Ocular Immunology and Inflammation
ISSN: 0927-3948 (Print) 1744-5078 (Online) Journal homepage: http://www.tandfonline.com/loi/ioii20
Foveal Serous Retinal Detachment in Juvenile Idiopathic Arthritis-associated Uveitis Feng Liang MD, Celine Terrada MD, PhD, Ghislaine Ducos de Lahitte MD, Pierre Quartier MD, PhD, Phuc Lehoang MD, PhD, Jennifer E. Thorne MD & Bahram Bodaghi MD, PhD To cite this article: Feng Liang MD, Celine Terrada MD, PhD, Ghislaine Ducos de Lahitte MD, Pierre Quartier MD, PhD, Phuc Lehoang MD, PhD, Jennifer E. Thorne MD & Bahram Bodaghi MD, PhD (2015): Foveal Serous Retinal Detachment in Juvenile Idiopathic Arthritis-associated Uveitis, Ocular Immunology and Inflammation, DOI: 10.3109/09273948.2015.1012297 To link to this article: http://dx.doi.org/10.3109/09273948.2015.1012297
Published online: 14 Jul 2015.
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Date: 15 October 2015, At: 03:32
Ocular Immunology & Inflammation, Early Online, 1–6, 2015 ! Informa Healthcare USA, Inc. ISSN: 0927-3948 print / 1744-5078 online DOI: 10.3109/09273948.2015.1012297
ORIGINAL ARTICLE
Foveal Serous Retinal Detachment in Juvenile Idiopathic Arthritis-associated Uveitis Feng Liang, MD1*, Celine Terrada, MD, PhD1, Ghislaine Ducos de Lahitte, MD1, Pierre Quartier, MD, PhD2, Phuc Lehoang, MD, PhD1, Jennifer E. Thorne, MD3,4, and Bahram Bodaghi, MD, PhD1
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1
Department of Ophthalmology, University of Paris VI, Pitie´-Salpeˆtrie`re Hospital, Paris, France, 2Unit of Immuno-Hematology and Pediatric Rheumatology, Necker-Enfants Malades Hospital, Paris, France, 3 Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, and 4 Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA
ABSTRACT Purpose: In juvenile idiopathic arthritis (JIA)-associated uveitis complicated by foveal serous retinal detachment (FSRD), we documented the relationship between best corrected visual acuity (BCVA), level of anterior chamber flare and OCT features. Methods: Nine children (15 eyes) with FSRD were identified among 38 children with JIA-associated maculopathy. Outcome measures included BCVA, ocular inflammatory activity quantified by laser flare photometry and the macular profile analyzed by OCT. Results: The diagnosis of FSRD led to intensification of the treatment using subtenon’s injection of triamcinolone or systemic immunomodulatory therapy. The improvement of BCVA at presentation (0.46 logMAR) was significant at 36 months follow-up (0.15 logMAR). The resolution of FSRD along with visual improvement (p = 0.0032) correlated with improvement in anterior chamber flare (p = 0.01). Conclusion: FSRD is a complication of chronic JIA-associated uveitis that responds well to intensification of immunomodulation. Visual improvement is correlated with FSRD resolution and with flare photometry values. Keywords: Flare, foveal serous retinal detachment, juvenile idiopathic arthritis, OCT, uveitis
Juvenile idiopathic arthritis (JIA)-associated uveitis (JIAAU) is the most common cause of pediatric uveitis.1–3 JIAAU may be complicated by cataract, glaucoma, band keratopathy, posterior synechiae, and/or ocular hypotony.1,2,4,5 Occurring in 20% of children with JIA, chronic uveitis leads to significant visual impairment in one-third of affected eyes.1,4 Recently, optical coherence tomography (OCT) revealed that macular changes may be found in more than 80% of cases.6 Four OCT patterns of maculopathy were described by OCT imaging: perifoveal thickening, macular edema, foveal serous retinal detachment (FSRD), and macular atrophy.6
Although uveitic macular edema has been studied extensively, the occurrence of FSRD remains unclear. The subgroup of patients with FSRD of this previous study was interesting and worthy to be detailed. The aim of this study is to characterize the evolution of FSRD in JIAAU and to describe its response to therapy.
