CHRONIC CYCLITIS: CORTICOSTEROID THERAPY* William A. Godfrey, MD (BY INVITATION), Ronald E. Smith, MD (BY INVITATION), AND Samuel J. Kimura, MD
BY
IN TWO PREVIOUS PUBLICATIONS, WE DESCRIBED THE CLINICAL FEATURES, COURSE,
and complications of chronic cyclitis in 100 patients.12 Evaluation of therapy in this disease, also known as "pars planitis",34 "peripheral uveitis", 5'6'7 or "vitritis", 8 has been difficult due to the variable course and the lack of controlled clinical studies. Although the original purpose of our study was to determine the clinical features and course of this disease, we have attempted to retrospectively evaluate the effectiveness of corticosteroids in the therapy ofchronic cyclitis. The results suggest that corticosteroids, particularly when given as periocular injections, are of value in the management of selected cases. Periocular corticosteroid therapy deserves further study in a controlled prospective clinical trial. MATERIALS AND METHODS
The methods used in this study are recorded in detail in the previous reports. 1,2 Briefly, the records of patients with the diagnosis of chronic cyclitis were retrieved from the Uveitis Survey files of the Francis I. Proctor Foundation for research in ophthalmology at the University of California Medical Center (San Francisco). All cases had a minimum followup of four years and all met the following criteria: (1) gradual onset in one or both eyes with blurred vision or floaters as the initial symptom, (2) absent or minimal photophobia, (3) minimal anterior chamber reaction, and (4) presence of vitreous cells and opacities. Exudate over the pars plana-ora serrata region inferiorly is a unique feature of this disease and *From the Francis I. Proctor Foundation for Research in Ophthalmology and the Department of Ophthalmology, University of California, San Francisco Medical Center, San Francisco, California. Supported in part by Research Grant Number 2 Pol EY00310 from NIH; USPHS 1 FO 3EY 51530 (Dr. Godfrey) and USPHS EY51583-01 (Dr. Smith). TR. AM. OPHTH. Soc., vol. LXXIV, 1976
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is often present to some degree, particularly in the more severe cases. However, since earlier clinical examinations did not always include scleral depression, the presence ofsuch exudate was not used as a criterion. The first 100 patients available for follow-up underwent a repeat ocular examination by at least two of the authors. The details of the examination technique, grading systems, etc. are recorded elsewhere. 1-2 Data relating to specific therapy and clinical response were obtained from the uveitis files, from the referring ophthalmologists, and from the patients themselves. Since our preliminary analysis indicated that cystoid macular edema and resultant late postcystoid macular degeneration was the leading cause of permanent decreased visual acuity in most cases,'1 2 special attention was given to treatment of macular edema. Therapeutic response was measured by the effect of therapy upon visual acuity and macular edema as documented by clinical and fluorescein angiographic examination. Therapeutic responses were noted as "improved" (improvement of two or more lines on the Snellen chart or retention of 20/30 vision [which was felt to be decreased due to other causes] with decrease in the macular edema by clinical examination or fluorescein angiography) or "unimproved" (no improvement in visual acuity [20/40 or worse] and no change in macular edema or gradual worsening on vision and macular edema by clinical examination or fluorescein angiography). Only cases with adequate treatment history and follow-up examinations and well documented uveitis survey records and/or primary ophthalmologists' records were included for the purpose of analysis. All eyes included in the more detailed study had decreased vision (20/30 or less) on the basis of documented cystoid macular edema or postcystoid macular degeneration. Three groups were selected for evaluation of corticosteroid treatment of macular edema: I. No therapy or topical corticosteroids only. II. Systemic (oral) corticosteroids. (a) low dose (equivalent to adult dose of 15 mg of prednisone or less daily) (b) higher dose (equivalent to adult dose of 20 mg of prednisone or more daily) III. Periocular corticosteroids. Response to therapy in each patient was analyzed one to two months after initiation of the particular mode of therapy (for example, oral corticosteroids. If no improvement, or worsening, in vision and macular edema was noted, that treatment episode was considered a failure ("unim-
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proved"). If another mode of therapy was then initiated (for example, periocular steroids), this eye was then considered a separate treatment episode and the response to this mode of therapy evaluated after an additional one to two months of observation. Complications felt to be related to corticosteroid therapy, rather than the natural course of the disease, were documented. RESULTS
The 100 cases re-examined and analyzed during this study represented almost half of the 250 cases of chronic cyclitis seen at the Uveitis Clinic between January 1954 and January 1969. There were 44 females and 56 males with the age of onset from 4 years to 58 years of age and a median and arithmetic mean of 23 years. All patients were white with the exception of one black. The interval from the onset of symptoms to the final examination at the Uveitis Clinic ranged from 4 to 26 years with a median and arithmetic mean of 10.5 years. Most cases were bilateral or became bilateral in the followup period so that a total of 182 eyes were affected. Classification of disease course, severity, duration, and complications are subjects detailed in the previous reports. 1.2 THERAPY
Most eyes (94%) received corticosteroid therapy of some type, usually by more than one route during the course of their disease. Topical corticosteroids were used in 68% (124 eyes) of all the involved eyes. Systemic (oral) corticosteroids were employed in 76% (138 eyes) and periocular injections were administered in 43% (78 eyes). Eleven eyes had received no treatment of any kind. Most eyes received more than one type of therapy. Seventy-four eyes with macular edema and representing a total of 107 treatment episodes had adequately documented records for this more detailed study of therapeutic response: Group I - 7 eyes; Group II - 62 eyes treated; Group III - 38 eyes treated. GROUP I - NO THERAPY OR TOPICAL CORTICOSTEROIDS ONLY (TABLE I)
Although 11 eyes received no treatment, there were an additional 16 eyes that received only topical corticosteroids. Of these 27 eyes that received no treatment or only topical corticosteroids, macular edema was noted in 9 of these eyes but decreased vision was present in only 7 eyes. At final
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examination, 8 eyes had decreased vision (20/40 or less). In 7 eyes the decreased vision was due to postcystoid macular degeneration. The only other eye with decreased vision had a nuclear cataract felt to be unrelated to corticosteroids or the disease process. GROUP II - SYSTEMIC (ORAL) CORTICOSTEROIDS (TABLE I)
