ANTERIOR AND HYPOPYON*

BY Leonardo P. DAlessandro, MD (BY INVITATION), DavidJ. Forster, MD (BY INVITATION), AND Narsing A. Rao, MD

INTRODUCTION ANTERIOR UVEITIS IS THE MOST COMMON FORM OF INTRAOCULAR INFLAM- mation seen by the ophthalmologist. When severe, anterior uveitis can result in the formation of hypopyon within the anterior chamber. Hypo- pyon in endogenous anterior uveitis has been related classically to Beh- get's syndrome.1-3 A few investigators have also reported the occasional observation of hypopyon in association with herpetic keratouveitis,4'5 Reiter's syndrome, and ankylosing spondylitis.6-8 We undertook a study to determine the incidence, as well as the most common causes, of hypopyon in patients with acute endogenous anterior uveitis.

MATERIALS AND METHODS Medical records of all patients with endogenous anterior uveitis referred to our institution from 1984 to 1990 were reviewed. For each patient, information was obtained regarding the presence or absence ofhypopyon as determined by slit lamp examination, as well as medical history, review of systems, and results of laboratory investigations performed. Laboratory investigations had been performed using a tailored ap- proach and included any or all of the following: tests for antinuclear antibodies, angiotensin-converting enzyme, rheumatoid factor, and HLA- B27 and HLA-B5; syphilis serologic studies, tuberculin skin testing; chest radiography; and radiologic examination of the lumbosacral spine. Patients with concurrent posterior uveitis ( or choroiditis), as well those who had recently undergone ocular surgery or sustained pene- trating trauma to the eye, were excluded. *From the A. Ray Irvine Jr, MD, Ophthalmic Pathology Laboratory of the Doheny Eye Institute, and the Department of , University of Southern California, Los Angeles. This study was supported in part by core grant EY03040 from the National Eye Institute, Bethesda, and by an unrestricted grant from Research to Prevent Blindness, Inc, New York.

TR. AM. OPHTH. Soc. vol. LXXXIX, 1991 304 Rao et al

RESULTS A total of216 cases ofanterior uveitis were identified. Ofthese, 155 were classified as acute, endogenous anterior uveitis (AAU) in that the symp- toms had an acute onset and the inflammation persisted for less than 3 months. These patients also met the other criteria for inclusion in this study. Hypopyon developed in 11 (7.1%) of the 155 patients. The hypo- pyon occupied from 5% to 15% ofthe anterior chamber: in five patients it filled about 5%, in another five it filled 10%, and in the remaining patient it filled about 15% of the anterior chamber. The characteristics of the 11 patients who had hypopyon secondary to anterior uveitis are summarized in Table I. The age ofthe patients ranged from 10 to 63 years (mean, 37 years), and there was no apparent predilec- tion for either sex. Overall, a slight majority (55%) ofpatients were white, but hypopyon was seen in other races as well (three Orientals, one black, and one Hispanic). In all cases the hypopyon was unilateral, and in none were there "mutton fat" keratic precipitates. The inflammation was acute in all cases and recurrent in eight. The hypopyon occurred in the first episode of acute uveitis in only four cases; in the remaining seven, the hypopyon was seen with recurrent episodes of AAU. No patient had a recurrent hypo- pyon. Four ofthe 11 patients with hypopyon also had fibrinous membrane formation in the anterior chamber. In two cases there was a pronounced spillover of inflammatory cells into the anterior vitreous. Visual acuity at the time of the hypopyon was 20/200 or less in six patients and 20/100 to 20/50 in the other five. Ten of the patients were treated with topical corticosteroids, topical mydriatic agents, and systemic (oral) corticoster- oids or deposteroid injection(s) in sub-Tenon's space. The remaining patient received topical steroids every 2 hours and mydriatics only. Visual acuity in all patients improved by an average of 5 Snellen lines. After 2 weeks of treatment, visual acuity was 20/40 or better in ten patients and 20/70 in one. In all cases the hypopyon disappeared within the first 10 days of treatment. In terms of HLA association, 9 (82%) of the 11 patients with AAU in whom hypopyon developed were positive for HLA-B27. Two of these HLA-B27-positive patients had Reiter's syndrome and one had ankylosing spondylitis; all three of these patients were male. The remaining six patients positive for HLA-B27 had no documented systemic illness at the time oflast examination; four ofthese patients did complain oflower back pain, but radiologic examinations of the lumbosacral region were normal. Of the patients negative for HLA-B27 who had hypopyon, one patient, aged 63, had mixed connective tissue disease (MCTD) and another, aged Anterior Uveitis 305

