Background
Bietti crystalline dystrophy (BCD) is an autosomal recessive retinal dystrophy characterized by numerous tiny sparkling yellow-white spots at the posterior pole of the fundus. The causative gene has been identified as CYP4V2 [
1,
2]. In 1937, Bietti first reported three patients with BCD [
3,
4]. Since then, research on the disease has continued, but the natural progression and pathogenesis of BCD remain poorly understood. Most previous work has been reported as cross-sectional studies [
5‐
8], gene research [
1,
2,
9‐
12], and case reports [
6,
13‐
15]. Very few of these studies have used fundus fluorescein angiography (FFA) to characterize BCD and those that did utilized FFA images that mostly involved the posterior pole of the fundus rather than the whole retina. Few articles have reported on long-term observations of BCD [
16‐
18], and most of those that did are only case reports and lack comparisons before and after the examinations. To our knowledge, no studies have used FFA to follow the progression of BCD in patients.
The aim of the present study was to outline the phenotype of BCD more clearly and to obtain a better understanding of the natural course of the disease. Here, we present 12 cases of BCD focusing on its progression via FFA images with the goal of identifying the features of BCD development.
Discussion
The natural progression of BCD remains poorly understood, with few reports of follow-up appearing in the published literature. The previous staging methods for BCD have included the Yuzawa staging [
21], fundus fluorescein angiography staging [
5], and electrophysiological staging [
19]. The Yuzawa staging is widely used [
5,
19,
22‐
25], but most of these studies are cross-sectional studies or case reports with small numbers of cases. We followed up 12 patients with BCD to observe the natural progression of BCD.
We found that the expansion of the RPE-choriocapillaris complex atrophy was not centrifugal. This result is different from that of the previous studies. The Yuzawa staging was based on the finding of three patients [
21]. Its 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,
19,
23,
26] and thus agreed with this description. We think the reason for this difference is the small numbers of patients in the previous studies, the even fewer cases of total retinal observation, and the focus on changes in the posterior pole retina in most existing studies. Halford et al [
26] reported that atrophied areas of the RPE and choroid tend to develop at the posterior pole, become confluent, and expand centrifugally to involve the peripheral retina, but they only observed 55° autofluorescence in the fundus images, not a total retinal image. Consequently, the conclusion that BCD is a centrifugal expansion disease is incomplete. Mataftsi et al [
5] made jigsaw observations in six patients, but they all involved advanced stages of the disease, and the entire retinal was attacked; the conclusion that BCD is a centrifugal expansion is not justified. However, Mataftsi et al [
5] found one patient who 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 is consistent with our observation: atrophy in the posterior pole and peripheral choroid appeared before mid-peripheral atrophy.
Some reports have suggested centrifugal expansion of the visual defect based on the central scotoma seen with the 30° visual field test [
1,
19,
27]. However, Liu et al [
28] confirmed the visual field features using the 85° visual field test. They found that 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 that are not found centrally. This is consistent with our observation of lesions occurring first in the centre and periphery and then eventually extending to the mid-periphery.
In the same retinal area, our FFA results showed that RPE atrophy occurs first, followed by choroidal vessel atrophy, in agreement with previous research, including that by Yuzawa and coauthors [
21]. Immunohistochemistry analyses have revealed that CYP4V2 is highly expressed in the choroid and RPE, but relatively less expressed in the retinal outer and inner nuclear layers, retinal ganglion cells, and corneal epithelial cells, in accordance with the BCD phenotype [
29]. The FFA images revealed changes mainly in the RPE and choroid, so RPE dysfunction has been considered the primary change in BCD [
19,
26,
30]. One view holds that vascular endothelial growth factor (VEGF) is produced by the RPE and is necessary for choroidal maintenance [
31]; therefore, a lack of VEGF caused by an RPE disorder may play a role in choroidal thinning.
We re-examined the FFA images in the previous literature, and we found that those images can also be divided into the two atrophy types we have mentioned before. Type 1 shows choriocapillaris atrophy first appearing at the macula [
7,
11,
26,
32,
33], and type 2 shows choriocapillaris atrophy first appearing around the macular area and along the superior and inferior vascular arcades and nasal side of the optic disc [
7,
14]. The numbers of patients are significantly smaller for type 2 than for type 1. For example, Wang et al [
7] reported that of the 4 patients examined, 3 were type 1 and 1 was type 2. This is the same with our study. In the present study, only 3 (P6, 11, and 12) of the 12 patients were type 2. Apart from the macular area changes caused by CNV of the left eye of P6, the macular area of the other 5 eyes of the 3 patients showed slow changes, and the RPE-choriocapillaris atrophy of the mid-periphery and periphery was significantly aggravated. This suggests that type 2 patients can preserve better vision for a longer time, so these pattern differences may aid in the evaluation of the patient’s prognosis. Given the small number of patients we studied, more types can be found in the future. This needs further research in the future.
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 P6 and P11 had homozygous c.802-8_810del17insGC mutations, while P12 was heterozygous for the c.802-8_810del17insGC and c.332T > C; p. l111T mutations. In this study, P1 and P7 also had homozygous c.802-8_810del17insGC mutations, 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 this study, we also used the Yuzawa staging as a cross-sectional staging method according to the width and depth of the BCD lesions. Since the Yuzawa staging has been used widely for many years, its application in this study was intended as a convenience for the readers to understand the condition of the eyes of our patients. It was not meant to indicate the natural progression of the disease.
In the early stage of BCD, is difficult to distinguish the type of progression in eyes with disordered pigment epithelium and no choriocapillaris 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; only the image of the choroidal great vessels is left.
This study had several limitations. First, there was a small number of included eyes and a 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. Second, the present study lacked multimodal imaging comparisons, but we performed cross-sectional research on multimodal patient imaging. We hope to perform multimodal imaging comparisons in the near future. Third, our study lacked patients transitioning from stage 1 to stage 2, but it is difficult to locate BCD patients with early-stage disease because the visual acuity of patients at this stage is not substantially damaged, so they seldom come to the hospital. This needs further research in the future.
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