Diabetic macular edema with pachychoroid features

Diabetic macular edema (DME) is the most common cause of vision loss in diabetic retinopathy (DR), and its prevalence increases up to 28–29% in patients with a diabetes duration greater than 20 years [1]. Since Otani et al. [2] reported three patterns of DME, namely, diffuse swelling, cystoid macular edema (CME) and serous macular detachment (SMD), using optical coherence tomography (OCT), the clinical manifestations of each type of DME, including detailed morphologic classifications, have been described [3]. OCT can discriminate DME types, including those with SMD, which is difficult to diagnose by biomicroscopy or fluorescein angiography (FA) [4]. More recently, diffuse and focal edema have been described based on the different pathophysiologies of DME development: diffuse edema is thought to result from disrupted retinal vessel integrity induced by the generalized breakdown of the inner blood-retinal barrier (BRB) [5], whereas focal edema results from microaneurysms, with pathology observed primarily in the outer retina [6]. When diffuse leakage occurs in the inner retina, fluid collects mainly in the inner nuclear layer (INL), resulting in a diffuse edema pattern.

Among the various patterns of DME, the importance of SMD in diffuse or focal edema has not been adequately depicted. Although the prevalence of SMD is quite high, approximately ranging from 10 to 30% [2, 4, 7, 8], the pathogenesis and functional consequences of SMD remain controversial [4, 8, 9]. Inner and/or outer BRB compromise are the main causes for the development of macular edema in diabetic eyes; however, the genesis of SMD in these eyes seems involve a complex process. The inner plexiform layer (IPL) and outer plexiform layer (OPL) constitute 2 diffusion barriers of intraretinal fluid distribution [6]. The excessive intraretinal fluid from the disruption of the inner BRB has been hypothesized to reach the subretinal space because the external limiting membrane (ELM) is not impermeable to fluid and albumin [3, 10, 11]. If a large water load is not removed properly by the retinal pigment epithelium (RPE) (failure of the RPE pump), SMD could occur. One good example of SMD occurrence from inner BRB breakdown is in cases of retinal vein occlusion (RVO); the prevalence of SMD in RVO is much higher than that in DME. Excess fluid that reaches the subretinal space from rapidly increased intraretinal fluid in RVO might exceed the RPE active transport mechanism [2, 7]. However, this mechanism of SMD development from inner BRB disruption hardly explains the occurrence of SMD without substantial retinal fluid accumulation or when DME is focal (fluid in only the outer plexiform/outer nuclear layer [OPL/ONL]) and far from the macula [8], especially the nasal location. Thus, subretinal fluid accumulation may occur in DME with outer BRB breakdown, and choroidal circulation also leaks into the subretinal space.

There have been different reports regarding choroidal thickness (CT) during DR and DME. Some authors reported that the choroid thins during the progression of DR, reflecting decreased choroidal circulation and vascular insufficiency in DR and DME [12‐16] whereas others reported no significant association between CT and DR or DME [17, 18]. In contrast, some authors found that CT increased with the severity of DR and in eyes with DME [19, 20]. There could be several explanations for these divergent reports, including not adjusting for age and refractive error and not using enhanced depth imaging OCT (EDI OCT), but studies of heterogeneous eyes with different prevailing pathophysiologies involved in the development of DME might be a major reason. Choroidal thickening is a manifestation observed in various disorders affecting the retina and choroid, including recently described pachychoroid spectrum diseases. Pachychoroid spectrum diseases, including pachychoroid pigment epitheliopathy (PPE), pachychoroid neovasculopathy (PNV), and central serous chorioretinopathy (CSC), have common characteristics: diffuse or focal areas of increased CT, dilated choroidal vessels (pachyvessels), and thinning or absence of inner choroid (the choriocapillaris [CC] and Sattler’s layer) overlying pachyvessels [21‐25]. Although a number of studies have described various manifestations of these diseases, their pathophysiologies remain debatable. In particular, the influence of pachychoroid features on the manifestations of various forms of DME has not been studied.

