Non-Neovascular Age-Related Macular Degeneration
Ricardo N. Louzada, MD; Nadia K. Waheed, MD, MPH; Jay S. Duker, MD; and Mark Lane, MBBS Honors
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in adults older than 50 years in developed countries.1–3 Non-neovascular or dry AMD accounts for 85% to 90% of all cases of macular degeneration.
Clinically, the hallmark lesion of dry AMD is drusen, which can be observed on fundoscopic examination as yellow deposits underneath the retina (Figure 16-1A). Large areas of retinal pigment epithelial (RPE) atrophy are the characteristic finding of late-stage dry AMD, and these lesions are commonly known as geographic atrophy (GA) (Figures 16-2A to 16-2D).4–7
Early AMD is often asymptomatic. However, as the condition progresses into the central macula (Figures 16-2E and 16-2F), there is gradual vision loss that is topographically associated with the site of photoreceptor destruction.
EARLY AGE-RELATED MACULAR DEGENERATION
The pathogenesis of the progression of early dry AMD through intermediate AMD to GA, as well as its occasional conversion to active wet AMD, remains poorly understood. Drusen, pigmentary changes, and photoreceptor and RPE loss can appear clinically on fundoscopic examination as focal white-yellow excrescences deep to the retina, and they vary in number, size, shape, and distribution (see Figure 16-1A).8,9 Despite the limited clinical symptoms in early AMD, it is possible to visualize this condition on optical coherence tomography (OCT) (Figure 16-1B). Drusen are visible as hyper-reflective material between Bruch’s membrane and the RPE.10–12 High-definition (HD) spectral domain (SD)-OCT B-scans can also be used to assess the ultrastructure of drusen and to evaluate for evidence of disruption (or the lack thereof) of adjacent retinal layers. In Figure 16-1D, the RPE overlying the drusen appears to be mostly intact while there is loss of RPE overlying an area of GA, as well as some disruption of the RPE at the margins of the GA seen in Figure 16-2F.
Multiple histological studies have investigated the relationship between the RPE, Bruch’s membrane, and the choriocapillaris (CC) in the pathogenesis of AMD. The choroid is an extensive vascular network that consists of an outer macrovascular layer and an inner capillary layer called the CC that is below Bruch’s membrane. It provides 70% of the total blood flow to the eye, providing nutrients and removing waste products from the outer retinal structures.13
With regard to this relationship, 2 conflicting hypotheses are often cited. The first hypothesis states that the pathogenesis of AMD is linked to an initial RPE loss that causes secondary CC loss and photoreceptor degeneration. This is supported by histopathological data that suggest the loss in CC underlying RPE atrophy is rarely complete, with small constricted capillaries often still noted.14–17 The second hypothesis indicates that the initial insult is CC breakdown that causes RPE atrophy, consequently leading to the dysfunction and death of the photoreceptors that are commonly seen in AMD.18
Figure 16-1. Flow impairment under drusen. OCT Zeiss Cirrus HD-OCT with AngioPlex (Carl Zeiss Meditec Inc). (A) Color fundus photograph of the left eye illustrating small, intermediate, and large drusen. The dashed square represents the area scanned in the 6 × 6 mm OCTA scan seen in (C) The red line represents the level of the OCT B scan in (D). (B) The 6 × 6 mm OCTA at the level of the choriocapillaris (CC) and (C) the 3 × 3 mm OCTA at the level of the CC. The drusen shown are associated with areas of decreased signal in the CC, indicated by the white arrows, that may suggest flow impairment. (D) Corresponding cross-sectional OCT 6 mm with the segmentation at the level of the CC. (E) Corresponding structural 6 × 6 mm en face OCT image at the level of the CC and (F) corresponding structural 3 × 3 mm en face OCT image at the level of the CC. Both (E) and (F) show good penetrance of OCT signal at this level. This strongly suggests that the reduced signal noted on the OCTA scans in (B) and (C) represents true loss of flow in the CC and not artifactual dark areas seen as a result of blocked signal due to overlying drusen or pigment.
Figure 16-2. Multimodal image of GA. (A) Color fundus photography of the right eye of a patient with dry AMD and a large central GA (yellow arrowheads) with surrounding drusen (white arrows). (B) Fundus auto-fluorescence (FAF). FAF allows improved visualization of the GA areas and borders compared to fundus photography. (C) High-definition scanning laser ophthalmoscope image. Visualization of corresponding GA using the RS-3000 Advance (Nidek Inc). (D) A 6 × 6 mm OCTA at the level of the choriocapillaris (CC) underlying the GA. The image shows some mild loss of CC beneath the GA. This OCTA image was obtained using the Avanti RTVue XR with AngioVue software for OCTA (Optovue Inc). (F) Corresponding OCT B-scan using the RS-3000 Advance, 12 mm HD scan through the GA. The choroidal OCT setting (EDI-OCT) and with ultra-fine sensitive mode was used. Increased signal intensity is noted due to the loss of RPE; this gives a reverse shadowing pattern. The red line in (E) shows the approximate segmentation level used to obtain the OCTA in (D).
