Diabetic Macular Ischemia
Diabetic Macular Ischemia (DMI) is most closely recognized by the following codes as per the International Classification of Diseases (ICD) nomenclature:
- 362.84: Retinal Ischemia
- H35.82: Retinal Ischemia
The human macula is defined as an oval shaped, pigmented area near the center of the retina, with a diameter of around 5.5 mm (Figure 1). DMI is the presence of occlusion, atrophy and/or loss of retinal capillaries in the macula, with narrowing or obliteration of precapillary arterioles, in patients with diabetes mellitus. It may be associated with an enlarged and/or irregular foveal avascular zone (FAZ), or enlargement of non-contiguous avascular spaces in the macula, most clearly demonstrated by ancillary testing with fluorescein angiography (FA) or optical coherence tomography angiography (OCTA).
Under the mentorship of Isaac Michaelson, Norman Ashton was the first pathologist to publish extensively on the arterial and capillary involvement in DR, using India ink preparations stained by periodic acid-Schiff method in post-mortem eyes (Figure 2). Hyaline degeneration of the terminal arterioles and pre-capillary vessels led to the gradual occlusion of their lumen, resulting in obliteration of the arteries and capillary beds with formation of new vessels on the venous side of the capillary network. Follow-up studies by Bresnick, Cogan and Kuwabara demonstrated acellular capillaries in ischemic areas.
Pathophysiology and Histology
Pericyte loss and endothelial cell damage are some of the earliest signs of vascular changes in DR. Pericytes play a role in regulating vascular tone, while producing elements of the basement membrane and extracellular matrix. Endothelial cells form intercellular tight junctions that work as the blood-ocular barrier, regulating the diffusion of macro-molecules. Damage to these histologic components leads to vascular deregulation, and involves different structural, molecular and inflammatory mechanisms, leading to closure of the capillary lumen. Abnormal endothelial cells may also induce leukostasis, further worsening vascular occlusion. Moreover, there is thickening of the capillary basement membrane, with type III and IV collagen deposition. This results in decreased access of oxygen and micronutrients to the sensory retina, which may stimulate expression of vascular endothelial growth factor (VEGF). Gradual atrophy of the capillary vasculature at the macula creates larger inter-capillary spaces, resulting in long-term hypoxia and further vascular obliteration, leading eventually to photoreceptor damage if severe. Concomitant macular edema may be present, as the atrophic capillary bed may leak fluid into the retina, typically accumulating in the inner nuclear (INL) or outer plexiform layers (OPL).
The histology of the retinal vascular structure differs at different regions going from center to periphery. Density of capillaries is highest in the macula, with a gradual decrease towards the periphery. There are 3 retinal vascular layers in the macula (superficial, intermediate and deep capillary plexus), 2 in the mid-periphery and only a single vascular layer in the far-periphery. There are differential patterns of ischemia in diabetic patients; some patients have primarily posterior pole or mid-peripheral ischemia, some have ischemia predominantly in the far-periphery, and others have a more generalized ischemia involving the entire retina. Patients with predominantly peripheral ischemia also show less change in central macular perfusion over time compared to those with more centralized ischemia. It is unclear why individual patients develop distinct patterns of ischemia. Recent data has suggested that systemic factors such as anemia and renal disease may predispose to more peripheral ischemia.
DMI is not a disease entity that has typically been identified in major DR population studies, likely because of the need for ancillary testing to confirm the diagnosis. Prevalence data is sparse, but there are limited studies that can estimate the prevalence of DMI.
In a retrospective study by Sim et al. of 488 patients with Type 2 DM with available FAs, using the Early Treatment Diabetic Retinopathy Study (ETDRS) standard photo definitions of DMI, the incidence was 39.7% none, 18.4% questionable, 25.2% mild, 11% moderate, and 5.6% severe. Concomitant DME and DMI is common, with evidence of some DMI found in 29.4% of cases with clinically significant macular edema (CSME), and among those eyes, 19.4% were found to have DMI in the moderate to severe category. In terms of DR severity, eyes with more severe disease had DMI in majority of cases, with proliferative DR (PDR) having 77.2% with DMI, and severe non-proliferative diabetic retinopathy (NPDR) having 59.7% with DMI. Among eyes with less DR and no DR, 46% still had some form of DMI, but majority only had mild or questionable DMI which may just represent variants of normal FAZ. Regardless of the actual population prevalence of DMI, it presently remains an important cause of vision loss.
