Discussion
To identify vascular alterations in STGD is an important prerequisite for defining disease pathophysiology, individual prognosis and the optimal time point for therapeutic interventions in the future. However, little is known about the microvascular alterations associated with STGD. Former studies using fluorescein or indocyanine green angiography already detected vascular changes in STGD.5 10 These studies, however, were limited by low imaging resolutions and dye leakiness which precluded exact quantification of the microvascular network. The advent of OCTA has enabled in-depth imaging and analysis of the retinal and choroidal vasculature in chorioretinal disease.6 The present study aimed to characterise vascular changes in STGD using dSS-OCTA. All our patients with STGD exhibited vascular alterations in the retina and choroidea that increased with age and disease stage, indicating progressive vascular decay over the disease course. Furthermore, increased vascular damage seems to be associated with decreased vision.
Few investigations have examined the retinal and choroidal vasculature in patients with STGD using OCTA.3 7 11 Mastropasqua et al assessed the CC in 12 patients with STGD using OCTA and detected an extensive loss of the CC in areas of RPE atrophy.11 Guduru et al quantitatively assessed the CC in STGD and demonstrated that the RPE loss was more pronounced than the concomitant CC loss indicating primary RPE degeneration followed by vascular atrophy.7 Both studies, however, were limited by the use of spectral domain OCTA (SD-OCTA) technology, which is prone to image artefacts when assessing the choroidal vasculature.6 To overcome this limitation, we employed dSS-OCTA, as it delivers more accurate imaging of the CC thanks to its longer wavelength and better sensitivity roll-off.12 13 We distinguished two different CC textures in STGD: a central area of complete CC atrophy which permitted direct visualisation of deep choroidal vessels and a surrounding area of rarefied CC. These data support fluorescein angiography findings demonstrating a progressively hyperfluorescence in the borders of the area of atrophy in STGD, while the centre was isohypofluorescent.10 While all patients with STGD revealed areas of rarefied CC in our study, areas of CC atrophy were predominantly found in more advanced STGD stages. In line with this observation, we detected a positive correlation between the time since first diagnosis and the area of CC atrophy, indicating progressive vascular decay in the CC layer. Prospective studies entailing longitudinal follow-up are warranted to clarify whether the areas of CC rarefication eventually become atrophic, and whether they precede or follow RPE atrophy during the disease course.
To the best of our knowledge, the ORCC layer has not been examined in STGD so far. Hitherto this layer has mainly been used to visualise features of type I and type II choroidal neovascularization (CNV).14 15 The ORCC slab includes parts of the outer retina, the RPE and, to a small degree, the CC, and reveals a homogeneous architecture in healthy individuals. Patients with STGD, however, exhibit an ORCC slab emitting irregular and rarefied OCTA signals, and areas revealing a total loss of retinal signal texture with uncovered large-callipered vessels which increase with duration and stage of disease. Although recent studies indicate that SS-OCTA is capable of delivering ORCC angiograms with better image quality than SD-OCTA,16 the projection artefacts from the inner retinal vessels (reduced in density in STGD) cannot be completely ruled out. Furthermore, shadowing artefacts from lipofuscin-containing flecks or window defects from atrophic RPE may enhance the area of alterations in the ORCC. Since the affected area in the ORCC was significantly larger than the SCP, DCP and CC, it is likely that a combination of the aforementioned phenomena contributes to the changes observed in the ORCC, and that the ORCC represents an overall measure to visualise retinal, RPE and choroidal anomalies in STGD.
