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| REVIEW ARTICLE |
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| Year : 2021 | Volume
: 8
| Issue : 2 | Page : 39-43 |
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Optical coherence tomography biomarkers in diabetic macular edema
Amira Mohamed Mostafa1, Mohamed Ashraf2, Ahmed Abdel Razak Souka3, Karim Adly Raafat4
1 Imaging Unit - iCare Eye Hospital, Alexandria, Egypt
2 Department of Opthalmology, Alexandria Faculty of Medicine, Cairo, Egypt; Joslin Diabetes Center, Beetham Eye Institute, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
3 Department of Opthalmology, Alexandria Faculty of Medicine, Cairo, Egypt
4 Department of Ophthalmology, Kasr Al Ainy School of Medicine, Cairo, Egypt
| Date of Submission | 25-Apr-2022 |
| Date of Acceptance | 27-May-2022 |
| Date of Web Publication | 01-Sep-2022 |
Correspondence Address:
Dr. Amira Mohamed Mostafa
iCare Eye Hospital, Somed Building #3 - El Mahmoudeya Axis – Smouha, P. O. 21648, Alexandria
Egypt
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/erj.erj_3_22
Biomarkers are defined as measurable objective indicators that can be used to assess normal physiological process, pathological process and/or tissue response to pharmacological therapeutic agents. In this review article, we address the most notable structural changes encountered in DME patients and their impact on treatment planning and outcomes.
Keywords: Biomarkers, diabetic macular edema, fluorescein angiography, optical coherence tomography, optical coherence tomography angiography, retinopathy
How to cite this article:
Mostafa AM, Ashraf M, Souka AA, Raafat KA. Optical coherence tomography biomarkers in diabetic macular edema. Egypt Retina J 2021;8:39-43 |
| Introduction | |  |
In the current era of anti-vascular endothelial growth factors (VEGF) agents, optical coherence tomography (OCT) has become the most important tool in diagnosis, follow-up, and decision in the treatment of diabetic macular edema (DME). Retinal thickness is the most common quantitative measure obtained from OCT by segmenting internal limiting membrane as the inner retinal boundary and retinal pigment epithelium (RPE) as its outer boundary; allowing the generation of both two- and three-dimensional thickness maps [Figure 1].
However, many studies that used OCT-derived thickness measurements have failed to find a consistent correlation between automatically measured retinal thickness and visual acuity (VA) outcome, even when using more accurate segmentation algorithms, due to the fact that macular thickness is just one of the several variables that can affect VA. This failure has motivated clinical imaging researchers to pursuit the identification of novel OCT-derived anatomic biomarkers, i.e., a measurable objective indicator that can be used to assess normal physiologic process, pathologic process presence and severity, and pharmacologic response to therapeutic intervention, that can be employed to provide prognostic information crucial for appropriate patient counseling and treatment planning.
[TAG:2]Pattern of Edema [/TAG:2]
On OCT, DME is usually seen as an area of retinal thickening that is often associated with loss of foveal depression. Three patterns of DME, using OCT, have been described in literature, namely spongiform edema, cystic edema, and serous neurosensory detachment (NSD) [Figure 2]. Spongiform thickening that involves foveal zone usually occurs at outer plexiform layer (OPL), while cystic spaces usually form in inner nuclear layer (INL) and OPL, and NSD accumulates as extracellular fluid pools between RPE and outer retinal layers (ORL). Such difference in edema level may modulate visual function in DME patients either alone or in association with other variables such as thickness and vitreomacular interface changes. | Figure 2: OCT patterns of DME. Upper row: Left: Diffuse retinal thickening, Middle: cystoid macular edema, Right: subretinal fluid. Lower row: Left: Vitreomacular adhesion with no traction, Right: Posterior hyaloid traction and tractional retinal detachment. OCT: Optical coherence tomography, DME: Diabetic macular edema
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In a study by Alkuraya et al.,[1] they found that best-corrected VA (BCVA) was significantly worse in patients with OCT Types 3 and 4 (NSD and VMT; respectively), but they also reported significantly better VA in those with OCT Type 1, i.e., spongiform pattern. They were also in partial agreement with Kang et al.[2] and Yamamoto et al.[3] who reported better VA in patients with spongiform edema but a worse VA in patients with cystoid pattern, a finding that could be related to the associated intracytoplasmic swelling of Müller cells and secondary neuronal degeneration. In addition, in another study by Pelosini et al.,[4] they found that the cross-sectional area of retinal tissue between the plexiform layers in cystoid macular edema that is formed of both Müller and bipolar cell fibers could predict 80% of VA whereas macular thickness could only predict 14%. Al Faran et al[5] in addition studied the effect of treatment on these fibers; finding that presence and central location of bridging retinal processes within the central 1 mm subfield to be significantly associated with visual improvement.
