Basal laminar drusen (Cuticular drusen)

Key points at a glance

Key Points at a Glance

• Basal laminar drusen (cuticular drusen) is a type of age-related macular degeneration spectrum, characterized by the accumulation of numerous small yellow drusen between the retinal pigment epithelium (RPE) basement membrane and Bruch’s membrane.
• It occurs at a younger age (mean 57.9 years) than typical AMD, and 60–92.1% of patients are female. ¹⁾
• Characteristic findings include a “stars-in-the-sky” pattern on fluorescein angiography (FA) and a “saw-tooth” pattern on OCT. ¹⁾
• There is a strong association with CFH gene mutation (p.Tyr402His), and abnormalities in the alternative complement pathway underlie the pathology. ¹⁾
• There is no treatment for drusen themselves; early detection and appropriate treatment of complications (choroidal neovascularization, geographic atrophy) are key.
• In younger patients, renal diseases such as membranoproliferative glomerulonephritis (MPGN) may coexist, and systemic evaluation may be necessary. ¹⁾

1. What is Basal Laminar Drusen (Cuticular Drusen)?

Basal laminar drusen (BLD) is a disease concept first described by Gass in 1977 as numerous small yellow drusen scattered in the fundus. The “stars-in-the-sky” pattern on fluorescein angiography (FA) is characteristic. ¹⁾

Initially named “basal laminar drusen” as nodular thickening of the RPE basement membrane, subsequent research revealed that deposits occur between the RPE basement membrane and the inner collagenous layer of Bruch’s membrane, i.e., the same location as typical soft drusen. Therefore, the term “cuticular drusen” is now recommended. ¹⁾

Although it belongs to the age-related macular degeneration (AMD) spectrum, it has the following features distinct from typical AMD:

• Age of onset: Relatively young, mean 57.9 ± 13.4 years
• Sex difference: 60–92.1% of patients are female. The probability of being female is about 5 times that of typical AMD. ¹⁾
• Drusen size: Small, uniform drusen 50–75 μm in diameter. ¹⁾
• Distribution: May extend from the posterior pole to the periphery and around the optic disc.

Q Are basal laminar drusen and age-related macular degeneration the same disease?

A

Although it is part of the age-related macular degeneration spectrum, it has unique features such as relatively younger age of onset, female predominance, characteristic “stars-in-the-sky” and “saw-tooth” imaging findings, and strong association with CFH gene mutations. It is also considered a precursor lesion of age-related macular degeneration and may progress to macular complications during long-term follow-up. ¹⁾

2. Main symptoms and clinical findings

Basal Laminar Drusen image

Egle Preiksaitiene; Viktorija Gurskytė; Violeta Mikštienė; Rasa Strupaitė-Šileikienė; Ramūnas Dzindzalieta; Gunda Petraitytė. Evidence for the Pathogenicity of a CFH Variant in a Multigenerational Family with Cuticular Drusen. Medicina (Kaunas). 2025 Sep 11; 61(9):1649 Figure 2. PMCID: PMC12472062. License: CC BY.

Fundus photographs of the proband’s right eye (A) and left eye (B) show numerous small, hard, yellow drusen in the posterior poles.

Subjective symptoms

In the early stages, subjective symptoms are scarce, and most patients remain asymptomatic until later in life. Even if drusen are present in the macula, there are no symptoms unless the outer retinal layers are damaged.

If drusen persist for a long time, RPE dysfunction leads to outer retinal damage. When the fovea is involved, the following symptoms appear.

• Vision loss: due to foveal outer retinal damage or complications (choroidal neovascularization, geographic atrophy)
• Metamorphopsia (distortion): when choroidal neovascularization (CNV) or vitelliform lesions are present
• Central scotoma: appears in advanced cases of geographic atrophy (GA)

Clinical findings

On dilated fundus examination, numerous small yellow drusen are observed throughout the retina. They are recognized as multiple hard, elevated yellowish-white drusen beneath the RPE.

The clinical phenotype is classified into three types. ¹⁾

Phenotype 1

Distribution: Type concentrated in the macular area.

Complication risk: Lowest among the three types, with a 5-year estimated incidence of GA of 12.9%.

Phenotype 2

Distribution: Type scattered in the posterior pole, extending to the periphery and nasal side.

Complication risk: 5-year estimated incidence of GA is 38.7%. MNV risk is also high.

Phenotype 3

Distribution: Type with mixed large drusen (>200 μm).

Complication risk: Highest, with a 5-year estimated incidence of GA of 43.6%.

Main clinical findings are shown below.

