Dexamethasone intravitreal implant (Ozurdex) for the treatment of pediatric uveitis Monica L. Bratton, MD, Yu-Guang He, MD, and David R. Weakley, MD PURPOSE
To report our experience using Ozurdex (Allergan, Irvine, CA), a biodegradable intravitreal implant containing of 0.7 mg of dexamethasone approved for use in adults with noninfectious uveitis in adults, in the treatment of pediatric uveitis. The medical records of consecutive patients with noninfectious posterior uveitis who were unresponsive to standard treatment and subsequently received the Ozurdex implant from March 2011 to March 2013 were retrospectively reviewed.
A total of 14 eyes of 11 patients (mean age, 10.1 years; range 4-12) received 22 Ozurdex implants during the study period. Of the 11 patients, 7 had idiopathic intermediate or posterior uveitis, 1 had sympathetic ophthalmia, 2 had juvenile idiopathic arthritis, and 1 had sarcoidosis. All patients were uncontrolled with standard treatment, including topical or sub-Tenon’s or systemic corticosteriods and/or immune-modulation. Visual acuity improved after Ozurdex implant in 5 of 8 patients (63%). Intraocular inflammation was controlled or improved after 17 of 22 of implants (12 eyes [77%]). The frequency of topical corticosteroids was decreased and/or discontinued after 18 of 22 implants (12 eyes [82%]). Complications included implant migration into the anterior chamber (4 aphakic eyes), increased intraocular pressure (5 eyes), and progression of a preexisting cataract (1 eye). The uveitis reoccurred in 57% of eyes at 4.3 months (2-7 months) after injection.
The Ozurdex implant in combination with systemic immunomodulatory therapy resulted in improved visual acuity, control of intraocular inflammation, and a decrease in corticosteroid use. In the majority of eyes the uveitis reoccurred around 4 months after injection. The adverse events in our study are similar to those identified in adult studies. ( J AAPOS 2014;18:110-113)
veitis in children is a continuing challenge for ophthalmologists. The condition often has an insidious onset, and symptoms, including vision loss, may not be noticed. Although often idiopathic, pediatric uveitis may be associated with specific etiologies, including juvenile idiopathic arthritis (JIA), ankylosing spondylitis, sarcoidosis, Adamantiades-Behc¸et disease, Vogt-Koyanagi-Harada syndrome, Reiter syndrome, pars planitis, and sympathetic ophthalmia.1 Posterior, intermediate, and panuveitis can be particularly difficult to control, rarely respond to topical therapy alone, and can cause significant visual loss.2,3
Author affiliations: Department of Ophthalmology, University of Texas Southwestern, Dallas, Texas This study was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc., New York, NY. Presented as a poster at the 39th Annual Meeting of the American Association for Pediatric Ophthalmology and Strabismus, Boston, Massachusetts, April 3-7, 2013. Submitted July 16, 2013. Revision accepted November 11, 2013. Correspondence: Yu-Guang He, MD, 935 Medical District Drive, MS F6.02, Dallas, Texas 75235 (email: [email protected]
). Copyright Ó 2014 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2013.11.014
Currently, corticosteroids, administered topically, periocularly, or intravitreally, are the primary treatment for noninfectious uveitis.3 Topical therapy alone is rarely efficacious, and systemic corticosteroids carry the risk of side effects, including Cushingoid changes, hypertension, osteoporosis, and growth suppression, which is of particular concern in children.4 Administration of periocular or intravitreal corticosteroids in children can be challenging and carry risk of ptosis, cataract, retinal detachment, endophthalmitis, and elevation in intraocular pressure (IOP).4-7 Additionally, in our practice, intravitreal steroid treatment of posterior uveitis in post-vitrectomy eyes has been noted to introduce significant flare into the vitreous cavity, obstructing the clinical examinations. Often, systemic therapy with steroid-sparing agents is used depending on the severity of the uveitis or, in the cases of an associated systemic disease, to control other disease-related symptoms.1,3 The dexamethasone intravitreal implant (Ozurdex; Allergan Inc, Irvine, CA) is a biodegradable polymer composed of 0.7 mg of dexamethasone and apolylactic acid-co-glycolic acid. The polymer dissolves in vivo into lactic acid and glycolic acid, which are eventually converted to carbon dioxide and water. As the implant disintegrates, dexamethasone is slowly released within the eye over a 6-month period, with peak intravitreal concentrations
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occurring during the first 2 months.8 The Ozurdex device has been approved by the US Food and Drug Administration for use in treatment of macular edema due to retinal vein occlusions and for noninfectious, posterior uveitis in adults. 9 We are aware of only one previous study evaluating the effectiveness of the Ozurdex implant in the treatment of pediatric uveitis and one case report of a child with juvenile arthritis who received the implant 1 month prior to cataract surgery.10-11 The purpose of this study is to report our experience with the Ozurdex implant in the treatment of pediatric uveitis.
