Role of Microaneurysms in Diabetic Macular Edema: History
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Contributor:
Yoshihiro Takamura
,
Yutaka Yamada
,
Masaru Inatani

Microaneurysms (MAs), a characteristic feature in diabetic retinopathy (DR) and diabetic macular edema (DME), can be detected by fluorescein angiography, optical coherence tomography (OCT) and OCT angiography. These instrumental analyses demonstrated a geographic and functional association between MA and ischemic areas. MA turnover, the production and loss of MA, reflects the activity of DME and DR. Several cytokines are involved in the pathogenesis of MAs, which is characterized by pericyte loss and endothelial cell proliferation in a vascular endothelial growth factor (VEGF)-dependent or -independent manner. Ischemia and MAs localized in the deep retinal layers are characteristic of refractory DME cases. Even in the current anti-VEGF era, laser photocoagulation targeting MAs in the focal residual edema is still an effective therapeutic tool, but it is necessary to be creative in accurately identifying the location of MAs and performing highly precise and minimally invasive coagulation. MAs play a distinctive and important role in the pathogenesis of the onset, progression of DR and DME, and response to anti-VEGF treatment. Further research on MA is significant not only for understanding the pathogenesis of DME but also for improving the effectiveness of treatment.

  • diabetic retinopathy
  • diabetic macular edema
  • microaneurysms

1. Introduction

Diabetic retinopathy (DR) and diabetic macular edema (DME) are the major causes of acquired visual impairment with the background of the currently growing number of the patients with diabetes mellitus [1]. Microaneurysms (MAs), formed by proliferating endothelial cells (ECs) and pericytes loss due to chronic hyperglycemia, is a typical feature in DR and DME and can be a marker indicating their activity [2]. The treatment of DR and DME has traditionally involved photocoagulation for retinal ischemic areas and Mas; however, it has currently shifted to anti-vascular endothelial growth factor (VEGF) therapy [1]. To date, ranibizumab, aflibercept, brolucizumab, and faricimab have been approved for the treatment of DME in Japan. Frequently repeated injections of intravitreal anti-VEGF agents have the promising effects in improving visual acuity and retinal thickness; nevertheless, it is reported that there are still 40% of cases that are refractory with poor response to this treatment [3].

2. Clinical Feature of Microaneurysms

2.1. Diabetic Retinopathy (DR)

DR results from changes in retinal microvascular structures and blood flow due to persistent hyperglycemia [4]. MAs are usually the earliest manifestations of DR and appear as tiny red dots scattered throughout the retina as well as the hallmark of clinical diagnosis of DR. If the MAs that leak were not present in the macular area, MAs do not have any manifestations and do not affect the vision of patients; however, early recognition of MAs can lead to early detection and treatment of DR that will reduce the likelihood of vision loss. MAs cannot be distinguished from tiny dot hemorrhages, and they can be occasionally undetectable ophthalmoscopically. For this reason, fluorescein angiography (FA) has been considered the gold standard for the detection of MAs, visualized as hyperfluorescent dots on early phase, while the dot hemorrhages are visualized as hypofluorescent dots (Figure 1) [5].
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Figure 1. Microaneurysms detected by fluorescein angiography and optical coherence tomography angiography (OCTA). (A) Both microaneurysms (MAs) and dot hemorrhages are shown as red dots on fundus photographs. (B) MAs are depicted as hyperfluorescent (black arrowheads), and dot are depicted as hemorrhages as hypofluorescent (white arrows) on fluorescein angiography (FA). In the detection of MAs by OCTA (C), some MAs depicted by FA (D) are detected (red arrows), while others are not (yellow arrowheads).

2.2. DME

Diabetic macular edema (DME), which can be classified as focal or diffuse based on FA findings, is the leading cause of visual impairment in patients with DR [6]. DME can occur at any stage of DR, and macular edema with the leakage from MAs can cause vision loss. Prolonged hyperglycemia leads to chronic damage of the retinal microvasculature and hypoxia, resulting in increased intraocular concentrations of vascular endothelial growth factor (VEGF) and elevated vascular permeability [7]. MAs and compromised vessels due to the disruption of the blood–retinal barrier (BRB) are the main cause of focal and diffuse edema, respectively [1]. Typical of focal DME, edema is formed by leakage from MAs, eventually forming hard exudates consisting of lipoprotein residues of serous leakage from damaged vessels and MAs. The accumulation of pin-point leakage from MAs is detected in the early phase, while diffuse leakage starts from the early phase and persists until the late phase. Automatic grading is helpful for the quick diagnosis of DME according to the shortest distance from the hard exudates to the fovea [8][9].