On the other hand, regarding the presence of NSD, researchers of RIDE and RISE studies stated that the presence of subretinal fluid (SRF) in the ranibizumab (RBZ)-treated group predicted a final BCVA >20/40 (P = 0.0002), visual gains of 15 letters or more (P = 0.004), and a final central retinal thickness (CRT) of 250 or less (P = 0.002), while in sham group, its presence was associated with VA loss of 15 letters or more assuming that it would be a bad prognostic factor for VA in patients not receiving anti-VEGF treatment.[6] Furthermore, in the Diabetic Retinopathy Clinical Research Network (DRCR.net) retina network protocol I, the presence of SRF was associated with higher VA gains, but did not affect changes in OCT.[7]
| Choroidal Thickness | | |
It has been proven that choroidal thickness in diabetic patients is thinner than normal due to the systemic vascular effects of diabetes; resulting in vascular constriction and choriocapillaris loss secondary to hypoxia in association with early diabetic choroidopathy.[8],[9] However, several reports admitted that choroidal thickness usually increases in diabetic patients with increasing diabetic retinopathy (DR) severity as well as with the presence of DME, especially of SRF pattern.[10],[11] Such findings were explained by increasing choroidal blood flow in severe nonproliferative DR (NPDR) and proliferative DR (PDR) patients as well as increasing expression of VEGF and other cytokines mediating choroidal vasodilatation and vascular permeability.[10],[12]
In a recent study by Rayess et al.,[10] the effect of baseline choroidal thickness in cases of DME on response to anti-VEGF was studied. The study found that cases with greater baseline subfoveal choroidal thickness were associated with a better anatomic (odds ratio [OR] = 1.12 for every 10 mm increase, P = 0.03) and functional response (OR = 8.45 for >200 mm vs. <200 mm, P = 0.008). In addition, the subfoveal choroidal thickness decreased significantly after 3 monthly anti-VEGF injections (P < 0.0001). This can be explained by VEGF downregulation with macular edema treatment with a subsequent decrease in choroidal blood flow and hence thickness. This explanation is supported by the presence of significant reduction in macular edema as well as VA improvement at the same time point.
[TAG:2]Outer Retinal Biomarkers [/TAG:2]
Advancements in OCT technology in recent years allowed many researchers to look into the morphological changes happening in outer retinal hyper-reflective bands [Figure 3] in patients with various retinal diseases including diabetic retinopathy, especially with some investigators reporting a paradoxical change in VA in response to changes in OCT-measured thickness. | Figure 3: Representation of multiple retinal changes in association with diabetic macular edema. Epiretinal membranes are highlighted by the red arrows, disruption of the EZ and ELM (yellow star) adjacent to an area of intact EZ and ELM (white arrowheads). EZ: Ellipsoid zone, ELM: External limiting membrane
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Mori et al. reported the recovery of photoreceptors postintravitreal RBZ in patients with DME. They reported that the ellipsoid zone “(EZ)” improved in most eyes (34/38 eyes) with a discontinuous EZ at baseline.[13] It was also preserved in most eyes (16/21) with a complete EZ at baseline for the 1-year follow-up. VA improvement was associated with shortening of the disrupted EZ (P < 0.001) but not with the decrease in CRT (P = 0.093) at 1 year.
Such improvement was attributed to improving retinal neuronal dysfunction related to anti-VEGF treatment, in addition to the relief of edema-related deformity on the underlying photoreceptors.[14],[15]
Older reports studied photoreceptor outer segment (PROS) length, i.e., the distance between the EZ and RPE lines, as a biomarker of VA in DME patients.[16],[17],[18],[19] Forooghian et al.[17] found an abnormally-short PROS length in the central subfield in DME patients (mean: 30 ± 9 μm) using a prototype segmentation of EZ line, a measurement shorter than the normal length of 25–63 μm (mean: 40.5 μm in the foveal zone).[18],[19] Eyes with more areas of PROS shortening over the entire macular grid showed poor VA, and the correlation between VA and PROS length was greater than that with macular thickness. They related such shortening to the effect of tissue ischemia, lipid and fluid exudation, as well as the accumulation of toxic metabolic waste products and inflammatory mediators in DME patients on photoreceptors.[18] Similarly, Alasil et al.[20] concluded that several OCT-derived parameters, in particular PROS thickness, were observed to correlate with VA in patients with DME. Their study revealed a mean PROS thickness of 31 ± 10 μm in the foveal subfield, in addition to a significant correlation between VA and both PROS thickness and integrity.