• Presence of large drusen (>200 μm): Found in 25–59.3% of cases, and in those aged 60 years or older, it is accompanied by pigmentary abnormalities¹⁾
• Extension to the peripapillary area: Observed in 63.3–75.3% of cases¹⁾
• Pigmentary RPE changes: Most common associated finding (47.5%)
• OCT findings: Triangular elevation of the RPE-BL, characteristic “saw-tooth” pattern¹⁾

On OCT, it is classified into three types.¹⁾

• Type 1 (33%): Shallow RPE-BL elevation
• Type 2 (49%): Serrated pattern (most typical)
• Type 3 (18%): Mound pattern

3. Causes and Risk Factors

The etiology of basal laminar drusen is not fully understood. Currently identified risk factors are listed below.

Genetic Factors

• CFH gene p.Tyr402His variant: The strongest association has been confirmed. The histidine allele frequency is 70% in patients with cuticular drusen and age-related macular degeneration, higher than in typical age-related macular degeneration (55%)¹⁾
• Rare variants of the CFH gene: Identified in 8.8% of patients. p.Arg1210Cys is presumed to be specific to cuticular drusen¹⁾
• FBLN5 gene mutations: Association has been reported¹⁾
• Common high-risk SNPs for age-related macular degeneration: Associated with CFH, ARMS2, CFB, C2, C3, APOE¹⁾

Sex Differences and Family History

• 60–92.1% of patients are female, and being female is an independent risk factor¹⁾
• 44–53% of BLD patients have a family history of age-related macular degeneration

Association with Systemic Diseases

• MPGN (membranoproliferative glomerulonephritis) type II: Abnormalities in the alternative complement pathway cause similar deposits in both the eye and kidney. All long-term MPGN patients (>16 months) show drusen-like deposits¹⁾
• C3 glomerulonephritis: Similar ocular findings have been reported¹⁾
• Cuticular drusen are observed in 80% of patients with dense deposit disease.

Prevention and Daily Care

• Even if there is no change in vision, have regular eye exams from a young age (in your 50s).
• If there is a family history of AMD or basal laminar drusen, early ophthalmologic follow-up is especially important.
• If you have a diagnosis of kidney disease (such as MPGN), we recommend also having an eye examination.
• Self-monitoring with an Amsler chart at home is useful for early detection of complications.

Q Why is it related to kidney disease?

A

This is because abnormalities in the alternative complement pathway due to CFH gene mutations cause similar deposits in both the eye (between the RPE and Bruch’s membrane) and the kidney (glomerular basement membrane). Especially in young patients (ages 5–30), screening for MPGN and atypical hemolytic uremic syndrome (aHUS) is recommended. ¹⁾

4. Diagnosis and Examination Methods

Diagnosis involves combining multiple imaging modalities. Confirmation with at least three of the following is recommended: color fundus photography (CFP), SD-OCT, FA, and fundus autofluorescence (FAF). ¹⁾

Typical findings for each examination are shown below.

Examination Method	Typical Findings	Notes
Color Fundus Photography (CFP)	Numerous small yellow drusen	Scattered from the posterior pole to the periphery
FA	”Starry-sky” pattern	Multiple hyperfluorescent spots in the arteriovenous phase 1)
FAF	Central hypoautofluorescence with hyperautofluorescent rim	Accurate identification rate: 62% in present cases, 100% in absent cases 1)
SD-OCT	Triangular elevation of RPE-BL, “saw-tooth”	Classified into 3 types 1)

ICG angiography (ICGA): Shows early hyperfluorescence, but drusen cannot be detected in about 50% of cases. ¹⁾

Key points for differential diagnosis

• Hard drusen and soft drusen: Differentiated by size, shape, and OCT findings. Hard drusen are uniform with distinct margins, while soft drusen are larger with indistinct margins ¹⁾
• Reticular pseudodrusen: Distribution pattern on OCT and FAF is different
• Autosomal dominant drusen: Differentiated by family history and genetic testing
• Pattern macular dystrophy and Best disease: Electrophysiological and genetic testing are useful
• Differentiation from pigment epithelial detachment (PED): On OCT, low reflectivity inside the elevated RPE indicates PED; high reflectivity indicates drusen.

5. Standard Treatment

No established treatment exists to eliminate drusen themselves. Isolated basal laminar drusen do not require treatment; regular follow-up is the standard.

The following complication rates have been reported. ¹⁾

• Choroidal neovascularization (MNV/CNV): Detected in 12.5%; 76.7% are type 1 MNV. Higher risk in phenotypes 2 and 3.
• Geographic atrophy (GA): 18.5–25%; occurs in 9.2% even in those aged 60 or younger.
• Vitelliform lesions: 24.2% in Caucasians, 1.2% in Asians; 30% associated with MNV.

Treatment strategies according to complications are shown below.

When CNV is present

Intravitreal anti-VEGF injection: First-line treatment. Use ranibizumab, aflibercept, brolucizumab, etc.