2.3. Distribution Pattern of MAs in Diffuse DME

Using ultra-widefield FA, a study showed that the larger the area of non-perfused retina and the greater the severity of DR, the more likely it is to be diffuse DME; conversely, the smaller the level of ischemia, the greater the possibility of focal DME [10]. This finding suggests that the type of DME progresses from focal to diffuse as retinal ischemia worsens. MAs are usually seen in the border areas of CDOs in DR [11]; this association results in a characteristic distribution of MAs in diffuse DME (Figure 2) [12]. There were more MAs in the periphery than in the central area of the edema. Although CDOs in the periphery of the edema are small, they have a large circumference and have fine irregularities and fragmentation. Furthermore, since there are more CDOs in the periphery of the edema, there are also more MAs adjacent to them as compared to CDOs in the center of the edema [12]. Active leakage from several MAs in the edema periphery would contribute to the expansion of edematous areas. In fact, severe ischemia leads to large size edema that extends beyond the macular area [13].
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Figure 2. Marking of microaneurysms and capillary dropouts in a merged image. (A) Distribution of microaneurysms (MAs) in the center (yellow circle) and periphery (green circle) of diabetic macular edema (DME). (B) Distribution of the capillary dropouts (CDOs) in the center (blue area) and periphery (orange area) of DME.

3. Pathology of MAs in DR and DME

3.1. VEGF May Potentially Induce the Development of MAs

MA formation may be induced by intravitreal injection of VEGF as demonstrated by a study using monkey eyes [14]. This finding suggests that the formation of MAs with leakage may be an indicator of VEGF-mediated pathology. The development of MAs may also be enhanced by CDOs, which is a possible source of VEGF, near the MAs. It showed that approximately 80% of MAs were adjacent to CDOs [12]. Dilated shunt vessels with MAs are adjacent to non-perfused acellular capillaries in the retina of patients with DR. It is possible that vessel dilation results in imbalances in fluid flow and viscosity, resulting in the further formation of dilated shunt vessels and MAs neighboring non-perfused capillaries [11]. Contrary to the induction of MA by VEGF, anti-VEGF treatment of DME reduces the number of MAs. Sugimoto et al. reported that the reduction rate of MAs after three times injections of aflibercept was 50.4 ± 21.2% [15]. Therefore, VEGF is thought to be involved in the pathogenesis of both the production and loss of MAs.
In the mouse retina, the loss of pericytes causes endothelial inflammation and perivascular macrophage infiltration [16][17]. Macrophage-derived VEGF activates the VEGF-receptor 2 in ECs. Furthermore, in Mas, ECs without pericytes cause an elevation of angiopoietin-2 (Ang2) levels [16][17]. In normal vessels, vascular stability and homeostasis are maintained by Ang1-tyrosine-protein kinase receptor (Tie2) signaling [18].
ANG/Tie2 signaling is functional in pericytes and plays an important role in DR progression. In pericytes undergoing apoptosis induced by hyperglycemia, Ang1 promotes cell survival, whereas Ang2 promotes apoptosis [19]. Under normal glycemic conditions, Ang1 or Ang2 does not exert any influence on apoptotic cells.

3.2. Mechanisms of Pericyte Dropout

The theory that VEGF produced by ischemia induces MA formation does not explain why MAs are the first morphological abnormality in DR as there is also a VEGF-independent mechanism for MA formation. MAs are accompanied by endothelial hyperplasia resulting from aberrant proliferation, basement membrane thickening, and a decreased number of pericytes [2][20]. Pericyte loss occurs in both diabetic and galactose-fed dogs and is characterized by changes in retinal vessels, such as MAs, hemorrhage, and the formation of non-perfused areas, similar to those seen in human DR [21][22][23]. Experimental evidence suggests that these changes can be prevented by aldose reductase inhibitors (ARI) [21][24][25].
Apoptosis was not observed in galactose-exposed retinal ECs that have low AR content and activity. On the other hand, AR-overexpressing ECs showed decreased cell viability and polyol accumulation, similar to that in pericytes. This suggests that the physiological difference in response to hyperglycemia is attributable to the level of AR expression and is not a cell-specific feature of pericytes and ECs. A study employing a co-culture system of pericytes and ECs exposed to a high-glucose medium demonstrated that there was an increased proliferation of ECs as the number of pericytes decreased. Biochemical assays disclosed that the levels of active transforming growth factor-beta (TGF-β) in media were linked to EC growth. Supplying active TGF-β to a co-culture medium containing high-glucose restored the inhibitory activity against EC growth. 

