Early Onset Drusen - Part I

Starry Sky - the classic description of the appearance of cuticular drusen on the early phase of a fluorescein angiogram. Cuticular drusen is a common form of early onset drusen.

This is the first part of a series of articles looking at early onset drusen. Patients with early onset drusen are commonly referred to medical retina specialists, and an accurate diagnosis is crucial to the management of these patients.

Definition

Early onset drusen is defined as the presence of drusen in patients younger than the age of 50. The age of 50 is chose because the presence of drusen or other features suggestive of age related macula degeneration in patients younger than 50 is suggestive of inherited macula dystrophy (Flaxel et al., 2020).

Many of these patients may have a family history of early onset drusen.

Types of early onset drusen

Cuticular drusen

These are small hard drusen that can occur in early adulthood. On colour photographs, they are small yellow lesions with individual druse at 30 um. They are visible on infrared imaging as hyperreflective lesions. On early arteriovenous phase of fluorescein angiogram, they are hyperfluorescent resulting at the typical ‘starry sky’ appearance. Fundus autofluorescent imaging shows that these lesions are hypoautofluorescent with surrounding hyperautofluorescent ring. OCT shows that these lesions are sub-retinal pigment epithelium (RPE), and on histology cuticular drusen are located in the same anatomical plane as hard and soft drusen (Balaratnasingam et al., 2018).

Multimodal imaging of cuticular drusen (A: colour photograph, B: red free, C: fluorescein angiogram, D: autofluorescence, E: OCT), from Balaratnasingam et al., 2018

Over time, drusen resorption, coalescence, and RPE changes can occur. In a cohort of patients with cuticular drusen, adult vitelliform lesions are reported in 24% of patients, neovascularsation in 12.5% (mostly type I, with a few type II cases, and no type III cases), and atrophy in 25% (Balaratnasingam et al., 2018).

There is an association between cuticular drusen and complement factor H variants (Grassi, 2007; Taylor et al., 2019).

Large colloid drusen

This is a newly reported drusen subtype seen in younger patients. The mean age of diagnosis in a cohort of patients with large colloid drusen was 35 years (Guigui et al., 2013). These drusen are dome shaped on OCT, with mean height of 199 um and mean width of 419 um (Guigui et al., 2013). They are hypofluorescent in early phase and hyperfluorescent in late phase on fluorescein angiogram.

Infrared and OCT imaging of large colloid drusen, from Baptista et al., 2020

Large colloid drusen is not associated with pigmentary changes or adult vitelliform lesions. However, there are a few case reports suggesting that geographic atrophy, macula neovascularsation and polypoidal choroidal vasculopathy can complicate large colloid drusen (Carnevali & Querques, 2017; Mathis et al., 2016).  

There is one reported association between loss-of-function complement factor H variants and large colloid drusen (Taylor et al., 2019). Otherwise, little is know about the heritability and the genetic basis of large colloid drusen.

Malattia Leventinese (Familial Dominant Drusen)

Malattia Leventinese, or familial dominant drusen (OMIM 126600), is a rare form of early onset drusen. This was first described in 1925 by Vogt in a cohort of patients in Switzerland (Querques et al., 2013). Patients often have impaired acuity ranging from 6/9 to 6/60, and impaired dark adaptation (Michaelides et al., 2006; Querques et al., 2013). Clinical findings of this condition include early onset round drusenoid deposits in both the macula and parapapillary area (drusen abutting disc is common in this condition, and the absence of drusen abutting disc makes this condition much less likely), with small drusen arranged in a radial pattern temporal to the macula (Querques et al., 2013), though the findings can be variable (Michaelides et al., 2006). Some of these drusen, especially large drusen, are hyperautofluorescent.

The genetic basis of malattia leventinese is well documented. The causative gene is EFEMP1, and the disease is caused by the R345W variant (Stone et al., 1999).