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The Effect of Structural Alteration on Anterior Ocular Inflammation
T H E E F F E C T O F STRUCTURAL ALTERATION ON A N T E R I O R OCULAR INFLAMMATION SAMUEL B. ARONSON, M.D., THOMAS E. MOORE, JR., M.D.,
AND
DENIS M. O ' D A Y , M.B.B.S. San Francisco, California
Several factors are responsible for the morphologic variation seen in clinical disease patterns produced by a single etiologic agent. These include differences in the degree of the host response as well as the structural in tegrity of the eye prior to infection. Varia tions in inflammatory severity most likely re flect degree of host response, while atypical clinical pictures are the result of alterations in ocular structure. This study examines the relationship between altered ocular structure and the inflammatory process in the anterior eye.
(Fig. 1-top). Only monocular cases were in cluded in this study so that in every case the other eye served as a control. The epithelial defect in the involved eye provides an en trance for an exogenous inflammogenic stimulus to penetrate the corneal stroma and produce an inflammatory reaction. During the past six years, we have classi fied 23 cases of epithelial structural altera tion. This group includes 16 cases of corneal abrasion and seven cases of primary infec tious epithelial disease (Table 1). The pri mary disease factor, or destruction of cor-
METHODS
Definition of structural alteration syn dromes—For purposes of this study, the cases presented here are defined as structural alteration syndromes. Two distinct types of inflammatory disease emerge in this general category: (1) alteration or disruption of the corneal epithelium caused by abrasion or in fection, and (2) functional alteration in ocu lar vascular permeability (altered O V P ) caused by a previous, adequately severe in flammation. In the first group, the corneal epithelium is usually altered by mechanical abrasion but also may be secondarily altered by primary infectious involvement, e.g., the dendrite of herpes simplex. The subsequent inflammatory patterns are either central or peripheral corneal disease or anterior uveitis
CENTRAL
PERIPHERAL
From the Eye Research Laboratories, Depart SMALL MOLECULAR VARIATION ment of Ophthalmology, and the Clinical Laborato ries, San Francisco General Hospital, University of California School of Medicine, San Francisco, Cal ifornia. Dr. Arsonson is the recipient of a USPHS Research Career Development Award K3 EY 31, 653. This investigation was supported in part by USPHS Grants EY 00246 and EY 00408. Reprint requests to Samuel B. Aronson, M.D., Fig. 1 (Aronson, Moore, and O'Day). Effect of Department of Ophthalmology, Room 1505, San Francisco General Hospital, 1001 Potrero Avenue, structural alteration on clinical morphololgy in cor neal epithelial defects. San Francisco, California 94110. 886
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neal epithelium, was identified on the bases of history (corneal abrasion) and ocular signs on examination (corneal foreign body, contact lens abrasion, epithelial dendrite in herpes simplex, dermatomal configuration of herpes zoster, and superficial punctate keratitis in the adenovirus group). Infection was identified by (1) a positive conjunctival cul ture for pathogenic microbes (Staphylococcus aureus and Moraxella) or indigenous bacteria (Staphylococcus albus and diphtheroids), or (2) if the culture was nega tive, evidence of upper respiratory viral syn dromes ( U R I ) in the community. (This lat ter group was limited only to corneal abra sion syndromes, since separating primary and superimposing infections is extremely difficult.) Only cases with positive bilateral conjunctival cultures or with equivalent clin ical conjunctival signs are included in this series. The technique for bacterial isolation was the standard qualitative technique used in our laboratories, i.e., primary plating of con junctival fornix swab samples on blood and chocolate agar. A positive control group was compiled during the past two years. This group in cludes cases of corneal abrasion without stromal inflammation and infectious cases in TABLE 1 CASES WITH A PRIMARY EPITHELIAL DEFECT AND SECONDARY INFECTIOUS SUPERIMPOSITION
Primary Classification
No. Cases
Mechanical Abrasion: Contact lens 7 Foreign body S Other 4 Total 16 Infectious Etiology: Herpes simplex Adenovirus Herpes zoster Total
3 3 1 7
Secondary Agent Identified Culture 4 4 3 11
Clinical Syndrome
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which stromal disease was either absent (dendritic keratitis) or typical of the pri mary disease (disciform keratitis). Con junctival cultures were negative in all of these cases (Table 1). Immunologie evaluation, by previously de scribed techniques,1 included: (1) simple protein electrophoresis, (2) qualitative immunoelectrophoresis, (3) quantitative immunoglobulin evaluation for IgA, IgM, and IgG, (4) early IgG determination, and (5) BiC/BiA determination. Patients were grouped by clinical classification for com parison. A second group, altered O V P (Fig. 2 ) , in cludes cases with structural changes resulting from an adequately severe primary inflamma tion of the cornea or uvea. Morphologically, they are characterized by active or inactive corneal neovascularization and clinical evi dence of previous iritis (such signs include pigmentary or fibrinous KP, lens precipitates, anterior and posterior synechiae, and iris atrophy or neovascularization). This predis position phenomenon was studied only in pa tients with unilateral structural alteration so that the uninvolved eye could serve as a si multaneous control. The study was similarly limited to etiologies of exogenous stimuli, since identification techniques for these stim uli are highly reproducible in contrast to those used for endogenous recurrent inflam mation. (It is important to note that recur rent uveitis probably is a manifestation of this same mechanism, but the superimposing stimulus is extremely difficult to identify.) The models studied were divided into cor neal and uveal cases and are depicted in Fig ure 1-B. A total of 31 corneal and 11 uveal cases were studied (Table 2 ) . In every case, the patient had been followed for a period of time in which structural changes were free of active inflammatory signs. When each pa tient presented with inflammatory exacerba tion, exogenous stimulus was identified in both the inflamed and noninflamed eyes, ei ther by identification of the microbe culture or by syndromal pattern, as described above.
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Cases were excluded when cultures or conjunctival clinical signs were not the same in both eyes. A positive control series was also compiled for the altered OVP group (Table 2), which included patients whose (1) initial exciting organism was recultured from the lower conjunctival fornix, or (2) recurrent uveal disease (epithelial dendrite in herpes simplex keratitis) was clinically evident. All patients in broth groups were evalu ated by immunologie testing, as described previously. A gradient comparison was es tablished with control and normal series.
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CORNEAL
STIMULUS
UVEAL
STIMULUS
RESULTS
Abrasion of the corneal epithelium with consequent structural alteration can be traced to several obvious sources: contact lenses, foreign bodies, fingernail scratches, ultraviolet ray destruction, and so forth. Or dinarily, the abrasion is without sequelae. However, if it coincides with conjunctivitis, such an abrasion can provoke stromal infil trate formation, stromal neovascularization, or acute iritis. The prevalent form of this re action occurs in monocular contact lens wearers. In Case 1, the patient suffered a corneal abrasion during an episode of follicular conjunctivitis, which was followed by superficial stromal infiltrate formation. CASE REPORTS
Case 1—A 23-year-old Caucasian woman with myopia had worn a monocular contact lens for over two years. She had had two previous abrasions of the corneal epithelium without infiltrate formation; both resolved within 48 hours after patching. This
TABLE 2 CASES WITH ALTERED OCULAR VASCULAR PERMEABILITY
Infectious Agent
Corneal
Uveal
Pathogenic bacteria Indigenous bacteria Virus Total Control
14 5 12 31 38
3 1 7 11 17
Fig. 2 (Aronson, Moore, and O'Day). Effect of structural alteration on clinical morphology in al tered vascular permeability. time she presented with severe pain and photopho bia of six hours' duration. Her history revealed a severe "cold" 10 days previously which had re solved; however, she noted "itchy eyes" for about three or four days. Slit-lamp examination showed a bilateral follicular conjunctivitis. Her left eye (con tact lens) demonstrated superficial stromal infil trates in a ring-like distribution (Fig. 3-A) ; with fluorescein, a ring of punctate staining was noted (Fig. 3-B). The anterior chamber demonstrated an occasional cell and 1+ flare. The cornea of the right eye showed some fine epithelial infiltrates but other wise was free of disease. Physical examination re vealed preauricular adenopathy and apparent in crease in nasopharyngeal follicle formation. The pa tient was treated with Prednefrin Forte® 1% four times daily for three days. After stromal infiltrates resolved, her left eye was patched for 24 hours, during which time the epithelium healed completely. Two days later she resumed wearing the contact lens and has since remained symptom-free.
The second most frequent reaction is infil trate formation with or without neovascular ization following foreign body penetration of the corneal epithelium. In Case 2, the pa tient demonstrated a peripheral corneal ep ithelial defect from a steel particle embedded in the anterior corneal stroma, surrounded by stromal infiltrate and superficial neovas cularization.
