Dot type
Morphology: Small, round to oval yellowish-white dots scattered.
Distribution: Irregularly arranged around the macula. Most common form.
OCT findings: Small hyperreflective deposits on the surface of the RPE.
Reticular Drusen
Key Points at a Glance
Section titled “Key Points at a Glance”1. What is Reticular Drusen?
Section titled “1. What is Reticular Drusen?”Reticular drusen (also called reticular pseudodrusen [RPD] or subretinal drusenoid deposits [SDD]) are yellowish-white deposits that accumulate on the inner surface of the retinal pigment epithelium (RPE), i.e., in the subretinal space. On fundus photographs, they appear as a yellowish-white reticular or dot-like pattern.
First described in 1990, SDD are located in the subretinal space on the surface of the RPE, in contrast to typical drusen, which lie between Bruch’s membrane and the RPE (sub-RPE space). In terms of composition, they lack the esterified cholesterol and calcified components found in typical soft drusen and are hydrophobic deposits rich in neutral lipids.
RPD is observed in approximately 29% of patients with age-related macular degeneration, and it is distributed bilaterally and symmetrically. It is particularly strongly associated with atrophic age-related macular degeneration (geographic atrophy; GA) and retinal pigment epithelial detachment (RAP; retinal angiomatous proliferation), and the risk of progression to GA and CNV (choroidal neovascularization) is reported to be about twice as high compared to soft drusen 2).
Not limited to age-related macular degeneration, associations with systemic diseases that cause choroidal ischemia have also been reported. SDD has been shown to appear in preeclampsia (prevalence of SDD 32.7%) and malignant hypertension (23.4%) 2).
SDD is a dynamic structure that can regress or disappear with changes in disease status. Cases have been reported where SDD disappeared due to dissolution by subretinal fluid (SRF) and phagocytosis by macrophages 1), and cases where it markedly shrank with vitamin A supplementation 3).
Q
What is the difference between ordinary drusen and reticular drusen?
A
While typical soft drusen are located between Bruch’s membrane and the RPE (sub-RPE space), SDD are present in the subretinal space on the surface of the RPE. Their composition also differs; SDD are hydrophobic deposits rich in neutral lipids, lacking esterified cholesterol and calcification. The risk of progression to age-related macular degeneration is about twice that of soft drusen2).
2. Main symptoms and clinical findings
Section titled “2. Main symptoms and clinical findings”Subjective symptoms
Section titled “Subjective symptoms”The subjective symptoms of SDD vary depending on the extent and stage of progression of the lesions.
- Dark adaptation disorder: Due to its predilection for the superior macula (area with highest rod density), decreased vision in dim light and delayed adaptation often appear as initial symptoms3).
- Visual acuity loss: Occurs with progression to GA or CNV. It often remains mild until the fovea is affected.
- Visual field defect: Absolute scotoma appears as GA enlarges.
- Metamorphopsia: Occurs when CNV is present.
Clinical Findings
Section titled “Clinical Findings”Fundus examination reveals yellowish-white bodies distributed in a reticular, punctate, or ribbon-like pattern. They often spread from the superior and superotemporal perifoveal area to the mid-periphery.
SDD morphology is classified into the following three types.
Ribbon type
Morphology: A pattern of punctate lesions arranged in a linear or arciform configuration.
Distribution: May be arranged along the vascular arcades.
OCT findings: Continuous hyperreflective band along the RPE surface.
Peripheral type
Morphology: Pale reticular lesions extending from the mid-periphery to the periphery.
Distribution: Easily overlooked on routine fundus examination.
OCT findings: Flat deposits on the RPE. Confirmed by wide-field imaging.
According to the Zweifel classification by OCT, SDD is divided into the following three types.
| Type | OCT findings | Characteristics |
|---|---|---|
| Type 1 | Granular hyperreflectivity on RPE surface | Earliest stage. Difficult to confirm with FAF/NIR |
| Type 2 | Triangular hat-shaped protrusion on RPE | Typical finding. Can be confirmed with each modality |
| Type 3 | Spherical hyperreflective body on RPE | Largest. Also called vertebral or cone-shaped |
In SDD cases complicated by HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), scattered black dot-like lesions (Elschnig spots) were observed simultaneously 2).
