Dr Zhichao Wu
Dr Lauren Ayton
BOptom PhD GCOT FACO
Associate Professor Peter Keller
BAppSc(Optom) MBA MHEth PGCertOcTher PhD
Professor Robyn Guymer
MBBS PhD FRANZCO FAHMS
The presence of drusen is considered the hallmark feature of age-related macular degeneration (AMD), with the presence of pigmentary abnormalities further contributing to the risk of developing advanced, vision-threatening complications including choroidal neovascularisation (CNV) and geographic atrophy (GA).
Drusen are focal deposits of extracellular debris that accumulate between the retinal pigment epithelium (RPE) and Bruch’s membrane (BM), and are described clinically by their size and characteristics. For example, large, soft drusen typically have indistinct borders while cuticular or basal laminar drusen appear as a multitude of small (25-75 µm diameter) discrete and uniformly-sized yellow lesions.
However, another distinct clinical feature, termed ‘reticular pseudodrusen’ (RPD) was first recognised more than two decades ago. These lesions are uniquely characterised by their appearance as ill-defined networks of broad, interlacing ribbons on clinical examination and fundus photography. The significance of these lesions became increasingly important because they were often found in eyes with late AMD. It was therefore suggested that they were an important risk factor.
With the advent of multimodal imaging modalities including high-resolution, spectral domain optical coherence tomography (SD-OCT), several studies subsequently reported that the RPD observed clinically and on colour fundus photographs were actually deposits above the RPE, as opposed to accumulations below the RPE that are characteristic of drusen.1 The term ‘subretinal drusenoid deposits’ was therefore proposed, and the localisation of these lesions to the subretinal space was subsequently confirmed in a histological study.2
The increasing use of SD-OCT along with near-infrared reflectance (NIR) and fundus autofluorescence (FAF) imaging in medical retina practice led to the recognition that RPD were present more often than had been previously thought because they are often not recognised on clinical examination and colour fundus photography.
For example, RPD was detected in only 20 per cent of eyes on colour fundus photography when they were present on SD-OCT scans.3
With these imaging modalities, RPD has been reported to be present in as many as 62 per cent of eyes with GA.4 For neovascular AMD, RPD has been reported to be present in 14 per cent of eyes with typical (classic or occult) CNV, but up to 39 per cent in eyes with retinal angiomatous proliferation (RAP).5
However, this prevalence is also likely to be underestimated because RPD have been observed to disappear with the development of CNV. This is most likely the reason that we and others have found that RPD were present in between 41 per cent and 58 per cent of fellow eyes of individuals with unilateral CNV.6,7
|Figure 1. Appearance of reticular pseudodrusen (RPD) on colour fundus photography, near-infrared reflectance (NIR) imaging and spectral-domain optical coherence tomography (SD-OCT) scans. Dashed lines indicate areas where the SD-OCT scans (numbered) were taken. On SD-OCT, RPD can appear as either broader subretinal accumulations or lesions with sharper peaks.
Identification of reticular pseudodrusen
The detection and identification of RPD can be most reliably performed using a combination of SD-OCT and NIR. NIR imaging is helpful at detecting these lesions because they appear most distinct in the near-infrared spectrum, but SD-OCT imaging is required to confirm the subretinal location of these lesions and distinguish them from other features similar in appearance.
On NIR, these lesions are often seen as groups of hypo-reflective lesions against a mildly hyper-reflective background, with a target appearance (slightly greater central reflectivity against the hypo-reflective lesion) often associated with subretinal accumulations with sharper peaks. On the other hand, lesions that appear as hypo-reflective ribbons on NIR imaging are often associated with broader subretinal accumulations on SD-OCT.8 An example is shown in Figure 1 to illustrate these features.
It is important to note that most current analysis parameters on OCT imaging are not suitable for identifying RPD. For example, retinal thickness or RPE elevation maps will fail to identify these lesions due to their negligible influence on overall retinal thickness and because of their subretinal location, respectively. This is illustrated in Figure 2, where drusen-associated RPE elevation is detected but RPD are missed without looking carefully at the SD-OCT scans.
Figure 2. Reticular pseudodrusen (RPD) distinguished from typical drusen
A: This figure illustrates how RPD can be missed on grading of a colour fundus photograph but detected on near-infrared reflectance (NIR) imaging and spectral-domain optical coherence tomography (SD-OCT) scans (shown at the bottom of each example). RPD are also missed when considering the retinal pigment epithelium (RPE) elevation maps generated by some SD-OCT devices.