The inner segment (IS) extends between the EZ and external limiting membrane (ELM) and contains the Golgi, ER, and mitochondria which are responsible for protein and lipid synthesis, and contains ion exchangers and channels that set the resting membrane potential and contribute to the light stimulated response of photoreceptors.[18] Wong et al.[21] added the length of the IS to that of the PROS length to derive whole ORL thickness and reported good correlation between ORL thickness and VA (r = 0.65, r < 0.001) with greater thickness associated with better vision.
[TAG:2]Hyperreflective Foci [/TAG:2]
The exact nature of hyperreflective foci is not yet clearly defined. Current theories suggest that they could be extravasated lipoproteins or degenerated photoreceptor segments or activated microglial cells caused by an intra-retinal pro-inflammatory state.[22],[23] They are seen in association with any pattern of macular edema either cystic, spongiform, or SRF type [Figure 4].[24] | >Figure 4: Hyper-reflective foci “red arrows” in foveal and parafoveal zone
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Many reports worldwide described the behavior of these foci in DME patients receiving anti-VEGF treatment.[24] They reported that HF foci tend to decrease significantly with treatment and that such decrease is correlated with improvement in retinal sensitivity and VA.[22],[25] Furthermore, their presence especially in the outer retina was found to correlate with the final length of EZ-ELM distorted segments as well as final VA.[22]
Other investigators found a correlation between the presence and density of such foci and severity of macular edema. They also found a decrease in HF with macular edema treatment as early as 1-month posttreatment, but this decrease did not correlate with either the change in VA or reduction in macular edema.[22],[25]
| Vitreomacular Interface Abnormalities | | |
The role of the vitreous and vitreomacular interface in the development of macular edema has been studied over years. Nasrallah et al., and Hikichi et al.,[26],[27] found a significantly lower prevalence of posterior vitreous detachment in patients with DME compared to those without, and further posterior hyaloid separation can cause spontaneous resolution of edema. Other groups also confirmed that vitreoretinal separation seemed to be beneficial for patients with DME associated with vitreomacular traction, as well as those without visible traction or thickening.[28],[29] Stefansson advocated the role of improved transvitreal oxygenation after vitreous detachment as one of the possible mechanisms.[30]
In a post hoc analysis of DRCR protocol I, researchers found that the absence of surface wrinkling is one of four factors identified to be associated with better VA in RBZ-treated patients with DME.[7] In a separate study, Brasil et al.[31] found that the presence of ERMs had a significant negative influence on visual outcome 3 months after intravitreal triamcinolone acetonide. This finding was observed in patients with both spongiform edema and cystoid macular edema. Patients with baseline NSD had a small improvement in vision.
In the READ-3 study, Sadiq et al.[32] reported that patients presenting with DME and vitreomacular adhesion (VMA) had significantly greater improvement in vision at 6 months (+11 letters in the VMA group vs. 7 letters in the no VMA group, P = 0.007). The authors suggested that patients with VMA have a greater potential for improvement in VA and that its presence should not preclude initiation of treatment.
| Disorganized Retinal Inner Layers | | |
Disorganization of retinal inner layers or Disorganized Retinal Inner Layers (DRIL) is defined as the inability to follow boundaries of ganglion cell layer inner plexiform layer complex, INL and/or OPL over the central 1 mm foveal zone of the Early Treatment Diabetic Retinopathy Study grid regardless of presence or absence of macular edema.[33]
Sun et al.[33] were first to describe DRIL sign and its importance as a VA biomarker in patients with center-involved DME. They reported that worse baseline DRIL was correlated with worse baseline VA. They also reported that increase in DRIL was associated with worsening VA; with an increase of 300 μm from baseline to 4 months predicting a decrease of 1 line at 8 months. Furthermore, patients with an increase in DRIL rarely showed VA improvements. Conversely, a decrease in DRIL of 250 μ or more at 4 months was associated with VA improvements of 1 line or more in over 75% of eyes.
| In summary | | |
Multiple studies worldwide that looked for different factors that may affect either anatomic or functional outcomes in DME-treated patients. In general, VA at the time of treatment initiation, younger age, and less severe retinopathy level were all found to be associated with better visual outcomes in DME patients. Worse baseline VA was associated with better visual gains, but final VA was less than those with better baseline VA “ceiling effect.” Younger patients also tend to have better visual outcomes as their retina is to tolerate the edema without much structural damage. In addition, patients having NPDR logically have higher visual amplitude compared to those with either active or quiescent PDR as the extent of retinal ischemia and retinal damage from PRP scarring would limit visual improvement with treatment.
Regarding OCT parameters, patients with spongiform edema or SRF seem to have better visual outcomes, while the presence of intact cystic spaces does not affect treatment outcomes using anti-VEGFs. In addition, for more new parameters both DRIL and DROL were found to be associated with less favorable anatomic and visual outcomes in DME-treated patients. Finally, choroidal thickness might be a novel marker for response with very limited studies looking at its effects on treatment.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
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