Subjects and Methods The study was approved by the Institutional Review Board at University of Texas Southwestern and Children’s Medical Center and conformed to the requirements of the US Health Insurance Portability and Accountability Act of 1996. The records of all patients under 18 years of age who were unresponsive to standard uveitis treatment modalities and subsequently had Ozurdex implant placed at Children’s Medical Center in Dallas, Texas, over a 24-month period, from March 2011 to March 2013, were retrospectively reviewed. The implant was injected into the vitreous cavity through the pars plana under general anesthesia in the operating suite per the manufacturer’s guidelines (Figure 1).12 For each patient the following demographic information was collected: sex, race, age at diagnosis, age at implantation, and length of follow-up. Uveitis was delineated by clinical description, anatomic location, affected eye/laterality, etiology, and prior therapy. We evaluated visual acuity and graded the severity of inflammation immediately prior to implantation and at most recent follow-up, as well as any complications. Visual acuity assessments were made after the first implantation only. For patients that had implants in both eyes, one eye was randomly chosen for statistical calculations. Anterior chamber cell and flare and vitreous cell were documented according to the Standardization of Uveitis Nomenclature (SUN) grading scheme.13,14 Outcome measures included: (1) improvement in visual acuity, defined as improvement in one or more Snellen lines, (2) improvement of intraocular inflammation, defined as a decrease by one step of grading in the number of cells in the anterior chamber or vitreous per high-power field as defined by the SUN grading scheme,14 and (3) reduction of use of topical and/or systemic anti-inflammatory agents.
Results A total of 14 eyes of 11 patients were included. Patients were all diagnosed with noninfectious uveitis prior to the treatment. The mean age at diagnosis of uveitis was 7 years (range, 2-9). The average age at time of Ozurdex implantation was 10.1 years (range, 4-12). All patients had a comprehensive evaluation by pediatric rheumatology to rule out any associated diseases. Of the 11 patients, 7 were diagnosed with intermediate or posterior uveitis and no associated systemic disease was found, 2 had uveitis associated with JIA, 1 had panuveitis associated with systemic sarcoidosis, and 1 had posterior uveitis with pre-
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FIG 1. Ozurdex injection technique. The intravitreal injection procedure is carried out under controlled aseptic conditions. Adequate anesthesia and povidone-iodine 5% is applied. The overlying conjunctiva is displaced with a cotton tip applicator. The long axis of the applicator should be held parallel to the limbus, approximately 2–3 mm away, and the sclera is engaged at an oblique angle, with the bevel of the needle up. The tip of the needle is advanced within the sclera for approximately 1 mm, the redirected toward the center of the eye and advanced until the vitreous cavity is entered. The actuator button is depressed until a click is heard.
sumed sympathetic ophthalmia (Table 1). Patients were treated with antimetabolites prior to 21 of 22 insertions, including methotrexate, mycophenolate mofetil, and/or adalimumab. Average time of antimetabolite use prior to first implantation was 2.5 years. All eyes had previous and/or current topical steroid treatment, and 4 eyes had previous sub-Tenon’s corticosteroid injections. Four patients had previous oral corticosteroids, and 10 patients had used antimetabolites prior to the first injection (e-Supplement 1, available at jaapos.org). Eight eyes received 1 implant; 5 eyes, 2 implants (approximately 6 months apart); and 1 eye, 4 implants (approximately 3 months apart). Average follow-up time from first implantation to most recent examination was 11.3 months. For patients who received 1 implant, the average follow-up was 7.9 months. For patients who received multiple implants, the average follow-up was 14.2 months. Visual acuity improved by one or more Snellen lines within 1-3 months after the first Ozurdex implant in 5 of 8 patients (8 eyes [63%]). The mean baseline visual acuity of 0.90 logMAR improved to 0.71 logMAR (P 5 0.18) by paired t test. Five eyes underwent concurrent cataract extraction, band keratopathy treatment, and/or vitrectomy surgery at the time of Ozurdex implantation and were excluded from visual acuity assessment. One patient could not perform Snellen visual acuity testing and was not included in the statistical evaluation. Intraocular inflammation was improved at 1-3 months after injection in 17 of 22 insertions (12 eyes [77%]), although vitreous evaluation was limited in 4 eyes due to
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Table 1. Patient characteristics Patient 1 2 3 4 5 6 7 8 9 10 11
Age at diagnosis, years
Age at first implant, years
Systemic disease associations
OS OD OS OU OU OD OD OS OS OU OS
M F M F M F F M F F F
Hispanic Black Hispanic Hispanic Hispanic White Black Hispanic Black Black Black
9 2 6 9 5 4 8 9 5 7 6
11 12 11 10 11 4 9 9 7 9 6
None found Sarcoidosis None found None found None found Sympathetic ophthalmia None found None found JIA None found JIA
Pars planitis Panuveitis Pars planitis Pars planitis Pars planitis Posterior uveitis Anterior uveitis Pars Planitis Anterior uveitis Panuveitis Panuveitis
5.1 11.7 15.9 12.7 19.3 22 12.4 7.3 3 8 7.5
JIA, juvenile idiopathic arthritis; OD, right eye; OS, left eye; OU, both eyes.
