Purpose
To evaluate outcomes in birdshot chorioretinopathy following intravitreal implantation of a fluocinolone acetonide–containing drug delivery device.
Design
Retrospective, multicenter, interventional case study.
Methods
University- and community-based tertiary care. Twenty-two HLA-A29+ birdshot patients (36 eyes) were implanted with a sustained-release corticosteroid device and followed for up to 3 years. Main outcome measures were Snellen acuity, intraocular inflammation, adjunctive therapy, cataract, ocular hypertension, or glaucoma. Paired Wilcoxon statistics were used to analyze visual acuities; paired McNemar statistics were used to analyze presence or absence of other outcomes.
Results
Nineteen of 22 patients (32 eyes) completed 12 months of follow-up with improvement in median visual acuity ( P = .015 ) . Prior to implantation, 18 of 22 patients (82%) received immunosuppressive therapy versus 1 of 19 (5%) by 12 months ( P < .001). Eyes with zero vitreous haze increased from 7 of 27 scored eyes (26%) at baseline to 30 of 30 eyes (100%) by 12 months ( P < .001). Cystoid macular edema decreased from 13 of 36 eyes (36%) at baseline to 2 of 32 eyes (6%) at 12 months ( P = .006). Five of 24 phakic eyes at baseline exited the study before surgery; all other eyes received cataract surgery. One hundred percent of study eyes had ocular hypertension, required intraocular pressure–lowering therapy, or had glaucoma surgery by 12 months.
Conclusions
Implantation of a fluocinolone acetonide–containing intraocular device in birdshot chorioretinopathy can improve vision, control inflammation, and eliminate systemic therapy. There is a high incidence of cataract progression and intraocular hypertension or glaucoma.
Birdshot chorioretinopathy was identified in 1980 and accounts for approximately 8% of posterior uveitis in the US. It is associated with the HLA-A29 allele, with 1 of the highest odds ratios for a histocompatibility allele, although it is rarely familial. Factors that lead to disease initiation are unknown; autoimmunity to retinal antigens in a genetically predisposed individual has been proposed.
Early-stage disease is characterized by retinal vascular leakage, while the mid phase shows increasing prominence of “birdshot” choroidal lesions. The late stage is typified by cystoid macular edema (CME), vascular attenuation, and retinal pigment epithelial (RPE), choroidal, and optic nerve atrophy. Although 20% of patients may achieve remission without treatment, most have a relentlessly progressive course. Birdshot can remain active and produce severe vision loss over 2 to 3 decades.
Disease course is monitored by visual acuity, anterior chamber and vitreous cellular reaction, retinal vascular leakage, and the appearance of the chorioretinal lesions. Ancillary testing such as fluorescein angiography (FA), indocyanine green angiography (ICG), optical coherence tomography (OCT), perimetry, and electroretinography are also often used to monitor disease activity.
Immunosuppressive treatment is reported to reduce vision loss from cystoid macular edema and to lessen visual field loss. Regional or systemic corticosteroids can reduce retinovascular leakage and improve vision. Corticosteroids are often combined with cyclosporine or replaced from the outset by immunosuppressive drugs. Since there are no known or suspected systemic associations with birdshot chorioretinopathy, intraocular drug delivery provides a potentially useful alternative to immunosuppressive medication or systemic corticosteroids.
We report our experience with implantation of an FDA-approved, sustained-release intraocular implantable drug delivery device containing fluocinolone acetonide in 1 or both eyes of 22 patients with birdshot chorioretinopathy.
Methods
Surgical logs were reviewed to identify patients with birdshot chorioretinopathy who were implanted with fluocinolone acetonide–containing drug delivery devices (Retisert, Bausch & Lomb, Rochester, New York, USA) from May 2001 to October 2008 at Bascom Palmer Eye Institute, the University of Illinois at Chicago, and Texas Retina Associates. Clinical diagnoses were based on typical choroidal inflammatory lesions associated with vitritis and past or current retinal vasculitis. Patients were excluded from the study if they were not HLA-A29 positive. Inclusion in the study was not dependent on a required length of follow-up. Both eyes were considered for the study if both were implanted. All eligible patients and eyes were included in the study.
