Diabetic Macular Ischemia

Key Points at a Glance

Highlights of This Disease

• Diabetic macular ischemia (DMI) is a condition in which the foveal avascular zone (FAZ) enlarges due to capillary occlusion and loss in the macula.
• In a study of 488 cases of diabetic retinopathy, moderate to severe DMI was found in 16.6%.
• In diabetic patients with poor vision despite the absence of diabetic macular edema (DME), DMI should be suspected.
• Fluorescein angiography (FA) is the gold standard for diagnosis, but non-invasive OCT angiography (OCTA) is widely used as a complementary test.
• There is currently no established specific treatment for DMI; systemic management (blood glucose, blood pressure, lipids) is fundamental.
• Combined adaptive optics OCT (AO-OCT) and microperimetry have shown that photoreceptor density decreases by approximately 40% in areas of deep capillary plexus (DCP) nonperfusion. ¹⁾

1. What Is Diabetic Macular Ischemia?

Diabetic macular ischemia (DMI) is a condition in diabetic patients where retinal capillaries in the macula become occluded, atrophied, and lost, with narrowing and occlusion of precapillary arterioles. It is visualized as enlargement and irregularity of the foveal avascular zone (FAZ) and expansion of discontinuous avascular areas in the macula on fluorescein angiography (FA) or optical coherence tomography angiography (OCTA).

Historically, Norman Ashton first described in detail the involvement of arteries and capillaries in diabetic retinopathy through postmortem studies using peripheral iris synechiae staining and India ink injection. Pathologically, the process involves hyaline degeneration of terminal arterioles and precapillary vessels → luminal occlusion → loss of arteriolar and capillary beds → formation of venous neovascularization.

Diabetic maculopathy is classified into three types: macular edema, ischemic maculopathy, and retinal pigment epitheliopathy; DMI corresponds to ischemic maculopathy.

Prevalence is closely related to the severity of diabetic retinopathy.

DMI Severity	Incidence
None	39.7%
Suspected	18.4%
Mild	25.2%
Moderate	11.0%
Severe	5.6%

DMI occurs in 29.4% of CSME (clinically significant macular edema) cases, of which 19.4% are moderate to severe. DMI is also found in 77.2% of proliferative diabetic retinopathy (PDR) and 59.7% of severe non-proliferative diabetic retinopathy (NPDR) cases.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

• Decreased vision: Suspect DMI when visual acuity is poor despite the absence of foveal-involving DME.
• Blurred vision: Overall unclear vision.
• Central scotoma: Defect in central visual field
• Visual field defect: Localized visual field loss corresponding to ischemic area
• Progressive or stable vision loss: Common in patients with advanced DR history

Clinical Findings

DMI findings are sometimes characterized as a “featureless retina.” The foveal reflex becomes poor, and hemorrhages, microaneurysms, exudates, soft exudates, and neovascularization disappear or become mild.

Subjective Symptoms

Vision loss: Poor vision even without DME.

Blurred vision/central scotoma: Functional decline due to macular ischemia.

Visual field defect: Localized defect corresponding to ischemic area.

Clinical Findings

Featureless retina: Poor foveal reflex, disappearance or reduction of hemorrhages and exudates.

Ghost vessels: Residual shadows of capillaries that have lost perfusion.

Arteriolar narrowing: In moderate to severe DMI, mean arteriolar diameter is narrowed.

Functional Tests

Microperimetry: Retinal sensitivity is markedly reduced in DCP non-perfusion areas. ¹⁾

AO-OCT: In DCP non-perfusion areas, photoreceptor signal density (IS/OS, COST) is reduced by approximately 40%. ¹⁾

Regarding the correlation between DMI severity and visual acuity, significant visual acuity reduction is observed in moderate to severe DMI. The VA-FAZ correlation has been reported as R² = 0.41–0.51, and papillo-macular ischemia is independently associated with visual acuity reduction.

