright within the eye-ground cup of sky: she rides as glowing optic disk, providing light for moving trail of jet that finely glides as artery of silver wire. Around the moon her distant halo softly glows, with flag-pole marker thrusting up from ground. Across the sky an autumn breeze now flows aloft, and spreads a lucent veil of cloud within the moonlit ring—choroidal flush of lacy white, with darker blots—a shroud soon pierced by punctate stars in silver hush. As optic moon still gleams in fundus sky, she stirs a vision deep behind the eye. J. David Andrews
M.D.
Nashville, Tennessee R O B E R T H. P O I R I E R ,
M.D.
San Antonio, Texas D A N B. J O N E S ,
M.D.
Houston, Texas AND J A M E S H. E L L I O T T ,
M.D.
Nashville, Tennessee
The introduction of idoxuridine (IDU) in 1961 1 provided the first effective meth od of control of herpes simplex viral rep lication in corneal epithelium and permit ted the use of corticosteroids to control inflammation in stromal keratitis. 2 De spite the established value of IDU in herpes simplex epithelial keratitis, the development of an alternative antiviral agent was necessary. IDU is a potentially toxic drug and this toxicity may contrib ute to the morbidity of herpetic keratitis 3 : treatment failures may result from ac quired resistance to the compound. IDU may fail to prevent recurrence of epitheli al keratitis in patients receiving combined therapy with corticosteroids for stromal keratitis and uveitis. Laboratory investi gations and preliminary clinical trials 4 suggested that vidarabine* (adenine arab-
inoside, ara-A) may be effective in cases of herpes simplex keratitis that manifest ed resistance or toxicity to IDU. M A T E R I A L AND M E T H O D S
From the Department of Ophthalmology, Vanderbilt University School of Medicine, Nashville, Ten nessee (Drs. O'Day and Elliott); Division of Oph thalmology, University of Texas Medical School, San Antonio (Dr. Poirier); and the Department of Ophthalmology, Baylor College of Medicine, Hous ton, Texas (Dr. Jones). This study was supported in part by National Eye Institute grants EY-00344 and EY-00055 (Drs. Elliott and O'Day), and by an unre stricted grant from Research to Prevent Blindness, Inc. Reprint requests to Denis M. O'Day, M.D., De partment of Ophthalmology, Vanderbilt University School of Medicine, Nashville, TN 37232. *Parke, Davis & Company provided the vidara bine ointment used in our study.
Patient selection—We chose consec utive, unselected cases among patients referred to the three centers for manage ment of herpes simplex keratitis. The cri teria for admission to the trial were: (1) active herpes simplex epithelial keratitis; and (2) failure of IDU therapy as evi denced by progressive increase in ulcer size during treatment, absence of re sponse by the seventh day of therapy, or IDU toxicity demonstrated by an adverse reaction to current therapy or a history of drug toxicity. Observations and documentation—A complete ocular history and examination were recorded on admission to the study. The diagnosis of active herpes simplex epithelial keratitis was established by slit-lamp examination and staining of the lesions with rose bengal. The area of dendritic ulcération was calculated by assuming the width of the ulcer to be 0.1 mm and measuring the length of the major branches with the variable slit on the Haag-Streit 900 or eyepiece reticule (pattern 30-50-13) on the Zeiss 100/16 slit lamp. This technique was used through out the trial. The area of a geographic (ameboid) ulcer was determined by calcu-
642
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HERPES SIMPLEX KERATITIS
lating the product of the major length and width. On alternate days, we questioned the patient for symptoms of drug toler ance, examined the anterior segment of the eye, and measured the corneal epithe lial lesions during the first week of thera py and generally at weekly intervals while the patient was receiving treatment. Treatment with vidarabine—Patients were instructed to apply one-half inch of vidarabine 3 % ointment, five times daily, in the lower conjunctival sac. When com plete reepithelialization was achieved, the dose was reduced to twice daily for seven days and then discontinued. Treat ment failed if (1) the area of epithelial keratitis was no smaller by day 7, or (2) complete epithelialization had not oc curred by day 14. In patients receiving topical corticosteroids for stromal keratitis or uveitis, vidarabine was continued, five times dai ly, after reepithelialization had occurred in an attempt to prevent a recurrence of active epithelial keratitis. RESULTS
