Identification of Drusen Characteristics in Age-Related Macular Degeneration by Polarization-Sensitive Optical Coherence Tomography.

PURPOSE: To describe qualitative characteristics of drusen in eyes with nonadvanced age-related macular degeneration (AMD) using polarization-sensitive optical coherence tomography (OCT).
DESIGN: Cross-sectional study.
METHODS: Twenty-five eyes of 25 patients with early to intermediate (nonadvanced) AMD were imaged with polarization-sensitive OCT using macular volume scans. All individual drusen in each B-scan were manually delineated by experts certified by a reading center and graded for 6 different morphologic characteristics based on a defined classification scheme, including the presence of internal depolarizing structures and associated depolarizing foci. With the use of a custom-made software, the central B-scan of each individual druse was selected and used to analyze its location, diameter, and characteristics and assess the prevalence of the different features and relations between them.
RESULTS: Using the macular volume scans, 6224 individual drusen could be identified, including their position within the retina, their characteristics, and their association with any pigmentary alterations. The most common drusen type was a convex-shaped druse with homogeneous medium internal reflectivity and no depolarizing contents (55.3% of drusen). A total of 30.5% of the drusen exhibited internal depolarizing material; 0.3% presented overlying hyperreflective foci, and in 54.5% the foci were also depolarizing. Significant correlations were found between the diameter of the drusen and their distribution throughout the retina, shape, homogeneity of internal reflectivity, presence of internal depolarizing characteristics, and presence of overlying foci (P < .001 each). Significant relations were found between reflectivity, homogeneity, and polarization-sensitive internal characteristics (P < .001).
CONCLUSIONS: Polarization-sensitive OCT reveals characteristic morphologic features of different druse types highlighting the pathophysiological spectrum of early to intermediate AMD.

The presence of drusen and pigmentary changes within the retina are a characteristic finding of early and intermediate age-related macular degeneration (AMD), the leading cause of irreversible blindness in developed countries. The increase of drusen size is widely recognized as an indicator for progression toward advanced stages of AMD, as well as the development of pigmentary changes, seen as hyperreflective foci in the inner retinal layers in spectral-domain optical coherence tomography (OCT) images. However, the progression rates of AMD disease can vary between individual patients, and drusen themselves show different growth patterns. Furthermore, studies underlined that drusen individually present a wide spectrum of different compositions and, consequently, different morphologic features in histologic sections. In vivo, drusen morphology was investigated using spectral-domain OCT imaging, and several distinct characteristics were identified. These different morphologic features, including the presence of hyperreflective foci, might represent ongoing biologic dynamics in the course of the disease that might lead to neurodegenerative processes and loss of visual function.

Polarization-sensitive spectral-domain OCT is a technology based on spectral-domain OCT. It provides the same high-resolution images as spectral-domain-based devices, which measure the intensity of the backscattered light. As additional information, polarization-sensitive OCT is able to identify the polarization state. An overview of this selective imaging technique has recently been presented.

Studies could show that most cellular parts of the retina preserve the polarization state of the incoming and reflected light, with the exception of melanin. Melanin is found mostly in retinal pigment epithelium (RPE) cell organelles, but was observed in other structures too, including pathologic alterations such as pigmentary changes and inside of drusen.

In previous work of our group, which outlined the performance of a drusen segmentation algorithm based on polarization-sensitive information, we also found that some drusen featured additional depolarizing characteristics that provoked “errors” in the automated delineation of the drusen contour, but that may in fact represent additional characteristics relevant for disease progression. The prognostic value of drusen-related morphologic features is completely unknown. Many proposals for staging disease activity have been made based on the appearance or imaging features of drusen observed using such aids as the scanning laser ophthalmoscope and, recently, spectral-domain OCT.

In this study, the characteristics of drusen and pigmentary changes in early and intermediate AMD using polarization-sensitive OCT were systematically investigated. Based on a previous attempt to classify drusen morphology seen in intensity-based spectral-domain OCT, additional polarization-sensitive features of drusen were characterized. The detected characteristics were correlated to known risk factors for disease progression such as drusen size or the presence of overlying pigmentary alterations, with the aim of gaining new insights into drusen composition and their role in AMD disease.