band keratopathy, secondary membranes, or cataract. Frequency of topical corticosteroids was decreased after 8 of 22 insertions (7 eyes) and discontinued after 10 of 22 insertions (5 eyes) at 1-3 months. A recurrence of inflammation after insertion was noted in 8 of 14 eyes (10 of 22 injections) at a mean of 4.3 months after insertion (range, 2-7 months). Repeat insertions were performed once in 5 eyes and 3 times in 1 eye. (Pre- and postimplant vision, inflammation, and postimplant topical steroid use are provided in e-Supplement 2, available at jaapos.org.) Complications noted within 6 months of implantation included elevated IOP (.10 mm Hg increase from average baseline requiring treatment) in 5 eyes, cataract progression requiring surgery in 1 eye, and implant migration into the anterior chamber in 4 eyes. All patients with increased IOP were managed successfully with standard medications; none required surgery. The 4 migrated implants did not require removal or cause corneal damage.
Discussion Intermediate, posterior, or panuveitis are often difficult to treat entities in children and frequently require periocular corticosteroids, systemic corticosteroids, and/or other systemic antimetabolites, with potential for side effects. Recently, implantable intravitreal devices allowing for slow, sustained intraocular release of corticosteroids have been approved by the FDA approved for the treatment of uveitis in adults, although the use of these devices in children has been limited and their safety and effectiveness have not been established. The Retisert implant (Bausch & Lomb Inc, Rochester, NY) was the first approved device for treatment of noninfectious posterior uveitis. This permanent implant consists of a tablet of fluocinolone acetonide encased in silicone, which is secured within the vitreous cavity using an 80 nonabsorbable polypropylene suture. It is active for up to 30 months after implantation.15 In the only study of this device in children, Patel and colleagues16 performed a retrospective chart review of the Retisert implant in 6 eyes of 4 patients (mean age, 9.2 years) with intractable pos-
terior uveitis. Three eyes (50%) had improvement in visual acuity .3 lines and all 6 eyes maintained control of inflammation without topical steroids. Complications included elevated IOP (4 eyes), with 2 eyes requiring glaucoma surgery. One eye developed a visually significant cataract requiring surgical removal. The second device to be approved for use in adults was the Ozurdex implant. In the only previous pediatric study to date, Taylor and colleagues10 evaluated its use in uveitis in 14 eyes of 11 children. Of the 14 eyes, 13 (93%) had control of inflammation and/or resolution of cystoid macular edema within 1 month of injection; however, 31% of patients relapsed within 6 months. Adverse events were limited to elevated IOP in 4 eyes (29%). Cordero-Coma and colleagues11 recently reported a case of a 6-year-old child with juvenile idiopathic arthritis who underwent Ozurdex injection 1 month prior to cataract surgery. The authors found that inflammation was well controlled postoperatively and the patient did not develop any complications related to the implant. In the present study we treated 14 eyes of 11 patients with the Ozurdex implant for refractory intermediate or posterior uveitis. Visual acuity improved in 63% of patients with measurable acuity, intraocular inflammation was controlled or improved after 77% of insertions, and topical corticosteroid administration was decreased or discontinued after 82% of insertions. Follow-up time for patients with multiple implants was longer (14.2 vs 7.9 months), suggesting that repeat implants may be necessary for long-term control. All 11 patients also underwent concurrent systemic immunomodulatory therapy. Given the fact that these medications can take several weeks to months to achieve systemic effects,17 the Oxurdex implant may be effectively used as a bridging therapy. Complications were similar to those previously reported with implantable steroid devices10,16,18,19 and included elevated IOP, cataract progression, and implant migration into the anterior chamber. A recurrence or increase of uveitis was noted in 57% of eyes at a mean of 4.3 months after injection. Some reasons for failure to respond/recurrence include poor compliance with other
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Volume 18 Number 2 / April 2014 anti-inflammatory medications and aggressive intraocular disease. Additionally, the Ozurdex implant lasts only 6 months, a likely factor in recurrence seen in some patients several months after implantation, necessitating another implant or an increase in topical steroid use.8 Limitations of this study include its retrospective design, small sample size, and the fact that the data was gathered based on multiple different physician examinations after Ozurdex implant. Additionally, given our status as a tertiary referral center, the patients examined may not be representative of all pediatric uveitis patients.
