Birdshot Retinochoroidopathy

Key Points at a Glance

Highlights of This Disease

• Birdshot retinochoroidopathy (BSCR) is a chronic bilateral posterior uveitis characterized by fundus lesions resembling shotgun pellet scars, distributed from the posterior pole to the equator in both eyes.
• Association with HLA-A29 is found in 80–98% of patients, with a relative risk 50–224 times higher than the general population (approximately 7%) ³⁾.
• HLA-A29 positivity is reported to be high in Caucasians, but its significance as a diagnostic aid is limited in Japanese individuals due to the low prevalence of HLA-A29 carriers ⁶⁾.
• Without treatment, visual function progressively declines, with 16–22% of patients having visual acuity of 0.1 or less within 10 years.
• Long-term management with steroids and immunosuppressants (mycophenolate mofetil, methotrexate) is the standard.
• Delayed 30-Hz flicker ERG is the most sensitive electrophysiological finding for monitoring.

1. What is Birdshot Retinochoroidopathy?

Birdshot retinochoroidopathy (BSCR), also called birdshot chorioretinopathy, is a chronic bilateral posterior uveitis. It is named for the multifocal cream-colored to yellow-orange choroidal lesions scattered like shotgun pellet scars from the posterior pole to the periphery. It is also referred to as vitiliginous chorioretinitis.

First reported by Dr. Franceschetti and colleagues in 1949, it was named “Birdshot Retinochoroidopathy” by Ryan and Maumenee in 1980. In Japan, it is a relatively rare disease, typically onset between 40 and 60 years of age, with a slight female predominance.

The Uveitis Clinical Practice Guidelines (Jpn J Ophthalmol 2019;123(6):635-696) classify it as HLA-A29-associated uveitis ⁶⁾. The association with HLA-A29 is found in nearly all cases, strongly suggesting an autoimmune etiology. An association with retinal S-antigen has also been reported.

HLA-A29 positivity is reported to be high in Caucasians (80–98%) ³⁾, but its diagnostic utility may be limited in Japanese individuals due to the low prevalence of HLA-A29 carriers ⁶⁾.

Disease Characteristics

Age of onset: 40–60 years

Sex difference: Slightly more common in women

Affected eyes: Bilateral

Course: Chronic. Progresses with repeated relapses and remissions

Key examination findings

HLA-A29: Positive in 80–98% of patients (Caucasians)

Fundus: Multiple cream-colored choroidal lesions centered on the posterior pole

FA: Lesions show hyperfluorescence but no leakage

Electroretinogram: Cone-mediated 30 Hz flicker delay has high sensitivity

Q What is birdshot chorioretinopathy?

A

It is a chronic posterior uveitis characterized by multiple choroidal lesions resembling birdshot pellets, bilaterally distributed mainly in the posterior pole. It is rare in Japan and slightly more common in women aged 40–60. It is strongly associated with HLA-A29 and considered an autoimmune disease. Without appropriate treatment, visual function progressively declines, requiring long-term management.

2. Main symptoms and clinical findings

Subjective symptoms

The most common symptom is decreased vision (68%), followed by floaters (29%), night blindness (25%), color vision abnormalities (20%), photophobia (19%), and photopsia (17%). Visual impairment usually becomes prominent in the late stage of the disease. Even if central vision is well maintained, visual field defects (diffuse narrowing, central scotoma, enlarged blind spot) may precede, leading to significant diagnostic delay.

Systemic associations include hypertension, vitiligo, skin malignancies, hearing loss, and mood disorders.

Clinical findings

Anterior segment: Anterior chamber inflammation is minimal or absent, and it is characteristic that anterior segment inflammation is mild ¹⁾. Posterior synechiae and keratic precipitates are usually not observed.

Posterior segment: Vitreous inflammation ranges from absent to moderate, with fine dust-like opacities. As the disease progresses, multifocal cream-colored to yellow-orange oval or round choroidal lesions, starting around the optic nerve, are scattered at the level of the choroid, mainly in the equatorial region. The size of individual lesions is about 1/4 to 1/2 of the optic disc diameter, and they may coalesce. Lesions tend to spread radially from the optic disc toward the periphery.

Complications may include cystoid macular edema (CME), optic disc edema, retinal vasculitis, and subretinal neovascularization. Cystoid macular edema has been reported in up to 84% of birdshot chorioretinopathy cases, which is more frequent than in other uveitis (about 30%).