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Fig. 3 (Aronson, Moore, and O'Day). (A) Case 1, subepithelial infiltrates, corresponding to epithelial defects. (B) Same eye, fluorescein stain of left cornea. Note ring-like staining. (C) Case 2, showing infiltrate surrounding the corneal foreign body. (D) Same eye following corticosteroid therapy. Infil trate has disappeared. (E) Case 3, central epithelial ulcer with hypopyon (fluorescein stain). (F) Same eye, fluorescein stain showing remaining punctate areas after corticosteroid therapy. Case 2—A 48-year-old Caucasian man, a machin ist, complained of pain and photophobia of three days' duration. While sanding steel 10 days before, he felt something enter his left eye; since he was free of pain, he did not consult a doctor. Slit-lamp examination revealed a minute piece of steel embed ded in the anterior corneal stroma and piercing the corneal epithelium. Surrounding it was a small "rust ring" approximately 1.0 to 1.5 mm in diame ter. In turn, this was surrounded by a diffuse zone of flocculent white infiltrate. An occasional cell and minimal flare were noted in the anterior chamber.
The upper and lower eyelid margins of both eyes showed marked hypertrophy and some scarring. Collarettes surrounded cilia ; a folliculopapillary re action of the palpebral conjunctiva was also pres ent. His right cornea showed no involvement. Conjunctival cultures of both eyes grew prolific Staph. aureus. To demonstrate the relationship between the su perimposing agent (SA) and the inflammatory re action, the patient was treated with ( 1 ) Prednef rin Forte® 1% drops to the left eye hourly from six A.M. to 10 P.M. for five days; (2) Neosporin®
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drops to each eye were given every two (waking) hours for five days, without removing the foreign body. At the end of this period the infiltrate had resolved; a small rust ring surrounded the foreign body (Fig. 3-D). The foreign body was now re moved; the corneal epithelium regenerated within 48 hours, leaving minimal residual scarring. The pa tient remained free of Staph. aureus for three months but demonstrated recurrence of the orga nism on reculture at that time. However, he was now free of corneal inflammatory signs. Iritis as the presenting anterior segment sign is less frequent. We have seen only six cases with this pattern. Case 3 demonstrated a severe iritis concomitant with follicular conjunctivitis following a fingernail scratch of the cornea. Case 3—A 20-year-old Negro woman had a sev ere URI and "itchy eyes" of one week's duration. The night before she presented, her right cornea was scratched by her infant. On presentation, the patient complained of severe pain and photophobia. Ocular examination revealed bilateral follicular conjuncti vitis. The right eye showed a central epithelial de fect of about 3 to 4 mm (Fig. 3-E). The stroma was free of infiltrate, but the anterior chamber demonstrated a 4 + cellular reaction with hypopyon. The cornea and anterior chamber of her left eye were free of inflammation. On physical examination she demonstrated bilateral preauricular adenopathy and showed a moderate nasopharyngitis. Therapy included (1) subconjunctival corticosteroid injections for two days (Decadron, 0.8 ml, xy locaine 2%, 0.2 ml) and (2) Prednefrin Forte® 1% drops hoursly (six A.M. to 10 P.M.) for five days. By the end of the fifth day, she was completely free of inflammation, although punctate staining was present (Fig. 3-F). All medication was stopped at this time. T h e superimposed infection variant is characterized by superimposition of Staph. aureus or epidermidis upon a viral inflamma tory lesion which had produced a n epithelial defect. I n Case 4, an epithelial dendrite was the initial presenting lesion. Following ep ithelial scraping, superimposition of staphylococcal-induced central stromal ball-like in filtrates plus a severe anterior chamber reac tion occurred. Case 4—A 54-year-old Caucasian man had had a bowel resection for adenocarcinoma of the colon six months before presentation of his ocular lesion. When seen, he demonstrated a dendritic epithelial lesion (Fig. 4-A) which was treated with IUDR hourly for two days and then scraped with a moist cotton applicator. Two days later, there were sev
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eral ball-like infiltrates in the anterior corneal stroma (Fig. 4-B) as well as moderate cells and flare. Re-examination revealed severe hypertrophy of the eyelid margins of both eyes, as well as con junctiva! hyperemia overlying folliculopapillary hy pertrophy. Staph. aureus grew on culture of both eyes. The patient was treated now with daily sub conjunctival corticosteroid injections (Decadron, 0.8 ml, xylocaine, 0.2 ml), topical Prednefrm Forte 1%, hourly drops from six A.M. to 10 P.M., as well as hourly IUDR. At the end of 48 hours, the pa tient demonstrated a hypopyon and stromal ball-like opacities (Fig. 4-C). Review of immunologie tests showed markedly diminished early IgG and IgM (93), and bactériologie results showed the presence of Staph. aureus. (This review indicated a relative immunologie incompetence; the uncon trolled staphylococcal organism had produced a PMN response in spite of subconjunctival cortico steroid therapy. Therefore, it was decided that the number of staphylococcal organisms must first be diminished, and then maximal corticosteroid ther apy resumed.) The patient was treated for two days with hourly Neosporin drops and twice daily Neo sporin ointment scrubs of the eyelid margins without appreciable benefit. He was then restarted on daily subconjunctival corticosteroid injections, hourly corticosteroid drops, and hourly IUDR drops (per above) as well as the Neosporin medication. This time the infection cleared rapidly with complete res olution of the anterior chamber in one week and stromal clearing by 10 days (Fig. 4-D). On the eighth day of Neosporin treatment, the patient dem onstrated a filamentary keratitis. After Gantrisin was substituted for Neosporin, this cleared within 48 hours. He was withdrawn from medication and has remained free of corneal inflammatory signs. (Within two weeks of discontinuation of sulfonamides, however, he showed positive cultures for Staph. aureus and recurrence of blepharoconjunctivitis and has been placed on period Gantrisin scrubs.) Twenty-three cases constitute our overall experience with superimposition of an infec tious agent on epithelial defects (Table 3 ) . These include 18 bacterial superimpositions (13 Staph. aureus, three Staph. albus, two Moraxella) and five probable superimposi tions of a viral agent. As noted earlier, we have evaluated the same types of epithelial lesions in which atypical stromal or anterior chamber disease did not occur (Table 1). By definition none of the cases evaluated showed evidence of concomitant microbial infection. Immune globulin evaluation of the three groups revealed no appreciable differences among (1) superimposition disease, (2) pos-
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Fig. 4 (Aronson, Moore, and O'Day). (A) Case 4, presenting dendrite lesion. (B) Same eye, epi thelial healing. Superficial and deep infiltrates have appeared. (C) Same eye, demonstrating corneal infiltrates plus hypopyon, after corticosteroid and IUDR therapy. (D) Same eye, clearing after combined Neosporin and corticosteroid therapy. (E) Case 5, herpes zoster. (F) Same eye, demonstrating initial corneal clearing after corticosteroid therapy. (G) Same eye, demonstrating severe cornea! infection secondary to Staphylococcus aureus. ( H ) Same eye, demonstrating a clear cornea following keratoplasty.
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TABLE 3 FREQUENCY OF SUPERIMPOSING AGENTS IN EPITHELIAL DENUDATION SYNDROMES
Total Cases
Mechanical abrasion Contact lens Foreign body Other Total Primary infectious etiology Herpes simplex Adenovirus or TRIC agent Herpes zoster Total
Bacteria Staph. aureus
Moraxella
Staph. albus
URI
7 5 4 16
4 3 2 9
1
1
1
1
1 2 2 S
3 3 1 7
2 1 1 4
1
1 1
1
2
itive control, and (3) normal control groups (Table 4 ) . However, if superimposition groups are subclassified by superimposing agent, Staph. aureus patients may demon strate low IgM values, while U R I syn dromes with uveitis show relatively high IgM values (Table 5). The other two groups are within normal limits. Patients with altered OVP of the cornea, which predisposed to inflammatory recur rence, always demonstrated inflammatory exacerbation at the site of corneal neovascularization. Specificity of the microorganism stimulating recurrence may be variable within a given patient. In Case 5, herpes zoster produced the initial inflammatory le sion and recurrent inflammation was traced to Staph. aureus. Case. 5—This 49-year-old Caucasian alcoholic (patient 42 in an earlier report 2 ) was first seen with severe herpes zoster involvement of the left side of his face (Fig. 4 - E ) , as well as demonstrat ing a total cutaneous varicella reaction. On initial presentation he also demonstrated epithelial dendrites, eccentric disciform keratitis, and iritis (Fig. 4 - F ) . Treatment included hourly topical corticosteroid (prednisolone acetate 1%) and topical I U D R for approximately three weeks. His ocular disease was well resolved by the end of one month. The cornea showed some pericentral scarring with lowgrade neovascularization. H e was followed for about one year, when he went on a prolonged alcohol "binge" and was lost from followup for 10 weeks. On reappearing, he demonstrated a severe central corneal ulcer with
marked excavation of the anterior stroma and descemetocele of the left eye (Fig. 4-G). The cornea of the right eye was free of inflammation. How ever, he showed acute congestive conjunctivitis, both bulbar and palpebral, eyelid margin hypertro phy with some bilaterally symmetrical exudate. A profuse growth of Staph. aureus was cultured from each eye. Treatment included subconjunctival corticosteroid injection (as before), left eye, once daily
TABLE 4 C A S E S WITH ALTERED OVP AND A SECONDARY STIMULUS
Secondary Agent Identified Clinical Groupc
r*„' Cases
Corneal neo vascularization Uveal change
10 11
Culture
Clinical Syndrome
8 1
2 10
TABLE 5 CASES WITH ALTERED OVP AND RECURRENCE OF A PRIMARY STIMULUS
Secondary Agent Identified No. Clinical Group Cases Corneal neo vascularization
23
Culture
Clinical Syndrome
5
18
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for five days, prednisolone acetate 1% drops hourly, Neosporin drops hourly, and Neosporin ointment scrubs of the lids twice daily. The right eye re ceived Neosporin drops hourly and Neosporin oint ment eyelid scrubs twice daily. The patient's left cornea perforated on the seventh posttreatment day, and a penetrating keratoplasty was performed on day 11. When last seen 10 months postoperation, he had a clear graft with visual acuity > 20/40 (Fig. 4-H).
