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    Clinical Follow-Up of Birdshot Chorioretinopathy

    By Timothy M. Janetos, MD, MBA, and Debra A. Goldstein, MD
    Edit­ed by Bennie H. Jeng, MD
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    Birdshot chorioretinopathy (BSCR) is a bilateral, chronic, posterior uveitis characterized by cream-colored lesions primarily in the poste­rior pole. It is typically accompanied by vitritis, retinal vasculitis, and cystoid macular edema (CME). BSCR is rare, affecting approximately 8% of patients with posterior uveitis.1 It has a slight female preponderance and usually manifests in the fourth or fifth decade of life. There is a strong association between BSCR and the HLA-A29 allele.

    Ocular symptoms can precede the diagnosis by several years and include shimmering photopsias, floaters, nyc­talopia, and blurred vision. However, visual acuity (VA) is often preserved even with end stage disease. Given the chronic nature of BSCR, management usually requires long-term immuno­suppression.

    Disease monitoring traditionally has been conducted with visual field testing and full-field electroretinog­raphy (ERG), but these modalities are cumbersome and detect only the sequelae of intraocular inflammation, making them impractical for real-time disease-management decisions. A ben­eficial alternative approach to disease monitoring is based on OCT with enhanced depth imaging (OCT-EDI), widefield fundus autofluorescence (FAF), and, if indicated, fluorescein an­giography (FA) and indocyanine green angiography (ICGA).

    (1) Color fundus photo. (2) Fluorescein angiography and indocyanine green angiography.
    SIGNS. (1) Classic funduscopic appearance of BSCR: ovoid cream-colored lesions. (2) FA and ICGA (late frame) of the right eye. Note the large-vessel vasculitis (left) and multiple hypocyanescent lesions (right).

    Determining the Diagnosis

    A consensus document on BSCR diagnosis was released in 2006.2 The diagnostic criteria are bilateral disease, low-grade inflammation of the anterior chamber (£1+ cell), low-grade vitreous inflammation (£2+ vitreous haze), and at least three peripapillary cream-col­ored lesions (Fig. 1). It is important to note that these classic lesions may not necessarily be present until the patient has experienced symptoms for several years. Other findings that support the diagnosis include HLA-A29 positiv­ity, retinal vasculitis, and CME. The exclusion criteria are significant keratic precipitates, posterior synechiae, and a diagnosis of any other infectious, inflammatory, or neoplastic condition that can lead to multifocal choroiditis.

    Imaging. Several imaging modalities may help to establish the diagnosis. ICGA can depict the birdshot lesions as multiple scattered hypocyanescent spots (Fig. 2). Often, the number of spots detected by ICGA is much greater than that seen clinically. FA may reveal vasculitis of large veins or smaller vessels, which may have a fern-like appearance. OCT also can be used to identify characteristics of late-stage BSCR, such as diffuse retinal thinning, a thin choroid, and loss of the ellipsoid zone (EZ) with hyperreflective outer retinal foci.3

    Monitoring the Disease

    The following approach to patient monitoring is recommended.

    Signs and symptoms. There is no replacement for a thorough clinical his­tory and exam. Symptoms are key; for example, patients with disease activity often describe shimmering photopsias, which improve or resolve with treat­ment. VA, however, is not an appropri­ate indicator for monitoring disease activity, as patients can have end-stage disease with significant retinal atrophy but still maintain good central VA, providing false reassurance to provid­ers. Certainly, a decline in VA warrants investigation and should raise suspicion for CME.

    Other indicators of disease activ­ity include vitreous inflammation or clinically apparent retinal vasculitis. Vasculitis of the larger vessels may be seen as subtle venous pinching at the vascular arcades, warranting further in­vestigation with FA. However, in many cases, especially those involving smaller retinal vessels, the vasculitis associated with BSCR is subclinical and identifi­able only by FA. Thickness mapping on OCT of the macula can reveal retinal thickening, especially at the vascular arcades, which may clue the clinician to active vasculitis (Fig. 3).4

    OCT-EDI and FAF. OCT-EDI to evaluate the choroid is invaluable for monitoring disease activity.5 Choroidal thickness and reflectivity have been exten­sively studied in BSCR. Compared with age-matched controls, the choroid is thinner in quiescent disease. During active disease, choroidal thickness in­creases and may be accompanied by a hyporeflective choroid with loss of vascular markings, which may denote in­flammatory infiltration (Fig. 4). Hyporeflective foci within the choroid have also been identified as active lesions, but they do not always correlate with the clinically apparent birdshot lesions.

    OCT and FAF can be used to iden­tify EZ disruption in BSCR. Acute EZ disruption may occur, and associated diffuse punctiform hyper-autofluo­rescence (hyper-FAF) may be detected by FAF (Fig. 4).3,6 Left untreated, EZ disruption may lead to further outer retinal atrophy. If the disruption is extramacular, OCT (nasal to the optic nerve) and widefield FAF can be useful for detecting changes.

    FAF can additionally reveal various BSCR patterns.7 For example, chronic BSCR often includes multiple patterns of hypo-FAF, such as peripapillary, li­chenoid, and macular hypo-FAF in the case of resolved CME. These are linked to chronic atrophy of the outer retina and the retinal pigment epithelium.

