**2. Cuticular Drusen**

Cuticular drusen were first described by Gass in 1977 and consist of a subtype of drusen characterized by being much more numerous than small hard drusen [6]. They frequently coalesce revealing a diffuse appearance. On fluorescein angiography (FA), they are seen as a starry-sky fluorescence pattern that is most evident during the early arteriovenous phase. Some authors suggested that cuticular drusen are often initially visible in the peripheral or midperipheral retina, where the rodto-cone ratio is the highest [7, 8]. On fundus autofluorescence (FAF), the lesions have a central hypoautofluorescent area with a rim of hyperautofluorescence. The central hypoautofluorescent area corresponds to the area of central hyperfluorescence on FA.

Based on studies with light microscopy and transmission electron microscopy, the location of cuticular drusen was determined to be at the same of hard small drusen and soft drusen: between the inner collagenous layer of the Bruch's membrane and the basal lamina of the RPE [9, 10]. Cuticular drusen are small with steep sides and contain a dense hyalinized component that is identical to hard drusen. This contrasts with soft drusen, which are larger and have sloping sides.

On B-Scan SD-OCT, cuticular drusen are located beneath the RPE and imprint the area below with a pattern of hyperreflectivity alternated with hyporreflectivity, providing an aspect similar to a barcode sign. This aspect is due to the thinning of the RPE at the apex of the drusen and thickening at the base of the drusen. On SD-OCT, the height of drusen did not correlate with the area of hyperfluorescence on FA or hypoautofluorescence on FAF (**Figure 1**).

#### **Figure 1.**

*Cuticular drusen. Type 1 (green arrowhead): Shallow elevations of the RPE and basal laminar band. Type 2 (red arrowhead): Triangular shape resulting in a saw-tooth appearance and hyporreflective internal contents. Type 3 (yellow arrowhead): Mound-shaped elevations of the RPE and basal laminar band with hyporreflective internal contents.*

The morphological features of cuticular drusen seen on SD OCT B-scans can be categorized into 3 patterns:

1.Type 1 (33%): characterized by shallow elevations of the RPE


Near infra-red (NIR) images showed variable reflectivity patterns of cuticular drusen: hyporreflective centers with a surrounding hyperreflective margin in 53.9%, diffuse hyperreflectivity in 15.2%, heterogeneous reflectivity in 3.9%, and a combination of these patterns in 27.0%. These variations of aspects demonstrate that the accurate detection of the cuticular drusen phenotype requires the integration of data from more than one imaging method [11].

In a very extensive multimodal analysis, cuticular drusen were shown to be involved in the formation of: RPE clumping, large drusen, vitelliform lesions and subretinal neovascular membranes [11]. In the entire cohort of this study, new pigmentary RPE abnormalities were identified in 47.5% of eyes, large drusen in 45.4%, drusen resorption in 58.3% and drusen coalescence in 70.8%.

Acquired vitelliform lesions (AVL) involving the central macula were seen in 24.2% of the eyes in the study. However, visual acuity in eyes with AVLs was not significantly different from that in eyes without AVLs [11].

Geographic atrophy (GA) was identified in the macula of 25% of the eyes. The frequency of atrophy in patients older than 60 years was significantly greater than in those that were 60 years-old or younger (42.9% vs. 9.4%; p < 0.001). Visual acuity (VA) in eyes with atrophy was significantly worse than in those without atrophy (0.32 vs. 0.14 logMAR; p < 0.001) [11].

Twelve percent of the cases were complicated by choroidal neovascularization. The frequency of neovascularization in patients older than 60 years was significantly higher than in those that were 60 years-old or younger (19.6% vs. 6.2%; p < 0.014). The vast majority of cases (76.7%) were of type 1 neovascularization, while 9 cases were a mixture of type 1 and 2 lesions. There were no cases of type 3 macular neovascularization [11–13].

## **3. Reticular Drusen**

Reticular pseudodrusen are multiple yellowish-white lesions arranged in a reticular network pattern. A distinction between conventional drusen and pseudodrusen was first made in 1990 by Mimoun et al. [14]. More recently the knowledge on pseudodrusen, more accurately called subretinal drusenoid deposits (SDDs), has expanded.

Reticular pseudodrusen have an increased visibility in blue light. On FAF imaging, reticular drusen are shown as numerous spots of reduced autofluorescence, with brighter lines in-between. SDDs frequently spares the fovea and usually are distributed at the superior macula, which has the highest rod-photoreceptor density [15]*.* Such topographic characteristic is probably related to a rod-photoreceptor association [16–18].

The fluorescein angiographic findings of subretinal drusenoid deposits are subtle, ranging from no demonstrable change to minimal hypofluorescence.

On NIR photography, reticular drusen are hyporreflective lesions, most of them with a lighter center, on a hyperreflective background. The area superior to the fovea, which has the highest rod-photoreceptor density, is the most commonly involved. The fovea, however, is typically spared [15].

The reticular pattern may not be needed for diagnosis, but most studies have required at least five reticular pseudodrusen lesions and multiple imaging modalities for confirmation of the diagnosis.

Histologic evaluation of these deposits revealed aggregation of material in the subretinal space between photoreceptors and the RPE. SDDs contain some proteins that are common to soft drusen but differ in lipid composition. There is a decrease in the number of photoreceptor nuclei above the deposits. These deposits are interconnected, forming a branching pattern [19].

SDDs contain some proteins that are common to soft drusen but differ in lipid composition.

On OCT scans, these lesions are shown as collections of granular hyperreflective deposits located between the RPE layer and the ellipsoid zone (**Figure 2**). These deposits are more commonly seen in older eyes with thinner choroids. Currently, it was shown that retinal thinning in early AMD with reticular pseudodrusen was accompanied by choroidal and retinal vascular loss, which suggests that eyes with reticular pseudodrusen may have limited compliance with changes in ocular perfusion pressure at the level of choroidal and retinal vasculature [20].

OCT has been used to classify SDD into three subtypes [21]:


#### **Figure 2.**

*Reticular drusen. The pink arrowhead indicates a stage 1 lesion where diffuse hyperreflective material between the RPE and ellipsoid layer without elevation of the ellipsoid layer. The red arrowhead indicates a stage 2 lesion with increased accumulation of hyperreflective material and distortion of the ellipsoid layer. The yellow arrowhead indicates a stage 3 lesion that has a characteristic conical shape and has punctured through the ellipsoid layer.*

Many studies reported that SDDs are strong independent risk factors for late AMD. GA and type 3 neovascularization are particularly associated with SDD. Outer retinal atrophy develops in eyes with regression of SDD, a newly recognized form of late AMD [19, 22]*.*