Methods

In this observational cross-sectional study, we evaluated the polarization-sensitive OCT volume scans of 25 eyes of 25 patients with drusen of AREDS (Age-Related Eye Disease Study) categories 2 and 3. All examinations were performed at the Department of Ophthalmology, Medical University of Vienna. The study protocol was approved by the ethics committee of the Medical University of Vienna and adhered to the Declaration of Helsinki (2008). In this study protocol, all examinations listed below were included, and the patients had to give their informed consent before inclusion to the study.

Patients

Patients were selected according to the standard AREDS classification. Only eyes with drusen of the AREDS categories 2 and 3 were included in the study. Category 2 is defined as the presence of extensive small (<63 μm in diameter) or nonextensive intermediate drusen (between 63 μm and 125 μm) with or without pigment epithelial abnormalities in at least 1 eye. Category 3 requires extensive intermediate or large (≥125 μm) drusen and/or noncentral geographic atrophy in at least 1 eye. Eyes were examined ophthalmoscopically by an experienced retinologist and selected for study inclusion.

Patients presenting with ocular media opacity due to cornea or lens changes or other diseases potentially influencing scan quality such as macular edema were excluded. Patients with a history of ocular trauma or surgery other than uncomplicated cataract surgery were also excluded.

Imaging Protocol

Patients meeting the protocol criteria were informed about the study aims and procedures. After patients had given informed consent, they were included in the study and underwent a complete and standardized ophthalmic examination. The best-corrected visual acuity (BCVA) was obtained and mydriatic eye drops were administered. At maximum mydriasis, eyes were scanned with a conventional spectral-domain OCT (Spectralis; Heidelberg Engineering, Heidelberg, Germany) using a macular volume scan (97 × 1024 scan pattern covering an area of 20 × 20 degrees, with an averaging of 20 frames). Furthermore, eyes were scanned with the polarization-sensitive OCT using the 64 × 1024 volume scan pattern (ie, 64 B-scans consisting of 1024 A-scans) covering an area of 17.6 × 19.0 degree.

Technology of the Polarization-Sensitive Optical Coherence Tomography Device

The polarization-sensitive OCT images analyzed in this study were obtained using a prototype engineered by the Center for Medical Physics and Biomedical Engineering, Medical University of Vienna. To summarize, the system is able to retrieve the following parameters simultaneously: intensity of the backscattered light (as in standard spectral-domain OCT imaging), retardation (phase shift between 2 orthogonal linear polarization states caused by birefringence), fast axis orientation (birefringent axis orientation of the sample relative to the orientation of the instrument), and degree of polarization uniformity. A superluminescent diode (Superlum Diodes, Inc, Moscow, Russia) centered at 839 nm with a full width at half maximum bandwidth of 58 nm served as the light source. The laser power incident on the cornea was well below the laser safety standards. Scanning laser ophthalmoscope images scanned by the instrument and OCT B-scan images were recorded and displayed in real time to allow an optimized alignment of the eye under investigation. Three-dimensional (3D) datasets covering a scan field of 17.6 × 19.0 degrees (approximately 6.2 × 6.7 mm2) with an imaging depth of 3.3 mm in air were recorded at an operating speed of 20 000 A-scans per second. One out of 3 sampling patterns (64 × 1024, 128 × 512, 256 × 256) could be selected. Only datasets recorded with the 64 × 1024 scan pattern were used in the study. Scans of unacceptable quality (eg, motion artifacts) were dismissed and repeated until satisfactory results were achieved.

Classification of Drusen

Two expert readers (F. Schlanitz and M. Platzer) independently graded the OCT images of each patient. Individual B-scans were reviewed and every druse observed in these images was manually segmented. Each detectable localized pigment epithelial elevation larger than 25 μm in diameter was regarded as a druse entity in accordance with the histopathologic definition of drusen and based on other studies that have identified drusen in OCT images. Drusen were further categorized as small (<63 μm in diameter), intermediate (between 63 and 125 μm), and large (between 125 and 350 μm). RPE elevations wider than 350 μm in diameter were classified as drusenoid pigment epithelial detachments according to the AREDS classification.