Datlinger et al. (2021) used AO-OCT and microperimetry to show that in DCP non-perfusion areas, photoreceptor signal density (IS/OS and COST) decreased by approximately 40%, and retinal sensitivity in the same area was also markedly reduced. ¹⁾

Q Does diabetic macular ischemia always cause vision loss?

A

Mild DMI may not have a significant impact on visual acuity. In moderate to severe cases, a significant correlation with visual acuity reduction is observed (VA-FAZ correlation R² = 0.41–0.51), and papillo-macular ischemia is also independently associated with visual acuity reduction. If visual acuity is poor despite the absence of DME, evaluation of DMI using tests described in the “Diagnosis and Testing Methods” section is important.

3. Causes and Risk Factors

Risk factors for DMI reflect those for diabetic retinopathy in general.

• Duration of DM: Longer disease duration increases DMI risk
• HbA1c (glycemic control): Persistent hyperglycemia promotes capillary damage
• Hypertension: Impairs regulation of retinal blood flow
• Dyslipidemia: Promotes arteriosclerosis of retinal vessels
• Age and ethnicity: Higher risk in older adults and certain ethnic groups (e.g., Asian, African descent)
• Systemic factors such as anemia and kidney disease may promote peripheral ischemia

The presence of DMI is associated with increased severity of DME and DR. Medical management (control of blood glucose, blood pressure, and lipids) is effective in slowing the progression of retinopathy.

Notably, spontaneous reperfusion of capillary non-perfusion areas (NPA) has been reported in a case with improved glycemic control (HbA1c from 6.1% to 5.6%). ²⁾

Prevention and Daily Care

• Keep your blood glucose (HbA1c) within target range. Good blood glucose control slows the progression of retinopathy.
• Managing blood pressure and lipids is also important to slow retinopathy progression. Continue systemic management in collaboration with your internist or diabetologist.
• Once diagnosed with diabetes, have regular eye exams (dilated fundus examination) even if you have no symptoms. Early detection is crucial.

4. Diagnosis and Examination Methods

Diabetic Macular Ischemia image

Julien Gozlan; Pierre Ingrand; Olivier Lichtwitz; Agathe Cazet-Supervielle; Léa Benoudis; Michele Boissonnot; Samy Hadjadj; Nicolas Leveziel. Retinal microvascular alterations related to diabetes assessed by optical coherence tomography angiography: A cross-sectional analysis. Medicine (Baltimore). 2017 Apr 14; 96(15):e6427. Figure 1. PMCID: PMC5403069. License: CC BY.

Optical coherence tomography angiography superficial capillary scan of a right eye with moderate nonproliferative diabetic maculopathy. The foveal avascular zone is enlarged, and perifoveal capillary dropout is visible around the central macula. The paired panels outline the avascular zone and adjacent nonperfused areas.

Fluorescein Angiography (FA)

FA is the gold standard for diagnosing DMI.

• FA findings: Enlargement of the FAZ (large hypofluorescent patches), capillary dilation, and widening of intercapillary spaces.
• Normal FAZ diameter: Average 0.53–0.73 mm. In diabetic eyes, average 0.79 mm (range 0.66–0.91 mm).
• Diagnostic threshold: Clinically, an FAZ diameter >0.5 mm suggests DMI.

Disadvantages of FA include invasiveness (intravenous contrast injection), risk of complications (mortality risk about 1 in 200,000), and a procedure time of 20 minutes or more.

OCTA (Optical Coherence Tomography Angiography)

OCTA is a non-invasive, high-resolution examination that allows layer-specific analysis of the SCP (superficial capillary plexus), DCP (deep capillary plexus), and CC (choriocapillaris).

• Advantages: FAZ boundaries can be visualized without dye leakage. Non-perfusion areas (NPA) can be detected more extensively than with FA ²⁾
• Disadvantages: Artifacts, detection limits at low blood flow velocities
• NPA classification: Two types of NPA exist: (1) NPA with retinal thinning (detectable by FFA), (2) NPA without retinal thinning (detectable only by OCTA) ²⁾
• OCTA macular nonperfusion quantification correlates with DR severity and can detect preclinical microvascular changes ³⁾

OCT and AO-OCT

• OCT: Thinning or loss of the inner retinal layers at the fovea is associated with visual acuity loss ³⁾
• AO-OCT (adaptive optics-OCT): Enables three-dimensional visualization of individual cone photoreceptors, achieving DMI assessment at the photoreceptor level ¹⁾

A comparison of the characteristics of FA and OCTA is shown below.