Photodynamic therapy (PDT): Considered when anti-VEGF is ineffective or contraindicated.

When GA is present

No effective treatment: No established method to halt progression.

Continued observation: Regular examinations to detect CNV early.

Vitelliform lesions

Observation: May regress spontaneously.

Cases with CNV: Consider anti-VEGF therapy.

About supplements

The efficacy of AREDS (Age-Related Eye Disease Study) supplements for patients with basal laminar drusen has not been established. Common AREDS formulations include Ocuvite PreserVision 2 (3 tablets, 3 times daily) and Sante Lutax 20+ Vitamin & Mineral (3 tablets, 3 times daily).

Self-monitoring

Daily monitoring with an Amsler chart can detect early changes in metamorphopsia and central scotoma.

Precautions in treatment

• Since there is no treatment for drusen themselves, early detection of complications (choroidal neovascularization, GA) is most important.
• MNV is particularly high risk in Phenotypes 2 and 3; consider shortening observation intervals for these phenotypes. ¹⁾
• GA occurs in 9.2% of younger patients (≤60 years), so age should not be a reason for complacency. ¹⁾
• In young-onset cases (5–30 years), screening for MPGN and aHUS is also recommended.

Q Is there a treatment?

A

Currently, there is no treatment to eliminate drusen themselves. If CNV is present, intravitreal anti-VEGF injection or photodynamic therapy (PDT) may be indicated. There is no established treatment for GA, and continuous observation is important. See “Standard treatment” section for details.

6. Pathophysiology and detailed pathogenesis

Basal laminar drusen are polymorphous material that accumulates between the RPE basement membrane and the inner collagenous layer of Bruch’s membrane. Their components include membranous debris, unesterified cholesterol, and complement.

Formation Mechanism

RPE is responsible for lipoprotein excretion, but its metabolic turnover deteriorates with age. Degenerated extracellular matrix accumulates, forming the basis of drusen. Overactivation of the complement cascade due to CFH gene mutations (especially Tyr402His) accelerates this process. ¹⁾

Drusen Life Cycle

Cuticular drusen are dynamic and undergo cycles of growth, fusion, and regression. ¹⁾

• Growth/Fusion Phase: Individual drusen enlarge and fuse with adjacent drusen
• Regression Phase: Accumulation of RPE abnormalities leads to drusen regression → RPE atrophy → geographic atrophy
• Neovascularization: Disruption of Bruch’s membrane triggers invasion of new blood vessels from the choroid (CNV formation)

Course of Vitelliform Lesions

Vitelliform lesions progress in the following order. ¹⁾

1. Formation of vitelliform material
2. Increased choroidal vascular hyperpermeability
3. RPE atrophy
4. Choroidal thinning

Q Why does it also occur in young people?

A

Carriers of rare CFH gene variants (e.g., p.Arg1210Cys) tend to develop the disease at a younger age. Chronic overactivation of the alternative complement pathway due to CFH mutations is thought to cause drusen formation earlier than in typical AMD. ¹⁾

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7. Latest Research and Future Prospects (Investigational Stage)

For Patients: Please Read Carefully

The following content 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.

Therapies Targeting the Complement Pathway

Since abnormalities in the alternative complement pathway due to CFH gene mutations form the pathological basis, compounds targeting the complement pathway are being actively researched. Because systemic administration carries a high risk of side effects, local (intraocular) administration is attracting attention as a promising approach.

Prognostic Prediction Using Multimodal Imaging

Advances in multimodal imaging are enabling early identification of patients at high risk for complications. ¹⁾ Phenotype classification (1–3) is useful for prognosis prediction, and Phenotypes 2 and 3, as high-risk groups for GA and MNV, require particularly careful follow-up. ¹⁾

Potential for Personalized Medicine

Advances in genetic analysis are expected to enable personalized medicine based on variants in AMD-related genes, including the CFH gene. In particular, carriers of rare variants (e.g., p.Arg1210Cys) may become targets for early screening and intervention.

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8. References

1. Fragiotta S, Fernandez-Avellaneda P, Breazzano MP, Scuderi G. Clinical manifestations of cuticular drusen: current perspectives. Clin Ophthalmol. 2021;15:3877-3887.
2. van de Ven JP, Boon CJ, Smailhodzic D, Lechanteur YT, den Hollander AI, Hoyng CB, et al. Short-term changes of Basal laminar drusen on spectral-domain optical coherence tomography. Am J Ophthalmol. 2012;154(3):560-7. PMID: 22626619.
3. Russell SR, Mullins RF, Schneider BL, Hageman GS. Location, substructure, and composition of basal laminar drusen compared with drusen associated with aging and age-related macular degeneration. Am J Ophthalmol. 2000;129(2):205-14. PMID: 10682974.