- Email: [email protected]
Ocular Hypotony in Patients With Juvenile Idiopathic Arthritis–Associated Uveitis
Ocular Hypotony in Patients With Juvenile Idiopathic Arthritis–Associated Uveitis ¨ HM, CHRISTOPH TAPPEINER, MARC A. BREITBACH, BEATRIX ZUREK-IMHOFF, MICHAEL R.R. BO CARSTEN HEINZ, AND ARND HEILIGENHAUS PURPOSE:
To analyze occurrence, risk factors, and course of ocular hypotony (OH) in juvenile idiopathic arthritis–associated uveitis (JIAU). DESIGN: Cohort study. METHODS: Epidemiologic and ophthalmologic data at baseline and during follow-up of JIAU patients with and without ocular hypotony were evaluated. RESULTS: OH developed in 57 of the 365 JIAU patients during the follow-up (mean 4.5 ± 3.5 years). In 40 patients with follow-up ‡12 months, OH was unrelated to previous ocular surgery: risk factors at baseline (univariate logistic regression analysis) included longer total duration of uveitis (odds ratio [OR] 1.13, P < .001), bilateral uveitis (OR 3.51, P [ .009), low visual acuity (OR 5.1, P [ .001), high laser-flare (LF) values (OR 1.74, P [ .01), and presence of posterior synechiae (OR 3.28, P [ .004). Increased anterior chamber (AC) cell and LF values were observed within 3 months prior to onset of transient (£3 months; 37.5%) or persistent OH (>3 months; 62.5%). AC cell and LF values decreased within 3 months after onset of transient OH, while LF levels remained elevated ‡12 months in persistent OH. Optic disc edema and epiretinal membrane formation was found more frequently after OH onset. CONCLUSIONS: OH was observed in 15.6% of JIAU patients. Longer total uveitis duration, bilateral uveitis, low visual acuity, high AC flare and LF grades, and presence of posterior synechiae at baseline were risk factors for subsequent OH. Burden of OH might be improved with immunosuppression. (Am J Ophthalmol 2017;173:45–55. Ó 2016 Elsevier Inc. All rights reserved.)
J
UVENILE IDIOPATHIC ARTHRITIS (JIA) IS THE MOST
common systemic disease associated with childhood uveitis.1 In previous publications, the incidence of JIA-associated uveitis (JIAU) varied between 9% and 25%.2–6 Vision-threatening complications related to JIAU have been reported in 23%–67% of cases, including cataract, glaucoma, macular edema, optic disc edema, and epiretinal membranes.6–12 Ocular hypotony (OH) associated with uveitis was noted in about 3%–9% of these patients,9,13–16 supposedly secondary to inflammation, ciliary traction, surgery, and atrophic processes.15,16 Different pathophysiological mechanisms underlying OH have been discussed previously. An increased uveoscleral outflow (eg, owing to elevated levels of prostaglandins during the acute inflammatory processes) may cause OH.17–19 Furthermore, secondary morphologic changes in chronic uveitis, such as cyclitic membranes, impaired ciliary body epithelium, or an atrophic ciliary body owing to chronic and/or ongoing inflammation, may decrease ciliary body secretion.19 It would be desirable to determine potential predictors of OH in order to identify JIAU patients at risk already at an early stage. This information could help in optimizing the anti-inflammatory treatment for JIAU patients and potentially prevent OH and its deleterious complication ocular phthisis. The aim of this study was to evaluate occurrence, risk factors, and clinical course of ocular hypotony in a larger cohort of children with JIA-associated uveitis.
METHODS MEDICAL RECORDS OF ALL CHILDREN WITH JIA-ASSOCIATED
Accepted for publication Sep 14, 2016. From the Department of Ophthalmology, at St. Franziskus Hospital, Muenster, Germany (M.R.R.B., C.T., M.A.B., B.Z.-I., C.H., A.H.); Department of Ophthalmology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (C.T.); and University of Duisburg-Essen, Essen, Germany (C.H., A.H.). Michael R.R. Bo¨hm is currently affiliated with the Department of Ophthalmology, Clinic for Diseases of the Anterior Segments of the Eyes, Essen University Hospital, Essen, Germany. Inquiries to Michael R.R. Bo¨hm, Department of Ophthalmology, Clinic for Diseases of the Anterior Segments of the Eyes, Essen University Hospital, Hufelandstr. 55, 45147 Essen, Germany; e-mail: Michael. [email protected] 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2016.09.018
©
2016
uveitis followed up between April 3, 2001 and November 28, 2013 at the Department of Ophthalmology at St. Franziskus Hospital, Muenster, Germany, were retrospectively reviewed. The study was conducted in accordance with the Declaration of Helsinki. Approval from the ethics committee is not required for retrospective chart reviews in Germany. Only patients who were referred to the uveitis center within the first year of uveitis onset were included in this study. Juvenile idiopathic arthritis was defined in accordance with the International League of Associations for Rheumatology (ILAR).20 Rheumatologic examinations included a review of systems, laboratory tests (eg, HLA-B27, complete
ELSEVIER INC. ALL
RIGHTS RESERVED.
45
TABLE 1. Occurrence of Ocular Hypotony in Patients With Juvenile Idiopathic Arthritis–Associated Uveitis: Baseline Characteristics of All Patients
Patients, n (%) Female sex, n (%) Age at baseline, y, mean (SD) Age at JIA onset, y, mean (SD) Age at uveitis onset, y, mean (SD) Duration of uveitis at baseline of study, mo (SD) Polyarthritis RF positive Polyarthritis RF negative Systemic arthritis Oligoarthritis, persistent Oligoarthritis, extended Psoriatic arthritis Enthesitis-related arthritis Undifferentiated arthritis ANA positivity, n Uveitis-related eye complications Previous eye surgery
JIA Uveitis,
JIA Uveitis, Patients
JIA Uveitis, Patients With Ocular Hypotony
P Valuea Comparing Patients With and Without
Total Group
Without Ocular Hypotony
During Follow-up
Ocular Hypotony
365 (100) 254 (69.6) 7.8 (4.1) 3.7 (3.1) 5.5 (3.8) 32.4 (41.9) 3 (0.8%) 34 (9.3%) 1 (0.3%) 266 (73.0%) 51 (14.0%) 2 (0.5%) 6 (1.6%) 2 (0.5%) 272 (74.5%) 150 (41.2%) 28 (7.7%)
308 (84.4) 218 (70.8) 7.7 (4.2) 3.5 (3.0) 5.6 (4.0) 30.4 (40.8) 3 (1.0%) 29 (9.4%) 0 (0%) 227 (73.7%) 40 (13.0%) 2 (0.6%) 6 (1.9%) 1 (0.3) 227 (73.7%) 108 (35.1%) 15 (4.9%)
57 (15.6) 36 (62.7) 8.4 (4.1) 4.4 (3.4) 4.8 (2.7) 41.9 (46.1) 0 (0%) 5 (8.6%) 1 (1.8%) 39 (68.4%) 11 (19.3%) 0 (0%) 0 (0%) 1 (1.8%) 45 (78.9%) 42 (73.7%) 13 (22.8%)
n/a .3 .02 .03 .06 .09 .5
.2 <.001 <.001
ANA ¼ antinuclear antibody; JIA ¼ juvenile idiopathic arthritis; n/a ¼ not applicable; RF ¼ rheumatoid factor. a Mann-Whitney U test or x2 test (for categorical data); P < .05 statistically significant.
blood count, urinalysis, angiotensin-converting enzyme, rheumatoid factor, and antinuclear antibodies [ANA]), and chest radiograph examination, if appropriate. Patients with uveitis unrelated to JIA were excluded. Uveitis was classified according to the Standardization of Uveitis Nomenclature (SUN) Working Group as anterior, intermediate, posterior, or panuveitis.21,22 All data were reported using a standardized protocol, documenting the medical history, unilateral or bilateral disease, duration of uveitis, best-corrected visual acuity (BCVA), slit-lamp examination, tonometry, and funduscopy.13,23 The clinical assessment for each patient was verified by a second observer at each visit. BCVA was measured with ageappropriate tests (eg, Lea and E-tests for children <7 years, and numbers and Snellen tests for adolescents) and the results converted to logMAR units for statistical analysis. Intraocular pressure (IOP) was measured using Goldmann tonometry (Haag Streit, Koeniz, Switzerland) or with an iCARE TA01i tonometer (Icare Finland Oy, Vantaa, Finland). In this study, an IOP <6 mm Hg was defined as OH.9,24 The first visit of the patient at the uveitis clinic was defined as baseline. In cases of bilateral OH, the eye with the lower pressure and more severe OH-related ophthalmologic signs was selected for further analysis, whereas in the control group the right eye was always used for the analysis. Data about the onset, course, and duration of OH were gathered. Therefore, the ophthalmologic findings 12 and 3 months before OH onset, at the onset of OH, and also 46
3, 6, and 12 months thereafter were evaluated. Uveitisrelated structural complications were documented, for example band keratopathy, synechiae and cataract formation, macular edema, epiretinal membrane formation, _21 mm Hg), and glaucoma ocular hypertension (IOP > (pathologic cupping of the optic disc and/or glaucomatous visual field defects). If macular edema was suspected, it was confirmed by optical coherence tomography (Stratus OCT III; Carl Zeiss Meditec, Jena, Germany) and/or fluorescein angiography (Spectralis HRA-OCT; Heidelberg Engineering, Heidelberg, Germany). Anterior chamber cells (ACC) were graded according to SUN.22 Active uveitis was _0.5þ cells in the AC. Laserdefined as the presence of > flare (LF) photometry measurements were performed with a KOWA FM-500 device (Kowa Company, Ltd, Electronics and Optics Division, Tokyo, Japan) as a routine examination at every visit according to the protocol of the Laser-Cell Flare Photometry Medical Advisory Board.23,25,26 LF values were expressed as photon units/ _20 pu/ms) millisecond (pu/ms). Patients with low LF (< were distinguished from those with high LF (>20 pu/ ms).23,27 Any topical and systemic anti-inflammatory treatments (including dosages) were reported for each visit, as well as all previous ocular surgical procedures. At the occurrence of OH, topical corticosteroids were increased, and systemic corticosteroids and immunosuppression were adjusted to the individual uveitis course at the discretion of the treating ophthalmologists.
AMERICAN JOURNAL OF OPHTHALMOLOGY
JANUARY 2017
FIGURE 1. Onset of ocular hypotony (OH) in patients with juvenile idiopathic arthritis–associated uveitis. an [ 9 patients with bilateral OH, in whom non-surgery-associated hypotony was found in 1 eye and surgery-associated hypotony in the other eye.
Statistical analysis was performed using MedCalc Statistical Software version 15.2 (MedCalc Software, Ostend, Belgium). Normal data distribution was checked by using the Kolmogorov-Smirnov test. The x2 test or McNemar test was applied for categorical data, and Student t test, Mann-Whitney U test, or Friedman test were used for statistical analysis of numerical data when appropriate. Correlation between 2 variables was determined by calculating Pearson correlation coefficient r. Univariate and multivariable regression analysis were performed to calculate odds ratios (OR) and the 95% confidence interval (CI) for determining baseline risk factors of OH. A stepwise backward logistic regression was used for multivariable analysis. P values less than .05 were considered to be statistically significant.
