Our examination of multimodal images of 8 eyes of 4 BCD patients (P1, P2, P3, and P4) at different time intervals of 10, 16, 20, and 20 months, respectively, revealed expansion of the areas of hypo-AF and hypo-IRAF but a decrease in the hyper-AF spots and hyper-IRAF spots. FFA showed that the lesion area expanded and the hypo-fluorescence area with severe atrophy also expanded. OCT showed thinning of both the retina and choroid and progressive atrophy of the outer nuclear layer, EZ, and RPE, as well as significant thinning of diameter of the choroidal macrovascularities.
The four patients ranged in age from 29 to 38 years, which is the common onset age of BCD [15, 16]. The results of gene examinations were all showed BCD-related gene alleles [17, 18]. The BCVA (ETDRS) of all 8 eyes significantly decreased. Color fundus photography showed yellowish crystalline deposits in the posterior fundus. The number of yellowish crystalline deposits declined by the last examination, which was consistent with previous studies [12, 15, 19, 20]. The deposition of yellowish crystalline lipids is caused by abnormal expression of the CYP4V2 gene in the human retina and RPE [16, 21, 22], and it is reduced with atrophy of the retina and RPE.
Comparison of P1F, P2F, P3F, and P4F versus P1L, P2L, P3L, and P4L indicated a wider range of hypo-AF and hypo-IRAF at the posterior fundus, and a partial merging together of the patchy hypo-AF. Choroidal macrovascular morphology was observed in the hypo-IRAF. The junction of hypo-AF and the normal retina and hypo-IRAF and the normal retina of P1 showed the presence of hyper-AF spots and hyper-IRAF spots. The number of hyper-AF spots was significantly greater than the number of hyper-IRAF spots. The position of the hyper-IRAF spots corresponds to the hyper-AF spots, but the hyper-IRAF spots is smaller than hyper-AF spots.
FAF is known to represent mainly fluorescence of lipofuscin [23], while IRAF is mainly melanin fluorescence [24]. Some studies had also observed hyper-AF and hyper-IRAF in AMD. The degradation products of melanin may also be added to lipofuscin with increasing age [25]; therefore, we considered that this phenomenon might also be caused by the accumulation of lipofuscin and melanin degradation products in damaged RPE cells.
The FAF of P2, P3, and P4 showed hyper-AF spots, while the IRAF of P2, P3, and P4 showed choroidal macrovascular morphology in the hypo-IRAF. No hyper-IRAF spots were observed. Considering that the dysfunction of the RPE produced more lipofuscin than melanin degradation products. In P1, hyper-AF spots and hyper-IRAF spots appeared in the hypo-AF and hypo-IRAF peripheral areas. Some hyper-AF spots were observed between the patchy hypo-AF of P2, P3, and P4, which was consistent with the findings of Kojima et al [26], and was considered due to retention of some functions by the impaired RPE.
We had the 4 patients do puzzles for the two FFA examinations to provide a more intuitive and comprehensive view of the progression of the disease. The retinal choroid atrophy was significantly worse in all 8 eyes of the 4 patients in the last than in the first examination, in agreement with previous reports [11, 12]. The left eye and right eye of each patient were essentially the same, but differed among the 4 patients. Normal retinal fluorescence was observed in the mid-peripheral part in P1, and expansion of the lesions was observed from the posterior pole and peripheral parts to the normal retina in the mid-peripheral part. Partial normal retinal fluorescence was observed at the temporal side of the P2 both eyes macular area, and P2L showed a reduction in the area of the normal retina, with expansion of the peripheral lesions to the normal retina. The P3 macular area retina showed no obvious changes, but the surrounding lesions were obviously atrophy aggravations. The P4 both eyes showed less atrophy in the superior temporal area and in the temporal side of the macular area and the inferior peripheral area. The rest of the region was severely atrophied and showed choroidal vascular fluorescence. P4L showed further shrinkage of the less atrophy areas, and the areas with severer atrophy were further extended, with clearer of choroidal macrovascularities. This situation differed from previous research indicating that BCD is an eccentric extension starting from the posterior pole [27, 28, 29, 30]. BCD may not develop exclusively by posterior polar eccentricity as, at least in some cases, the lesion develops from the posterior and peripheral parts and extends to the mid-peripheral part, and the temporal retinal atrophy develops relatively later. This may occur because the temporal retina is farther away from the posterior pole of the BCD initiation site.
In this study, OCT was applied for the first time to quantify the changes in the retina and choroid. The P1 left eye showed increased retinal thickness due to macular edema, an aggravated atrophy of the EZ and RPE, and a thinner choroid. The P1 right eye, P2 both eyes, and P4 both eyes showed thinner retinas, with increased atrophy of the outer retinal nuclear layer, EZ, and RPE and a thinner choroid. The diameter of choroidal macrovascularities was shortened in P1, P2, and P4, consistent with the degenerative properties of the BCD lesions [31]. Our view is that the decrease in the diameter of the choroidal vessels is only one of the reasons for choroidal thinning. We observed that choroidal capillaries also become thinner; however, because the difficulty in defining the boundary of the capillary layer made obtaining specific data impossible. Previous studies have reported reductions in choroidal capillary blood flow, as determined by OCTA [32].
No change, or a change of only a few micrometers, was observed in the P3 macular area measurements, except that the retinal thickness of the right eye fovea thinned to 17 µm, which we did not consider statistically significant. The combination of FAF and FFA results indicated a progression in the retinal choroidal lesions other than in the macular area, but no significant FAF and FFA changes were noted in the macular area. The reflection of the EZ in the P3 macular area was missing. Determining whether this is related to the P3 gene phenotype will require further study on more cases. It was not reported in previous cases [11, 12].
The ORT was first reported in 2009 [33], and it appears in OCT as a low-reflective oval space with a highly reflective boundary in the outer nuclear layer. Since the first report, ORTs have been associated with poor visual prognosis [34, 35, 36]. In our study, ORTs were observed in the two examinations of all 8 eyes, confirming their high incidence in BCD and in agreement with previous results [26, 37]. Two patients in our case showed intraretinal cystoid cavities in the inner nuclear layer in the macular area, suggesting that macular edema is common in BCD. The macular edema in P1 and P4 starts from a zero baseline and progresses from less to more, with adverse effects on the patients' visual acuity. Many previous reports have documented BCD macular cystoid edema [6, 8, 31, 38, 39], but the pathogenesis of the macular cystoid edema is still unclear. The consensus is that it may be the same as the pathogenesis of cystic macular disease in retinal dystrophy, which is caused mainly by damage to the blood-retinal barrier [8, 37, 38]. The exact pathogenesis needs further study.
This study had several limitations, including the small number of included eyes and the lack of primary patient observation. However, considering the rarity of the disease and reviewing the previous literature, our study on the progression of BCD using multimodal images provides one of the largest numbers of images and the largest number of patients. Another limitation is that the large retinal vessels of the P2L right eye and the P4F left eye showed only slight fluorescence in the FAF due to the intravenous injection of the fluorescein sodium test fluid, and this had an impact on the accuracy of our FAF inspections. A third limitation is that the FFA evaluation was not well planned, so the puzzles were inconsistent and some fundus area pictures were missing. A fourth limitation was that the first examination of the 4 patients was retrospective. Therefore, the horizontal B-scan OCT of the P1F left eye and P2F left eye did not cross the fovea, but slightly deviated from the fovea. Consequently, in the last examination, we used this slightly off-fovea layer for comparison.