Q
Can reticular drusen be found on a routine fundus examination?
A
They are easily underrecognized on standard color fundus photography 4). Detection accuracy is maximized by combining multimodal imaging with FAF (fundus autofluorescence), NIR (near-infrared reflectance), and SD-OCT. In particular, SDD is clearly visualized as hyporeflective spots on NIR.
3. Causes and Risk Factors
Section titled “3. Causes and Risk Factors”The main underlying diseases and risk factors for SDD are shown below.
- Aging and age-related macular degeneration: The most common background. It occurs in about 29% of patients with age-related macular degeneration. Age-related decline in RPE function is involved.
- Choriocapillaris ischemia: The central pathology of SDD. Reduced choroidal blood flow promotes RPE metabolic dysfunction and SDD formation 2, 3).
- HELLP syndrome and preeclampsia: Choroidal ischemia due to hypertensive disorders of pregnancy. The prevalence of SDD in preeclampsia was reported as 32.7%, and in malignant hypertension as 23.4% 2). A case of HELLP syndrome in a 17-year-old primipara with SDD and Elschnig spots has been reported 2).
- Vitamin A deficiency: In malnourished patients with serum vitamin A <2.5 μg/dL, SDD and ellipsoid zone (EZ) disruption are observed, which markedly improve after supplementation 3). This is thought to involve impaired lipid recycling between RPE and Müller cells 3).
- Risk of age-related macular degeneration progression: In the 2024 updated AREDS, RPD was incorporated as one of the risk factors. The 5-year progression rate of age-related macular degeneration in RPD cases with four risk factors reaches 72%, significantly exceeding the 50% rate in cases without RPD 4).
4. Diagnosis and Testing Methods
Section titled “4. Diagnosis and Testing Methods”SDD is easily underrecognized on routine fundus examination, and multimodal imaging is key to diagnosis.
Multimodal Imaging
Section titled “Multimodal Imaging”FAF (fundus autofluorescence), NIR (near-infrared reflectance), and SD-OCT are the best for visualizing SDD 4).
FAF
Findings: SDD appears as decreased autofluorescence (hypofluorescent spots).
Features: Useful for assessing the distribution of extensive lesions. Also used for evaluating association with GA.
Limitations: Detection of early type 1 lesions may be difficult.
NIR (Near-Infrared Reflectance)
Findings: SDD is clearly visualized as low-reflective spots.
Features: One of the modalities with the highest detection sensitivity for SDD. Used in combination with FAF.
Advantages: Easily captures changes in the deep RPE layer containing melanin.
SD-OCT
Findings: Triangular hat-shaped or spherical hyperreflective deposits on the RPE surface (subretinal space).
Features: Staging according to Zweifel classification (types 1–3) is possible. Disruption or loss of the ellipsoid zone (EZ) is also assessed.
OCTA findings: May be accompanied by decreased vascular density of the choriocapillaris plate 3).
Comparison with FA and ICGA
Section titled “Comparison with FA and ICGA”Fluorescein angiography (FA) has low sensitivity for detecting SDD and is not recommended as a first-line test. However, FA and ICGA (indocyanine green angiography) are useful for evaluating the presence of CNV.
Differential Diagnosis
Section titled “Differential Diagnosis”OCT is used to differentiate SDD from soft drusen (located in the sub-RPE space), basal laminar deposits (BLD), and outer retinal tubulations (ORT). The key point for differentiation is that SDD is located on the inner surface of the RPE.
For details, refer to the “Pathophysiology” section.
5. Standard Treatment
Section titled “5. Standard Treatment”Currently, there is no established direct treatment for SDD. The goal of treatment is to suppress progression to age-related macular degeneration and preserve vision when CNV is present.