ASSOCIATION OF OCULAR HYPOTONY WITH OCULAR SURGERY: In 21 patients (25 eyes), OH was observed after
RESULTS PATIENT CHARACTERISTICS:
A total of 365 patients with JIA-associated uveitis were identified in the uveitis center database. Epidemiologic data for these patients are shown in Table 1. JIAU patients were predominantly of female sex (69.6%), had early onset of arthritis, and were ANA positive (74.5%), and the majority was classified as having persistent oligoarthritis (73.0%). In 150 patients (41.2%), uveitis-related secondary complications were documented already at baseline, for example, band
VOL. 173
keratopathy (17.5%), posterior synechiae (3.8%), optic disc edema (10.7%), and epiretinal membrane formation (3.8%). The mean follow-up at our clinic was 4.5 6 3.5 years. Ocular surgery had been performed in 28 patients (7.7%) before study inclusion and in another 28 patients (14.8%) during the subsequent observation period. Out of 365 JIA patients, OH was reported in 57 patients (15.6%) (Figure 1, Table 1). Patient demographics did not differ between patients with or without OH occurrence with regard to sex, JIA subtype, ANA positivity, age at uveitis onset, and duration of uveitis at baseline (P > .05, each), whereas OH patients were older at JIA onset, were older at study baseline, and had more uveitis-related eye complications and previous eye operations (Table 1). The incidence rate for OH was 0.02/person-year in the total group of patients included in the study.
previous ocular surgery (Figure 1; 21 eyes after glaucoma surgery, 2 eyes after cataract surgery, and another 2 eyes after other intraocular operations). In these patients, OH was noted at a mean of 5.3 6 12.4 months following ocular surgery. PREDICTORS FOR THE OCCURRENCE OF OCULAR HYPOTONY IN PATIENTS WITHOUT OCULAR SURGERY:
To investigate the predictors for the occurrence of OH unrelated to ocular surgery, all JIAU patients who did not have prior surgical ocular interventions within the previous
OCULAR HYPOTONY IN CHILDHOOD UVEITIS
47
TABLE 2. Patients With Juvenile Idiopathic Arthritis–Associated Uveitis: Occurrence of Ocular Hypotony Without a Temporal Association to Previous Ocular Surgery (Characteristics at Baseline) Univariate Regression Analysisb
JIA Uveitis, With Ocular JIA Uveitis, Hypotony Not Associated Without Ocular Hypotony, Parameter
Female sex, n (%) Bilateral uveitis, n (%) Subtype of JIA ANA positivity, n (%) Age at JIA onset, y, mean (SD) Age at uveitis onset, y, mean (SD) Total uveitis duration (mo) between initial documentation and final follow-up at our institution (SD) Uveitis duration (y) before hypotony, mean (SD) BCVA (mean logMAR 6 SD) IOP in mm Hg (mean 6 SD) LF, photon units/msec (mean 6 SD)c ACC grade (mean 6 SD)d Anterior chamber flare (mean 6 SD)d Posterior synechiae (%) Topical corticosteroids, n (%) Systemic corticosteroids, n (%) csDMARDs, n (%) bDMARDs, n (%)
With Previous Surgery (N ¼ 40)
No Previous Surgery (N ¼ 293)
26 (65.0) 34 (85.0)
194 (66.1) 184 (62.6)
.9 .02
1.06 3.51
0.48–2.2 1.37–9.04
33 (82.5) 3.5 (2.5) 4.8 (3.0) 86.5 (48.5)
89 (77.4) 3.77 (2.9) 5.9 (3.4) 74.1 (3.8)
.4 .9 .02 <.001
3.34 0.9 0.9 1.13
0.41–27.37 0.79–1.02 0.79–1.02 1.01–1.21
9.4 (15.8) 0.5 (60.6) 13.4 (4.9) 58.7 (101.8) 0.5 (0.6) 0.9 (1.0) 45.0 27 (67.5) 11 (27.5) 27 (67.5) 2 (5.0)
n.a. 0.2 (60.2) 14.0 (2.7) 39.8 (76.4) 0.7 (0.9) 0.5 (0.8) 26.1 192 (65.5) 43 (14.7) 171 (58.3) 7 (2.41)
.07 .2 .006 .4 .009 .006 .8 .1 .3 .8
5.10 0.95 1.74 0.67 1.74 3.28 1.2 2.27 1.61 2.02
1.77–14.75 0.85–1.06 1.13–2.67 0.40–1.14 1.13–2.67 1.47–7.32 0.55–2.62 0.95–5.39 0.74–3.50 0.32–12.54
P Valuea OR
95% CI
P Value
.95 .009 >.05 .2 .08 .08 <.001
.0008 .36 .013 .11 .013 .004 .65 .06 .27 .46
ACC ¼ anterior chamber cells; BCVA ¼ best-corrected visual acuity; bDMARDs ¼ biological disease-modifying antirheumatic drugs; CI ¼ confidence interval; csDMARDs ¼ conventional synthetic disease-modifying antirheumatic drugs; IOP ¼ intraocular pressure; IS ¼ immunosuppressive medication; JIA ¼ juvenile idiopathic arthritis; LF ¼ laser-flare photometry; OR ¼ odds ratio. _12 months were included in the analysis. Patients with follow-up > P < .05 statistically significant. a Mann-Whitney U test or x2 test (for categorical data). b Risk of occurrence of ocular hypotony was calculated with univariate regression analysis, and corresponding odds ratios, 95% confidence intervals, and P values are shown. c Kowa laser-flare device. d By slit lamp.
12 months were further analyzed. Patients with a follow-up _12 months were included in this analysis (40 patients). of > This group was compared with patients in whom OH did not occur and without previous surgery (293 patients _12 months). At baseline, OH patients with a follow-up > were also younger at onset of uveitis, but the 2 groups did not differ with respect to sex, JIA type, and ANA positivity. Furthermore, IOP, ACC grade, and lens status were similar in the 2 groups (Table 2). Univariate logistic regression analysis found a higher OH risk in patients with bilateral uveitis (OR 3.51, 95% CI 1.37–9.04; P ¼ .009), longer total uveitis duration (OR 1.13, 95% CI 1.01–1.21, P < .001), lower BCVA (OR 5.1, 95% CI 1.77–14.75, P ¼ .0008), higher LF values (OR 1.74, 95% CI 1.13–2.67, P ¼ .013), and presence of posterior synechiae at first examination (OR 3.28, 95% CI 1.47–7.32, P ¼ .004). Results of the univariate regression analysis are shown in Table 2. 48
In a multivariable logistic regression analysis, only a younger age at onset of JIA (OR 1.18, 95% CI 1.03–1.36, P ¼ .02), bilaterality of uveitis (OR 5.3, 95% CI 1.16– 23.9, P ¼ .03), and poor BCVA at first examination (OR 4.6, 95% CI 1.05–19.7, P ¼ .04) were independently associated with the onset of OH during the course of uveitis in JIA, whereas neither other clinical findings nor topical and systemic treatment at baseline were independently associated with a higher risk for OH (P > .05, each). No relationships between associated risk factors, generated subgroups, and different lengths of follow-up periods have been found, whereas the risk increased with the lengths of the follow-up period. COURSE OF OCULAR HYPOTONY UNRELATED TO PREVIOUS EYE SURGERY: Eyes with OH not associated with pre-
vious surgical procedures revealed a mean IOP of 4.3 6 2.0 mm Hg at a mean OH duration of 9.5 6 22.7 months.
AMERICAN JOURNAL OF OPHTHALMOLOGY
JANUARY 2017
TABLE 3. Patients With Juvenile Arthritis–Associated Uveitis: Characteristics at Baseline Related to Duration of Ocular Hypotony
Parameter
Female sex, n (%) Bilateral uveitis, n (%) Subtype of JIA Age at JIA onset, y, mean (SD) Age at uveitis onset, y, mean (SD) Uveitis duration (mo) at initial documentation at institution (SD) Uveitis duration before hypotony, y, mean (SD) BCVA (mean logMAR 6 SD) Intraocular pressure in mm Hg (mean 6 SD) LFM, photon units/msec (mean 6 SD)c ACC grade (mean 6 SD)d Anterior chamber flare (mean 6 SD)d Posterior synechiae (%) Topical steroids, n (%) Systemic corticosteroids, n (%) csDMARDs, n (%) bDMARDs, n (%)
_3 Months Ocular Hypotony <
Ocular Hypotony >3 Months
(N ¼ 15)
(N ¼ 25)
Univariate Regression Analysisb P Valuea
OR
95% CI
P Value
.81 .03 >.05 .98 .05 .08
9 (60.0) 11 (73.3)
17 (68.0) 24 (96.0)
.9 .04
1.18 12.0
0.3–4.69 1.24–116.2
3.5 (3.6) 5.6 (3.7) 32.6 (35.1)
3.5 (1.8) 4.2 (1.9) 58.9 (57.6)
.3 .1 .07
1.0 1.25 1.0
0.75–1.35 0.98–1.60 0.97–1.00
2.1 (2.4) 0.4 (0.5) 12.1 (6.3) 81.7 (149.2) 0.6 (0.6) 1.1 (0.8) 60.0 10 (66.7) 7 (46.7) 9 (60) 1 (6.67)
3.7 (2.8) 0.5 (0.7) 14.2 (3.7) 45.3 (59.8) 0.4 (0.5) 0.7 (1.1) 36.0 17 (68.0) 4 (16.0) 18 (72.0) 1 (4.0)
.08 .5 .04 .6 .4 .1 .5 .9 .06 .9 .7
0.79 0.76 0.91 1.00 1.66 1.45 0.5 0.85 5.25 1.43 1.85
0.59–1.04 0.24–2.40 0.78–1.06 0.99–1.01 0.5–5.47 0.71–2.97 0.12–2.06 0.2–3.56 1.18–23.46 0.35–5.79 0.11–32.0
.1 .64 .21 .33 .41 .31 .34 .82 .03 .62 .67
ACC ¼ anterior chamber cells; BCVA ¼ best-corrected visual acuity; bDMARDs ¼ biological disease-modifying antirheumatic drugs; CI ¼ confidence interval; csDMARDs ¼ conventional synthetic disease-modifying antirheumatic drugs; IOP ¼ intraocular pressure; IS ¼ immunosuppressive medication; JIA ¼ juvenile idiopathic arthritis; LFM ¼ laser-flare photometry; OR ¼ odds ratio. _12 months were included in the analysis. Patients with follow-up > P < .05 statistically significant. a Mann-Whitney U test or x2 test (for categorical data). b _3 months) and persistent (>3 months) ocular Univariate regression analysis was performed to assess predicting factors for transient (< hypotony. Odds ratios, 95% confidence intervals, and P values are shown. c Kowa laser-flare device. d By slit lamp.
_3 months (tranIn 37.5% of these eyes, OH duration was < sient OH) and in another 62.5% >3 months (persistent OH). A total of 4 eyes (8.9%) developed phthisis bulbi after a mean uveitis duration of 32.4 6 25.2 months and after a mean OH duration of 20.3 6 10.1 months, respectively. In an attempt to define predictive factors for transient or persistent OH course, the clinical data at initial documentation at our institution were analyzed. Patients with persistent OH revealed a higher rate of bilateral uveitis (96.0% vs 73.3%; P ¼ .04), interestingly had a higher IOP (14.2 6 3.7 mm Hg vs 12.1 6 6.3 mm Hg; P ¼ .04), and had received systemic corticosteroids slightly less frequently (16.0% vs 46.7%; P ¼ .06) at initial examination as compared with the group with transient OH, with the latter not reaching the level of significance. The groups did not differ in sex, type of JIA, age at onset of JIA or JIAassociated uveitis, BCVA, LF values, ACC grade, anterior chamber flare grade, or presence of posterior synechiae (Table 3). Univariate logistic regression analysis revealed a higher risk for transient OH for patients with bilateral onset of VOL. 173
uveitis (OR 12.0, 95% CI 1.24–116.2, P ¼ .03) and systemic use of corticosteroids (OR 5.25, 95% CI 1.18– 23.46, P ¼ .03). Table 3 summarizes baseline characteristics and results of univariate regression analysis owing to course of ocular hypotony. Multivariable regression analysis did not reveal any significant association of these parameters with the time courses of OH. OPHTHALMOLOGIC FINDINGS BEFORE AND AFTER ONSET OF OCULAR HYPOTONY: No significant difference
in BCVA values prior to OH and during the subsequent follow-up examinations was found (Tables 4 and 5). The mean ACC grades at the time point of OH onset were higher than at the visits 12 and 3 months before OH developed (P < .05, each; Table 4). In 64.5% of eyes with OH, LF values remained elevated up to 12 months after OH onset. The majority of patients with OH presented with elevated LF values (>20 photon units/ms) at the visits 12 months (70.4%) and 3 months (77.8%) prior to OH occurrence (Table 4). ACC grades significantly decreased
OCULAR HYPOTONY IN CHILDHOOD UVEITIS
49
TABLE 4. Occurrence of Ocular Hypotony in Patients With Juvenile Idiopathic Arthritis–Associated Uveitis: Ocular Findings Before and at Onset of Ocular Hypotony
BCVA logMAR (mean 6 SD) _0.2 logMAR (10 letters) (%) BCVA loss > IOP in mm Hg (mean 6 SD) AC cell grade (mean 6 SD) LFM in photon units/msec (mean 6 SD) _20 (%) LFM change > Keratic precipitates (%) Posterior synechiae (%) Band keratopathy (%) Cataract formation (%) Aphakia (%) IOL (%) Iris rubeosis (%) Optic disc edema (%) Macular edema (%) Epiretinal membrane formation (%)
12 Months Before Onset of Hypotony
3 Months Before Onset of Hypotony
0.41 6 0.58
0.45 6 0.37 30.8 10.2 6 3.8 0.4 6 0.6 89.5 6 139.1 77.8 44.4 47.4 62.2 20.8 20.8 25.0 0 37.5 9.3 13.3
9.9 6 4.7 0.4 6 0.8 51.9 6 55.2 70.4 36.0 52.2 57.7 25.8 19.4 22.6 0 31.8 9.5 19.1
P Valuea,b
ns ns ns <.05 ns ns ns ns ns
ns ns ns ns
At Onset of Hypotony
0.53 6 0.54 25.0 4.3 6 4.8 0.9 6 1.0 98.7 6 124.9 80.9 51.2 61.9 56.4 21.4 14.3 26.2 5.9 55.2 14.8 32.3
P Valuea,c
ns ns <.05 <.05 <.05 ns ns ns ns ns
ns ns ns ns
AC ¼ anterior chamber; BCVA ¼ best-corrected visual acuity; IOL ¼ intraocular lens; IOP ¼ intraocular pressure; LFM ¼ laser-flare photometry; ns ¼ not significant; OH ¼ ocular hypotony. P < .05 statistically significant. a Friedman test or McNemar test (for categorical data). b Twelve months prior to OH vs 3 months prior to OH. c Three months prior to OH vs OH onset.
