The natural progression of BCD remains poorly understood, with few follow-up cases appearing in the published literature. The previous staging methods for BCD have included the Yuzawa staging , fundus fluorescein angiography staging , and electrophysiological staging . The Yuzawa staging is widely used [5, 20, 23, 24, 25, 26], but most of these studies have been cross-sectional ones or case reports with only small numbers of observed cases. We followed up 12 patients with BCD to determine the natural progression of the disease, and our discussion focuses on the breadth and depth of the fundus lesion of BCD.
Our first focus is on the sequence of BCD lesion occurrences. We found that the posterior pole retina was the first to be attacked, followed by the peripheral retina. Both the posterior and peripheral lesions extended to the mid-periphery, finally all the retina was attacked. The disease progresses more rapidly on the nasal side retina of optic disc, whereas the retina in the mid-peripheral part of the temporal side of the macular area is involved last.
The Yuzawa staging is used widely and divides the disease into three stages. However, these stages were based on three patients, with only one patient followed up for five years, and lesions have occurred throughout the fundus of this patient at the initial visit. The two other patients were cross-sectional observations. They described the first stage of the lesion confined to the macular area, the second stage beyond the posterior pole, and the third stage involving the totalretina. This description tends to give the impression of a centrifugal expansion.
Many subsequent studies have stated that “Yuzawa described a centrifugal expansion of the RPE-choriocapillaris complex atrophy, from the macular area towards the periphery, occurring in three stages” [5, 20, 24, 27], and they agreed with this description. By contrast, our observations were different. In our opinion, the reasons for this difference were the small case numbers in the previous studies, with even fewer cases of total retinal observation, and a focus of attention on the changes in the posterior pole retina.
Halford et al  reported that atrophy of areas of the RPE and choroid tended to develop at the posterior pole, became confluent, and expanded centrifugally to involve peripheral retina, but they only observed a 55° autofluorescence in the fundus images, not a total retinal involvement. Consequently, the conclusion that BCD is a centrifugal expansion disease is questionable. Mataftsi et al  conducted jigsaw observations in six patients, but all were advanced cases. According to the Yuzawa staging, all patients were stage 3 and had complete retinal involvement, so the conclusion that BCD is a centrifugal expansion was not justified. However, Mataftsi et al  found one patient with mild disease that showed a significant difference, as atrophic changes in the choriocapillaris were evident not only in the posterior pole but also at the equator level, at the eccentricity of the vortex veins. This finding was consistent with our observation: the atrophy in the posterior pole and peripheral choroid appeared before the mid-peripheral atrophy. Mataftsi et al  also performed an FFA staging of BCD, but the number of cases was small and all cases were advanced. Therefore, this FFA staging was not comprehensive and will not be discussed further in this article.
Some reports have suggested a centrifugal expansion of the visual defect based on the centralscotoma seen with the 30° visual field test [1, 20, 28]. However, Liu et al  confirmed the visual field features using the 85° visual field test. They found that the peripheral and central scotomas initially appear, but as the disease progresses, these expand and combine, ultimately resulting in visual islands only in the mid-periphery, which are not found centrally. This is consistent with our observation of lesions occurring first in the center and periphery and then eventually extending to the mid-periphery.
In this study, we also used the Yuzawa staging, regarding it as a cross-sectional staging method according to the width and depth of the BCD lesions. We simplified the Yuzawa staging as follows: stage 1 consisted of a lesion confined to the posterior pole with only RPE atrophy; stage 2 consisted of a lesion beyond the posterior pole or with choroid atrophy; and stage 3 consisted of total retinal involvement. Since the Yuzawa staging has been used widely for a long time, the application of Yuzawa staging in this study was intended as a convenience for readers to understand the condition of the eyes of our patients. It was not meant to indicate the natural progression of the disease.
