Birdshot Chorioretinopathy (Birdshot Uveitis) 

Updated: May 29, 2019
Author: Hemang K Pandya, MD; Chief Editor: C Stephen Foster, MD, FACS, FACR, FAAO, FARVO 

Overview

Background

Birdshot chorioretinopathy, also known as birdshot uveitis, birdshot retinopathy, or HLA-A29 uveitis, is an uncommon chronic posterior uveitis characterized by vitritis and multiple ovoid spots, which are orange to cream in color and hypopigmented. These spots are mainly distributed in the posterior pole and in the mid periphery of the retina. The classic presentation is described to "resemble the pattern seen with birdshot in the scatter from a shotgun."

Birdshot chorioretinopathy was first described by Franceschetti and Bable in 1949. In 1980, Ryan and Maumenee coined the term birdshot.[1] Gass described birdshot chorioretinopathy as vitiliginous choroiditis because of the similarities of the fundus lesion to cutaneous vitiligo.

Birdshot chorioretinopathy may indeed represent a clinical disease that has only recently come into existence, and one may wonder what factors from recent times have allowed it to emerge, such as a new strain of virus, an environmental factor, or some yet unrecognized participant in the development of this disease.

Pathophysiology

The cause for birdshot chorioretinopathy is unknown. A strong link to the presence of the human leukocyte antigen A29 (HLA-A29) molecule exists, suggesting that the disease may result from an inherited immune dysregulation. Multiple case series report 80-93.1% HLA-A29 positivity for patients with birdshot chorioretinopathy, with a relative risk ratio from 50 to 224. This is the strongest HLA association with any known disease.[2]

LeHoang and coauthors reported a series of European patients in which all patients who were HLA-A29 positive with birdshot chorioretinopathy expressed the HLA-A29 type 2 subtype.[3] Both the HLA-A29 type 1 subtype and the HLA-A29 type 2 subtype respond to serologic tests but migrate differently on 1-dimensional electrofocusing gel electrophoresis. Their results suggested that the HLA-A29 type 2 subtype is the risk factor for birdshot chorioretinopathy and that the HLA-A29 type 1 subtype actually may be protective against developing the disease. However, Levinson and coauthors found that both subtypes were associated with disease in patients in the United States.[4]

Nussenblatt and colleagues also found a link with human leukocyte antigen B12 (HLA-B12), which has been confirmed by several other authors.[5] The link to HLA-B12 is less strong, with a relative risk ratio from 2.7 to 7. Most individuals who are HLA-A29 or HLA-B12 positive do not have birdshot chorioretinopathy, which obviously implies that other factors are required to provoke the onset of the disease.

Pathogenesis

Class I major histocompatibility (MHC) molecules play an important regulatory role in the immune response. Retinal autoimmunity may play an important role in the pathogenesis of the development of the intraocular inflammation activity for individuals who are HLA-A29 positive because of a genetic immune regulation.

Strong in vitro cell-mediated responses to various retinal autoantigens, including self-antigen (S-Ag) and interphotoreceptor retinoid-binding protein (IRBP), have been observed in patients with birdshot chorioretinopathy. Autoreactive T cells produce interleukin 2 (IL-2) in response to autoantigens, but, during disease quiescence or during therapy with cyclosporine, IL-2 levels are not detectable.[6]

The precise mechanism that might lead to this retinal autoimmunity is unknown. Further research is necessary to reveal the immune mechanism that leads to this rare condition.

Many theories have been proposed to explain the genesis of autoimmunity in the genetically predisposed individual.

Receptor mechanism and concomitant infection: MHC antigen provides a specific cell marker for binding of an infectious microorganism, such as Borrelia burgdorferi and Coxiella burnetii.

Common embryologic origin: The retina and the pineal gland share a common embryological origin. Experimental studies show that animals immunized with S-Ag and IRBP develop pinealitis in addition to experimental autoimmune uveitis (EAU).

Epidemiology

Frequency

United States

Birdshot chorioretinopathy is a rare disease. There are few reports that address the incidence of birdshot chorioretinopathy. In the United States, one uveitis clinic reported 7 out of 600 patients (1.2%) with this diagnosis. Since and including 1980, 59 cases have presented to the National Eye Institute (NEI).

International

In Europe, at 14 eye clinics, only 102 cases of birdshot chorioretinopathy were diagnosed from 1980-1986.