Segmentation and classification of the drusen was done using a custom-made Matlab program (Matlab 7.1; Mathworks Inc, Natick, Massachusetts, USA) with a graphical user interface. With the help of this program, every single druse in each B-scan was manually segmented and classified using the druse classification system introduced by Khanifar and associates. This classification encompasses the shape of the RPE elevation (convex, ie, dome-shaped; concave, ie, pointed; or saw-toothed), the reflectivity of the druse (low, medium, or high, in relation to the photoreceptor layer), the homogeneity of the druse's content (homogeneous reflectivity, inhomogeneous with central core/focus of hyperreflectivity and inhomogeneous without a central core), and the presence or absence of hyperreflective foci above the druse.

To classify the polarization-sensitive information, this classification system was expanded to include 2 additional categories: depolarizing structures within the druse (absence of depolarizing material, single depolarizing core within the druse, inhomogeneous depolarizing structures within the druse, and a complete fill-out of the druse with depolarizing material) and the presence or absence of depolarizing foci above the druse (Figure 1). These details can only be obtained using the detection mode of a polarization-sensitive OCT. A summary of the categories and grading is shown in Table 1.

Figure 1

Classification of macular drusen. Every elevation of the retinal pigment epithelium detectable in the single B-scans (Top left image) was delineated. In a next step, drusen were classified using 3 internal druse characteristics based on the spectral-domain optical coherence tomography classification (shape, reflectivity, and homogeneity, center and right area) and for specific depolarizing characteristics (foci and content, right and bottom area—the red color in the B-scans represents depolarizing structures segmented based on the degree of polarization uniformity calculation). Note that foci could be hyperreflective and/or depolarizing (foci, blue vs yellow arrow, respectively). Finally, the central slice of each single druse was selected (Bottom left images) and its position on the retina was noted for further statistical calculations.

Table 1

Classification Scheme for the Grading of Macular Drusen, Based on the Classification Scheme by Khanifar and associates

Classification	Description
Shape
Convex	Dome-shaped RPE elevation
Concave	Pointed RPE elevation
Saw-toothed	Small, jagged elevations of RPE
Reflectivity
Low	Isoreflective or hyporeflective relative to the photoreceptor layer
Medium	Hyperreflective relative to the photoreceptor layer and hyporeflective relative to the RPE
High	Isoreflective or hyperreflective relative to the RPE
Homogeneity
Homogeneous	Relatively uniform internal reflectivity
Nonhomogeneous with a central core	Varying internal reflectivity with a distinct single focus of hyperreflectivity
Nonhomogeneous without a central core
Hyperreflective foci
The presence or absence of hyperreflective points within the neurosensory retina overlying areas of RPE elevations
Depolarizing structures within the druse
Absence of depolarizing material
Depolarizing core	Single depolarizing focus within the druse
Depolarizing material	Varying, inhomogeneous distribution of depolarizing material within the druse
Complete fill-out	If the complete druse content produces a depolarizing signal
Depolarizing foci
The presence or absence of depolarizing points within the neurosensory retina overlying areas of RPE elevations

RPE = retinal pigment epithelium.

Data Analysis and Statistical Methods

Statistical analysis was carried out using PASW Statistics 18.0 (SPSS Inc, Chicago, Illinois, USA) and Matlab (Matlab 7.1; Mathworks Inc).