Fluorescein angiography findings: On fluorescein angiography (FA), choroidal lesions show hyperfluorescence in both early and late phases but no leakage, which is a differentiating point from Behçet’s disease ¹⁾. Macular edema and optic disc hyperfluorescence are also visualized. On indocyanine green angiography (ICGA), active choroiditis lesions appear as hypofluorescent spots, and ICGA has higher sensitivity for detecting choroidal lesions than FA ¹⁾. EDI-OCT may show suprachoroidal fluid accumulation.

Electrophysiological findings: The electroretinogram is markedly reduced, and the L/D ratio of the electrooculogram (EOG) is decreased. In the early stage, it shows a negative-type waveform with a disproportionate reduction of b-wave amplitude relative to a-wave amplitude. As the disease progresses, a-wave amplitude also decreases. Detection of cone-mediated 30-Hz flicker delay is considered the most sensitive method for evaluating and monitoring birdshot chorioretinopathy.

Q What does the fundus look like in birdshot chorioretinopathy?

A

From the posterior pole to the equator, numerous cream-colored to yellow-orange round or oval lesions, about 1/4 to 1/2 disc diameter in size, are scattered at the level of the choroid. They characteristically spread radially from the optic disc toward the periphery, described as “birdshot pellets.” On fluorescein angiography, these lesions show hyperfluorescence but no leakage.

3. Causes and Risk Factors

Genetic Risk Factors

The association between birdshot chorioretinopathy and the HLA-A29 allele is one of the strongest genetic associations known for any disease. The HLA-A29 positivity rate is 80–98% in white patients ³⁾, with a relative risk increased by 50–224 times. How HLA-A29 triggers autoimmunity is unknown, but hypotheses include allele-specific presentation of certain self-peptides or activation of T cells through HLA protein stability ³⁾.

Risk Factor	Details
HLA-A29	Positive in 80–98% of white patients. Relative risk 50–224 times compared to the general population (about 7%) 3)
Sex and age	Ages 40–60, slightly more common in women
Race	More frequently reported in families of Northern European descent
Retinal S-antigen	Association suggested but mechanism unknown

HLA-A29 positivity is reported to be high in Caucasians, but since the number of HLA-A29 carriers is low in Japanese people⁶⁾, the value of using HLA-A29 testing as a diagnostic aid is limited. For Japanese cases, reliance on clinical diagnostic criteria that do not use HLA-A29 (SUN 2021) is important⁵⁾.

Q Can Japanese people develop birdshot chorioretinopathy?

A

Although rare, cases have been reported. While HLA-A29 positivity is 80–98% in Caucasians³⁾, the number of HLA-A29 carriers is low in Japanese people⁶⁾. Therefore, in diagnosis, it is necessary to emphasize the clinical findings of the SUN 2021 classification criteria rather than relying excessively on HLA-A29 testing. Even if HLA-A29 is negative in bilateral posterior uveitis in patients aged 40–60, this disease cannot be excluded.

Daily life precautions

Birdshot chorioretinopathy is a disease in which visual function progressively declines without treatment. Even if central vision is good, the visual field may narrow, so it is important to continue regular visual field tests and follow-up with ERG. While using immunosuppressive drugs, attention to infections is necessary; if fever or malaise persists, consult your doctor promptly.

4. Diagnosis and examination methods

Diagnostic criteria (SUN 2021 revision)

In 2021, the Standardization of Uveitis Nomenclature (SUN) Working Group published classification criteria using a machine learning model⁵⁾.

Classification is made if all of criteria 1–3 below are met, or if criterion 4 is met:

1. Characteristic bilateral multifocal choroiditis (cream-colored or yellow-orange ovoid/round lesions) on fundus examination
2. Anterior chamber inflammation absent or minimal (anterior chamber cells absent or minimal, no keratic precipitates or posterior synechiae)
3. Vitreous haze absent or moderate
4. Or, multifocal choroiditis plus HLA-A29 positivity, and characteristic findings on fundus examination or ICG angiography

Exclude if: positive syphilis serology, evidence of sarcoidosis (bilateral hilar lymphadenopathy, non-caseating granuloma), or evidence of intraocular lymphoma.