6 months after OH onset (P < .05), whereas LF values remained elevated until 12 months after OH onset (Table 5). Although hypotony disappeared within 3 months (transient OH) in 15 children with OH (37.5%), the low IOP levels persisted for >3 months (persistent OH) in another 25 patients (62.5%). The median IOP in the group of patients with transient OH increased from 5 mm Hg at OH occurrence, to 12 mm Hg at 3 months (increase of IOP <3 mm Hg, 3–5 mm Hg, and >5 mm Hg in 20%, 20%, and 60% of patients, respectively). In the patients with transient OH, the low IOP was associated with high ACC grades (P < .05) and LF values (P < .05) as compared to the previous time points. Thereafter, the mean ACC grades and LF values decreased significantly within 3 months (P < .05) (Figure 2, Table 5). In the patients with persistent OH, the AC cell grades and LF values were already increased at 3 months prior to OH onset and were further slightly increased at the time point of OH onset (Figure 3). Whereas the percentages of patients with band keratopathy and cataract formation did not significantly increase between the time points at 12 and 3 months prior to OH occurrence and at the time OH occurred, a slight increase in complications such as posterior synechiae, rubeosis iridis, optic disc edema, macular edema, and epiretinal membrane formation was observed during this time period, 50
although it did not reach statistical significance (each P > .05; Table 4). At the visits 3 and 6 months after OH onset, the rate of optic disc edema and epiretinal membrane formation was significantly lower in patients with transient than in those with persistent OH (Table 5). TREATMENT BEFORE AND AFTER OCCURRENCE OF HYPOTONY: Owing to the severity of JIAU disease, the
majority of our patients were treated with conventional synthetic (cs) and/or biological (b) disease-modifying antirheumatic drugs (DMARDs): methotrexate (62.7% of patients) was the preferred csDMARD and adalimumab (25.6% of patients) was the most frequently used bDMARD before OH onset. Topical corticosteroid therapy was generally adjusted to uveitis activity at the discretion of the treating ophthalmologist, with nearly 51.9% and 25.9% of patients being _3 or >3 times daily treated with corticosteroid eye drops < (mean, 2.8 6 3.0), respectively, in the <12 months before OH onset (data not shown). Whereas 57.9% of pa_3 months before tients received topical corticosteroids < onset of OH, all patients were treated with topical corticosteroids (mean 3.6 6 3.3 drops/day) after OH developed. Furthermore, the percentage of patients taking systemic corticosteroids increased from 22.9% before to 40.0% after occurrence of OH (P > .05). After onset of OH, patients received csDMARDs more often than
AMERICAN JOURNAL OF OPHTHALMOLOGY
JANUARY 2017
VOL. 173 TABLE 5. Occurrence of Ocular Hypotony in Patients With Juvenile Idiopathic Arthritis–Associated Uveitis: Ocular Findings At and After Onset of Ocular Hypotony Onset of Hypotony
3 Months After Onset of Hypotony
OCULAR HYPOTONY IN CHILDHOOD UVEITIS
Duration of hypotony (mo) BCVA (mean 6 SD) IOP (mm Hg 6 SD)
< _3 0.44 6 0.36 4.9 6 1.5
>3 0.57 6 0.61 4.0 6 2.2
< _3 0.49 6 0.6 11.7 6 3.4
>3 0.75 6 0.54 5.1 6 3.5
ACC (mean 6 SD)
1.1 6 1.1
1.0 6 1.0
0.6 6 1.1
0.9 6 0.3
LFM (photon units/msec) (mean 6 SD) 94.4 6 117.1 108.3 6 129.9 72.3 6 104.8 _20 (%) LFM change > Keratic precipitates (%) Posterior synechiae (%) Band keratopathy (%) Cataract (%) Iris rubeosis (%) Optic disc edema (%)
57.1 64.3 41.7 26.7 4.2 40.0
Macular edema (%) Epiretinal membrane (%)
10.0 20.0
78.9 6 106.5
48.2 60.7 62.9 27.9 6.9 63.2
57.1 40.0 54.0 43.3 27.0 0 30.0
18.9 45.5 54.6 62.2 27.3 0 58.3
17.6 38.1
9.1 22.2
9.0 40.0
P Valuea,b
nsc,d,e <.05c,e nsd <.05c,e nsd nsc,d,e <.05e nsc,d,e nsc,d,e nsc,d,e nsc,d,e nsc,d nsc,d <.05e nsc,d nsc,d <.05e
6 Months After Onset of Hypotony
< _3 0.33 6 0.39 11.4 6 3.7
>3 0.44 6 0.53 7.4 6 3.7
0.3 6 0.7
0.4 6 0.9
45.4 6 57.4
80.9 6 108.5
0 25.0 60.0 46.2 26.7 0 30.0
44.4 25.0 57.6 62.9 26.1 0 50.0
5.0 18.2
6.7 41.2
P Valuea,b
nsc,d,e nsc <.05d,e nsc,e <.05d <.05c,e nsd <.05e nsc,d,e nsc,d,e nsc,d,e nsc,d,e nsc,d nsc,d <.05e nsc,d nsc,d <.05e
12 Months After Onset of Hypotony
< _3 0.57 6 0.7 11.45 6 4.1
>3 0.61 6 0.59 7.89 6 4.0
0.4 6 1.0
0.3 6 0.5
25.6 6 16.9
81.9 6 109.2
P Valuea,b
nsc,d,e nsc,e <.05d nsc,d,e
20.0 30.0 58.0 46.4 31.7 0 11.11
21.4 41.2 57.9 61.1 38.9 3.3 23.08
<.05c,e nsd nse nsc,d,e nsc,d,e nsc,d,e nsc,d,e nsc,d nsc,d,e
5.0 30
6.2 46.7
nsc,d nsc,d,e
AC ¼ anterior chamber; BCVA ¼ best-corrected visual acuity; IOL ¼ intraocular lens; IOP ¼ intraocular pressure; LFM ¼ laser-flare photometry; ns ¼ not significant. P < .05 statistically significant. a Compared to last time point: Friedman test and McNemar test (for categorial data). b Acute vs chronic ocular hypotony: Mann-Whitney U test or x2 test (for categorial data). c _3 months group. Compared to last time point: < d Compared to last time point: >3 months group. e _3 months group and >3 months group. Comparison between <
51
FIGURE 2. Onset of ocular hypotony (OH) in patients with juvenile idiopathic arthritis–associated uveitis. Course of intraocular pressure, laser flare photometry values, and anterior chamber cell grade in transient ocular hypotony (£3 months). Course is presented 3 months before and up to 12 months after occurrence of ocular hypotony. Mean values with standard deviation error bars are presented. *P < .05. ACC [ anterior chamber cell grade; IOP [ intraocular pressure; LF [ laser flare photometry value; OH [ ocular hypotony.
before (81.5% vs 69.3%; P ¼ .03) and also received a tumor necrosis factor inhibitor more often, and the number of patients that were switched from a csDMARD to a bDMARD increased.
DISCUSSION IN THIS STUDY WE ANALYZED THE OCCURRENCE AND
course of OH in a large cohort of JIAU at a single tertiary uveitis center. Up to now, only limited data on this issue were available for uveitis in general, and data for JIAU were even scarcer.15,16,28–30 In our study, we found an occurrence of OH in about 15% of our patients with JIAU (mean follow-up time 4.5 years), which was higher than in previous publications, where a prevalence of OH between 3% and 9% was reported.9,13–16 The different frequencies might be explained by different patient populations, potential selection bias, differences in follow-up time, treatment patterns, and also OH definitions. The disease severity of our patient group is emphasized by the high rate of ocular comorbidity. Different definitions of OH can be found in the literature, ranging from an IOP <6 to <8 mm Hg.31 An IOP less than 6 mm Hg at 2 consecutive visits was used in our study, which is in accordance with the previously published outcome measures for JIAU.24 Furthermore, we distin_3 months duration) from persistent guished transient (< (>3 months) OH in order to identify the potential longterm risk. 52
Thirteen of our 365 patients (25 eyes) developed OH after previous ocular surgery, in particular after glaucoma surgery (21 eyes). OH occurring after previous intraocular surgery in patients with JIA-associated uveitis is often related to surgically induced inflammation.32–34 This highlights the need for appropriate anti-inflammatory treatment, in particular at the time of eye surgery. Moreover, an appropriate anti-inflammatory treatment, in particular at the time of eye surgery, is mandatory. The high OH incidence after glaucoma surgery is well known, even in patients without uveitis. Whereas numerous data about the incidence, severity, and duration of OH after ocular and especially glaucoma surgery can be found in the literature,35 there is only little information about uveitis36 and particularly JIAU.9,13–16 The vast majority of OH incidences in our study population, however, were related to inflammatory components: high LF and AC flare and posterior synechiae were valid risk factors for OH occurrence. Apparently, the risk of developing OH in patients without previous ocular surgery increases with binocular disease and young age at JIA recognition. The findings of a higher mean age at JIA recognition in all patients with onset of OH, including those with previous ocular surgery, may be explained by a potential delayed JIA recognition in this group. This may have also led to a delayed uveitis diagnosis in some patients, as uveitis screening understandably starts only after recognition of systemic disease.37 Poor visual acuity represents another risk factor for OH, as it was commonly related to other ocular complications in eyes with a severe course of uveitis.
AMERICAN JOURNAL OF OPHTHALMOLOGY
JANUARY 2017
FIGURE 3. Onset of ocular hypotony (OH) in patients with juvenile idiopathic arthritis–associated uveitis. Course of intraocular pressure, laser flare photometry values, and anterior chamber cell grade in persistent ocular hypotony (>3 months). Course is presented 3 months before and up to 12 months after occurrence of ocular hypotony. Mean values with standard deviation error bars are presented. *P < 0.05. ACC [ anterior chamber cell grade; IOP [ intraocular pressure; LF [ laser flare photometry value; OH [ ocular hypotony.