B: An example showing an eye with typical drusen that appears to have groups of hypo-reflective lesions on NIR imaging but without any subretinal drusenoid deposits on SD-OCT imaging. While both examples are characterised by similar drusen volume, RPD are present in the first example (A) and pigmentary abnormalities are present in the second example (B), and the latter is associated with reduced mesopic microperimetric sensitivity.
Clinical implications of reticular pseudodrusen
When monitoring eyes with the early stages of AMD, the presence of RPD is an important risk factor to note for patient management. The currently available evidence suggests that the presence of RPD is an independent risk factor for the development of GA in the fellow eye of patients with unilateral CNV, in addition to the presence of large drusen and pigmentary abnormalities.6,7
RPD have also been reported to confer an increased risk of progression to late AMD in patients without such advanced complications in either eye, but these findings stemmed from an epidemiological study that relied on detection of RPD on colour fundus photographs.9 Prospective studies are now underway to better characterise the risk of progression when RPD are present in intermediate AMD.
The findings regarding the impact of RPD on visual function have also varied throughout literature, depending on the type of patients examined, the techniques used to evaluate visual function and analysis performed. Results also vary depending on whether other confounding factors such as drusen and pigmentary abnormalities were present.
A comprehensive discussion can be found in our recent publication. In short, we were unable to demonstrate a significant influence of RPD on mesopic microperimetric sensitivity, involving measurements of luminance increment using a method similar to conventional perimetry, but found that the presence and extent of drusen and pigmentary abnormalities had a detrimental effect on the sensitivity.10
A recent study reported scotopic microperimetry was reduced in areas with RPD,11 consistent with suggestions from histological findings that rod photoreceptors may be preferentially affected in areas of RPD. This is an important finding when seeking to understand the impact of RPD on visual function, and further studies are now being carried out at the Centre for Eye Research Australia to investigate this. For now, optometrists should be aware of this new clinical entity and understand its implication as a risk factor for progression of AMD to vision loss.
- Zweifel SA, Spaide RF, Curcio CA, Malek G, Imamura Y. Reticular pseudodrusen are subretinal drusenoid deposits. Ophthalmology 2010; 117: 2: 303-312.
- Curcio CA, Messinger JD, Sloan KR et al. Subretinal drusenoid deposits in non-neovacular age-related macular degeneration: morphology, prevalence, topography, and biogenesis model. Retina 2013; 33: 2: 265-276.
- Zweifel SA, Imamura Y, Spaide TC, Fujiwara T, Spaide RF. Prevalence and significance of subretinal drusenoid deposits (reticular pseudodrusen) in age-related macular degeneration. Ophthalmology 2010; 117: 9: 1775-1781.
- Schmitz-Valckenberg S, Alten F, Steinberg JS et al. Reticular drusen associated with geographic atrophy in age-related macular degeneration. Invest Ophthalmol Vis Sci 2011; 52: 9: 5009-5015.
- Yoneyama S, Sakurada Y, Mabuchi F et al. Genetic and clinical factors associated with reticular pseudodrusen in exudative age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2014: 252: 9: 1435-1441.
- Finger RP, Wu Z , Luu CD et al. Reticular pseudodrusen: a risk factor for geographic atrophy in fellow eyes of individuals with unilateral choroidal neovascularization. Ophthalmology 2014; 121: 1252-1256.
- Hogg RE, Silva R, Staurenghi G et al. Clinical characteristics of reticular pseudodrusen in the fellow eye of patients with unilateral neovascular age-related macular degeneration. Ophthalmology 2014; 121: 9: 1748-1755.
- Suzuki M, Sato T, Spaide RF. Pseudodrusen subtypes as delineated by multimodal imaging of the fundus. Am J Ophthalmol 2014; 157: 5: 1005-1012.
- Klein R, Meuer SM, Knudtson MD, Iyengar SK, Klein BEK. The epidemiology of retinal reticular drusen. Am J Ophthalmol 2008; 145: 2: 317-326.
- Wu Z, Ayton LN, Makeyeva G, Guymer RH, Luu CD. Impact of reticular pseudodrusen on microperimetry and multifocal electroretinography in intermediate age-related macular degeneration. Invest Ophthalmol Vis Sci 2015; 56: 3: 2100-2106.
- Steinberg JS, Fitzke FW, Fimmers R et al. Scotopic and photopic microperimetry in patients with reticular drusen and age-related macular degeneration. JAMA Ophthalmology 2015; 133: 6: 690-697.