MATERIAL AND METHODS The records of children with JIAAU and OCT evidence of maculopathy, who were managed
*This work was presented as a poster at the ARVO 2009 annual meeting. Received 8 May 2014; revised 21 January 2015; accepted 22 January 2015; published online 10 July 2015 Correspondence: Bahram Bodaghi, Department of Ophthalmology, Pitie´-Salpeˆtrie`re Hospital, University of Paris VI, 47-83 Boulevard de l’Hoˆpital, Cedex 13, 75651 Paris, France. E-mail: [email protected]
1
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between April 2005 and July 2011 at the Department of Ophthalmology of the Pitie-Salpetriere Hospital (Paris, France), were reviewed retrospectively. The study was performed in adherence to the tenets of the Declaration of Helsinki and approved by a local ethics committee. Anterior chamber flare measured by laser flare photometry and presence of FSRD demonstrated by OCT were used to assess the effectiveness of additional immunomodulating therapy. Improvement of ocular inflammation was defined as at least a 30% reduction of anterior chamber flare and resolution of FSRD on OCT. Children were examined monthly for 3 months, then every 3 months thereafter for a median follow-up time of 33 months (range: 12–44 months). At each visit, ophthalmologic examination included best corrected visual acuity (BCVA), slit-lamp examination, tonometry, and dilated fundus examination. Snellen visual acuity was converted to a logarithm of the minimum angle of resolution (logMAR) for analyses. Ocular inflammation activity was quantified by slitlamp examination following the SUN classification of anterior chamber flare and cells.7 Laser flare photometry (FC500-Kowa, Japan) was done at each visit. The mean of 10 consecutive measures was determined. Normal flare values are below 7 ph/ms.8 Macular profile was analyzed using an OCT Stratus 3 (Version 4, Carl Zeiss Meditec, USA). A macular map was generated from 6 radial scans. Foveal thickness (FT) was defined by the mean retinal thickness of the central 1000 mm.6 Perifoveolar thickness (PFT) was the average of the retinal thickness in the central 3000 mm. Macular edema was defined by an FT greater than 252 mm, and the perifoveolar thickening was defined by a PFT greater than 288 mm. The reference of values of macula edema and perifoveolar thickening were based on the literature.6,9 FSRD was defined by the presence of retrofoveolar subretinal fluid visualized on OCT. Results are expressed as means with standard deviation (SD). Statistical analysis was performed by using the Wilcoxon test, correlation test, and pairedsamples Student t-test with nominal p values. A p value of 50.05 was considered statistically significant.
RESULTS Of 38 children with JIAAU of a previous OCT study of JIAAU,6 9 children (8 female, 1 male) having FSRD in at least 1 eye as demonstrated by OCT testing were included in this study. All 9 children had the pauciarticular subtype of JIA and were antinuclear antibody (ANA) positive. One child tested positive for the HLA-B27 haplotype as well. All children had asymptomatic, bilateral chronic anterior uveitis. Fifteen of 18 eyes had FSRD.
Six (66.7%) children had bilateral FSRD. The mean age at the onset of JIA was 3.6 ± 0.75 years and 4.1 ± 1.1 years at the onset of uveitis. The mean age at the diagnosis of FSRD by OCT was 7.6 ± 2.2 years. FSRD was diagnosed a mean time of 2.75 ± 0.67 years after the diagnosis of uveitis. At the time of first detection on OCT, 20% (3/15 eyes) of FSRD were observed without other macular abnormalities, 66.7% (10 eyes) were associated with perifoveolar thickening, 46.7% (7 eyes) with diffuse macular edema, and 13.3% (2 eyes) with cystoid macular edema. The mean BCVA for each feature was 0.40 ± 0.30 logMAR, 0.42 ± 0.33 logMAR, 0.54 ± 0.35 logMAR (p = .26), and 0.68 ± 0.29 logMAR (p = .13), respectively. At first detection of FSRD, the baseline mean flare values were 177 ± 99 photon/ms. Seven of 15 eyes (47%) had 1 + or more anterior chamber cells, 3 (20%) had trace anterior chamber cells, and 5 (33.3%) had no cells. Two eyes (13.3%) had mild vitreous inflammation and 1 (6.7%) had papillitis. Anterior segment complications, including posterior synechiae (86.7%, 13 eyes), cataract (80%, 12 eyes), band keratopathy (60%, 9 eyes), and glaucoma (20%, 3 eyes) were present in all children. Among eyes with cataract, 7 eyes underwent cataract surgery 8–42 months (median = 17 months) before the occurrence of FSRD, and 3 eyes underwent cataract surgery 24–30 months (median = 25 months) after the first detection of FSRD. At presentation, 5 of 9 children were treated with prednisone, 6 with methotrexate (MTX), and 4 with naproxen. The discovery of FSRD led to the addition of periocular corticosteroid injection, systemic immunomodulatory therapy (MTX, azathioprine), or antiTNFa agents (etanercept, infliximab, or adalimumab). Dosages of medications were sub-Tenon injection of triamcinolone 5 mg (n = 2); azathioprine 4 mg/kg/day (n = 1); methotrexate 0.4–1 mg/kg/weekly (n = 3); etanercept 0.4 mg/kg twice weekly (n = 3); infliximab 4–5 mg/kg at 2-week intervals initially, then tapered to 6-week intervals (n = 5); and adalimumab 1.5 mg/ kg at 2-week intervals (n = 3). The FSRD responded quickly to changes in immunomodulatory therapy. At 6 months, FSRD resolved in 14 of 15 eyes and mean BCVA improved to 0.22 ± 0.20 logMAR (p = 0.0087). Both FT and PFT were unchanged (p = 0.15 and 0.26, respectively), as was the diffuse macula edema (p = .15). Children demonstrated a rapid response of anterior chamber inflammation. The reduction of flare measured by laser flare photometry was 40.6% (p = 0.0028) and 34.1% (p = 0.001) at 6 and 36 months compared with initial exam. Decreased flare correlated also with decreased FSRD. At 12 months follow-up, BCVA continued to improve to 0.19 ± 0.20 logMAR (p = 0.0015) and FT began to decrease (p = 0.03). At 36 months follow-up, final BCVA was 0.15 ± 0.096 logMAR (p = 0.0032), with significant Ocular Immunology & Inflammation
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2015 Informa Healthcare USA, Inc.
