Corticosteroid Therapy in Central Stromal Keratitis*

CORTICOSTEROID T H E R A P Y IN CENTRAL STROMAL KERATITIS* SAMUEL B. ARONSON, M.D., AND THOMAS E. MOORE, JR.,

M.D.

San Francisco, California

Use of adrenal corticosteroids in central corneal inflammatory disease has been heat­ edly discussed during the past 15 years.1"9 Kaufman10 and Thomas 11 have recom­ mended topical corticosteroid therapy (com­ bined with IUDR) for disciform lesions in herpetic keratitis, while Thygeson12 has cau­ tioned that they may encourage virus prolif­ eration and lead to catastrophic events. Theo­ dore13 believes that some cases of deep stromal herpes cannot be controlled without corti­ costeroids. DeVoe14 has emphasized that corticosteroid therapy in herpes simplex kera­ titis should not be condemned on the basis of rabbit experiments. Corticosteroids may be used guard­ edly15'16 in herpes zoster keratitis; they probably should be avoided17 in central bacterial ulcers. However, corticosteroids are the treatment of choice18'19 in allergic cor­ neal disease. The general consensus indicates that the use of corticosteroids depends upon the etiologic agent involved rather than the degree of structural alteration. Specific therapy is always preferable but, when it is not successful, nonspecific (corticosteroid) therapy may be used. Following extensive experimental evalua­ tion of the mechanisms of inflammatory reac­ tivity in the rabbit and guinea pig cornea,20"22 From the Eye Research Laboratories, Depart­ ment of Ophthalmology, and the Clinical Laborato­ ries, San Francisco General Hospital, University of California Medical Center. This study was sup­ ported in part by USPHS Grants NB04310 and NB07912. Dr. Aronson is the recipient of USPHS Research Career Development Award K3-NB-31, 653. * The generic term, central stromal keratitis, was selected to describe the inflammatory lesions which most frequently involve the central zone of the cor­ neal stroma and to separate this group of diseases from peripheral corneal disease. Other terms used in the ophthalmic literature to describe this type of lesion are disciform keratitis, metaherpetic keratitis, keratitis profunda, interstitial keratitis, stromal ulcer and so forth. 873

we concluded that, although specific clini­ cal corneal morphology may vary with dif­ ferent etiologic agents, the mechanism of corneal inflammation is probably uniform. In the presence of either immune or toxic stimulus, polymorphonuclear leukocyte ( P M N ) chemotaxis and degranulation pro­ vide the basis for destruction of the corneal parenchyma. From this standpoint, stromal keratitis can be considered to function as a single disease. The best way to inhibit such destructive change is to control the polymor­ phonuclear leukocytes ; adrenal corticoste­ roids readily achieve this goal.23'24 The subsequent report evaluates our ex­ perience in the use of high dosage topical corticosteroid therapy in patients with cen­ tral stromal keratitis. MATERIALS AND METHODS

All patients included in this study mani­ fested some degree of central corneal stro­ mal inflammation. They were selected ran­ domly from clinic and consultation services at San Francisco General Hospital and the University of California Hospitals. The first 15 patients who were treated with high dos­ age topical corticosteroids were hospitalized during the course of active disease. Subse­ quently, patients were either hospitalized or treated as out-patients while on therapy, de­ pending upon the severity of their disease. In-patients were examined daily by slitlamp microscopy; out-patients were similarly ex­ amined a minimum of three times a week. At least two observers ( S . B. A. and T. E. M., Jr.,) examined each patient at the time of the initial morphologic classification (ta­ bles 1, 4, 6 and 8) and at the time of optimal morphologic improvement. After cessation of therapy, patients who had inactive disease were followed at three-month intervals. Central corneal stromal disease has been classified according to morphologic criteria

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AMERICAN JOURNAL OF OPHTHALMOLOGY

ACTIVE INFLAMMATORY DISEASE FRONTAL

SAGGITAL

A. Epithelium:

B. Stroma:

JUNE, 1969

tis not involving the epithelium would be designated A 1; B 3 , G . In inactive disease, changes have been classified as shown in Figure 2. Etiologic classification was simultaneously performed whenever possible. Etiologic diag­ noses were subdivided into (1) herpes sim­ plex (table 1), (2) herpes zoster (table 4), (3) central bacterial corneal ulcers (table 6) and (4) miscellaneous diagnoses (table 8 ) . The diagnosis of herpes simplex was made only when one of us saw (1) a dendri­ tic figure or elicited a strong collaborative history of a dendritic figure from the refer-

INACTIVE INFLAMMATORY DISEASE FRONTAL

SAGGITAL

D. Epithelium:

E. Stroma: Fig. 1 (Aronson and Moore). Classification of clinical morphologic changes during active inflammation. (A) Epithelium: (1) intact, (2) punctate change (3) dendritic lesion, (4) large central ulcér­ ation. (B) Stroma: (1) infiltration of anterior stroma, (2) disciform keratitis, (3) disciform keratitis with superficial vascularization, (4) disciform keratitis with deep vascularization. (C) Endothe­ lium, anterior chamber: (1) endothelial changes with keratic precipitates, (2) descemetocele or per­ foration with hypopyon.

and defined as inflammatory involvement of all or part of the central third of the corneal stroma. Central corneal inflammation has been subclassified into active and inactive disease. In active disease, evidence of polymorphonuclear leukocyte infiltration is noted in the epithelium, stroma or endothelium ; Figure 1 shows the classification. Corneal lesions have been classified alpha-numerically ; for ex­ ample, a patient with severe disciform kerati­

Fig. 2 (Aronson and Moore). Classification of clinical morphologic changes following cessation, of active inflammation. (D) Epithelium: (1) intact epithelium, (2) bullous change. (E) Stroma: (1) peripheral scarring with ghost vessel formation, (2) central scarring with ghost vessels, (3) central stromal edema, (4) vascularized central stromal edema. (F) Endothelium: (1) decompensation.

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CENTRAL STROMAL KERATITIS TABLE 1

PATIENTS WITH HERPES SIMPLEX TREATED WITH TOPICAL CORTICOSTEROIDS Age Race Sex

Morphology Active Pretreatment

Inactive Posttreatment

Duration of Therapy

Visual Acuity Recurrence* Before

After

1 2 3 4 5 6 7 8

48 Wo* 52 Wo" 47Wo* 2Wc? 50WÇ 59 Wo* 44 W 9 48 Wo"

R) R) R) P) R) R) R) R)

Aj, A
B 4 , C, B<, d (ecc) B 4 , C, Bi A L B„, C, (ecc) A2, B4> d (ecc) A,, B 2 A4, B 4 , d (ecc)

D 2 , E4, Fi D,, Ej, Fi Di, Ej, Fi D„Fj D,,E, D2, E 2 D,,E, D,, Ej, F ,

4wk 3wk 4 wk lwk 2wk 2wk 3wk 4 wk

20/400 20/400 20/400 20/80 20/400 20/400 20/200

<20/200 20/50 20/200 — (clear) 20/20 20/100 20/25 20/50

9 1U 11 12 13

79 Wd" 42 Wo" 29 Wo" 56 Bo" 58 Wo"

R) R) R) R) R)

A,, B, Au B,, A,, B,, As, B 3 , A,, B 4 ,

D, D,, Ej, F , Di,Ei D,,E, D 2 , E4, Fi

2wk 3wk 3wk + 3wk 3wk

20/80 20/200 20/200 20/400 HM

20/20 20/30 20/20 20/30 <20/400

14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37

52 Wo" 56 W 9 20 Wo* 47 W 9 48 Wo" 48 Wo" 55 Wo" 32 W 9 47 Wo" 46 Wo" 5W9 44 Wo" 4B9 64 W 9 58 W 9 94 Wo" 53 W 9 15 W 9 71Wo" 24 W 9 34 Wo" 83 W 9 45 W 9 72 W 9

R) A4, B,, d R) A4, B 4 , C 2 R) A4, B 4 , d R) A4, B4, Ci R) A«, B,, d R) A4. B 4 , d R) A4, B 2 , C, R) A«, B,, C, r R) Ai, B 4 , d R) A4, B 4 , d R) A,, B,, d P) A,, B 2 R) A4, B4, Ci [R) A4, B«, d r R) Perf. Flap ,R) A«, B4, d ,R) A,, B 2 R) A,, B 4 , Ci (ecc) R) A4, Bi R) Aj, B , ,R) A2, B4, d 'R) A,, B,, Ci R) A2, B 2 , d (ecc) (P) A,, B!

Ci (ecc) C, (ecc) C, (ecc) C,

Perf. Di, E 4 , F , D4, E4, F , D,, E 4 , F , Di, E 2 , F t D, E4, F , D„, Ei, F , D,, E 2 , F , D,, E4, Fj D2, E4, F ! Di, E,, F , D,,E, D,,EÎ

D,, Ei, F , Perf. Flap D L E 2 , Fi D1(E2 D2, E 2 D,,Ei D,,E, Di, E 2 D „ E2, F , D,,Ej Di.Ei

10 wk 12 wk 5 da 3wk 4 wk 2wk 10 da lwk 3wk 6 wk 8wk 4 wk 8wk 4 wk 9 da 3wk 3wk 6 wk 6 wk 6 wk 4 wk 6 wk 8wk 3wk

—

HM HM 20/400 20/400 20/200 FC FC FC HM 20/100 20/400 20/50 20/200 20/400 LP LP 20/30 20/400 20/60 20/3020/80 20/200 20/40020/100

K 2, l y r K 0,3yr 4,2yr K 0,2yr Maintenance + conj. flap 0,2yr 1, l y r Maintenance 2, l y r K, 2 in second

eye HM 2, HM K K 20/400 § K 20/400 1, l y r 20/60 FC K FC § K FC K HM 20/100 K 20/400 § 1, l y r 20/20 20/200 § 20/400 § LP K LP K 20/25 Maintenance 20/50 20/60 (cat) 20/20 1, < 6 mo 20/20 1, < 6 mo 20/200 20/50 ± 20/30-

t t t

t t

Morphology (pretreatment): (P) = primary attack; (R)= recurrent attack; (ecc) = eccentric lesion. Visual acuity (after) : (cat) = cataract accounting for diminished visual acuity. Recurrence:* is expressed as the number of recurrences in the given period of time; K = keratoplasty per­ formed; f = insufficient follow-up, performed; § = herpes virus identified in corneal button.

ring physician;25 (2) the virus was isolated on culture; (3) the virus 26 was identified in corneal tissue by electron microscopy.* Herpes zoster ophthalmicus was diag­ nosed in the presence of a well-described zoster syndrome, that is, discrete segmental dermatome involvement of the Vi cranial nerve. * Culture and electron microscopic identification were performed by Dr. Chandler R. Dawson, Fran­ cis I. Proctor Foundation for Research in Ophthal­ mology.