AREDS2 Supplements
Section titled “AREDS2 Supplements”The Japanese clinical guidelines for age-related macular degeneration recommend AREDS2 formulation (vitamin C 500 mg, vitamin E 400 IU, lutein 10 mg, zeaxanthin 2 mg, zinc 80 mg, copper 2 mg) to reduce the risk of intermediate to advanced age-related macular degeneration. Since patients with RPD have many risk factors for progression to age-related macular degeneration, the indication for supplements should be actively evaluated.
Anti-VEGF therapy
Section titled “Anti-VEGF therapy”When CNV (choroidal neovascularization) is present, Japanese clinical guidelines for age-related macular degeneration recommend anti-VEGF drugs (e.g., ranibizumab, aflibercept) as first-line treatment. SDD is strongly associated with RAP, and anti-VEGF therapy is also indicated when RAP is present.
Vitamin A supplementation
Section titled “Vitamin A supplementation”In SDD associated with vitamin A deficiency, a case has been reported in which vitamin A supplementation led to a marked reduction in SDD and reconstitution of the ellipsoid zone (EZ) after 8 months 3). In malnourished patients, checking serum vitamin A levels is important.
Treatment of the underlying disease and spontaneous regression
Section titled “Treatment of the underlying disease and spontaneous regression”In HELLP syndrome and preeclampsia, the condition improves after delivery, and spontaneous regression of SDD may occur. In a previous case, complete resolution over 4 years has been reported 2). Additionally, cases have been reported where SDD resolved or regressed after rhegmatogenous retinal detachment (RRD) surgery due to the presence of subretinal fluid, suggesting that dissolution of neutral lipids by SRF and phagocytosis by macrophages are mechanisms of regression 1).
Q
Is treatment always necessary if reticular drusen are present?
A
Even if SDD is present, direct therapeutic intervention is difficult at stages where no findings of age-related macular degeneration progression such as CNV or GA are observed. The basics are evaluation of AREDS2 supplement indications and regular ophthalmologic follow-up. When CNV is present, anti-VEGF therapy should be initiated early.
6. Pathophysiology and Detailed Pathogenesis
Section titled “6. Pathophysiology and Detailed Pathogenesis”Location and Composition of SDD
Section titled “Location and Composition of SDD”SDD accumulates on the inner surface of the RPE (subretinal space). This is fundamentally different from typical soft drusen, which form between Bruch’s membrane and the RPE (sub-RPE space).
In terms of composition, SDD lacks esterified cholesterol and calcification, and is a hydrophobic deposit rich in neutral lipids 3). This compositional difference leads to distinct imaging findings (hyperreflective foci on OCT) compared to soft drusen.
Choriocapillaris Ischemia Hypothesis
Section titled “Choriocapillaris Ischemia Hypothesis”Reduced blood flow in the choriocapillaris (CC) is considered a major pathology of SDD. Studies using OCTA (optical coherence tomography angiography) have confirmed decreased vascular density in the choriocapillaris in SDD cases 3). The occurrence of SDD in HELLP syndrome, preeclampsia, and malignant hypertension supports that choroidal ischemia is a common mechanism for SDD formation 2).
RPE-Müller Cell Lipid Recycling Impairment Hypothesis
Section titled “RPE-Müller Cell Lipid Recycling Impairment Hypothesis”The predilection of SDD for the superior macula coincides with the region of highest rod photoreceptor density 3). There is a recycling pathway in which lipid components of rod outer segments (mainly DHA; docosahexaenoic acid) are processed by the RPE and then resupplied to rods via Müller cells. It has been hypothesized that when this pathway is impaired due to vitamin A deficiency or reduced RPE function, lipids accumulate on the RPE surface, forming SDD 3).
Regression Mechanism
Section titled “Regression Mechanism”SDD is a dynamic structure and can regress through the following mechanisms.
A case was reported in which a subretinal vertical void formed after rhegmatogenous retinal detachment (RRD), and SDD disappeared within 3 months 1). It is inferred that lipid-soluble components in the SRF dissolved the neutral lipids of SDD, and macrophages phagocytosed the residue, leading to disappearance. Near-complete disappearance was confirmed on FAF after 2 years 1).