Mortality/Morbidity

Birdshot chorioretinopathy is a potentially blinding disease. Although some ophthalmologists describe patients with birdshot chorioretinopathy in whom the disease process runs a relatively benign course, where good visual acuity is preserved with minimal therapy, many patients experience a severe course with loss of functional vision, with permanent macular pathology secondary to uncontrolled inflammation and undertreated macular edema. The author strongly believes that if the disease process of a patient with birdshot chorioretinopathy demonstrates the ability to cause significant inflammation (particularly if significant vasculitis is present) or vision-affecting macular edema, then it is imperative that treatment options be pursued aggressively to control the disease process.

Race

Most patients are of Caucasian background.

Sex

Gender preference is not clear, as some studies showed predilection for women, but other studies showed no significant sexual predilection.

Age

Birdshot chorioretinopathy typically occurs during the middle age, presenting at an average age of 50 years, with an age range of 35-70 years.

Prognosis

Birdshot chorioretinopathy is a chronic disease that is characterized by multiple exacerbations and remissions. Birdshot chorioretinopathy tends to stabilize over a 3- to 4-year period. However, greater than one third of patients reach a visual acuity of 20/200 or worse. Visual loss is most commonly the result of cystoid macular edema and optic nerve atrophy. Corticosteroid therapy does not alter this long-term outcome.

One series described deterioration on ERG and visual field or significant visual morbidity in 10 of 15 patients during follow-up. Of note, most patients in the series either had no treatment or treatment with steroids alone (ie, no immunomodulatory therapy).

Rothova and Schooneveld described a man with birdshot chorioretinopathy for 20 years, undergoing alternative therapy (low-voltage therapy and multivitamins) as his only treatment. His end-stage picture consisted of multiple birdshot lesions, attenuated vessels, disk pallor, and pigmentary deposits similar to those seen in retinitis pigmentosa. He was legally blind. It is quite clear that, if uncontrolled, birdshot chorioretinopathy usually has a progressive course, with significant ocular morbidity as the consequences.

 

Presentation

History

The course of birdshot chorioretinopathy, like other autoimmune diseases, is characterized by exacerbations and remissions. The principle-presenting symptom is gradual, painless vision loss, frequently complicating of floaters that may initially involve one eye but later affect the fellow eye.

A study was conducted on NEI population with birdshot chorioretinopathy (n=59). This study showed that the most common complaint of NEI population was decreased vision (68%), floaters (29%), nyctalopia (25%), dyschromatopsia (20%), glare (19%), and photopsia (17%).

Other less frequent symptoms are as follows:

  • Decreased vision - 68%
  • Floaters - 29%
  • Nyctalopia - 15%
  • Dyschromatopsia - 12%
  • Glare - 19%
  • Photopsia - 17%
  • Fluctuating vision - 7%
  • Pain - 7%
  • Decreases depth of perception - 5%
  • Shimmering vision - 3%
  • Metamorphopsia - 3%
  • Decreased peripheral vision - 3%

Physical

Decreased visual acuity in the initial stages of birdshot chorioretinopathy is often mild; in many cases, visual acuity is not worse than 20/40 and rarely below 20/80. Visual dysfunction, however, can be pronounced and yet go undetected if the patient is not assessed with electroretinography and SITA-SWAP visual field testing, which typically show obvious abnormalities early in the disease course. Significant impairment most often is related to the presence of macular edema, but macular involvement by an active lesion, atrophic scar, severe vitritis, and choroidal neovascular membrane are other potential causes of more significant visual acuity loss.

Slit lamp biomicroscopy usually reveals a quiet eye, with anterior chamber cells only in instances in which significant vitreal reaction is present, and, rarely, one may see nongranulomatous keratic precipitates on the corneal endothelium and iridocapsular synechiae.

The major signs are seen in the posterior segment of the eye. Vitritis is typical, but neither "snowballs" nor a pars plana exudate is present.

Birdshot chorioretinopathy lesions

The classic birdshot chorioretinopathy lesions are small, from one fourth to one and one half times the size of a disk diameter, although they may appear larger if they become confluent.