Bacterial ulcers included Pneumococcus, Moraxella, Pseudomonas, and Staphylococcus which were diagnosed by smear and culture.* The fungus isolated from Patient 63 was demonstrated to be Candida albicans by smear and culture at the U.S. Public Health Service Hospital, San Francisco. Miscellaneous conditions included intersti­ tial keratitis of unknown etiology, probat Bactériologie culture was performed by Dr. W. Keith Hadley, chief, Microbiology Laboratory, San Francisco General Hospital.

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AMERICAN JOURNAL OF OPHTHALMOLOGY

ble allergic reactions and possible herpes simplex keratitis. Diagnostic criteria for the last group were based on ancillary signs of herpes keratitis which included (1) recur­ rent inflammatory disease and (2) decreased corneal sensitivity. Two groups of patients free of active in­ flammatory disease were treated with topical corticosteroids according to protocol for seven to 14 days prior to corneal surgery. The first group consisted of 29 patients, in­ cluding patients with keratoconus, Fuchs' dystrophy, aphakic bullous keratopathy and corneal scarring without vascularization. The second group was composed of 46 pa­ tients with inactive corneal inflammation. Both groups were carefully evaluated by biomicroscopy before corticosteroid therapy and prior to surgery. IMMUNOLOGIC EVALUATION

All patients included in this series were evaluated for nonspecific inflammatory re­ sponsiveness by a battery of immunologic tests, including serum protein electrophoresis, qualitative immunoelectrophoresis, quantita­ tive immune globulin determination, comple­ ment evaluation and quantitative early IgG determination.27 Patients were then classified on a normal population distribution curve. Although several patients demonstrated a marked diminution in a single immunoglobulin, none of them showed over-all (pan) hypogammaglobulinemia. Diminution in IgA or IgM deficiency was not felt to be a con­ traindication to corticosteroid therapy. (Immunoglobulin and complement values in these patients will be published as part of a larger manuscript on the role of immunoglobulins in ocular inflammatory disease.28) THERAPY

Adrenocorticosteroid (prednisolone ace­ tate 1% suspension, Prednefrin Forte®) drops were administered to the involved eye every hour between 6:00 A.M. and 10:00 P.M. (17 drops/day). In general this treat­ ment schedule was followed for from three

JUNE, 1969

to six weeks. If marked neovascularization and/or corneal necrosis was present, subconjunctival corticosteroid injections (1.0 ml dexamethazone, Decadron,® 4.0 mg/ml; 0.2 ml Xylocaine® 2%) were given adjacent to the neovascularized area at daily intervals until the severity of the reaction had sub­ sided (up to 14 days). If no response oc­ curred within 10 days (particularly in inac­ tive disease), the topical drops were tapered off and discontinued. Upon clearing of the corneal inflamma­ tory reaction, most patients were rapidly withdrawn from hourly topical application. A typical over-all corticosteroid course would be: hourly corticosteroids, three weeks ; four times/day corticosteroids two to seven days ; one time/day corticosteroids, two to five days ; discontinuation. If inflamma­ tion recurred, patients were restarted on hourly corticosteroids and rapidly reduced to zero as clinical signs subsided. Only a small percentage of patients seemed to require maintenance corticosteroid therapy. Such in­ dividuals were maintained on the lowest pos­ sible dosage, such as one drop every two or three days. When evidence of microbial involvement was present, specific therapy was adminis­ tered in conjunction with corticosteroids. In active herpetic (epithelial) disease, IUDR drops were administered hourly (6:00 A.M. to 10:00 P.M.) if epithelial staining was present. When fluorescein staining had cleared, IUDR was used four times/ day during active corticosteroid medication. Be­ fore starting on high dosage topical cortico­ steroids, 22 patients (1, 2, 8, 10, 11, 15-23, 27, 28,30,31, 33-37) had been treated for stromal herpetic keratitis for from one month to two years with IUDR (varying dosage), epithe­ lial cryotherapy, epithelial debridement with or without iodine cauterization, multiple top­ ical antibiotics, topical corticosteroids (not exceeding four times/day) and various sys­ temic regimens. Topical antibiotics were used in bacterial ulcers every hour from 6:00 A.M. to 10:00

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TABLE 2 CLINICAL IMPROVEMENT IN H E R P E S SIMPLEX KERATITIS FOLLOWING CORTICOSTEROID THERAPY

Initial Clinical Classification

Total Patients

Final Visual Acuity >20/60

5 3 9 13 7

B, B2

B 2 _4, Ci (ecc) B2-4, C i B 2 _4, C 2

37

TOTALS

P.M. Neosporin® was used to treat Pseudomonas and Moraxella ; Gantrisin® or Neospo­ rin for Pneumococcus ; and Neosporin for Staphylococcus. Systemic antibiotics were used in Patients 47, 49, 50, 53, 54, 60 and 61 ; maximal doses of systemic amphotericin B was used in Patient 63. All systemic anti­ biotics were discontinued before topical cor­ ticosteroid medication was begun. Topical antibiotic therapy was continued hourly until corneal cultures were negative, then four times/day. Epithelial regeneration was encouraged by discontinuing topical medication and tightly patching the involved eye (24-72 hours). Such patching was frequently alternated with topical corticosteroid therapy in order to keep the corneal stroma free of inflamma­ tion during the re-epithelization process. Penetrating keratoplasty was undertaken in almost every eye in which visual acuity was less than 20/100 after inflammatory in­ activity had been achieved.* Once the patient's disease had reached sustained inactivity, follow-up evaluations were performed at three-month intervals. Carefully recorded recurrence of inflamma­ tion (clinical or subclinical) will be pre­ sented in this paper. RESULTS ETIOLOGIC CLASSIFICATION OF PATIENTS

Herpes simplex keratitis. Topical corticosteroids were used in conjunction with * To be discussed in a subsequent publication.

Improved VA < 20/60 on Steroid

Not Improved on Steroid

12 6 18

18

topical IUDR (table 1) in patients demon­ strating corneal stromal and anterior-cham­ ber inflammation, whether active epithelial involvement was present or absent. Careful patient management helped to avoid severe complications in all but one case. Of the 37 patients treated in this manner, 18 recovered 20/60 vision or better without subsequent keratoplasty (table 2). Corneal scarring or endothelial damage with bullous keratopathy was sufficient in most of the remaining cases to necessitate penetrating keratoplasty. The degree to which corticosteroid ther­ apy achieved good visual acuity depended on the morphologic picture initially presented by the herpetic keratitis. The prognosis (without keratoplasty) was best in those in­ dividuals with (1) anterior stromal involve­ ment (A1.4, B ^ ) or (2) eccentric disciform keratitis in which the central endothelium had been spared (A^.,, B3,4, d). Six­ teen of the 17 patients who achieved good vision without keratoplasty presented initially with no evidence of central endothelial in­ volvement. Variation in the clinical course of the dis­ ease during corticosteroid therapy also de­ pended upon the severity of the presenting lesion. Patient 3 demonstrated an interest­ ing clinical course, since his active herpes was treated with topical corticosteroids and no specific treatment. His clinical course clearly indicated (1) virus proliferation in the corneal epithelium while on corticoste­ roids (fig. 3-B), (2) simultaneous disappear-

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AMERICAN JOURNAL OF OPHTHALMOLOGY

JUNE, 1969

Fig. 3 (Aronson and Moore). Schematic demonstration of inflammatory changes in herpes simplex keratitis treated with topical corticosteroid, Patient 3. (A) Presteroid therapy, active disciform keratitis with an epithelial dendrite and anterior chamber reaction (A3, B», Ci). (B) Seven days following topical corticosteroids, evidence of stromal and anterior chamber clear­ ing accompanied by complete loss of epithelium (C). Approximately 24 hours after cessation of steroids : severe stromal and anterior cham­ ber reaction, an area of peripheral cornea (9- to 11-o'clock positions) showed marked thinning. (D) Sev­ enteen days after restarting corticosteroid therapy with alternate patch­ ing; the cornea is now completely re-epithelized, a relatively dense central stromal scar remains (D, E2, F.).

ance of stromal inflammation despite en­ hanced epithelial involvement (fig. 3-B) and (3) the explosive nature of the stromal in­ flammatory reaction produced by abrupt ces­ sation of corticosteroids (figs. 3-C and 4-A). Patient 3, a 47-year-old white, unemployed man, was seen in the Fall of 1964 with a history of re­ duced visual acuity in the left eye for approxi­ mately one month. He had had no previous examina­ tion or treatment. Initial examination revealed vis­ ual acuity to be <20/400. A well-demarcated den­ dritic lesion in the central corneal epithelium over­ lay a large central zone of disciform keratitis. Endothelial and anterior-chamber changes were noted (active classification As, B4, G, fig. 3-A). Corneal culture for herpes simplex virus was positive; im­ munologie studies were within normal limits.

The patient was admitted to the hospital and started on topical prednisolone acetate 1% drops (per description) in an attempt to evaluate the role of corticosteroids in acute herpes keratitis (the po­ tential risk was carefully explained before initiation therapy). The patient's progress was followed daily. By the seventh day, an interesting dichotomy occurred: whereas the corneal stroma, anterior chamber and limbus appeared to be relatively free of active in­ flammation, the epithelial lesion had markedly en­ larged and epithelial ulcération extended from lim­ bus to limbus. The margins of this ulcer appeared hazy and edematous, giving the impression of active cytolysis (fig. 3-B). At this point topical corticosteroid medication was stopped abruptly, and the patient's eye was patched for 24 hours in an attempt to encourage re-epithelization. When next seen (after approxi-

Fig. 4 (Aronson and Moore). Corticosteroid-treated herpes simplex keratitis patients. (A) Patient 3, four days after resumption of topical corticosteroids. Note the relative clearing of the corneal stroma, the degree of re-epithelization and the area of peripheral disease (arrows). (B) Same patient, three weeks after discontinuation of corticosteroids. Note the central corneal scar and scar in the area of peripheral corneal thinning at the 11-o'clock position. (C) Patient 11, before corticosteroid therapy. Note the dense disciform lesion with peripheral neovascularization. (D) Same patient three months after the start of topical corticosteroids. (E) Patient 35, before corticosteroids. Note peripheral corneal infiltrate and central scar. (F) Same patient after six weeks of topical corticosteroids ; a dense central scar remains. (G) Patient 14, 10 days after the start of corticosteroid therapy. Note area of peripheral corneal thinning. (H) Same patient four weeks after corticosteroid therapy. Note the peripheral corneal perfora­ tion and extension of infiltrative edema into the central cornea.