The same disease pattern is apparently produced by nonpathogenic bacteria. How ever, such a diagnosis requires a prolific growth on culture of the indigenous agent during active inflammation and absent dur ing disease remission. Recurrent iritis of exogenous origin can occur in the absence of a distinguishable corneal lesion. In Case 6, a monocular iritis re curred at yearly intervals following a severe URI. Case 6—A 23-year-old Negro animal caretaker had a history of five bouts of iritis in his right eye ; his left eye was consistently free of inflammation. Routine ocular examination revealed an occasional pigmentary KP in his right eye; his left anterior chamber was structurally intact. The next winter he presented with severe pain and photophobia in his right eye of one and one-half days' duration. He remarked that his whole family had been sick with the "flu" for about two weeks. He personally had experienced some lassitude but no distinct evidence of URL On ocular examination he demonstrated a marked follicular conjunctivitis in both eyes. In ad dition, his right eye demonstrated moderate cells and flare (2 to 3 + ) , fine KP, and iris and limbal injection. His right cornea was free of active in flammatory signs. The patient was treated with topical corticosteroid drops, Prednefrin Forte® 1% (six A.M. to 10 P.M.) ; his iritis resolved within one week. At no time did the opposite eye show signs of corneal or uveal inflammation, although the conjunctival reac tion was judged to be equivalent to that of the right eye.
We have observed a total of 21 cases of corneal or uveal inflammatory recurrence in which the exacerbating agent differed from the initial exciting agent (Table 4 ) . (In re current monocular uveitis, this is speculative, since the initial agent was identified in only one case.) In eight of 10 corneal cases, the recurrent agents were recovered and in cluded Staph. aureus (5), staphylococcal epidermidis (1), Moraxella (1), and TRIC
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agent ( 1 ). In the uveal case, the initial iritis followed ocular contusion ; Staph aureus was isolated during the subsequent attack. It must be emphasized that recurrent in flammation also can be produced by reinfec tion with the initial disease-producing mi crobe (Table 5). (We have included only corneal cases. As already noted, the initiat ing agent in monocular iritis was identified so rarely that these cases were classified in the secondary agent group.) Of 16 cases so classified, five bacterial ulcers recurred ( Staphylococcus, 2; Pseudomonas, 2 ; Mo raxella, 1). Eight herpes simplex cases (den dritic ulcer) had subsequent dendrites, and three TRIC cases (smears) were reisolated. In the herpes cases, disease was evident only in the involved eye, while in the bacterial and TRIC group, the microbe was isolated from both eyes. (In our series, herpes simplex is a syndromal diagnosis. Two dendritic patients were cultured bilaterally with isolation of the agent from each eye.) Immunologie testing in these groups re vealed no difference between secondary and primary recurrent agent groups (Table 5). In general, the overall immune globulin status was slightly greater than normal. DISCUSSION
Validity in evaluation of superimposition disease—Two forms of structural alteration have been considered: (1) the corneal ep ithelial defect, and (2) altered ocular vascu lar permeability ( O V P ) . These syndromes either modify the clinical course of inflam mation or intensify the reaction. In general, these models are inductive. Thus, we have included only patients with unilateral ocular structural change so that the uninvolved eye served as simultaneous control. Further more, this study was limited to syndromes of exogenous microbial origin, so that compara tive culture results or clinical syndromal evaluation could be correlated for both in volved and control eyes. The case was in cluded only when cultures and clinical signs were the same in both eyes.
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We believe this control technique is relia ble in cases where bacteria have been cul tured bilaterally. In such an instance, the pathogenic agent is cultured from both eyes, and yet, only the structurally altered eye (the only identifiable variable) demonstrates corneal or uveal inflammation. In the syndromal cases (upper respiratory viruses), the con trol eye is of less value, for we are presum ing that the secondary sign of conjunctival inflammation indicates bilateral involvement. In either case, the measurements are, at best, semiquantitative; it is plausible that the structurally altered eye has many more mi crobes in contact with it than the control eye. Positive control groups were evaluated to better control some of the nonidentified vari ables. We also evaluated patients with corneal epithelial defects who did not develop corneal or uveal disease. These individuals had similar structural alteration to the exper imental group but showed no evidence of su perimposition of the primary or a secondary infectious agent. All patients included in the altered OVP series were first seen during an inactive phase of corneal inflammation and were identified as inactive by culture or con junctival syndromal signs. At the time of in flammatory exacerbation, a positive culture on clinical identification was made. We have purposely established rigid crite ria for the formulation of this syndrome. Undoubtedly, a great many virus diseases such as herpes simplex,3 unilateral infections of the cornea, and bilateral corneal and uveal disease, may also demonstrate this phenome non. The examples of recurrent infections such as herpes simplex or trachoma,* may represent an example of superimposition of a second agent upon a primary disease which destroys epithelium. Although bilateral cases appear to represent ideal examples of the syndrome once it has been validated, they cannot be used as examples for validating the syndrome. Finally, we have examined the role, if any of immunologie variation in predisposing to ward ocular disease.
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Occurrence and pathogenesis of the ep ithelial defect syndromes—The epithelial de fect syndromes have been subdivided into those of abrasive (mechanical) origin and those of infectious origin. Identification of the former is relatively apparent, since no stromal or anterior chamber disease will oc cur in the absence of an exogenous infec tious agent. This has been demonstrated in the germfree guinea pig. 5 · 6 When a tre phined button of epithelium is removed or nylon suture is placed through the cornea and tied, no neovascularization will develop. In the cases of the epithelial infection, however, superimposition disease is more difficult to validate. In reality, our position is based on the fact that the pattern of corneal inflammation is more typical of the superim posing agent than of the primary infective agent. Patient 4 showed several ball-like in filtrates underlying a zone of denuded ep itheliums which had been infected by herpes simplex. These lesions resembled the limbal ball infiltrates seen in Staph. aureus infec tions. The importance of the corneal epithelium as a barrier to toxic and immune stimuli can not be overestimated.8'9 The age-old hypoth esis that stromal inflammatory reactions oc cur as a result of corneal "irritation" 10 fol lowing epithelial denuding represents an ex tension of the mechanical injury hypothesis but is most likely incorrect. In this hypothe sis, the irritative stimulus is an undeter mined mechanical or environmental stimulus to the cornea.11 Realistically, such an agent disrupts the epithelium, just as the agents described in the corneal abrasion group in this paper. Such a disruption provides a por tal of entry for toxic or immunogenic agents into the corneal stroma or anterior chamber to excite an inflammatory reaction. The in fectious epithelial process is identical to the abrasive process in that both provide an en trance for the secondary agent. Davis and Gamble12 are probably accurate in their inter pretation of this type of reaction as immuno genic.