An important finding is the increase in AC flare and cells prior to the occurrence of OH. Furthermore, eyes with high LF values, indicating a breakdown of the blood-aqueous barrier (BAB),23,27 were found to be at high risk for subsequent OH. This is in accordance with previous findings, where high LF was identified as a significant risk factor for subsequent ocular complications such as OH and for a poorer visual outcome.23,38 It may be speculated from the data that a less frequent use of systemic corticosteroids put the patients at an increased risk for OH, in particular when OH persisted for >3 months. In this circumstance, inflammatory activity might have been apparent, but occult inflammation of the ciliary body may potentially also have been present (without AC cells), which puts the patient at risk of being undertreated. Here, LF helped detect smoldering uveitis activity, especially if AC cells were not present. Intraocular inflammation may decrease aqueous production, increase uveoscleral outflow, and cause supraciliary or suprachoroidal leakage.17–19 Consequently, OH related to inflammation may be reversible with appropriate antiinflammatory medication in order to achieve uveitis inactivity.15,18,24 However, an irreversible decrease in aqueous humor production in the ciliary body may result from concomitant atrophy or ischemia of the uveal tissue, from ciliary traction, or iatrogenically as a long-term consequence of ocular surgery,12,18,39 and may ultimately cause irreversible ocular phthisis in selected cases.19 Increased LF values and AC cells are important measures for disrupting the BAB and also appear to be valuable VOL. 173
indicators for the subsequent OH course and the related ocular complications. Indeed, our data show that typical consequences of transient OH were found more often in these instances, for example optic disc edema and epiretinal membrane formation. This indicates that children with a more severe course of disease, namely a breakdown of the BAB, are at a particularly high risk for OH already at initial stages of disease. Accordingly, children with a high uveitis activity developed secondary ocular complications more often during the subsequent disease course.13 Although most of our patients were treated with topical and systemic corticosteroids, and also DMARDs already before the onset of OH, the topical corticosteroid dosages were increased after OH developed, or conventional synthetic and/or biological DMARDs were added or switched at the discretion of the treating ophthalmologist. This may be important for reversing and restoring ciliary body function. Further studies are required that confirm the value of immunosuppression for the management of JIA-related OH. The AC cell grades decreased within 3 months after transient OH (Figure 2) and within 6 months after occurrence of persistent OH (Figure 3) developed. However, whereas the LF values returned to normal in transient OH, they remained high in eyes with a chronic disruption of the BAB, although the anti-inflammatory treatment was escalated. This probably documents the advanced, and potentially irreversible, tissue damage in these eyes, eventually leading to poor visual prognosis and ocular phthisis.19,40
OCULAR HYPOTONY IN CHILDHOOD UVEITIS
53
This study has certain limitations, such as the retrospective study design with differential follow-up and referral patterns. The patient cohort at a tertiary uveitis center may produce a selection bias in favor of more severe cases. Data from registries on representative population-based cohorts of JIAU children might provide further insight on the OH risk and its course in future investigations. However, standardized protocols for JIAU were used routinely for the documentation in this study, and patients were seen by 2 JIAU specialists in order to provide reliable data. The presented study focused on the presentation of mean values for changes of the relevant parameters such as the IOP. The definition used in this study for resolution may be based on minimal changes that could be clinically unimportant in some individuals. Therefore, the percentage of patients in the transient OH group with an IOP increase of 3–5 mm Hg and >5 mm Hg was also provided in the results sections; however, it is unclear which increase of IOP is clinically relevant for the individual patient. As the mean follow-up in the present study was only 4.5 years,
the OH rate over the long-term course might even be higher than estimated by our observation. The follow-up varied between the patients in our cohort. The total uveitis duration between initial documentation and final followup at our institution was significantly longer in JIA uveitis cases with OH than without OH. This is supporting the notion that OH is a late manifestation of disease. This notion may not significantly change if all patients had the same length of follow-up. This study shows that OH represents a significant risk factor in JIAU patients with long-lasting disease courses. Therefore, determining risk factors for OH, such as bilaterality of JIA uveitis, young age at disease onset, increased AC flare and LF grades, and posterior synechiae, might be useful for identifying children at risk for subsequent OH occurrence, probably already at an early stage of disease. Further prospective studies are needed to optimize immunomodulatory treatment in this risk group of JIA uveitis in order to prevent potentially irreversible OH and its deleterious consequences.
FUNDING/SUPPORT: INNOVATIVE MEDIZINISCHE FORSCHUNG (IMF) OF THE WESTFALIAN WILHELMS-UNIVERSITY OF ¨ 221307; German Research Foundation (DFG), Bonn, Germany, grant BO 4556/1-1 (M.R.R.B.); IFORES support of Mu¨nster, Germany, grant I-BO the Faculty of Medicine of the University Duisburg/Essen, Essen, Germany (M.R.R.B.); Bundesministerium fu¨r Bildung und Forschung (BMBF), Berlin, Germany, grant 01ER1504C (A.H.). Financial Disclosures: Michael R.R. Bo¨hm: travel grant from The Association for Research in Vision and Ophthalmology (ARVO) for annual meeting of the ARVO in Seattle, Washington, USA (2013); travel grant from Novartis Pharma GmbH, Nuremberg, Germany for Novartis - Meeting ‘‘VEGF and beyond’’ in Berlin, Germany (2014). Carsten Heinz: lectures for Bayer, Leverkusen, Germany, and Novartis, Nuremberg, Germany; Advisory Board for Desitin, Hamburg, Germany, and AbbVie, Wiesbaden, Germany. Arnd Heiligenhaus: German Research Foundation (DFG), Bonn, Germany, grant HE 1877/19-1. The following authors have no financial disclosures: Christoph Tappeiner, Marc A. Breitbach, and Beatrix Zurek-Imhoff. All authors attest that they meet the current ICMJE criteria for authorship.
REFERENCES 1. Petty RE. Growing pains: the ILAR classification of juvenile idiopathic arthritis. J Rheumatol 2001;28(5):927–928. 2. Ravelli A, Felici E, Magni-Manzoni S, et al. Patients with antinuclear antibody-positive juvenile idiopathic arthritis constitute a homogeneous subgroup irrespective of the course of joint disease. Arthritis Rheum 2005;52(3):826–832. 3. Kanski JJ. Juvenile arthritis and uveitis. Surv Ophthalmol 1990;34(4):253–267. 4. Kotaniemi K, Kautiainen H, Karma A, Aho K. Occurrence of uveitis in recently diagnosed juvenile chronic arthritis: a prospective study. Ophthalmology 2001;108(11):2071–2075. 5. Carvounis PE, Herman DC, Cha S, Burke JP. Incidence and outcomes of uveitis in juvenile rheumatoid arthritis, a synthesis of the literature. Graefes Arch Clin Exp Ophthalmol 2006; 244(3):281–290. 6. Tappeiner C, Klotsche J, Schenck S, Niewerth M, Minden K, Heiligenhaus A. Temporal change in prevalence and complications of uveitis associated with juvenile idiopathic arthritis: data from a cross-sectional analysis of a prospective nationwide study. Clin Exp Rheumatol 2015;33(6):936–944. 7. Davis JL, Dacanay LM, Holland GN, Berrocal AM, Giese MJ, Feuer WJ. Laser flare photometry and complications of chronic uveitis in children. Am J Ophthalmol 2003;135(6): 763–771.
54
8. Sabri K, Saurenmann RK, Silverman ED, Levin AV. Course, complications, and outcome of juvenile arthritis-related uveitis. J AAPOS 2008;12(6):539–545. 9. Thorne JE, Woreta F, Kedhar SR, Dunn JP, Jabs DA. Juvenile idiopathic arthritis-associated uveitis: incidence of ocular complications and visual acuity loss. Am J Ophthalmol 2007; 143(5):840–846. 10. Thorne JE, Woreta FA, Dunn JP, Jabs DA. Risk of cataract development among children with juvenile idiopathic arthritis-related uveitis treated with topical corticosteroids. Ophthalmology 2010;117(7):1436–1441. 11. Foster CS, Havrlikova K, Baltatzis S, Christen WG, MerayoLloves J. Secondary glaucoma in patients with juvenile rheumatoid arthritis-associated iridocyclitis. Acta Ophthalmol Scand 2000;78(5):576–579. 12. Vitale AT, Graham E, de Boer JH. Juvenile idiopathic arthritis-associated uveitis: clinical features and complications, risk factors for severe course, and visual outcome. Ocul Immunol Inflamm 2013;21(6):478–485. 13. Heiligenhaus A, Niewerth M, Ganser G, Heinz C, Minden K, German Uveitis in Childhood Study Group. Prevalence and complications of uveitis in juvenile idiopathic arthritis in a population-based nation-wide study in Germany: suggested modification of the current screening guidelines. Rheumatology (Oxford) 2007;46(6): 1015–1019.
AMERICAN JOURNAL OF OPHTHALMOLOGY
JANUARY 2017
14. de Boer J, Wulffraat N, Rothova A. Visual loss in uveitis of childhood. Br J Ophthalmol 2003;87(7):879–884. 15. Sen HN, Drye LT, Goldstein DA, et al. Hypotony in patients with uveitis: The Multicenter Uveitis Steroid Treatment (MUST) Trial. Ocul Immunol Inflamm 2012;20(2):104–112. 16. Loh AR, Acharya NR. Incidence rates and risk factors for ocular complications and vision loss in HLA-B27associated uveitis. Am J Ophthalmol 2010;150(4):534–542e2. 17. Mermoud A, Baerveldt G, Minckler DS, Lee MB, Rao NA. Measurement of rabbit intraocular pressure with the TonoPen. Ophthalmologica 1995;209(5):275–277. 18. Toris CB, Pederson JE. Aqueous humor dynamics in experimental iridocyclitis. Invest Ophthalmol Vis Sci 1987;28(3): 477–481. 19. Tran VT, Mermoud A, Herbort CP. Appraisal and management of ocular hypotony and glaucoma associated with uveitis. Int Ophthalmol Clin 2000;40(2):175–203. 20. Petty RE, Southwood TR, Manners P, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 2004;31(2):390–392. 21. Brooks P, Hochberg M. Outcome measures and classification criteria for the rheumatic diseases. A compilation of data from OMERACT (Outcome Measures for Arthritis Clinical Trials), ILAR (International League of Associations for Rheumatology), regional leagues and other groups. Rheumatology (Oxford) 2001;40(8):896–906. 22. Jabs DA, Nussenblatt RB, Rosenbaum JT, Standardization of Uveitis Nomenclature Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol 2005; 140(3):509–516. 23. Tappeiner C, Heinz C, Roesel M, Heiligenhaus A. Elevated laser flare values correlate with complicated course of anterior uveitis in patients with juvenile idiopathic arthritis. Acta Ophthalmol 2011;89(6):e521–e527. 24. Heiligenhaus A, Foeldvari I, Edelsten C, et al. Proposed outcome measures for prospective clinical trials in juvenile idiopathic arthritis-associated uveitis: a consensus effort from the multinational interdisciplinary working group for uveitis in childhood. Arthritis Care Res (Hoboken) 2012; 64(9):1365–1372. 25. Gonzales CA, Ladas JG, Davis JL, Feuer WJ, Holland GN. Relationships between laser flare photometry values and complications of uveitis. Arch Ophthalmol 2001;119(12):1763–1769. 26. Ladas JG, Wheeler NC, Morhun PJ, Rimmer SO, Holland GN. Laser flare-cell photometry: methodology and clinical applications. Surv Ophthalmol 2005;50(1):27–47.
VOL. 173
27. Ladas JG, Yu F, Loo R, et al. Relationship between aqueous humor protein level and outflow facility in patients with uveitis. Invest Ophthalmol Vis Sci 2001;42(11): 2584–2588. 28. Kump LI, Castaneda RA, Androudi SN, Reed GF, Foster CS. Visual outcomes in children with juvenile idiopathic arthritis-associated uveitis. Ophthalmology 2006;113(10): 1874–1877. 29. Tugal-Tutkun I, Havrlikova K, Power WJ, Foster CS. Changing patterns in uveitis of childhood. Ophthalmology 1996; 103(3):375–383. 30. Smith JA, Mackensen F, Sen HN, et al. Epidemiology and course of disease in childhood uveitis. Ophthalmology 2009; 116(8):1544–1551e1. 31. Pederson J, Hypotony. In: Tasman WJE, ed. Duane’s Clinical Ophthalmology. Philadelphia, PA: Lippincott-Raven; 1999:1–8. 32. Kotaniemi K, Penttila H. Intraocular lens implantation in patients with juvenile idiopathic arthritis-associated uveitis. Ophthalmic Res 2006;38(6):318–323. 33. Meacock WR, Spalton DJ, Bender L, et al. Steroid prophylaxis in eyes with uveitis undergoing phacoemulsification. Br J Ophthalmol 2004;88(9):1122–1124. 34. Phatak S, Lowder C, Pavesio C. Controversies in intraocular lens implantation in pediatric uveitis. J Ophthalmic Inflamm Infect 2016;6(1):12. 35. Schubert HD. Postsurgical hypotony: relationship to fistulization, inflammation, chorioretinal lesions, and the vitreous. Surv Ophthalmol 1996;41(2):97–125. 36. Edmunds B, Thompson JR, Salmon JF, Wormald RP. The National Survey of Trabeculectomy. III. Early and late complications. Eye (Lond) 2002;16(3):297–303. 37. Heiligenhaus A, Heinz C, Edelsten C, Kotaniemi K, Minden K. Review for disease of the year: epidemiology of juvenile idiopathic arthritis and its associated uveitis: the probable risk factors. Ocul Immunol Inflamm 2013; 21(3):180–191. 38. Holland GN. A reconsideration of anterior chamber flare and its clinical relevance for children with chronic anterior uveitis (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc 2007;105:344–364. 39. Roters S, Szurman P, Engels BF, Bartz-Schmidt KU, Krieglstein GK. Ultrasound biomicroscopy in chronic ocular hypotony: its impact on diagnosis and management. Retina 2002;22(5):581–588. 40. Kim HS, Lee EH, Sungjoo KY, Joo CK. Immunopathogenesis of experimental melanin-protein induced uveitis. Korean J Ophthalmol 1998;12(1):14–18.