Thus, this study was designed to determine the clinical manifestations of DME with or without pachychoroid features using multimodal retinal imaging. In this study, we investigated whether particular types of macular edema are more common in diabetic eyes with pachychoroid phenotypes.

This study included 495 eyes of 495 patients with DR (mean age 58.66 ± 12.69 years, 304 men and 191 women). The number of eyes with pachychoroid features in each group is described in Table 1. In the control group and groups 1A, 1B, 2A and 2B, 108 (37.9%), 26 (70.3%), 27 (62.8%), 32 (45.7%) and 21 (35.0%) eyes had pachychoroid phenotypes, respectively. The frequency of pachychoroid phenotypes was significantly higher in group 1 than in the control group (P < 0.001). The ratio of pachychoroid phenotypes was significantly higher in group 1 (66.3%) than in group 2 (40.8%, P < 0.001). The demographic characteristics of the patients from each group are shown in Table 1. There were no significant differences in age, sex, and the prevalence of hypertension, dyslipidemia, cardiovascular diseases and kidney diseases among the groups.

The mean logMAR BCVA at baseline was 0.16 ± 0.28. Among all groups, the BCVA in the control group (0.07 ± 0.17) was better than that in the other groups, and the BCVA in group 1B (0.36 ± 0.38) was worse than that in the other groups. In the DME groups, no significant difference in BCVA was found between groups 1A, 1B, 2A and 2B (ANOVA, P = 0.516) (Fig. 1a). A similar trend was observed only when patients with pachychoroid phenotypes were analyzed (Fig. 1a); the BCVA in the control group (0.08 ± 0.23) was better than that in the other groups, and the BCVA in group 1B (0.37 ± 0.46) was worse than that in the other groups. In DME eyes, no significant difference in BCVA was found between groups 1A, 1B, 2A and 2B (Kruskal-Wallis test, P = 0.107).

In the present study, pachychoroid phenotypes were more frequent in diabetic eyes with SMD than in those without SMD. We also observed a certain type of focal edema that might be derived from direct RPE leakage and is associated with pachychoroid phenotypes (Supplemental Fig. 1 and 3). Progressive thickening of the choroid or a thickened choroid with the progression of DR or the presence of DME has been reported [8, 13, 20]. SMD is reportedly related to increased CT, increased CC permeability and outer BRB dysfunction. Based on the findings of the present study, we suggest that there may be specific types of DME associated with pachychoroid characteristics in addition to CT changes along with DR and/or DME. This idea can also explain the very divergent reports regarding CT and DR and/or DME thus far [12‐20]. Proteinaceous exudate in the subretinal space might be at least partially caused by excessive leakage from the CC.

When we analyzed eyes with pachychoroid phenotypes in the control and groups 1A, 1B, 2A and 2B, no significant difference in SFCT or BCVA was found between group 1B and group 2B. However, CMT and the thickness of the inner/outer retinal layers were significantly higher in group 1B (all P < 0.001). Additionally, no difference in SFCT or BCVA was found between group 1A and group 2A. Nevertheless, CMT and the thickness of the inner/outer retinal layers were significantly larger in group 1A than in group 1B (all P < 0.001). Thus, SMD may develop with large neural retinal fluid accumulation, but no correlation was found between the presence of SMD and visual acuity, consistent with findings in other studies [8, 11, 26]. As Gaucher et al. [8] described, functional impairment of the RPE and choroidal changes could lead to SMD in diabetic eyes, in addition to insufficient passive resorption of intraretinal fluid for the development of SMD. Nonperfusion of the CC causes ischemic damage or necrosis of the RPE and breakdown of outer BRB, resulting in the development of SMD [12, 13]. Loss of the CC or decreased choroidal blood flow may result in a hypoxic environment around the RPE, followed by upregulation of VEGF production by the RPE [8, 27]. In histologic studies of the diabetic choroid, choroidal neovascularization (CNV) that was associated with areas of CC loss at or peripheral to the equator was observed [28]. FA and ICGA of these patients show filling delay of the choroid, indicating CC nonperfusion in the early phase and multiple hyperfluorescent spots in the middle to late phase [29]. In our study, macular ischemia, which appears as decreased CC flow on OCTA, was detected in 14 (42.86%) and 9 (66.67%) eyes in groups 1A and 1B, respectively. As Gaudric et al. [30] hypothesized, if choroidal ischemia is moderate, passage of fluid through the RPE could lead to SMD; in contrast, RPE cell death occurs with a greater extent of choroidal ischemia.