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Distribution and severity of the subse quent disease depends upon the intrinsic inflammogenic properties of the secondary agent. Generally speaking, if the inflammogenic molecule has a large configuration, the reaction will probably be predominantly cor neal ; if the molecule is small, it will be pre dominantly anterior chamber. This interpre tation is based on experimental findings in rabbit keratitis. 13 Keyhole limpet hemocyanin (1.8 million M. W.) produced an ante rior keratitis free of iritis despite denudation of corneal epithelium, while sulfanilic acid (173 M. W.) produced an iritis which was further enhanced by epithelial denuding. Other investigators14·15 have demonstrated the poor diffusion properties of large mole cules in the corneal stroma. Undoubtedly, the location of the lesion is determined by the site of the primary epithelial destructive process. The actual pathway through which inflam mation is produced is undoubtedly the acute inflammatory pathway.16 If necrotizing toxicity were responsible for the epithelial de fect, more parenchymal destruction of the corneal stroma should be evident since direct cell necrosis would be occurring. The abun dance of gamma globulin in both the corneal stroma and uvea facilitates the initial inflammogenic binding, which leads to complement fixation and polymorphonuclear chemotaxis. Therefore, the reaction is the same as that in central stromal keratitis 2 and peripheral cor neal infiltrative disease,17 although the func tion of the etiologic agent is somewhat dif ferent. Occurrence and pathogenesis of altered OVP syndrome—Only corneal and anterior uveal models of the altered O V P syndromes were included so that we could identify the secondary etiologic agent which produced in flammation. In the corneal syndromes, the principal primary etiologic agent which pro duced unilateral stromal keratitis was the herpes simplex virus. Other primary agents were the bacteria Moraxella and Pseudomonas. During the inactive stage of keratitis,
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the stroma clears with involution of most blood vessels, which become ghost vessels. The corneal epithelium usually remains in tact. Another permanent sequela is scarring which may present as stromal thinning and endothelial disease, principally characterized by pigmentary deposition. In cases initially diagnosed as herpes simplex keratitis, recur rent inflammation was assigned to the superimposition group when a secondary agent such as staphylococcus was identified bilat erally in the absence of a recurrent dendrite. We are aware that such clinical recurrence has been routinely identified as recurrent herpes simplex keratitis.18 · 18 However, it is important to note that in the absence of an epithelial dendrite (in primary or recurrent disciform disease) herpes simplex virus is seldom recovered.20·21 We prefer to incrimi nate the identifiable agent as the cause of the inflammatory recurrence. In the bacterial cases, however, the primary bacterium was never recovered and was discounted as the cause of recurrent inflammation. In the uveitis group, as noted above, the primary cause of anterior uveitis was not identified except in one case. In recurrent monocular iritis, almost every case coincided with a U R I syndrome. The single bacterial case most likely represents an extremely atypical form. The basis for naming this group of dis ease altered ocular vascular permeability syndromes derives from a series of experi ments which demonstrated that permanent structural change within the cornea or uvea produces a change in their vascular perme ability.22 This change was measured as a ki netic phenomenon, i.e., a greater amount of human serum albumin or human gamma globulin accumulates within the tissue extravascular space. Translation of this extravascular protein accumulation into predisposi tion toward inflammatory recurrence is obvi ous : any agent which stimulates the acute in flammatory pathway, i.e., toxic or immune, will now have increased gamma globulin, as nonspecific or specific molecule, with which
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to react. For example,23'24 in the case of an immunogenic stimulus more antibody will be presented in the previously traumatized eye, expediting an adequate antigen-antibody re action to produce active inflammation. As Figure 2 demonstrates, both eyes receive the same amount of stimulus, yet only the eye with altered structure becomes inflamed. In the epithelial defect model, the configu ration of the stimulus is apparently the ma jor determinant of disease ; in this model, structural alteration determines the site of the inflammatory reaction. When corneal vascular permeability has been altered, the cornea reacts ; similarly, if uveal structure has been altered, the uvea reacts. It is impor tant to emphasize, however, that the stimu lating agent must be able to reach the area of structural alteration. In our experience, ei ther the staphylococcus or the URI virus exacerbated corneal disease, while the URI virus usually exacerbated uveitis. As dis cussed in the epithelial defect syndromes, it seems likely that the URI virus configu ration is small enough to pass into the uvea, while the larger staphylococcus components are arrested in the cornea. Immunologie aspects of these syndromes —It is particularly interesting to note that no variation in immune globulin values occur red when the altered epithelium cases were grouped together (Table 4) or evaluated by specific etiology (Table 5). Diminished IgM levels in patients with recalcitrant staphylococcal blepharoconjunctivitis were described previously for another series of patients 25 ; elevated IgM in patients with recurrent iritis was also presented in another context. 17 · 26 Apparently, immune status is not related to the structural defect, although it probably plays an important role in the primary homeostasis between the infectious agent and the host. Once structural change has occur red, this relationship no longer continues to be significant. The clinical significance of the superimpo sition syndromes is relatively self-evident. In the altered epithelium models, treatment
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must focus on the secondary agent to ensure a successful therapeutic result with minimal structural change. Frequently, such treat ment is provided unconsciously by the use of a prophylactic agent such as Gantrisin, after a corneal abrasion. In other cases, however, as in Case 4, presumed herpes simplex keratouveitis, treatment continues for a pro longed period without control of the disease. Optimal therapy can only be achieved when the total disease picture has been de scribed. Recognition of the secondary agent is therefore critical to effective treatment. The importance of this recognition is em phasized when the therapist utilizes simulta neous corticosteroid therapy to minimize permanent structural damage. In such a case, failure to recognize and treat the total etiologic complex may precipitate more serious sequelae. In altered OVP cases, recognition of the secondary causative agent clarifies the im portance of the involved tissue's high suscep tibility to many infectious agents. The tissue is truly an area of locus minoris resistentice.27 Once the pathogenetic mechanism is under stood, the therapeutic objective becomes clearly evident : to prevent further structural damage by controlling active inflammation. This can be achieved most effectively by combined high dosage corticosteroid and specific therapy. SUMMARY
The relationship of altered ocular struc ture to the inflammatory process in the ante rior eye was evaluated in two distinct types of disease which have been defined as struc tural alteration syndromes. The first type is the corneal epithelium defect syndrome, which is produced by abrasion or primary infectious involvement of the epithelium ; the second is the altered ocular vascular perme ability syndrome ( O V P ) , which represents a functional alteration in OVP produced by an adequately severe primary inflammation. In both cases, structural alteration produced by the primary episode markedly affects the
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course of clinical disease by facilitating su perimposition of a secondary agent or pre disposing the eye to subsequent inflamma tory attacks. ACKNOWLEDGMENT
We thank W. K. Hadley, M.D., who evaluated the cultures. REFERENCES
1. Firestone, H. J., Werner, M., and Aronson, S. B. : Thin agarose gel immunologie methods. Am. J. Clin. Path. 51:769, 1969. 2. Aronson, S. B., and Moore, T. E., Jr. : Corticosteroid therapy in central stromal keratitis. Am. J.Ophth. 67:873, 1969. 3. Gunderson, T. : Herpes cornea with special reference to its treatment with strong solution of iodine. Arch. Ophth. 15:22S, 1936. 4. Dawson, C. R., Togni, B., and Moore, T. E., Jr. : Structural changes in chronic herpetic keratitis. Arch. Ophth. 79:740, 1968. 5. McMaster, P. R. B., Aronson, S. B., and Moore, T. E., Jr. : Suture toxicity in the germf ree guinea pig. Arch. Ophth. In press. 6. Aronson, S. B., McMaster, P. R., Moore, T. E., Jr., and Coon, M. A. : Toxicity of the cyanoacrylates. Arch. Ophth. In press. 7. Goodner, E. K. : Routine preoperative and postsurgical management. In Hogan, M. J.: Inter national Ophthalmology Clinics Medical and Sur gical Management of Glaucoma, vol. 3. Boston, Lit tle, Brown, 1963, p. 119. 8. 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. 9. Aronson, S. B., Yamamoto, E. A., Enterline, M. L., and Bedford, M. J. : Mechanisms of the host response in the eye. V. Anterior ocular disease pro duced by non-necrotizing toxic agents. Arch. Ophth. 78:384, 1967. 10. Kaufman, H. E., and Gasset, A. R. : Clinical experience with the epikeratoprosthesis. Am. J. Ophth. 67 :38, 1969. 11. Thomas, C. : The Cornea. Springfield, Illinois, Thomas, 1965, p. 394. 12. Davis, P., and Gamble, C. N. : Staphylococcal hypersensitivity and iritis. Canad. J. Ophth. 4:27, 1969.
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13. 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. 14. Maurice, D. M. : The permeability of the cor nea. In Duke-Elder, S., and Perkins, E. S. (eds.) : The Transparency of the Cornea. Oxford, England, Blackwell Scientific Publications, 1960, p. 67. 15. Stock, F. L., and Aronson, S. B. : Corneal immune globulin distribution. Arch. Ophth. In press. 16. Cochrane, C. B., Ward, P. A., and MullerEberhard, H. J. : Further studies on the chemotactic factor and its formation in vivo. J. Immunol. 11 : 141, 1966. 17. Aronson, S. B., Elliott, J. H , Moore, T. E., Jr., and O'Day, D. M.: Peripheral corneal inflam matory disease. Am. J. Ophth. In press. 18. 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. 19. Jones, B. R. : Prospects in treating viral dis ease of the eye. Tr. Ophth. Soc. U.K. 87 :537, 1967. 20. Jawetz, E., Okumoto, M., and Sonne, M. : Studies on herpes simplex. J. Immunol. 83:486, 1959. 21. Rosebury, T. H. : Microorganisms Indigenous to Man. New York, McGraw-Hill, 1962, p. 435. 22. Aronson, S. B., Fish, M. B., Pollycove, M., and Coon, M. A.: Altered vascular permeability in the eye following inflammation. Arch. Ophth. In press. 23. Gamble, C. N., Aronson, S. B., and Brescia, F. B. : Recurrent immunogenic uveitis. I. The ocu lar Auer reaction. Arch. Ophth. In press. 24. Gamble, C. N., Aronson, S. B., and Brescia, F. B. : Recurrent immunogenic uveitis. II. Pathogenesis of the Auer reaction. Arch. Ophth. In press. 25. Bettman, J. W., Jr., and Aronson, S. B.: Host response in infectious disease: a correlative study between disease severity and circulating immunoglobulins in blepharoconjunctivitis. Arch. Ophth. 82:30, 1969. 26. Aronson, S. B. : The role of nonspecific tests in uveitis. In Clinical Methods in Uveitis. St. Louis, Mosby, 1968, p. 185. 27. Dawson, C. R., Wood, T. R., Rose, L., and Hanna, L.: Experimental inclusion conjunctivitis in man. III. Keratitis and other complications. Arch. Ophth. 78 :341, 1967.