OCULAR HYPOTONY IN CHILDHOOD UVEITIS
55
To analyze occurrence, risk factors, and course of ocular hypotony (OH) in juvenile idiopathic arthritis–associated uveitis (JIAU). DESIGN: Cohort study. METHODS: Epidemiologic and ophthalmologic data at baseline and during follow-up of JIAU patients with and without ocular hypotony were evaluated. RESULTS: OH developed in 57 of the 365 JIAU patients during the follow-up (mean 4.5 ± 3.5 years). In 40 patients with follow-up ‡12 months, OH was unrelated to previous ocular surgery: risk factors at baseline (univariate logistic regression analysis) included longer total duration of uveitis (odds ratio [OR] 1.13, P < .001), bilateral uveitis (OR 3.51, P [ .009), low visual acuity (OR 5.1, P [ .001), high laser-flare (LF) values (OR 1.74, P [ .01), and presence of posterior synechiae (OR 3.28, P [ .004). Increased anterior chamber (AC) cell and LF values were observed within 3 months prior to onset of transient (£3 months; 37.5%) or persistent OH (>3 months; 62.5%). AC cell and LF values decreased within 3 months after onset of transient OH, while LF levels remained elevated ‡12 months in persistent OH. Optic disc edema and epiretinal membrane formation was found more frequently after OH onset. CONCLUSIONS: OH was observed in 15.6% of JIAU patients. Longer total uveitis duration, bilateral uveitis, low visual acuity, high AC flare and LF grades, and presence of posterior synechiae at baseline were risk factors for subsequent OH. Burden of OH might be improved with immunosuppression. (Am J Ophthalmol 2017;173:45–55. Ó 2016 Elsevier Inc. All rights reserved.)
J
UVENILE IDIOPATHIC ARTHRITIS (JIA) IS THE MOST
common systemic disease associated with childhood uveitis.1 In previous publications, the incidence of JIA-associated uveitis (JIAU) varied between 9% and 25%.2–6 Vision-threatening complications related to JIAU have been reported in 23%–67% of cases, including cataract, glaucoma, macular edema, optic disc edema, and epiretinal membranes.6–12 Ocular hypotony (OH) associated with uveitis was noted in about 3%–9% of these patients,9,13–16 supposedly secondary to inflammation, ciliary traction, surgery, and atrophic processes.15,16 Different pathophysiological mechanisms underlying OH have been discussed previously. An increased uveoscleral outflow (eg, owing to elevated levels of prostaglandins during the acute inflammatory processes) may cause OH.17–19 Furthermore, secondary morphologic changes in chronic uveitis, such as cyclitic membranes, impaired ciliary body epithelium, or an atrophic ciliary body owing to chronic and/or ongoing inflammation, may decrease ciliary body secretion.19 It would be desirable to determine potential predictors of OH in order to identify JIAU patients at risk already at an early stage. This information could help in optimizing the anti-inflammatory treatment for JIAU patients and potentially prevent OH and its deleterious complication ocular phthisis. The aim of this study was to evaluate occurrence, risk factors, and clinical course of ocular hypotony in a larger cohort of children with JIA-associated uveitis.
METHODS MEDICAL RECORDS OF ALL CHILDREN WITH JIA-ASSOCIATED
Accepted for publication Sep 14, 2016. From the Department of Ophthalmology, at St. Franziskus Hospital, Muenster, Germany (M.R.R.B., C.T., M.A.B., B.Z.-I., C.H., A.H.); Department of Ophthalmology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (C.T.); and University of Duisburg-Essen, Essen, Germany (C.H., A.H.). Michael R.R. Bo¨hm is currently affiliated with the Department of Ophthalmology, Clinic for Diseases of the Anterior Segments of the Eyes, Essen University Hospital, Essen, Germany. Inquiries to Michael R.R. Bo¨hm, Department of Ophthalmology, Clinic for Diseases of the Anterior Segments of the Eyes, Essen University Hospital, Hufelandstr. 55, 45147 Essen, Germany; e-mail: Michael. [email protected] 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2016.09.018
©
2016
uveitis followed up between April 3, 2001 and November 28, 2013 at the Department of Ophthalmology at St. Franziskus Hospital, Muenster, Germany, were retrospectively reviewed. The study was conducted in accordance with the Declaration of Helsinki. Approval from the ethics committee is not required for retrospective chart reviews in Germany. Only patients who were referred to the uveitis center within the first year of uveitis onset were included in this study. Juvenile idiopathic arthritis was defined in accordance with the International League of Associations for Rheumatology (ILAR).20 Rheumatologic examinations included a review of systems, laboratory tests (eg, HLA-B27, complete
ELSEVIER INC. ALL
RIGHTS RESERVED.
45
TABLE 1. Occurrence of Ocular Hypotony in Patients With Juvenile Idiopathic Arthritis–Associated Uveitis: Baseline Characteristics of All Patients
Patients, n (%) Female sex, n (%) Age at baseline, y, mean (SD) Age at JIA onset, y, mean (SD) Age at uveitis onset, y, mean (SD) Duration of uveitis at baseline of study, mo (SD) Polyarthritis RF positive Polyarthritis RF negative Systemic arthritis Oligoarthritis, persistent Oligoarthritis, extended Psoriatic arthritis Enthesitis-related arthritis Undifferentiated arthritis ANA positivity, n Uveitis-related eye complications Previous eye surgery
JIA Uveitis,
JIA Uveitis, Patients
JIA Uveitis, Patients With Ocular Hypotony
P Valuea Comparing Patients With and Without
Total Group
Without Ocular Hypotony
During Follow-up
Ocular Hypotony
365 (100) 254 (69.6) 7.8 (4.1) 3.7 (3.1) 5.5 (3.8) 32.4 (41.9) 3 (0.8%) 34 (9.3%) 1 (0.3%) 266 (73.0%) 51 (14.0%) 2 (0.5%) 6 (1.6%) 2 (0.5%) 272 (74.5%) 150 (41.2%) 28 (7.7%)
308 (84.4) 218 (70.8) 7.7 (4.2) 3.5 (3.0) 5.6 (4.0) 30.4 (40.8) 3 (1.0%) 29 (9.4%) 0 (0%) 227 (73.7%) 40 (13.0%) 2 (0.6%) 6 (1.9%) 1 (0.3) 227 (73.7%) 108 (35.1%) 15 (4.9%)
57 (15.6) 36 (62.7) 8.4 (4.1) 4.4 (3.4) 4.8 (2.7) 41.9 (46.1) 0 (0%) 5 (8.6%) 1 (1.8%) 39 (68.4%) 11 (19.3%) 0 (0%) 0 (0%) 1 (1.8%) 45 (78.9%) 42 (73.7%) 13 (22.8%)
n/a .3 .02 .03 .06 .09 .5
.2 <.001 <.001
ANA ¼ antinuclear antibody; JIA ¼ juvenile idiopathic arthritis; n/a ¼ not applicable; RF ¼ rheumatoid factor. a Mann-Whitney U test or x2 test (for categorical data); P < .05 statistically significant.
blood count, urinalysis, angiotensin-converting enzyme, rheumatoid factor, and antinuclear antibodies [ANA]), and chest radiograph examination, if appropriate. Patients with uveitis unrelated to JIA were excluded. Uveitis was classified according to the Standardization of Uveitis Nomenclature (SUN) Working Group as anterior, intermediate, posterior, or panuveitis.21,22 All data were reported using a standardized protocol, documenting the medical history, unilateral or bilateral disease, duration of uveitis, best-corrected visual acuity (BCVA), slit-lamp examination, tonometry, and funduscopy.13,23 The clinical assessment for each patient was verified by a second observer at each visit. BCVA was measured with ageappropriate tests (eg, Lea and E-tests for children <7 years, and numbers and Snellen tests for adolescents) and the results converted to logMAR units for statistical analysis. Intraocular pressure (IOP) was measured using Goldmann tonometry (Haag Streit, Koeniz, Switzerland) or with an iCARE TA01i tonometer (Icare Finland Oy, Vantaa, Finland). In this study, an IOP <6 mm Hg was defined as OH.9,24 The first visit of the patient at the uveitis clinic was defined as baseline. In cases of bilateral OH, the eye with the lower pressure and more severe OH-related ophthalmologic signs was selected for further analysis, whereas in the control group the right eye was always used for the analysis. Data about the onset, course, and duration of OH were gathered. Therefore, the ophthalmologic findings 12 and 3 months before OH onset, at the onset of OH, and also 46
3, 6, and 12 months thereafter were evaluated. Uveitisrelated structural complications were documented, for example band keratopathy, synechiae and cataract formation, macular edema, epiretinal membrane formation, _21 mm Hg), and glaucoma ocular hypertension (IOP > (pathologic cupping of the optic disc and/or glaucomatous visual field defects). If macular edema was suspected, it was confirmed by optical coherence tomography (Stratus OCT III; Carl Zeiss Meditec, Jena, Germany) and/or fluorescein angiography (Spectralis HRA-OCT; Heidelberg Engineering, Heidelberg, Germany). Anterior chamber cells (ACC) were graded according to SUN.22 Active uveitis was _0.5þ cells in the AC. Laserdefined as the presence of > flare (LF) photometry measurements were performed with a KOWA FM-500 device (Kowa Company, Ltd, Electronics and Optics Division, Tokyo, Japan) as a routine examination at every visit according to the protocol of the Laser-Cell Flare Photometry Medical Advisory Board.23,25,26 LF values were expressed as photon units/ _20 pu/ms) millisecond (pu/ms). Patients with low LF (< were distinguished from those with high LF (>20 pu/ ms).23,27 Any topical and systemic anti-inflammatory treatments (including dosages) were reported for each visit, as well as all previous ocular surgical procedures. At the occurrence of OH, topical corticosteroids were increased, and systemic corticosteroids and immunosuppression were adjusted to the individual uveitis course at the discretion of the treating ophthalmologists.
AMERICAN JOURNAL OF OPHTHALMOLOGY
JANUARY 2017
FIGURE 1. Onset of ocular hypotony (OH) in patients with juvenile idiopathic arthritis–associated uveitis. an [ 9 patients with bilateral OH, in whom non-surgery-associated hypotony was found in 1 eye and surgery-associated hypotony in the other eye.
Statistical analysis was performed using MedCalc Statistical Software version 15.2 (MedCalc Software, Ostend, Belgium). Normal data distribution was checked by using the Kolmogorov-Smirnov test. The x2 test or McNemar test was applied for categorical data, and Student t test, Mann-Whitney U test, or Friedman test were used for statistical analysis of numerical data when appropriate. Correlation between 2 variables was determined by calculating Pearson correlation coefficient r. Univariate and multivariable regression analysis were performed to calculate odds ratios (OR) and the 95% confidence interval (CI) for determining baseline risk factors of OH. A stepwise backward logistic regression was used for multivariable analysis. P values less than .05 were considered to be statistically significant.