The task of evaluating the 62 treatment episodes of macular edema in Group 2 was difficult due to the great variation of treatment schedules used by the various ophthalmologists. In an attempt to present this data more clearly, these were divided into those that received low dosages of oral corticosteroids and those that received higher therapeutic range dosages of oral corticosteroids as defined below. A. Low Dosage: Of 22 eyes receiving adult equivalent of 15 mg of prednisone or less daily, 9 (41%) improved and 13 (59%) worsened or remained unchanged. B. Higher Dosage: of 40 eyes receiving an adult equivalent of 20 mg of prednisone or more daily, 24 eyes (60%) improved and 16 eyes (40%) remained unchanged or worsened. In many instances, the disease course varied with recurrence of the macular edema requiring resumption of corticosteroids. GROUP III - PERIOCULAR INJECTIONS (TABLE I)
Thirty-eight eyes had single or multiple injections of periocular corticosteroids. Twenty-seven eyes (71%) improved. Improvement was temporary in many cases, requiring repeated injections over a period of months. Eleven eyes (29%) worsened or remained unchanged. Eighteen (47%) had a visual acuity of 20/30 or better at final examination. COMPLICATIONS OF CORTICOSTEROID THERAPY (TABLE II)
Cataracts, usually posterior subcapsular or posterior cortical, developed in 76 eyes (42%). Many of these were felt to be on the basis of long term corticosteroid usage but this was impossible to document.9 Glaucoma was observed in 15 eyes. This was probably related to corticosteroid therapy in 11 eyes. Pressure elevations developed following cataract extraction in two eyes and in association with retinal detachment in two additional eyes. Only six eyes required medication for glaucoma at the time of the final examination. No accidental intraocular injections of corticosteroids were reported. Systemic side effects of oral corticosteroids including Cushingoid facies, osteoporosis, mental changes, and gastrointestinal problems, etc. were noted as a result of the treatment of 12 eyes.
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Godfrey, Smith, and Kimura DISCUSSION
Various therapeutic regimens have been employed in patients with chronic cyclitis. Although corticosteroids have been the mainstay of therapy and have been recommended by most authorities,10'11 no controlled clinical trials have been performed to document these clinical impressions. The use ofimmunosuppressive and cytotoxic agents has been reported by some investigators but these are usually reserved for intractable cases which fail to respond to corticosteroids. A limited amount of success has been ascribed to the use of such potentially dangerous drugs. 12'13'14'15"16 Cryotherapy to the pars plana and peripheral retina has been performed but the results are inconclusive especially with reference to the effect of this procedure on existing macular edema. 17 The current study was not designed as a clinical trial of corticosteroids but rather as a retrospective analysis of 100 cases to obtain data regarding the course of the disease." 2 With this information, it was hoped that appropriate clinical therapeutic trials could be designed which would take into consideration the varying course of this disease. Although not a controlled study, the present analysis of the effect of corticosteroid therapy in this group of patients suggests a definite role for corticosteroids in the treatment of selected cases of chronic cyclitis. Since most of the eyes in our series received some form of corticosteroid therapy-topical, periocular, or systemic-statistical appraisal of the efficacy of corticosteroids versus no therapy was impossible. There were 27 eyes which had no therapy or only topical corticosteroids. Since it is reasonable to assume that topical corticosteroids would have little or no effect on vitreous inflammation or cystoid macular edema, these untreated or "minimally" treated eyes provide a group of cases with which to compare more heavily medicated eyes. It was obvious, from the course of these 27 eyes, that if macular edema affecting vision did not develop, the signs and symptoms gradually decreased with minimal visual impairment or other complications. On the other hand, if macular edema with decreased vision was present and persisted, the eyes rarely regained normal vision but progressed to development of chronic macular changes and permanent damage to central visual function. The implication of this observation in these "untreated" eyes, is that the major indication for treatment in chronic cyclitis is the presence of cystoid macular edema with decreased visual acuity. This is further supported by our previously reported causes of long term vision morbidity in the 100 cases of chronic cyclitis. 12 We found that of all eyes with final vision of 20/40 or worse at the last examination, 74% had macular changes compatible with postcystoid macular edema and consistent with the
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decrease in vision. Vitreous opacities were rarely dense enough to for this kind of decreased visual acuity at the final examination and other causes of decreased vision (such as cataracts, retinal detachment, etc.) were infrequent. Assuming that cystoid macular edema with decreased vision is the primary indication for therapy, the question remains as to whether periocular or systemic administration of corticosteroids has any beneficial effect. The nature of our follow-up information, the multiple treatment schedules employed by the various referring ophthalmologists, and the total lack of controls preclude any definitive analysis of this problem in the
account
present series.
Despite these obvious limitations, the rapid improvement of visual acuity with reduction in macular edema and vitreous opacities in selected cases following periocular injection or higher dosage oral systemic corticosteroids (Table I) suggests the value of such therapy. In numerous eyes, the lack of persistent therapy over a period of years or lack of patient cooperation seemed to coincide with a poor final visual acuity with chronic macular changes. In five well documented cases, for example, the ophthalmologist and patient persevered in a well planned therapeutic and
followup management plan with subsequent minimal changes in the macula due to the recurrent macular edema, and good visual acuity was retained for several years. These cases were later lost to follow-up and received no additional corticosteroid therapy and, at the time of the final examination, had marked decrease in vision due to permanent postcystoid macular changes. Until the etiology of this chronic eye disease is determined, therapy is merely suppressive at best, allowing the disease to run its course without the serious complications of macular edema and degeneration. We have the definite clinical impression based on observations made on this large TABLE I: THERAPEUTIC RESPONSE IN EYES WITH DECREASED VISION DUE TO MACULAR EDEMA'
Response No. Eyes With Unimproved Decreased Vision Improved Corticosteroids 7 (100%) 0 7 (0%) I. No treatment or topical only II. Systemic oral corticosteroid 9 (41%) 13 (59%) 22 A. Low dosage2 16 (40%) 24 (60%) 40 B. Higher dosage3 11 (29%) 27 (71%) 38 III. Periocular injection4 1. Response documented one to two months after treatment. Multiple treatment episodes often occurred in a single eye. 2. Low dose: Equivalent of 15 mgm of prednisone daily or less. 3. Higher dose: Equivalent to 20 mgm of prednisone daily or more. 4. One or more injection per treatment episode.