Fifty-six cases of active herpes simplex epithelial keratitis occurred among 54 pa tients who entered the trial (Table 1). Two patients (T-3, Table 2, V-10, Table 3) re-entered the trial two and five months, respectively, after resolution of epithelial keratitis. Forty-nine cases of keratitis (90%) had not healed after IDU therapy (Table 1) and in five of these, IDU toxicity TABLE 1 HERPES SIMPLEX KERATITIS TREATED WITH VIDARABINE Basis for alternative therapy to IDU
Source Vanderbilt Hospital University of Texas Baylor College of Medicine Totals
Drug Toxicity
Treatment Failure and Drug Toxicity
16
3
7
2
3 2
21
2
44
7
No. of Cases
Treatment Failure
22 11 23 56
0 5
643
was also observed simultaneously. The remaining seven cases received alternate therapy with vidarabine on the basis of previous toxic reaction to IDU. Two types of epithelial keratitis were represented in this series. In Group 1, patients had dendritic or geographic epi thelial keratitis with and without subse quent stromal keratitis or uveitis (Table 2). In Group 2, patients developed active epithelial keratitis during corticosteroid therapy for active stromal keratitis or uve itis (Table 3). Group 1—This group consisted of pa tients with dendritic (23) and geographic (12) ulcers (Table 2). None had received corticosteroids for the current disease be fore entry into the trial. Thirty-two cases (91%) were classified as IDU-treatment failures, the mean duration of therapy being 22 days (range, five to 119 days). The mean area of epithelial ulcération among the 35 cases was 2.6 mm. 2 Twenty-eight cases (80%) achieved complete reepithelialization by day 14 with vidarabine and were classified as treatment successes. The mean healing time in this subgroup was 7.3 days. Five patients (V-5, T-5, B-18, B-19, B-45, Table 2) had persistent epithelial ulcération on day 14 and were classified as treatment failures. Each of these patients continued to receive vidarabine, five times daily, since there had been inactivation of the active epithelial disease and reepitheliali zation was occurring. All cases healed on prolonged therapy, the mean healing time being 21 days (range, 15 to 30 days). Two patients had increased areas of epithelial ulcération after seven days of vidarabine therapy. In one (V-17, Table 2), vidara bine was continued, five times daily, and the ulcer healed by day 26. The other patient (V-3, Table 2) was removed from the trial and represents the only complete failure in Group 1. On entry to the trial 19 of the 35 cases had stromal inflammation underlying the
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TABLE 2 HERPES SIMPLEX KERATITIS TREATED WITH VIDARABINE IN GROUP 1
Case No. V-3 V-4 V-5 V-7 V-8 V-9 V-ll V-12 V-17 V-18 V-20 T-l T-3t T-5 T-6 T-9 T-ll T-13 B-16 B-18 Β-1Θ B-26 B-27 B-28 B-36 B-40 Β-4Ι B-44 B-45 B-46 B-48 B-49 B-51 B-52 B-53
Basis for Alternate Therapy to IDU Failure Failure Failure and toxicity Failure Failure Failure and toxicity Failure Failure Failure Failure Failure and toxicity Failure and toxicity Toxicity Toxicity Failure Failure Failure Failure Failure Failure Failure Failure Failure Toxicity Failure Failure Failure Failure Failure Failure Failure Failure Failure Failure Failure
Duration of IDU Therapy, days
Initial Size, mm 2
Ulcer Type
Stromal Keratitis
Uveitis
Days Vidarabine to Heal Therapy, Ulcer days
10 10 28
0.8 0.5 25.0
Dendritic Geographic Geographic
Present Absent Present
Present Absent Present
Failed 9 30
7 7 10
0.7 0.3 1.6
Dendritic Dendritic Geographic
Absent Absent Absent
Absent Absent Absent
14 13 19 10 56
0.3 0.3 0.3 0.7 0.1
Geographic Dendritic Dendritic Dendritic Geographic
Absent Absent Absent Absent Absent
8
0.5
Dendritic
_* _* 14
0.2 0.4 0.2 0.5 0.2 0.3 12.1 0.5 4.6 3.0 0.3 0.1 0.2 0.7 0.1 0.1 9.Θ 0.3 0.8 1.3 5.7 18.2 0.4
Dendritic Dendritic Dendritic Dendritic Dendritic Dendritic Geographic Dendritic Geographic Geographic Dendritic Dendritic Dendritic Geographic Dendritic Dendritic Geographic Dendritic Dendritic Geographic Dendritic Geographic Dendritic
10 33 23 119 46 32 37 10
-*
14 33 5 10 18 14 13 28 5 20 45
Concomitant Cortico steroid Therapy
Visual Acuity Initial
Final
7 20 30
Yes No No
20/400 20/70 HM
20/400 20/70 20/200
4 5 3
13 14 21
No No Yes
20/60 20/40 CF
20/20 20/40 20/30
Present Absent Absent Absent Absent