ASSOCIATION OF OCULAR HYPOTONY WITH OCULAR SURGERY: In 21 patients (25 eyes), OH was observed after
RESULTS PATIENT CHARACTERISTICS:
A total of 365 patients with JIA-associated uveitis were identified in the uveitis center database. Epidemiologic data for these patients are shown in Table 1. JIAU patients were predominantly of female sex (69.6%), had early onset of arthritis, and were ANA positive (74.5%), and the majority was classified as having persistent oligoarthritis (73.0%). In 150 patients (41.2%), uveitis-related secondary complications were documented already at baseline, for example, band
VOL. 173
keratopathy (17.5%), posterior synechiae (3.8%), optic disc edema (10.7%), and epiretinal membrane formation (3.8%). The mean follow-up at our clinic was 4.5 6 3.5 years. Ocular surgery had been performed in 28 patients (7.7%) before study inclusion and in another 28 patients (14.8%) during the subsequent observation period. Out of 365 JIA patients, OH was reported in 57 patients (15.6%) (Figure 1, Table 1). Patient demographics did not differ between patients with or without OH occurrence with regard to sex, JIA subtype, ANA positivity, age at uveitis onset, and duration of uveitis at baseline (P > .05, each), whereas OH patients were older at JIA onset, were older at study baseline, and had more uveitis-related eye complications and previous eye operations (Table 1). The incidence rate for OH was 0.02/person-year in the total group of patients included in the study.
previous ocular surgery (Figure 1; 21 eyes after glaucoma surgery, 2 eyes after cataract surgery, and another 2 eyes after other intraocular operations). In these patients, OH was noted at a mean of 5.3 6 12.4 months following ocular surgery. PREDICTORS FOR THE OCCURRENCE OF OCULAR HYPOTONY IN PATIENTS WITHOUT OCULAR SURGERY:
To investigate the predictors for the occurrence of OH unrelated to ocular surgery, all JIAU patients who did not have prior surgical ocular interventions within the previous
OCULAR HYPOTONY IN CHILDHOOD UVEITIS
47
TABLE 2. Patients With Juvenile Idiopathic Arthritis–Associated Uveitis: Occurrence of Ocular Hypotony Without a Temporal Association to Previous Ocular Surgery (Characteristics at Baseline) Univariate Regression Analysisb
JIA Uveitis, With Ocular JIA Uveitis, Hypotony Not Associated Without Ocular Hypotony, Parameter
Female sex, n (%) Bilateral uveitis, n (%) Subtype of JIA ANA positivity, n (%) Age at JIA onset, y, mean (SD) Age at uveitis onset, y, mean (SD) Total uveitis duration (mo) between initial documentation and final follow-up at our institution (SD) Uveitis duration (y) before hypotony, mean (SD) BCVA (mean logMAR 6 SD) IOP in mm Hg (mean 6 SD) LF, photon units/msec (mean 6 SD)c ACC grade (mean 6 SD)d Anterior chamber flare (mean 6 SD)d Posterior synechiae (%) Topical corticosteroids, n (%) Systemic corticosteroids, n (%) csDMARDs, n (%) bDMARDs, n (%)
With Previous Surgery (N ¼ 40)
No Previous Surgery (N ¼ 293)
26 (65.0) 34 (85.0)
194 (66.1) 184 (62.6)
.9 .02
1.06 3.51
0.48–2.2 1.37–9.04
33 (82.5) 3.5 (2.5) 4.8 (3.0) 86.5 (48.5)
89 (77.4) 3.77 (2.9) 5.9 (3.4) 74.1 (3.8)
.4 .9 .02 <.001
3.34 0.9 0.9 1.13
0.41–27.37 0.79–1.02 0.79–1.02 1.01–1.21
9.4 (15.8) 0.5 (60.6) 13.4 (4.9) 58.7 (101.8) 0.5 (0.6) 0.9 (1.0) 45.0 27 (67.5) 11 (27.5) 27 (67.5) 2 (5.0)
n.a. 0.2 (60.2) 14.0 (2.7) 39.8 (76.4) 0.7 (0.9) 0.5 (0.8) 26.1 192 (65.5) 43 (14.7) 171 (58.3) 7 (2.41)
.07 .2 .006 .4 .009 .006 .8 .1 .3 .8
5.10 0.95 1.74 0.67 1.74 3.28 1.2 2.27 1.61 2.02
1.77–14.75 0.85–1.06 1.13–2.67 0.40–1.14 1.13–2.67 1.47–7.32 0.55–2.62 0.95–5.39 0.74–3.50 0.32–12.54
P Valuea OR
95% CI
P Value
.95 .009 >.05 .2 .08 .08 <.001
.0008 .36 .013 .11 .013 .004 .65 .06 .27 .46
ACC ¼ anterior chamber cells; BCVA ¼ best-corrected visual acuity; bDMARDs ¼ biological disease-modifying antirheumatic drugs; CI ¼ confidence interval; csDMARDs ¼ conventional synthetic disease-modifying antirheumatic drugs; IOP ¼ intraocular pressure; IS ¼ immunosuppressive medication; JIA ¼ juvenile idiopathic arthritis; LF ¼ laser-flare photometry; OR ¼ odds ratio. _12 months were included in the analysis. Patients with follow-up > P < .05 statistically significant. a Mann-Whitney U test or x2 test (for categorical data). b Risk of occurrence of ocular hypotony was calculated with univariate regression analysis, and corresponding odds ratios, 95% confidence intervals, and P values are shown. c Kowa laser-flare device. d By slit lamp.
12 months were further analyzed. Patients with a follow-up _12 months were included in this analysis (40 patients). of > This group was compared with patients in whom OH did not occur and without previous surgery (293 patients _12 months). At baseline, OH patients with a follow-up > were also younger at onset of uveitis, but the 2 groups did not differ with respect to sex, JIA type, and ANA positivity. Furthermore, IOP, ACC grade, and lens status were similar in the 2 groups (Table 2). Univariate logistic regression analysis found a higher OH risk in patients with bilateral uveitis (OR 3.51, 95% CI 1.37–9.04; P ¼ .009), longer total uveitis duration (OR 1.13, 95% CI 1.01–1.21, P < .001), lower BCVA (OR 5.1, 95% CI 1.77–14.75, P ¼ .0008), higher LF values (OR 1.74, 95% CI 1.13–2.67, P ¼ .013), and presence of posterior synechiae at first examination (OR 3.28, 95% CI 1.47–7.32, P ¼ .004). Results of the univariate regression analysis are shown in Table 2. 48
In a multivariable logistic regression analysis, only a younger age at onset of JIA (OR 1.18, 95% CI 1.03–1.36, P ¼ .02), bilaterality of uveitis (OR 5.3, 95% CI 1.16– 23.9, P ¼ .03), and poor BCVA at first examination (OR 4.6, 95% CI 1.05–19.7, P ¼ .04) were independently associated with the onset of OH during the course of uveitis in JIA, whereas neither other clinical findings nor topical and systemic treatment at baseline were independently associated with a higher risk for OH (P > .05, each). No relationships between associated risk factors, generated subgroups, and different lengths of follow-up periods have been found, whereas the risk increased with the lengths of the follow-up period. COURSE OF OCULAR HYPOTONY UNRELATED TO PREVIOUS EYE SURGERY: Eyes with OH not associated with pre-
vious surgical procedures revealed a mean IOP of 4.3 6 2.0 mm Hg at a mean OH duration of 9.5 6 22.7 months.
AMERICAN JOURNAL OF OPHTHALMOLOGY
JANUARY 2017
TABLE 3. Patients With Juvenile Arthritis–Associated Uveitis: Characteristics at Baseline Related to Duration of Ocular Hypotony
Parameter
Female sex, n (%) Bilateral uveitis, n (%) Subtype of JIA Age at JIA onset, y, mean (SD) Age at uveitis onset, y, mean (SD) Uveitis duration (mo) at initial documentation at institution (SD) Uveitis duration before hypotony, y, mean (SD) BCVA (mean logMAR 6 SD) Intraocular pressure in mm Hg (mean 6 SD) LFM, photon units/msec (mean 6 SD)c ACC grade (mean 6 SD)d Anterior chamber flare (mean 6 SD)d Posterior synechiae (%) Topical steroids, n (%) Systemic corticosteroids, n (%) csDMARDs, n (%) bDMARDs, n (%)
_3 Months Ocular Hypotony <
Ocular Hypotony >3 Months
(N ¼ 15)
(N ¼ 25)
Univariate Regression Analysisb P Valuea
OR
95% CI
P Value
.81 .03 >.05 .98 .05 .08
9 (60.0) 11 (73.3)
17 (68.0) 24 (96.0)
.9 .04
1.18 12.0
0.3–4.69 1.24–116.2
3.5 (3.6) 5.6 (3.7) 32.6 (35.1)
3.5 (1.8) 4.2 (1.9) 58.9 (57.6)
.3 .1 .07
1.0 1.25 1.0
0.75–1.35 0.98–1.60 0.97–1.00
2.1 (2.4) 0.4 (0.5) 12.1 (6.3) 81.7 (149.2) 0.6 (0.6) 1.1 (0.8) 60.0 10 (66.7) 7 (46.7) 9 (60) 1 (6.67)
3.7 (2.8) 0.5 (0.7) 14.2 (3.7) 45.3 (59.8) 0.4 (0.5) 0.7 (1.1) 36.0 17 (68.0) 4 (16.0) 18 (72.0) 1 (4.0)
.08 .5 .04 .6 .4 .1 .5 .9 .06 .9 .7
0.79 0.76 0.91 1.00 1.66 1.45 0.5 0.85 5.25 1.43 1.85
0.59–1.04 0.24–2.40 0.78–1.06 0.99–1.01 0.5–5.47 0.71–2.97 0.12–2.06 0.2–3.56 1.18–23.46 0.35–5.79 0.11–32.0
.1 .64 .21 .33 .41 .31 .34 .82 .03 .62 .67
ACC ¼ anterior chamber cells; BCVA ¼ best-corrected visual acuity; bDMARDs ¼ biological disease-modifying antirheumatic drugs; CI ¼ confidence interval; csDMARDs ¼ conventional synthetic disease-modifying antirheumatic drugs; IOP ¼ intraocular pressure; IS ¼ immunosuppressive medication; JIA ¼ juvenile idiopathic arthritis; LFM ¼ laser-flare photometry; OR ¼ odds ratio. _12 months were included in the analysis. Patients with follow-up > P < .05 statistically significant. a Mann-Whitney U test or x2 test (for categorical data). b _3 months) and persistent (>3 months) ocular Univariate regression analysis was performed to assess predicting factors for transient (< hypotony. Odds ratios, 95% confidence intervals, and P values are shown. c Kowa laser-flare device. d By slit lamp.
_3 months (tranIn 37.5% of these eyes, OH duration was < sient OH) and in another 62.5% >3 months (persistent OH). A total of 4 eyes (8.9%) developed phthisis bulbi after a mean uveitis duration of 32.4 6 25.2 months and after a mean OH duration of 20.3 6 10.1 months, respectively. In an attempt to define predictive factors for transient or persistent OH course, the clinical data at initial documentation at our institution were analyzed. Patients with persistent OH revealed a higher rate of bilateral uveitis (96.0% vs 73.3%; P ¼ .04), interestingly had a higher IOP (14.2 6 3.7 mm Hg vs 12.1 6 6.3 mm Hg; P ¼ .04), and had received systemic corticosteroids slightly less frequently (16.0% vs 46.7%; P ¼ .06) at initial examination as compared with the group with transient OH, with the latter not reaching the level of significance. The groups did not differ in sex, type of JIA, age at onset of JIA or JIAassociated uveitis, BCVA, LF values, ACC grade, anterior chamber flare grade, or presence of posterior synechiae (Table 3). Univariate logistic regression analysis revealed a higher risk for transient OH for patients with bilateral onset of VOL. 173
uveitis (OR 12.0, 95% CI 1.24–116.2, P ¼ .03) and systemic use of corticosteroids (OR 5.25, 95% CI 1.18– 23.46, P ¼ .03). Table 3 summarizes baseline characteristics and results of univariate regression analysis owing to course of ocular hypotony. Multivariable regression analysis did not reveal any significant association of these parameters with the time courses of OH. OPHTHALMOLOGIC FINDINGS BEFORE AND AFTER ONSET OF OCULAR HYPOTONY: No significant difference
in BCVA values prior to OH and during the subsequent follow-up examinations was found (Tables 4 and 5). The mean ACC grades at the time point of OH onset were higher than at the visits 12 and 3 months before OH developed (P < .05, each; Table 4). In 64.5% of eyes with OH, LF values remained elevated up to 12 months after OH onset. The majority of patients with OH presented with elevated LF values (>20 photon units/ms) at the visits 12 months (70.4%) and 3 months (77.8%) prior to OH occurrence (Table 4). ACC grades significantly decreased
OCULAR HYPOTONY IN CHILDHOOD UVEITIS
49
TABLE 4. Occurrence of Ocular Hypotony in Patients With Juvenile Idiopathic Arthritis–Associated Uveitis: Ocular Findings Before and at Onset of Ocular Hypotony
BCVA logMAR (mean 6 SD) _0.2 logMAR (10 letters) (%) BCVA loss > IOP in mm Hg (mean 6 SD) AC cell grade (mean 6 SD) LFM in photon units/msec (mean 6 SD) _20 (%) LFM change > Keratic precipitates (%) Posterior synechiae (%) Band keratopathy (%) Cataract formation (%) Aphakia (%) IOL (%) Iris rubeosis (%) Optic disc edema (%) Macular edema (%) Epiretinal membrane formation (%)
12 Months Before Onset of Hypotony
3 Months Before Onset of Hypotony
0.41 6 0.58
0.45 6 0.37 30.8 10.2 6 3.8 0.4 6 0.6 89.5 6 139.1 77.8 44.4 47.4 62.2 20.8 20.8 25.0 0 37.5 9.3 13.3
9.9 6 4.7 0.4 6 0.8 51.9 6 55.2 70.4 36.0 52.2 57.7 25.8 19.4 22.6 0 31.8 9.5 19.1
P Valuea,b
ns ns ns <.05 ns ns ns ns ns
ns ns ns ns
At Onset of Hypotony
0.53 6 0.54 25.0 4.3 6 4.8 0.9 6 1.0 98.7 6 124.9 80.9 51.2 61.9 56.4 21.4 14.3 26.2 5.9 55.2 14.8 32.3
P Valuea,c
ns ns <.05 <.05 <.05 ns ns ns ns ns
ns ns ns ns
AC ¼ anterior chamber; BCVA ¼ best-corrected visual acuity; IOL ¼ intraocular lens; IOP ¼ intraocular pressure; LFM ¼ laser-flare photometry; ns ¼ not significant; OH ¼ ocular hypotony. P < .05 statistically significant. a Friedman test or McNemar test (for categorical data). b Twelve months prior to OH vs 3 months prior to OH. c Three months prior to OH vs OH onset.