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4- + G 306 Rao et al 40, had idiopathic uveitis; both patients were white women. In both cases hypopyon occurred during recurrent episodes of uveitis. At the time of the hypopyon, visual acuity was 20/200 in the patient with MCTD and 20/70 in the patient with idiopathic uveitis. Both patients were treated with topical steroids, mydriatic agents, and systemic (oral) corticosteroid; after 2 weeks of treatment, visual acuity improved to 20/70 in the patient with MCTD (this patient also had a history of ) and to 20/40 in the patient with idiopathic uveitis. Complicatidns were relatively uncommon in this group ofpatients, but follow-up was not long enought to make a definitive statement regarding long-term sequelae. Posterior synechiae developed in three patients. Bilateral posterior subcapsular and early de- veloped in a 10-year-old Vietnameses boy (case 3) who had a 4-year history of recurrent bilateral iridocyclitis. This boy was diagnosed as having ankylosing spondylitis, and he had a brother who also had ankylosing spondylitis. This patient underwent bilateral pars plana lensectomy and , and at last examination visual acuity was 20/60 in each eye. Of the 155 cases of AAU, 62 (40%) were positive for HLA-B27 and 93 were negative for HLA-B27; of the 11 patients with hypopyon, 9 were positive for HLA-B27 and only 2 were negative. Thus, the incidence of hypopyon was 14.5% among AAU patients who were positive for HLA- B27, but only 2.2% among AAU patients who were negative for HLA- B27. Chi-square analysis of these two groups revealed significantly in- creased occurrence of hypopyon in the HLA-B27 group (P < 0.003). Two patients with Behcet's syndrome and anterior uveitis were included in the group of 155 patients, but hypopyon did not develop in these patients.