The manually outlined location, diameter, height, and the 6 characteristics of druse morphology identified were allocated to a matrix. Using this matrix, the Matlab program displayed a map for each eye representing the location and extent of the drusen. Using this map, the central slice of each delineated druse was selected and its characteristics were transferred into SPSS for further statistical analysis (Figure 1, bottom left images). In addition, graders indicated the location of each druse within the standard AREDS grading grid. This grid consists of a central circle centered at the fovea with 1000 μm diameter (zone 1), and a second circle with 3000 μm and a third with 6000 μm diameter (zone 2 and 3, respectively). The rate of agreement on the classification of drusen characteristics between the 2 graders was assessed by calculating the percentage of agreement. The prevalence of each characteristic, and the druse diameter and distribution within the AREDS grid, were compared using the Kruskal-Wallis test with subsequent Mann-Whitney U tests. Owing to the large number of different factors, the results were corrected for multiple testing using the Shaffer correction. A corrected P value below 5% was considered significant.

Results

Number and Size of Drusen

Twenty-five eyes of 25 patients presenting with AREDS categories 2 and 3 were examined. The patients' mean age was 72 years (standard deviation [SD] ±6, range 60–85), and 14 were women. The mean BCVA was 0.9 (SD ±0.17, range 0.6–1.25), and 5 patients were pseudophakic. In total, 8729 RPE elevations were found and analyzed in the single B-scans. The mean druse area per eye was 6.0 mm2. Using the 3D drusen maps, 6224 single drusen were identified and their central slice was further analyzed. The mean number of drusen <350 μm in diameter per eye was 237 (SD ±136, range 25–645) with a mean diameter of 114 μm (SD ±69 μm, range 29–345 μm). Of all drusen, 25.2% were small, 41.6% intermediate, and 32.2% large. Drusenoid pigment epithelial detachments with a diameter ≥350 μm were found in 23 eyes, with a mean number of 12 individual drusenoid pigment epithelial detachments per eye (SD ±13, range 0–53). Therefore, a total of 291 individual drusenoid pigment epithelial detachments were detected, with a mean diameter of 504 μm (SD ±163 μm, range 351–1370 μm).

Morphology of Drusen

The prevalence of each of the 6 morphologic druse characteristics is shown in Table 2. A convex contour was seen in 88.9% of all drusen and 96.2% of all drusenoid pigment epithelial detachments. Regarding the internal reflectivity, 90.5% of the drusen and 95.9% of the drusenoid pigment epithelial detachments exhibited a medium reflectivity. The internal reflectivity was homogeneous in 79.5% of the drusen and 69.4% of the drusenoid pigment epithelial detachments. The most common internal depolarizing characteristic was a nonhomogeneous distribution of depolarizing structures, which was present in 17.8% of all drusen and 19.6% of all drusenoid pigment epithelial detachments. A total of 68.5% of all drusen and 72.9% of all drusenoid pigment epithelial detachments showed no internal depolarizing signal. Hyperreflective foci were present in 16 single drusen (0.3%) and 12 drusenoid pigment epithelial detachments (4.1%). Overlying depolarizing foci were observed in 9 drusen (0.2%) and 10 drusenoid pigment epithelial detachments (3.4%). By combining the drusen characteristics, different “types” of drusen can be generated, as described by Khanifar and associates. The most common drusen type observed in this study was convex shaped, with medium, homogeneous internal reflectivity and nondepolarizing contents, and no overlying foci (55.3% of drusen and 53.6% of drusenoid pigment epithelial detachments). The most common type with internal depolarizing characteristics was convex shaped, with medium and homogeneous internal reflectivity, and patchy depolarizing contents (8.7% of drusen and 7.3% of drusenoid pigment epithelial detachments).

Table 2

Prevalence of the Morphologic Characteristics of Macular Drusen Found in this Study

