AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Birdshot retinochoroidopathy (BSRC) is one of the causes of chronic posterior uveitis that has been described only in recent years. It is defined by its stereotypical clinical presentation, which was first described by Ryan and Maumenee in 1980. The classic presentation is the presence of multiple small white or yellow spots scattered about the posterior pole, "resembling the pattern seen with birdshot in the scatter from a shotgun."

Case series of this entity had not been reported until the 1980s, and it is unlikely that great ophthalmologists of the past had missed an entity with such a unique clinical appearance. BSRC 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 BSRC is unknown. A strong link to the presence of 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 BSRC, with a relative risk ratio from 50 to 224. This is the strongest HLA association with any known disease. Nussenblatt and colleagues also found a link with human leukocyte antigen B12 (HLA-B12), which has been confirmed by several other authors. 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 BSRC, which obviously implies that other factors are required to provoke the onset of the disease.

LeHoang and coauthors reported a series of European patients in which all patients who were HLA-A29 positive with BSRC expressed the HLA-A29 type 2 subtype. 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 BSRC 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.

Table. Relative Risk of Birdshot Retinochoroidopathy

Other studies show that patients with BSRC have a high incidence of in vitro cell-mediated response to retinal antigens. De Smet and colleagues have shown that patients with BSRC have significantly higher incidence of sensitivity to S-antigen and, to a lesser degree, interphotoreceptor retinoid-binding protein when compared with controls. This suggests that autoimmunity against a retinal protein antigen may play a role in its pathogenesis. Additionally, experiments in which monkeys were sensitized and then exposed to retinal S-antigen developed fundus findings not unlike BSRC seen in humans.

Despite this knowledge, the roles of the HLA-A29 molecule and the sensitivity to retinal antigens in BSRC have not been determined. One hypothesis is that HLA-A29, by molecular mimicry, predisposes to autoimmunity against retinal antigens, with an infectious agent, such as a virus, potentially acting as a trigger to the immune reaction. This is similar to hypotheses of autoimmunity in human leukocyte antigen B27 (HLA-B27) positive patients, in which some experts believe that infection with gram-negative organisms may be a triggering event to molecular mimicry-based autoimmune inflammation. However, no such association of BSRC with infections has been clearly shown yet. Further research is necessary to uncover the immune mechanisms that lead to this rare disease.

Frequency

United States

BSRC is a rare disease.

Mortality/Morbidity

BSRC is a potentially blinding disease. Although some ophthalmologists describe patients with BSRC 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 BSRC 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

A slight predominance may exist in women.

Age

Most patients present in their 30s and 40s, with an age range of 35-70 years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The course of BSRC is characterized by exacerbations and remissions. If episodes of inflammation are not controlled, it is a progressive disease, with threat to central vision.

• Initially, patient symptoms are mild.
• • The most common complaint is decreased vision, and patients also may complain of floaters.
  • Some patients may note a decrease in color perception or night vision.
  • The disorder is painless, and photophobia is not a prominent symptom.
  • Most patients eventually develop bilateral involvement, although it initially may present asymmetrically.

Physical

Decreased visual acuity in the initial stages of BSRC is often mild; in many cases, visual acuity is not worse than 20/40 and rarely below 20/80. 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.

• 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.
  • Macular edema may be present, and, in some cases, an epiretinal membrane develops.
  • The optic nerve can be involved in the inflammatory process, and severe inflammation or repeated episodes may lead to peripapillary atrophy.
  • Disk edema had a strong association with macular edema in at least one report, although this may simply be an indicator of severe inflammation.
  • The degree of retinal vasculitis varies from case to case and may be difficult to appreciate on funduscopy. Most often, changes in the caliber of the vessels and increased tortuosity may be the only clinical indicators of vasculopathy.
  • Frank perivascular exudates and sheathing are only seen in moderate-to-severe inflammation.
  • Intraretinal hemorrhages may (rarely) recur in the posterior pole.
• BSRC lesions
• • The classic BSRC 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 are pale yellow or cream-colored spots 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. The second type of lesion is an atrophic one, more sharply demarcated, round, and "punched out." These atrophic lesions can be seen easily by either 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 BSRC 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 BSRC 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.
• Appearance of BSRC lesions on fluorescein angiography
• • The appearance of BSRC lesions on fluorescein angiography (FA) is typically less striking than their funduscopic appearance. The early angiographic phases usually show no particular fluorescence patterns, although early hyperfluorescence or hypofluorescence has been reported. The later phases show moderate hyperfluorescence of the lesions.
  • Evidence of vasculitis, characterized by leakage from vessels or late vessel wall staining, can be apparent and more marked than one might expect from the funduscopic examination. Disk leakage and macular edema also may be seen on FA.
• The appearance of the BSRC lesions may present well after the initial onset of uveitis. In some patients, the disease first presents as a vitritis with vasculitis, with no characteristic fundus lesions. It may take up to 8 years for the characteristic fundus lesions to appear and, hence, occasionally can result in a delayed diagnosis.