Feature	FA	OCTA
Invasiveness	Yes	No
Layer-specific analysis	Not possible	Possible
NPA detection range	Limited	Extensive

FA

Gold standard: Visualizes FAZ enlargement and capillary dropout.

Invasive: Requires intravenous contrast injection. Mortality risk approximately 1 in 200,000.

Time required: Takes 20 minutes or more.

OCTA

Non-invasive, high resolution: Enables layer-specific analysis of SCP/DCP/CC.

NPA quantification: Correlates with DR severity. Also detects preclinical changes. ³⁾

Two types of NPA detection: Detection range differs from FA depending on the presence or absence of thinning. ²⁾

Q Which is better for DMI diagnosis, OCTA or FA?

A

FA is the gold standard but invasive. OCTA is non-invasive and has the advantage of detecting more extensive NPA than FA. ²⁾ In particular, early NPA without retinal thinning (NPA without thinning) can be detected only by OCTA. The characteristics of both are complementary, and it is desirable to use them appropriately depending on the clinical situation.

5. Standard Treatment

Direct Treatment for DMI

Currently, there is no established specific treatment for DMI. There is no direct treatment for macular ischemia without DME, and systemic management is fundamental.

Good glycemic control has been reported to potentially contribute to natural reperfusion of NPAs, ²⁾ and medical management (blood glucose, blood pressure, lipids) is the basic strategy for suppressing retinopathy progression.

In stages beyond severe NPDR, consideration of PRP (panretinal photocoagulation) or anti-VEGF therapy is recommended. ³⁾

Treatment when DME is present

When DMI is complicated by DME, the following treatments are performed.

• Anti-VEGF drugs (first-line): Ranibizumab (Lucentis) 0.5 mg/0.05 mL per injection, aflibercept (Eylea) 2 mg/0.05 mL per injection. The effect is temporary and frequent injections may be required.
• Intravitreal triamcinolone: MacuAid 4 mg/0.1 mL per injection. There is a risk of cataract progression and increased intraocular pressure.
• Focal/grid photocoagulation: Adjunctive treatment for DME.

Precautions in treatment

• No specific treatment for DMI has been established. Accurate differentiation of whether vision loss is due to DMI or DME is essential for determining treatment strategy.
• Anti-VEGF drugs treat DME but do not improve ischemia itself. The risk of infection and patient burden due to frequent injections must also be considered.
• When using triamcinolone, attention must be paid to cataract progression and increased intraocular pressure, and regular follow-up is essential.

Q Can diabetic macular ischemia be improved with treatment?

A

Currently, there is no established specific treatment for DMI. Systemic management (blood glucose, blood pressure, lipids) is fundamental, and there are case reports of natural reperfusion of NPAs with good glycemic control. ²⁾ When DME is present, edema is treated with anti-VEGF drugs, etc., but ischemia itself cannot be directly improved.

6. Pathophysiology and detailed pathogenesis

Initial changes: damage to pericytes and endothelial cells

Pericyte loss and endothelial cell damage are the earliest signs of vascular changes in DR.

• Pericytes: regulate vascular tone and produce basement membrane and extracellular matrix components
• Endothelial cells: form the blood-retinal barrier via tight junctions

Progressive thickening of the capillary basement membrane due to deposition of type III and IV collagen leads to luminal narrowing. Leukostasis also occurs, and abnormal endothelial cells exacerbate vascular occlusion.

