This study showed that the GCIPL thickness after treatment with resolved macular edema in RVO eyes was thinner than that in fellow eyes and healthy controls, correlated with the visual acuity and the maximum CMT thickness. Although no significant difference in opposite area was detected between 2 eyes of BRVO patients, the affected-area mean GCIPL thickness was statistically decreased in occluded eyes.
Reasons for GCIPL thinning may be complicated which have not yet been elucidated completely. One possibility could be the systemic risk factors, such as increasing age, hypertension, diabetes mellitus, dyslipidemia [14, 15]. Almost all RVO patients are accompanied by these risks or other hypercoagulable and inflammatory conditions in both our study and others, which may exert potential roles in the neurodegeneration of RVO. A study demonstrated that retinal ganglion cell (RGC) neurons are vulnerable to damage prior to the onset of apparent microvascular diabetic retinopathy (DR) damage, and such RGC damage may be progressive with subsequent severe forms of DR development [16]. Shin et al. reported age and hypertension should be considered as risk factors of RVO by analyzing the longitudinal changes in peripapillary retinal nerve fiber layer (RNFL) thickness over time [17]. Beyond specific systemic diseases, individuals with metabolic syndrome were found having thinner inner retinal layers in OCT segmentation analysis, which suggests that the inherent factors, such as dysfunctional adipose tissue-derived chronic inflammation and insulin resistance, might have an effect on neurodegeneration [18, 19].
Therefore, although there are certain differences in each of the risk factors, they may share the same processes that cause the subclinical inflammation with the production of reactive oxygen species and cytokines, microvascular endothelium damage as well as leukostasis, eventually leading to local tissue hypoxia and capillary non-perfusion [3, 20–22].
The above mechanisms help explain the existing subclinical abnormalities in the fellow eyes of RVO patients considering both eyes share the general risk factors, and this could also be reflected in our findings that the GCIPL thickness of fellow eyes was still thinner than that of healthy controls. Unlike our results presented structural changes, an adaptive optics scanning light ophthalmoscope fluorescein angiography showed decreased foveal microvascular density and increased non-perfused capillaries in fellow eyes of unilateral RVO patients compared with the healthy eyes [21]. The latter showed visible microvascular changes, and these findings from another perspective stress that general risk factors and subclinical pathological changes in RVO patients are worthy of more attention.
In addition to systemic factors, RVO itself could be a cause of GCIPL thickness defects accompanied by characteristic retinal edema and hemorrhages. Given the pivotal role of retinal cells in the transduction of visual pathway, any loss of connectivity among these cells would compromise the visual function. The bipolar cells acted as the only communication between the photoreceptors and the ganglion cells have a degree of elasticity. The axons would be stretched owing to excessive fluid accumulation and as a result, some would break with exceeding the elastic limits and the transmission pathway may be lost [23]. This concept underlines the correlations between increasing retinal thickness determined by OCT and GCIPL thinning and decreased visual acuity, which could be interpreted as the accumulated fluid within retina reducing input from the damaged photoreceptors to the ganglion cells, leading to visual impairments eventually. The results highlight that good vision occurs not only associated with the status of the photoreceptors and the external limiting membrane, but also ,and even more importantly, the integrity of passing tissue in inner retina.
Finally, one could hold the opinion that the possible influence of anti-VEGF treatment on injured RGCs after an ischemic insult, which is currently under investigation with inconsistent data in the literature [24–26]. In our subgroup analysis based on the “dried retina” after anti-VEGF injections, the opposite area in the BRVO eyes and its corresponding area in fellow eyes had no difference suggesting the intravitreal injections had no effect on the ganglion cells loss. Instead, the affected area in occluded eyes had a significant GCIPL thinning either comparing with the opposite area in the same eye or its corresponding in fellow eyes. Furthermore, no significant difference was observed based on the different anti-VEGF times. Therefore, it may be RVO itself, not anti-VEGF effect, causing the GCL thickness further decreased in the occluded area in RVO eyes.
To our knowledge, to quantify the GCIPL thickness alterations is unreliable in case of macular swelling, even providing misleading information. An increase in retinal thickness could lead to significant decrease in signal strength and the magnitude of this decrease parallel central retinal thickness and total retinal volume [27]. This is consistent with the theory “volume-scattering effect” in which light is scattered across the increased three dimensional space of the elevated retina [28]. Moreover, recently, Lee et al. illustrated that the repeatability of GCL parameter in BRVO affected eyes was lower in eyes before treatment than that after treatment, owing to the frequent auto-segmentation errors and unstable gaze with visual damage [9]. Hence, to improve the accuracy, this study was performed with anatomy-improved unilateral RVO cases and scans with obvious segmentation errors as well as low signal strength were ruled out using Cirrus HD-OCT proved with lowest occurrence of any artifacts [29].
Undoubtedly, several limitations exist in this study: firstly, some data, such as the maximum macular thickness duration, the persistent time of systemic diseases, the history of oral contraceptives and smoking habits which all probably affect the GCIPL thickness changes, are missing owing to its retrospective nature. Secondly, although we exclude the correlation between anti-VEGF treatment and the decrease of GCIPL thickness, a longer follow-up with intensive intravitreal injections may be needed to testify this point in future study. Moreover, no superonasal and inferonasal BRVO patients were included in this study, and this may cause bias when comparing the affected and opposite area in the same eye. However, the primary goal of our subgroup analysis was to compare the corresponding areas of the BRVO eyes with those of the contralateral eyes to verify the effect of anti-VEGF on GCIPL degeneration.
In conclusion, despite the anatomic improvements of normal CMT values after anti-VEGF treatment in RVO, the RGC loss and visual impairment may be irreversible. Rather than anti-VEGF, systemic factors and the RVO itself should be responsible for the GCIPL thinning. Therefore, the improvement of systemic disorders is crucial for prevention and prognosis of RVO, and the integrity of the GCIPL and inner retina should be taken into account for ophthalmologists when formulating treatment plans. We believe that the findings in our study would be helpful for the management and prognosis assessment of RVO patients.