11 4 26 7 7
20 17 26 24 48
Yes No No No Yes
20/200 20/40 20/100 20/70 20/400
20/200 20/40 20/40 20/50 20/200
Absent
Absent
10
21
No
20/30
20/20
Absent Present Present Present Absent Present Present Present Present Present Present Absent Absent Present Present Present Present Absent Present Present Present Present Absent
Absent Absent Absent Present Absent Present Present Absent Present Absent Absent Absent Absent Present Absent Present Present Absent Present Absent Absent Present Absent
14 21 7 3 5 7 14 15 18 3 7 7 5 7 2 2 19 7 6 7 12 10 7
21 65 35 20 10 21 28 52 25 58 13 7 12 14 14 239 72 14 14 13 19 17 14
No No No No No No No No No Yes No No No No No Yes Yes No No Yes No No No
20/20 20/200 HM 20/30 20/40 20/50 20/400 20/70 20/40 HM 8/20 20/30 20/20 20/80 20/50 20/30 20/400 20/60 20/70 20/20 20/60 20/100 20/60
20/20 20/200 15/400 20/20 20/20 20/20 20/200 20/40 20/50 20/50 20/40 20/30 20/30 20/50 20/20 20/50 20/100 20/50 20/25 20/20 20/30 20/25 20/25
*History of toxic reaction to IDU; not administered for this episode. fRe-entry of Case T-l.
epithelial keratitis. Fourteen resolved without additional anti-inflammatory therapy. Of the remaining five, four (B-26, B-44, B-45, B-49, Table 2) resolved after topical corticosteroid administration ini tiated after epithelial healing with contin uation of vidarabine therapy. Three other patients (V-9, V - l l , V-30, Table 2) devel oped stromal keratitis during the study and required topical corticosteroid thera py for inactivation of inflammation. There was no recurrence of active epithe lial keratitis among these seven patients receiving combined vidarabine and corti costeroid therapy. Group 2—Twenty-one cases (Table 3) entered the trial with active epithelial keratitis complicating stromal keratitis and uveitis. Thirteen (62%) had geo
graphic ulcération. Seventeen had devel oped epithelial keratitis during combined IDU and corticosteroid therapy or had failed to heal following the addition of IDU. The mean duration of treatment with IDU in this subgroup was 59 days (range, six to 420 days). The mean area of ulcération among the 21 cases was 7.2 mm. 2 Eleven cases (52%) achieved complete reepithelialization by day 14 and were classified as treatment successes. All of these patients continued to receive topical corticosteroid therapy for control of stro mal inflammation during the period of reepithelialization. The mean healing rate was 6.6 days. Two patients (V-14, V-23) were re moved from the trial as treatment failures
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TABLE 3 HERPES SIMPLEX KERATITIS TREATED WITH VIDARABINE IN GROUP 2
Case No. V-l V-2 V-6
v-iot V-13 V-14 V-16 V-19 V-21 V-22 V-23 T-2 T-8 T-10 T-12 B-3 B-9 B-23 B-25 B-29 B-31
Basis for Alternate Therapy to IDU
Duration of IDU Therapy, days
Initial Size, mm 2
Ulcer Type
Stromal Keratitis
Uveitis
4.5
Geographic
Present
Present
Days Vidarabine to Heal Therapy, Ulcer days 2
HM
HM
358
Yes
20/400
30 266 244 7 234 51
Yes Yes Yes Yes Yes Yes
20/200 HM 20/400 CF 20/60 CF
3 21 Failed 33 20 5 5
130 56 14 101 47 93 20
Yes Yes Yes Yes Yes Yes Yes
20/70 20/200 20/70 20/200 20/70 HM 20/40
20/200 20/200 20/70 20/25 20/15 20/40 20/20
21 12 21 7 3 14
28 75 28 73 66 86
No Yes No Yes Yes Yes
20/40 20/40 20/50 N.D.t 20/400 15/400
20/30 20/40 20/70 N.D.t 2/200 20/200
-*
18
Geographic
Present
Present
48
Failure Toxicity Toxicity Failure Failure Failure and toxicity Failure Failure Failure Failure Failure Failure Failure and toxicity Failure Failure Failure Failure Failure Toxicity
28
180 42
3.9 60.0 0.5 1.8 2.0 0.6
Geographic Geographic Dendritic Geographic Geographic Dendritic
Present Present Present Present Present Present
Present Present Absent Present Present Present
21 5 4 Failed 47 14
420 7 10 14 8 7 10
0.4 0.7 0.5 24.8 0.3 18.0 0.3
Geographic Dendritic Dendritic Geographic Dendritic Geographic Dendritic
Present Absent Present Present Present Present Present
Present Present Present Present Absent Present Present
88 6 28 28 32
0.5 1.9 6.7 3.2 0.3 2.0
Dendritic Geographic Geographic Geographic Dendritic Geographic
Present Present Present Present Absent Present
Present Absent Present Absent Absent Absent
-*
Final
CFat 6 ft 20/400 HM 20/400 CF 20/80 CF
31
-* _* 14
Visual Acuity Initial
Yes
Failure and toxicity Toxicity
134
Concomitant Corticosteroid Therapy
*History of toxic reaction to IDU; not administered for this episode. tRe-entry of Case V-l. tVisual acuity not determined: 9-month-old infant.