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AMERICAN JOURNAL OF OPHTHALMOLOGY

mately 18 hours), the patient complained of severe pain and demonstrated marked limbal engorgement with conjunctival chemosis. The corneal epithelium remained unchanged ; however, the stroma gave evi­ dence of massive recurrence of infiltrates. The pe­ ripheral cornea adjacent to the limbus (10-o'clock to 12-o'clock meridian) showed the marked thin­ ning suggestive of impending descemetocele. Severe iritis with hypoyon also was present (fig. 3-C). It was assumed that a massive antigen-antibody reac­ tion had occurred, which, if not interrupted immediately, would probably terminate in corneal perforation. Hourly corticosteroid drops were restarted and hourly I U D R drops were given simultaneously. Daily subconjunctival corticosteroid injections were administered adjacent to the area of impending per­ foration for three days (fig. 4 - A ) . Seven days after resumption of therapy, the eye had become remarkably quiet. The area of impend­ ing perforation had thickened appreciably ; how­ ever, the cornea still remained denuded of epithe­ lium. To encourage epithelial proliferation, topical medication was alternated with tight patching at 48-hour intervals. Following 17 days of this regi­ men, the epithelium had completely covered the cor­ nea and the stroma was relatively clear (fig. 3-D). Visual acuity was still reduced to 20/200, which was attributed to stromal scarring and distortion of the visual axis (fig. 4-B). Because the patient had been in the hospital for five weeks, keratoplasty was deferred, and he was discharged and followed as an out-patient for two months. No topical medi­ cation was required during this time. At the end of this period a successful penetrating keratoplasty was performed. Patient

11, who presented with a mini­

mally vascularized anterior stromal responded rapidly to t h e r a p y a n d

lesion,

achieved

v i s u a l a c u i t y of 2 0 / 2 0 (fig. 3 - A a n d B ) . Patient 11, a 29-year-old white evangelical minis­ ter, was diagnosed as having herpes kerato-iritis six weeks before referral. Therapy included topical I U D R hourly (at waking) plus two debridgements of the corneal epithelium. At the time of our initial evaluation, visual acuity was < 20/200. The corneal lesion was characterized by epithelial stippling over­ lying a large area of dense stromal infiltrative opa­ city (fig. 4-C). The most peripheral aspect of the lesion showed deep vascularization. Although wrin­ kles were present in Descemet's membrane, distinct keratic percipitates were absent. The lesion was classified as A2, B a . The patient was started on hourly corticosteroid drops and I U D R every two hours. By the 12th day, visual acuity had returned to the 20/30. After three weeks, medication was lowered to four times/day and maintained for one month by which time uncorrected visual acuity had improved to 20/20. Only minimal evidence of corneal scarring lead to the inactive classification Di, Ei (fig. 4 - D ) . Following discontinuation of corticosteroid drops, corneal in­

JUNE, 1969

filtration tended to recur at the lesion site ; therefore the patient has been treated intermittently with topical corticosteroids (two drops/week). H e has been followed for one and a half years on this regi­ men without evidence of significant recurrence.

In contrast, Patient 35, who presented with A2, B 3 , Ci, was treated intensively with topical corticosteroids without demonstrating visual improvement (fig. 3-C and D ) . The factor limiting her improvement was the degree of initial central corneal scarring. Patient 35, an 83-year-old white woman, had experienced chronic herpes keratitis throughout the previous nine months. A dendritic ulcer was noted at the time of the initial examination. Previous ther­ apy had included intermittent IUDR, corticosteroid drops (maximum dosage four times/day) and epithelial debridement. At the initial evaluation, she demonstrated multiple punctate irregularities throughout the corneal epithelium, a dense central corneal scar, infiltrates extending throughout the corneal stroma and superficial neovascularization nasally and inferiorly. T h e anterior chamber ap­ peared to be clear. She was classified As, B 3 , G (fig. 3-E). Maximum visual acuity was 20/200. The patient was placed on hourly topical cor­ ticosteroids and I U D R four times/day and main­ tained on this therapy for six weeks, at the end of which she demonstrated marked clearing of the cor­ neal infiltrates and involution of vascularity. How­ ever, the central stromal scars remained. The in­ active classification was Di, E 2, Fi (fig. 3-F). Her vision could not be improved to better than 20/200. The patient decided to postpone keratoplasty. Since the initial improvement, she has experienced two episodes of recurrent inflammation each of which cleared with topical corticosteroid therapy.

Complications noted during treatment of active herpes simplex with corticosteroids include : ( 1) proliferation of the agent in the corneal epithelium of the treated eye (Pa­ tient 3) ; (2) occurrence of dendritic kerati­ tis in the opposite, nontreated eye (Patient 13) ; (3) peripheral ringlike ulcération lead­ ing to descemetocele and perforation (Pa­ tient 14) ; (4) apparent extension of the her­ pes virus into the donor graft following ker­ atoplasty from a retained focus of stromal herpes (Patients 14, 16, 20 and23). 2 e Patient 13, treated with topical corticosteroids and I D U in the involved eye on two separate occasions, developed an epithelial dendrite in the noninvolved eye. Each time, the dendrite occurred within five days after initiation of therapy, and probably rep­ resented interocular transfer of corticosteroids. These dendritic lesions were easily controlled on

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topical IUDR therapy (every hour for three days) Visual acuity was maintained at 20/20. Subsequently his uninvolved eye has been protected from recur­ rence with simultaneous bilateral IUDR when corticosteroid drops are used in the first eye. Patient 14 was the only one who did not improve while on corticosteroid therapy. T h e probable explanation for this untoward clini­ cal course is that scierai vasculitis with vas­ cular occlusion developed adjacent to the area of perforation. 3 0 · 3 1 Following this vas­ cular occlusion, the peripheral cornea under­ went ischémie necrosis. Patient 14, a 52-year-old white man, presented with a deep peripheral corneal ulcer of the left eye. The epithelium adjacent and central to the ulcer showed punctuate staining. Superficial corneal neovascularization and limbal hypertrophy were present. Visual acuity was hand motion at two feet. The active classification was A<, B3, G, The patient was treated with subconjunctival dexamethazone injection adjacent to the lesion every other day for one week and topical corticosteroid drops hourly. Topical IUDR every two hours was started after one week.. During therapy, the central cornea cleared and the superficial vascularization diminished (fig. 4-G). However, in the fourth week of therapy, the area of ulcération became markedly thinned and progressed to perforation. Corticosteroids were discontinued (fig. 4-H) and a conjunctival flap was performed. Subsequently this patient under­ went penetrating keratoplasty. Electron microscopy of the corneal button demonstrated herpes virus throughout the corneal stroma. Recurrence of stromal keratitis was fre­ quently noted in the nonoperated group of patients (table 3 A ) . ( T w o patients, 8 and 11, who never sustained inflammatory inactivity while completely off corticosteroid therapy, have been included in the recurrence group. ) T h e rate of recurrence seemed to be related to the structural condition of the cornea once the disease became inactive. Patients dem­ onstrating marked vascularization of the corneal stroma and endothelial damage were most prone to recurrence (table 3 B ) , whereas patients free of corneal vascularization and endothelial disease showed no evidence of recurrence. It would appear that structural alteration strongly predisposes the eye to fu­ ture inflammation. A s previously noted, a matched control group of herpes patients, untreated with

881 TABLE 3A

RECURRENCE OF STROMAL INFLAMMATION FOLLOWING CESSATION OF CORTICOSTEROIDS

Clinical Classification Herpes simplex Herpes zoster (exclusive of keratoplasty and follow-up) Bacterial ulcer Miscellaneous TOTALS

Total Cases

No. Recurrences

% Recur­ rence

14* 5

ut 3t

79 60

7 S

n 2

29 40

31

18

58

* Five additional patients have been followed for < six months without evidence of recurrent inflam­ mation. t Includespatientsonmaintenancecorticosteroids. t Three other patients were positive for patho­ genic bacteria in the absence of clinical inflamma­ tion. topical corticosteroids, has not been evalu­ ated. However, 22 of the 37 patients com­ posing the corticosteroid group had pre­ viously received other therapeutic measures before being started on high dosage topical corticosteroid therapy. I n eace case, the con­ dition of these patients remained stable or deteriorated during the prior regimen. Al­ though not an ideal control group, this group under previous therapy indicates the efficacy of topical corticosteroid therapy. H E R P E S ZOSTER

N i n e patients with herpes zoster keratitis have been treated with topical corticosteroids (table 4 ) . Inactivation of inflammatory dis­ ease was achieved in every case. Seven of nine patients demonstrated a final visual acuity of better than 2 0 / 6 0 . It did not ap­ pear necessary to supplement corticosteroids with specific treatment in this disease, al­ though when a dendritic lesion was simulta­ neously encountered (Patients 40 and 4 5 ) , topical I U D R drops were added to the thera­ peutic regimen. Irreversible severe structural alteration and central corneal structural change were seen less frequently in herpes zoster than in herpes simplex, although every case demon­ strated a simultaneous iritis. Subsequent

AMERICAN JOURNAL OF OPHTHALMOLOGY

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JUNE, 1969

TABLE 3B RELATIONSHIP BETWEEN THE DEGREE OF STRUCTURAL CHANGE AND RECURRENCE OF INFLAMMATION Clinical Classification

Etiologic Diagnosis

B2

Bl

B2-4i, Ci (ecc)

B 2 _4, C l

7 3

4

Recurrences Herpes simplex Herpes zoster Bacterial ulcer Other diagnoses TOTAL

No Recurrences Herpes simplex Herpes zoster Bacterial ulcer Other diagnoses

2

1

2

3 1

TOTAL

4

5

B2-1, C 2

1

1 1

1

11

6

1

2 2 4

2

X - B i , B2 vs B2-4, Ci (ecc); B2-4, Ci, B2_4, C2 = 17.6, P > 0.001. keratoplasty was required less frequently in herpes zoster (two of nine patients). One patient (40) whose disease had previously resolved leaving severe, eccentric scarring, showed gradual progression of inflammatory infiltrate into the visual axis. The progres­ sion was arrested by maintaining the patient on topical corticosteroids drops. Patient 40, a 69-year-old white housewife, had been treated by Dr. M. Quickert according to our described protocol. She had a history of herpes zoster ophthalmicus with corneal and facial involve­ ment one and one-half years earlier (fig. S-A). Dur­ ing this period she developed a discrete dendritic

figure in the corneal epithelium and the possibility of herpes simplex superinfection was considered. Throughout this period she demonstrated progres­ sive inflammatory infiltration and neovascularization of the supero-temporal cornea, which gradually extended into the visual axis (fig. 5-B). When we saw her, visual acuity had diminished to 20/80. Her eye was chronically inflamed. Active inflamma­ tion Ai, B4, Ci was present. She was started on hourly corticosteroid drops and showed marked improvement in visual acuity to 20/25 within one month (fig. 5-C). Although the eye became quiet, lipoidal deposition and scarring remained in the peripheral cornea (fig. S-D). This patient has not been able to discontinue cor­ ticosteroid drops (prednisolone acetate 1% once or twice/day), principally because she claims marked

