Association of Reticular Pseudodrusen and Early Onset Drusen

Purpose. To report an association between reticular pseudodrusen, located above the retinal pigment epithelium (RPE), and Early Onset Drusen (EOD) as described using Spectral-Domain Optical Coherence Tomography (SD-OCT). Methods. Eight patients (16 eyes) with EOD were examined. EOD were classified into three entities called Large Colloid Drusen (LCD), Malattia Leventinese (ML), and Cuticular Drusen (CD). Best-corrected visual acuity, fundus examination, color fundus photographs, fundus autofluorescence (FAF), fluorescein angiography (FA), indocyanine green angiography (ICGA), and SD-OCT were performed in all study patients. Results. Four patients had LCD, 2 had ML, and 2 had CD. Reticular pseudodrusen were observed with SD-OCT in all study patients; all these patients had hyperreflective lesions above and below the RPE. Conclusion. Early Onset Drusen appear to be associated with reticular pseudodrusen. SD-OCT is helpful in distinguishing the location of the deposits that are above and below the RPE in EOD. Further studies are needed to understand the role of reticular pseudodrusen in the pathophysiology of EOD.


Introduction
"Soft drusen" are defined as deposits located between the retinal pigment epithelium (RPE) and the inner collagenous layer of Bruch's membrane [1]. These lesions usually appear after the age of 50 and are usually associated with AMD [2]. Younger people can have similar deposits called "Early Onset Drusen" (EOD). These lesions have been recently classified into three entities called Large Colloid Drusen (LCD), Malattia Leventinese (ML), and Cuticular Drusen (CD) [3]. Recent papers have described the multimodal morphological features of EOD as deposits classically located under the RPE similar to the soft drusen observed in AMD [4][5][6]. Reticular pseudodrusen, frequently associated with AMD, have been described using SD-OCT. Our purpose was to report a frequent association of reticular pseudodrusen, located above the RPE, and EOD using Spectral-Domain Optical Coherence Tomography (SD-OCT).

Patients and Methods
Patients with Early Onset Drusen underwent a comprehensive ophthalmologic examination which included bestcorrected visual acuity (BCVA), fundus examination, color fundus photographs, multicolor images, fundus autofluorescence (FAF), fluorescein angiography (FA), indocyanine green angiography (ICGA), and Spectral-Domain (Cirrus, Carl Zeiss-Meditec, Dublin, CA, USA; and Spectralis Heidelberg Retinal Angiography OCT, Heidelberg Engineering, Heidelberg, Germany) Optical Coherence Tomography (SD-OCT). Informed consent was obtained as required by the French bioethical legislation (CE 20130319 11 BWF), in agreement with the Declaration of Helsinki for research involving human subjects. The diagnosis of the specific EOD entity was based on fundus biomicroscopy, angiography, and OCT features [3]. Large Colloid Drusen (LCD) are identified on fundus examination as large, bilateral, and yellowish   lesions located in the macular area and/or in the periphery of the retina. LCD are hyperautofluorescent and appear in the late phase of ICGA, as a hypofluorescent centre surrounded by a hyperfluorescent halo ( Figure 1). This halo is bordered by a hypofluorescent ring, termed as a "donut effect" [5].
In  the macular area [6]. FAF shows hyperautofluorescence of the larger drusen. In the late phase of ICGA, large drusen are hyperfluorescent, showing a hypofluorescent halo (Figure 2). Cuticular Drusen (CD) are small, round, and yellowish lesions randomly scattered in the macula and in the middle periphery of the retina [4]. In the late phase of FA, the drusen are hyperfluorescent with a typical "stars-in-the-sky" pattern ( Figure 3).