Causes

The cause for BSRC is unknown.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Intermediate uveitis
Multifocal choroiditis
Multiple evanescent white dot syndrome
Reticulum cell sarcoma
Panuveitis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Blood testing for HLA-A29 helps to support the diagnosis, but not all patients with BSRC 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 BSRC. 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. However, their series of patients was small (ie, 9 patients).
• Testing for baseline renal function is necessary in those patients most likely to need cyclosporine therapy.

Imaging Studies

• FA may be helpful in the investigation of patients with suspected BSRC.
• • FA is less helpful in the examination of the classic BSRC lesions but is more helpful in detecting the presence and severity of vasculitis.
  • FA is useful in confirming the presence of macular edema in those cases with significant visual loss. FA also confirms the presence of vessel leakage and disk leakage when clinical examination of the fundus does not correlate with the visual acuity or severity of the patient's symptoms.

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 BSRC activity and response to therapy is being investigated.
• • Hirose and colleagues reported on the details of ERG findings in a series of 15 patients with BSRC. The ERG appeared "supernormal" early in the course of BSRC, a type of pattern seen in many inflammatory diseases, possibly representing increased retinal irritability.
  • The ERG evolves into a negative pattern ERG, characterized by a decrease in b-wave amplitude, with no affect 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 BSRC, 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 retinal pigment epithelium (RPE) dysfunction. 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

Currently, only one report describes the histopathological findings of BSRC. Gaudio and colleagues described the histologic findings of an eye on a 54-year-old man who was positive for the HLA-A29 gene that displayed fundus features characteristic of the disease. The histopathological findings consisted of multiple foci of predominantly lymphocytic infiltrate at various levels of the deep choroid, with additional lymphocytic foci involving the optic nerve head and along the retinal vasculature. Rare plasma and epithelioid cells were seen, with an absence of necrosis. The RPE appeared uninvolved.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 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.

Cyclosporine has been shown to have a beneficial effect on BSRC inflammation in retrospective case series. 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 Foster reported a series of 19 cases of BSRC, which demonstrated that cyclosporine treatment with lower dosages, from 2.5-5 mg/kg, can be effective. 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.

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 BSRC; however, the small size of the study precludes any comment on the efficacy of any single drug. LeHoang and colleagues reported the use of intravenous immunoglobulin in a series of 18 patients as initial therapy for active BSRC, and they noted stable vision in 33 of 36 eyes over a mean follow-up period of 39 months.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Drug Category: Immunosuppressive agents

May have a beneficial effect on BSRC inflammation.

Drug Category: Corticosteroids

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.

Drug Category: Antifungal agents

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.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• 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, FA is 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.

Complications

• The most common complication of this disorder is macular edema. This usually responds to a periocular injection of steroid. Oral nonsteroidal drugs also may have a beneficial effect; this currently is being investigated. Topical nonsteroidal drugs are believed to not be effective in uveitis-associated macular edema.
• Subretinal choroidal neovascularization has been reported in patients with BSRC. In many cases, the neovascular membranes developed in the peripapillary region in an area of peripapillary atrophy, although one case report demonstrated the development of a membrane at a "birdshot scar" some distance from the disk. In other cases, the membrane may present as a focal serous retinal detachment, with the neovascular membrane evident on FA. One case report described a patient with peripheral retinal neovascularization. Successful treatment of neovascular membranes with directed photocoagulation has been reported.