61/F
71/M
72/F
120/F
120/F
120/F
156/F
96/F
2
3
4
5
6
7
8
9
±
±
±
±
±
+/+
±
±
±
ANA/HLA B27
Posterior synechiae, cataract, BK
Cataract, BK
Posterior synechiae, cataract, BK
Posterior synechiae, cataract, BK, glaucoma
Posterior synechiae, cataract, glaucoma
Posterior synechiae, BK, glaucoma
Posterior synechiae, cataract, BK, papillitis
Posterior synechiae, papillitis
Posterior synechiae, cataract
Ocular complications at initial exam
OU
OD
OD
OU
OU
OS
OU
OU
OU
FSRD (OD/OS/ OU)
PFT Diffuse ME PFT CME
PFT
PFT
Diffuse ME
PFT
Diffuse ME
PFT CME
PFT Diffuse ME
Other associated maculopathy
Prednisone + MTX (F) Prednisone + MTX + infliximab (S)
MTX + etanercept (F) Prednisone + MTX + adalimumab (F) Prednisone + MTX + infliximab (S) MTX + etanercept (F) MTX + adalimumab (DC) MTX + infliximab (S) Prednisone (F) MTX + etanercept (F) Prednisone + MTX + infliximab (S) Naproxen (F) Naproxen + periocular triamcinolone injection (S) Prednisone (F) MTX (S) Prednisone + MTX + azathioprine (F) Prednisone + MTX + infliximab (S) Prednisone (F) Periocular triamcinolone injection (S) Prednisone + MTX (F) + adalimumab (S)
Treatment
Treatments at the time of diagnosis of FSRD (first line of the table) and after the detection of FSRD are documented. FSRD, foveolar serous retinal detachment; PFT, perifoveolar thickening; ME, macular edema; CME, cystoids macular edema; MTX, methotrexate; BK, band keratopathy; F, failure, S, success.
65/F
1
Case
Age (months)/ gender
TABLE 1. Demographics and clinical characteristics.
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Foveal Serous Retinal Detachment and JIA 3
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FIGURE 1. Foveal serous retinal detachment (FSRD) with perifoveolar thickening on OCT (top). Complete resolution of FSRD 6 months after infliximab (bottom).
decrease of FT (p = 0.004). PFT remained unchanged (p = 0.33). FSRD persisted in only 1 eye (Table 1). The 3 patients treated with etanercept (cases 1, 2, 3) did not show resolution of FSRD on OCT and subsequently were switched to adalimumab (cases 1, 2) or infliximab (case 3). Case 1 finally was treated with infliximab for joint inflammation that was refractory to adalimumab therapy. In case 2, adalimumab was discontinued due to adverse psychological events, leading to severe inflammatory relapse with diffuse macular edema and FSRD. Cystoid macular edema occurred 3 months later. Infliximab finally controlled ocular inflammation and led to a complete resolution of cystoid macular edema and FSRD (Figure 1). Case 6 was a nonresponder to azathioprine and case 8 did not respond to MTX. In these 2 latter cases, the treatment was switched to infliximab. Case 9 had persistent ocular inflammation despite high-dose MTX and required infliximab. Table 2 summarizes the treatments for each case.
DISCUSSION FSRD is a fairly common complication in severe JIAAU, accounting for 23% of macular complications in JIAAU.6 Indeed, FSRD probably occurs more frequently than most ophthalmologists realize, and it resolves with treatment of the inflammation, with good visual acuity results. It seems that FSRD in JIAAU may be a marker of undertreatment with systemic immunosuppression. In our series, the majority of children (8/9) had risk
factors of severe JIAAU (pauciarticular subtype, young age, and ANA positivity). Compared with previously reported series of JIAAU in which children with FSRD had higher frequencies of complications: posterior synechiae 87% versus 28%,1,2 cataract 80% versus 23%,1,2 band keratopathy 60% versus 32%.1,2 At the initial examination, although 33% of eyes had no cells, the mean flare (177 photon/ms) was much higher than normal level (7 photon/ms),8,10,11 despite the fact that 8 of 9 children are treated with MTX and systemic corticosteroids. This confirmed that the laser flare measurement was helpful and more sensitive than clinical examination in detecting subclinical relapse. Consistent with previous reports,11–13 FSRD was associated with a worse VA in patients with JIAAU, but it responded well to corticosteroids. We showed that FSRD responded quickly to initial intensive therapy, since the FSRD resolved in 14 of 15 (93%) eyes at the 6-month follow-up visit. Furthermore, visual loss due to FSRD in JIAAU also improved as a result of intensive immunosuppressive therapy, independent of the persistence of macular thickening. The effects of intensive therapy persisted until the last follow-up. Our results show that chronic uveitis was associated with later FSRD and it was probably associated with early macular thickening in children with JIAAU, which conformed to previous studies.14 The significance of findings relating to flare is interesting and potentially useful for practitioners. In our series, high laser flare values at baseline correlated with the presence of FSRD. After additional immunomodulatory therapy, statistically significant Ocular Immunology & Inflammation
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2015 Informa Healthcare USA, Inc.