Interestingly, among 18 eyes without definite microaneurysms in group 2A (the focal edema group), we noted that 13 eyes with pachychoroid features showed greater CMT than that in 5 eyes without pachychoroid features (358.23 and 251.20 μm, P = 0.019, Table 3), suggesting that an RPE leak accompanied by pachychoroid phenotypes may be a major contributing mechanism for macular edema in these patients. No difference in BCVA between these two subgroups was found (P = 0.387, Table 3). When we analyzed 52 eyes with microaneurysms in which a leak from microaneurysms was the major mechanism of macular edema, there was no difference in CMT between 19 eyes with pachychoroid features and 33 eyes without pachychoroid features (336.58 and 342.79 μm, P = 0.676). However, BCVA was better in 19 eyes with pachychoroid features than in 33 eyes without pachychoroid features (0.02 and 0.20, P = 0.044). These findings collectively suggest that eyes with edema from an RPE leak in pachychoroid phenotypes could develop during the course of DR. Thus, these features might not necessarily indicate a chronic course or a poorer prognosis. Remarkably, 7 of 18 eyes without definite microaneurysms in group 2A showed intraretinal fluid accumulation in the nasal macula (Supplemental Fig. 3). Regarding the possible mechanism associated with this unusual location of macular edema in eyes with DME, these eyes may share overlapping features with peripapillary pachychoroid syndrome (PPS), a recently described type of pachychoroid spectrum disease [31]. Although 4 of 16 cases with PPS in the study by Phasukkijwatana et al. [31] had underlying DM, it remains unclear whether DM and/or DME with pachychoroid features can be included in the clinical spectrum of PPS, which is characterized by peripapillary choroidal thickening associated with nasal macular intraretinal and/or subretinal fluid and occasional disc edema. Although the pathophysiological mechanisms of PPS are not completely known [29], similar or shared mechanisms of RPE dysfunction and subsequent fluid leakage into the intraretinal space due to high hydrostatic pressure from peripapillary choroidal congestion are likely operating in our nasally located focal DME eyes with pachychoroid features and without microaneurysms.

This study has several limitations. First, the study design is retrospective, and only images and data collected at the initial presentation were analyzed. Future longitudinal studies including the association of changes in OCT parameters after the treatment of DME are needed. However, the strengths of the present study included a large number of consecutive DR patients in one tertiary hospital. In addition, DME patients were divided into four groups, and the analysis was further conducted on subgroups according to the presence or absence of pachychoroid phenotypes for the first time. Second, the definition of pachychoroid phenotypes has not been clarified; however, we have defined them as defined in previous studies as much as possible [21‐25]. Finally, OCTA examination was not conducted on all patients; thus, the definite relationship between CC ischemia and outer retinal damage or edema should be evaluated in future studies. In addition, OCTA could possibly be used to find MA that were not observed in OCT or FA. However, a recent study reported that FA counted a significantly higher number of MAs compared with the five different OCTA devices, including ours (Spectralis OCTA, Heidelberg, Germany) [32]. When compared with FA, Spectralis OCTA showed a sensitivity of 43%, specificity of 55%, positive predictive value (PPV) of 81% and negative predictive value (NPV) of 17%. Due to the lower PPV and NPV, OCTA still has weaknesses in defining the presence or absence of MAs. Another study reported that MAs that appear hyporeflective on structural OCT have a lower detection rate on OCTA [33]. Nevertheless, the possibility of finding new MAs with OCTA exists, and large population studies will be needed in the future.

In conclusion, SMD and focal edema from RPE leakage may be clinical manifestations of DME with pachychoroid phenotypes. A better understanding of choroidal disturbances in DME is important for accurate evaluation and treatment of DME.