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series of patients, that corticosteroids, especially via periocular administration, have a beneficial effect on the course of the disease in many patients. Currently, it is our practice to inject long-acting corticosteroid preparations, such as depot methylprednisolone or triamcinalone peri-
ocularly at intervals of three to five weeks.18 Careful monitoring of visual acuity, macular edema, intraocular pressure, and vitreous reaction is mandatory. If the macula "dries up" clinically and angiographically, therapy is discontinued, even if vision does not improve. Regular evaluations are continued for the detection of the frequently recurring macular edema. Eyes with cystoid macular edema, either clinically or on fluorescein studies, but with normal vision, are not treated. Although this paper is restricted to the evaluation of corticosteroid therapy, dilation of the pupils is indicated if there is a tendency toward synechiae formation, particularly if Koeppe nodules are present. Occasionally, patients without macular edema may complain of marked impairment of visual function due to the myriad of vitreous cells and opacities during active stages of the disease. These cases frequently respond to a sub-Tenon injection of corticosteroids. Such therapy, however, is cautiously administered and never continued on a long term basis since the vitreous usually clears over a period of years with no further complications related to the vitreous itself. Complications of corticosteroid therapy in our series included the usual problems related to this drug (Table II). Glaucoma and cataracts were observed. Undoubtedly, many instances of cataract formation were related to the chronic inflammatory process itself and not the corticosteroids. Although inadvertant intraocular injection of periocular corticosteroids has been reported with disastrous complication, 19.20 this was not encounTABLE II: COMPLICATIONS OF CORTICOSTEROID THERAPY (173 EYES)
Complications Cataract*
Number of Eyes
Percentage of Eyes
76 11 0 0 0 8 4
44%
Glaucoma 6% Accidental intraocular injection 0 Orbital fat atrophy 0 Extraocular muscle palsy 0 Cushingoid appearance** 20% Other systemic effects of steroids** 10% *Relation to corticosteroid therapy often unclear. **Percentage of eyes being treated in which this complication occurred = number of eyes being treated in which this complication was noted] 100 total number eyes being treated with highe'r dose corticosteroids J
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tered in our series. However, this must always be considered, especially when multiple injections must be given for a period of years. Similarly, no extraocular muscle palsies or orbital fat atrophy were found in our cases. Avoiding injections directly over muscle insertions usually prevents the former complication. SUMMARY
It is our definite clinical impression that corticosteroid therapy, especially when given by the periocular route, has a place in the management of chronic cyclitis. Certainly the information obtained by this retrospective study supplies enough justification for clinical trials of periocular corticosteroids designed specifically as prospective controlled studies. REFERENCES 1. Smith RE, Godfrey WA, Kimura SJ: Chronic cyclitis. I. Course and visual prognosis.
Trans Am Acad Ophthalmol Otolaryngol 77:760-778, 1973. 2. Smith RE, Godfrey WA, Kimura SJ: Complications ofchronic cyclitis. AmJ Ophthalmol
(in press). 3. Welch RB, Maumanee AE, Wahlen HE: Peripheral posterior segment inflammation, vitreous opacities and edema of the posterior pole: Pars planitis. Arch Ophthalmol 64:540-549, 1960. 4. Maumanee AE: Clinical entities in "Uveitis": An approach to the study of intraocular
inflammation. Am J Ophthalmol 69:1-27, 1970. 5. Schepens CL: L'inflammation de le region de l'ora serrata et ses sequelles. Bull Soc Fr Ophtalmol 63:114-125, 1950. 6. Brockhurst RJ, Schepens CL, Okamura ID: Uveitis: III. Peripheral uveitis: Pathogenesis, etiology and treatment. Am J Ophthalmol 51:19-26, 1961. 7. Brockhurst RJ, Schepens CL: Uveitis: IV. Peripheral uveitis: The complication of retinal detachment. Arch Ophthalmol 80:747-753, 1968. 8. Gass JDM: Fluorescein angiography in endogenous intraocular inflammation. In Aronson S., et al (eds.). Clinical Methods in Uveitis, St. Louis, C.V. Mosby, 1968 pp 202-229. 9. Spaeth GL, vonSallmann L: Corticosteroids and cataracts. Int Ophthalmol Clin 6:915-928, 1966. 10. Hogan MJ, Kimura SJ, O'Connor GR: Peripheral retinitis and chronic cyclitis in children. Trans Ophthalmol Soc UK 85:39, 1965. 11. Kimura SJ, Hogan MJ: Chronic cyclitis. Arch Ophthalmol 71:193-201, 1964. 12. Godfrey WA, Epstein WV, O'Connor GR, Kimura SJ, Hogan MJ, Nozik RA: The use of chlorambucil in intractable idiopathic uveitis. Am J Ophthalmol 78:415-429, 1974. 13. Gills JP, Buckley CE: Oral cyclophosphamide in the treatment of uveitis. Trans Am Acad Ophthalmol Otolaryngol 74:505-507, 1970. 14. Wong VG: Immunosuppressive therapy of ocular inflammatory diseases. Arch Ophthalmol 81:628-637, 1969. 15. Newell FW, Krill AE: Treatment of uveitis with azathioprine (Imuran). Trans Ophthalmol Soc UK 87:499-511, 1967. 16. Newell FW, Krill AE, Thomson A: The treatment of uveitis with 6-mercaptopurine. Am J Ophthalmol 61:1250-1255, 1966.
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17. Aaberg TM, Cesarz TG, Flicldnger MD: Treatment of peripheral uveoretinitis by cryotherapy. Am J Ophthalmol 75:685-688, 1973. 18. Nozik RA: Periocular injection of steroids. Trans Am Acad Ophthalmol Otolaryngol 76:695, 1972. 19. Giles CL: Bulbar perforation. Am J Ophthalmol 77:438441, 1974. 20. Schlaegel TF Jr, Wilson FM: Accidental intraocular injection of depocorticosteroids. Trans Am Acad Ophthalmol Otolaryngol 78:847-855, 1974.