FT, foveal thickness; PFT, perifoveolar thickness. D flare = (final flare – initial flare)/initial flare expressed in percentile. All statistics were compared between baseline and M6, M12, M18, M36.
0.010 34.1 0.011 31.9 0.0010 18.3 0.0028 40.6
113 ± 57 101 ± 62 99 ± 77 0.0096 105 ± 75 176 ± 99
15/15 7/15 eyes (46.7%)
295 ± 42
261 ± 50
0.15 ± 0.096 0.0032 188 ± 38 0.0040 304 ± 24 0.33 1/15 2/15 eyes (13.3%) 0.0096 0.15 ± 0.10 0.0015 207 ± 14 0.030 314 ± 11 0.21 1/15 0/15 eyes (0%) 0.0018 0.19 ± 0.20 0.0039 196 ± 27 0.0015 304 ± 24 0.32 1/15 3/15 eyes (20%) 0.020 0.22 ± 0.20 0.0087 229 ± 48 0.12 315 ± 30 0.20 1/15 2/15 eyes (13.3%) 0.46 ± 0.36
BCVA (logMAR) p FT (mm) p PFT (mm) p FSRD (eyes) Anterior chamber cells 1 + at biomicroscopy (eyes) p Anterior chamber flare (photon/ms) p D flare (%)
36 months follow-up 18 months follow-up 12 months follow-up 6 months follow-up Initial
TABLE 2. Best corrected visual acuity (BCVA), optical coherence tomography, ophthalmological characterization, and flare evolution after additional immunosuppressive therapy.
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Foveal Serous Retinal Detachment and JIA 5 decrease of flare photometry values correlated with the resolution of FSRD, although flare values are still high, above normal level from month 6 to 36 due to chronic alteration of the blood–ocular barrier. Consequently, the flare photometry values could be a prognostic factor for the development of FSRD in JIAAU. Change of flare should be considered a predictive outcome after additional immunomodulatory therapy. FSRD is a complication of JIAAU. Presence of FSRD and increased flare photometry values correlated with each other and with loss of visual acuity. Improvements in FSRD and in flare readings corresponded with visual improvement among patients in which the immunosuppressive drug therapy was maximized. Use of OCT to monitor for FSRD and use of laser flare photometry to monitor flare may be useful in guiding therapeutic decisions in these patients.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. Funding/support was provided by the Research to Prevent Blindness, Sybil B. Harrington Special Scholars, and the Kids Uveitis Research and Education (KURE) Fund (JET).
REFERENCES 1. Saurenmann RK, Levin AV, Feldman BM, et al. Prevalence, risk factors, and outcome of uveitis in juvenile idiopathic arthritis: a long-term followup study. Arthritis Rheum. 2007; 56:647–657. 2. Woreta F, Thorne JE, Jabs DA, et al. Risk factors for ocular complications and poor visual acuity at presentation among patients with uveitis associated with juvenile idiopathic arthritis. Am J Ophthalmol. 2007;143:647–655. 3. Foeldvari I, Nielsen S, Ku¨mmerle-Deschner J, et al. Tumor necrosis factor-alpha blocker in treatment of juvenile idiopathic arthritis-associated uveitis refractory to second-line agents: results of a multinational survey. J Rheumatol. 2007;34:1146–1150. 4. Thorne JE, Woreta F, Kedhar SR, et al. Juvenile idiopathic arthritis-associated uveitis: incidence of ocular complications and visual acuity loss. Am J Ophthalmol. 2007;143: 840–846. 5. Kump LI, Castan˜eda RA, Androudi SN, et al. Visual outcomes in children with juvenile idiopathic arthritisassociated uveitis. Ophthalmology. 2006;113:1874–1877. 6. Ducos de lahitte G, Terrada C, Tran TH, et al. Maculopathy in uveitis of juvenile idiopathic arthritis: an optical coherence tomography study. Br J Ophthalmol. 2008;92: 64–69. 7. Jabs DA, Nussenblatt RB, Rosenbaum JT; Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting
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F. Liang et al. 11. Gonzales CA, Ladas JG, Davis JL, et al. Relationships between laser flare photometry values and complications of uveitis. Arch Ophthalmol. 2001;119:1763–1769. 12. Ossewaarde-van Norel J, Berg EM, Sijssens KM, Rothova A. Subfoveal serous retinal detachment in patients with uveitic macular edema. Arch Ophthalmol. 2011;129:158–162. 13. Tran TH, de Smet MD, Bodaghi B, et al. Uveitic macular oedema: correlation between optical coherence tomography patterns with visual acuity and fluorescein angiography. Br J Ophthalmol. 2008;92:922–927. 14. 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;21:478–485.