Figure 16-3. OCTA artifacts in dry AMD. Example of OCTA signal loss on SD-OCT. (A) A 3 × 3 mm en face OCTA at the level of the choriocapillaris (CC). Notice the dark areas seen in the OCTA (yellow arrows) that may represent loss of flow at the level of the CC or loss of OCT signal. (B) The corresponding cross-sectional OCT scan. (C) The corresponding 3 × 3 mm en face OCT. Since the yellow arrows show dark areas consistent with poor OCT signal penetrance or low SD-OCT signal, it can be concluded that the dark areas seen on the OCTA in (A) actually represent loss of signal rather than true loss of flow. Even though there could be loss of CC flow underlying these areas in addition to the loss of signal, all that can be concluded from these scans is that the signal penetration under the drusen is too poor to make any conclusive determination regarding CC flow. Despite the apparently contradicting hypotheses regarding the pathogenesis of AMD, many papers have indicated that the site of drusen formation is not random but is influenced by CC dysfunction, with drusen more likely to form at sites of insufficient CC perfusion, secondary to vascular endothelial cell loss. The advent of optical coherence tomography angiography (OCTA) increases the probability that these questions might soon be answered, and it is hoped that this technology will vastly improve our knowledge and monitoring of the condition.13 OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IN DRY AGE-RELATED MACULAR DEGENERATION OCTA is a relatively new, noninvasive technology that generates depth-resolved images of the vasculature of the retina and choroid by acquiring repeated B-scans from the same location. Erythrocyte movement within vessels generates a decorrelation signal that is displayed as a grayscale image. There are currently 2 commercial SD-OCTA devices that are available. The first is the RTVue XR Avanti with AngioVue software for OCTA (Optovue Inc), which operates with a wavelength of ~840 nm and a scan rate of 70 kHz A-scans/second. The second device is the Zeiss Cirrus HD-OCT (Carl Zeiss Meditec Inc), which operates at a ~840 nm wavelength and 68,000 A-scans/second. Recent advancements in OCTA technology permit evaluation of the individual layers of the retina that can then be correlated and cross-registered with structural OCT scans. Using this methodology, it is possible to visualize the site of drusen and to correlate this with vascular changes in the CC both underneath and surrounding drusen (Figures 16-1B, 16-1C, 16-1E, and 16-1F). It has been noted that early dry AMD is associated with focal areas of CC loss and a general reduction in CC density when compared to age-matched normal controls. These OCTA findings are supported by histopathological data that have noted that drusen form over areas devoid of capillary lumens and extend into the intercapillary pillars, and that increased drusen density is associated with a reduction in the vascular density of the CC (see Figure 16-1B).19–23 In evaluating the CC underlying areas of drusen, however, it is important to be cognizant that signal attenuation may occur as the OCT signal penetrates through the RPE and into the choroid, especially in areas with RPE clumping or hyper-reflective material in the outer retina. As a result of this, it may not be possible to generate a decorrelation signal beneath the areas of drusen, and this gives the false appearance of CC defect when looking at the OCTA image, when, in fact, it is a shadow artifact. This is demonstrated in Figures 16-3A and 16-3B, where dark areas on the OCTA image actually correspond to areas of signal loss and shadowing, and a consequent inability to generate OCTA signal, rather than a true loss of the CC. This can be verified by looking at the structural en face image at the level of the CC (Figures 16-3B and 16-3C), which shows dark areas consistent with signal loss underlying the drusen. This problem is somewhat but not completely mitigated by the better penetrance that occurs in the longer wavelength swept source (SS)-OCT devices. Figure 16-4. OCTA and varying interscan time analysis (VISTA) flow maps of GA. (A) A 6 × 6 mm en face OCT of a patient with GA. Note the well-demarcated margins of the RPE loss in GA. (B) En face projection of the OCTA volume at the level of the choriocapillaris (CC). There is loss of CC underlying the area of GA, marked by the dashed red line. There is also impaired flow in the CC beyond the margins of the GA, for example, as seen in the areas surrounded by the dotted blue lines. (C) En face projection of the OCTA volume at the level of the CC, using double the interscan time seen in image B, and therefore increasing sensitivity to slow flow. Note that there is still quite a profound loss of CC underlying the area of the GA. However, at the margins of the atrophy (white and yellow square), as well as outside the margins (blue outline), increasing the interscan time allows for the detection of more vessels with slower flow that are evident by the greater vascular density in the white and yellow squares, as well as in the blue outlines. This suggests that while the area under the GA has a loss of flow in the CC, the areas around the GA show flow impairment characterized by a slowing of flow. (D) This is a color-coded map that chromatically represents the information obtained from the VISTA images above. Red represents fast flow and blue represents very slow flow. In the area of GA, CC has reduced flow and the larger choroidal blood vessels with high-flow velocities can be visualized as having migrated into this space. At the margins of the atrophy, there is decreased flow but not as profound a loss of flow in the CC as is seen underlying the GA.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