DISCUSSION
DR ROBERT B. WELCH. I am indeed honored to have been asked to open the discussion of the paper by Drs Godfrey, Smith, and Kimura on the treatment of chronic cyclitis by corticosteroid therapy. It was 16 years ago this month that I submitted for publication a paper entitled Peripheral posterior segment inflammation, vitreous opacities and edema of the posterior pole with a subtitle of "Pars Planitis" (Arch Ophthalmol 64:540-549, 1960). Few people remember the lead title to the paper, yet the term, pars planitis, has stuck in spite of causing disconcertion to grammarian and purist alike. For an affront to their sensitivities I apologize, yet the term was suggested to focus attention to the fact that this was an entity that required indirect ophthalmoscopy and scleral depression to fully appreciate. With this method of examination a clinical syndrome was recognized consisting of exudation into the vitreous base which was usually inferior and often formed a dense "snowbank" over the ora and pars plana. Nodular exudations occurred at the ora serrata, on the surface of the peripheral retina, and often extended into vitreous. There was sheathing of peripheral retinal vessels and the vitreous contained many fine opacities. Edema of the disc, peripapillary retina, and macula occurred in a high percentage of the cases. It was a disease of the young with 67% under the age of 25 and occurred bilaterally in over 90% of the cases. In the present report, the authors report their experience with 100 patients with chronic cyclitis and attempt to evaluate the effectiveness of steroid therapy in their management. They recognize a variety of names for this entity and state that it has been referred to as "pars planitis", "peripheral uveitis", and "vitritis" by various investigators. They also accept that exudate over the pars plana-ora serrata region is a unique feature of this disease, yet the presence of such exudate was not used as one of their criteria, since the early cases did not have scleral depression as a part of the examination. With the advent of fluorescein fundus evaluation, macular edema was found to be due to cystoid maculopathy from leakage of the perifoveal capillaries. The course of this disease is often chronic with remissions and exacerbations regardless of the mode of therapy. Some cases do indeed respond to steroids initially, but many show decrease in vision while still on steroids and others improve when steroids are discontinued. Suggested therapy for pars planitis has included steroids, antimetabolites, cryotherapy, diathermy, and even the discontinuance of cigarette smoking.
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The authors recognize that since most eyes in their study received some form of steroid therapy and many received more than one type, evaluation of treatment modality versus no treatment would be impossible. Their Group I consists of 11 eyes with no treatment and 16 eyes with topical steroids only. These they combine as their no treatment group and 26% had decreased vision of 20/40 or worse at final evaluation due to cystoid macular changes. Thus, 74% escaped visual decrease from posterior pole edema. Group III consists of patients who received periocular steroid injections, often in multiple treatment episodes and 47% of these eyes had 20/30 vision at final examination. Since planitis is a chronic disease, it would be of interest to compare the length of follow-up of the two groups. The authors recognize the pitfalls of chronic steroid therapy and thus suggest short term periocular injections as a possible mode of therapy. They suggest a prospective controlled study to fully evaluate this situation. Although it would be interesting to know just how many of their 100 patients received scleral depression to fulfill a criterion of this entity that I consider important, we should remember that even with scleral depression the "so-called experts" often disagree over the diagnosis of pars planitis in a particular case. A snowbank per se does not make the diagnosis of pars planitis any more than lipid deposition in retina makes the diagnosis ofCoats' disease. An old toxocara infection may indeed show a snowbank. Green and Maumenee have pathological material on eyes with "snowbanks" but none oftheir histological specimens are from patients with active disease. The fact remains that we have no more idea of what pars planitis is today than when I recorded that infamous term 16 years ago. DR WILLIAM RICHARD GREEN. Mr President, Mr Secretary, members and guests. We have recently studied the histopathologic features of eyes from seven patients with this entity followed for various periods of time, mostly by Dr A. E. Maumenee. In five instances the eyes were obtained surgically and in two of the cases both eyes were obtained postmortem. Most of these eyes showed the changes toward the end of the spectrum of the disease-including secondary glaucoma, cataract, and phthisis bulbi in two cases. We were particularly interested to determine what the nature ofthe "snowbank" material is, and we resorted to histochemical and electron microscopic studies. In those eyes with earlier manifestations of the disease, we found that the snowbank opacity in the vitreous consisted of posteriorly detached and condensed vitreous
with variable degrees of proliferation of the nonpigmented ciliary epithelium, vascular contributions from the retina, and astrocytic proliferation extending from the peripheral retina into the vitreous. There was also production of new collagen with large diameter (approximately 240 k) fibrils. In none of these eyes was significant uveal inflammation observed. An unanticipated finding was the presence of a retinal phlebitis in all five of the cases that did not have phthisis bulbi. The presence of the phlebitis was thought to be of some significance in that it may be a contributing factor in the development of the cystoid macular edema and disk edema. With this inflammatory
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component involving the retinal vessels, one might expect a beneficial response to corticosteroid therapy. Thank you. DR IRVING LEOPOLD. I would like to mention a patient who was seen by Dr Michael Hogan some 20 years ago when he was Visiting Professor at the Wills Hospital. She was a 20-year-old woman who had developed pars planitis and over the subsequent years no etiology could be found. She then had frequent attacks of macular edema which responded very nicely each time to systemic corticosteroids. It was found when the corticosteroids were stopped her macular edema would flare, so she was kept on a maintenance dose of 2.5 mg ofprednisone a week on the average over a 15-year period. Approximately two years ago she came in with a little lump in her groin which when biopsied was found to be a lymphosarcoma. Although this may not be any more than a post hoc ergo propter hoc type of fallacious reasoning-that is "something which follows after an event or drug does not necessarily mean it happened because of it" but this long-standing immunosuppressive therapy could possibly lead to malignancy, usually of the blood dyscrasia type, so that when we do use our steroids in this fashion all of these patients ought to be watched for this entity as well as other complications which may develop. It might be enlightening to analyze the 100 patients in the study presented today for their status in regard to immunocompetence, blood dyscrasia, etc., at the present time as well as the cause of death of those who are no longer with us. DR WILLIAM GODFREY. I would like to thank Doctor Welch for his comments and for his complimentary and contributing discussion. I would like to thank the other discussants for their additional comments and insight into this area of ocular inflammation and I would like to thank you for allowing me the opportunity of presenting this paper.