AND
DENIS M. O ' D A Y , M.B.B.S. San Francisco, California
Several factors are responsible for the morphologic variation seen in clinical disease patterns produced by a single etiologic agent. These include differences in the degree of the host response as well as the structural in tegrity of the eye prior to infection. Varia tions in inflammatory severity most likely re flect degree of host response, while atypical clinical pictures are the result of alterations in ocular structure. This study examines the relationship between altered ocular structure and the inflammatory process in the anterior eye.
(Fig. 1-top). Only monocular cases were in cluded in this study so that in every case the other eye served as a control. The epithelial defect in the involved eye provides an en trance for an exogenous inflammogenic stimulus to penetrate the corneal stroma and produce an inflammatory reaction. During the past six years, we have classi fied 23 cases of epithelial structural altera tion. This group includes 16 cases of corneal abrasion and seven cases of primary infec tious epithelial disease (Table 1). The pri mary disease factor, or destruction of cor-
METHODS
Definition of structural alteration syn dromes—For purposes of this study, the cases presented here are defined as structural alteration syndromes. Two distinct types of inflammatory disease emerge in this general category: (1) alteration or disruption of the corneal epithelium caused by abrasion or in fection, and (2) functional alteration in ocu lar vascular permeability (altered O V P ) caused by a previous, adequately severe in flammation. In the first group, the corneal epithelium is usually altered by mechanical abrasion but also may be secondarily altered by primary infectious involvement, e.g., the dendrite of herpes simplex. The subsequent inflammatory patterns are either central or peripheral corneal disease or anterior uveitis
CENTRAL
PERIPHERAL
From the Eye Research Laboratories, Depart SMALL MOLECULAR VARIATION ment of Ophthalmology, and the Clinical Laborato ries, San Francisco General Hospital, University of California School of Medicine, San Francisco, Cal ifornia. Dr. Arsonson is the recipient of a USPHS Research Career Development Award K3 EY 31, 653. This investigation was supported in part by USPHS Grants EY 00246 and EY 00408. Reprint requests to Samuel B. Aronson, M.D., Fig. 1 (Aronson, Moore, and O'Day). Effect of Department of Ophthalmology, Room 1505, San Francisco General Hospital, 1001 Potrero Avenue, structural alteration on clinical morphololgy in cor neal epithelial defects. San Francisco, California 94110. 886
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neal epithelium, was identified on the bases of history (corneal abrasion) and ocular signs on examination (corneal foreign body, contact lens abrasion, epithelial dendrite in herpes simplex, dermatomal configuration of herpes zoster, and superficial punctate keratitis in the adenovirus group). Infection was identified by (1) a positive conjunctival cul ture for pathogenic microbes (Staphylococcus aureus and Moraxella) or indigenous bacteria (Staphylococcus albus and diphtheroids), or (2) if the culture was nega tive, evidence of upper respiratory viral syn dromes ( U R I ) in the community. (This lat ter group was limited only to corneal abra sion syndromes, since separating primary and superimposing infections is extremely difficult.) Only cases with positive bilateral conjunctival cultures or with equivalent clin ical conjunctival signs are included in this series. The technique for bacterial isolation was the standard qualitative technique used in our laboratories, i.e., primary plating of con junctival fornix swab samples on blood and chocolate agar. A positive control group was compiled during the past two years. This group in cludes cases of corneal abrasion without stromal inflammation and infectious cases in TABLE 1 CASES WITH A PRIMARY EPITHELIAL DEFECT AND SECONDARY INFECTIOUS SUPERIMPOSITION
Primary Classification
No. Cases
Mechanical Abrasion: Contact lens 7 Foreign body S Other 4 Total 16 Infectious Etiology: Herpes simplex Adenovirus Herpes zoster Total
3 3 1 7
Secondary Agent Identified Culture 4 4 3 11
Clinical Syndrome
887
which stromal disease was either absent (dendritic keratitis) or typical of the pri mary disease (disciform keratitis). Con junctival cultures were negative in all of these cases (Table 1). Immunologie evaluation, by previously de scribed techniques,1 included: (1) simple protein electrophoresis, (2) qualitative immunoelectrophoresis, (3) quantitative immunoglobulin evaluation for IgA, IgM, and IgG, (4) early IgG determination, and (5) BiC/BiA determination. Patients were grouped by clinical classification for com parison. A second group, altered O V P (Fig. 2 ) , in cludes cases with structural changes resulting from an adequately severe primary inflamma tion of the cornea or uvea. Morphologically, they are characterized by active or inactive corneal neovascularization and clinical evi dence of previous iritis (such signs include pigmentary or fibrinous KP, lens precipitates, anterior and posterior synechiae, and iris atrophy or neovascularization). This predis position phenomenon was studied only in pa tients with unilateral structural alteration so that the uninvolved eye could serve as a si multaneous control. The study was similarly limited to etiologies of exogenous stimuli, since identification techniques for these stim uli are highly reproducible in contrast to those used for endogenous recurrent inflam mation. (It is important to note that recur rent uveitis probably is a manifestation of this same mechanism, but the superimposing stimulus is extremely difficult to identify.) The models studied were divided into cor neal and uveal cases and are depicted in Fig ure 1-B. A total of 31 corneal and 11 uveal cases were studied (Table 2 ) . In every case, the patient had been followed for a period of time in which structural changes were free of active inflammatory signs. When each pa tient presented with inflammatory exacerba tion, exogenous stimulus was identified in both the inflamed and noninflamed eyes, ei ther by identification of the microbe culture or by syndromal pattern, as described above.
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Cases were excluded when cultures or conjunctival clinical signs were not the same in both eyes. A positive control series was also compiled for the altered OVP group (Table 2), which included patients whose (1) initial exciting organism was recultured from the lower conjunctival fornix, or (2) recurrent uveal disease (epithelial dendrite in herpes simplex keratitis) was clinically evident. All patients in broth groups were evalu ated by immunologie testing, as described previously. A gradient comparison was es tablished with control and normal series.
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CORNEAL
STIMULUS
UVEAL
STIMULUS
RESULTS
Abrasion of the corneal epithelium with consequent structural alteration can be traced to several obvious sources: contact lenses, foreign bodies, fingernail scratches, ultraviolet ray destruction, and so forth. Or dinarily, the abrasion is without sequelae. However, if it coincides with conjunctivitis, such an abrasion can provoke stromal infil trate formation, stromal neovascularization, or acute iritis. The prevalent form of this re action occurs in monocular contact lens wearers. In Case 1, the patient suffered a corneal abrasion during an episode of follicular conjunctivitis, which was followed by superficial stromal infiltrate formation. CASE REPORTS
Case 1—A 23-year-old Caucasian woman with myopia had worn a monocular contact lens for over two years. She had had two previous abrasions of the corneal epithelium without infiltrate formation; both resolved within 48 hours after patching. This
TABLE 2 CASES WITH ALTERED OCULAR VASCULAR PERMEABILITY
Infectious Agent
Corneal
Uveal
Pathogenic bacteria Indigenous bacteria Virus Total Control
14 5 12 31 38
3 1 7 11 17
Fig. 2 (Aronson, Moore, and O'Day). Effect of structural alteration on clinical morphology in al tered vascular permeability. time she presented with severe pain and photopho bia of six hours' duration. Her history revealed a severe "cold" 10 days previously which had re solved; however, she noted "itchy eyes" for about three or four days. Slit-lamp examination showed a bilateral follicular conjunctivitis. Her left eye (con tact lens) demonstrated superficial stromal infil trates in a ring-like distribution (Fig. 3-A) ; with fluorescein, a ring of punctate staining was noted (Fig. 3-B). The anterior chamber demonstrated an occasional cell and 1+ flare. The cornea of the right eye showed some fine epithelial infiltrates but other wise was free of disease. Physical examination re vealed preauricular adenopathy and apparent in crease in nasopharyngeal follicle formation. The pa tient was treated with Prednefrin Forte® 1% four times daily for three days. After stromal infiltrates resolved, her left eye was patched for 24 hours, during which time the epithelium healed completely. Two days later she resumed wearing the contact lens and has since remained symptom-free.
The second most frequent reaction is infil trate formation with or without neovascular ization following foreign body penetration of the corneal epithelium. In Case 2, the pa tient demonstrated a peripheral corneal ep ithelial defect from a steel particle embedded in the anterior corneal stroma, surrounded by stromal infiltrate and superficial neovas cularization.
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Fig. 3 (Aronson, Moore, and O'Day). (A) Case 1, subepithelial infiltrates, corresponding to epithelial defects. (B) Same eye, fluorescein stain of left cornea. Note ring-like staining. (C) Case 2, showing infiltrate surrounding the corneal foreign body. (D) Same eye following corticosteroid therapy. Infil trate has disappeared. (E) Case 3, central epithelial ulcer with hypopyon (fluorescein stain). (F) Same eye, fluorescein stain showing remaining punctate areas after corticosteroid therapy. Case 2—A 48-year-old Caucasian man, a machin ist, complained of pain and photophobia of three days' duration. While sanding steel 10 days before, he felt something enter his left eye; since he was free of pain, he did not consult a doctor. Slit-lamp examination revealed a minute piece of steel embed ded in the anterior corneal stroma and piercing the corneal epithelium. Surrounding it was a small "rust ring" approximately 1.0 to 1.5 mm in diame ter. In turn, this was surrounded by a diffuse zone of flocculent white infiltrate. An occasional cell and minimal flare were noted in the anterior chamber.
