In DME, liquid accumulation can occur in intracellular or extracellular spaces due to cytotoxic or vasogenic process (14). Several patterns of macula edema depending on the location of intracellular or extracellular fluid have been first described by Otani et al (15). Investigators have found variable results for visual and anatomic improvement in different groups after anti-VEGF treatment (4-7, 16-22).
In our current study, changes in OCT parameters over time after IVR treatment were observed. Compared with group 2 without morphology changes, group 1 showed a significant higher CMT at 2nd year (p=0.001), which may indicate poor response to anti-VEGF therapy and other different key mechanisms involved in the development of DME in patients of group 1. This finding may imply the possible strategy for shifting to dexamethasone therapy or even surgical treatment.
Pathologic fibrocellular changes at the vitreomacular interface are present in eyes with DME irrespective of the type of macular edema as classified by SD-OCT.
Among three subtypes of DME, patients with CME or DRT had higher risk of development of VIMA than those with SRD. In accordance with the immunostaining result conducted by Haguenau, F. et al, which eyes with DRT and CME were most intensely positive for active myofibroblasts and the enzyme matrix metalloproteinase-9 (MMP-9) (23), our finding addressed the tendency for progression to proliferative disease in DRT and CME groups.
Though vasogenic or inflammatory etiology of DME is very difficult to distinguish from OCT, we found a succession of change from DRT to CME/SRD and from CME to SRD. In contrary, none of eyes with pure SRD transform into CME type after IVR treatment in our observation, except the coexistent of initial VIMA. As vasogenic changes secondary to hyperglycemia begins the cascade of macular edema formation by causing a failure in the RPE pump function (14, 24, 25), we supposed SRD may be an indicator of earlier stage DME, which respond well to IVR and seldom transform into other subtypes under intravitreal anti-VEGF therapy. Apparently, this finding correlates well with previous studies which the presence of subretinal fluid implied better response to treatment (11, 26). We further infer that individual differences of RPE function contributed to the presence of this early sign, which could explain why part of patients developed SRD with longer DME duration and disease progression, as the schematic diagram illustrated in Figure 2.
On the aspect of VIMA groups, any alterations of OCT morphology like newly developed CME, SRD, or macula contracture in the development and progression of DME, could occur with previous exiting vitreomacular interface abnormality. One eye with ERM further developed macula pucker by 12 months. The CMT outcome at 2nd year follow-up showed an average of 390.5 ± 75.3 µm in VIMA group, patients with morphological changes, which had considerable discrepancy in our previous work of favorable improvement in reduction of CMT in VMIA group with consistent IVR injections (13). This finding implies that patients with poor response, underlying physical mechanisms of pathogenesis other than VEGF may be involved and receive benefit from the treatment of surgical relief of traction (27).
Nevertheless, among the eyes developed ERM during the anti-VEGF treatment course, the CMT outcome at 2nd year showed a better resolution of 19.33 µm with shorter follow up period compared with VIMA group, though there is no statistically significant (p= 0.62).
We still assume this difference may be caused by distinct mechanisms of ERM formation. Previous reports have mentioned that anti-VEGF agents may be involved in the fibrotic process in diabetic eyes, which may be induced by the intravitreal injection method or angio-fibrotic switch of VEGF and CTGF in PDR (28). Besides, long-term intravitreal injection attributing to repetition of volume expansion may accelerate posterior vitreous detachment, which is beneficial in the natural history of DME (29). The ERM associated with posterior vitreous detachment may instead provide a tension force toward the retina to prevent macula edema from progression in patients whose epiretinal membranes initiated secondary to the vasculopathy process at macula and repetition of intravitreal injections. Most importantly, though CMT could achieve favorable results, symptoms of retinal distortion resulting from ERMs are still considered as a surgical indication.
On the aspect of the association between DM retinopathy and cardiovascular events such as stroke or CAD, previous studies have addressed patents with type 2 diabetes and DME or PDR has an increased risk of cardiovascular events (30). In our present study, we found DME patient with stroke had a 6.4-fold increase in the relative risk of developing into another DME subtypes. This finding may account for the relationship between stroke and more severe diabetes or the relevant confounding factors related to stroke. Moreover, for patients who regular use aspirin, the anti-inflammatory agent may be a confounding factor which may block the gap junction communication between the RPE cells, damage retinal microenvironment (31), and possibly worsen the progression of DME.
Our study has several limitations. First, because our research is a nonrandomized and uncontrolled study, data were collected retrospectively from a relatively small number of patients without standardized treatment regimen. Second, due to the reimbursement limitations, most patients were undertreated with a mean number of injections over 24 months. We overcame difficulties that may have derived from poor-quality images, previous treatments or short follow-up period, resulting in relative large number of excluded cases. Yet, eyes with different duration of DME, control of DM, and timing for injections were not evaluated, reflecting real-life conditions in daily practice.
In summary, macula edema disappeared rapidly after IVR treatment and might recur or even evolve to other subtypes over time, which may indicate a disease progression with poor outcome. Pathologic fibrocellular changes at the vitreomacular interface were the most common type of change and presented in all eyes with DME irrespective of the type of macular edema as classified by SD-OCT. We suppose SRD may be an indicator of earlier stage DME, which respond well to IVR and seldom transform into other subtypes under intravitreal anti-VEGF therapy.
Future research may focus on exploring different etiologies in DME to establish more precise and individualized treatments, which will be increasingly important issues.