Continuing Education Activity

Birdshot chorioretinopathy (BCR) is an unusual form of chronic, bilateral, posterior uveitis with a distinguishing clinical phenotype and a strong association with HLA-A29. This disease predominantly affects middle-aged individuals and more often affects females than males. Early in the course of this disease, patients may present with mild symptoms, delaying treatment that can often result in permanent visual dysfunction. The disease is permanent, chronic, and progressive, resulting in irreversible ocular damage. This activity will help the clinician gain a deeper understanding of this disease, its diagnosis, and treatment.

Objectives:

• Identify the etiology of birdshot chorioretinopathy.
• Describe the appropriate evaluation of patients with suspected birdshot chorioretinopathy.
• Review the treatment and management options available for birdshot chorioretinopathy.
• Outline interprofessional team strategies for improving care coordination and communication to advance birdshot chorioretinopathy and improve outcomes.

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Introduction

Birdshot chorioretinopathy (BCR) is a form of chronic, bilateral, posterior uveitis with a distinguishing clinical phenotype and a strong association with HLA-A29. This disease predominantly affects individuals of middle age and more often affects females than males.[1] Early in the course of this disease, patients may present with mild symptoms, delaying treatment that can often result in permanent vision changes. This disease is permanent, chronic, and progressive, resulting in irreversible ocular damage.

Historically, the first recognition of BCR as a distinct entity was the description by Franceschetti and Babel in 1949 of “candle wax spot chorioretinopathy,” in which they reported a 65-year-old woman with discrete depigmented lesions.[2] The first use of the term “birdshot retinochoroidopathy” was in 1980 when Ryan and Maumenee discussed 13 patients with a particular syndrome characterized by a white, painless eye with minimal anterior segment inflammation, but with vitritis, retinal vascular leakage, and cream-colored spots at the level of the retinal pigment epithelium (RPE) or deeper retinal layers. The condition was further explored and defined by Gass and others. Since the recognition of BCR, physicians have improved treatment options and outcomes. A breakthrough was recognizing the immunogenicity of the disease and its pathogenesis.

Etiology

The etiology of this condition remains unclear, but it is thought to be related to an autoimmune disease. It may be linked to HLA-A29 due to the presence of this marker in an overwhelming percentage of cases, but triggers for the autoimmune disease remain unclear.

Epidemiology

Birdshot chorioretinopathy is an unusual cause of ocular inflammation, and obtaining reliable incidence and prevalence data is difficult due to the rarity of the disease. Studies from Europe and the United States report that BCR accounts for between 0.5% and 1.5% of the uveitis cases seen in specialist uveitis practices.[3][4] BCR is predominantly seen in the middle-aged, and some reports appear to be more common in females. In a systematic review from 2005, Shah et al. reported a mean age of disease onset of 53.0 years (512 patients), and a 54.1 % female preponderance (522 patients).[5] Birdshot chorioretinopathy is most prevalent in White populations, is most commonly diagnosed in people of Northern European ancestry, with only the occasional case report of BCR in Latino-Hispanic, African-American, and Japanese people.[6] The ethnic distribution is relevant to HLA-A29. HLA-A29 subtypes can be observed in many patients, with each subtype having a different prevalence.[7]

Pathophysiology

Recent research has demonstrated that the HLA-A29 gene itself is central to the pathogenesis of the disease.[8][9] It is thought that the enzyme ERAP2 may contribute to the genetic mutation.[10] This enzyme is thought to be part of antigen processing for presentation by class I MHC molecules.[11] This has been recognized in a number of other conditions, such as Crohn disease and psoriasis. There is strong evidence of selective antigen processing by ERAP2 with HLA-A29, enabling a unique immunogenic signal leading to BCR.[12] There is continuing debate as to whether BCR is primarily a disease of the choroid or the retina. The indistinct appearance of the lesions, lack of associated RPE pigmentary changes, and the angiographic features of the lesions suggest these lesions are located in the deep choroidal stroma and are associated with the choroidal veins. It is important to recognize that the retinal and choroidal changes are not necessarily concordant and that this reflects our ability to monitor the disease and may reflect different aspects of its pathogenesis.

Histopathology

Multiple foci of lymphocytes are at various levels of the choroid, prelaminar optic nerve head, and surrounding retinal blood vessels. This may indicate primary disease of the choroid with secondary involvement of the retina.[13]

History and Physical

Early symptoms include floaters, blurred vision, and decreased vision. Later symptoms in the course of the disease include nyctalopia, diminished contrast sensitivity, and decreased color vision. Fundus examination reveals vitreous inflammation associated with multiple yellow-white choroiditis spots that are often initially observed inferior to the optic nerve head. These lesions are usually 500 to 1500 micrometers in diameter. The typical "birdshot" appearance and distribution of lesions give the disease its name. As the disease progresses, the lesions become more confluent and linear around the veins, eventually becoming more atrophic in appearance.