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clinical data. Results of the First International Workshop. Am J Ophthalmol. 2005;140:509–516. Review. 8. Tappeiner C, Heinz C, Roesel M, et al. Elevated laser flare values correlate with complicated course of anterior uveitis in patients with juvenile idiopathic arthritis. Acta Ophthalmol. 2011;89:e521–e527. 9. Abedi G, Patal P, Doros G, et al. Transitioning from stratus OCT to cirrus OCT: a comparison and a proposed equation to convert central subfield macular thickness measurements in healthy subjects. Graefes Arch Clin Exp Ophthalmol. 2011;249:1353–1357. 10. Davis JL, Dacanay LM, Holland GN, et al. Laser flare photometry and complications of chronic uveitis in children. Am J Ophthalmol. 2003;135:763–771.
Ocular Immunology & Inflammation
ISSN: 0927-3948 (Print) 1744-5078 (Online) Journal homepage: http://www.tandfonline.com/loi/ioii20
Foveal Serous Retinal Detachment in Juvenile Idiopathic Arthritis-associated Uveitis Feng Liang MD, Celine Terrada MD, PhD, Ghislaine Ducos de Lahitte MD, Pierre Quartier MD, PhD, Phuc Lehoang MD, PhD, Jennifer E. Thorne MD & Bahram Bodaghi MD, PhD To cite this article: Feng Liang MD, Celine Terrada MD, PhD, Ghislaine Ducos de Lahitte MD, Pierre Quartier MD, PhD, Phuc Lehoang MD, PhD, Jennifer E. Thorne MD & Bahram Bodaghi MD, PhD (2015): Foveal Serous Retinal Detachment in Juvenile Idiopathic Arthritis-associated Uveitis, Ocular Immunology and Inflammation, DOI: 10.3109/09273948.2015.1012297 To link to this article: http://dx.doi.org/10.3109/09273948.2015.1012297
Published online: 14 Jul 2015.
Submit your article to this journal
Article views: 9
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View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ioii20 Download by: [University of Otago]
Date: 15 October 2015, At: 03:32
Ocular Immunology & Inflammation, Early Online, 1–6, 2015 ! Informa Healthcare USA, Inc. ISSN: 0927-3948 print / 1744-5078 online DOI: 10.3109/09273948.2015.1012297
ORIGINAL ARTICLE
Foveal Serous Retinal Detachment in Juvenile Idiopathic Arthritis-associated Uveitis Feng Liang, MD1*, Celine Terrada, MD, PhD1, Ghislaine Ducos de Lahitte, MD1, Pierre Quartier, MD, PhD2, Phuc Lehoang, MD, PhD1, Jennifer E. Thorne, MD3,4, and Bahram Bodaghi, MD, PhD1
Downloaded by [University of Otago] at 03:32 15 October 2015
1
Department of Ophthalmology, University of Paris VI, Pitie´-Salpeˆtrie`re Hospital, Paris, France, 2Unit of Immuno-Hematology and Pediatric Rheumatology, Necker-Enfants Malades Hospital, Paris, France, 3 Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, and 4 Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA
ABSTRACT Purpose: In juvenile idiopathic arthritis (JIA)-associated uveitis complicated by foveal serous retinal detachment (FSRD), we documented the relationship between best corrected visual acuity (BCVA), level of anterior chamber flare and OCT features. Methods: Nine children (15 eyes) with FSRD were identified among 38 children with JIA-associated maculopathy. Outcome measures included BCVA, ocular inflammatory activity quantified by laser flare photometry and the macular profile analyzed by OCT. Results: The diagnosis of FSRD led to intensification of the treatment using subtenon’s injection of triamcinolone or systemic immunomodulatory therapy. The improvement of BCVA at presentation (0.46 logMAR) was significant at 36 months follow-up (0.15 logMAR). The resolution of FSRD along with visual improvement (p = 0.0032) correlated with improvement in anterior chamber flare (p = 0.01). Conclusion: FSRD is a complication of chronic JIA-associated uveitis that responds well to intensification of immunomodulation. Visual improvement is correlated with FSRD resolution and with flare photometry values. Keywords: Flare, foveal serous retinal detachment, juvenile idiopathic arthritis, OCT, uveitis
Juvenile idiopathic arthritis (JIA)-associated uveitis (JIAAU) is the most common cause of pediatric uveitis.1–3 JIAAU may be complicated by cataract, glaucoma, band keratopathy, posterior synechiae, and/or ocular hypotony.1,2,4,5 Occurring in 20% of children with JIA, chronic uveitis leads to significant visual impairment in one-third of affected eyes.1,4 Recently, optical coherence tomography (OCT) revealed that macular changes may be found in more than 80% of cases.6 Four OCT patterns of maculopathy were described by OCT imaging: perifoveal thickening, macular edema, foveal serous retinal detachment (FSRD), and macular atrophy.6
Although uveitic macular edema has been studied extensively, the occurrence of FSRD remains unclear. The subgroup of patients with FSRD of this previous study was interesting and worthy to be detailed. The aim of this study is to characterize the evolution of FSRD in JIAAU and to describe its response to therapy.