Drusen Morphology	Small		Intermediate		Large		Drusenoid Pigment Epithelial Detachments
	No.	%	No.	%	No.	%	No.	%
Shape
Concave	170	11.4%	253	10.3%	118	6.0%	4	1.4%
Convex	1299	87.0%	2165	87.7%	1809	91.7%	280	96.2%
Saw-toothed	0	0.0%	10	0.4%	29	1.5%	6	2.1%
Not classifiable	24	1.6%	40	1.6%	16	0.8%	1	0.3%
Reflectivity
Low	21	1.4%	25	1.0%	28	1.4%	5	1.7%
Medium	1348	90.3%	2226	90.2%	1798	91.2%	279	95.9%
High	96	6.4%	187	7.6%	110	5.6%	2	0.7%
Not classifiable	28	1.9%	30	1.2%	36	1.8%	5	1.7%
Homogeneity
Homogenous	1323	88.6%	2008	81.4%	1386	70.3%	202	69.4%
Nonhomogenous + core	51	3.4%	180	7.3%	253	12.8%	30	10.3%
Nonhomogenous	88	5.9%	242	9.8%	292	14.8%	53	18.2%
Not classifiable	31	2.1%	38	1.5%	41	2.1%	6	2.1%
Depolarizing contents
Nondepolarizing	1224	82.0%	1716	69.5%	1123	56.9%	212	72.9%
Nonhomogenous + core	44	2.9%	144	5.8%	246	12.5%	18	6.2%
Nonhomogenous depolarizing	125	8.4%	422	17.1%	507	25.7%	57	19.6%
Complete fill-out	98	6.6%	166	6.7%	61	3.1%	1	0.3%
Not classifiable	2	0.1%	20	0.8%	35	1.8%	3	1.0%
Hyperreflective foci
Absence	1492	99.9%	2463	99.8%	1962	99.5%	279	95.9%
Presence	1	0.1%	5	0.2%	10	0.5%	12	4.1%
Depolarizing foci
Absence	1493	100.0%	2462	99.8%	1968	99.8%	281	96.6%
Presence	0	0.0%	5	0.2%	4	0.2%	10	3.4%

Drusen shape significantly correlated with the size of the druse (P < .001), with concave RPE elevations being significantly smaller and saw-toothed drusen significantly larger in diameter (Figure 2, Left). The mean diameter was 98 μm for concave, 135 μm for convex, and 244 μm for saw-toothed elevations. Furthermore, drusen size also correlated with the homogeneity of internal reflectivity, with drusen consisting of nonhomogeneous reflectivity, with or without cores, being significantly larger in diameter than drusen with a homogeneous content (P < .001) (Figure 2, Center). Regarding internal depolarizing characteristics, the diameter of drusen and drusenoid pigment epithelial detachments with nonhomogeneous depolarizing structures, with central cores (mean diameter 160 μm) or without central cores (mean diameter 154 μm), was significantly larger than that of RPE elevations without any internal depolarizing signal (mean diameter 126 μm) and was completely filled out by depolarizing material (mean diameter 91 μm) (P < .001) (Figure 2, Right). Concave RPE elevations showed a nonhomogeneous internal reflectivity significantly more often than convex RPE elevations (29.5% of the concave-vs 8.9% of convex-shaped) (P < .001).

Figure 2

Correlations between the size of drusen and imaging characteristics. (Left) Relation between the size of the druse and its shape. (Center) Relation between size and homogeneity of internal reflectivity. (Right) Relation between size and depolarizing druse content.

Significant relations were found between depolarizing drusen characteristics and their internal reflectivity and homogeneity (P < .001) (Figure 3). Drusen with high internal reflectivity were significantly more likely to show nonhomogeneous internal depolarizing signals or be completely filled out with depolarizing material (30.3% vs 43.0% of drusen, P < .001). A single depolarizing core within drusen was significantly related to a hyperreflective core seen in intensity images (P < .001), although 52.9% of these cores did not exhibit any depolarization. Consistently, a nonhomogeneous depolarization was found more frequently in drusen with a nonhomogeneous internal reflectivity (P < .001).

Figure 3

Relations between internal depolarizing characteristics of macular drusen, their reflectivity, and the homogeneity of their content.

Significant correlations were found between the presence of overlying foci and the homogeneity of internal reflectivity (P < .01). A total of 2.1% of drusen with a nonhomogeneous reflectivity had overlying hyperreflective foci, which was in 62.0% also depolarizing. In contrast, 0.8% of drusen with either homogeneous reflectivity or an internal core had overlying foci. Interestingly, the presence of hyperreflective as well as depolarizing foci was statistically significantly associated with a larger diameter of the RPE elevation (mean diameter 401 μm and 416 μm, for the presence of hyperreflective and depolarizing foci, respectively). Significantly more foci were found in retinal zones 2 and 3 (P < .001), with 57.1% of all depolarizing foci located in zone 2, followed by 42.9% in zone 3. Likewise, 45.5% of hyperreflective foci were found in zone 2 and 48.5% in zone 3.