Evaluation

Fluorescein angiography often shows leaking from the retinal vessels and nerve head. Leakage can often produce cystoid macular edema and is thought to be the leading cause of visual loss in patients with BCR. If there is clinical suspicion for BCR, the following can help confirm the diagnosis: HLA-A29, syphilis serology, ACE level in all cases; interferon-gamma release assay and/or a Mantoux test in selected high-risk cases; chest x-ray (looking for evidence of sarcoidosis or TB) in all cases; Indocyanine green angiography (ICG), fluorescein angiography (FA), and electroretinography (ERG) in all cases.

Over the years, a number of diagnostic criteria have been proposed. Essential criteria are (1) bilateral disease; (2) three or more characteristic birdshot lesions inferior or nasal to the disk in one eye; (3) low-grade anterior chamber inflammation (no more than 1+ cells in the anterior chamber on the SUN score); (4) low-grade vitreous inflammation (no more than 2+ on the NEI/SUN vitreous haze score). Birdshot lesions are defined as being “cream-colored, irregular or elongated, choroidal lesions with indistinct borders, the long axis of which is radial to the optic disk.”

Treatment / Management

Treatment is typically managed by steroids and steroid-sparing immunomodulatory therapy. Steroids can be given either by mouth or directly into the eye by injection or implant. There is increasing use of steroids being placed into the eye to help control the progression of BCR. The use of steroids can cause an elevation of intraocular pressure, and if left untreated, can result in permanent vision loss. When using steroids, it is important to monitor intraocular pressure, as this can often be asymptomatic to the patient until permanent vision loss has occurred. Many of the steroid-sparing immunomodulatory therapies currently used have significant side effects, and this should be discussed with the patient in detail. Unfortunately, there is not one regimen of therapy that is effective for all patients, and many combinations may need to be trialed to control the ocular inflammation. The goal of therapy is to find the lowest amount of medication needed to suppress the ocular inflammation. Often, a patient may need to follow up with a rheumatologist or nephrologist for testing and management of these immunomodulatory therapies. With the use of IMTs, visual acuity can remain stable or can improve by 78.6% to 89.3%.[14][15][16][17]

Differential Diagnosis

Infectious

• Tuberculosis
• Syphilis
• Ocular histoplasmosis syndrome

Non-infectious

• Sarcoidosis
• Vogt-Koyanagi-Harada syndrome
• Sympathetic ophthalmia
• Acute posterior multifocal placoid pigment epitheliopathy (APMPPE)
• Multiple evanescent white dot syndrome (MEWDS)
• Multifocal choroiditis and panuveitis (MCP)
• Punctate inner choroidopathy (PIC)

Lymphoma can masquerade as birdshot retinopathy.

Toxicity and Adverse Effect Management

This is dependent on the immunosuppressant regimen assigned to each patient and/or whether they are an ocular steroid "responder." Depending on the medications chosen, it may require frequent intraocular pressure measurements, liver function tests, complete blood counts, and other metabolic profiles. Signs of toxicity should prompt the physician to decrease the medication or switch medications altogether.

Prognosis

Birdshot chorioretinopathy is a progressive disease with the potential for significant visual impairment due to anatomical and functional complications.

Complications

Common causes of visual loss in BCR include refractory cystoid macular edema (CME), macular scarring, development of choroidal neovascular membrane, and cellophane maculopathy. Diffuse retinal dysfunction associated with the long duration of the disease is recognized as a statistically significant risk factor for vision loss.

Consultations

Rheumatology and ophthalmology should work in tandem to control this complicated inflammatory disorder.

Deterrence and Patient Education

Birdshot is an eye disease that an ophthalmologist should follow. Sudden changes in vision or symptoms should prompt an evaluation by an ophthalmologist. Even if the vision is fine, an eye exam may be needed to detect low levels of inflammation. Discuss plans for care and follow up with a local ophthalmologist.

Enhancing Healthcare Team Outcomes

Care coordination by physicians, nurses, and pharmacists will be required. Often, multiple physicians will monitor the status of the patient. An ophthalmologist will follow the ocular inflammation and vision, while a rheumatologist or nephrologist may be required to assist in the management of complex immunosuppressant therapies. The goal is to safely control the inflammation while using the least amount of medications and preserve vision in our patients.

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References

1.

Minos E, Barry RJ, Southworth S, Folkard A, Murray PI, Duker JS, Keane PA, Denniston AK. Birdshot chorioretinopathy: current knowledge and new concepts in pathophysiology, diagnosis, monitoring and treatment. Orphanet J Rare Dis. 2016 May 12;11(1):61. [PMC free article: PMC4866419] [PubMed: 27175923]

2.