on days 7 and 14, respectively, because of an increase in the area of epithelial ulcér ation. Eight patients had persistent epi thelial ulcération after two weeks of vi darabine therapy and were classified as treatment failures. Vidarabine therapy was continued, five times daily, in these eight cases. Five of these patients (V-2, V-6, V-16, T-2, T-8, Table 3) had inactive herpes simplex epithelial disease before or after day 14 (Table 4), and had epitheli al defects due to other mechanisms. In the remaining three cases (V-22, V-3, V-23, Table 3), there was progressive daily healing although active epithelial disease was still present at day 14. In this group of eight patients, complete reepithelialization occurred in 21 to 48 days (mean, 29 days). Nineteen patients (95%) in Group 2 had active stromal keratitis and one patient had severe iritis at entry to the trial. One developed stromal and uveal inflamma tion during the trial. All were receiving topical corticosteroids and with two ex
ceptions this was continued throughout the trial. The stromal keratitis in these two patients was resolved on vidarabine alone after termination of corticosteroid therapy. In 16 of the remaining 19, com bined vidarabine and corticosteroid ther apy led to inactivation of corneal and uveal inflammation before or after epithe lial healing. Of the two failures removed from the study, one patient (V-23, Table 3) had resolution of epithelial and stromal keratitis following debridement. The case of the other patient (V-14, Table 3) pro gressed to descemetocele formation. Ac tive herpes simplex epithelial keratitis did not recur in 19 patients receiving com bined vidarabine and corticosteroid ther apy. Results of frequent biomicroscopic ex amination and rose bengal staining reaf firmed our concept that reepithelialization of herpes simplex epithelial keratitis progresses in two stages during effective antiviral therapy 5 : Stage 1. Progression from an active to
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inactive viral ulcer—The first observable development was the disappearance of the heaped-up, opaque cells at the ulcer margins. This loss of diseased epithelial cells frequently gave the impression of an adverse enlargement of the area of ulcéra tion. The margins of intact epithelium be came flat and smooth, and lost their coarse, punctate staining with rose bengal. Dendritiform lesions lost their characteristic ragged appearance and geo graphic ulcers became round. Rose ben gal pooled in the area of deepithelialization and stained the remaining abnormal epithelial cells in the base of the ulcer. This response was generally accompa nied by a decrease in the fine, cellular infiltrate within the underlying anterior stroma. The epithelial defect was indis tinguishable from an indolent or trophic epithelial defect and could be classified as an "inactive" epithelial ulcer (Figs. 1 and 2). Stage 2. Complete reepithelialization —This stage was characterized by pro gressive growth of the smooth margin of new epithelial cells. Border cells ap peared normal without rose bengal stain ing. There were fine, irregular lines of punctate epithelial granularity at the final junction of reepithelialization. This line occasionally simulated active herpes sim-
Fig. 1 (O'Day and associates). Case B-45. Large geographic ulcer stained with rose bengal before therapy with vidarabine.
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Fig. 2 (O'Day and associates). Case B-45. After five days of treatment with vidarabine, ulcer as sumed appearance of an inactive or trophic lesion.
plex epithelial keratitis but was readily distinguished by biomicroscopic exami nation and rose bengal staining (Fig. 3). These two stages of healing were most evident in patients with geographic epi thelial keratitis complicated by stromal keratitis (Group 2). Because we recog nized these patterns, we successfully pro longed vidarabine therapy in both groups and combined therapy with corticosteroids. We did not observe reactivation compatible with viral replication in any of our cases. Representative examples of two-staged healing are summarized in Table 4. No patient developed a toxic or allergic reaction to vidarabine. One noted mild, transient, stinging discomfort immediate-
Fig. 3 (O'Day and associates). Case B-45. After 19 days of treatment with vidarabine, the ulcer is healed, apart from punctate stain with rose bengal.