The upper and lower eyelid margins of both eyes showed marked hypertrophy and some scarring. Collarettes surrounded cilia ; a folliculopapillary re action of the palpebral conjunctiva was also pres ent. His right cornea showed no involvement. Conjunctival cultures of both eyes grew prolific Staph. aureus. To demonstrate the relationship between the su perimposing agent (SA) and the inflammatory re action, the patient was treated with ( 1 ) Prednef rin Forte® 1% drops to the left eye hourly from six A.M. to 10 P.M. for five days; (2) Neosporin®
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drops to each eye were given every two (waking) hours for five days, without removing the foreign body. At the end of this period the infiltrate had resolved; a small rust ring surrounded the foreign body (Fig. 3-D). The foreign body was now re moved; the corneal epithelium regenerated within 48 hours, leaving minimal residual scarring. The pa tient remained free of Staph. aureus for three months but demonstrated recurrence of the orga nism on reculture at that time. However, he was now free of corneal inflammatory signs. Iritis as the presenting anterior segment sign is less frequent. We have seen only six cases with this pattern. Case 3 demonstrated a severe iritis concomitant with follicular conjunctivitis following a fingernail scratch of the cornea. Case 3—A 20-year-old Negro woman had a sev ere URI and "itchy eyes" of one week's duration. The night before she presented, her right cornea was scratched by her infant. On presentation, the patient complained of severe pain and photophobia. Ocular examination revealed bilateral follicular conjuncti vitis. The right eye showed a central epithelial de fect of about 3 to 4 mm (Fig. 3-E). The stroma was free of infiltrate, but the anterior chamber demonstrated a 4 + cellular reaction with hypopyon. The cornea and anterior chamber of her left eye were free of inflammation. On physical examination she demonstrated bilateral preauricular adenopathy and showed a moderate nasopharyngitis. Therapy included (1) subconjunctival corticosteroid injections for two days (Decadron, 0.8 ml, xy locaine 2%, 0.2 ml) and (2) Prednefrin Forte® 1% drops hoursly (six A.M. to 10 P.M.) for five days. By the end of the fifth day, she was completely free of inflammation, although punctate staining was present (Fig. 3-F). All medication was stopped at this time. T h e superimposed infection variant is characterized by superimposition of Staph. aureus or epidermidis upon a viral inflamma tory lesion which had produced a n epithelial defect. I n Case 4, an epithelial dendrite was the initial presenting lesion. Following ep ithelial scraping, superimposition of staphylococcal-induced central stromal ball-like in filtrates plus a severe anterior chamber reac tion occurred. Case 4—A 54-year-old Caucasian man had had a bowel resection for adenocarcinoma of the colon six months before presentation of his ocular lesion. When seen, he demonstrated a dendritic epithelial lesion (Fig. 4-A) which was treated with IUDR hourly for two days and then scraped with a moist cotton applicator. Two days later, there were sev
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eral ball-like infiltrates in the anterior corneal stroma (Fig. 4-B) as well as moderate cells and flare. Re-examination revealed severe hypertrophy of the eyelid margins of both eyes, as well as con junctiva! hyperemia overlying folliculopapillary hy pertrophy. Staph. aureus grew on culture of both eyes. The patient was treated now with daily sub conjunctival corticosteroid injections (Decadron, 0.8 ml, xylocaine, 0.2 ml), topical Prednefrm Forte 1%, hourly drops from six A.M. to 10 P.M., as well as hourly IUDR. At the end of 48 hours, the pa tient demonstrated a hypopyon and stromal ball-like opacities (Fig. 4-C). Review of immunologie tests showed markedly diminished early IgG and IgM (93), and bactériologie results showed the presence of Staph. aureus. (This review indicated a relative immunologie incompetence; the uncon trolled staphylococcal organism had produced a PMN response in spite of subconjunctival cortico steroid therapy. Therefore, it was decided that the number of staphylococcal organisms must first be diminished, and then maximal corticosteroid ther apy resumed.) The patient was treated for two days with hourly Neosporin drops and twice daily Neo sporin ointment scrubs of the eyelid margins without appreciable benefit. He was then restarted on daily subconjunctival corticosteroid injections, hourly corticosteroid drops, and hourly IUDR drops (per above) as well as the Neosporin medication. This time the infection cleared rapidly with complete res olution of the anterior chamber in one week and stromal clearing by 10 days (Fig. 4-D). On the eighth day of Neosporin treatment, the patient dem onstrated a filamentary keratitis. After Gantrisin was substituted for Neosporin, this cleared within 48 hours. He was withdrawn from medication and has remained free of corneal inflammatory signs. (Within two weeks of discontinuation of sulfonamides, however, he showed positive cultures for Staph. aureus and recurrence of blepharoconjunctivitis and has been placed on period Gantrisin scrubs.) Twenty-three cases constitute our overall experience with superimposition of an infec tious agent on epithelial defects (Table 3 ) . These include 18 bacterial superimpositions (13 Staph. aureus, three Staph. albus, two Moraxella) and five probable superimposi tions of a viral agent. As noted earlier, we have evaluated the same types of epithelial lesions in which atypical stromal or anterior chamber disease did not occur (Table 1). By definition none of the cases evaluated showed evidence of concomitant microbial infection. Immune globulin evaluation of the three groups revealed no appreciable differences among (1) superimposition disease, (2) pos-
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Fig. 4 (Aronson, Moore, and O'Day). (A) Case 4, presenting dendrite lesion. (B) Same eye, epi thelial healing. Superficial and deep infiltrates have appeared. (C) Same eye, demonstrating corneal infiltrates plus hypopyon, after corticosteroid and IUDR therapy. (D) Same eye, clearing after combined Neosporin and corticosteroid therapy. (E) Case 5, herpes zoster. (F) Same eye, demonstrating initial corneal clearing after corticosteroid therapy. (G) Same eye, demonstrating severe cornea! infection secondary to Staphylococcus aureus. ( H ) Same eye, demonstrating a clear cornea following keratoplasty.
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TABLE 3 FREQUENCY OF SUPERIMPOSING AGENTS IN EPITHELIAL DENUDATION SYNDROMES
Total Cases
Mechanical abrasion Contact lens Foreign body Other Total Primary infectious etiology Herpes simplex Adenovirus or TRIC agent Herpes zoster Total
Bacteria Staph. aureus
Moraxella
Staph. albus
URI
7 5 4 16
4 3 2 9
1
1
1
1
1 2 2 S
3 3 1 7
2 1 1 4
1
1 1
1
2
itive control, and (3) normal control groups (Table 4 ) . However, if superimposition groups are subclassified by superimposing agent, Staph. aureus patients may demon strate low IgM values, while U R I syn dromes with uveitis show relatively high IgM values (Table 5). The other two groups are within normal limits. Patients with altered OVP of the cornea, which predisposed to inflammatory recur rence, always demonstrated inflammatory exacerbation at the site of corneal neovascularization. Specificity of the microorganism stimulating recurrence may be variable within a given patient. In Case 5, herpes zoster produced the initial inflammatory le sion and recurrent inflammation was traced to Staph. aureus. Case. 5—This 49-year-old Caucasian alcoholic (patient 42 in an earlier report 2 ) was first seen with severe herpes zoster involvement of the left side of his face (Fig. 4 - E ) , as well as demonstrat ing a total cutaneous varicella reaction. On initial presentation he also demonstrated epithelial dendrites, eccentric disciform keratitis, and iritis (Fig. 4 - F ) . Treatment included hourly topical corticosteroid (prednisolone acetate 1%) and topical I U D R for approximately three weeks. His ocular disease was well resolved by the end of one month. The cornea showed some pericentral scarring with lowgrade neovascularization. H e was followed for about one year, when he went on a prolonged alcohol "binge" and was lost from followup for 10 weeks. On reappearing, he demonstrated a severe central corneal ulcer with
marked excavation of the anterior stroma and descemetocele of the left eye (Fig. 4-G). The cornea of the right eye was free of inflammation. How ever, he showed acute congestive conjunctivitis, both bulbar and palpebral, eyelid margin hypertro phy with some bilaterally symmetrical exudate. A profuse growth of Staph. aureus was cultured from each eye. Treatment included subconjunctival corticosteroid injection (as before), left eye, once daily
TABLE 4 C A S E S WITH ALTERED OVP AND A SECONDARY STIMULUS
Secondary Agent Identified Clinical Groupc
r*„' Cases
Corneal neo vascularization Uveal change
10 11
Culture
Clinical Syndrome
8 1
2 10
TABLE 5 CASES WITH ALTERED OVP AND RECURRENCE OF A PRIMARY STIMULUS
Secondary Agent Identified No. Clinical Group Cases Corneal neo vascularization
23
Culture
Clinical Syndrome
5
18
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for five days, prednisolone acetate 1% drops hourly, Neosporin drops hourly, and Neosporin ointment scrubs of the lids twice daily. The right eye re ceived Neosporin drops hourly and Neosporin oint ment eyelid scrubs twice daily. The patient's left cornea perforated on the seventh posttreatment day, and a penetrating keratoplasty was performed on day 11. When last seen 10 months postoperation, he had a clear graft with visual acuity > 20/40 (Fig. 4-H).