Two types of lesions are described; the first is not sharply demarcated and is slightly oval. These spots are pale yellow or cream in color and are seen most easily on indirect ophthalmoscopy; they are very subtle and may escape detection by slit lamp examination with 78 diopter (D) or 90 D lens. These lesions represent the earliest form of the lesions. It is critical to emphasize the utility of indocyanine green angiography in assessing any patient who might have birdshot chorioretinopathy, since typical choroidal lesions are seen with this imaging modality much earlier than with fluorescein angiography.

The second type of lesion is an atrophic one, more sharply demarcated, round, and "punched out." These atrophic lesions can be seen easily either by indirect ophthalmoscopy or by direct 78 D or 90 D examination.

Several case reports hypothesize that the initial subtle lesions evolve into the atrophic lesions, although most reports describe birdshot chorioretinopathy lesions as having a stable appearance over time. Patients may have both kinds of lesions present simultaneously. Characteristically, neither is associated with increased pigmentation, and this can help distinguish these lesions from similar-appearing entities, such as presumed ocular histoplasmosis syndrome.

The birdshot chorioretinopathy lesions usually are scattered around the posterior pole and can extend to the equator. In most cases, they do not extend more peripherally. They usually are flat, although, in active lesions, they may be associated with a slight elevation.

The appearance of the birdshot chorioretinopathy lesions may present well after the initial onset of uveitis. In some patients, the disease first presents as a vitritis with vasculitis, most obvious on fluorescein angiography, with no characteristic fundus lesions. It may take up to 8 years for the characteristic fundus lesions to appear on ophthalmoscopy and, hence, occasionally can result in a delayed diagnosis.

Causes

The cause of birdshot chorioretinopathy is unknown.

Complications

The following are potential complications:

  • Chronic cystoid macular edema – 50%; the most common cause of reduced central visual acuity

  • Epiretinal membrane - 10%

  • Macular pucker

  • Choroidal neovascularization

  • Peripapillary subretinal neovascularization - 6%

  • Retinal neovascularization located on the optic disc

  • Peripheral retinal neovascularization with capillary nonperfusion

  • Optic nerve atrophy

  • Other complications, such as cataract, glaucoma, and rhegmatogenous retinal detachment

 

DDx

Differential Diagnoses

 

Workup

Laboratory Studies

Blood testing for HLA-A29 helps to support the diagnosis, but not all patients with birdshot chorioretinopathy are HLA-A29 positive. One must note that false-negative results with HLA-A29 testing may occur, and repeat blood testing is warranted in situations where clinical suspicion is high.

Other blood testing is not diagnostically helpful for patients with suspected birdshot chorioretinopathy. Fuerst and colleagues performed serologic testing of various markers of immune system activity and found elevated C4 levels; alpha-1-antitrypsin; C-reactive protein; rheumatoid factor; serum immunoglobulin G (IgG), immunoglobulin M (IgM), and immunoglobulin A (IgA); properdin factor B; and C3 were in the reference range.[7] However, their series of patients was small (ie, 9 patients).[7]

Testing for baseline renal function is necessary in those patients most likely to need cyclosporine therapy.

Purified protein derivative (PPD) may be performed.

Imaging Studies

Fluorescein angiography

Early cream-colored lesions, which are active sometimes, may present as isofluorescence, and this occurs when the lesion is deep or when the retinal pigment epithelium (RPE) and the choriocapillaris are intact. If there is disruption to any one of them, the lesion will be fluorescent, especially in the late phase. Late focal depigmentation or an atrophic lesion presents as hypofluorescence in the early phase and as diffuse hyperfluorescence in the late phase.

Retinal vascular system and cystoid macular edema: Delayed in the filling time and prolongation of the arteriovenous transient phase; hyperfluorescence of the optic disc and the macula that form cystoid macular edema

Indocyanine green angiography

Indocyanine green angiography (ICG) provides the additional dimensions of the choroidal lesion analysis in birdshot chorioretinopathy.

ICG reveals well-delineated hypofluorescence choroidal spots in the mid phase of the study. These hypofluorescent spots not only correspond to the location of the birdshot chorioretinopathy lesions but also are far more numerous than those seen on either fluorescein angiography or clinically. These choroidal lesions assume a vasotropic distribution bordered by medium- to large-sized choroidal blood vessels.

