Hyperreflective Foci (HRF) in Optical Coherence Tomography

Key Points at a Glance

Key Points of This Disease

• Hyperreflective foci (HRF) are small dot-like lesions less than 30 μm observed on OCT images, without posterior shadowing.
• Observed in various diseases such as uveitis, age-related macular degeneration, diabetic retinopathy, and retinal vein occlusion.
• Histologically, it is thought to originate from activated microglial cells, RPE cell migration, macrophage infiltration, and accumulation of lipids and proteins.
• The presence of HRF serves as a biomarker for inflammatory processes and aging, and may indicate disease progression and treatment response.
• Differentiation from hard exudates (with posterior shadowing, confined to the outer plexiform layer) and retinal vessels (over 30 μm) is important.
• In uveitic macular edema, it shows a positive correlation with central foveal thickness and decreases in response to treatment.

1. What are hyperreflective foci in optical coherence tomography?

Hyperreflective foci (HRF) are small, round, dot-shaped hyperreflective lesions observed on spectral-domain (SD) or swept-source (SS) OCT. They were first reported in patients with exudative age-related macular degeneration in 2009 and later confirmed in patients with diabetic macular edema. Since then, research has progressed on their potential as biomarkers of disease progression and treatment response in various retinal diseases.

In ophthalmology, HRF refers to dot-shaped lesions found in the retina, vitreous, or choroid (distinct from hyperreflective foci in other organs)¹⁾. Since their discovery, they have been observed in a wide range of ocular diseases, including age-related macular degeneration, diabetic retinopathy, retinal vein occlusion, retinal dystrophy, and uveitic macular edema¹⁾.

Q Do HRF have the same meaning in all ophthalmic diseases?

A

The origin and significance of HRF vary by disease. In age-related macular degeneration, they serve as markers of disease progression; in DR, as biomarkers of inflammation and ischemia. In uveitis, they may indicate treatment response. A common feature across diseases is that they represent “indicators of inflammatory processes”¹⁾.

2. Main symptoms and clinical findings

Subjective symptoms

HRF itself is not a lesion that causes symptoms; subjective symptoms associated with the underlying disease are prominent.

• Decreased visual acuity: due to macular edema or destruction of retinal structure.
• Metamorphopsia/distortion: when HRF accumulates in the macula.
• Floaters: when associated with uveitis accompanied by vitritis.

Clinical Findings

The morphological characteristics of HRF are as follows.

• Size: Less than 30 μm. Reflectivity similar to the retinal nerve fiber layer (RNFL).
• Posterior shadowing: Generally absent (key differentiating feature from hard exudates).
• Distribution: Scattered throughout the full thickness of the retina; clinically significant within 1500 μm of the fovea.
• Corresponding fundus findings: No visible lesions on ophthalmoscopy.

A comparison with the main differential diagnoses is shown below.

Finding	HRF	Hard exudate	Retinal vessel
Size	<30μm	Various	>30μm
Posterior shadow	None	Present	Present
Main layer	Full thickness	Outer plexiform layer	Inner layer

Choroidal hyperreflective foci (Choroidal HRF; HCF) have recently attracted attention, and it is important to differentiate between normal findings derived from the pigment of ordinary choroidal melanocytes and pathological ones¹⁾.

3. Causes and Risk Factors

The histological correlate of HRF has not been fully elucidated, but several etiologies have been proposed ¹⁾.

• Activated microglial cells: Microglia activated by ischemia/inflammation become amoeboid and enlarged, observed as HRF. They trigger an inflammatory response with upregulation of VEGF.
• RPE cell migration: Occurs due to destruction and migration of retinal pigment epithelium (RPE) cells. More common in patients with fundus pigment changes.
• Macrophage infiltration: Macrophages that have phagocytosed lipids act as precursors of hard exudates.
• Protein/lipid leakage: Protein leakage and lipid accumulation due to breakdown of the blood-ocular barrier.
• Photoreceptor breakdown products: Products generated after disruption of the ellipsoid zone (EZ) and external limiting membrane (ELM).

Association with diseases: In uveitis, inflammatory cytokines such as IL-6 increase; in diabetic retinopathy, hyperglycemia-induced neurodegeneration and microvascular damage induce activated microglia ¹⁾.

Use as a biomarker

Semi-automated and fully automated counting protocols are available for research purposes, but their practical use in daily clinical practice has not progressed. Currently, manual counting is the standard, which is a major limitation.

4. Diagnosis and Examination Methods

HRF is identified by OCT examination. The diagnostic points are as follows.

OCT diagnostic criteria:

• Dot-shaped hyperreflective lesions smaller than 30 μm.
• Reflectivity equivalent to the RNFL.
• No posterior shadowing.
• Can be distributed across all retinal layers (outer, inner, full thickness).

Criteria for clinical significance: Macular HRF within 1500 μm of the fovea has the highest clinical significance.

Distribution characteristics by disease

The distribution and significance of HRF vary by disease.