BY
IN TWO PREVIOUS PUBLICATIONS, WE DESCRIBED THE CLINICAL FEATURES, COURSE,
and complications of chronic cyclitis in 100 patients.12 Evaluation of therapy in this disease, also known as "pars planitis",34 "peripheral uveitis", 5'6'7 or "vitritis", 8 has been difficult due to the variable course and the lack of controlled clinical studies. Although the original purpose of our study was to determine the clinical features and course of this disease, we have attempted to retrospectively evaluate the effectiveness of corticosteroids in the therapy ofchronic cyclitis. The results suggest that corticosteroids, particularly when given as periocular injections, are of value in the management of selected cases. Periocular corticosteroid therapy deserves further study in a controlled prospective clinical trial. MATERIALS AND METHODS
The methods used in this study are recorded in detail in the previous reports. 1,2 Briefly, the records of patients with the diagnosis of chronic cyclitis were retrieved from the Uveitis Survey files of the Francis I. Proctor Foundation for research in ophthalmology at the University of California Medical Center (San Francisco). All cases had a minimum followup of four years and all met the following criteria: (1) gradual onset in one or both eyes with blurred vision or floaters as the initial symptom, (2) absent or minimal photophobia, (3) minimal anterior chamber reaction, and (4) presence of vitreous cells and opacities. Exudate over the pars plana-ora serrata region inferiorly is a unique feature of this disease and *From the Francis I. Proctor Foundation for Research in Ophthalmology and the Department of Ophthalmology, University of California, San Francisco Medical Center, San Francisco, California. Supported in part by Research Grant Number 2 Pol EY00310 from NIH; USPHS 1 FO 3EY 51530 (Dr. Godfrey) and USPHS EY51583-01 (Dr. Smith). TR. AM. OPHTH. Soc., vol. LXXIV, 1976
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is often present to some degree, particularly in the more severe cases. However, since earlier clinical examinations did not always include scleral depression, the presence ofsuch exudate was not used as a criterion. The first 100 patients available for follow-up underwent a repeat ocular examination by at least two of the authors. The details of the examination technique, grading systems, etc. are recorded elsewhere. 1-2 Data relating to specific therapy and clinical response were obtained from the uveitis files, from the referring ophthalmologists, and from the patients themselves. Since our preliminary analysis indicated that cystoid macular edema and resultant late postcystoid macular degeneration was the leading cause of permanent decreased visual acuity in most cases,'1 2 special attention was given to treatment of macular edema. Therapeutic response was measured by the effect of therapy upon visual acuity and macular edema as documented by clinical and fluorescein angiographic examination. Therapeutic responses were noted as "improved" (improvement of two or more lines on the Snellen chart or retention of 20/30 vision [which was felt to be decreased due to other causes] with decrease in the macular edema by clinical examination or fluorescein angiography) or "unimproved" (no improvement in visual acuity [20/40 or worse] and no change in macular edema or gradual worsening on vision and macular edema by clinical examination or fluorescein angiography). Only cases with adequate treatment history and follow-up examinations and well documented uveitis survey records and/or primary ophthalmologists' records were included for the purpose of analysis. All eyes included in the more detailed study had decreased vision (20/30 or less) on the basis of documented cystoid macular edema or postcystoid macular degeneration. Three groups were selected for evaluation of corticosteroid treatment of macular edema: I. No therapy or topical corticosteroids only. II. Systemic (oral) corticosteroids. (a) low dose (equivalent to adult dose of 15 mg of prednisone or less daily) (b) higher dose (equivalent to adult dose of 20 mg of prednisone or more daily) III. Periocular corticosteroids. Response to therapy in each patient was analyzed one to two months after initiation of the particular mode of therapy (for example, oral corticosteroids. If no improvement, or worsening, in vision and macular edema was noted, that treatment episode was considered a failure ("unim-
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proved"). If another mode of therapy was then initiated (for example, periocular steroids), this eye was then considered a separate treatment episode and the response to this mode of therapy evaluated after an additional one to two months of observation. Complications felt to be related to corticosteroid therapy, rather than the natural course of the disease, were documented. RESULTS
The 100 cases re-examined and analyzed during this study represented almost half of the 250 cases of chronic cyclitis seen at the Uveitis Clinic between January 1954 and January 1969. There were 44 females and 56 males with the age of onset from 4 years to 58 years of age and a median and arithmetic mean of 23 years. All patients were white with the exception of one black. The interval from the onset of symptoms to the final examination at the Uveitis Clinic ranged from 4 to 26 years with a median and arithmetic mean of 10.5 years. Most cases were bilateral or became bilateral in the followup period so that a total of 182 eyes were affected. Classification of disease course, severity, duration, and complications are subjects detailed in the previous reports. 1.2 THERAPY
Most eyes (94%) received corticosteroid therapy of some type, usually by more than one route during the course of their disease. Topical corticosteroids were used in 68% (124 eyes) of all the involved eyes. Systemic (oral) corticosteroids were employed in 76% (138 eyes) and periocular injections were administered in 43% (78 eyes). Eleven eyes had received no treatment of any kind. Most eyes received more than one type of therapy. Seventy-four eyes with macular edema and representing a total of 107 treatment episodes had adequately documented records for this more detailed study of therapeutic response: Group I - 7 eyes; Group II - 62 eyes treated; Group III - 38 eyes treated. GROUP I - NO THERAPY OR TOPICAL CORTICOSTEROIDS ONLY (TABLE I)
Although 11 eyes received no treatment, there were an additional 16 eyes that received only topical corticosteroids. Of these 27 eyes that received no treatment or only topical corticosteroids, macular edema was noted in 9 of these eyes but decreased vision was present in only 7 eyes. At final
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examination, 8 eyes had decreased vision (20/40 or less). In 7 eyes the decreased vision was due to postcystoid macular degeneration. The only other eye with decreased vision had a nuclear cataract felt to be unrelated to corticosteroids or the disease process. GROUP II - SYSTEMIC (ORAL) CORTICOSTEROIDS (TABLE I)
The task of evaluating the 62 treatment episodes of macular edema in Group 2 was difficult due to the great variation of treatment schedules used by the various ophthalmologists. In an attempt to present this data more clearly, these were divided into those that received low dosages of oral corticosteroids and those that received higher therapeutic range dosages of oral corticosteroids as defined below. A. Low Dosage: Of 22 eyes receiving adult equivalent of 15 mg of prednisone or less daily, 9 (41%) improved and 13 (59%) worsened or remained unchanged. B. Higher Dosage: of 40 eyes receiving an adult equivalent of 20 mg of prednisone or more daily, 24 eyes (60%) improved and 16 eyes (40%) remained unchanged or worsened. In many instances, the disease course varied with recurrence of the macular edema requiring resumption of corticosteroids. GROUP III - PERIOCULAR INJECTIONS (TABLE I)
Thirty-eight eyes had single or multiple injections of periocular corticosteroids. Twenty-seven eyes (71%) improved. Improvement was temporary in many cases, requiring repeated injections over a period of months. Eleven eyes (29%) worsened or remained unchanged. Eighteen (47%) had a visual acuity of 20/30 or better at final examination. COMPLICATIONS OF CORTICOSTEROID THERAPY (TABLE II)
Cataracts, usually posterior subcapsular or posterior cortical, developed in 76 eyes (42%). Many of these were felt to be on the basis of long term corticosteroid usage but this was impossible to document.9 Glaucoma was observed in 15 eyes. This was probably related to corticosteroid therapy in 11 eyes. Pressure elevations developed following cataract extraction in two eyes and in association with retinal detachment in two additional eyes. Only six eyes required medication for glaucoma at the time of the final examination. No accidental intraocular injections of corticosteroids were reported. Systemic side effects of oral corticosteroids including Cushingoid facies, osteoporosis, mental changes, and gastrointestinal problems, etc. were noted as a result of the treatment of 12 eyes.