    About ICGA. Although the number and size of lesions on ICGA can de-crease with treatment and in some cases may be the main marker of disease ac­tivity, this is a relatively difficult marker to routinely follow, and, in many cases, lesions remain despite treatment.8

    Therefore, OCT-EDI and widefield FAF are the optimal modalities for routine monitoring of disease activity. Additional testing, including ICGA and FA, may be helpful for monitoring responses to changes in therapy and to check the status of characteristics iden­tified by OCT, such as increased retinal thickness.

    OCT-EDI and FA.
    VASCULITIS. OCT-EDI and FA of another patient with BSCR shows diffuse fern-pattern vasculitis of the small vessels. The en face OCT thickness map showed thickening (red) of the vasculature in the macula, suggesting active vasculitis, which was confirmed by FA. Although OCT did not show CME, it detected discontinuity and disruption of the EZ.

    FAF and OCT-EDI.
    INITIAL VISIT. FAF and OCT-EDI images of the patient’s right eye (4A) and left eye (4B), obtained at the initial consultation. FAF demonstrated areas of peripapillary and scattered hypoautofluorescence and punctate hyper-autofluorescence. OCTEDI showed a thickened infiltrated choroid, with patchy areas of outer retinal and EZ disruption (arrowheads denote areas of greatest prominence). CME was apparent in the right eye. VA at this visit was 20/40 in the right eye and 20/20 in the left eye.

    OCT-EDI.
    FOLLOW-UP VISIT. Follow-up OCT-EDI images. (5A) One month after injection of a dexamethasone implant into the right eye, the CME and choroidal infiltration had resolved, and reconstitution of the EZ had begun. (5B) Seven months into adalimumab treatment, there was further evidence of resolution of choroidal infiltration and reconstitution of the EZ, as well as epiretinal membrane formation in the right eye. VA at this visit was 20/25+2 in the right eye and 20/20 in the left eye.

    Treatment and Prognosis

    BSCR generally requires long-term therapy, which may be systemic or local.

    Systemic therapy. Long-term immunomodulatory therapy (IMT) is the preferred treatment option for many patients. Although there are no randomized controlled studies of BSCR treatments, ample cohort studies have demonstrated disease control and quiescence with use of IMT. Moreover, this therapy can stabilize the VF and lowers the risk of long-term choroidal thinning.9

    Many IMT regimens have been used to treat BSCR, including anti­metabolites, cyclosporine, anti–tumor necrosis factor (TNF) agents, and interleukin (IL)-2 and IL-6 receptor blockers. The only systemic IMT approved for uveitis treatment is the TNF inhibitor adalimumab. All system­ic therapies except for adalimumab are used off label.

    Local therapy. Given that BSCR is strictly ocular (not systemic), long-act­ing steroid implants may be a viable alternative to systemic IMT for patients who have contraindications to IMT or prefer only local treatment.

    Long-acting steroid implants include the .59-mg fluocinolone acetonide intravitreal implant (Retisert; Bausch + Lomb), the .19-mg insert (Iluvien; Al­imera Sciences), and the .18-mg insert (Yutiq; EyePoint Pharmaceuticals). Retisert has demonstrated high resolution rates for retinal vasculitis and clinical inflammation and has allowed for suc­cessful weaning from systemic IMT.10 However, all patients with Retisert implants will require cataract surgery, and many will need glaucoma surgery to control IOP.10

    The Iluvien implant has been specifically studied in BSCR and has pro­duced good control of retinal vascu­litis and CME in patients with this condition. However, many cases have required systemic IMT to resolve cho­roidal infiltration, indicating that low­er-dose implants may not necessarily be sufficient to control the disease.11 There are currently no studies evaluating the utility of the Yutiq implant in BSCR.

    Both Retisert and Yutiq are FDA approved to treat noninfectious inter­mediate uveitis, posterior uveitis, and panuveitis. Iluvien is not FDA approved to treat any type of uveitis.

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    1 Shah KH et al. Surv Ophthalmol. 2005;50(6):519-541.

    2 Levinson RD et al. Am J Ophthalmol. 2006;141(1):185-187.

    3 Kopplin LJ et al. J Vitreoretin Dis. 2019;3(4):235-241.

    4 Thomas AS et al. Retina. 2019;39(5):956-963.

    5 Böni C et al. Investig Opthalmology Vis Sci. 2016;57(9):OCT591-OCT599.

    6 Teussink MM et al. Acta Ophthalmol (Copenh). 2016;94(8):815-823.

    7 Semécas R et al. Graefes Arch Clin Exp Ophthal­mol. 2017;255(7):1333-1339.

    8 Cao JH et al. Retina. 2016;36(9):1751-1757.

    9 You C et al. Ocul Immunol Inflamm. 2020;28(6):966-974.

    10 Rush RB et al. Am J Ophthalmol. 2011;151(4):630-636.

    11 Ajamil-Rodanes S et al. Br J Ophthalmol. 2022;106(2):234-240.

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    Dr. Janetos is a uveitis fellow and Dr. Goldstein is director of the uveitis service as well as the Magerstadt Professor of Ophthalmology. Both are at Northwestern University Feinberg School of Medicine in Chicago. Financial disclosures: Dr. Janetos: None. Dr. Goldstein: AbbVie: C; Allergan: C; Bausch + Lomb: C.