4. Clinical Role of MAs in the Management of DR and DME

4.1. MA Turnover Is a Biomarker for Disease Activity and Treatment

MAs do not remain stable in the retina in DR and DME for long periods of time. The appearance and disappearance of MAs, defined as MA turnover, represent a dynamic process and reflects disease activity, and it can be a predictor of DR and DME progression. A 5-year prospective longitudinal study demonstrated that MA turnover and MA formation rates are related to the development of vision-threatening complications, such as DME and proliferative DR, and the worsening of DR [26].

4.2. MAs Is Associated with Resistance to Anti-VEGF Therapy

In DME treatment, anti-VEGF therapy is effective for reducing the retinal thickness and decreasing the size of edematous areas; however, residual focal edema frequently remains, as seen in 65.8% of cases after the first injection [27]. An analysis using a 3D mode OCT map wherein an edematous area was divided into 100 sections showed that the reduction in retinal thickness after anti-VEGF therapy varied in regions of the DME [28]. A 10–20% reduction in retinal thickness accounted for approximately 40% of the total edematous areas, whereas only 6.4% of the edematous areas showed a reduction in retinal thickness of 30% or more. Areas with a reduction in retinal thickness of less than 5% were indicative of refractoriness to anti-VEGF therapy, and they accounted for approximately 10% of the edematous areas. These results suggest that the edema-improving effect of anti-VEGF therapy varies by site and that some sites are less responsive than others.

4.3. Direct Photocoagulation Aiming MAs

After anti-VEGF injection into the areas involved in DME, the appearance of the fovea usually returns to almost normal; however, focal edema often persists in the paracentral area. If injections are discontinued because edema has improved in the central area and results in improved visual acuity, the residual perifoveal edema may expand and affect the central areas, as shown by the sample case in Figure 3. Hence, MAs within the residual edema should be targets of additional treatment.
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Figure 3. Microaneurysms in areas of residual edema after anti-VEGF treatment. (a) Optical coherence tomography (OCT) map and cross-sectional images show a representative case of diabetic macular edema (DME) and its improvement (b,d) and recurrence (c) after anti-VEGF treatment. (e) Merged images show microaneurysms (MAs) in areas of residual focal edema. (f) After direct photocoagulation aiming MAs, focal edema improved, and recurrence was not observed.
Excessive conventional laser therapy has several complications such as night vision, the impairment of contrast and visual-field sensitivity, choroidal neovascularization, and the enlargement of laser scars [29]. The subthreshold micropulse laser (SMPL) is a relatively new retinal laser technology that has proven to be safer for retinal tissue than conventional continuous wavelength lasers. SMPL hardly induces the formation of retinal scars and retinal damages, and several studies have shown that this SMPL is effective treatment for DME, in terms of the improvement of visual function and the retinal thickness.

5. Conclusions

MAs, the earliest pathological changes observed in DR, are accompanied by pericyte loss and EC proliferation. Relating to retinal ischemia, several cytokines such as VEGF, ANG-2 and TGF-beta are associated with the synthesis of MAs and pathology including leakage. In diffuse DME, MAs frequently develop in the periphery of edema, and leakage from MAs may contribute to edema expansion. The effectiveness of anti-VEGF agents is relatively less for the MAs. High-dense MAs were observed in areas where there was residual focal edema and where retinal thickness was minimally reduced after anti-VEGF treatment. Although the repeated injections of anti-VEGF agent are gold standard, direct photocoagulation that targets MAs in residual focal edema after anti-VEGF therapy is also effective, and several efforts have been attempted to improve therapeutic outcomes. MAs play a distinctive and important role in the pathogenesis of the onset, progression, and treatment response in DR and DME.

This entry is adapted from the peer-reviewed paper 10.3390/medicina59030435

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