Baseline data were recorded for 1 month (± 2 weeks) before implantation. Follow-up data were collected at 4 months (± 1 month), 1 year (± 2 months), 2 years (± 4 months), and 3 years (± 4 months) after implantation, the expected duration of effect of the implant. Clinical information collected included age, local and systemic therapies for uveitis or glaucoma, best-corrected Snellen visual acuity, lens status (no, mild, moderate, or severe opacity), intraocular pressure (IOP), glaucoma history, anterior chamber and vitreous inflammation, and the presence of CME and epiretinal membranes.
The fluorescein angiographic findings, Humphrey visual field mean deviation in decibels, ERG cone B flicker amplitude, and ERG cone B flicker latency were recorded if available. Fluorescein angiograms were graded according to the following scale: 0 = no retinal vascular leakage; 1 = large vessel leakage; 2 = small vessel leakage in the posterior pole; 3 = CME; 4 = RPE atrophy in the posterior pole.
Treatment with the device was provided according to the clinician’s best medical judgment based on subjective complaints, visual acuity, clinical assessment of the degree of inflammation, response to prior treatment, and the individual patient’s preference for treatment or participation in a clinical trial. Information ascertained from Humphrey visual fields, FA, ICG, and electroretinography (ERG) were also used in management decisions.
The main outcome measures were Snellen visual acuity, the need for either local or systemic therapy to control intraocular inflammation, control of intraocular inflammation, cataract progression, and the development or progression of glaucoma. Paired Wilcoxon statistics were used to analyze visual acuities; paired McNemar statistics were used to analyze presence or absence of other outcomes.
Results
Twenty-two patients met eligibility criteria and were included in this series. Fourteen patients were bilaterally implanted and 8 were unilaterally implanted, for a total of 36 eyes. All patients had bilateral disease. The age at implantation of the first eye averaged 59.7 years (SD = 10.1, range: 39 to 78). Median (range) of follow-up was 24 (4, 36) months. Seven of 20 patients (35%) were taking antihypertensive medications and 1 of 20 patients (5%) was receiving medical therapy for diabetes mellitus. Median (range) of best-corrected Snellen visual acuity was 20/50 (20/20, 20/400) at baseline. Best-corrected Snellen visual acuity improved at a statistically significant level at all follow-up points ( Table 1 ).
| Baseline | Month 4 | Month 12 | Month 24 | Month 36 | |
|---|---|---|---|---|---|
| Number of eyes | 36 | 36 | 32 | 16 | 9 |
| Snellen acuity | |||||
| Median (range) | 20/50 (20/20, 20/400) | 20/40 (20/20, 20/200) | 20/40 (20/15, 20/200) | 20/30 (20/20, 20/200) | 20/30 (20/20, 20/150) |
| P value a | .003 | .015 | .018 | .011 | |
| Intraocular pressure | |||||
| Mean (SD) [range] | 16.2 (6.5) [9, 47] | 17.6 (5.6) [6, 27] | 17.1 (6.8) [4, 32] | 14.7 (4.8) [7, 22] | 16.7 (6.9) [8, 29] |