6 months after OH onset (P < .05), whereas LF values remained elevated until 12 months after OH onset (Table 5). Although hypotony disappeared within 3 months (transient OH) in 15 children with OH (37.5%), the low IOP levels persisted for >3 months (persistent OH) in another 25 patients (62.5%). The median IOP in the group of patients with transient OH increased from 5 mm Hg at OH occurrence, to 12 mm Hg at 3 months (increase of IOP <3 mm Hg, 3–5 mm Hg, and >5 mm Hg in 20%, 20%, and 60% of patients, respectively). In the patients with transient OH, the low IOP was associated with high ACC grades (P < .05) and LF values (P < .05) as compared to the previous time points. Thereafter, the mean ACC grades and LF values decreased significantly within 3 months (P < .05) (Figure 2, Table 5). In the patients with persistent OH, the AC cell grades and LF values were already increased at 3 months prior to OH onset and were further slightly increased at the time point of OH onset (Figure 3). Whereas the percentages of patients with band keratopathy and cataract formation did not significantly increase between the time points at 12 and 3 months prior to OH occurrence and at the time OH occurred, a slight increase in complications such as posterior synechiae, rubeosis iridis, optic disc edema, macular edema, and epiretinal membrane formation was observed during this time period, 50
although it did not reach statistical significance (each P > .05; Table 4). At the visits 3 and 6 months after OH onset, the rate of optic disc edema and epiretinal membrane formation was significantly lower in patients with transient than in those with persistent OH (Table 5). TREATMENT BEFORE AND AFTER OCCURRENCE OF HYPOTONY: Owing to the severity of JIAU disease, the
majority of our patients were treated with conventional synthetic (cs) and/or biological (b) disease-modifying antirheumatic drugs (DMARDs): methotrexate (62.7% of patients) was the preferred csDMARD and adalimumab (25.6% of patients) was the most frequently used bDMARD before OH onset. Topical corticosteroid therapy was generally adjusted to uveitis activity at the discretion of the treating ophthalmologist, with nearly 51.9% and 25.9% of patients being _3 or >3 times daily treated with corticosteroid eye drops < (mean, 2.8 6 3.0), respectively, in the <12 months before OH onset (data not shown). Whereas 57.9% of pa_3 months before tients received topical corticosteroids < onset of OH, all patients were treated with topical corticosteroids (mean 3.6 6 3.3 drops/day) after OH developed. Furthermore, the percentage of patients taking systemic corticosteroids increased from 22.9% before to 40.0% after occurrence of OH (P > .05). After onset of OH, patients received csDMARDs more often than
AMERICAN JOURNAL OF OPHTHALMOLOGY
JANUARY 2017
VOL. 173 TABLE 5. Occurrence of Ocular Hypotony in Patients With Juvenile Idiopathic Arthritis–Associated Uveitis: Ocular Findings At and After Onset of Ocular Hypotony Onset of Hypotony
3 Months After Onset of Hypotony
OCULAR HYPOTONY IN CHILDHOOD UVEITIS
Duration of hypotony (mo) BCVA (mean 6 SD) IOP (mm Hg 6 SD)
< _3 0.44 6 0.36 4.9 6 1.5
>3 0.57 6 0.61 4.0 6 2.2
< _3 0.49 6 0.6 11.7 6 3.4
>3 0.75 6 0.54 5.1 6 3.5
ACC (mean 6 SD)
1.1 6 1.1
1.0 6 1.0
0.6 6 1.1
0.9 6 0.3
LFM (photon units/msec) (mean 6 SD) 94.4 6 117.1 108.3 6 129.9 72.3 6 104.8 _20 (%) LFM change > Keratic precipitates (%) Posterior synechiae (%) Band keratopathy (%) Cataract (%) Iris rubeosis (%) Optic disc edema (%)
57.1 64.3 41.7 26.7 4.2 40.0
Macular edema (%) Epiretinal membrane (%)
10.0 20.0
78.9 6 106.5
48.2 60.7 62.9 27.9 6.9 63.2
57.1 40.0 54.0 43.3 27.0 0 30.0
18.9 45.5 54.6 62.2 27.3 0 58.3
17.6 38.1
9.1 22.2
9.0 40.0
P Valuea,b
nsc,d,e <.05c,e nsd <.05c,e nsd nsc,d,e <.05e nsc,d,e nsc,d,e nsc,d,e nsc,d,e nsc,d nsc,d <.05e nsc,d nsc,d <.05e
6 Months After Onset of Hypotony
< _3 0.33 6 0.39 11.4 6 3.7
>3 0.44 6 0.53 7.4 6 3.7
0.3 6 0.7
0.4 6 0.9
45.4 6 57.4
80.9 6 108.5
0 25.0 60.0 46.2 26.7 0 30.0
44.4 25.0 57.6 62.9 26.1 0 50.0
5.0 18.2
6.7 41.2
P Valuea,b
nsc,d,e nsc <.05d,e nsc,e <.05d <.05c,e nsd <.05e nsc,d,e nsc,d,e nsc,d,e nsc,d,e nsc,d nsc,d <.05e nsc,d nsc,d <.05e
12 Months After Onset of Hypotony
< _3 0.57 6 0.7 11.45 6 4.1
>3 0.61 6 0.59 7.89 6 4.0
0.4 6 1.0
0.3 6 0.5
25.6 6 16.9
81.9 6 109.2
P Valuea,b
nsc,d,e nsc,e <.05d nsc,d,e
20.0 30.0 58.0 46.4 31.7 0 11.11
21.4 41.2 57.9 61.1 38.9 3.3 23.08
<.05c,e nsd nse nsc,d,e nsc,d,e nsc,d,e nsc,d,e nsc,d nsc,d,e
5.0 30
6.2 46.7
nsc,d nsc,d,e
AC ¼ anterior chamber; BCVA ¼ best-corrected visual acuity; IOL ¼ intraocular lens; IOP ¼ intraocular pressure; LFM ¼ laser-flare photometry; ns ¼ not significant. P < .05 statistically significant. a Compared to last time point: Friedman test and McNemar test (for categorial data). b Acute vs chronic ocular hypotony: Mann-Whitney U test or x2 test (for categorial data). c _3 months group. Compared to last time point: < d Compared to last time point: >3 months group. e _3 months group and >3 months group. Comparison between <
51
FIGURE 2. Onset of ocular hypotony (OH) in patients with juvenile idiopathic arthritis–associated uveitis. Course of intraocular pressure, laser flare photometry values, and anterior chamber cell grade in transient ocular hypotony (£3 months). Course is presented 3 months before and up to 12 months after occurrence of ocular hypotony. Mean values with standard deviation error bars are presented. *P < .05. ACC [ anterior chamber cell grade; IOP [ intraocular pressure; LF [ laser flare photometry value; OH [ ocular hypotony.
before (81.5% vs 69.3%; P ¼ .03) and also received a tumor necrosis factor inhibitor more often, and the number of patients that were switched from a csDMARD to a bDMARD increased.
DISCUSSION IN THIS STUDY WE ANALYZED THE OCCURRENCE AND
course of OH in a large cohort of JIAU at a single tertiary uveitis center. Up to now, only limited data on this issue were available for uveitis in general, and data for JIAU were even scarcer.15,16,28–30 In our study, we found an occurrence of OH in about 15% of our patients with JIAU (mean follow-up time 4.5 years), which was higher than in previous publications, where a prevalence of OH between 3% and 9% was reported.9,13–16 The different frequencies might be explained by different patient populations, potential selection bias, differences in follow-up time, treatment patterns, and also OH definitions. The disease severity of our patient group is emphasized by the high rate of ocular comorbidity. Different definitions of OH can be found in the literature, ranging from an IOP <6 to <8 mm Hg.31 An IOP less than 6 mm Hg at 2 consecutive visits was used in our study, which is in accordance with the previously published outcome measures for JIAU.24 Furthermore, we distin_3 months duration) from persistent guished transient (< (>3 months) OH in order to identify the potential longterm risk. 52
Thirteen of our 365 patients (25 eyes) developed OH after previous ocular surgery, in particular after glaucoma surgery (21 eyes). OH occurring after previous intraocular surgery in patients with JIA-associated uveitis is often related to surgically induced inflammation.32–34 This highlights the need for appropriate anti-inflammatory treatment, in particular at the time of eye surgery. Moreover, an appropriate anti-inflammatory treatment, in particular at the time of eye surgery, is mandatory. The high OH incidence after glaucoma surgery is well known, even in patients without uveitis. Whereas numerous data about the incidence, severity, and duration of OH after ocular and especially glaucoma surgery can be found in the literature,35 there is only little information about uveitis36 and particularly JIAU.9,13–16 The vast majority of OH incidences in our study population, however, were related to inflammatory components: high LF and AC flare and posterior synechiae were valid risk factors for OH occurrence. Apparently, the risk of developing OH in patients without previous ocular surgery increases with binocular disease and young age at JIA recognition. The findings of a higher mean age at JIA recognition in all patients with onset of OH, including those with previous ocular surgery, may be explained by a potential delayed JIA recognition in this group. This may have also led to a delayed uveitis diagnosis in some patients, as uveitis screening understandably starts only after recognition of systemic disease.37 Poor visual acuity represents another risk factor for OH, as it was commonly related to other ocular complications in eyes with a severe course of uveitis.
AMERICAN JOURNAL OF OPHTHALMOLOGY
JANUARY 2017
FIGURE 3. Onset of ocular hypotony (OH) in patients with juvenile idiopathic arthritis–associated uveitis. Course of intraocular pressure, laser flare photometry values, and anterior chamber cell grade in persistent ocular hypotony (>3 months). Course is presented 3 months before and up to 12 months after occurrence of ocular hypotony. Mean values with standard deviation error bars are presented. *P < 0.05. ACC [ anterior chamber cell grade; IOP [ intraocular pressure; LF [ laser flare photometry value; OH [ ocular hypotony.