DISCUSSION In this series of patients with anterior uveitis, the most common cause of hypopyon was HLA-B27-related iridocyclitis, accounting for 82% (9 of 11) of the cases. However, the incidence of hypopyon among HLA-B27- positive patients with AAU was 14.5%. All nine patients had characteristic features of HLA-B27-related anterior uveitis: they were young to middle- aged and had acute, unilateral or alternating unilateral, severe episodes of anterior inflammation. Four patients also had associated fibrinous mem- brane formation in the anterior chamber, but none of the patients had mutton fat keratic precipitates. These findings (including the absence of keratic precipitates) have been described by several investigators7-16 and are typical ofHLA-B27-related AAU; however, none ofthese investigators found as high an incidence of hypopyon in association with the anterior uveitis as was noted in our study. Anterior Uveitis 307 Typically, our patients had been treated initially with intensive (every 1 to 2 hours) topical corticosteroids for their acute anterior uveitis; how- ever, in spite of this treatment, hypopyon developed, and the majority of the patients required supplemental systemic corticosteroids (generally 60 to 80 mg of prednisone daily) to bring the inflammation under control. The exception was one patient who responded well to intensive topical treatment. In all cases, the hypopyon resolved after several days of systemic corticosteroid treatment. None of our patients, including the two with Behcet's syndrome, had recurrent hypopyon, although this is the classic pattern seen in patients with this syndrome.1 Two other patients, excluded from this series because they also had evidence of retinal vasculitis, had Behcet's syndrome with the characteristic recurrent hypopyon. Overall, there did not appear to be a sex predilection among the patients in whom hypopyon developed. However, among patients who were positive for HLA-B27, hypopyon was seen more frequently in males than in females (ratio, 2:1). Furthermore, all three patients who had hypopyon associated with an HLA-B27-related systemic disease were male. Of interest in our patients was the wide distribution of cases with respect to race or ethnic origin. HLA-B27-related iridocyclitis is typically described as occurring in whites. However, ofour 11 cases ofhypopyon in HLA-B27-related AAU, only 4 patients (44%) were white; 3 patients (33%) were Oriental, 1 (11%) was black, and 1 was Hispanic. In addition, among the 53 HLA-B27-positive patients who did not have hypopyon, 37 (70%) were white, 8 (15%) were Hispanic, 5 (9%) were Oriental, 2 (4%) were black, and 1 (2%) was Asian Indian. To our knowledge, this racial distribu- tion has not been reported in previous series.8 13,16 Our study did not include long-term follow-up, so no conclusions can be drawn regarding the long-term prognosis of these patients. In the short-term, however, all but one of our patients maintained good visual acuity with no evidence ofcataracts or . The one exception was a child (case 3), who had a more severe course, with frequent recurrences over several years. Bilateral posterior subcapsular cataracts and early band keratopathy developed in one eye, and the patient subsequently under- went bilateral pars plana lensectomy and vitrectomy. Visual acuity at the time of the last visit was 20/60 in each eye. The data concerning prognosis in HLA-B27-related anterior uveitis have been somewhat contradictory. Some investigators have reported a good prognosis,11"5 while others have not.10 1 In a recent report, Roth- ova and associates13 suggested that the visual outcome and incidence of complications are probably related to the number of recurrences of the 308 Rao et al uveitis. Our study of 53 patients with HLA-B27-related anterior uveitis without hypopyon seems to support this conclusion. Of the six patients (11%) in this group who had a final visual acuity of20/60 or worse, all had eight or more recurrences of AAU and, ultimately, posterior subcapsular or cystoid . The present study indicates that HLA-B27-related iridocyclitis is the most common cause of hypopyon in patients with endogenous anterior uveitis. While HLA-B27-related AAU is seen most frequently in whites, it can also be seen in patients of other racial groups, including blacks, Hispanics, and Orientals (Table I). Patients presenting with hypopyon certainly need to be questioned about any history of trauma, surgery, intravenous drug abuse, or immunosuppression that may predispose to infectious , as well as about a history of oral or genital ulcers, or dermatologic manifestations, which may be seen in patients with Beh9get's syndrome. However, patients also need to be questioned regarding a history oflower back pain (ankylosing spondylitis), arthritis or urethritis (Reiter's syndrome), and gastrointestinal abnormalities (inflam- matory bowel disease), since any of these entities may be present in patients who are positive for HLA-B27. All patients, regardless of race, who present with hypopyon secondary to anterior uveitis should be evaluated for the presence of the HLA-B27 haplotype, and other appro- priate investigations (eg, sacroiliac films, rheumatologic evaluation) should be obtained based on the patient's history. Patients can be coun- seled that, overall, the prognosis for visual acuity is good but that fre- quent recurrences increase the risk of complications and of diminished visual acuity. Longer follow-up is needed on a large series ofpatients who have uveitis with hypopyon to determine how their prognosis compares with that of patients with AAU who do not have hypopyon.

REFERENCES 1. Mishima S, Masuda K, Izawa Y, et al: Behget's disease in Japan: Ophthalmologic aspects. Trans Am Ophthalmol Soc 1979; 77:225-279. 2. Michelson JB, Chisari FV: Behget's disease. Surv Ophthalmol 1982; 26:190-203. 3. Colvard DM, Robertson DM, O'Duffy JD: The ocular manifestations of Behget's dis- ease. Arch Ophthalmol 1977; 95:1813-1817. 4. Dawson CR, Togni B: Herpes simplex eye infections: Clinical manifestations, patho- genesis and management. Surv Ophthalmol 1976; 21:121-135. 5. Thygeson P: The changing characteristics of herpes zoster keratouveitis. Trans Pac Coast Oto-Ophthalmol Soc 1974; 55:129-136. 6. Lee DA, Barker SM, Su WPD, et al: The clinical diagnosis of Reiter's syndrome: Ophthalmic and nonophthalmic aspects. Ophthalmology 1986; 93:350-356. 7. Rosenbaum JT: Characterization ofuveitis associated with spondyloarthritis. J Rheuma- tol 1989; 16:792-796. 8. Ehlers N, Kissmeyer-Nielsen F, Kjerbye KE, et al: HL-A 27 in acute and chronic uveitis. Lancet 1974; 1:99. Anterior Uveitis 309