Results
A total of 8 patients presenting with EOD (4 LCD, 2 ML, and 2 CD) were included in this study (Table 1). All the patients were women, and the mean age at diagnosis was 40 years (35-50). SD-OCT of the 4 LCD patients showed 2 kinds of deposits at different locations from the RPE: (i) convex colloid drusen with variable reflectivity classically described in LCD were observed between the RPE and Bruch's membrane similar to soft drusen (Figures 4-6), and (ii) round or triangular hyperreflective lesions located between the RPE and the external limiting membrane or the outer plexiform layer (Figures 4-6); the location of these deposits matches the description of reticular pseudodrusen. These subretinal deposits were associated with colloid drusen in all the four patients affected by LCD. Two LCD patients had several hyporeflective cysts in the inner retina without choroidal neovascularization (Figures 4 and 5); one of these patients also had an epimacular membrane ( Figure 5). Patients with ML also showed 2 distinct kinds of deposits on SD-OCT. The first kind was large and round colloidlike drusen corresponding to focal or diffuse deposition of hyperreflective material between the RPE and Bruch's membrane within the posterior pole. These deposits were associated with a focal dome-shaped or diffuse RPE elevation above Bruch's membrane. The second kind of deposit was a hyperreflective lesion located above the RPE (Figures 7 and  8).
In Cuticular Drusen (CD), SD-OCT again showed 2 different kinds of deposits: confluent small "dome-shaped" RPE elevations and "sawtooth" RPE elevations (Figure 9). In the "sawtooth" RPE elevations, the deposits appeared to be above the RPE.

Discussion
The diagnosis of Early Onset Drusen (EOD) is classically based on fundus examination and angiographic features. Recently, SD-OCT has been used to detect the different EOD entities and to define drusen as deposits observed under the RPE [4][5][6]. Our study, using SD-OCT, has demonstrated the association between reticular pseudodrusen and EOD. SD-OCT with high resolution allows the histologic imaging of drusen and located them below or above the RPE. In all our 8 study patients, hyperreflective lesions located above the RPE were observed. These images may clinically correspond with reticular pseudodrusen. To our knowledge, this is the first report of this association between reticular pseudodrusen and the three entities of EOD.
Reticular pseudodrusen in AMD have been described by Querques et al. using SD-OCT as hyperreflective material located not below but above the RPE [7]. In 2007, Cohen et al. described these pseudodrusen as a yellowish pattern in the macula frequently associated with AMD [8].
Recently, Curcio et al. reported a pathological description of subretinal drusenoid deposits (SDDs) located above the RPE and associated with photoreceptor perturbation [9]. under the RPE. SDD and BlinD were associated and, respectively, detected in 85% and 90% of donor eyes with AMD. More information about the histopathology of SDD would facilitate understanding of its role in AMD pathophysiology and in EOD [10][11][12] Curcio et al. hypothesized that the RPE is a polarized and bidirectional secretor of lipoproteins participating in lesion formation above and below the RPE [9]. This hypothesis could explain the simultaneous presence of soft drusen and reticular pseudodrusen in patients with EOD and AMD.
In conclusion, soft drusen and reticular pseudodrusen seem to be frequently associated in EOD. SD-OCT is helpful in distinguishing the location of the deposits above and below the RPE in EOD. Soft drusen are located below the RPE layers while reticular pseudodrusen are located above the RPE. These two distinct lesions frequently occur simultaneously in young patients affected by hereditary drusen. A new clinical classification of Early Onset Drusen should include the presence of reticular pseudodrusen. Further studies are needed to understand their role in the physiopathology of EOD.

Consent
The study was performed with informed consent and following all the guidelines for experimental investigation in human subjects required by the Ethics Committee with the number CE 20130319 11 BWF. Another kind of deposit is seen above the RPE (white arrow). A hyperreflective haze is also seen located in the external nuclear layer close to plexiform layer (black arrow). Figure 9: Patient affected by Cuticular Drusen in both eyes. SD-OCT shows some Cuticular Drusen as small RPE elevations (white arrowhead) and others deposits as "sawtooth" RPE elevations above the RPE (white arrow).