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Godfrey, Smith, and Kimura DISCUSSION
Various therapeutic regimens have been employed in patients with chronic cyclitis. Although corticosteroids have been the mainstay of therapy and have been recommended by most authorities,10'11 no controlled clinical trials have been performed to document these clinical impressions. The use ofimmunosuppressive and cytotoxic agents has been reported by some investigators but these are usually reserved for intractable cases which fail to respond to corticosteroids. A limited amount of success has been ascribed to the use of such potentially dangerous drugs. 12'13'14'15"16 Cryotherapy to the pars plana and peripheral retina has been performed but the results are inconclusive especially with reference to the effect of this procedure on existing macular edema. 17 The current study was not designed as a clinical trial of corticosteroids but rather as a retrospective analysis of 100 cases to obtain data regarding the course of the disease." 2 With this information, it was hoped that appropriate clinical therapeutic trials could be designed which would take into consideration the varying course of this disease. Although not a controlled study, the present analysis of the effect of corticosteroid therapy in this group of patients suggests a definite role for corticosteroids in the treatment of selected cases of chronic cyclitis. Since most of the eyes in our series received some form of corticosteroid therapy-topical, periocular, or systemic-statistical appraisal of the efficacy of corticosteroids versus no therapy was impossible. There were 27 eyes which had no therapy or only topical corticosteroids. Since it is reasonable to assume that topical corticosteroids would have little or no effect on vitreous inflammation or cystoid macular edema, these untreated or "minimally" treated eyes provide a group of cases with which to compare more heavily medicated eyes. It was obvious, from the course of these 27 eyes, that if macular edema affecting vision did not develop, the signs and symptoms gradually decreased with minimal visual impairment or other complications. On the other hand, if macular edema with decreased vision was present and persisted, the eyes rarely regained normal vision but progressed to development of chronic macular changes and permanent damage to central visual function. The implication of this observation in these "untreated" eyes, is that the major indication for treatment in chronic cyclitis is the presence of cystoid macular edema with decreased visual acuity. This is further supported by our previously reported causes of long term vision morbidity in the 100 cases of chronic cyclitis. 12 We found that of all eyes with final vision of 20/40 or worse at the last examination, 74% had macular changes compatible with postcystoid macular edema and consistent with the
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decrease in vision. Vitreous opacities were rarely dense enough to for this kind of decreased visual acuity at the final examination and other causes of decreased vision (such as cataracts, retinal detachment, etc.) were infrequent. Assuming that cystoid macular edema with decreased vision is the primary indication for therapy, the question remains as to whether periocular or systemic administration of corticosteroids has any beneficial effect. The nature of our follow-up information, the multiple treatment schedules employed by the various referring ophthalmologists, and the total lack of controls preclude any definitive analysis of this problem in the
account
present series.
Despite these obvious limitations, the rapid improvement of visual acuity with reduction in macular edema and vitreous opacities in selected cases following periocular injection or higher dosage oral systemic corticosteroids (Table I) suggests the value of such therapy. In numerous eyes, the lack of persistent therapy over a period of years or lack of patient cooperation seemed to coincide with a poor final visual acuity with chronic macular changes. In five well documented cases, for example, the ophthalmologist and patient persevered in a well planned therapeutic and
followup management plan with subsequent minimal changes in the macula due to the recurrent macular edema, and good visual acuity was retained for several years. These cases were later lost to follow-up and received no additional corticosteroid therapy and, at the time of the final examination, had marked decrease in vision due to permanent postcystoid macular changes. Until the etiology of this chronic eye disease is determined, therapy is merely suppressive at best, allowing the disease to run its course without the serious complications of macular edema and degeneration. We have the definite clinical impression based on observations made on this large TABLE I: THERAPEUTIC RESPONSE IN EYES WITH DECREASED VISION DUE TO MACULAR EDEMA'
Response No. Eyes With Unimproved Decreased Vision Improved Corticosteroids 7 (100%) 0 7 (0%) I. No treatment or topical only II. Systemic oral corticosteroid 9 (41%) 13 (59%) 22 A. Low dosage2 16 (40%) 24 (60%) 40 B. Higher dosage3 11 (29%) 27 (71%) 38 III. Periocular injection4 1. Response documented one to two months after treatment. Multiple treatment episodes often occurred in a single eye. 2. Low dose: Equivalent of 15 mgm of prednisone daily or less. 3. Higher dose: Equivalent to 20 mgm of prednisone daily or more. 4. One or more injection per treatment episode.