FRANCESCHETTI A, BABEL J. [Chorioretinitis with "candle spots," a manifestation of Besnier-Boeck disease]. Ophthalmologica. 1949 Oct-Nov;118(4-5):701-10. [PubMed: 15401026]

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Jones NP. The Manchester Uveitis Clinic: The first 3000 patients, 2: Uveitis Manifestations, Complications, Medical and Surgical Management. Ocul Immunol Inflamm. 2015 Apr;23(2):127-34. [PubMed: 25393634]

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Jones NP. The Manchester Uveitis Clinic: the first 3000 patients--epidemiology and casemix. Ocul Immunol Inflamm. 2015 Apr;23(2):118-26. [PubMed: 24295124]

5.

Shah KH, Levinson RD, Yu F, Goldhardt R, Gordon LK, Gonzales CR, Heckenlively JR, Kappel PJ, Holland GN. Birdshot chorioretinopathy. Surv Ophthalmol. 2005 Nov-Dec;50(6):519-41. [PubMed: 16263368]

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Saito W, Yamamoto S, Mitamura Y, Takeuchi S. [Birdshot chorioretinopathy--a case report and a case study in Japanese patients]. Nippon Ganka Gakkai Zasshi. 2002 Apr;106(4):229-35. [PubMed: 11979983]

7.

Lages V, Skvortsova N, Jeannin B, Gasc A, Herbort CP. Low-grade "benign" birdshot retinochoroiditis: prevalence and characteristics. Int Ophthalmol. 2019 Sep;39(9):2111-2120. [PubMed: 30474776]

8.

Donvito B, Monnet D, Tabary T, Delair E, Vittier M, Réveil B, Sivaradjam R, Edelson C, Philbert F, Brézin AP, Cohen JH. Different HLA class IA region complotypes for HLA-A29.2 and -A29.1 antigens, identical in birdshot retinochoroidopathy patients or healthy individuals. Invest Ophthalmol Vis Sci. 2005 Sep;46(9):3227-32. [PubMed: 16123423]

9.

Donvito B, Monnet D, Tabary T, Delair E, Vittier M, Réveil B, Chiquet C, Brézin AP, Cohen JH. A new HLA extended haplotype containing the A*2910 allele in birdshot retinochoroidopathy: susceptibility narrowed to the HLA molecule itself. Invest Ophthalmol Vis Sci. 2010 May;51(5):2525-8. [PubMed: 19959637]

10.

Kuiper JJ, Van Setten J, Ripke S, Van 'T Slot R, Mulder F, Missotten T, Baarsma GS, Francioli LC, Pulit SL, De Kovel CG, Ten Dam-Van Loon N, Den Hollander AI, Huis in het Veld P, Hoyng CB, Cordero-Coma M, Martín J, Llorenç V, Arya B, Thomas D, Bakker SC, Ophoff RA, Rothova A, De Bakker PI, Mutis T, Koeleman BP. A genome-wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy. Hum Mol Genet. 2014 Nov 15;23(22):6081-7. [PMC free article: PMC4204766] [PubMed: 24957906]

11.

Saveanu L, Carroll O, Lindo V, Del Val M, Lopez D, Lepelletier Y, Greer F, Schomburg L, Fruci D, Niedermann G, van Endert PM. Concerted peptide trimming by human ERAP1 and ERAP2 aminopeptidase complexes in the endoplasmic reticulum. Nat Immunol. 2005 Jul;6(7):689-97. [PubMed: 15908954]

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Kuiper J, Rothova A, de Boer J, Radstake T. The immunopathogenesis of birdshot chorioretinopathy; a bird of many feathers. Prog Retin Eye Res. 2015 Jan;44:99-110. [PubMed: 25434765]

13.

Gaudio PA, Kaye DB, Crawford JB. Histopathology of birdshot retinochoroidopathy. Br J Ophthalmol. 2002 Dec;86(12):1439-41. [PMC free article: PMC1771424] [PubMed: 12446382]

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Kiss S, Ahmed M, Letko E, Foster CS. Long-term follow-up of patients with birdshot retinochoroidopathy treated with corticosteroid-sparing systemic immunomodulatory therapy. Ophthalmology. 2005 Jun;112(6):1066-71. [PubMed: 15936442]

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Pohlmann D, Winterhalter S, Pleyer U. [White dot syndromes : Principles, diagnostics, and treatment]. Ophthalmologe. 2019 Dec;116(12):1235-1256. [PubMed: 31748943]

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Acaba-Berrocal LA, Lucio-Alvarez JA, Mashayekhi A, Ho AC, Dunn JP, Shields CL. Birdshot-like Chorioretinopathy Associated With Pembrolizumab Treatment. JAMA Ophthalmol. 2018 Oct 01;136(10):1205-1207. [PubMed: 30054605]

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Disclosure: Reece Bergstrom declares no relevant financial relationships with ineligible companies.

Disclosure: Craig Czyz declares no relevant financial relationships with ineligible companies.