| Local anti-inflammatory therapy | |||||
| Eyes (%) | 18 (50) | 1 (3) | 4 (13) | 4 (25) | 4 (44) |
| P value b | <.001 | .006 | .29 | 1.0 | |
| Immunosuppressive therapy | |||||
| n/N patients (%) | 18/22 (82) | 5/22 (23) | 1/19 (5) | 0/12 (0) | 0/6 (0) |
| P value b | <.001 | <.001 | <.001 | .031 | |
| AC cells, 0.5 – 2+ c | |||||
| Eyes (%) c | 9 (25) | 1 (3) | 0 | 1 (6) | 0 |
| P value b | .021 | .016 | .38 | .50 | |
| AC flare, 1 – 2+ c | |||||
| Eyes (%) | 10 (28) | 2 (6) | 5 (16) | 1 (6) | 0 |
| P value b | 0.039 | 0.51 | 0.63 | 1.0 | |
| Vitreous cells d | |||||
| Eyes (%) | |||||
| 0 – trace | 10 (28) | 24 (67) | 29 (91) | 13 (81) | 9 (100) |
| 1 | 10 (28) | 11 (31) | 3 (9) | 3 (19) | 0 |
| 2 | 15 (42) | 1 (3) | 0 | 0 | 0 |
| 3 | 1 (3) | 0 | 0 | 0 | 0 |
| P value b | .001 | <.001 | .031 | .38 | |
| Vitreous haze score c | |||||
| Eyes (%) | |||||
| 0 | 7 (26) | 34 (94) | 30 (100) | 16 (100) | 8 (89) |
| 0.5 | 2 (7) | 2 (6) | 0 | 0 | 1 (11) |
| 1 | 14 (52) | 0 | 0 | 0 | 0 |
| 2 | 4 (15) | 0 | 0 | 0 | 0 |
| Unavailable | 9 | 0 | 2 | 0 | 0 |
| P value b | <.001 | <.001 | .004 | .25 | |
| Cataract status, eyes (%) | |||||
| Mild or no cataract | 18 (50) | 11 (31) | 3 (9) | 0 | 0 |
| Moderate cataract | 5 (14) | 7 (19) | 3 (10) | 0 | 0 |
| Severe or mature cataract | 1 (3) | 1 (3) | 2 (6) | 0 | 0 |
| Pseudophakia | 12 (33) | 17 (47) | 24 (75) | 16 (100) | 9 (100) |
| New pseudophakia | 5 | 10 | 4 | 0 | |
| Intraocular pressure | |||||
| Mean (SD) [range] | 16.2 (6.5) [9, 47] | 17.6 (5.6) [6, 27] | 17.1 (6.8) [4, 32] | 14.7 (4.8) [7, 22] | 16.7 (6.9) [8, 29] |
| Glaucoma status, eyes (%) | |||||
| IOP<25, no medical therapy | 30 (83) | 18 (50) | 5 (16) | 2 (12) | 0 |
| IOP>25 or medical therapy | 6 (17) | 16 (44) | 19 (59) | 10 (63) | 4 (44) |
| New medical therapy | 11 | 11 | 3 | 0 | |
| Trabeculectomy or GDI | 0 | 2 (6) | 8 (25) | 4 (25) | 5 (56) |
| New glaucoma surgery | 2 | 6 | 2 | 2 | |
| Cystoid macular edema | |||||
| Eyes (%) | 13 (36) | 6 (17) | 2 (6) | 0 | 0 |
| P value b | .016 | .006 | .016 | .13 | |
| Epiretinal membrane | |||||
| Eyes (%) | 8 (23) | 9 (25) | 11 (34) | 6 (38) | 5 (56) |
| P value b | 1.0 | .5 | 1.0 | .5 |
a Paired Wilcoxon test. Compared to baseline.
b Paired McNemar test (none versus any). Compared to baseline.
c Inflammatory scores recorded according the Standard Uveitis Nomenclature consensus document.
d Vitreous cells were recorded according to the conventions of the individual investigators.
Eighteen of 36 eyes (50%) were treated with local therapy at baseline ( Table 1 ). Eleven (31%) were receiving topical corticosteroids, 5 (14%) topical nonsteroidal anti-inflammatories, 5 (14%) had received intravitreal triamcinolone acetonide, and 2 (6%) had received posterior sub-Tenon triamcinolone acetonide. Three eyes received more than one form of local therapy. Table 1 summarizes the statistically significant decrease in local therapy during the study.
