Ultrastructural imaging biomarkers in diabetic macular edema: A major review

Abstract

Diabetic macular edema (DME) is a vision-threatening complication of diabetic retinopathy and causes significant morbidity in patients. Anti-vascular endothelial growth factor (VEGF) agents are the mainstay of treatment for DME, with steroid implants being used for the treatment of anti-VEGF resistant eyes. Over the years, several classification systems have been devised to describe the patterns of DME using optical coherence tomography (OCT). With the advent of effective treatments, it has become imperative that imaging cues are not merely used for classifying the disease but also as biomarkers for prognostication of disease activity and treatment response. In this aspect, newer imaging findings such as hyperreflective dots, photoreceptor integrity, and disorganization of retinal inner layers have been characterized in detail by several authors. Macular perfusion analysis using OCT angiography is the latest in the armamentarium for imaging DME. In this narrative review, we have summarized all relevant literature related to the ultrastructural imaging-based biomarkers of DME and their correlation to treatment.

Figure 1

Different patterns of CMT changes and cystoid spaces in diabetic macular edema by spectral-domain optical coherence tomography. a) Diffuse retinal thickening with cystoid spaces present in the inner nuclear layer (INL) and outer plexiform layer (OPL). b) Large foveal cystoid spaces with intraretinal hyperreflective material. c) Small cysts with hard exudates showing signal blocking beneath and hyperreflective foci. d) Diffuse retinal thickening and intraretinal cystoid spaces indicative of cystoid macular edema, accompanied by subfoveal neurosensory detachment (NSD)

Figure 2

Representative cases of ellipsoid zone (EZ) disruption in patients with diabetic retinopathy. a) OCT image of an 82-year-old female patient, with proliferative diabetic retinopathy and DME, showing degenerative changes in the ellipsoid zone (yellow arrowheads marking extent). b) OCT image shows persistent cystic space with hyper-reflective deposits at the fovea and disrupted ellipsoid zone (yellow arrowheads marking extent) in a 65-year-old male patient who received three loading doses of intravitreal anti-VEGF injections

Figure 3

Optical coherence tomography scans showing an illustrative case of hyperreflective foci in diabetic macular edema. a) Scans reveal the presence of intraretinal hyperreflective foci. b) The pearl necklace sign is characterized by a ring of small dot-like, adjacent hyperreflective lesions that accumulated around the inner wall of a large intraretinal cystic space (yellow arrowhead)

Figure 4

a) Optical coherence tomography image of a 70-year-old patient with severe non-proliferative diabetic retinopathy presenting with epiretinal membrane, cystoid spaces, disorganization of retinal inner layers (DRIL) (yellow arrowhead), and EZ loss (green line with arrowheads showing extent). b and c) Superficial capillary plexus (SCP) and deep capillary plexus (DCP) on OCT-angiography of the same patient demonstrating macular ischemia characterized by enlarged foveal avascular zone (FAZ) and capillary dropouts outside FAZ

Figure 5

Detection of intraretinal microvascular abnormalities (IRMA) using en-face optical coherence tomography angiography (OCTA) images (6 × 6 mm scans). En-face OCTA image of the superficial capillary plexus (SCP) demonstrates IRMA (yellow arrowhead) in a patient with severe diabetic retinopathy. Structural OCT with a flow overlay of OCTA data confirms intraretinal flow below the inner limiting membrane consisting of IRMA

Figure 6

Optical coherence tomography angiography (OCTA) scans showing representative examples of various types of retinal ischemia in diabetic patients. a) En-face superficial retina segmentation slab from en-face 3 × 3 mm optical coherence tomography angiography imaging of a patient with diabetic retinopathy showing enlargement and irregularity of the foveal avascular zone, widening of the perifoveal capillary spaces and varying degree of capillary nonperfusion. b) similarly, en face 6 × 6 mm OCT angiography image of the superficial capillary plexus (SCP) centered on the macula showing enlarged, irregular foveal avascular zone (FAZ) and areas of reduced signals representing SCP ischemia (yellow arrow). c) En face 6 × 6 mm OCT angiography image of the superficial capillary plexus (SCP showing a decorrelation signal exhibited by the cotton wool spot (CWS) nasally to the fovea, and the corresponding B-scans reveal the swelling of the RNFL. d) Superficial capillary plexus in 6 × 6 mm scans reveal nonperfusion areas around the inferior vascular arcade. The corresponding OCT scan shows thinning of the inner nuclear layer and upward expansion of the outer nuclear layer (yellow arrowhead) denoting retinal ischemic perivascular lesions (RIPLs)

Figure 7

Suspended scattering particles in motion observed in diabetic macular edema on optical coherence tomography angiography (OCTA). En face 6 × 6 mm OCTA images of the superficial capillary plexus (a, c) and deep capillary plexus (b) demonstrate areas of extravascular flow signal near the border of the foveal avascular zone corresponding with SSPiM (yellow arrowheads). d-f) Corresponding OCT B-scans with flow overlay reveal the presence of flow signals associated with intraretinal cysts

Figure 8

a) A 63-year-old female patient who developed diabetic macular edema (DME) along with vitreomacular traction at the fovea responded poorly to a set of loading intravitreal injections. b) Treatment naive 50-year-old male patient with proliferative diabetic retinopathy and DME with an extensive epiretinal membrane over the macula along with traction from fibrovascular proliferation at the optic nerve head; in addition, there is significant foveal ellipsoid zone disruption (yellow arrowhead)