Interobserver agreement in grading druse characteristics was best for evaluating the drusen shape (Cohen's kappa coefficient κ = 0.75) and for grading depolarizing features (depolarizing drusen content: κ = 0.69, depolarizing foci: κ = 0.66). The interobserver agreement for hyperreflecting foci (κ = 0.49), the integrity of the inner segment/outer segment band (κ = 0.49), and the internal reflectivity (κ=0.42) was lower, and no consent was found for grading the homogeneity of the drusen content (κ = 0.1).

Discussion

In this study, we systematically evaluated the prevalence and morphology of drusen in early AMD using a high-resolution imaging modality that could identify different druse characteristics based on selective detection of intrinsic, tissue-specific signals.

To date, a broad spectrum of drusen types has been observed in spectral-domain OCT images, and discussion has arisen as to whether these characteristics might represent sensitive biomarkers for progression toward advanced AMD. Histologic studies unveiled the different morphologic characteristics of drusen. However, conventional OCT imaging based on the intensity of backscattered light only offers a partial analysis of the precise morphology of these features. Imaging polarization-sensitive characteristics reveals additional aspects of drusen morphology, which might lead to better insight into pathomorphologic changes and thus into underlying pathophysiologic processes.

The 64 × 1024 scan pattern used in this study has the advantage of a high resolution within the B-scan images, and therefore enables a detailed examination of retinal structures within a horizontal cross section. On the other hand, the vertical separation of B-scans is about 100 μm. This leads to an undersampling in the y direction and therefore an underestimation of the number of small drusen, which limits their statistical interpretation in this study.

However, in contrast to other studies, which used either the single macular scan or the entire cross-sectional volume scan to evaluate morphologic structures seen in AMD, we identified and analyzed the most central slice of each pathologic structure that extended over 2 or more adjacent B-scans. Therefore, imaging artifacts caused by incomplete cross-sectioning of drusen were largely avoided. This method allowed the measuring of the prevalence of drusen characteristics and their specific distribution throughout the retina in the study population. The morphologic drusen characteristics were classified based on findings in AMD eyes from previous polarization-sensitive OCT studies. The intergrader agreement was shown to be better for grading depolarizing characteristics, whereas the agreement in the grading of the reflectivity of the drusen content, based on intensity images, was less distinct. In grading the homogeneity of the drusen content, no agreement was achieved.

Melanin has been identified as the main cause for depolarization of backscattered light. Consequently, RPE cells produce a characteristic depolarization signal in polarization-sensitive OCT images. However, additional depolarizing signals may occur in other locations within the retina, especially in a disease-affected eye. Owing to its high depth resolution, polarization-sensitive OCT enables a clear spatial distinction between the RPE layer (if present) and unrelated structures. Intracellular melanin granules, physiologically present in intact RPE cells, are also a pathognomonic constituent of specific cells such as macrophages and dendritic cells associated with the immune system and were found in a somewhat disorganized condition within drusen, possibly as a residue of degradation processes. An additional AMD-relevant cause for depolarization might be the presence of mineralized components, clinically referred to as “calcifications” of drusen. Hence, polarization-sensitive OCT can also identify RPE-associated pathologic changes in great detail.

Evaluation of the internal structure of drusen otherwise inaccessible to conventional spectral-domain OCT imaging was a major focus in this study. The top left image in Figure 4 shows 2 neighboring drusen that appear similar in the intensity image (below), but the left druse displays depolarizing contents in the polarization-sensitive image (above), whereas the right druse does not. In polarization-sensitive OCT analysis, a substantial proportion of drusen (30.5%) and drusenoid pigment epithelial detachments (26.1%) contained internal depolarizing characteristics, highlighting the intensity of metabolic activity in the pathophysiology of drusen formation. As one of the hallmarks of AMD progression, drusen represent not only a mere misalignment of the RPE but, more importantly, a biologic degradation process. A heterogeneous internal reflectivity observed by spectral-domain OCT has been shown to be associated statistically significantly with progression to geographic atrophy.