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TWO-STAGE HEALING O F HERPES SIMPLEX EPITHELIAL ULCERATION
Case No.
Initial Size of Ulcer, mm2
V-2 V-6 V-16 T-2 T-8 B-45
18.0 3.9 2.0 24.8 0.3 9.6
Ulcer Type
Days From Vidarabine Therapy to Inactive Ulcer
Size of Inactive Ulcer, mm2
Additional Days to Complete Healing
Geographic Geographic Geographic Geographic Dendritic Geographic
10 7 21 21 14 5
10.5 2.0 0.8 4.7 0.2 3.8
38 14 26 12 7 14
ly after application of the ointment which did not require termination of therapy. Nine patients have now received vidara bine for more than three months (93 to 358 days) without adverse reaction. DISCUSSION
Epithelial ulcération due to active her pes simplex viral replication in epithelial cells occurs in two major sequences. It may develop as the initial disease process with little or no stromal inflammation, or it may arise intercurrently in an eye in which active stromal keratitis is the major therapeutic problem. In the first situation, represented by the patients in Group 1, the therapeutic failure of IDU from resis tance or toxicity is a serious matter. The morbidity of the disease is prolonged and the delay in reepithelialization increases the likelihood of anterior stromal scarring with impaired visual acuity. This situa tion requires an alternate form of therapy effective against active epithelial keratitis. Although mechanical debridement may be used successfully in this instance, our results show that vidarabine is an effec tive, nontoxic, convenient form of thera py. This alternate antiviral compound avoids the difficulties of debridement in younger patients and eliminates the re quirement of patching and daily reexamination. The development of active epithelial keratitis in patients with stromal inflam mation is a more severe problem. Control
647
of the stromal keratitis by corticosteroid therapy is initially compromised, thereby threatening the preservation of structural integrity of the cornea and useful vision. Healing of the epithelial ulcer is crucial to the inactivation of stromal inflamma tion but the management is complicated if there is manifest IDU resistance or toxicity. Debridement is unwise in the presence of large ameboid ulcers or active stromal disease. Without an effective anti viral agent, corticosteroid therapy for the stromal disease must be administered cautiously and may have to be abandoned in an attempt to reestablish epithelial continuity. The greatest impact of a sec ond effective antiviral agent will be in such cases of herpetic keratouveitis with intercurrent epithelial disease. When designing a multicentered trial of vidarabine in herpes simplex epithelial keratitis, of which this series was a part, the collaborators established a limit of 14 days for reepithelialization as a measure of successful antiviral therapy. Our docu mentation of two-staged healing of epi thelial ulcération emphasises the necessi ty for considering the multiple factors which may influence epithelial regenera tion, of which viral replication in epithe lial cells is only one. Vidarabine therapy is directed toward inhibition of viral rep lication alone and may not influence other determinants of epithelial healing. As demonstrated in this series, an ulcer can lose the morphologic characteristics asso ciated with active viral replication with out necessarily progressing to healing. In Stage 1 of this process, the ulcer loses the dendritiform edges and heaped-up opaque balloon cells along the ulcer mar gin characteristic of active viral replica tion and assumes the appearance of an indolent epithelial ulcer. In Stage 2, the ulcer heals without regressing to the ac tive stage, a process that may require extension of therapy for several weeks. The geographic ulcer in Case V-2 (Tables
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3 and 4) was indistinguished from a tro phic or inactive ulcer on day 10 of vidarabine therapy and achieved complete reepithelialization 38 days after additional therapy. By the conventional criteria of the study, this type of case would be classified as a treatment failure. A more realistic end point for judging the efficacy of vidarabine and other antiviral agents would be the stage of inactivation of viral replication in the epithelium. Although virologie confirmation is not feasible, the same clinical features used to identify cases of inclusion in this and previous studies of antiviral agents apply and seem adequate. Reference to this stage as the end point reduces the realistic incidence of drug failure. The availability of vidara bine as an effective nontoxic alternate agent diminishes the requirement for pre cise distinction of the transition from Stage 1 to Stage 2 healing by the inexperi enced clinician and facilitates prolonga tion of therapy during final healing. Vidarabine therapy successfully inacti vated the stromal inflammation in Group 2 cases despite active epithelial disease. There are three potential mechanisms by which vidarabine may contribute to ef fective management of active stromal keratitis. 