TABLE 4 H E R P E S ZOSTER

Pa­ tient

Age Race Sex

38 39 40 41 42 43 44 45 46

6OW0" 58 Wo* 69 W 9 64 W 9 49 Wo" 78 W 9 29 Wo" 48 Wo" 10W 9

Morphology Active Pretreatment (P) (R) (R) (P) (R) (R) (R) (P) (P)

B 3 , Ci (ecc) A,, B 3 , Ci (ecc) A,, B 4 , Ci (ecc) Au B 4 , C, A3> B 2 , C, (ecc) A,, B 4 , C, A, B 2 , Ci (ecc) A,, B 4 , C, (ecc) Ao, B,, C, (ecc) AÏ,

Inactive Posttreatment Di,E2 D,, Es Di, E2> F ! D,, Ei, F , D,,E, D,, Ei Di, Ej Di, E 2 D,, E s

Duration of Therapy

Visual Acuity Before

After

4 wk 4 wk 8wk 1 wk 3wk 3wk 2wk 3wk 4 wk

HM 20/400 20/80 20/400 20/80 HM 20/400 20/400 20/70

20/50 (cat) 20/50 20/25 20/400 20/25 H M (cat) 20/40 20/40 20/25

Recurrence* l,3yr

t

Maintenance K 1, l y r K 0, l y r

t

0,lyr

Morphology (pretreatment): (P) = primary attack; (R) = recurrent attack; (ecc) = eccentric lesion. Visual acuity (after): (cat) = cataract accounting for diminished visual acuity. Recurrence* is expressed as the number of recurrences in the given period of time; K = keratoplasty performed;! = insufficient follow-up.

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883

CENTRAL STROMAL KERAT1TIS

Fig. 5 (Aronson and Moore). Corticosteroid-treated herpes zoster (Patient 60). ( A ) Dermatomal distribution of the herpes zoster lesion. ( B ) Corneal lesion before corticosteroid therapy. Note corneal haze. ( C ) Corneal lesion after 10 days of corticosteroid therapy. ( D ) Corneal lesion six weeks after corticosteroid therapy. Note the corneal luster and the involution of the peripheral corneal neovascularization (photographs courtesy of Dr. Marvin Quickert). symptomatic relief while on medication. She has been followed for longer than one and one-half years by Dr. Quickert without significant exacerbation of her corneal disease.

The rate of recurrence (60%) was diffi­ cult to evaluate since only a small number of cases were involved (table 3A). BACTERIAL AND FUNGAL DISEASE

From 17 patients, presenting with hypopyon ulcer, bacteria or fungus was isolated (table 6). (This series does not include pa­ tients who developed bacterial ulcers in cor­ neal grafts, which will be discussed in a sub­ sequent report on keratoplasty.) Bacterial isolations included Moraxella, Pneumococcus, Pseudomonas and Staphylococcus aureus. The fungus cases demonstrated Candida albicans. Once again the degree of ther­ apeutic success depended upon the severity

of the presenting lesion (table 7). Three pa­ tients demonstrated superficial stromal in­ volvement, while four showed eccentric stro­ mal lesions. In each case, a final visual acuity of >20/60 (or equivalent) was achieved. Patient 53, for example, with an eccentric pneumococcal ulcer, responded extremely well to therapy.

TABLE 5 CLINICAL IMPROVEMENT IN H E R P E S ZOSTER KERATIT1S FOLLOWING CORTICOSTEROID THERAPY

Initial Clinical Classification B 2 _4,Ci (ecc) BÎ_I, Ci TOTAL

Total Final Improved Not PaVA VA < 20/60 Imtients > 20/60 on Steroids proved

AMERICAN JOURNAL OF OPHTHALMOLOGY

884

J U N E , 1969

TABLE 6 BACTERIAL AND FUNGAL INVOLVEMENT

Morphology

Age

Pa.· . tiant

Race r. sex

Active Pretreatment

Inactive Posttreatment

Duration of Therapy

Visual Acuity Before

After

Re-

(Moraxella) 47 68 Wo" 48 48 Wo* 49 60 Wo* 50 56 Wd" 51 74Wo"

(P) (P) (P) (P) (P)

A4, B 4 , Ci A4, B,, C, A2, B,, Ci (ecc) A2, B 2 A2, B,

D2, Di, D,, Di, D,,

E3, Fi E 2 , Fi E2 E2 E2

2wk 3wk 3wk 3wk 3wk

HM HM 20/80 HM 20/200

20/400 20/200 20/20 20/25 20/40

K K § 0, 2 y r 0, 2 y r

(Pneumococcus) 52 46 W 9 53 49 Wo* 54 72 W 9 55 94 Wo*

(P) (P) (P) (P)

A2, A4, A2, A4,

B2 B 4 , Ci (ecc) B 3 , C, B4, C2

D,, Di, D,, Di,

E2 E2 E 2 , F, E 4 , Fi

3wk <3wk 3wk 2wk

20/400 HM FC LP

20/25 20/40 20/100 LP

§ 0, 1 y r t 1, 1 yr §

(Staphylococcus) 56 78 Wo* 57 35 W 9 58 64 Wo* 59 52 Wo"

(P) (P) (P) (P)

A4, A4, A4, A4,

B4, G B 3 , Ci (ecc) B 3 , C, B 8 , Ci (ecc)

D,, E2, F , Di, E 2 D„E2 Di, E 2 (ecc)

4 wk 4 wk 4 wk 3wk

<20/400 20/80 FC FC

20/200 20/20 20/200 FCf

1, < l y r 0, 1 y r t § §

(Pseudomonas) 60 53 W 9 61 75 Wo" 62 72 Wc*

(P) A4, B 4 , C 2 (P) A2, B 3 , C, (P) A4, B 4 , C 2

D 2 , E 2 , Fi Di, E2, F! D,, E4, F,

4 wk 3wk 21 wk

LP HM HM

HM 20/80 HM

0, 1 y r j

(Candida albicans) 63 51 W 9

(P) A4, B 4 , C2

D 2 , E 2 , Fi

4 wk

LP

HM

tt

K

Morphology (pretreatment): (P) = primary attack; (R) = recurrent attack; (ecc)= eccentric lesion. Recurrence: * = is expressed as the number of recurrences in the given time period. Visual acuity (after): f = patient with optic atrophy. j = positive culture for pathogenic bacteria without clinical inflammation § = insufficient follow-up. # = patient developed a Pseudomonas ulcer in her donor cornea following keratoplasty. f t = patient died. K = keratoplasty. Patient 53, a 49-year-old Mexican farm laborer, presented with severe pain, redness and diminished vision in the right eye of more than one-week dura-

TABLE 7 CLINICAL IMPROVEMENT IN BACTERIAL AND FUNGAL

KERATITIS

FOLLOWING

CORTICOSTEROID THERAPY

Initial Total Clinical Classification Patients Bi or B 2 B2_4,Ci(ecc) B2_4,Cl B 4 ,C 2 (perf)

3 4 6 4

Final Visual Acuity >20/60

Improved VA < 20/60 on Steroid

6 4

10 17 Totals: * Patient 59, with optic atrophy, counted as >20/60.

tion. Initial ocular examination showed that vision was reduced to hand movements. A large pericentral corneal ulcer, extending through two thirds of the corneal stroma, was surrounded by dense infiltrate. A 4 + aqueous cellular response with hypopyon gave an active classification A4, B4, G (fig. 6-A). Bac­ tériologie smears and culture revealed Pneumococ­ cus. Immunologie tests were normal. The patient was initially started on intravenous penicillin (20 X 10" units/day) and topical Neosporin drops hourly. After 48 hours with no apparent improvement, topical corticosteroid drops (hourly) were added. Intravenous medication was discontinued after five days. After nine days, the clinical picture remained un­ changed. Careful review of the patient's chart re­ vealed that the corticosteroid drops had been placed in the uninvolved eye during the seven-day period. Hourly corticosteroids were then started to the in­ volved eye; in addition, subconjunctival corticoster­ oid injections were given every other day for three times. After 10 days, the eye had cleared markedly. By the 17th day, maximal visual acuity was 20/40

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CENTRAL STROMAL KERATITIS

(contact lens) and the inflammation had resolved (fig. 6-B). Corticosteroid treatment was discon­ tinued. The patient demonstrated no recurrence dur­ ing the succeeding year.

Resolution of severe central lesions that involved the visual axis and surrounding cornea always resulted in poor vision, re­ quiring subsequent keratoplasty. Patients 60 and 63 demonstrate such an outcome. Patient 60, a 53-year-old white woman, was seen at another hospital with a perforated corneal ulcer and endophthalmitis of more than one week's dura­ tion. Pseudomonas was noted on smear and cul­ ture. During this hospitalization, the patient received intravenous antibiotics : penicillin 40 X 10" units/ day, Streptomycin® 2.0 gm/day, and Chloromycetin® 2.0 gm/day for two days in preparation for enucleation. However, because of the patient's poor pulmonary function, she was considered too poor an anesthetic risk to undergo the surgery. Following this decision, she was transferred to San Francisco General Hospital where the referring diagnosis of Pseudomonas keratouveitis was confirmed. At the time of admission, her visual acuity was good light perception in the left eye. The cornea showed a large central perforation with a knuckle of iris prolapsed into the wound. The remainder of the cornea was opaque. There were confluent infil­ trates throughout the corneal stroma and circum­ ferential neovascularization of the peripheral cornea, active classification At, B3, G (fig. 6-C). Im­ munologie studies demonstrated diminution of IgM. The patient was started on hourly topical and daily subconjunctival corticosteroid injections and hourly Neosporin drops. The peripheral corneal stroma cleared after one week and subcon­ junctival corticosteroid injections were discon­ tinued. Maximal corneal clearing occurred after three weeks when the patient demonstrated a clear peripheral cornea with relatively inactive vascularization and central corneal scarring with iris in­ carceration (fig. 6-D). The anterior chamber was of 2+ - 3 + in depth. A dense, mature cataract was noted through the pupil, inactive classification D2, E2, F,. Penetrating keratoplasty was postponed to im­ prove the patient's pulmonary function. After six weeks, she seemed to be a reasonable anesthetic risk and successful penetrating keratoplasty was performed. Patient 63, a 51-year-old white woman, was seen by Dr. W. Richards and Dr. J. Arrington at the USPHS Hospital for central corneal ulcération, descemetocele, hypopyon and possible endophthal­ mitis. Following repeated culture, Candida albicans was demonstrated in the cornea and on the oral and vaginal mucosa. The patient was initially started on topical Nystatin® for one week. This medication was changed to intravenous amphotericin B for two weeks and later to subconjunctival amphotericin B for 10 days, without apparent improvement.