The same disease pattern is apparently produced by nonpathogenic bacteria. How ever, such a diagnosis requires a prolific growth on culture of the indigenous agent during active inflammation and absent dur ing disease remission. Recurrent iritis of exogenous origin can occur in the absence of a distinguishable corneal lesion. In Case 6, a monocular iritis re curred at yearly intervals following a severe URI. Case 6—A 23-year-old Negro animal caretaker had a history of five bouts of iritis in his right eye ; his left eye was consistently free of inflammation. Routine ocular examination revealed an occasional pigmentary KP in his right eye; his left anterior chamber was structurally intact. The next winter he presented with severe pain and photophobia in his right eye of one and one-half days' duration. He remarked that his whole family had been sick with the "flu" for about two weeks. He personally had experienced some lassitude but no distinct evidence of URL On ocular examination he demonstrated a marked follicular conjunctivitis in both eyes. In ad dition, his right eye demonstrated moderate cells and flare (2 to 3 + ) , fine KP, and iris and limbal injection. His right cornea was free of active in flammatory signs. The patient was treated with topical corticosteroid drops, Prednefrin Forte® 1% (six A.M. to 10 P.M.) ; his iritis resolved within one week. At no time did the opposite eye show signs of corneal or uveal inflammation, although the conjunctival reac tion was judged to be equivalent to that of the right eye.
We have observed a total of 21 cases of corneal or uveal inflammatory recurrence in which the exacerbating agent differed from the initial exciting agent (Table 4 ) . (In re current monocular uveitis, this is speculative, since the initial agent was identified in only one case.) In eight of 10 corneal cases, the recurrent agents were recovered and in cluded Staph. aureus (5), staphylococcal epidermidis (1), Moraxella (1), and TRIC
893
agent ( 1 ). In the uveal case, the initial iritis followed ocular contusion ; Staph aureus was isolated during the subsequent attack. It must be emphasized that recurrent in flammation also can be produced by reinfec tion with the initial disease-producing mi crobe (Table 5). (We have included only corneal cases. As already noted, the initiat ing agent in monocular iritis was identified so rarely that these cases were classified in the secondary agent group.) Of 16 cases so classified, five bacterial ulcers recurred ( Staphylococcus, 2; Pseudomonas, 2 ; Mo raxella, 1). Eight herpes simplex cases (den dritic ulcer) had subsequent dendrites, and three TRIC cases (smears) were reisolated. In the herpes cases, disease was evident only in the involved eye, while in the bacterial and TRIC group, the microbe was isolated from both eyes. (In our series, herpes simplex is a syndromal diagnosis. Two dendritic patients were cultured bilaterally with isolation of the agent from each eye.) Immunologie testing in these groups re vealed no difference between secondary and primary recurrent agent groups (Table 5). In general, the overall immune globulin status was slightly greater than normal. DISCUSSION
Validity in evaluation of superimposition disease—Two forms of structural alteration have been considered: (1) the corneal ep ithelial defect, and (2) altered ocular vascu lar permeability ( O V P ) . These syndromes either modify the clinical course of inflam mation or intensify the reaction. In general, these models are inductive. Thus, we have included only patients with unilateral ocular structural change so that the uninvolved eye served as simultaneous control. Further more, this study was limited to syndromes of exogenous microbial origin, so that compara tive culture results or clinical syndromal evaluation could be correlated for both in volved and control eyes. The case was in cluded only when cultures and clinical signs were the same in both eyes.
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We believe this control technique is relia ble in cases where bacteria have been cul tured bilaterally. In such an instance, the pathogenic agent is cultured from both eyes, and yet, only the structurally altered eye (the only identifiable variable) demonstrates corneal or uveal inflammation. In the syndromal cases (upper respiratory viruses), the con trol eye is of less value, for we are presum ing that the secondary sign of conjunctival inflammation indicates bilateral involvement. In either case, the measurements are, at best, semiquantitative; it is plausible that the structurally altered eye has many more mi crobes in contact with it than the control eye. Positive control groups were evaluated to better control some of the nonidentified vari ables. We also evaluated patients with corneal epithelial defects who did not develop corneal or uveal disease. These individuals had similar structural alteration to the exper imental group but showed no evidence of su perimposition of the primary or a secondary infectious agent. All patients included in the altered OVP series were first seen during an inactive phase of corneal inflammation and were identified as inactive by culture or con junctival syndromal signs. At the time of in flammatory exacerbation, a positive culture on clinical identification was made. We have purposely established rigid crite ria for the formulation of this syndrome. Undoubtedly, a great many virus diseases such as herpes simplex,3 unilateral infections of the cornea, and bilateral corneal and uveal disease, may also demonstrate this phenome non. The examples of recurrent infections such as herpes simplex or trachoma,* may represent an example of superimposition of a second agent upon a primary disease which destroys epithelium. Although bilateral cases appear to represent ideal examples of the syndrome once it has been validated, they cannot be used as examples for validating the syndrome. Finally, we have examined the role, if any of immunologie variation in predisposing to ward ocular disease.
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Occurrence and pathogenesis of the ep ithelial defect syndromes—The epithelial de fect syndromes have been subdivided into those of abrasive (mechanical) origin and those of infectious origin. Identification of the former is relatively apparent, since no stromal or anterior chamber disease will oc cur in the absence of an exogenous infec tious agent. This has been demonstrated in the germfree guinea pig. 5 · 6 When a tre phined button of epithelium is removed or nylon suture is placed through the cornea and tied, no neovascularization will develop. In the cases of the epithelial infection, however, superimposition disease is more difficult to validate. In reality, our position is based on the fact that the pattern of corneal inflammation is more typical of the superim posing agent than of the primary infective agent. Patient 4 showed several ball-like in filtrates underlying a zone of denuded ep itheliums which had been infected by herpes simplex. These lesions resembled the limbal ball infiltrates seen in Staph. aureus infec tions. The importance of the corneal epithelium as a barrier to toxic and immune stimuli can not be overestimated.8'9 The age-old hypoth esis that stromal inflammatory reactions oc cur as a result of corneal "irritation" 10 fol lowing epithelial denuding represents an ex tension of the mechanical injury hypothesis but is most likely incorrect. In this hypothe sis, the irritative stimulus is an undeter mined mechanical or environmental stimulus to the cornea.11 Realistically, such an agent disrupts the epithelium, just as the agents described in the corneal abrasion group in this paper. Such a disruption provides a por tal of entry for toxic or immunogenic agents into the corneal stroma or anterior chamber to excite an inflammatory reaction. The in fectious epithelial process is identical to the abrasive process in that both provide an en trance for the secondary agent. Davis and Gamble12 are probably accurate in their inter pretation of this type of reaction as immuno genic.
