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.

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 major breakthrough was recognizing the immunogenicity of the disease and 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][10][11] It is thought that the enzyme ERAP2 may contribute to the genetic mutation.[11] This enzyme is thought to be part of antigen processing for presentation by class I MHC molecule.[12] 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.[10] 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 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 distributions of lesions gives 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 regiment 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 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 regiment assigned to each patient and/or if 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 should be followed by an ophthalmologist. Sudden changes in vision or symptoms should prompt an evaluation by an ophthalmologist. Even if the vision is fine, an eye exam can be needed to detect low levels of inflammation. Discuss plans for care and follow up with a local ophthalmologist.

Enhancing Healthcare Team Outcomes

Care of 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 assists 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.