Seventeen of 22 patients (77%) were receiving systemic immunosuppressive therapy prior to implantation ( Table 1 ). Seven patients (32%) were taking oral prednisone: 2 as a single agent, 2 with cyclosporine, 1 with tacrolimus, 1 with mycophenolate mofetil, and 1 with both cyclosporine and mycophenolate. Five patients (23%) were taking mycophenolate mofetil as a single agent, 2 patients (9%) were taking cyclosporine, and 2 patients (9%) were taking tacrolimus. One patient (5%) was taking methotrexate and infliximab. There was a statistically significant decrease in the proportion of patients receiving immunosuppressive therapy at 4, 12, and 24 months compared to baseline, P < .001, with no patients taking immunosuppressive medication by 24 months.
Anterior chamber cells and flare were present in 25% to 28% of eyes at baseline. There was a statistically significant decrease in anterior inflammation by the 4-month follow-up visit ( Table 1 ) that persisted at 12 months. Similarly, a statistically significant decline in vitreous cell scores was seen at the 4-month, 12-month, and 24-month follow-up visits ( Table 1 ). At the 12-month mark when 19 of 22 patients (86%) were still being followed, all 30 eyes with available haze scores had vitreous haze of 0, compared to 7 of 27 eyes (26%) at baseline ( P = .001).
At baseline 12 of 36 eyes (33%) were pseudophakic ( Table 1 ). The cumulative proportion of pseudophakic eyes rose to 75% (24/32) by 12 months and was 100% (9/9) by 3 years among eyes remaining in the study. Five eyes exited the study before cataract surgery was performed, 1 at 4 months and 4 at 12 months. Five of 24 phakic eyes (21%) underwent surgery by 4 months and 10 of 18 phakic eyes (56%) by 12 months. All 4 remaining phakic eyes were operated by 24 months.
Mean IOP was in the normal range throughout the study ( Table 1 ). Prior to implantation, 30 of 36 eyes (83%) had an IOP less than 25 mm Hg without IOP-lowering medical therapy, and 6 eyes of 5 patients either had higher pressure or were using pressure-lowering medication ( Table 1 ). The proportion of eyes with normal pressures steadily declined during the study ( Table 1 ). Twenty-six of the 30 eyes (87%) without high pressure at baseline developed pressures greater than 25 mm Hg or required medical pressure-lowering therapy during the study and 23 had done so by the 12-month visit. Seven of the 30 initially normal eyes (28%) required surgical glaucoma treatment, as did 5 of the 6 eyes (83%) with initially elevated pressures. By 3 years, all 9 eyes were being treated medically or had received glaucoma surgery. Although relatively few patients completed the 3-year follow-up visit, only 4 of 36 eyes (11%) were lost to follow-up before either the medical or surgical glaucoma endpoint was reached. Two eyes (1 patient) with no ocular hypertension or glaucoma surgery were lost at the 4-month visit and 2 eyes (2 patients) were lost at the 24-month visit; therefore, glaucoma status was ascertainable for 32 of 36 (89%) of study eyes. However, there were 2 patients on glaucoma medication at 4 months, 10 patients on medication at 12 months, and 4 patients at 24 months with no follow-up, and these patients were at risk for further glaucoma surgery.
The prevalence of CME decreased from 13 of 36 eyes (36%) to 6 of 36 eyes (17%) and 2 of 32 eyes (7%) at 4 and 12 months ( P = .16 and P = .006) ( Table 1 ). The cumulative proportion of epiretinal membrane formation was higher by the end of the study, but the results were not statistically significant.
Fluorescein angiography results were available for 25 of 36 study eyes (69%) at baseline ( Table 2 ). Eyes with baseline angiograms had repeat angiograms at follow-up visits if they continued in the study. Angiography scores at each time point are given in Table 2 . The proportion of eyes with retinal vascular leakage decreased during follow-up, whereas RPE atrophy became more prevalent. By month 12, 80% (12/15) of eyes either had no leakage or had atrophy, increasing to 90% (9/10 eyes) by month 24 and 100% (6/6 eyes) by month 36.