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Distribution and severity of the subse quent disease depends upon the intrinsic inflammogenic properties of the secondary agent. Generally speaking, if the inflammogenic molecule has a large configuration, the reaction will probably be predominantly cor neal ; if the molecule is small, it will be pre dominantly anterior chamber. This interpre tation is based on experimental findings in rabbit keratitis. 13 Keyhole limpet hemocyanin (1.8 million M. W.) produced an ante rior keratitis free of iritis despite denudation of corneal epithelium, while sulfanilic acid (173 M. W.) produced an iritis which was further enhanced by epithelial denuding. Other investigators14·15 have demonstrated the poor diffusion properties of large mole cules in the corneal stroma. Undoubtedly, the location of the lesion is determined by the site of the primary epithelial destructive process. The actual pathway through which inflam mation is produced is undoubtedly the acute inflammatory pathway.16 If necrotizing toxicity were responsible for the epithelial de fect, more parenchymal destruction of the corneal stroma should be evident since direct cell necrosis would be occurring. The abun dance of gamma globulin in both the corneal stroma and uvea facilitates the initial inflammogenic binding, which leads to complement fixation and polymorphonuclear chemotaxis. Therefore, the reaction is the same as that in central stromal keratitis 2 and peripheral cor neal infiltrative disease,17 although the func tion of the etiologic agent is somewhat dif ferent. Occurrence and pathogenesis of altered OVP syndrome—Only corneal and anterior uveal models of the altered O V P syndromes were included so that we could identify the secondary etiologic agent which produced in flammation. In the corneal syndromes, the principal primary etiologic agent which pro duced unilateral stromal keratitis was the herpes simplex virus. Other primary agents were the bacteria Moraxella and Pseudomonas. During the inactive stage of keratitis,
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the stroma clears with involution of most blood vessels, which become ghost vessels. The corneal epithelium usually remains in tact. Another permanent sequela is scarring which may present as stromal thinning and endothelial disease, principally characterized by pigmentary deposition. In cases initially diagnosed as herpes simplex keratitis, recur rent inflammation was assigned to the superimposition group when a secondary agent such as staphylococcus was identified bilat erally in the absence of a recurrent dendrite. We are aware that such clinical recurrence has been routinely identified as recurrent herpes simplex keratitis.18 · 18 However, it is important to note that in the absence of an epithelial dendrite (in primary or recurrent disciform disease) herpes simplex virus is seldom recovered.20·21 We prefer to incrimi nate the identifiable agent as the cause of the inflammatory recurrence. In the bacterial cases, however, the primary bacterium was never recovered and was discounted as the cause of recurrent inflammation. In the uveitis group, as noted above, the primary cause of anterior uveitis was not identified except in one case. In recurrent monocular iritis, almost every case coincided with a U R I syndrome. The single bacterial case most likely represents an extremely atypical form. The basis for naming this group of dis ease altered ocular vascular permeability syndromes derives from a series of experi ments which demonstrated that permanent structural change within the cornea or uvea produces a change in their vascular perme ability.22 This change was measured as a ki netic phenomenon, i.e., a greater amount of human serum albumin or human gamma globulin accumulates within the tissue extravascular space. Translation of this extravascular protein accumulation into predisposi tion toward inflammatory recurrence is obvi ous : any agent which stimulates the acute in flammatory pathway, i.e., toxic or immune, will now have increased gamma globulin, as nonspecific or specific molecule, with which
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to react. For example,23'24 in the case of an immunogenic stimulus more antibody will be presented in the previously traumatized eye, expediting an adequate antigen-antibody re action to produce active inflammation. As Figure 2 demonstrates, both eyes receive the same amount of stimulus, yet only the eye with altered structure becomes inflamed. In the epithelial defect model, the configu ration of the stimulus is apparently the ma jor determinant of disease ; in this model, structural alteration determines the site of the inflammatory reaction. When corneal vascular permeability has been altered, the cornea reacts ; similarly, if uveal structure has been altered, the uvea reacts. It is impor tant to emphasize, however, that the stimu lating agent must be able to reach the area of structural alteration. In our experience, ei ther the staphylococcus or the URI virus exacerbated corneal disease, while the URI virus usually exacerbated uveitis. As dis cussed in the epithelial defect syndromes, it seems likely that the URI virus configu ration is small enough to pass into the uvea, while the larger staphylococcus components are arrested in the cornea. Immunologie aspects of these syndromes —It is particularly interesting to note that no variation in immune globulin values occur red when the altered epithelium cases were grouped together (Table 4) or evaluated by specific etiology (Table 5). Diminished IgM levels in patients with recalcitrant staphylococcal blepharoconjunctivitis were described previously for another series of patients 25 ; elevated IgM in patients with recurrent iritis was also presented in another context. 17 · 26 Apparently, immune status is not related to the structural defect, although it probably plays an important role in the primary homeostasis between the infectious agent and the host. Once structural change has occur red, this relationship no longer continues to be significant. The clinical significance of the superimpo sition syndromes is relatively self-evident. In the altered epithelium models, treatment
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must focus on the secondary agent to ensure a successful therapeutic result with minimal structural change. Frequently, such treat ment is provided unconsciously by the use of a prophylactic agent such as Gantrisin, after a corneal abrasion. In other cases, however, as in Case 4, presumed herpes simplex keratouveitis, treatment continues for a pro longed period without control of the disease. Optimal therapy can only be achieved when the total disease picture has been de scribed. Recognition of the secondary agent is therefore critical to effective treatment. The importance of this recognition is em phasized when the therapist utilizes simulta neous corticosteroid therapy to minimize permanent structural damage. In such a case, failure to recognize and treat the total etiologic complex may precipitate more serious sequelae. In altered OVP cases, recognition of the secondary causative agent clarifies the im portance of the involved tissue's high suscep tibility to many infectious agents. The tissue is truly an area of locus minoris resistentice.27 Once the pathogenetic mechanism is under stood, the therapeutic objective becomes clearly evident : to prevent further structural damage by controlling active inflammation. This can be achieved most effectively by combined high dosage corticosteroid and specific therapy. SUMMARY
The relationship of altered ocular struc ture to the inflammatory process in the ante rior eye was evaluated in two distinct types of disease which have been defined as struc tural alteration syndromes. The first type is the corneal epithelium defect syndrome, which is produced by abrasion or primary infectious involvement of the epithelium ; the second is the altered ocular vascular perme ability syndrome ( O V P ) , which represents a functional alteration in OVP produced by an adequately severe primary inflammation. In both cases, structural alteration produced by the primary episode markedly affects the
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course of clinical disease by facilitating su perimposition of a secondary agent or pre disposing the eye to subsequent inflamma tory attacks. ACKNOWLEDGMENT
We thank W. K. Hadley, M.D., who evaluated the cultures. REFERENCES
1. Firestone, H. J., Werner, M., and Aronson, S. B. : Thin agarose gel immunologie methods. Am. J. Clin. Path. 51:769, 1969. 2. Aronson, S. B., and Moore, T. E., Jr. : Corticosteroid therapy in central stromal keratitis. Am. J.Ophth. 67:873, 1969. 3. Gunderson, T. : Herpes cornea with special reference to its treatment with strong solution of iodine. Arch. Ophth. 15:22S, 1936. 4. Dawson, C. R., Togni, B., and Moore, T. E., Jr. : Structural changes in chronic herpetic keratitis. Arch. Ophth. 79:740, 1968. 5. McMaster, P. R. B., Aronson, S. B., and Moore, T. E., Jr. : Suture toxicity in the germf ree guinea pig. Arch. Ophth. In press. 6. Aronson, S. B., McMaster, P. R., Moore, T. E., Jr., and Coon, M. A. : Toxicity of the cyanoacrylates. Arch. Ophth. In press. 7. Goodner, E. K. : Routine preoperative and postsurgical management. In Hogan, M. J.: Inter national Ophthalmology Clinics Medical and Sur gical Management of Glaucoma, vol. 3. Boston, Lit tle, Brown, 1963, p. 119. 8. 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. 9. Aronson, S. B., Yamamoto, E. A., Enterline, M. L., and Bedford, M. J. : Mechanisms of the host response in the eye. V. Anterior ocular disease pro duced by non-necrotizing toxic agents. Arch. Ophth. 78:384, 1967. 10. Kaufman, H. E., and Gasset, A. R. : Clinical experience with the epikeratoprosthesis. Am. J. Ophth. 67 :38, 1969. 11. Thomas, C. : The Cornea. Springfield, Illinois, Thomas, 1965, p. 394. 12. Davis, P., and Gamble, C. N. : Staphylococcal hypersensitivity and iritis. Canad. J. Ophth. 4:27, 1969.
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13. 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. 14. Maurice, D. M. : The permeability of the cor nea. In Duke-Elder, S., and Perkins, E. S. (eds.) : The Transparency of the Cornea. Oxford, England, Blackwell Scientific Publications, 1960, p. 67. 15. Stock, F. L., and Aronson, S. B. : Corneal immune globulin distribution. Arch. Ophth. In press. 16. Cochrane, C. B., Ward, P. A., and MullerEberhard, H. J. : Further studies on the chemotactic factor and its formation in vivo. J. Immunol. 11 : 141, 1966. 17. Aronson, S. B., Elliott, J. H , Moore, T. E., Jr., and O'Day, D. M.: Peripheral corneal inflam matory disease. Am. J. Ophth. In press. 18. 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. 19. Jones, B. R. : Prospects in treating viral dis ease of the eye. Tr. Ophth. Soc. U.K. 87 :537, 1967. 20. Jawetz, E., Okumoto, M., and Sonne, M. : Studies on herpes simplex. J. Immunol. 83:486, 1959. 21. Rosebury, T. H. : Microorganisms Indigenous to Man. New York, McGraw-Hill, 1962, p. 435. 22. Aronson, S. B., Fish, M. B., Pollycove, M., and Coon, M. A.: Altered vascular permeability in the eye following inflammation. Arch. Ophth. In press. 23. Gamble, C. N., Aronson, S. B., and Brescia, F. B. : Recurrent immunogenic uveitis. I. The ocu lar Auer reaction. Arch. Ophth. In press. 24. Gamble, C. N., Aronson, S. B., and Brescia, F. B. : Recurrent immunogenic uveitis. II. Pathogenesis of the Auer reaction. Arch. Ophth. In press. 25. Bettman, J. W., Jr., and Aronson, S. B.: Host response in infectious disease: a correlative study between disease severity and circulating immunoglobulins in blepharoconjunctivitis. Arch. Ophth. 82:30, 1969. 26. Aronson, S. B. : The role of nonspecific tests in uveitis. In Clinical Methods in Uveitis. St. Louis, Mosby, 1968, p. 185. 27. Dawson, C. R., Wood, T. R., Rose, L., and Hanna, L.: Experimental inclusion conjunctivitis in man. III. Keratitis and other complications. Arch. Ophth. 78 :341, 1967.