Epidemiology and Demographics

Although there have been no large studies to determine the prevalence of BSCR in the general population, it is certainly a rare disease. In the United States and Europe, BSCR comprises 0.5–1.5% of the cases seen in uveitis practices and 6.0–7.9% of posterior uveitis cases. By extrapolating from the overall prevalence of uveitis in the general population (38–115 cases/100,000 persons), Minos and colleagues arrived at an estimated prevalence of 0.2–1.7 cases/100,000 persons (Vadot et al. 1984; Gritz and Wong 2004; Minos et al. 2016). They further postulated that the true prevalence is at the lower end of the range because the referral centers conducting the studies likely have an overrepresentation of rare uveitis syndromes (Minos et al. 2016).

The onset of BSCR occurs most commonly in middle age. In a comprehensive review of 52 published studies, Shah and colleagues determined that 53 years (standard deviation ±9.4 years) was the mean age of onset (Shah et al. 2005). Although it is rare in childhood, cases have been reported in the teenage years (Pivetti-Pezzi 1996). Most of the larger case series report a slight female predominance. There are also substantial differences in prevalence by race, with Caucasian patients representing nearly all of the reported cases of BSCR (Shah et al. 2005). However, individual cases of BSCR have been reported in black and Hispanic patients, and a case series of patients has been reported in Japan (Saito et al. 2002; Baddar and Goldstein 2016; Knezevic et al. 2016). No cases have been reported from South Asia. Although some of the racial predilection may be due to HLA-A29 prevalence by race, this alone cannot completely explain the difference, as is discussed in the next section.

Genetics and Pathophysiology

Approximately 96% of BSCR patients are HLA-A29 positive, which is the strongest known association of an HLA allele with any disease. The association is so strong that other diagnoses should be considered if a patient is HLA-A29 negative (Brézin et al. 2011). However, the exact role of HLA-A29 in the pathogenesis remains unclear. Some of the controversy over the role of HLA-A29 comes from its racial distribution. The two main subtypes of the HLA-A29 allele, HLA-A∗29:01 and HLA-A∗29:02, have both been associated with BSCR. However, the vast majority of reported HLA-A29-positive BSCR patients have the HLA-A∗29:02 allele (Levinson et al. 2004; Brézin et al. 2011). The frequency of HLA-A∗29:02 in the United States is greatest in the Caucasian population at 4.34% and lowest in Asians at 0.1%. However, the frequency in African-Americans and Hispanics is 3.57% and 4.20%, respectively. Although the low frequency of HLA-A29 in Asians may be a protective factor, the frequency in Hispanics and African-Americans is similar overall to Caucasians. Unknown protective factors present in Hispanics and African-Americans, or unknown risk factors in Caucasians, are likely to explain the difference in BSCR prevalence despite similar HLA-A29 frequencies (Brézin et al. 2011).

Mice engineered to express a human HLA-A29 transgene derived from a patient affected by BSCR spontaneously develop a posterior uveitis similar to BSCR, providing the best evidence of a direct role for HLA-A29 in BSCR pathogenesis (Szpak et al. 2001). HLA-A29 codes for a major histocompatibility complex class 1 (MHC-I) protein, whose function is to present antigens to CD8 T cells. A recent genome-wide association study has also linked endoplasmic reticulum aminopeptidase 2 (ERAP2) with BSCR. ERAP2 is an enzyme that processes antigens for presentation by MHC-I molecules, which raises the interesting hypothesis that ERAP2 antigen processing in conjunction with HLA-A29 presentation may be sequential steps in the development of autoimmunity in BSCR patients (Kuiper et al. 2014b). Although more than 100 endogenous HLA-A29 ligands have been identified, none have been directly linked with BSCR (Boisgerault et al. 1996).

Consistent with the strong HLA-A29 association, T cells also appear to play an important role in BSCR pathogenesis. Histopathologic studies of enucleated BSCR eyes demonstrate choroidal lesions in which T cells predominate (Pulido et al. 2012). Vitreous samples from BSCR eyes are rich in T cells that react to retinal and choroidal extracts, and aqueous samples are rich in interleukin-17 (IL-17), a T-cell cytokine (Kuiper et al. 2011; 2014a).

Clinical Findings

Clinical Signs and Exam Findings

Anterior examination generally demonstrates a quiet anterior chamber, although low-grade cell may be present. Flare, keratic precipitates, and posterior synechiae are not typically seen.

The diagnosis of BSCR is made primarily on the basis of the fundus examination, and the most recent diagnostic criteria, defined in 2006, are summarized in Table 7.1. Early in the disease course, there may be no apparent fundus abnormalities, as development of chorioretinal lesions often lags behind symptom onset by several years (Godel et al. 1989). The classic finding in BSCR is birdshot lesions, which are creamy, ovoid choroidal lesions that are one eighth to one half disc diameter in size (Fig. 7.1). Birdshot lesions are often oriented with their long axis perpendicular to the disc and appear to radiate toward the periphery (Priem and Oosterhuis 1988). Lesions are typically concentrated near the optic disc and in the inferior and nasal quadrants (Fig. 7.1a). With time, the lesions may coalesce to form linear patterns or to create the appearance of peripapillary atrophy (Fig. 7.1b, c) (Ryan and Maumenee 1980; Gass 1981; Priem and Oosterhuis 1988). Eventually, the lesions may develop hyperpigmentation or become well-demarcated areas of atrophy. Other common findings are cystoid macular edema and epiretinal membranes. Retinal and choroidal neovascularization have also been reported (Priem and Oosterhuis 1988).

Examination of the vitreous frequently demonstrates anterior vitreous cells and vitreous haze. Snowballs and snowbanks are typically absent in BSCR patients. Retinal vasculitis is present with active disease and most commonly presents with phlebitis, which is characterized by venous beading and irregular venous caliber. With time, the arterioles become attenuated. Vessel sheathing is uncommon but may be present (Ryan and Maumenee 1980; Priem and Oosterhuis 1988). Examination of the optic disc may demonstrate edema, or in late stages, pallor (Priem and Oosterhuis 1988). Although the fundus exam is key to making the diagnosis of BSCR, additional imaging modalities are useful in confirming the diagnosis in uncertain cases and for monitoring disease activity.

Imaging

Fluorescein Angiography (FA)

Fluorescein angiography is a very versatile technique for diagnosing and monitoring BSCR, as it facilitates evaluation of most of the affected structures. BSCR patients frequently develop macular edema, which often has a petalloid appearance on FA. The retinal vasculitis, characterized by vascular leakage, arteriole attenuation, and irregular venous caliber, is also best evaluated by FA, since it may be subtle or undetectable on clinical exam. The optic disc may also demonstrate hyperfluorescence or leakage (Fig. 7.2). Although it is uncommon, choroidal neovascularization may occur in BSCR and is readily detected by FA (Priem and Oosterhuis 1988; Howe et al. 1997).