885

At the time of our initial evaluation, the patient demonstrated a central corneal descemetocele with iris incarceration, dense inflammatory infiltration of the inferior peripheral corneal stroma, 4 + cells and flare with hypopyon, active classification At, B4, G (fig. 6-E). Visual acuity was reduced to light perception. The patient was treated according to our protocol and, in addition, received daily subconjunc­ tival corticosteroid injections for seven days; so­ dium propionate 10% drops were used every two hours during the corticosteroid therapy. After one week, the peripheral cornea had cleared. After four weeks, the patient achieved maximum resolution, that is, clearing of the peripheral cornea, disappear­ ance of limbal hyperemia and scarring of the cen­ tral cornea with iris incarceration. The anterior chamber was 3 + in depth ; a dense cortical cataract was present (fig. 6-F). Visual acuity remained good light perception. The patient was maintained on low dosage corticosteroid therapy (four times daily) until a penetrating keratoplasty could be performed in about one month. The outcome of keratoplasty in not known for the patient refused all medication, signed herself out of the hospital and has been lost to follow-up.

Patient 62 offered an unusual opportunity to study histologically the effects of topical corticosteroids on corneal inflammation. Sec­ tions revealed a complete absence of polymorphonuclear leukocytes throughout the corneal stroma but particularly marked in the corneal area adjacent to the iris prolapse. This indicates the strong inhibitory effect of corticosteroids on polymorphonuclear leu­ kocytes. Patient 62 was a 72-year-old white man who was noted to have a Pseudomonas corneal ulcer while he was being treated on another service for terminal hepatic insufficiency and was in a hepatic coma. Ocular examination showed a central corneal perforation with incarcerated iris; the area of cor­ nea surrounding the perforation demonstrated a dense coalescence of corneal infiltrates, active clas­ sification A4 B4 C2 (fig. 6-G). Hourly corticosteroid drops and topical Neosporin were started. During the 17th day of this therapy, the patient died and his eyes were obtained for histologie evaluation. On section, the cornea showed evidence of marked scar­ ring at the site of the iris prolapse, with epithelization of the prolapsed iris. The corneal stroma and the iris stroma were completely free of acute inflam­ matory cells (fig. 6-H). Eight patients, 47, 49, 50, 54, 60, 61 and 63, were treated with systemic and topical antibiotics or antifungal agents for seven to 10 days before the initiation of corticoste­ roid therapy. N o clinical improvement was

886

AMERICAN JOURNAL OF OPHTHALMOLOGY

JUNE, 1969

Fig. 6 (Aronson and Moore). Corticosteroid-treated bacterial and fungal ulcer patients. (A) Patient 53 before corticosteroid treatment. Note the eccentric position of the pneumococcal ulcer and hypopyon. (B) Same patient after discontinuation of corticosteroids; a residual scar is present in the inferior cornea. The visual axis is clear (designated by a dot). (C) Patient 60 before corticosteroid therapy. Note perforated Pseudomonas corneal ulcer and opaque

VOL. 67, NO. 6

CENTRAL STROMAL KERATITIS

noted during the course of this therapy. However, introduction of topical corticosteroids resulted in marked improvement in each case. Two patients suffered recurrent inflam­ mation within the first year after therapy. In each case, the inactive lesion demonstrated severe structural alteration (tables 3B and 5). The pathogenic organism reappeared in the conjunctival sacs of three other patients in whom clinical inflammation was absent after topical antibiotics and corticosteroids had been discontinued (table 3A). OTHER DIAGNOSES

Active disease. This group includes pa­ tients with severe stromal disease in whom no microbial agent was identified and who do not fulfill the etiologic criteria of the preced­ ing groups. Alkali and other chemical keratitides have been eliminated in order to avoid confusion, since they probably represent combined toxic and ischémie necrosis. The diagnoses include possible herpes simplex and allergic keratitis (table 8). Corticosteroids were always used in these cases without coverage by specific therapy. No incident of induced viral disease occurred, for example, dendritic keratitis. As before, a satisfactory visual response depended on the severity of disease at the time of the initial observation (table 9). Superficial and eccen­ tric lesions usually offered a good visual prognosis, while deep central lesions re­ quired subsequent keratoplasty. Recurrence of corneal inflammation was seen less frequently in these diseases (table 3A). When recurrence did occur (Patients

887

70 and 73), the corneal structure had been severely altered and the ability of the cornea to remain quiescent was markedly compro­ mised. Inactive disease. Two groups of patients were treated preoperatively for seven to 14 days according to the corticosteroid protocol. In the first group were 29 patients with non­ inflammatory corneal disease and in the sec­ ond group, 46 patients with inactive inflam­ mation. At the end of the treatment period, no clinical change was noted in the corneas of the noninflammatory group. Patients with inactive inflammation usually demonstrated narrowing and involution of the neovascularizing blood vessels within the cornea and diminution of limbal vascularity. An occa­ sional patient demonstrated some clearing of corneal opacity, indicating that the diagnosis of inflammatory inactivity was not entirely accurate. No case showed evidence of deteri­ oration of the initial corneal status. IMMUNOLOGIC OBSERVATIONS

As already noted, immunologic studies were performed in every patient to avoid treating an immunologic cripple with corti­ costeroids. None of the patients tested dem­ onstrated a significant reduction in IgG. However, reductions in IgM were noted in some cases of herpes simplex and bacterial infections and in early IgG in recurrent in­ flammation. These changes appeared to rep­ resent an incomplete immunologic aberra­ tion, which may predispose an individual to the endemic existence of the microbe.32"35 For example, Patient 13 (diminished IgM) demonstrated recurrence of dendritic kerati-

cornea. (D) Same patient after three weeks of corticosteroid therapy. Note corneal clearing and healing of the corneal perforation. (E) Patient 63 on presentation USPHS Hospital, San Francisco. Note Candida albicans ulcer and hypopyon. (Patient suffered corneal perforation before the initiation of corticosteroid therapy.) (F) Same patient after four weeks of corticosteroid therapy. Note clearing of the cornea and anterior cham­ ber and incarceration of the prolapsed iris (photographs courtesy of Dr. W. Richards). (G) Patient 62 after seven days of corticosteroid therapy. Note iris prolapse. (H) Same patient after 17 days of corticosteroid therapy. Arrows indicate the area of corneal scarring free of polymorphonuclear leukocytes (Xl7). (Histologie sections fom the University of California Eye Pathology Labo­ ratory, courtesy of Drs. W. F. Spencer and J. B. Crawford.)

888

AMERICAN JOURNAL OF OPHTHALMOLOGY

J U N E , 1969

TABLE 8 MISCELLANEOUS DIAGNOSES IN ACTIVE DISEASE

Pa ya "

tient

(Possible 64 65 66 67 68 69 70 71 72

Morphology

A

2e Race Sex

Active Pretreatment

herpes) 59 Wo" 45 Wo" 21 W 9 61 Wrf1 27 W 9 75 Wo" 51 Wo" 19 W 9 71 Wo"

Inactive Posttreatment

A 2 , D2

D,,ES Dj, E,, F , D, D, E,, F , Di, E,, F , D,E3 D,,E2 D,,E D», E4> F ,

3wk 11 day 7 day 3wk 2wk 4 wk 2wk 2wk 3wk

A4> B 4 , Ci

Di,Ej Di, E 4 , F , Di, Ej, F,

2wk 4 wk 8wk

A2, B2, Ci A2, Bi A2, B 4 , C, Ai, B3, Ci Ai, B3> Ci A,, B<, Ci (ecc) A2, Bi A2, D4| C-l

(Allergic) 73 27 Wo" 74 48 Wo" 75 42 Wo"

Duration of Therapy

A 2 , 0 4 , (-1

A4, B 4 , C2 (ecc)

Visual Acuity Before 20/400 20/400 20/70 CF CF CF 20/80 20/50 <20/200 CF 20/400 20/70 +

Re-

After 20/100t 20/100 20/25 CF CF CF 20/25 20/20 <20/200

0, 2 y r K 0,1 yr K K K 1, l y r 0, l y r K

20/200 20/400 20/40

1, l y r K Î

Morphology (pretreatment): (ecc) = eccentric lesion. Recurrence * is expressed as the number of recurrences in the given time period. Visual acuity t = patient with amblyopia ex anopsia. j = insufficient follow-up. K = keratoplasty.

tis in his noninvolved eye every time he was treated with corticosteroids in the involved eye, and Patient 60 (diminished IgM) dem­ onstrated persistence of Pseudomonas in her conjunctiva when not on active antibiotic therapy. Such individuals were actively treated with topical corticosteroids, although they demonstrated partial immunologie anomalies. They have been closely followed for disease progression and recurrence dur­ ing and following cessation of treatment. TABLE 9 CLINICAL IMPROVEMENT IN OTHER STROMAL KERATITIS FOLLOWING CORTICOSTEROID THERAPY

, ... . 'mt.lal Total Clinical pat;ents Classification

Final Visual Acuity >2Q/^

Possible Herpes Bi or B 2 B2_4, Ci(ecc) B2-4, Cl

2 1 6

2 1

Allergic B2-4, Ci(ecc) B2-4, Ci

1 2

1

12

4

TOTALS

Improved VA<20/60 on Steroid

6

2 8

DISCUSSION

Corticosteroid effects on the clinical course of central stromal keratitis. Seventy-five pa­ tients with active central stromal disease have been evaluated during high dosage, topical corticosteroid therapy; 74 of the 75 patients demonstrated distinct improve­ ment of their corneal stromal inflamma­ tion, with resolution or marked regression of the active inflammatory process. Of this group, 36 achieved > 20/60 vision without keratoplasty ; the remainder showed such se­ vere structural change following resolution of their corneal inflammation that kerato plasty offered the only opportunity for im­ provement in vision (table 10). Once perma nent structural change has occurred, inflam­ matory inhibition can only prevent such change from becoming greater. It is important to note that therapy spe­ cific for each identified etiologic agent was administered concurrent with topical corticosteroids. It can be assumed that corticosteroids play some role in the over-all host re­ sponse to a given infectious agent. Specific control must be instituted to prevent over-