Ultra-high resolution optical coherence tomography

Ultra-high resolution optical coherence tomography (OCT) showed photoreceptor atrophy in several areas of both eyes. RPE degeneration was present underneath the areas of photoreceptor involvement. The inner retinal layers were hard to delineate because of the anatomical disorganization.[8]

Ultra-high resolution OCT imaging may help in understanding and following the progression of macular involvement in birdshot chorioretinopathy.

Chest radiography

Chest radiography may be performed.

Other Tests

Electrophysiologic testing may aid in determining the reason for complaints of problems with color perception or night vision. Both electro-oculograms (EOG) and electroretinograms (ERG) are affected. The presence of an abnormal electrophysiologic test may help distinguish it from other entities with similar funduscopic appearances. Currently, the use of serial ERGs as a tool to assist in monitoring birdshot chorioretinopathy activity and response to therapy is being investigated.

The ERG evolves into a negative pattern ERG, characterized by a decrease in b-wave amplitude, with no effect on a-wave amplitude. This occurs in diseases in which the retinal neural network function, corresponding to the b wave, is involved with progressive disease, but the photoreceptor function, represented by the a wave, initially is uninvolved.

In advanced birdshot chorioretinopathy, both a-wave and b-wave amplitudes are decreased, suggesting dysfunction of all retinal layers, including the photoreceptors.

EOG testing also was decreased in patients, representing RPE dysfunction.

Pattern evoked cortical potential (PECP) showed reduced amplitude and delayed response.

Dark adaptation abnormalities suggested that the rod system was more affected than cones. However, the case series was small, and more supportive data are needed to confirm these findings.

Histologic Findings

Only three histopathology studies have been obtained on the eyes of patients affected by birdshot chorioretinopathy.

Nussenblatt and coauthors described the histopathological findings of a single, phthisical eye enucleated from a patient with birdshot chorioretinopathy who exhibited a positive in vitro lymphocyte proliferative response to retinal S-Ag.[5] The histopathology revealed a mild lymphocytic response, whereas the retina was involved with a diffuse, chronic granulomatous inflammation.

Gaudio and coauthors described the histopathology of a blind, phthisical eye of a patient positive for the HLA-A29 gene and diagnosed with birdshot chorioretinopathy.[9] This study found aggregation of the lymphocytes with their foci in the deep choroid, with additional foci in the optic nerve head and along the retinal vasculature. These histopathological findings were noted to have a vasotropic distribution.

Pulido and coauthors treated a woman with both birdshot chorioretinopathy and ciliochoroidal melanoma who underwent enucleation. They concluded that birdshot chorioretinopathy is a nongranulomatous nodular infiltration of the choroid.[10]

 

Treatment

Medical Care

The appropriate level of treatment is determined by the severity of the inflammation. Conflicting reports exist regarding the efficacy of steroids. Some patients with mild inflammation may respond well to regional injection of steroids. Other patients require the use of systemic prednisone for control of the inflammation. Some patients may be controlled for a while on less than 10 mg/d, while other patients require higher doses. Long-term treatment, even 10 mg/d of steroids, is undesirable, considering the high risk of significant morbidity and mortality of such treatment. Many patients show no significant response to steroid therapy.

In addition, it is now very well documented that long-term outcomes of visual function are not altered with corticosteroid therapy.

Cyclosporine has been shown to have a beneficial effect on birdshot chorioretinopathy inflammation in retrospective case series.[11] Initial reports demonstrated improved visual acuity, decreased vitritis, and stabilization of eyes with cyclosporine dosages of 10 mg/kg/d. However, this dose also was associated with a high incidence of nephrotoxicity and hypertension. Vitale and colleagues reported a series of 19 cases of birdshot chorioretinopathy, which demonstrated that cyclosporine treatment with lower dosages, from 2.5-5 mg/kg, can be effective.[12] This series showed control of vitreal inflammation in 88.5% of eyes and improved or stable visual acuity in 83.3% of eyes. However, the low incidence of drug toxicity was most striking; there were only 2 cases of hypertension and no cases of nephrotoxicity.