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series of patients, that corticosteroids, especially via periocular administration, have a beneficial effect on the course of the disease in many patients. Currently, it is our practice to inject long-acting corticosteroid preparations, such as depot methylprednisolone or triamcinalone peri-
ocularly at intervals of three to five weeks.18 Careful monitoring of visual acuity, macular edema, intraocular pressure, and vitreous reaction is mandatory. If the macula "dries up" clinically and angiographically, therapy is discontinued, even if vision does not improve. Regular evaluations are continued for the detection of the frequently recurring macular edema. Eyes with cystoid macular edema, either clinically or on fluorescein studies, but with normal vision, are not treated. Although this paper is restricted to the evaluation of corticosteroid therapy, dilation of the pupils is indicated if there is a tendency toward synechiae formation, particularly if Koeppe nodules are present. Occasionally, patients without macular edema may complain of marked impairment of visual function due to the myriad of vitreous cells and opacities during active stages of the disease. These cases frequently respond to a sub-Tenon injection of corticosteroids. Such therapy, however, is cautiously administered and never continued on a long term basis since the vitreous usually clears over a period of years with no further complications related to the vitreous itself. Complications of corticosteroid therapy in our series included the usual problems related to this drug (Table II). Glaucoma and cataracts were observed. Undoubtedly, many instances of cataract formation were related to the chronic inflammatory process itself and not the corticosteroids. Although inadvertant intraocular injection of periocular corticosteroids has been reported with disastrous complication, 19.20 this was not encounTABLE II: COMPLICATIONS OF CORTICOSTEROID THERAPY (173 EYES)
Complications Cataract*
Number of Eyes
Percentage of Eyes
76 11 0 0 0 8 4
44%
Glaucoma 6% Accidental intraocular injection 0 Orbital fat atrophy 0 Extraocular muscle palsy 0 Cushingoid appearance** 20% Other systemic effects of steroids** 10% *Relation to corticosteroid therapy often unclear. **Percentage of eyes being treated in which this complication occurred = number of eyes being treated in which this complication was noted] 100 total number eyes being treated with highe'r dose corticosteroids J
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tered in our series. However, this must always be considered, especially when multiple injections must be given for a period of years. Similarly, no extraocular muscle palsies or orbital fat atrophy were found in our cases. Avoiding injections directly over muscle insertions usually prevents the former complication. SUMMARY
It is our definite clinical impression that corticosteroid therapy, especially when given by the periocular route, has a place in the management of chronic cyclitis. Certainly the information obtained by this retrospective study supplies enough justification for clinical trials of periocular corticosteroids designed specifically as prospective controlled studies. REFERENCES 1. Smith RE, Godfrey WA, Kimura SJ: Chronic cyclitis. I. Course and visual prognosis.
Trans Am Acad Ophthalmol Otolaryngol 77:760-778, 1973. 2. Smith RE, Godfrey WA, Kimura SJ: Complications ofchronic cyclitis. AmJ Ophthalmol
(in press). 3. Welch RB, Maumanee AE, Wahlen HE: Peripheral posterior segment inflammation, vitreous opacities and edema of the posterior pole: Pars planitis. Arch Ophthalmol 64:540-549, 1960. 4. Maumanee AE: Clinical entities in "Uveitis": An approach to the study of intraocular
inflammation. Am J Ophthalmol 69:1-27, 1970. 5. Schepens CL: L'inflammation de le region de l'ora serrata et ses sequelles. Bull Soc Fr Ophtalmol 63:114-125, 1950. 6. Brockhurst RJ, Schepens CL, Okamura ID: Uveitis: III. Peripheral uveitis: Pathogenesis, etiology and treatment. Am J Ophthalmol 51:19-26, 1961. 7. Brockhurst RJ, Schepens CL: Uveitis: IV. Peripheral uveitis: The complication of retinal detachment. Arch Ophthalmol 80:747-753, 1968. 8. Gass JDM: Fluorescein angiography in endogenous intraocular inflammation. In Aronson S., et al (eds.). Clinical Methods in Uveitis, St. Louis, C.V. Mosby, 1968 pp 202-229. 9. Spaeth GL, vonSallmann L: Corticosteroids and cataracts. Int Ophthalmol Clin 6:915-928, 1966. 10. Hogan MJ, Kimura SJ, O'Connor GR: Peripheral retinitis and chronic cyclitis in children. Trans Ophthalmol Soc UK 85:39, 1965. 11. Kimura SJ, Hogan MJ: Chronic cyclitis. Arch Ophthalmol 71:193-201, 1964. 12. Godfrey WA, Epstein WV, O'Connor GR, Kimura SJ, Hogan MJ, Nozik RA: The use of chlorambucil in intractable idiopathic uveitis. Am J Ophthalmol 78:415-429, 1974. 13. Gills JP, Buckley CE: Oral cyclophosphamide in the treatment of uveitis. Trans Am Acad Ophthalmol Otolaryngol 74:505-507, 1970. 14. Wong VG: Immunosuppressive therapy of ocular inflammatory diseases. Arch Ophthalmol 81:628-637, 1969. 15. Newell FW, Krill AE: Treatment of uveitis with azathioprine (Imuran). Trans Ophthalmol Soc UK 87:499-511, 1967. 16. Newell FW, Krill AE, Thomson A: The treatment of uveitis with 6-mercaptopurine. Am J Ophthalmol 61:1250-1255, 1966.
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17. Aaberg TM, Cesarz TG, Flicldnger MD: Treatment of peripheral uveoretinitis by cryotherapy. Am J Ophthalmol 75:685-688, 1973. 18. Nozik RA: Periocular injection of steroids. Trans Am Acad Ophthalmol Otolaryngol 76:695, 1972. 19. Giles CL: Bulbar perforation. Am J Ophthalmol 77:438441, 1974. 20. Schlaegel TF Jr, Wilson FM: Accidental intraocular injection of depocorticosteroids. Trans Am Acad Ophthalmol Otolaryngol 78:847-855, 1974.