MATERIAL AND METHODS The records of children with JIAAU and OCT evidence of maculopathy, who were managed
*This work was presented as a poster at the ARVO 2009 annual meeting. Received 8 May 2014; revised 21 January 2015; accepted 22 January 2015; published online 10 July 2015 Correspondence: Bahram Bodaghi, Department of Ophthalmology, Pitie´-Salpeˆtrie`re Hospital, University of Paris VI, 47-83 Boulevard de l’Hoˆpital, Cedex 13, 75651 Paris, France. E-mail: [email protected]
1
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2
F. Liang et al.
between April 2005 and July 2011 at the Department of Ophthalmology of the Pitie-Salpetriere Hospital (Paris, France), were reviewed retrospectively. The study was performed in adherence to the tenets of the Declaration of Helsinki and approved by a local ethics committee. Anterior chamber flare measured by laser flare photometry and presence of FSRD demonstrated by OCT were used to assess the effectiveness of additional immunomodulating therapy. Improvement of ocular inflammation was defined as at least a 30% reduction of anterior chamber flare and resolution of FSRD on OCT. Children were examined monthly for 3 months, then every 3 months thereafter for a median follow-up time of 33 months (range: 12–44 months). At each visit, ophthalmologic examination included best corrected visual acuity (BCVA), slit-lamp examination, tonometry, and dilated fundus examination. Snellen visual acuity was converted to a logarithm of the minimum angle of resolution (logMAR) for analyses. Ocular inflammation activity was quantified by slitlamp examination following the SUN classification of anterior chamber flare and cells.7 Laser flare photometry (FC500-Kowa, Japan) was done at each visit. The mean of 10 consecutive measures was determined. Normal flare values are below 7 ph/ms.8 Macular profile was analyzed using an OCT Stratus 3 (Version 4, Carl Zeiss Meditec, USA). A macular map was generated from 6 radial scans. Foveal thickness (FT) was defined by the mean retinal thickness of the central 1000 mm.6 Perifoveolar thickness (PFT) was the average of the retinal thickness in the central 3000 mm. Macular edema was defined by an FT greater than 252 mm, and the perifoveolar thickening was defined by a PFT greater than 288 mm. The reference of values of macula edema and perifoveolar thickening were based on the literature.6,9 FSRD was defined by the presence of retrofoveolar subretinal fluid visualized on OCT. Results are expressed as means with standard deviation (SD). Statistical analysis was performed by using the Wilcoxon test, correlation test, and pairedsamples Student t-test with nominal p values. A p value of 50.05 was considered statistically significant.
RESULTS Of 38 children with JIAAU of a previous OCT study of JIAAU,6 9 children (8 female, 1 male) having FSRD in at least 1 eye as demonstrated by OCT testing were included in this study. All 9 children had the pauciarticular subtype of JIA and were antinuclear antibody (ANA) positive. One child tested positive for the HLA-B27 haplotype as well. All children had asymptomatic, bilateral chronic anterior uveitis. Fifteen of 18 eyes had FSRD.
Six (66.7%) children had bilateral FSRD. The mean age at the onset of JIA was 3.6 ± 0.75 years and 4.1 ± 1.1 years at the onset of uveitis. The mean age at the diagnosis of FSRD by OCT was 7.6 ± 2.2 years. FSRD was diagnosed a mean time of 2.75 ± 0.67 years after the diagnosis of uveitis. At the time of first detection on OCT, 20% (3/15 eyes) of FSRD were observed without other macular abnormalities, 66.7% (10 eyes) were associated with perifoveolar thickening, 46.7% (7 eyes) with diffuse macular edema, and 13.3% (2 eyes) with cystoid macular edema. The mean BCVA for each feature was 0.40 ± 0.30 logMAR, 0.42 ± 0.33 logMAR, 0.54 ± 0.35 logMAR (p = .26), and 0.68 ± 0.29 logMAR (p = .13), respectively. At first detection of FSRD, the baseline mean flare values were 177 ± 99 photon/ms. Seven of 15 eyes (47%) had 1 + or more anterior chamber cells, 3 (20%) had trace anterior chamber cells, and 5 (33.3%) had no cells. Two eyes (13.3%) had mild vitreous inflammation and 1 (6.7%) had papillitis. Anterior segment complications, including posterior synechiae (86.7%, 13 eyes), cataract (80%, 12 eyes), band keratopathy (60%, 9 eyes), and glaucoma (20%, 3 eyes) were present in all children. Among eyes with cataract, 7 eyes underwent cataract surgery 8–42 months (median = 17 months) before