Figure 4

Examples of macular drusen characteristics. Each image consists of 2 parts, showing the depolarization signal (red) in the upper part and the sole intensity image, as in spectral-domain optical coherence tomography, in the lower part. (Top left) Two neighboring drusen, of which the left one displays depolarizing contents. (Top center) Hyperreflective druse completely filled out with depolarizing material. (Top right) Example of a saw-toothed druse formation spreading throughout the scan, with intermittent convex drusen and an irregular retinal pigment epithelium (RPE) layer. (Bottom left) Foci emanating from the RPE layer. (Bottom center and Bottom right) Depolarizing internal cores located at the base of the druse (center) or within the druse volume (right).

In this context, a particularly interesting internal druse feature is a single internal hyperreflective core: 7.9% of drusen showed such an internal hyperreflective core; about half of the lesions were seen as depolarizing in the polarization-sensitive OCT. Some of these cores were confluent with a similar structure within or beneath the Bruch membrane, expanding into the choroidal space (Figure 4, Bottom center and Bottom right). Whether these cores represent pigment-loaded, immune-associated cells, possibly emanating out of the choroid into the druse as shown in histopathologic studies, should be investigated in more detail.

The presence of overlying hyperreflective foci (Figure 4, Bottom left) was another feature that correlated statistically significantly with progression toward geographic atrophy, suggesting they could be a biomarker for AMD progression. These foci have been referred to as intraretinal RPE migration. Polarization-sensitive OCT, with its specificity and distinct contrast between the RPE layer and other reflective retinal structures, offers an ideal modality to monitor pigment-associated foci proliferation and dynamics during AMD disease. Figure 4 (Bottom left) shows a hyperreflective and depolarizing core above the druse that seems to emanate from the RPE layer. The fact that drusen with larger diameters were significantly more often accompanied by overlying foci supports the experience that drusen size is positively correlated with new atrophy as well as the hypothesis that RPE migration is facilitated by a progressive detachment of the RPE cells triggering migration toward retinal layers.

Consistently, the diameter of the druse correlated with several other characteristics, including its shape, its homogeneity, and the presence of related depolarizing structures. A complete fill-out with depolarizing material mainly seen in smaller drusen, as shown in Figure 4 (Top center), might be caused by a consequence of the reduced druse volume. However, the finding that a nonhomogeneous internal reflectivity, depolarizing or not and with or without cores, is present more frequently in larger drusen, indicating advanced RPE decomposition, is interesting. Further studies are planned, including follow-up analysis to determine whether the druse diameter alone, or the other biologic characteristics mentioned above, are responsible for the higher risk profile of large and inhomogeneous lesions.

The saw-toothed drusen formation was a rare but interesting finding in this study. Figure 4 (Top right) shows an example of such a formation extending throughout the B-scan, with intermittent convex- or concave-shaped drusen and a highly irregular overlying RPE layer in polarization-sensitive OCT. Histologic imaging suggests that this formation might represent cuticular or “basal laminar” drusen, which show a very similar aspect, as this drusen type appears in densely packed arrangements and tends to protrude into the RPE layer.

In conclusion, polarization-sensitive OCT, a high-resolution selective imaging modality, reveals distinct and characteristic features within drusen and pigmentary changes in eyes with early AMD. Quantitative and qualitative measurements of detailed features can be taken in a reliable and reproducible manner to determine their potential value in assessing the risk for disease progression. Polarization-enhanced selectivity for physiologic as well as pathologic RPE and other melanin-associated cells or structures enables a more detailed identification of the biologic origin and pathomechanisms of alterations, which might be important to obtain a more comprehensive understanding of the processes involved in AMD.