References 1. Kump LI, Cervantes-Casta~ neda RA, Androudi SN, Foster CS. Analysis of pediatric uveitis cases at a tertiary referral center. Ophthalmology 2005;112:1287-92. 2. Smith JA, Mackensen F, Sen HN, et al. Epidemiology and course of disease in childhood uveitis. Ophthalmology 2009;116:1544-51. 3. Cunningham E. Uveitis in children. Ocul Immunol Inflamm 2000;8: 251-61. 4. Carnahan MC, Goldstein DA. Ocular complications of topical, periocular, and systemic corticosteroids. Curr Opin Ophthalmol 2000;11: 478-83. 5. Byun YS, Park Y-H. Complications and safety profile of posterior subtenon injection of triamcinolone acetonide. J Ocul Pharmacol Ther 2009;25:159-62. 6. Inoue M, Takeda K, Morita K, Yamada M, Tanigawara Y, Oguchi Y. Vitreous concentrations of triamcinolone acetonide in human eyes after intravitreal or subtenon injection. Am J Ophthalmol 2004;138:1046-8. 7. van Kooij B, Rothova A, de Vries P. The pros and cons of intravitreal triamcinolone injections for uveitis and inflammatory cystoid macular edema. Ocul Immunol Inflamm 2006;14:73-85.
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8. Chang-Lin JE, Attar M, Acheampong AA, et al. Pharmacokinetics and pharmacodynamics of a sustained-release dexamethasone intravitreal implant. Invest Ophthalmol Vis Sci 2011;52:80-86. 9. Hunter RS, Lobo AM. Dexamethasone intravitreal implant for the treatment of noninfectious uveitis. Clin Ophthalmol 2011;5: 1613-21. 10. Taylor SRJ, Tomkins-Netzer O, Joshi L, Morarji J, McLoone E, Lightman S. Dexamethasone implant in pediatric uveitis. Ophthalmology 2012;119:2412. 11. Cordero-Coma M, Garzo I, Galan E, Franco M, Ruız de Morales JG. Preoperative cataract surgery use of an intravitreal dexamethasone implant (Ozurdex) in a patient with juvenile idiopathic arthritis and chronic anterior uveitis. J AAPOS 2013;17:632-4. 12. Ozurdex [package insert]. Irvine, CA: Allergan Inc; September 2010. 13. Intraocular inflammation and uveitis. Basic Science Series. Vol. 9. American Academy of Ophthalmology; 2009-2010. 14. Jabs DA, Nussenblatt RB, Rosenbaum JT, Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data: results of the first international workshop. Am J Ophthalmol 2005;140:509-16. 15. Retisert [package insert]. Rochester, NY: Bausch & Lomb Inc; March 2009. 16. Patel CC, Mandava N, Oliver SC, Braverman R, Quiroz-Mercado H, Olson JL. Treatment of intractable posterior uveitis in pediatric patients with the fluocinolone acetonide intravitreal implant (Retisert). Retina 2012;32:537-42. 17. Gallagher M, Quinones K, Cervantes-Casta~ neda RA, Yilmaz T, Foster CS. Biological response modifier therapy for refractory childhood uveitis. Br J Ophthalmol 2007;91:1341-4. 18. Haller JA, Bandello F, Belfort R Jr, et al., OZURDEX GENEVA Study Group. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology 2010;117:1134-46. 19. Lowder C, Belfort R Jr, Lightman S, et al. Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis. Arch Ophthalmol 2011;129:545-53.
An Eye on the Arts—the Arts on the Eye
I don’t know. Nor does my brother Guerrero, because I’ve infected him with a painful dream. He goes to bed in his new headquarters, the Alcazar in Seville, and his nights are unquiet because the painful gaze of the last Aztec king, Guatemuz, pierces them like a ghost. A cloud of blood covers his eyes. Whenever he feels his vision blur, he lowers his eyelids. One is made of gold, the other silver. When he wakes up, weeping over the fate of the Aztec nation, he realizes that instead of tears, down one cheek ran gold and down the other silver, cutting a furrow in them as a knife would, leaving a permanent wound in them which, may it please God, death has healed. —Carlos Fuentes, The Orange Tree (New York: Harper Perennial, 1995), 48. Contributed by Alex V. Levin, MD, MHSc, Philadelphia, Pennsylvania
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