DISCUSSION
DR ROBERT B. WELCH. I am indeed honored to have been asked to open the discussion of the paper by Drs Godfrey, Smith, and Kimura on the treatment of chronic cyclitis by corticosteroid therapy. It was 16 years ago this month that I submitted for publication a paper entitled Peripheral posterior segment inflammation, vitreous opacities and edema of the posterior pole with a subtitle of "Pars Planitis" (Arch Ophthalmol 64:540-549, 1960). Few people remember the lead title to the paper, yet the term, pars planitis, has stuck in spite of causing disconcertion to grammarian and purist alike. For an affront to their sensitivities I apologize, yet the term was suggested to focus attention to the fact that this was an entity that required indirect ophthalmoscopy and scleral depression to fully appreciate. With this method of examination a clinical syndrome was recognized consisting of exudation into the vitreous base which was usually inferior and often formed a dense "snowbank" over the ora and pars plana. Nodular exudations occurred at the ora serrata, on the surface of the peripheral retina, and often extended into vitreous. There was sheathing of peripheral retinal vessels and the vitreous contained many fine opacities. Edema of the disc, peripapillary retina, and macula occurred in a high percentage of the cases. It was a disease of the young with 67% under the age of 25 and occurred bilaterally in over 90% of the cases. In the present report, the authors report their experience with 100 patients with chronic cyclitis and attempt to evaluate the effectiveness of steroid therapy in their management. They recognize a variety of names for this entity and state that it has been referred to as "pars planitis", "peripheral uveitis", and "vitritis" by various investigators. They also accept that exudate over the pars plana-ora serrata region is a unique feature of this disease, yet the presence of such exudate was not used as one of their criteria, since the early cases did not have scleral depression as a part of the examination. With the advent of fluorescein fundus evaluation, macular edema was found to be due to cystoid maculopathy from leakage of the perifoveal capillaries. The course of this disease is often chronic with remissions and exacerbations regardless of the mode of therapy. Some cases do indeed respond to steroids initially, but many show decrease in vision while still on steroids and others improve when steroids are discontinued. Suggested therapy for pars planitis has included steroids, antimetabolites, cryotherapy, diathermy, and even the discontinuance of cigarette smoking.
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The authors recognize that since most eyes in their study received some form of steroid therapy and many received more than one type, evaluation of treatment modality versus no treatment would be impossible. Their Group I consists of 11 eyes with no treatment and 16 eyes with topical steroids only. These they combine as their no treatment group and 26% had decreased vision of 20/40 or worse at final evaluation due to cystoid macular changes. Thus, 74% escaped visual decrease from posterior pole edema. Group III consists of patients who received periocular steroid injections, often in multiple treatment episodes and 47% of these eyes had 20/30 vision at final examination. Since planitis is a chronic disease, it would be of interest to compare the length of follow-up of the two groups. The authors recognize the pitfalls of chronic steroid therapy and thus suggest short term periocular injections as a possible mode of therapy. They suggest a prospective controlled study to fully evaluate this situation. Although it would be interesting to know just how many of their 100 patients received scleral depression to fulfill a criterion of this entity that I consider important, we should remember that even with scleral depression the "so-called experts" often disagree over the diagnosis of pars planitis in a particular case. A snowbank per se does not make the diagnosis of pars planitis any more than lipid deposition in retina makes the diagnosis ofCoats' disease. An old toxocara infection may indeed show a snowbank. Green and Maumenee have pathological material on eyes with "snowbanks" but none oftheir histological specimens are from patients with active disease. The fact remains that we have no more idea of what pars planitis is today than when I recorded that infamous term 16 years ago. DR WILLIAM RICHARD GREEN. Mr President, Mr Secretary, members and guests. We have recently studied the histopathologic features of eyes from seven patients with this entity followed for various periods of time, mostly by Dr A. E. Maumenee. In five instances the eyes were obtained surgically and in two of the cases both eyes were obtained postmortem. Most of these eyes showed the changes toward the end of the spectrum of the disease-including secondary glaucoma, cataract, and phthisis bulbi in two cases. We were particularly interested to determine what the nature ofthe "snowbank" material is, and we resorted to histochemical and electron microscopic studies. In those eyes with earlier manifestations of the disease, we found that the snowbank opacity in the vitreous consisted of posteriorly detached and condensed vitreous
with variable degrees of proliferation of the nonpigmented ciliary epithelium, vascular contributions from the retina, and astrocytic proliferation extending from the peripheral retina into the vitreous. There was also production of new collagen with large diameter (approximately 240 k) fibrils. In none of these eyes was significant uveal inflammation observed. An unanticipated finding was the presence of a retinal phlebitis in all five of the cases that did not have phthisis bulbi. The presence of the phlebitis was thought to be of some significance in that it may be a contributing factor in the development of the cystoid macular edema and disk edema. With this inflammatory
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component involving the retinal vessels, one might expect a beneficial response to corticosteroid therapy. Thank you. DR IRVING LEOPOLD. I would like to mention a patient who was seen by Dr Michael Hogan some 20 years ago when he was Visiting Professor at the Wills Hospital. She was a 20-year-old woman who had developed pars planitis and over the subsequent years no etiology could be found. She then had frequent attacks of macular edema which responded very nicely each time to systemic corticosteroids. It was found when the corticosteroids were stopped her macular edema would flare, so she was kept on a maintenance dose of 2.5 mg ofprednisone a week on the average over a 15-year period. Approximately two years ago she came in with a little lump in her groin which when biopsied was found to be a lymphosarcoma. Although this may not be any more than a post hoc ergo propter hoc type of fallacious reasoning-that is "something which follows after an event or drug does not necessarily mean it happened because of it" but this long-standing immunosuppressive therapy could possibly lead to malignancy, usually of the blood dyscrasia type, so that when we do use our steroids in this fashion all of these patients ought to be watched for this entity as well as other complications which may develop. It might be enlightening to analyze the 100 patients in the study presented today for their status in regard to immunocompetence, blood dyscrasia, etc., at the present time as well as the cause of death of those who are no longer with us. DR WILLIAM GODFREY. I would like to thank Doctor Welch for his comments and for his complimentary and contributing discussion. I would like to thank the other discussants for their additional comments and insight into this area of ocular inflammation and I would like to thank you for allowing me the opportunity of presenting this paper.