We also examined the atrophy sequence of the BCD lesions and found two patterns of BCD atrophy. Type 1 showed RPE atrophy at the macular area, followed by choriocapillaris atrophy at the macula, then RPE atrophy at the peripheral retina, and subsequent extension of the macular and peripheral lesion to the mid-periphery; at the same time, the RPE atrophy extended to choriocapillaris atrophy and eventually all the RPE and choriocapillaris atrophied, exposing the choroid great vessels. Type 2 showed RPE atrophy at the posterior pole and peripheral retina, followed by choriocapillaris atrophy around the macular area, along the superior and inferior vascular arcades, and at optic disc nasal side. Subsequently, the posterior lesion and peripherallesion extended to the mid-periphery, with simultaneous transition of the RPE atrophy to choriocapillaris atrophy and, ultimately, full RPE and choriocapillaris atrophy, with exposure of the choroid great vessels, but the RPE atrophy of macular can persist for a long time. However, we found that the last area of atrophy at the most advanced stage of BCD was in the temporal peripheral retina, rather than the retinal area last attacked in the mid-periphery.
Mataftsi et al  found that peripheral retinal atrophy was relatively mild in the final stage of the disease, which is consistent with our findings. They hypothesized that the posterior ciliary arteries are selectively affected, whereas the anterior uveal circulation (ciliary body and anterior choroid) is preserved until late in the disease, although nevertheless insufficient for supplying the retro-equatorial choroid. We agree with this hypothesis, but it needs further confirmation.
Immunohistochemistry analyses have revealed that CYP4V2 is highly expressed in the choroid and the RPE, while relatively less expressed in the retinal outer and inner nuclear layers, retinal ganglion cells, and corneal epithelial cells, in accordance with the BCD phenotype . The FFA images revealed changes mainly in the RPE and choroid, so RPE dysfunction has been considered the primary change in BCD [20, 27, 31]. One view holds that vascular endothelial growth factor (VEGF) is produced by the RPE and is necessary for choroidal maintenance ; therefore, a lack of VEGF caused by an RPE disorder may play a role in choroidal thinning. Our FFA results showed that RPE atrophy occurs first, followed by choroidal vessels atrophy, in agreement with the previous research, including the research by Yuzawa et al .
We re-examined the FFA images in the previous literature, and we found that those images can be divided into the two atrophy types we have mentioned here. Type 1 shows choriocapillaris atrophy first appearing at the macula [7, 11, 27, 33, 34], and type 2 shows choriocapillaris atrophy firstappearing around the macular area and along the superior and inferior vascular arcades and optic disc nasal side [7, 15]. The case numbers are significantly smaller for type 2 than for type 1; for example, Wang et al  reported that, of the 4 patients examined, 3 were type 1 and 1 was type 2. In the present study, only 3 (P6, 11, and 12) of the 12 cases were type 2. Apart from the macular area changes caused by CNV of P6 left eye, the macular area of the other 5 eyes of the 3 cases showed slow changes and the RPE and choroid atrophy of the mid-periphery and periphery was significantly aggravated. This suggests that the type 2 patients can preserve better vision for a longer time, so these pattern differences may aid in the evaluation of a patient's prognosis.
The reason for these two different atrophy patterns is unknown. We looked at the gene mutation sites of P6, P11, and P12 and found that the P6 and P11 had homozygous mutations of c.802-8_810del17insGC, while P12 was heterozygous for a mutation of c.802-8_810del17insGC and c.332T > C; p. l111T. In this study, P1 and P7 also had homozygous mutations of c.802-8_810del17insGC, but their phenotypes differed from those of P6 and P11 (Table 2). Therefore, the specific causes of these differences need further observation and research.
In the early stage of BCD, distinguishing the progression type is not possible in eyes with disordered pigment epithelium and no choroid atrophy. Only patients with choriocapillaris atrophy can be typed. The type of progression also cannot be determined in patients at the end stage of the disease because the choriocapillaris and RPE are atrophied and no longer visible, leaving only the image of the choroidal great vessels. We propose adding the progression types to the staging criteria to provide a clearer understanding of how the disease progresses, without creating the misconception that the disease develops in a centrifugal way. The progression type cannot be distinguished in the early and the last stages, but the addition of progression typing, when possible, can help to clarify the characteristics of disease development, while providing a more accurate prognosis and a better understanding of the pathogenesis of BCD.
This study had several limitations, including the small number of included eyes and the lack of primary patient observations. However, considering the rarity of the disease and our review of the previous literature, our study on the progression of BCD using FFA picture jigsaws provides one of the largest collections of images and the largest number of patients. Finding BCD patients with early stage disease is difficult because the visual acuity of patients at this stage is not substantially damaged, so they seldom come to the hospital.