• Age-related macular degeneration: Distributed in the outer and inner layers. Functions as a disease progression marker.
• Diabetic retinopathy: Distributed across all layers. Correlates with elevated CD14, a macrophage/microglia-specific biomarker¹⁾.
• Uveitic macular edema: Distributed across all layers, showing a positive correlation with foveal retinal thickness. Decreases after treatment.

Q Can hard exudates and HRF be distinguished on OCT?

A

They can be distinguished. Hard exudates are accompanied by posterior shadowing, have irregular borders, are confined to the outer plexiform layer, and can be confirmed as yellow lesions on fundus examination. HRF clearly differs in that they have no posterior shadowing, are less than 30 μm, are distributed across all layers, and have no corresponding fundus lesions.

5. Standard Treatment

HRF itself is not a treatment target; changes in HRF are evaluated through treatment of the underlying disease.

Management of Uveitic Macular Edema

• Steroid therapy: HRF decreases in response to treatment due to suppression of inflammation. After edema resolves, residual HRF often remains in the inner retinal layers.
• Treatment response evaluation: Changes in the number and distribution of HRF can be used as auxiliary indicators of treatment efficacy.

Management of Diabetic Macular Edema

• Although it is established that the number of HRF decreases after treatment with anti-VEGF therapy or steroid implants, their precise role as predictors of treatment response remains unclear.
• A high number of HRF at baseline may be associated with poor response to anti-VEGF therapy, and dexamethasone implants may be beneficial in these patients.

Treatment Considerations

HRF can be used as a reference indicator of treatment response, but currently there is no standardized evaluation method as an imaging biomarker, and it should not be used as a primary criterion for treatment decisions. Treatment decisions should be based primarily on the activity of the underlying disease and changes in visual function.

6. Pathophysiology and Detailed Pathogenesis

The formation of HRF is a complex process, and its high reflectivity varies depending on the specific retinal pathology and disease ¹⁾. Multiple studies have identified common mechanisms across diseases.

Activated Microglial Pathway

When activated by ischemia and inflammation, microglia become hypertrophic and exhibit amoeboid morphological changes. This leads to:

1. Upregulation of VEGF
2. Production of inflammatory cytokines
3. Further microglial activation (feedback loop)

It has been shown that the increase in HRF at baseline correlates with an increase in CD14 (a macrophage/microglia-specific marker).

Relationship with Ellipsoid Zone (EZ) and External Limiting Membrane (ELM) Disruption

After disruption of the EZ and ELM, activated microglia migrate outward, presumably forming hyperreflective choroidal foci (HCF) ¹⁾. This has been confirmed to correlate with foveal atrophy in Stargardt disease.

Mechanisms in Retinal Dystrophy

In retinitis pigmentosa and Stargardt disease, HRF derived from disrupted RPE cells and pigment migration are seen in the inner retinal layers above the atrophic area, and migrate to the outer layers in later stages.

Differences Between Age-Related Macular Degeneration and Diabetic Retinopathy

In age-related macular degeneration, the causes differ between dry and wet types. Dry AMD may involve degenerated photoreceptors and RPE cells, while wet AMD may primarily involve activated microglia phagocytosing lipids ¹⁾. In diabetic retinopathy, hyperglycemia-induced neurodegeneration, microvascular abnormalities, and inflammation act in combination ¹⁾.

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7. Latest Research and Future Perspectives (Research Stage Reports)

For Patients: Please Read Carefully

The following content is currently at the research stage or under clinical trial and is not standard treatment available at general hospitals. This is reference information for professionals regarding future medical developments.

Scoping Review Findings (2025)

Mat Nor et al. (2025) published a scoping review in the Journal of Ophthalmology, examining 42 studies and reporting the following conclusions¹⁾.

There is consensus among researchers that HRF smaller than 30 μm are biomarkers of retinal inflammation across diseases. The size and localization of HRF correspond to disease manifestation. Age-related HRF can be distinguished from age-related macular degeneration by quantity and appearance.

Need for Animal Models and Tissue Studies

It has been pointed out that further studies using animal models and human tissue samples are essential to elucidate the basic pathological mechanisms of HRF¹⁾. Further research is needed to explain cross-disease variability and clarify its association with disease progression.

Choroidal HCF Studies in Vogt-Koyanagi-Harada Disease

In Vogt-Koyanagi-Harada disease, the quantitative relationship between sunset glow fundus (SGF) and HCF is being elucidated. HCF can be quantified using en face OCT and may serve as an indicator of changes in choroidal melanocytes.

Prospects for Automated Counting

Currently, several semi-automated and fully automated counting protocols have been developed for research purposes. If standardization in daily clinical practice is achieved, HRF is expected to be applied as a quantitative biomarker for treatment monitoring.

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8. References

1. Mat Nor MN, Green CR, Squirrell D, Acosta ML. Retinal Hyperreflective Foci Are Biomarkers of Ocular Disease: A Scoping Review With Evidence From Humans and Insights From Animal Models. J Ophthalmol. 2025;2025:9573587.