Required tests

Laboratory tests (to rule out other diseases):

• Complete blood count (CBC), syphilis testing (RPR/FTA-ABS)
• ACE and lysozyme (to rule out sarcoidosis)
• Chest X-ray and chest CT (to rule out sarcoidosis)
• Tuberculin skin test or QuantiFERON (to rule out tuberculosis)
• HLA-A29 testing

Ancillary tests:

• FAF (fundus autofluorescence): Confluent hypoautofluorescence around the optic disc is seen in 73% of cases and correlates with chronicity and severity
• FA (fluorescein angiography): Evaluates lesion hyperfluorescence, macular edema, optic disc hyperfluorescence, and vascular leakage¹⁾
• ICGA (Indocyanine Green Angiography): Excellent for assessing activity of choroidal lesions (high sensitivity from early disease) ¹⁾
• Optical Coherence Tomography (OCT): Evaluates choroidal lesions, cystoid macular edema, and retinal thinning. Loss of the ellipsoid zone is associated with worse visual prognosis
• OCTA: Identifies abnormal blood flow signals
• Visual Field Testing: Even with good central vision, diffuse narrowing, central scotoma, and enlarged blind spot occur frequently
• Electroretinography: 30Hz flicker delay is the most sensitive for monitoring

Differential Diagnosis

Differential Disease	Key Differentiating Points
Sarcoidosis	Most important. Systemic abnormalities (elevated ACE, bilateral hilar lymphadenopathy), periphlebitis
Multiple Evanescent White Dot Syndrome (MEWDS)	Unilateral, acute, spontaneous resolution, minimal anterior chamber inflammation
Acute Posterior Multifocal Placoid Pigment Epitheliopathy (APMPPE)	Acute onset, bilateral, relatively good prognosis
Syphilitic Uveitis	Positive syphilis serology
Tuberculous uveitis	Positive QuantiFERON, abnormal chest findings

5. Standard Treatment

Overview of Treatment

The mainstay of treatment for birdshot chorioretinopathy is a combination of corticosteroids and immunosuppressive therapy. Without treatment, most patients experience progressive decline in visual function, with 16–22% of patients having visual acuity of 0.1 or less after 10 years (compared to 4% for other types of uveitis).

Steroid Therapy

Systemic administration is started with prednisolone 0.5–1 mg/kg/day. A prescription example is prednisolone 5 mg × 8 tablets (40 mg) divided into two doses (6 tablets after breakfast, 2 tablets after lunch). Long-term maintenance with oral steroids alone (asymptomatic maintenance at <20 mg/day) is achieved in less than 15% of patients, so combination with immunosuppressive therapy is recommended. If macular edema persists despite systemic therapy, local steroid injections (sub-Tenon injection, intraocular implant) may also be used. In case of recurrence, consider steroid pulse therapy and oral cyclosporine.

Precautions for Steroid Implants

In birdshot chorioretinopathy, steroid implants are associated with a stronger intraocular pressure elevation response compared to other uveitides, with reports that up to 40% of patients require trabeculectomy and all patients require cataract surgery. The risk-benefit ratio should be carefully considered before use.

Immunosuppressive Therapy (for Steroid Sparing)

To minimize steroid side effects, immunosuppressive drugs are added early.

• Mycophenolate mofetil: Considered more effective than other antimetabolites for posterior uveitis and panuveitis, and is commonly used as a first-line agent in birdshot chorioretinopathy ⁴⁾
• Methotrexate: In randomized controlled trials, it showed a slightly higher treatment success rate than mycophenolate mofetil for posterior and panuveitis overall (no statistical significance)
• Cyclosporine (Neoral®): Considered as an immunosuppressive agent in case of recurrence
• Azathioprine: May be used in combination with corticosteroids or other immunosuppressive drugs ⁴⁾

The one-year treatment success rate with immunosuppressive therapy is estimated to be 67–90%.

The Uveitis Clinical Practice Guidelines describe a similar treatment approach with immunosuppressive drugs⁶⁾.

Biologic Agents

In refractory cases unresponsive to conventional immunosuppressants, step-up to biologic agents is indicated.

• Adalimumab: The most commonly used first-line biologic agent for birdshot chorioretinopathy (93.2%)⁴⁾. It has been shown to improve visual acuity and enable reduction of concomitant immunomodulatory therapy, but complete remission with monotherapy is difficult.
• Infliximab: A TNF-α inhibitor that demonstrates efficacy in refractory uveitis.
• Tocilizumab (anti-IL-6 receptor antibody): Successful cases have been reported, but evidence for its use in birdshot chorioretinopathy is currently limited.