Prognosis

• Some patients eventually may go into remission spontaneously. Although some authors believe that BSRC is self-limited after around 3-4 years, evidence from many other reports suggests otherwise, with some series reporting loss of useful vision in at least one eye in up to 40% of patients. A recently reported 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 BSRC 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, BSRC usually has a progressive course, with significant ocular morbidity as the consequences.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• BSRC is a potentially blinding disorder. Early referral to a uveitis specialist before significant vision is lost is recommended.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Bloch-Michel E, Frau E. Birdshot retinochoroidopathy and HLA-A29+ and HLA-A29- idiopathic retinal vasculitis: comparative study of 56 cases. Can J Ophthalmol. Dec 1991;26(7):361-6. [Medline].
• Brucker AJ, Deglin EA, Bene C, Hoffman ME. Subretinal choroidal neovascularization in birdshot retinochoroidopathy. Am J Ophthalmol. Jan 15 1985;99(1):40-4. [Medline].
• Caballero-Presencia A, Diaz-Guia E, Lopez-Lopez JM. Acute anterior ischemic optic neuropathy in birdshot retinochoroidopathy. Ophthalmologica. 1988;196(2):87-91. [Medline].
• de Smet MD, Yamamoto JH, Mochizuki M, et al. Cellular immune responses of patients with uveitis to retinal antigens and their fragments. Am J Ophthalmol. Aug 15 1990;110(2):135-42. [Medline].
• Fuerst DJ, Tessler HH, Fishman GA, et al. Birdshot retinochoroidopathy. Arch Ophthalmol. Feb 1984;102(2):214-9. [Medline].
• Gaudio PA, Kaye DB, Crawford JB. Histopathology of birdshot retinochoroidopathy. Br J Ophthalmol. Dec 2002;86(12):1439-41. [Medline].
• Godel V, Baruch E, Lazar M. Late development of chorioretinal lesions in birdshot retinochoroidopathy. Ann Ophthalmol. Feb 1989;21(2):49-52. [Medline].
• Hirose T, Katsumi O, Pruett RC, et al. Retinal function in birdshot retinochoroidopathy. Acta Ophthalmol (Copenh). Jun 1991;69(3):327-37. [Medline].
• Kaplan HJ, Aaberg TM. Birdshot retinochoroidopathy. Am J Ophthalmol. Dec 1980;90(6):773-82. [Medline].
• Kiss S, Ahmed M, Letko E. Long-term follow-up of patients with birdshot retinochoroidopathy treated with corticosteroid-sparing systemic immunomodulatory therapy. Ophthalmology. Jun 2005;112(6):1066-71. [Medline].
• LeHoang P, Cassoux N, George F. Intravenous immunoglobulin (IVIg) for the treatment of birdshot retinochoroidopathy. Ocul Immunol Inflamm. Mar 2000;8(1):49-57. [Medline].
• LeHoang P, Ozdemir N, Benhamou A, et al. HLA-A29.2 subtype associated with birdshot retinochoroidopathy. Am J Ophthalmol. Jan 15 1992;113(1):33-5. [Medline].
• Levinson RD, Gonzales CR. Birdshot retinochoroidopathy: immunopathogenesis, evaluation, and treatment. Ophthalmol Clin North Am. Sep 2002;15(3):343-50, vii. [Medline].
• Levinson RD, Rajalingam R, Park MS. Human leukocyte antigen A29 subtypes associated with birdshot retinochoroidopathy. Am J Ophthalmol. Oct 2004;138(4):631-4. [Medline].
• Noble KG, Greenberg J. Appearance of birdshot retinochoroidopathy in a patient with myelodysplasia syndrome. Am J Ophthalmol. Jan 1998;125(1):108-9. [Medline].
• Nussenblatt RB, Mittal KK, Ryan S, et al. Birdshot retinochoroidopathy associated with HLA-A29 antigen and immune responsiveness to retinal S-antigen. Am J Ophthalmol. Aug 1982;94(2):147-58. [Medline].
• Oh KT, Christmas NJ, Folk JC. Birdshot retinochoroiditis: long term follow-up of a chronically progressive disease. Am J Ophthalmol. May 2002;133(5):622-9. [Medline].
• Rosenberg PR, Noble KG, Walsh JB, Carr RE. Birdshot retinochoroidopathy. Ophthalmology. Mar 1984;91(3):304-6. [Medline].
• Ryan SJ, Maumenee AE. Birdshot retinochoroidopathy. Am J Ophthalmol. Jan 1980;89(1):31-45. [Medline].
• Soubrane G, Bokobza R, Coscas G. Late developing lesions in birdshot retinochoroidopathy. Am J Ophthalmol. Feb 15 1990;109(2):204-10. [Medline].
• Soubrane G, Coscas G, Binaghi M, et al. Birdshot retinochoroidopathy and subretinal new vessels. Br J Ophthalmol. Jul 1983;67(7):461-7. [Medline].
• Vitale AT, Rodriguez A, Foster CS. Low-dose cyclosporine therapy in the treatment of birdshot retinochoroidopathy. Ophthalmology. May 1994;101(5):822-31. [Medline].

Article Last Updated: Nov 8, 2005