CENTRAL STROMAL KERATITIS

VOL. 67, NO. 6

whelming proliferation of the agent. It is equally important to note that, when no etiologic agent was recovered, specific therapy was not used. To guard against error in di­ agnosis and to avoid or minimize complica­ tions, the patient must be seen frequently and started on appropriate therapy when an infectious agent has been identified. Topical corticosteroids have dramatically limited the severity of central stromal keratitis. Patients demonstrated rapid clearing of stromal infiltrates and neovascular involution soon after topical corticosteroid medication was instituted. The effect was especially marked in those patients who were treated with other medications for some time with­ out improvement (herpes simplex, bacterial ulcer). An adequate assessment of the ability of a medication to limit the severity of an inflam­ matory process demands strict attention to two details : 1. Classification of the initial morphologic picture in an attempt to determine whether it is possible to achieve an adequate visual re­ sult. 2. Estimation of the degree to which the organ can be returned to complete physio­ logic function. When stromal necrosis involves the visual T A B L E 10 R E S U L T S OF CORTICOSTEROID THERAPY IN ALL CASES

Result after Therapy Inflammatory resolution Visual acuity > 20/60 without keratoplasty Visual acuity > 20/60 when central endothelium is free of disease* Visual acuity > 2 0 / 6 0 (penetrating keratoplasty performed) Over-all visual acuity >20/60

N o

p

'

as s

no. 7c ImImproved proved

75

74

98.7

75

36

48

34

34

100

29

21 f

72

75

57

76

* Two patients improved to > 20/60 vision in the presence of endothelial disease. t A successful keratoplasty is defined as a clear donor cornea throughout it entirety.

889

axis or central endothelial damage has oc­ curred, the possibility of obtaining a good vi­ sual result is limited; therefore, evaluation of therapeutic success in returning complete function to an organ is confined within this limitation. Analyses of lesions not involving the central corneal axis brought 100% success in obtaining vision of > 20/60 when these two details were observed (table 10). Corticosteroid therapy appeared to shorten markedly the duration of inflamma­ tory activity. Few patients required more than four weeks of treatment to attain sus­ tained inactivity. Seldom were such symp­ toms as severe pain or incapacity to work encountered after administration of cortico­ steroid drops for several days. Withdrawal of this medication caused recurrence of clin­ ical inflammation in a number of patients ; reinstituting the therapy brought prompt control. Only three patients required contin­ uous maintenance corticosteroid for longer than three months. Patterson 36 and Kauf­ man37 advocated low or extremely low doses of topical corticosteroid and their results ap­ peared promising. However, we have had no experience with this type of regimen, pre­ ferring to use high doses for shorter periods of time. Recurrence of inflammation varied per­ ceptibly among the different etiologic groups. To evaluate this parameter more accurately, we eliminated all patients who had had pene­ trating keratoplasty. This made possible an assessment of the effect of inflammation on the corneal structure and measurement of re­ infection. In 18 of 31 patients (58%) fol­ lowed for longer than one year, the original corneal lesion caused recurrence of inflamma­ tion, and the herpes simplex group demon­ strated the highest incidence of recurrence. The evaluation of reinfection by the initial causative agent showed that, in nearly three fourths of herpes simplex recurrences (eight of 11), an epithelial dendrite reappeared be­ fore exacerbation of the stromal disease. No ancillary signs of herpes zoster were noted with recurrent corneal disease.

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AMERICAN JOURNAL OF OPHTHALMOLOGY

Only two of seven patients with bacterial keratitis demonstrated inflammatory recur­ rence and neither one showed evidence of the presenting pathogen. In contrast, three pa­ tients demonstrated reinfection with the pre­ senting pathogen in the absence of clinical corneal inflammation. The tendency to recurrent stromal kerati­ tis was related to the severity of the initial inflammatory process and the degree of per­ manent structural change (scarring and neovascularization) remaining after inactivation of the process. The 18 patients suffering in­ flammatory recurrence demonstrated severe corneal vascularization with endothelial in­ volvement, regardless of etiologic diagnosis. On the other hand, most of the recurrent cases showed minimal residual structural change (Α,Βι, or A,B 2 ). It would seem, therefore, that the tendency to recurrence re­ lates both to the specific etiologic agent and to the degree of structural alteration. The herpes simplex virus demonstrates a marked predilection to remain in ocular tis­ sues and to retain its virulent properties. This latent potential has been demonstrated in both the experimental animal and in man.38"40 The exact condition of the latent virus and the reason it does not cause overt disease cannot be readily determined. Simi­ lar latency has been postulated for the vari­ cella virus in herpes zoster; 41 however, the virus has not been demonstrated in the ab­ sence of disease. The circumstances surrounding bacteria are somewhat different. Some patients re­ tained a pathogenic microbe and were free of disease; others were free of the known pathogen when the disease recurred. In the inflammation-free group, the number of pathogenic organisms seemed inadequate for production of clinical inflammation. Perhaps a second event, such as traumatic denudation of the corneal epithelium, facilitates reacti­ vation of inflammation or, perhaps, the indi­ vidual becomes immunologically tolerant to the micro-organism. Some of these patients demonstrate an immunologie defect (for ex­

JUNE, 1969

ample, diminished IgM) which may permit . the pathogenic bacteria to become a part of their normal conjunctival flora, such individ­ uals must, of course, be carefully followed. The role of structural alteration in predis­ position to inflammatory recurrence is usu­ ally expressed as enhanced vascular perme- , ability at the site of the healed lesion.42 Such a vascular change leads to a markedly en­ hanced cellular and humoral response by the host to an inflammatory stimulus. A small stimulus normally would not provoke an in­ flammatory response, but clinical inflamma­ tion will occur in the presence of this height­ ened reactivity. Frequent reference has been made to the role of corticosteroids in facilitating recur­ rence of herpes simplex. The recurrence rate of 79%* reported by Thygeson and associates12 seem to substantiate this claim. However, there are no reports on recurrence rates for herpes simplex stromal keratitis in nonsteroid-treated patients, nor have we evaluated such a control population. Carroll43 found no difference in the over-all rate cl recurrence (43%) in epithelial herpes treatod with IDU or IDU + corticosteroids. Pei haps, the higher incidence of disease recur­ rence in our study can be explained by the s verity of the initial structural alteration en­ countered in our cases. If this is true, struc­ tural alteration rather than corticostero therapy would account for the remarkably high incidence of inflammatory recurrence in this type of herpes simplex keratitis. Mechanism of corticosteroid action in in­ flammatory suppression and wound healing. The effects of corticosteroids on inflamma­ tion have been postulated as operating at several levels,44"48 including lymphocytic in­ volution or interference with polymorphonuclear chemotaxis and interference with polymorphonuclear degranulation or lysosomal stabilization. The beneficial effect of corticosteroids in * In the herpes series, 34 of 37 patients presented with a history of previous episodes of recurrent herpetic keratitis.

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CENTRAL STROMAL KERATITIS

891

SEQUENTIAL STEPS IN ACUTE INFLAMMATION antigen toxic agent

antigen antibody complex polymorphonuclear degranulation

h

+

antibody

^

complement

hydrolytic enzyme release

antigen antibody complex

polymorphonuclear chemotaxis + degranulation

tissue necrosis

potential points of steroid activity Fig. 7 (Aronson and Moore). Sequential steps in acute inflammation.

corneal inflammation occurs as a result of the involution of the polymorphonuclear leukocytes. Whether this effect is brought about by direct action on the lysosome within the cell or by diminishing its chemotactic ability is not readily apparent. What is apparent is that the clinical and his%)logic inflammatory infiltrate in the cornea rapidly disappears in the presence of topical -corticosteroids (fig. 6-H). The active source of parenchymal destruction of polymorpho■juclear leukocytes is related to the group of •hydrolytic enzymes contained in its lysosomal granules. During polymorphonuclear debjranulation, these enzymes are released to react with protein parenchyma. Removal of the polymorphonuclear leukocyte and its hy­ drolytic enzyme systems, removes the major source of stromal destruction24'48 (fig. 7). Whether other corticosteroid effects, (for ex­ ample, decreased capillary permeability) are operative in this circumstance cannot be read­ ily determined. Nonbeneficial effects of corticosteroid therapy include lymphoid arrest,44 accumu­ lation of breakdown products of intravascular fibrin,30 inhibition of epithelial regeneration49 and stromal ground substance. Lymphoid in­ hibition or arrest is a two-edged sword: on the one hand, it diminishes the amount of antibody available to the cornea, thereby re­

ducing the effect of antibody in the inflam­ matory pathway (fig. 7) ; on the other hand, reduction of local antibody production per­ mits the infecting agent to proliferate more rapidly (for example, Patient 3). Abrupt discontinuation of corticosteroids precipitated an explosive necrotizing inflammatory reac­ tion, which probably represented a massive antigen-antibody reaction between large quantities of viral antigen and unchecked an­ tibody production, followed by an overwhel­ ming polymorphonuclear leukocyte reaction. If this reaction had not been interrupted immediately, the cornea would have perfor­ ated. The best explanation for the apparently high antibody titer following cessation of corticosteroid therapy is the synchronous cell hypothesis.50 Corticosteroids, like X-rays, remove most of the mature lymphoid ele­ ments. When lymphoid proliferation is al­ lowed to recur, the immature reaction is characterized by blast or immune recognition cells, which now produce overwhelming quantities of antibody to the herpes virus. This seems to be best avoided with simulta­ neous control of the herpes virus with IUDR. Such a rebound phenomenon for systemic corticosteroids in infectious disease has been described.51 Corticosteroid inhibition of fibrinoly-

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sin30·31 may readily lead to intravascular platelet aggregation, clotting and resultant ischémie necrosis of the peripheral cornea, as described in the Shwartzman reaction.31·52 Patient 14 demonstrated progressive deterio­ ration of the peripheral cornea while on topi­ cal corticosteroid and corneal perforation re­ sulted even though the central stromal keratitis improved. The peripheral location of this perforating lesion resembled that of le­ sions in alkali keratitis or gutter dystrophy. In alkali cases, the cornea thins and perfo­ rates adjacent to the area of ischémie sciera. Corticosteroids may actually enhance the de­ gree of ischémie necrosis. If such a mecha­ nism is in force, treatment must be aimed at re-establishment of a normal vascular supply to the sciera, as well as at inflammatory suppression. Wound-healing experiments53 have demonstrated the effect of corticoste­ roids on stromal mucopolysaccharides ; it is difficult to demonstrate this effect in central stromal keratitis. The mechanism by which corticosteroids inhibit epithelial proliferation remains ob­ scure. Whether lysosomal stabilization leads to a diminished rate of cellular division is unknown. To circumvent the inhibitory ef­ fects of corticosteroids, all medication to the involved eye is discontinued for 24 hours and the eye is tightly patched. This therapy has proved to be effective after stromal infil­ trates have receded. When stromal infiltrates recur during the patching period, corticoste­ roid drops are alternated with patching —48 hours corticosteroids, 48 hours patch­ ing ; such techniques have proved effective in almost every case. Contraindications to use of corticosteroids. It has already been indicated that there are no absolute contraindications to corticoste­ roid therapy, however problems will arise. Initially, it was assumed that a certain number of patients would be eliminated from the corticosteroid-treatment group be­ cause of immunologie incompetence. Immu­ nologie testing did not fulfill this prediction.