While the choroidal vasculature has attracted the most interest,8 considerably less is known about the retinal vasculature in STGD. Mastropasqua et al studied 12 patients with STGD and reported on a reduction in vessel density in the fovea within the SCP and DCP, a finding in line with ours.11 In contrast to Battaglia Parodi et al who examined 19 patients with STGD,3 our study revealed an enlarged FAZ in the SCP compared with the DCP, suggesting that the vascular damage is exacerbated in the inner retinal layers.3 This discrepancy may be attributed to the older and more advanced cohort analysed in our study which may exhibit more pronounced vascular decay in the SCP secondary to neuronal loss. However, the small sample sizes of our study and the aforementioned studies preclude definitive conclusions. Further studies are needed to determine any differences between the SCP and DCP with confidence. Nevertheless, our study supports the aforementioned OCTA investigations revealing a reduced vascular density in the inner retina, and demonstrates that these vascular changes worsen with time and advancing disease stages. It is currently unknown whether the decay of the inner retinal vessels in STGD is a primary or secondary consequence of the weakening metabolic demand in the degenerating neuroretina. The hypothesis of primary regression of the vasculature with secondary loss of neurons, however, is unlikely since the ABCA4 gene is predominantly expressed in photoreceptor cells17 and only weakly in endothelial cells in the central nervous system.18 Nevertheless, it is a possibility that cannot be entirely ruled out, and future studies are necessary to examine patients with STGD at a very early disease stage to prove or disprove that hypothesis. On the other hand, the vascular decay in the retina could be attributable to a reduced metabolic demand in the retina caused by progressing retinal degeneration. This hypothesis would be in line with findings demonstrating a correlation between macular vessel density and retinal atrophy11 and would be supported by our study showing a correlation between the disease duration and vascular degeneration. In any case, the considerable vascular decay in the inner retina may constitute an important feature of STGD pathology and may specifically exacerbate the progressive degeneration of photoreceptors and inner retinal neurons over the disease course. This finding is particularly important in the context of promising therapeutic interventions such as gene therapy or stem cell transplantation, which need to be administered at an early disease stage or at least guided by the vascular pattern as visualised on OCTA.
We acknowledge that our analysis has limitations, including subjective classification of the type of disease and the absence of longitudinal follow-up. Due to our cohort’s small size, the group size of the four different STGD stages varies between 2 and 22 eyes, which makes the classes harder to compare. Furthermore, our study enrolled only one patient presenting S4, which may have led to an overestimating or underestimating the OCTA findings at that stage. Using two eyes of a single patient might result in within-subject correlation. Nevertheless, since STGD is a rare disease, and although our cohort managed to attain a good size compared with previous studies,3 7 sample size is still small. Therefore, we decided, as did other investigators,3 7 to include both eyes of the patients with STGD in our study. We performed additional analyses only including the right eye of the patients. Due to smaller sample sizes, not all analyses that resulted in a significant level when using all eyes also reach significance when only using the right eye. Nevertheless, a trend toward significance becomes obvious in all our analyses (data not shown). Although carrying out multiple statistical tests in our study, we did not correct the p values due to small sample sizes. Therefore, some of the significant p values might be spurious. Furthermore, different dimensions of the OCTA scans may lead to different quantitative values.19 Nevertheless, in view of the higher precision of the 6×6 mm2 volume scan, we decided to prefer it, and it was only whenever the area to be measured exceeded the size of that scan that we opted to use the 9×9 mm2 volume scan. Furthermore, since 9×9 mm2 was the largest frame available, the areas of rarefied flow and atrophy in ORCC and CC may have been underestimated in some patients and therefore potential differences in eyes affected by large areas of rarefied flow and atrophy went undetected. Despite the existing body of evidence suggesting that the retinal plexuses merge at the edge of the FAZ, which may be thus considered a singular structure throughout the entire foveal thickness20 21 and increased variability of measurements when assessing the FAZ size at different segments,22 we chose to investigate the FAZ area separately in different retinal capillary plexuses (SCP and DCP) so as to compare our findings to the latest literature. As a result of choriocapillary atrophy, the large choroidal vessels are detected in the corresponding areas. Due to this limitation which prohibits a more objective measurement of, for example, perfusion density or vessel length density, we decided to manually detect the area of vascular changes/atrophy, as described before.7 Nevertheless, a more objective means of detecting vascular changes would be desirable. To the best of our knowledge, however, there is no such analysis procedure available that does justice to the present situation of patients with STGD. In light of these limitations, further prospective studies offering increased power, improved OCTA imaging technology and longitudinal follow-up data are warranted to determine the vascular phenotype of STGD with confidence.
In summary, to the best of our knowledge this is the first and largest cohort-based study investigating vascular changes in different stages of STGD using dSS-OCTA technology, which enables improved visualisation of the deep retinal and choriocapillary layers and thus fewer image artefacts. Our study confirms the essential findings of previous studies using angiography or SD-OCTA and illustrates with more detail the considerable vascular alterations in all layers of the retina and choroid in STGD which increase with the disease’s duration and advancing stage, indicating progressive vascular decay over the disease course. Furthermore, we demonstrated that increased vascular damage is associated with decreased vision. Further prospective and especially longitudinal OCTA studies are required to validate our results, which may have a significant impact on individual prognosis and the optimal timing for possible therapeutic interventions.