There are no population studies that specifically look at risk factors for development of DMI, but it is expected that they mirror risk factors for DR. Large scale studies on DR risk factors have consistently shown the association of age, ethnicity, duration of diabetes, glycosylated hemoglobin (HbA1c), blood pressure and lipid control with development and progression of retinopathy. Smaller studies have shown an association of DMI presence with DME, and increasing severity of DR.
Patients with DR may present with several patterns of non-perfusion with different rates of progression. In a study using wide-field fluorescein angiography of 152 eyes, Takashi et al. described four types of capillary nonperfusion in DR according to the predominant location of ischemia. These were namely peripheral (2.6%), midperipheral (61.2%), central (26.3%), and generalized (9.9%). The rate of enlargement of ischemia was faster in the peripheral type, midperipheral type, central type, and then generalized type in ascending order, and was positively correlated with the severity of DR.
Capillary dropout may develop in the macula even prior to the onset of clinically observable hemorrhages and/or microaneurysms (H/Mas). The FAZ and perifoveal intercapillary area generally increase in size as the severity of DR progresses, however there may be large amounts of variability among individual eyes. FAZ enlargement is estimated to be 5-10% per year of baseline area in eyes with known DMI, and more severe levels of DMI are associated with faster progression. Ischemia may remain stable or progress in the long run, and spontaneous improvement is generally not expected. The Early Treatment Diabetic Retinopathy Study (ETDRS) report number 19 published that during a 5-year follow-up, there was no significant progression in DMI severity based on the ETDRS DMI standard photos.
OCTA studies looking at 1-year outcomes showed that the extent of baseline non-perfusion was associated with DR progression (OR = 8.73, p=0.04), while baseline non-perfusion in the deeper layers were associated with eventual treatment (OR = 3.39, p=0.002). Other 1-year studies showed that decreased baseline vessel density (VD) in the superficial layers had greater risk of developing DME, while abnormalities in the deeper layers had greater risk for DR progression.
DMI is typically suspected in patients with advanced DR who present with poor vision despite having no central involved macular edema (ci-DME), and have an otherwise unremarkable ocular examination. A long history of quiescent PDR with prior pan-retinal photocoagulation, retinal thinning, along with stable or progressive vision loss is typical, however it may be present at any level of DR severity.
There are no specific physical examination findings that identify macular ischemia, and ancillary testing is needed for diagnosis. It may be present at any severity of DR, but is more commonly found in advanced stages. Prior authors have described a constellation of fundus findings termed “featureless retina” which may increase suspicion for DMI, but this is not always the case as ischemia may happen at any DR severity level. A central finding in featureless retina is a poor foveal reflex, which is a sign of neurosensory atrophy. Other secondary findings of featureless retina include quiescent PDR, with absence of h/mas, exudates, cotton wool spots, neovascularization, or if present are only mild. Sclerotic ghost vessels seen anywhere from the disc to the retinal periphery may be observed, along with extensive PRP scarring (Figure 3.) In moderate to severe DMI, the mean arteriolar caliber is narrower, compared to patients with less severe or no DMI.
Vision and DMI
Most studies show a low to moderate association of decreased vision with increasing DMI severity, but the association is stronger at more severe levels of ischemia.   In a study by Sim et al., DMI was only associated with reduced vision among eyes with moderate to severe ETDRS-DMI grades. Moreover, papillomacular ischemia was independently associated with significant vision loss, emphasizing that the location of ischemia is important to consider, aside from the overall severity of nonperfusion and FAZ outline abnormality. ETDRS report number 19 also had similar findings, with only the group with severe ischemia having decreased vision, although the number of eyes with severe DMI was low. Looking at regression models, there is moderate correlation between VA and size of FAZ, with Arend et al. having an R2 = 0.51, while DaCosta et al. having an R2 = 0.41. The relationship between vision and FAZ area is also mediated by age, with older patient age associated with more vision loss as the FAZ area increases.