Adalimumab therapy has been found effective in improving visual acuity in patients with refractory birdshot chorioretinopathy, although complete remission is rare.[13]

One suggestion is to initially start cyclosporine dosages at 2.5 mg/kg and then to increase to the level necessary to control the inflammation, while ensuring avoidance of drug adverse effects. The maximum dosage is 5 mg/kg according to this author. Monitoring for blood counts and renal function is performed every 4-6 weeks, along with blood pressure monitoring. Cyclosporine serum levels are not followed at these dosing regimens. Other potential adverse effects, such as hirsutism, paresthesias, tremor, and gingival hyperplasia, are not risks for morbidity, but are mentioned, since lowering of drug dosage or discontinuation of the medication may be indicated if such adverse effects occur to a point of affecting the quality of the patient's life.

One study reports the use of ketoconazole as adjunct therapy to cyclosporine. Ketoconazole delays metabolism of cyclosporine; hence, it may lower the dose of cyclosporine required to maintain control of inflammation. Silverstein and Wong demonstrated that cyclosporine trough levels could be maintained in a patient when the cyclosporine dosage was dropped from 200 mg/d (3 mg/kg) to 50 mg/d (0.75 mg/kg) with the addition of ketoconazole at 200 mg/d. This amounts to an 80% reduction of cyclosporine consumption. While this may be cost-saving, one cannot necessarily equate stabilization of cyclosporine serum levels with adequate control of inflammation nor with reduced potential toxicity. After all, the serum cyclosporine levels are still in the therapeutic range, and one might expect cyclosporine toxicity prevalence to be unchanged. Additionally, ketoconazole is not without potential adverse effects, especially the risk of hepatitis.

Other immunomodulatory therapies have been described. Kiss and colleagues reported the use of mycophenolate mofetil, azathioprine, methotrexate, and daclizumab in a series of 28 patients with birdshot chorioretinopathy; however, the small size of the study precludes any comment on the efficacy of any single drug.[14, 15, 11] LeHoang and colleagues reported the use of intravenous immunoglobulin in a series of 18 patients as initial therapy for active birdshot chorioretinopathy, and they noted stable vision in 33 of 36 eyes over a mean follow-up period of 39 months.[16] Daclizumab was withdrawn from the United States market because of diminished use and emergence of other effective therapies.

Long-Term Monitoring

Patients should be observed every 4-6 weeks. The patient is queried about visual quality, including color perception and vision at nighttime, and about symptoms of the potential adverse effects from the medications. The patient is examined, and blood tests and blood pressure measurement are performed. If the patient describes change in the quality of vision, despite a change in the visual acuity or evidence of active inflammation by examination, fluorescein angiography and indocyanine green angiography are performed to detect inflammation not seen readily on funduscopy, looking in particular for disk leakage or leakage from vessels. The use of serial ERGs as a tool to detect subclinical inflammation is being investigated.

This author believes in a zero tolerance for even minimal inflammation. When inflammation is not controlled, the dosage of the medication is increased; this is continued until the inflammation is controlled, the patient reaches the maximal tolerated dose, or the patient shows signs of drug toxicity. Although most cases can be controlled with this strategy, a small number of patients will have persistent inflammation despite regional steroids and maximally tolerated cyclosporine therapy. In these cases, combination immunosuppressive therapy may be indicated and will require management by a physician experienced in their use.

 

Medication

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Immunosuppressive agents

Class Summary

May have a beneficial effect on birdshot chorioretinopathy inflammation.

Cyclosporine (Sandimmune, Neoral)

Cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions, such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft-versus-host disease for a variety of organs. For children and adults, base dosing on ideal body weight. The dose of 10 mg/kg/d is associated with a high incidence of nephrotoxicity and hypertension.

Corticosteroids

Class Summary

Have both anti-inflammatory (glucocorticoid) and salt-retaining (mineralocorticoid) properties. Glucocorticoids have profound and varied metabolic effects. In addition, these agents modify the body's immune response to diverse stimuli.

Prednisone (Deltasone, Sterapred, Orasone, Meticorten)

Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.

Antifungal agents

Class Summary

Their mechanism of action may involve an alteration of RNA and DNA metabolism or an intracellular accumulation of peroxide that is toxic to the fungal cell. They also may inhibit P450 enzymes involved in drug metabolism.

Ketoconazole (Nizoral)

For use concomitantly with cyclosporine. Imidazole broad-spectrum antifungal agent that acts on several of the P450 enzymes, including the first step in cortisol synthesis, cholesterol side-chain cleavage, and conversion of 11-deoxycortisol to cortisol. Also increases levels of drugs metabolized by P450 enzymes, such as cyclosporine.