1. Inhibition of viral replication in the epithelium, thereby permitting the judi cious use of corticosteroids and enhanc ing the prospects for resolution of stromal keratitis or uveitis. 2. Direct antiviral activity in the stroma and anterior uvea by vidarabine or its hypoxanthine derivative. 6 One of us (R.H.P.) 7 established that the hypoxanthine deriva tive, not vidarabine, penetrates into the anterior chamber in small amounts in the presence of intact epithelium after appli cation of 3 % vidarabine ointment. 3. Reestablishment of the intact corneal epithelium as a contribution to the resolution of the stromal inflammation. 8 The results of this study do not permit
MAY, 1976
conclusions regarding the relative signifi cance of these potential mechanisms. Resolution of stromal keratitis in 23 of 27 cases (Groups 1 and 2) by combined vidarabine and corticosteroid therapy supports the efficacy of this approach in treating complicated herpes simplex kera titis. This study substantiates that vidara bine 3 % ointment is an effective alternate form of therapy in herpes simplex epithe lial keratitis and should enhance the pros pects of treating successfully complicated and refractory cases of stromal keratitis and uveitis. SUMMARY
Patients with active herpetic epithelial keratitis who had toxic reactions or were resistant to idoxuridine received vidara bine. Only one of 35 cases of herpetic epithelial keratitis without stromal dis ease failed to heal. Of 21 patients with active epithelial keratitis complicating stromal keratitis or uveitis, 11 had com plete reepithelialization by day 14. Two patients were removed from the trial as treatment failures. The remaining cases healed in 21 to 48 days. In most instances the stromal keratitis was inactivated when the epithelial ulcer healed. In our patients treated with vidarabine, healing of herpes simplex epithelial ulcers was biphasic: Stage 1, progression from an active to an inactive viral ulcer, and Stage 2, complete reepithelialization. REFERENCES 1. Kaufman, H. E., Nesburn, A. B., and Malone, E. D.: IDU therapy of herpes simplex. Arch. Ophthalmol. 67:583, 1961. 2. Aronson, S. B., and Moore, T. E., Jr.: Cortico steroid therapy in central stromal keratitis. Am. J. Ophthalmol. 67:873, 1969. 3. O'Day, D. M., and Jones, B. R.: Herpes simplex keratitis. In Clinical Ophthalmology. New York, Harper & Row, in press. 4. Pavan-Langston, D., and Dohlman, C. H.: A double-blind clinical study of adenine arabinoside therapy of viral keratoconjunctivitis. Am. J. Oph thalmol. 74:81, 1972. 5. O'Day, D. M., Jones, B. R., Poirier, R., Pilley,
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S., Chisholm, I., Steele, A., and Rice, N. S. C : Proflavine photodynamic viral inactivation in her pes simplex keratitis. Am. J. Ophthalmol. 79:941, 1975. 6. Pavan-Langston, D., Dohlman, C. H., Geary, P., and Sulzewski, D.: Intraocular penetration of ara-A and IDU. Therapeutic implication of clinical herpetic uveitis. Trans. Am. Acad. Ophthalmol. Otolaryngol. 77:455, 1973.
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7. Poirier, R. H., Kinkel, A. W., Ellison, A. C , and Lewis, R.: Intraocular penetration of topical 3 % adenine arabinoside. In Pavan-Langston, D., Bu chanan, R. A., and Alford, C. A. Jr.: Adenine Arabin oside: An Antiviral Agent. New York, Raven Press, 1975, p p . 307-312. 8. Aronson, S. B., Moore, T. E., and O'Day, D. M.: Effects of structural alterations on anterior ocular inflammation. Am. J. Ophthalmol. 70:886, 1970.
O P H T H A L M I C MINIATURE
The Visionary Moon The visionary moon is rising bright within the eye-ground cup of sky: she rides as glowing optic disk, providing light for moving trail of jet that finely glides as artery of silver wire. Around the moon her distant halo softly glows, with flag-pole marker thrusting up from ground. Across the sky an autumn breeze now flows aloft, and spreads a lucent veil of cloud within the moonlit ring—choroidal flush of lacy white, with darker blots—a shroud soon pierced by punctate stars in silver hush. As optic moon still gleams in fundus sky, she stirs a vision deep behind the eye. J. David Andrews