9. Mapstone R, Woodrow JC: HL-A 27 and acute anterior uveitis. BrJ Ophthalmrol 1975; 59:270-275. 10. Scharf J, Scharf J, Haim T, et al: Relation between HLA-B27 and clinical features in patients with acute anterior uveitis. Ann Ophthalmol 1982; 14:488-490. 11. Wakefield D, Easter J, Penny R: Clinical features of HLA-B27 anterior uveitis. Aust J Ophthalmol 1984; 12:191-196. 12. Beckingsale AB, Davies J, Gibson JM, et al: Acute anterior uveitis, ankylosing spondyli- tis, back pain, and HLA-B27. Br J Ophthalmol 1984; 68:741-745. 13. Rothova A, van Veenendaal WG, Linssen A, et al: Clinical features of acute anterior uveitis. Am J Ophthalmol 1987; 103:137-145. 14. Fearnley IR, Spalton DJ, Smith SE: Anterior segment fluorophotometry in acute anterior uveitis. Arch Ophthalmol 1987; 105:1550-1555. 15. Rothova A, Kijlstra A, Buitenhuis HJ, et al: HLA-B27 associated uveitis a distinct clinical entity?, in KM Saari (ed): Uveitis Update. Amsterdam, Excerpta Medica, 1984, pp 91-95. 16. Brewerton DA, Caffrey M, Nicholls A, et al: Acute anterior uveitis and HL-A 27. Lancet 1973; 2:994-996.