Progressive occlusion of the capillary network

Reduced oxygen and micronutrient supply stimulates VEGF expression, leading to progressive capillary atrophy → widening of intercapillary spaces → prolonged hypoxia → photoreceptor damage. As DR progresses, venous abnormalities, IRMA, severe hemorrhage, and exudation appear. ³⁾

Effects on macular vascular layers and photoreceptors

The macula has three retinal vascular layers (SCP, ICP/MCP, DCP). The DCP contributes 10–15% of oxygen supply to photoreceptors, ¹⁾ and its occlusion directly leads to photoreceptor damage.

Müller cells (MC) function as an energy source by supplying lactate to photoreceptors under perfusion impairment. ¹⁾ When MC damage occurs, in addition to cone, rod, and MC dysfunction, patchy loss of photoreceptor outer segments and capillary dropout are colocalized. ¹⁾

Classification of ischemic patterns

Ischemic patterns are classified into the following four types (Takashi et al. classification).

Ischemia type	Frequency
Peripheral type	2.6%
Mid-peripheral type	61.2%
Central type	26.3%
Extensive type	9.9%

Q Why are photoreceptors damaged?

A

Non-perfusion of the deep capillary plexus (DCP) reduces oxygen supply to photoreceptors (DCP contributes 10–15% of photoreceptor oxygen supply). ¹⁾ Müller cell damage also impairs energy supply to photoreceptors. Studies using AO-OCT have confirmed that photoreceptor signal density (IS/OS and COST) decreases by approximately 40% in areas of DCP non-perfusion. ¹⁾

---

7. Latest Research and Future Perspectives (Investigational Reports)

For patients: Please read carefully

The following information is currently under investigation or in clinical trials and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Advanced Imaging Assessment

Datlinger et al. (2021) demonstrated that the combination of AO-OCT and OCTA enables DMI assessment at the single cone photoreceptor level. They stated that an integrated research approach combining microperimetry and OCTA contributes to understanding the time course of DMI, and suggested that these advanced imaging parameters may serve as biomarkers in future therapeutic studies. ¹⁾

Capillary Occlusion Reversibility and Spontaneous Reperfusion

Conventionally, capillary occlusion was considered irreversible, but cases of spontaneous reperfusion have been reported.

Hou et al. (2022) observed spontaneous reperfusion of NPAs in diabetic patients whose HbA1c improved from 6.1% to 5.6%. They recorded the process of IRMA invading the NPA and forming new capillary networks over time using OCTA. ²⁾

This report suggests that NPAs may have two distinct characteristics. ²⁾

• NPA with thinning (late change): tends to have slower reperfusion
• NPA without thinning (early change): tends to reperfuse within 2 months; may represent a “window” for therapeutic intervention

Quantitative Biomarkers and Prognosis Prediction

In a 1-year OCTA follow-up study, the odds ratio (OR) for baseline nonperfusion and DR progression was 8.73, and the OR for deep nonperfusion and treatment intervention was 3.39, suggesting that OCTA nonperfusion indices may serve as prognostic biomarkers. The baseline FAZ area tends to expand by 5–10% per year in eyes with known DMI. Research on the application of AI to OCTA image analysis is also ongoing. ³⁾

Q Can occluded capillaries reopen?

A

Although rare, spontaneous reperfusion has been reported. Hou et al. (2022) reported the process of IRMA invading the NPA region and forming new capillary networks. ²⁾ In particular, NPAs without thinning (early changes) tend to reperfuse within 2 months. Good glycemic control may also promote reperfusion.

---

8. References

1. Datlinger F, Georgi T, Stegmann H, et al. Assessment of detailed photoreceptor structure and retinal sensitivity in diabetic macular ischemia using adaptive optics-OCT and microperimetry. Invest Ophthalmol Vis Sci. 2021;62(13):1.

2. Hou S, Chen L, Shan K, et al. Spontaneous retinal reperfusion of capillary nonperfusion areas in diabetic retinopathy. Case Rep Ophthalmol. 2022;13:818-824.

3. American Academy of Ophthalmology Retina/Vitreous Panel. Diabetic Retinopathy Preferred Practice Pattern. Ophthalmology. 2024.