OCTA results are more variable, as certain measurements may be highlighted in one study, and not in others. Most studies show that abnormalities in the superficial capillary plexus (SCP) and deep capillary plexus (DCP) are associated with decreased vision, although damage in the DCP may have a stronger effect. Aside from VA, microperimetry was also an endpoint used to asses functional deficit in OCTA DMI studies, with significant decreases in retinal sensitivity associated with vessel density (VD) abnormalities in prospective cohorts. These findings in OCTA are consistent with experimental studies showing that in the setting of hypoxia, the retinal microvasculature may be contributing more to the oxygen and nutrient demands of the outer retina. The choriocapillaries are the primary blood supply of the outer retina and fovea, but their metabolic supply may be decreased in the setting of hypoxia due to the failure of autoregulatory mechanisms of the choroidal vasculature. Nonperfusion of these capillary beds, seen in OCTA, contribute to photoreceptor loss and decreased vision.
The actual burden of vision loss from DMI is likely underreported, because of a number of other conditions more readily apparent in eye with severe DR. These include concurrent vitreous hemorrhage, retinal detachment, and DME, which becomes the focus of concern as they are recognized easily and have effective treatments available. However, DMI remains an important cause of visual impairment, and must be recognized in patients with a typical history and clinical findings.
Fluorescein angiography has been considered the gold standard for diagnosis of DMI, although now the role of OCTA is evolving. FA remains widely used today in the evaluation of DR, and was the first technique to describe the FAZ in vivo. FA findings in DMI include an enlarged FAZ, shown as a large hypofluorescent patch in macula. The area is surrounded by vascular angiographic changes, which include capillary dilation, and variable separation of intercapillary spaces showing capillary atrophy and nonperfusion. Leakage can be seen in the late phase, as demonstrated in Figure 4. In normal eyes, the mean diameter of the FAZ in FA is 0.53-0.73 mm, while in diabetic eyes the mean diameter was 0.79 mm with a range of 0.66-0.91 mm. In clinical practice, a FAZ diameter greater than 0.5 mm is suspicious for DMI, as normally it is expected to be around 0.5 mm - 0.6 mm, which corresponds the dashed inner circle of the grid (300 μm radius). FAZ area is also an important metric due to the hallmark irregular borders seen in eyes with DMI, where FAZ diameter cannot be interpreted accurately.
ETDRS report number 11 was a landmark trial that classified eyes with DMI into reference photographs. Eyes were classified according the size of the FAZ, capillary dilation, arteriolar abnormalities, and capillary loss. Arteriolar abnormalities included blurring of arteriolar contour, narrowing along the arteriolar course, broadening and/or staining of the arterial wall, and pruning or narrowing of perpendicular side branches. Table 1 outlines the grading schematic for capillary loss, FAZ size, and FAZ outline. Figure 5 shows the ETDRS standard photos used in the grading of DMI.
Disadvantages of FA include being an invasive test that requires venipuncture and intravascular injection of fluorescein dye, which has a risk of medical complications for patients. It is also a relatively time-consuming procedure with multiple steps that include preparation, injection of dye, photography, and post-injection monitoring potentially lasting 20 minutes or more.
Compared to FA, OCTA provides a fast, high-resolution, non-invasive technique that creates a 3-dimensional image of the retina and choroid, along with quantitative measures for various parameters. The captured image from OCTA is a reconstruction of the blood vessels, erythrocytes, and the capillary network, which can highlight the borders of the FAZ. Angiograms from different segmentation slabs are available, where the DCP, SCP, and choriocapillaries (CC) are commonly analyzed. Segmentation of a capillary network between the DCP and SCP is also possible, and is named the intermediate/middle capillary plexus (ICP/MCP). Figure 6 shows examples of the FAZ at different severity levels of DR, while Figure 7 explains the retinal layers involved with each segmentation slab. Various other quantitative parameters can be derived with OCTA, most common of which is vessel density (VD).