DISCUSSION DR DAVID KNOX. I would like to direct my remarks first to the data presented by Doctor DAlessandro and associates and second to my concepts of the utility of testing for HLA-B27. From 1984 to 1990, 216 patients with anterior uveitis were examined at the Uveitis Service at the University of Southern California, Los Angeles. Sixty-one patients had chronic inflammation, and 155 had acute inflammation. Of the 155 patients with acute inflammation, 62 (40%) had HLA-B27 tissue type. Nine (14%) of these had hypopyon. In contrast, only 2 (2.2%) of the 93 patients who were negative for HLA-B27 had hypopyon. There was no racial predominance, although there were slightly more men than women in this particular patient group. Most had recurrent episodes of iritis. These 11 patients were managed with corticosteroid: 1 with only topical agents, 7 with oral agents, and 3 with periocular injections. All improved in the period of observation. The paper does not present long-term follow-up information. It does not mention steroid glaucoma as a complication of periocular steroid injection. I have found that deposteroids are a particular risk. The authors urge us to obtain HLA tissue typing in our patients with anterior uveitis. They also urge us to search for histories of trauma, surgery, infections, immunosuppression, oral or genital aphthous ulcers, skin disease, gastrointestinal problems, urethritis, and arthritis affecting either the lower back or peripheral joints. They urge that x-rays of the sacroiliac joint and hematologic evaluation be performed. In addition to these historical features, I would encourage all ophthalmologists to add diet, allergy and psychosocial histories to their evaluation of patients with ocular inflammation. I also test patients for intestinal parasites. At this point in this discussion, I raise the question, "How important is it to determine HLA-B27?" At our hospital, for the general clinician, the immunoge- 310 Rao et al netics laboratory does only a full battery of all HLA types, which costs $250. This takes a week, unless someone asks for urgent testing, which can be done in 1 day. I do not routinely obtain HLA tissue typing in patients with ocular inflamma- tion. It does not help me manage the patients' acute problem. In the drafts of the paper sent to me, the authors did not emphasize the advantage of knowing the HLA-B27 tissue type in the management of their patients' ocular problems. One of my reasons for low emphasis of HLA-B27 tissue typing is that I cannot do anything about it. I am enough ofa surgeon to want to apply specific action to a problem. Ifthere were specific therapy for HLA-B27-associated uveitis, the often- associated ankylosing spondylitis, or Reiter's syndrome, then HLA-B27 could rise from the level of a research tool to one of clinical utility. There are, however, advantages for HLA-B27 tissue typing. I am indebted to my co-worker, Doctor A. Jabs, for the following aspects, which are considered important: classification, prognosis, choice of anti-inflammatory drug, and to support the diagnosis of either Reiter's syndrome or ankylosing spondylitis. We also know that patients with Crohn's disease who have peripheral arthritis and iritis are more likely to have HLA-B27 tissue type. HLA tissue typing has not helped us in our understanding of the pathophysiology of recurrent acute iritis. In summary, Doctor D'Alessandro and associates have shown us that in a patient with hypopyon, there is an increased risk that HLA-B27 tissue typing will be positive. It may allow us to reach a diagnosis of ankylosing spondylitis or Reiter's syndrome and in this way perhaps guide the management of those particular diseases. It does not seem to help us in the management of the acute ocular inflammation. My final question is directed to whether the prevalence of HLA-B27-associated anterior uveitis in this series is similar to the 1987 report (AmJ Ophthalmol 1987; 103:131-136) in which 24 (14%) of 167 anterior uveitis patients had either HLA- B27-positive tissue type or Reiter's syndrome. DR RICHARD C. TROUTMAN. Just a quick question Doctor Rao. Did you consider Lyme disease, since you are from the other end of the country where this is not prevalent, and do you have it in your exclusion list? Did you perform specific serologic testing in any of your cases? DR NARSING A. RAo. I do appreciate Doctor Knox raising some controversy regarding HLA-B27 testing, as well as summarizing the data. There are four reasons why HLA-B27 in acute uveitis patients is important. First, there is a significant association of HLA-B27 with various systemic diseases, particularly ankylosing spondylitis, Reiter's syndrome, and other ar- thropathies. Second, clinical presentation of HLA-B27 associated uveitis compared to non- HLA-B27 related anterior uveitis are somewhat different. From our study, it is apparent that HLA-B27 related uveitis patients develop acute severe anterior uveitis and recurrences more often than idiopathic non-HLA related uveitis. Because of multiple recurrences, HLA-B27 positive patients would like to know why they develop such recurrences. At least by knowing their HLA-B27 status, Anterior Uveitis 311 we can provide some explanation, particularly their genetic tendency to develop recurrences. Third, follow-up is particularly important in patients with HLA-B27, positive patients. Some of these patients, during follow-up examination may present with signs of ankylosing spondylitis. We know the ankylosing spondylitis patients can develop serious complications, like aortitisl.; Such patients should be referred to a cardiologist or internist for further evaluation and management of systemic disor- ders associated with ankylosing spondylitis. Fourth, the other point I would like to make relates to immunology. HLA-B27 is a class 1 antigen. Such antigens are known to play a significant role in antigen presentation, particularly viral related infections. It is possible that the HLA-B27 molecule may play a role in presentation of antigen and activation of cytotoxic T-lymphocytes. Such lymphocytes may be involved in the induction or recurrence of uveitis. Doctor Knox, the second question you raised is regarding how the present series of cases differ from our previous publication in the American Journal of Ophthalmology (1987; 103:131-135). In the previous study HLA-B27-positive patients were fewer and this is in part due to a limited number of patients tested for HLA-B27 prior to 1985. The present series ofcases represent the patients seen during 1984 to 1990. As mentioned in the presentation most of these patients were tested for HLA-B27. To answer Doctor Troutman's question regarding Lyme disease, we recognize association between uveitis and Lyme disease. We test patients for antibodies to Lyme borreliosis when there are manifestations suggestive ofatypical pars planitis or other intraocular inflammation, particularly if the patient presents a history of tick bite, arthritis, skin rash, or camping in rural areas. As I mentioned our approach to laboratory investigation has been a tailored approach based on clinical presentation and the history. Thank you very much.