JUNE, 1969

Every patient demonstrated normal or above normal values for IgG. This immune globulin was used as the basic marker of immunologie competence be­ cause, usually, it most closely parallels an in­ dividual's ability to respond to a chronic in­ flammatory stimulus.54 A diminished IgA or a diminished IgM alerted us to monitor the involved individuals more carefully for microbial latency and recurrent inflamma­ tion.55'56 These patients are seen more fre­ quently; cultures are taken at least every three months ; and, periodically, they are treated specifically by microbial suppression. At the first sign of an inflammatory recur­ rence, topical corticosteroids and specific ther­ apy are instituted. Patients require careful monitoring while under high dosage topical corticosteroid therapy. (Our patients were either hospital­ ized or seen as out-patients two or three times a week.) Constant attention must be given to changing clinical signs and the regi­ men must be adjusted accordingly. In our experience, irreversible complications may occur when the patient, or the referring phy­ sician, abruptly discontinues corticosteroid medication (see Patient 3). The high dosage regimen (every hour) should not be contin­ ued for more than eight weeks unless the pa­ tient has shown marked improvement with­ out complete resolution. In no case should this regimen be used for more than three months. We prefer rapid reduction in corti­ costeroid administration which leads to total discontinuation. Occasionally, however, a pa­ tient seems to require very low mainte­ nance doses for a prolonged period. Such patients should be seen no less frequently than once a month. We feel that the hazard of corticosteroidinduced glaucoma57'58 or cataract59'60 does not contraindicate the use of corticosteroids, since the primary disease may cause an infinitely greater irreversible visual loss. At least 10% of the patients demonstrated increased intraocular pressure while on cor-

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ticosteroids. Tension was always normalized with acetazolamide (Diamox,® 1,000 mg/ day/and/or miotic drops) and returned to normal levels after corticosteroids were dis­ continued. Almost every patient with severe anterior chamber disease (A,B,Cior2) showed some degree of cataractous change before initiation of corticosteroid therapy. Whether cortico­ steroids or active inflammation produced these progressive changes was not deter­ mine. No evidence of cataractous changes was seen in corticosteroid-treated patients in whom the change had not been demonstrated prior to corticosteroid therapy. Since the pe­ riod of active therapy is relatively short, ir­ reversible glaucoma or cataract should sel­ dom appear. Permanent glaucomatous and cataractous changes secondary to corticoste­ roid therapy usually occur in patients who have used this medication for several years. The role of corticosteroids in inactive inflammatory disease. High dosage topical cor­ ticosteroids were given preoperatively for seven to 14 days to 75 patients scheduled for keratoplasty. Not one of these patients dem­ onstrated an adverse corneal change and almost every one showed some involution of corneal neovascularization and several pa­ tients demonstrated some clearing of stromal infiltrates. This group of patients has been included in this study to emphasize that no complications occurred in an inactive test

893

medication produces a maximum concentra­ tion in the cornea, we utilize topical prepara­ tions when they are available. However, agents effective against many microbes are not supplied for local use (penicillin) ; in such cases, we employ systemic therapy. In our experience, IUDR every one or two hours has provided adequate control of active herpes simplex virus. Neosporin drops every hour are effective against Pseudomonas, Staphylococcus and Moraxella; sulfonamide and Neosporin every hour against Pneumococcus. These medications demonstrated maximum inhibition when sen­ sitivity tested in patients in this series. Al­ though these medications have given satis­ factory results, we would have preferred to use more effective cidal agents against cer­ tain bacteria. The first eight patients in the bacterial and fungal series had been treated with topi­ cal and systemic antibiotics prior to cortico­ steroid therapy. They reflect our initial cau­ tion in using high dosage topical corticoste­ roids in active bacterial and fungal disease. The next nine patients received antibiotics and corticosteroids simultaneously.* When a specific etiologic agent could not be identified, corticosteroids were used with­ out specific coverage. One must always be alert to recognize the earliest signs of occult or superimposed infection, to identify them and to institute immediately the appropriate • group within the first seven to 14 days of specific agent. therapy. It has already been emphasized that Strict adherence to these principles pre­ this is the minimal time for judging the vented serious complications in all but one efficacy of topical corticosteroid therapy. case. If the probable pathogenic mechanism in When the presence of corneal inflammation * Subsequent to this study we saw a patient with is in doubt, a seven to 10-day trial period of high-dosage topical corticosteroids is indi­ pan-hypogammaglobulinemia and Pseudomonas ker­ atitis. The microbe was resistant to Neosporin cated. drops and systemic Colistin®. While the patient was The role of specific therapy in the high- on topical corticosteroid therapy, the bacteria spread to the second eye. When topical Colimycin® (Wardosage corticosteroid regimen. If an etiologic ner-Chilcott) drops were given hourly, the agent agent can be identified or one is strongly was controlled and good vision (20/20) was re­ suspected (dendritic keratitis), the most ef- tained in the second eye. It should be emphasized that, in the presence of hypogammaglobulinemia, ■ fective specific agent should always be used the infectious agent must be controlled before simultaneously. Since we believe that local starting corticosteroid therapy.

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that patient had been properly evaluated, corneal perforation might have been avoided. Morphologic vs etiologic diagnosis. Both morphologic and etiologic criteria have been used to classify our cases. Morphologic criteria were selected in an attempt to elucidate the relationship between the severity of the initial active lesions and the status of the post-treatment inactive le­ sions. This relationship seemed important for we believe that the pathogenic mecha­ nism of central stromal keratitis is identical in every case no matter what the etiology. This process, characterized clinically by progressive formation of infiltrates in the central corneal stroma, represents polymorphonuclear leukocyte chemotaxis and is me­ diated by an immunologie, or toxic, combi­ nation of an external stimulus with gamma globulin and subsequent complement bind­ ing. The predominantly central stromal in­ volvement seems to be related to the break­ down of central epithelium and entry of the causative agent into the stroma, 20>21 Topical corticosteroids were used to attack the polymorphonuclear leukocytes, the cells predomi­ nating pathogenic mechanism. Etiologic criteria assisted in the evaluation of the variations specific microbes demon­ strated in the presence of corticosteroids. We believe that this study demonstrates the beneficial effect of corticosteroids on the pathogenic process. Since the response of the various etiologic agents to corticosteroids differs, specific ancillary therapy is required. When corticosteroids are withdrawn from a patient with herpes simplex, virus prolifera­ tion is enhanced and severe disease occurs. This necessitates controlling the rate of virus replication by adding IUDR to the treatment regimen. Keeping the evaluation of the pathogenic pathway of the corneal in­ flammation separate from the etiologic clas­ sification fosters better control of both the inflammatory reaction and the causative agent. SUMMARY

Active central stromal keratitis in 75 pa­

JUNE, 1969

tients was treated with high doses of topical corticosteroids and, when indicated, with specific ancilliary therapeutic agents. Inactivation of the inflammatory process was achieved in 74 of the 75 patients. The dura­ tion of active disease appeared to be short­ ened and its severity lessened. The recur­ rence of inflammation frequently seen in herpes simplex keratitis correlated well with the degree of residual structural change. Un­ desirable side-effects were seldom noted when corticosteroids were administered si­ multaneously with appropriate specific thera­ peutic agents. Preservation of the corneal structure by limiting the ravages of the in­ flammatory process is the specific indication for corticosteroid therapy. Room 1505, San Francisco General Hospital 1001 Potrero Avenue (94110) ACKNOWLEDGMENTS

We thank Drs. J. M. Arrington, J. B. Crawford, C. R. Dawson, W. K. Hadley, M. H. Quickert, W. W. Richards and W. H. Spencer for their assis­ tance. The following ophthalmology residents helped follow these patients : Drs. D. R. Anderson, J. W. Bettman, Jr., M. F. Choy, T. M. Dixon, T. F. Minas, R. E. Nasser, D. M. O'Day and R. D. Wayman. We also thank K. Sugai, M. Enterline, E. Benewith, M. Taylor and B. Goldfeller for technical and his­ tologie assistance ; H. Escobar for medical illustra­ tions ; D. Longanecker and C. Young for photogra­ phy ; M. Sucec for editorial assistance. REFERENCES

1. Schwartz, B. (ed.) : Corticosteroids and the eye. Internat. Ophth. Clinics VI. Boston, Little Brown, 1966. 2. Hogan, M. J., Thygeson, P. and Kimura, S. J. : Uses and abuses of adrenal steroids and corticotropin. Tr. Am. Ophth. Soc. 52:14S, 1954. 3. Gordon, D. M. : Prednisone and prednisolone in ocular disease. Am. J. Ophth. 41 :S93, 1956. 4. Kaufman, H. E. and Maloney, E. D.: IDU and hydrocortisone in experimental herpes simplex keratitis. Arch. Ophth. 68:396, 1962. 5. McCoy, G. A., and Leopold, I. H. : Steroid treatment of herpes simplex of the cornea. Am. J. Ophth. 49:1355, 1960. 6. Jawetz, E. et al : Studies on herpes simplex : X. The effect of corticosteroids on herpetic keratitis in the rabbit. J. Immunol. 83:486, 1959. 7. Scheie, H. G. and McLellan, T. G., Jr. : Treat­ ment of herpes zoster ophthalmicus with corticotropin and corticosteroids. Arch. Ophth. 62:579, 1959. 8. Dohlman, C. H. and Zucker, B. B. : Long-term treatment with idoxuridine and steroids : A compli-