OCTA potentially improves the visualization of the FAZ borders compared to FA, as there is no dye leakage that can obscure the margins, along with the ability to examine the vasculature of different retinal layers. With high quality image captures, OCTA can show details of the microvasculature and ischemia in higher resolution. The disadvantages of OCTA include susceptibility to artifacts, loss of vessel visualization if low flow rate or low image quality, and inaccurate FAZ measurements from shadows of edema or hemorrhage. Another challenge for its clinical use is that currently there are still no established normative databases for OCTA metrics. However, small-scale studies have started to explore age and sex matched databases on vessel density (VD) and foveal avascular zone. Results show females had higher VD compared to males, and increasing age was associated with an enlarging FAZ and decreasing VD. OCTA and FA were shown to have comparable size and shape of FAZ. However, OCTA measurements cannot be compared between different devices, despite having good reliability with measurements taken from the same machine. OCTA is still an evolving technology, and the challenges of interpreting the various parameters and addressing artifacts may be improved, as new hardware and software development continues.
Spectral Domain and Enhanced Depth Imaging Optical Coherence Tomography
Signs of DMI may be apparent in the retinal microstructure when viewed through SD-OCT. Fawzi et al. looked at DMI as a cause of photoreceptor compromise and outer retinal changes. They identified the area of ischemia seen through FA, OCTA, and adaptive optics scanning laser ophthalmoscopy (AOSLO), then mapped the corresponding area viewed through SDOCT. In areas of non-perfusion, there was an associated disruption of the external limiting membrane, IS/OS junction, along with thinning of the inner retina, photoreceptors, and ONL. See Figure 8 for an illustrative example. In contrast, a study by Dmuchowska et al. showed that SDOCT measurements of thickness and structure could not predict the FAZ size and outline, with the detection of DMI still reliant on FA or OCTA.
Enhanced depth imaging optical coherence tomography (EDI-OCT) allows the imaging of choroidal thickness, another possible parameter to monitor in DMI. The choroid is the principal vascular layer of the eye, and composes around 95% of ocular blood flow. It primarily supplies the outer layers, notably the photoreceptors, retinal pigment epithelium (RPE), and the outer retina. Choroidal thickness may be a biomarker for choroidal blood flow and tissue oxygenation. A study by Sheth et al. showed that eyes with DMI had significantly reduced choroidal thickness, compared to eyes that did not have DMI.
Other ancillary testing
Measurements from electroretinograms (ERGs) showing abnormal oscillatory potentials, along with delayed implicit times, may be signs of ischemia and microangiopathy. These are among the earliest signs of DR, with subtle ERG changes even before the onset of clinically apparent retinopathy. Studies using multifocal ERG (mfERG) on eyes with retinal vein occlusion similarly found that implicit times were longer among eyes with macular ischemia, compared to eyes with non-ischemic vein occlusion. Contrast sensitivity and color testing are other ancillary tests for DMI. Abnormal blood flow and the severity of nonperfusion as seen on FA are associated with tritan defects and loss of contrast sensitivity, and may occur even before onset of visual loss. Abnormal color vision tested through Farnsworth-Munsell 100 hue test was seen in 50% of patients enrolled in the ETDRS. Oxygen therapy has been shown to partially improve these abnormalities in visual function, indicating that hypoxia has a role in the disease process. Future clinical trials looking at DR and DMI are also starting to look at outcomes beyond visual acuity, FA and OCTA. Other measures include AOSLO, microperimetry, dark adaptometry, low luminance visual acuity, reading speed, and questionnaires about self-reported quality of life and visual function.