An important finding is the increase in AC flare and cells prior to the occurrence of OH. Furthermore, eyes with high LF values, indicating a breakdown of the blood-aqueous barrier (BAB),23,27 were found to be at high risk for subsequent OH. This is in accordance with previous findings, where high LF was identified as a significant risk factor for subsequent ocular complications such as OH and for a poorer visual outcome.23,38 It may be speculated from the data that a less frequent use of systemic corticosteroids put the patients at an increased risk for OH, in particular when OH persisted for >3 months. In this circumstance, inflammatory activity might have been apparent, but occult inflammation of the ciliary body may potentially also have been present (without AC cells), which puts the patient at risk of being undertreated. Here, LF helped detect smoldering uveitis activity, especially if AC cells were not present. Intraocular inflammation may decrease aqueous production, increase uveoscleral outflow, and cause supraciliary or suprachoroidal leakage.17–19 Consequently, OH related to inflammation may be reversible with appropriate antiinflammatory medication in order to achieve uveitis inactivity.15,18,24 However, an irreversible decrease in aqueous humor production in the ciliary body may result from concomitant atrophy or ischemia of the uveal tissue, from ciliary traction, or iatrogenically as a long-term consequence of ocular surgery,12,18,39 and may ultimately cause irreversible ocular phthisis in selected cases.19 Increased LF values and AC cells are important measures for disrupting the BAB and also appear to be valuable VOL. 173
indicators for the subsequent OH course and the related ocular complications. Indeed, our data show that typical consequences of transient OH were found more often in these instances, for example optic disc edema and epiretinal membrane formation. This indicates that children with a more severe course of disease, namely a breakdown of the BAB, are at a particularly high risk for OH already at initial stages of disease. Accordingly, children with a high uveitis activity developed secondary ocular complications more often during the subsequent disease course.13 Although most of our patients were treated with topical and systemic corticosteroids, and also DMARDs already before the onset of OH, the topical corticosteroid dosages were increased after OH developed, or conventional synthetic and/or biological DMARDs were added or switched at the discretion of the treating ophthalmologist. This may be important for reversing and restoring ciliary body function. Further studies are required that confirm the value of immunosuppression for the management of JIA-related OH. The AC cell grades decreased within 3 months after transient OH (Figure 2) and within 6 months after occurrence of persistent OH (Figure 3) developed. However, whereas the LF values returned to normal in transient OH, they remained high in eyes with a chronic disruption of the BAB, although the anti-inflammatory treatment was escalated. This probably documents the advanced, and potentially irreversible, tissue damage in these eyes, eventually leading to poor visual prognosis and ocular phthisis.19,40
OCULAR HYPOTONY IN CHILDHOOD UVEITIS
53
This study has certain limitations, such as the retrospective study design with differential follow-up and referral patterns. The patient cohort at a tertiary uveitis center may produce a selection bias in favor of more severe cases. Data from registries on representative population-based cohorts of JIAU children might provide further insight on the OH risk and its course in future investigations. However, standardized protocols for JIAU were used routinely for the documentation in this study, and patients were seen by 2 JIAU specialists in order to provide reliable data. The presented study focused on the presentation of mean values for changes of the relevant parameters such as the IOP. The definition used in this study for resolution may be based on minimal changes that could be clinically unimportant in some individuals. Therefore, the percentage of patients in the transient OH group with an IOP increase of 3–5 mm Hg and >5 mm Hg was also provided in the results sections; however, it is unclear which increase of IOP is clinically relevant for the individual patient. As the mean follow-up in the present study was only 4.5 years,
the OH rate over the long-term course might even be higher than estimated by our observation. The follow-up varied between the patients in our cohort. The total uveitis duration between initial documentation and final followup at our institution was significantly longer in JIA uveitis cases with OH than without OH. This is supporting the notion that OH is a late manifestation of disease. This notion may not significantly change if all patients had the same length of follow-up. This study shows that OH represents a significant risk factor in JIAU patients with long-lasting disease courses. Therefore, determining risk factors for OH, such as bilaterality of JIA uveitis, young age at disease onset, increased AC flare and LF grades, and posterior synechiae, might be useful for identifying children at risk for subsequent OH occurrence, probably already at an early stage of disease. Further prospective studies are needed to optimize immunomodulatory treatment in this risk group of JIA uveitis in order to prevent potentially irreversible OH and its deleterious consequences.
FUNDING/SUPPORT: INNOVATIVE MEDIZINISCHE FORSCHUNG (IMF) OF THE WESTFALIAN WILHELMS-UNIVERSITY OF ¨ 221307; German Research Foundation (DFG), Bonn, Germany, grant BO 4556/1-1 (M.R.R.B.); IFORES support of Mu¨nster, Germany, grant I-BO the Faculty of Medicine of the University Duisburg/Essen, Essen, Germany (M.R.R.B.); Bundesministerium fu¨r Bildung und Forschung (BMBF), Berlin, Germany, grant 01ER1504C (A.H.). Financial Disclosures: Michael R.R. Bo¨hm: travel grant from The Association for Research in Vision and Ophthalmology (ARVO) for annual meeting of the ARVO in Seattle, Washington, USA (2013); travel grant from Novartis Pharma GmbH, Nuremberg, Germany for Novartis - Meeting ‘‘VEGF and beyond’’ in Berlin, Germany (2014). Carsten Heinz: lectures for Bayer, Leverkusen, Germany, and Novartis, Nuremberg, Germany; Advisory Board for Desitin, Hamburg, Germany, and AbbVie, Wiesbaden, Germany. Arnd Heiligenhaus: German Research Foundation (DFG), Bonn, Germany, grant HE 1877/19-1. The following authors have no financial disclosures: Christoph Tappeiner, Marc A. Breitbach, and Beatrix Zurek-Imhoff. All authors attest that they meet the current ICMJE criteria for authorship.
REFERENCES 1. Petty RE. Growing pains: the ILAR classification of juvenile idiopathic arthritis. J Rheumatol 2001;28(5):927–928. 2. Ravelli A, Felici E, Magni-Manzoni S, et al. Patients with antinuclear antibody-positive juvenile idiopathic arthritis constitute a homogeneous subgroup irrespective of the course of joint disease. Arthritis Rheum 2005;52(3):826–832. 3. Kanski JJ. Juvenile arthritis and uveitis. Surv Ophthalmol 1990;34(4):253–267. 4. Kotaniemi K, Kautiainen H, Karma A, Aho K. Occurrence of uveitis in recently diagnosed juvenile chronic arthritis: a prospective study. Ophthalmology 2001;108(11):2071–2075. 5. Carvounis PE, Herman DC, Cha S, Burke JP. Incidence and outcomes of uveitis in juvenile rheumatoid arthritis, a synthesis of the literature. Graefes Arch Clin Exp Ophthalmol 2006; 244(3):281–290. 6. Tappeiner C, Klotsche J, Schenck S, Niewerth M, Minden K, Heiligenhaus A. Temporal change in prevalence and complications of uveitis associated with juvenile idiopathic arthritis: data from a cross-sectional analysis of a prospective nationwide study. Clin Exp Rheumatol 2015;33(6):936–944. 7. Davis JL, Dacanay LM, Holland GN, Berrocal AM, Giese MJ, Feuer WJ. Laser flare photometry and complications of chronic uveitis in children. Am J Ophthalmol 2003;135(6): 763–771.
54
8. Sabri K, Saurenmann RK, Silverman ED, Levin AV. Course, complications, and outcome of juvenile arthritis-related uveitis. J AAPOS 2008;12(6):539–545. 9. Thorne JE, Woreta F, Kedhar SR, Dunn JP, Jabs DA. Juvenile idiopathic arthritis-associated uveitis: incidence of ocular complications and visual acuity loss. Am J Ophthalmol 2007; 143(5):840–846. 10. Thorne JE, Woreta FA, Dunn JP, Jabs DA. Risk of cataract development among children with juvenile idiopathic arthritis-related uveitis treated with topical corticosteroids. Ophthalmology 2010;117(7):1436–1441. 11. Foster CS, Havrlikova K, Baltatzis S, Christen WG, MerayoLloves J. Secondary glaucoma in patients with juvenile rheumatoid arthritis-associated iridocyclitis. Acta Ophthalmol Scand 2000;78(5):576–579. 12. Vitale AT, Graham E, de Boer JH. Juvenile idiopathic arthritis-associated uveitis: clinical features and complications, risk factors for severe course, and visual outcome. Ocul Immunol Inflamm 2013;21(6):478–485. 13. Heiligenhaus A, Niewerth M, Ganser G, Heinz C, Minden K, German Uveitis in Childhood Study Group. Prevalence and complications of uveitis in juvenile idiopathic arthritis in a population-based nation-wide study in Germany: suggested modification of the current screening guidelines. Rheumatology (Oxford) 2007;46(6): 1015–1019.
AMERICAN JOURNAL OF OPHTHALMOLOGY
JANUARY 2017
14. de Boer J, Wulffraat N, Rothova A. Visual loss in uveitis of childhood. Br J Ophthalmol 2003;87(7):879–884. 15. Sen HN, Drye LT, Goldstein DA, et al. Hypotony in patients with uveitis: The Multicenter Uveitis Steroid Treatment (MUST) Trial. Ocul Immunol Inflamm 2012;20(2):104–112. 16. Loh AR, Acharya NR. Incidence rates and risk factors for ocular complications and vision loss in HLA-B27associated uveitis. Am J Ophthalmol 2010;150(4):534–542e2. 17. Mermoud A, Baerveldt G, Minckler DS, Lee MB, Rao NA. Measurement of rabbit intraocular pressure with the TonoPen. Ophthalmologica 1995;209(5):275–277. 18. Toris CB, Pederson JE. Aqueous humor dynamics in experimental iridocyclitis. Invest Ophthalmol Vis Sci 1987;28(3): 477–481. 19. Tran VT, Mermoud A, Herbort CP. Appraisal and management of ocular hypotony and glaucoma associated with uveitis. Int Ophthalmol Clin 2000;40(2):175–203. 20. Petty RE, Southwood TR, Manners P, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 2004;31(2):390–392. 21. Brooks P, Hochberg M. Outcome measures and classification criteria for the rheumatic diseases. A compilation of data from OMERACT (Outcome Measures for Arthritis Clinical Trials), ILAR (International League of Associations for Rheumatology), regional leagues and other groups. Rheumatology (Oxford) 2001;40(8):896–906. 22. Jabs DA, Nussenblatt RB, Rosenbaum JT, Standardization of Uveitis Nomenclature Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol 2005; 140(3):509–516. 23. Tappeiner C, Heinz C, Roesel M, Heiligenhaus A. Elevated laser flare values correlate with complicated course of anterior uveitis in patients with juvenile idiopathic arthritis. Acta Ophthalmol 2011;89(6):e521–e527. 24. Heiligenhaus A, Foeldvari I, Edelsten C, et al. Proposed outcome measures for prospective clinical trials in juvenile idiopathic arthritis-associated uveitis: a consensus effort from the multinational interdisciplinary working group for uveitis in childhood. Arthritis Care Res (Hoboken) 2012; 64(9):1365–1372. 25. Gonzales CA, Ladas JG, Davis JL, Feuer WJ, Holland GN. Relationships between laser flare photometry values and complications of uveitis. Arch Ophthalmol 2001;119(12):1763–1769. 26. Ladas JG, Wheeler NC, Morhun PJ, Rimmer SO, Holland GN. Laser flare-cell photometry: methodology and clinical applications. Surv Ophthalmol 2005;50(1):27–47.
VOL. 173
27. Ladas JG, Yu F, Loo R, et al. Relationship between aqueous humor protein level and outflow facility in patients with uveitis. Invest Ophthalmol Vis Sci 2001;42(11): 2584–2588. 28. Kump LI, Castaneda RA, Androudi SN, Reed GF, Foster CS. Visual outcomes in children with juvenile idiopathic arthritis-associated uveitis. Ophthalmology 2006;113(10): 1874–1877. 29. Tugal-Tutkun I, Havrlikova K, Power WJ, Foster CS. Changing patterns in uveitis of childhood. Ophthalmology 1996; 103(3):375–383. 30. Smith JA, Mackensen F, Sen HN, et al. Epidemiology and course of disease in childhood uveitis. Ophthalmology 2009; 116(8):1544–1551e1. 31. Pederson J, Hypotony. In: Tasman WJE, ed. Duane’s Clinical Ophthalmology. Philadelphia, PA: Lippincott-Raven; 1999:1–8. 32. Kotaniemi K, Penttila H. Intraocular lens implantation in patients with juvenile idiopathic arthritis-associated uveitis. Ophthalmic Res 2006;38(6):318–323. 33. Meacock WR, Spalton DJ, Bender L, et al. Steroid prophylaxis in eyes with uveitis undergoing phacoemulsification. Br J Ophthalmol 2004;88(9):1122–1124. 34. Phatak S, Lowder C, Pavesio C. Controversies in intraocular lens implantation in pediatric uveitis. J Ophthalmic Inflamm Infect 2016;6(1):12. 35. Schubert HD. Postsurgical hypotony: relationship to fistulization, inflammation, chorioretinal lesions, and the vitreous. Surv Ophthalmol 1996;41(2):97–125. 36. Edmunds B, Thompson JR, Salmon JF, Wormald RP. The National Survey of Trabeculectomy. III. Early and late complications. Eye (Lond) 2002;16(3):297–303. 37. Heiligenhaus A, Heinz C, Edelsten C, Kotaniemi K, Minden K. Review for disease of the year: epidemiology of juvenile idiopathic arthritis and its associated uveitis: the probable risk factors. Ocul Immunol Inflamm 2013; 21(3):180–191. 38. Holland GN. A reconsideration of anterior chamber flare and its clinical relevance for children with chronic anterior uveitis (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc 2007;105:344–364. 39. Roters S, Szurman P, Engels BF, Bartz-Schmidt KU, Krieglstein GK. Ultrasound biomicroscopy in chronic ocular hypotony: its impact on diagnosis and management. Retina 2002;22(5):581–588. 40. Kim HS, Lee EH, Sungjoo KY, Joo CK. Immunopathogenesis of experimental melanin-protein induced uveitis. Korean J Ophthalmol 1998;12(1):14–18.
OCULAR HYPOTONY IN CHILDHOOD UVEITIS
55