In regression due to vitamin A supplementation, restoration of the lipid recycling pathway between RPE and Müller cells is thought to have contributed to the disappearance of SDD 3).
7. Latest Research and Future Prospects (Research-Stage Reports)
Section titled “7. Latest Research and Future Prospects (Research-Stage Reports)”AREDS2024: Incorporation into Risk Stratification of RPD
Section titled “AREDS2024: Incorporation into Risk Stratification of RPD”In the AREDS2024 update, RPD was clearly established as an independent risk factor for the progression of age-related macular degeneration 4).
The AREDS2024 analysis showed that in patients with RPD and four risk factors, the 5-year progression rate of age-related macular degeneration reached 72%. This was significantly higher compared to cases without RPD (50%), confirming RPD as an independent risk factor 4). RPD may be underrecognized on routine fundus examination, highlighting the importance of active screening using FAF, NIR, and SD-OCT 4).
This finding is attracting attention as providing a basis for more aggressive monitoring and early intervention in patients with SDD.
SDD Regression after RRD: Significance as an Incidental Treatment Model
Section titled “SDD Regression after RRD: Significance as an Incidental Treatment Model”Forsaa et al. (2023) documented a case of SDD regression after RRD surgery in a 76-year-old man 1). Three months postoperatively, a subretinal vertical void was confirmed on OCT, and SDD disappeared gradually. FAF showed almost complete SDD resolution at two years. This incidental model suggests that SRF may act as a solvent for SDD components (neutral lipids) and is noted as a potential target for future pharmacological approaches.
HELLP syndrome and SDD: report of a young-onset case
Section titled “HELLP syndrome and SDD: report of a young-onset case”Durmaz Engin et al. (2024) reported a case of SDD associated with HELLP syndrome in a 17-year-old primipara 2). OCT showed marked retinal thickening of 438/443 μm with Elschnig spots. Postpartum follow-up confirmed complete resolution at four years, consistent with previous reports. This case demonstrates that relief of choroidal ischemia contributes to SDD regression and that SDD can occur in young individuals.
Vitamin A deficiency and SDD: demonstration of treatment reversibility
Section titled “Vitamin A deficiency and SDD: demonstration of treatment reversibility”Zatreanu et al. (2021) reported SDD with EZ disruption in a 67-year-old patient with serum vitamin A level <2.5 μg/dL 3). Eight months after vitamin A supplementation, SDD markedly decreased and EZ reconstitution was confirmed. OCTA simultaneously showed decreased vascular density in the choriocapillaris. This case provides initial evidence that SDD is potentially reversible, suggesting implications for developing therapies targeting the lipid recycling pathway between RPE and Müller cells.
Q
What direction is future therapeutic development for reticular drusen heading?
A
Current research focuses on three directions: (1) improvement of choriocapillaris blood flow, (2) restoration of the lipid recycling pathway between RPE and Müller cells (e.g., vitamin A), and (3) pharmacological dissolution approaches similar to SRF. All are at the experimental or case report stage and have not been established as standard treatment 1, 3).
8. References
Section titled “8. References”- Forsaa VA, Thomseth VM. Reticular pseudodrusen voids after rhegmatogenous retinal detachment. Case Rep Ophthalmol. 2023;14(1):400-404. doi:10.1159/000531676. PMID: 37901649.
- Durmaz Engin C, Karti O, Kandemir K. Subretinal drusenoid deposits in a patient with HELLP (hemolysis, elevated liver enzymes, low platelet) syndrome. Cureus. 2024;16(1):e52239. doi:10.7759/cureus.52239. PMID: 38352084.
- Zatreanu L, Honavar SG, Heur M. Macular thickness analysis and resolution of subretinal drusenoid deposits with optical coherence tomography in vitamin A deficiency-related retinopathy. Am J Ophthalmol Case Rep. 2021;21:101023. PMID: 33644494.
- American Academy of Ophthalmology. Age-Related Macular Degeneration Preferred Practice Pattern. AAO; 2024.