Clinical Case Diagnosis
A 63-year-old female with 35 years of type 2 diabetes, HbA1c of 7.5%, presents for follow-up. She has a long-term history of decreased vision in both eyes, 20/80 OD, 20/50 OS. Ophthalmology examination shows pseudophakia in both eyes with clear media. On fundus examination a “featureless retina” can be appreciated, with minimal hemorrhages and microaneurysms, along with a poor foveal reflex. There was a chronic neovascular frond with surrounding fibrovascular changes in the superior arcade, stable for multiple months. She had extensive panretinal photocoagulation in both eyes. OCTA shows irregularity of the FAZ border, along with multiple non-contiguous avascular spaces in the macula. SD-OCT shows significant central subfield thinning, with thickness of 204 μm, stable from previous exam. There was retinal thinning, outer retinal disorganization, disorganization of the retinal inner layers (DRIL), and IS/OS disruption noted on SD-OCT. See Figure 9 for the clinical case synthesis montage.
Macular ischemia may be present in many other retinal diseases, notably branch or central retinal vein/artery occlusion, sickle cell retinopathy, and venous stasis retinopathy.
Currently there are no FDA approved therapies for DMI, but there are a number of exploratory studies underway. Systemic high dose oxygen therapy has been tested as a possible therapy. The treatment regimen for the first month consists of 100% oxygen at 10L/min by face mask, starting at 1 hour twice daily, with a gradual monthly taper. Significant improvement in terms of best corrected vision, FAZ area, and central retinal thickness was observed in the oxygen cohort, compared to deterioration in the control and enalapril group. Even just 1 hour of 100% systemic oxygen at 10L/min has shown immediate improvement in terms of ERG b-wave amplitudes and central retinal thickness, in eyes with severe DMI. Systemic oxygen may help DMI through a number of mechanisms, namely by increasing the oxygen gradient between the blood and retina, reducing VEGF production, and by vasoconstriction, that results in less cystoid edema and ischemia. The HORNBILL study (NCT04424290) is a RCT that is investigating BI 764524, a compound injected intraocularly, as a possible treatment for DMI. The trial is currently undergoing enrollment.
Diabetic Macular Edema with Diabetic Macular Ischemia – Controversies and Response to Therapy
Anti-VEGF therapy for DME is not a contraindication in the setting of DMI. In theory, there may be a risk in using anti-VEGF on an eye with concurrent DMI and DME, as it may further worsen non-perfusion. However, real-world evidence suggests that DMI may remain stable despite the recurrent use of anti-VEGF medication, and long-term decrease in the capillary bed density is likely attributed to the disease course’s natural history. Despite this, extra caution must be taken with patients with the most severe levels of ischemia, or are expected to have frequent long-term therapy, as the available data only looks at relatively short timeframes. OCTA or FA ancillary studies may be recommended for these patients to trend the level of nonperfusion, aside from looking at the structural improvement with DME in SDOCT. Conversely, there are no large-scale randomized control trials showing how anti-VEGF therapy improves DMI, or promotes re-vascularization.
OCTA metrics of macular perfusion can be used a clinical marker to predict response of DME to anti-VEGF treatment. A study by Lee et al. classified eyes with DME into responders and non-responders, depending on whether they had a reduction of more than 50μm in central retinal thickness after three consecutive monthly VEGF injections. Non-responders had significantly more microaneurysms and a larger FAZ area in the deep capillary plexus (p<0.001), compared to responders. The deeper vascular layers may act as an outflow pathway in the removal of excess intra-retinal fluid, with impairment of these structures leading to further cystoid accumulation. Aside from anatomical outcomes, Chung et al. looked at 3 month visual outcomes after at least 1 anti-VEGF injection, compared between an ischemic and non-ischemic cohort. In ischemic eyes the mean VA significantly decreased from ~20/63 to ~20/80, while in the non-ischemic group the mean VA improved from ~20/100 to ~20/80. Moreover, significantly more eyes in the ischemic group experienced ≥1 or ≥3 ETDRS lines of visual loss. These results suggest how considering OCTA metrics can help predict response to anti-VEGF therapy, along with visual prognosis, among eyes with DMI and DME.
Monitoring the status of macular perfusion, especially among eyes expected to get frequent anti-VEGF injections with baseline severe DMI, may be done through FA or OCTA. The etiology of significant vision loss that occurs during the course of treatment should consider DMI, along with more apparent causes such as macular edema, vitreous hemorrhage, and cataract.
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