the occurrence of FSRD, and 3 eyes underwent cataract surgery 24–30 months (median = 25 months) after the first detection of FSRD. At presentation, 5 of 9 children were treated with prednisone, 6 with methotrexate (MTX), and 4 with naproxen. The discovery of FSRD led to the addition of periocular corticosteroid injection, systemic immunomodulatory therapy (MTX, azathioprine), or antiTNFa agents (etanercept, infliximab, or adalimumab). Dosages of medications were sub-Tenon injection of triamcinolone 5 mg (n = 2); azathioprine 4 mg/kg/day (n = 1); methotrexate 0.4–1 mg/kg/weekly (n = 3); etanercept 0.4 mg/kg twice weekly (n = 3); infliximab 4–5 mg/kg at 2-week intervals initially, then tapered to 6-week intervals (n = 5); and adalimumab 1.5 mg/ kg at 2-week intervals (n = 3). The FSRD responded quickly to changes in immunomodulatory therapy. At 6 months, FSRD resolved in 14 of 15 eyes and mean BCVA improved to 0.22 ± 0.20 logMAR (p = 0.0087). Both FT and PFT were unchanged (p = 0.15 and 0.26, respectively), as was the diffuse macula edema (p = .15). Children demonstrated a rapid response of anterior chamber inflammation. The reduction of flare measured by laser flare photometry was 40.6% (p = 0.0028) and 34.1% (p = 0.001) at 6 and 36 months compared with initial exam. Decreased flare correlated also with decreased FSRD. At 12 months follow-up, BCVA continued to improve to 0.19 ± 0.20 logMAR (p = 0.0015) and FT began to decrease (p = 0.03). At 36 months follow-up, final BCVA was 0.15 ± 0.096 logMAR (p = 0.0032), with significant Ocular Immunology & Inflammation
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61/F
71/M
72/F
120/F
120/F
120/F
156/F
96/F
2
3
4
5
6
7
8
9
±
±
±
±
±
+/+
±
±
±
ANA/HLA B27
Posterior synechiae, cataract, BK
Cataract, BK
Posterior synechiae, cataract, BK
Posterior synechiae, cataract, BK, glaucoma
Posterior synechiae, cataract, glaucoma
Posterior synechiae, BK, glaucoma
Posterior synechiae, cataract, BK, papillitis
Posterior synechiae, papillitis
Posterior synechiae, cataract
Ocular complications at initial exam
OU
OD
OD
OU
OU
OS
OU
OU
OU
FSRD (OD/OS/ OU)
PFT Diffuse ME PFT CME
PFT
PFT
Diffuse ME
PFT
Diffuse ME
PFT CME
PFT Diffuse ME
Other associated maculopathy
Prednisone + MTX (F) Prednisone + MTX + infliximab (S)
MTX + etanercept (F) Prednisone + MTX + adalimumab (F) Prednisone + MTX + infliximab (S) MTX + etanercept (F) MTX + adalimumab (DC) MTX + infliximab (S) Prednisone (F) MTX + etanercept (F) Prednisone + MTX + infliximab (S) Naproxen (F) Naproxen + periocular triamcinolone injection (S) Prednisone (F) MTX (S) Prednisone + MTX + azathioprine (F) Prednisone + MTX + infliximab (S) Prednisone (F) Periocular triamcinolone injection (S) Prednisone + MTX (F) + adalimumab (S)
Treatment
Treatments at the time of diagnosis of FSRD (first line of the table) and after the detection of FSRD are documented. FSRD, foveolar serous retinal detachment; PFT, perifoveolar thickening; ME, macular edema; CME, cystoids macular edema; MTX, methotrexate; BK, band keratopathy; F, failure, S, success.
65/F
1
Case
Age (months)/ gender
TABLE 1. Demographics and clinical characteristics.
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Foveal Serous Retinal Detachment and JIA 3
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4
F. Liang et al.
FIGURE 1. Foveal serous retinal detachment (FSRD) with perifoveolar thickening on OCT (top). Complete resolution of FSRD 6 months after infliximab (bottom).
decrease of FT (p = 0.004). PFT remained unchanged (p = 0.33). FSRD persisted in only 1 eye (Table 1). The 3 patients treated with etanercept (cases 1, 2, 3) did not show resolution of FSRD on OCT and subsequently were switched to adalimumab (cases 1, 2) or infliximab (case 3). Case 1 finally was treated with infliximab for joint inflammation that was refractory to adalimumab therapy. In case 2, adalimumab was discontinued due to adverse psychological events, leading to severe inflammatory relapse with diffuse macular edema and FSRD. Cystoid macular edema occurred 3 months later. Infliximab finally controlled ocular inflammation and led to a complete resolution of cystoid macular edema and FSRD (Figure 1). Case 6 was a nonresponder to azathioprine and case 8 did not respond to MTX. In these 2 latter cases, the treatment was switched to infliximab. Case 9 had persistent ocular inflammation despite high-dose MTX and required infliximab. Table 2 summarizes the treatments for each case.