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cation in herpetic keratitis. Arch. Ophth. 74:172, 1965. 9. Patterson, A. : Interstitial keratitis. Brit. J. Opth. 50:612, 1966. 10. Kaufman, H. E., Martola, E. L. and Dohl­ man, C. H. : Treatment of herpes simplex with IDU and corticosteroids. Arch. Ophth. 69:468, 1963. 11. Thomas, C. I., Purnell, E. W. and Rosenthal, M. S. : Treatment of herpetic keratitis with IDU and corticosteroids. Am. J. Ophth. 60:204, 1965. 12. Thygeson, P., Hogan, M. J. and Kimura, S. J. : The unfavorable effect of topical steroid therapy on herpetic keratitis. Tr. Am. Ophth. Soc. 58:245, 1960. 13. Theodore, F. H. : An appraisal of IDU in the treatment of herpetic keratitis. EENT Monthly 42 :88, 1963. 14. DeVoe, A. G. : Steroids and herpes simplex. Arch. Ophth. 68 :720, 1962. 15. Elliott, F. A. : Treatment of herpes zoster with high doses of prednisone. Lancet 2 :610, 1964. 16. Harrison, E. Q. : Complications of herpes zoster ophthalmicus. Am. J. Ophth. 60:1111, 1965. 17. Harbin, T. : Recurrence of a corneal Pseudomonas infection: After topical steroid therapy. Re­ port of a case. Am. J. Ophth. 58 :670, 1964. 18. Theodore, F. H. and Schlossman, A. : Ocular Allergy. Baltimore, Williams & Wilkins, 1958. 19. Leopold, I. H. : Treatment of eye disorders with anti-inflammatory steroids. Ann. N.Y. Acad. Sei. 82 :939, 1959. 20. Aronson., S. B., Goodner, E. K., Yamamoto, E. and Foreman, M. : Mechanisms of the host re­ sponse in the eye: I. Changes in the anterior eye following immunization to a heterologous antigen. Arch. Ophth. 73 :402, 1965. 21. Aronson, S. B., Martenet, A. C, Yamamoto, E. A. and Bedford, M. J. : Mechanisms of the host response in the eye: II. Variations in ocular disease produced by several different antigens. Arch. Ophth. 76:266, 1966. 22. Aronson, S. B., Enterline, M. L. and Bed­ ford, M. J. : Mechanisms of the host response in the eye : V. Anterior ocular disease produced by nonnecrotizing toxic agents. Arch. Ophth. 78:384, 1967. 23. Weissman, G. : Lysosomes. New England J. Med. 273:1143, 1965. 24. Weissman, G. and Dingle, J. : Release of lysosomal protease by ultraviolet irradiation and inhi­ bition by hydrocortisone. Exp. Cell Research 24:207, 1961. 25. Gundersen, T. : Herpes cornea with special reference to its treatment with strong solution of iodine. Arch. Ophth. 15:225, 1936. 26. Dawson, C. R. et al : Structural changes in chronic herpetic keratitis. Arch. Ophth. 79:740, 1968. 27. Aronson, S. B. : The role of nonspecific tests in uveitis. In (Aronson, S. B. et al, eds.) : Clinical Methods in Uveitis. St. Louis, Mosby, 1968, p. 185. 28. : Immunoglobulins in ocular inflamma­ tory disease, in preparation.

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29. Jensen, P. R., Aronson, S. B., Pollycove, M. et al : Mechanisms of the host response in the eye : III. Interocular antigen transfer. Arch. Ophth. 77 :814, 1967. 30. Stefanini, M. and Dameshek, W. : The Hemorrhagic Disorders : A Clinical and Therapeutic Ap­ proach. New York, Grune & Stratton, 1962. 31. McKay, D. G. : Disseminated Intravascular Coagulation : An Intermediary Mechanism of Dis­ ease. New York, Harper & Row, Hoeber Medical Division, 1965, 32. Smith, R. T. et al : The development of im­ mune response : Characterization of the response of the human infant and adult to Salmonella vaccines. Pediatrics 33 :163, 1964. 33. Sawaki, Y. et al : Patterns of human antibody reactions in coccidioidomycosis. J. Bact. 91:422, 1966. 34. Janeway, C. A., Rosen, F. S., Merler, E. and Alper, C. A. : The Gammaglobulins. Boston, Little Brown, 1967. 35. Davis, S. F., Schaller, J. and Wedgewood, R. J. : Job's syndrome : Recurrent "cold" staphylococcal abcesses. Lancet 1:1013, 1966. 36. Patterson, A. : Management of ocular herpes simplex. Brit. J. Ophth. 51:494, 1967. 37. Kaufman, H. E. : Management of ocular herpes simplex virus. Arch. Ophth. 73 :149, 1965. 38. Nesburn, A. B., Elliott, J. H. and Leibowitz, H. M. : Spontaneous reactivation of experimental herpes simplex keratitis in rabbits. Arch. Ophth. 78:523, 1967. 39. Brown, D. C. et al : Recurrent herpes simplex conjunctivitis. Arch. Ophth. 79 :733, 1968. 40. Kaufman, H. E., Brown, D. C. and Ellison, E. D. : Herpes virus in the lacrimal gland, conjunc­ tiva and cornea of man: A chronic infection. Am. J. Ophth. 65:32, 1968. 41. Simpson, R. E. H. : Studies on shingles : Is the virus ordinary chicken pox virus? Lancet 2:1299, 1954. 42. Aronson, S. B., Fish, M. B. and Pollycove, M. : Altered ocular vascular permeability following inflammation. Invest. Ophth. in press. 43. Carroll, J. M., Martola, E. L., Laibson, P. R. and Dohlman, C. H. : The recurrence of herpetic keratitis following idoxuridine therapy. Am. J. Ophth. 63:103, 1967. 44. Cope, C. L. : Adrenal Steroids and Disease. Philadelphia, Lippincott, 1964. 45. Ketchel, M. M., Favour, C. B. and Sturgis, S. H. : The in vitro action of hydrocortisone on leu­ cocyte migration. J. Exper. Med. 107:211, 1958. 46. von Morschlin, S. et al : Studies on the effect of cortisone and ACTH on phagocytosis of leuco­ cytes and macrophages. Acta Hemat. 9:277, 1953. 47. Long, D. A. : The influence of corticosteroids on immunological responses to bacterial infections. Internat. Arch. Allergy 105 :5, 1957. 48. Weissman, G. and Thomas, L. : Studies on ly­ sosomes: I. The effects of endotoxin tolerance and cortisone on the release of acid hydrolases from a granular fraction of rabbit liver. J. Exper. Med. 116:433, 1962.

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49. James, W. M., Power, J. L. and Ripple, P. H. : Experimental and clinical observation of the effects of cortisone in corneal lesions. Am. J. Ophth. 35:1298, 1952. 50. Dixon, F. J. and McConahey, P. J. : En­ hancement of antibody formation by whole body Xradiation. J. Exper. Med. 117:833, 1963. 51. Rose, B. : Histamine, hormones and hypersensitivity. J. Allergy 25:168, 1954. 52. Shwartzman, G. : A new phenomenon of local skin reactivity to B. thyphosus culture filtrate. Proc. Soc. Exper. Biol. Med. 25 :560, 1928. 53. Chen, R. W. and Postlewait, R. W. : The b:ochemistry of wound healing. Surg. Science 1:215, 1964. 54. Schultze, H. E. and Heremans, J. F. : The Molecular Biology of Human Proteins I and H. London, Elsevier, 1966-1967. 55. Bettman, J. W., Jr. and Aronson, S. B. : Host

JUNE, 1969

response in infectious disease: A correlative study between disease severity and circulating immunoglobulins in blepharoconjunctivitis. Arch. Ophth. in press. 56. Hobbs, J. R., Milner, R. D. G. and Watt, P. J. : Gamma-M deficiency predisposing to meningococcal septicaemia. Brit. Med. J. 4:583, 1967. 57. Becker, B. and Mills, D. W. : Corticosteroids and intraocular pressure. Arch. Ophth. 70:500, 1963. 58. Ballintine, E. J. : Glaucoma: Annual review. Arch. Ophth. 79:617, 1968. 59. Bettman, J. W., et al : Cataractogenic effect of corticosteroids on animals. Am. J. Ophth. 65:581, 1968. 60. Black, R. L. et al : Posterior subcapsular cat­ aract induced by corticosteroids in patients with rheumatoid arthritis, JAMA 14:166, 1960.

QUANTITATIVE SYSTEMIC CORTICOSTEROID EFFECT ON XENOGRAFT REACTION D. C. BROWN, M.D.,

E. D. ELLISON AND H. E. KAUFMAN,

M.D.

Gainesville, Florida

Previous studies1"3 have shown that sys­ temic corticosteroids can suppress rejection of corneal transplants during the period of drug administration. However, all authors have recorded a high incidence of toxicity and minimally effective doses of corticosteroid have not been determined. In addition, comparison of efficacy of various drugs and routes of administration is difficult because of the variety of antigenic stimuli. Introduction of full-thickness pig corneal buttons intralamellarly into rabbit corneas4'5 provides a satisfactory experimental model for obtaining graft reactions and has been used to study the dose response relationship of topical corticosteroids. This xenograft model was used in the following experiment to determine the dose-response relationship From the Department of Ophthalmology, College of Medicine, University of Florida. This research was supported in part by Research and Training Grants from the National Institute of Neurological Diseases and Blindness, National Institutes of Health, U. S. Public Health Service, Bethesda, Maryland.

of systemic dexamethasone and to permit comparison of the biologic effectiveness in the cornea of topical and systemic adminis­ tration of this corticosteroid. MATERIAL AND METHODS

Animals. Male and female pigmented rab­ bits weighing 1.5 to 2.5 kg were used throughout the experiment. The animals were housed in pairs, fed commercial rabbit pellets and given drinking water ad libitum. Donor corneas. Pig eyes were obtained from a local slaughter house within six hours after death. The whole eye was washed in sterile saline and cleaned of ad­ herent tissues. The debrided eyes were irri­ gated with neosporin antibiotic solution and stored over night at 4°C. Full-thickness 7mm buttons were removed from the pig cor­ nea immediately prior to transplantation. Intralamellar transplantation. Intralamellar pockets of about one half the thickness of the recipient rabbit cornea were created as described by Babel and Bourquin," and