6. Pathophysiology and Detailed Mechanisms

T-Cell-Mediated Autoimmunity

The pathophysiology of birdshot chorioretinopathy remains largely unknown, but it is widely considered a T-cell-mediated autoimmune disease. Histopathological examination of HLA-A29-positive eyes reveals multifocal lymphocytic infiltration at various levels of the choroid, around retinal vessels, and within the prelaminar optic nerve head.

How HLA molecules trigger autoimmunity is unclear, but hypotheses include allele-specific presentation of specific self-peptides or activation of T cells via HLA protein stability³⁾. It has also been proposed that an infection triggers T lymphocyte stimulation and expression of self-peptides.

Mechanisms of Choroidal Lesion Formation

Inflammatory exudates are thought to infiltrate the dissecting plane of the choroid, causing fibrosis, adhesion of choroidal stroma, and atrophic lesions. Choroidal involvement occurs independently of the retina, and retinal involvement leads to retinal vasculitis and cystoid macular edema¹⁾. OCT-A shows abnormal blood flow at the level of the choroidal stroma, while the choriocapillaris is reported to be relatively preserved in the early stages¹⁾.

Effects on Electroretinography

Functional impairment of both cone and rod systems is reflected in the electroretinogram. An early negative-type waveform suggests inflammatory effects on the inner retina (bipolar cells and ganglion cells) while photoreceptor function is relatively preserved. Early prolongation of the 30-Hz flicker (cone-mediated) indicates that the disease strongly affects the cone system.

7. Latest Research and Future Prospects

Refinement of Diagnostic Criteria

In 2021, the SUN working group updated the classification criteria using machine learning, improving the accuracy of early diagnosis ⁵⁾. The use of HLA-A29 testing and ICGA enables diagnosis in early stages when fundus lesions are unclear.

Advances in Multimodal Imaging

The introduction of OCT angiography (OCTA) allows non-invasive assessment of choroidal blood flow abnormalities. The pattern of low autofluorescence around the optic disc on FAF (seen in 73% of cases) is attracting attention as an indicator of chronicity and severity. Quantification of ellipsoid zone loss on OCT has improved prediction of visual prognosis ²⁾.

Progress in Biologic Agents

Adalimumab has become widely used as a first-line biologic for birdshot chorioretinopathy ⁴⁾, contributing to the maintenance of visual function in cases with inadequate response to conventional immunosuppressants. Reports on the efficacy of new classes of biologics such as tocilizumab are also accumulating.

Challenges and Prospects

• Elucidation of differences between individuals who carry HLA-A29 but do not develop the disease
• Development of diagnostic markers for HLA-A29-negative patients, including Japanese ⁶⁾
• Establishment of objective biomarkers of disease activity
• Standardization of optimal treatment initiation timing, duration, and tapering protocols

For Patients: Please Read Carefully

This article is intended to provide medical information and does not prescribe individual diagnosis or treatment. Decisions regarding treatment should always follow the instructions of a specialist. Dosage and administration of medications vary depending on individual conditions, so please consult your physician for actual prescriptions.

---

8. References

1. Testi I, Mahajan S, Napolitano P, et al. Multimodal imaging in posterior uveitis – a review. J Ophthalmic Inflamm Infect. 2021;11:32.
2. Wakefield D, et al. Birdshot Chorioretinopathy. Cureus. 2024;16:e58867.
3. Agrawal R, et al. The role of HLA-A29 in birdshot chorioretinopathy and immune checkpoint inhibitor-related uveitis. Am J Ophthalmol. 2025. doi:10.1016/j.ajo.2024.01.007
4. Tomkins-Netzer O, et al. Treatment of non-infectious uveitis with biologics: a survey of the International Ocular Inflammation Society. Br J Ophthalmol. 2022;106:482-488.
5. Standardization of Uveitis Nomenclature (SUN) Working Group. Classification criteria for birdshot chorioretinitis. Am J Ophthalmol. 2021;228:65-71.
6. 日本眼炎症学会・日本眼科学会. ぶどう膜炎診療ガイドライン（HLA-A29・脈絡網膜症記述）. 日本眼科学会雑誌. 2019;123(6):635-696.