DISCUSSION FSRD is a fairly common complication in severe JIAAU, accounting for 23% of macular complications in JIAAU.6 Indeed, FSRD probably occurs more frequently than most ophthalmologists realize, and it resolves with treatment of the inflammation, with good visual acuity results. It seems that FSRD in JIAAU may be a marker of undertreatment with systemic immunosuppression. In our series, the majority of children (8/9) had risk
factors of severe JIAAU (pauciarticular subtype, young age, and ANA positivity). Compared with previously reported series of JIAAU in which children with FSRD had higher frequencies of complications: posterior synechiae 87% versus 28%,1,2 cataract 80% versus 23%,1,2 band keratopathy 60% versus 32%.1,2 At the initial examination, although 33% of eyes had no cells, the mean flare (177 photon/ms) was much higher than normal level (7 photon/ms),8,10,11 despite the fact that 8 of 9 children are treated with MTX and systemic corticosteroids. This confirmed that the laser flare measurement was helpful and more sensitive than clinical examination in detecting subclinical relapse. Consistent with previous reports,11–13 FSRD was associated with a worse VA in patients with JIAAU, but it responded well to corticosteroids. We showed that FSRD responded quickly to initial intensive therapy, since the FSRD resolved in 14 of 15 (93%) eyes at the 6-month follow-up visit. Furthermore, visual loss due to FSRD in JIAAU also improved as a result of intensive immunosuppressive therapy, independent of the persistence of macular thickening. The effects of intensive therapy persisted until the last follow-up. Our results show that chronic uveitis was associated with later FSRD and it was probably associated with early macular thickening in children with JIAAU, which conformed to previous studies.14 The significance of findings relating to flare is interesting and potentially useful for practitioners. In our series, high laser flare values at baseline correlated with the presence of FSRD. After additional immunomodulatory therapy, statistically significant Ocular Immunology & Inflammation
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2015 Informa Healthcare USA, Inc.
FT, foveal thickness; PFT, perifoveolar thickness. D flare = (final flare – initial flare)/initial flare expressed in percentile. All statistics were compared between baseline and M6, M12, M18, M36.
0.010 34.1 0.011 31.9 0.0010 18.3 0.0028 40.6
113 ± 57 101 ± 62 99 ± 77 0.0096 105 ± 75 176 ± 99
15/15 7/15 eyes (46.7%)
295 ± 42
261 ± 50
0.15 ± 0.096 0.0032 188 ± 38 0.0040 304 ± 24 0.33 1/15 2/15 eyes (13.3%) 0.0096 0.15 ± 0.10 0.0015 207 ± 14 0.030 314 ± 11 0.21 1/15 0/15 eyes (0%) 0.0018 0.19 ± 0.20 0.0039 196 ± 27 0.0015 304 ± 24 0.32 1/15 3/15 eyes (20%) 0.020 0.22 ± 0.20 0.0087 229 ± 48 0.12 315 ± 30 0.20 1/15 2/15 eyes (13.3%) 0.46 ± 0.36
BCVA (logMAR) p FT (mm) p PFT (mm) p FSRD (eyes) Anterior chamber cells 1 + at biomicroscopy (eyes) p Anterior chamber flare (photon/ms) p D flare (%)
36 months follow-up 18 months follow-up 12 months follow-up 6 months follow-up Initial
TABLE 2. Best corrected visual acuity (BCVA), optical coherence tomography, ophthalmological characterization, and flare evolution after additional immunosuppressive therapy.
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Foveal Serous Retinal Detachment and JIA 5 decrease of flare photometry values correlated with the resolution of FSRD, although flare values are still high, above normal level from month 6 to 36 due to chronic alteration of the blood–ocular barrier. Consequently, the flare photometry values could be a prognostic factor for the development of FSRD in JIAAU. Change of flare should be considered a predictive outcome after additional immunomodulatory therapy. FSRD is a complication of JIAAU. Presence of FSRD and increased flare photometry values correlated with each other and with loss of visual acuity. Improvements in FSRD and in flare readings corresponded with visual improvement among patients in which the immunosuppressive drug therapy was maximized. Use of OCT to monitor for FSRD and use of laser flare photometry to monitor flare may be useful in guiding therapeutic decisions in these patients.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. Funding/support was provided by the Research to Prevent Blindness, Sybil B. Harrington Special Scholars, and the Kids Uveitis Research and Education (KURE) Fund (JET).
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clinical data. Results of the First International Workshop. Am J Ophthalmol. 2005;140:509–516. Review. 8. Tappeiner C, Heinz C, Roesel M, et al. Elevated laser flare values correlate with complicated course of anterior uveitis in patients with juvenile idiopathic arthritis. Acta Ophthalmol. 2011;89:e521–e527. 9. Abedi G, Patal P, Doros G, et al. Transitioning from stratus OCT to cirrus OCT: a comparison and a proposed equation to convert central subfield macular thickness measurements in healthy subjects. Graefes Arch Clin Exp Ophthalmol. 2011;249:1353–1357. 10. Davis JL, Dacanay LM, Holland GN, et al. Laser flare photometry and complications of chronic uveitis in children. Am J Ophthalmol. 2003;135:763–771.
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