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NEW PROPOSAL FOR THE PATHOPHYSIOLOGY OF TYPE 3 NEOVASCULARIZATION AS BASED ON MULTIMODAL IMAGING FINDINGS

Spaide, Richard F. MD

doi: 10.1097/IAE.0000000000002412
Original Study
Free

Purpose: To investigate the imaging characteristics of early Type 3 neovascularization and propose a new pathophysiologic sequence for early disease.

Methods: Patients were evaluated with a comprehensive ophthalmologic examination to include fundus photography, optical coherence tomography, optical coherence tomography angiography, fluorescein angiography, and volume-rendered optical coherence tomography angiography. Relevant literature was also reviewed.

Results: There were 10 eyes of 9 patients who had a mean age of 87 (range 79–93) years and 7 were women. The patients were seen to have distributed areas of cystoid macular edema, not necessarily contiguous with areas of fluorescein or optical coherence tomography angiographic evidence of neovascularization, which colocalized with each other. Areas of hemorrhage were not necessarily contiguous with observed neovascularization. In some patients, massive amounts of edema were imaged, although the associated neovascular invasion was small and did not reach deeper portions of the retina. These findings were readily responsive to intravitreal injections of anti–vascular endothelial growth factor (VEGF) medication. Review of published literature showed conflicting pathophysiologic proposals, which did not abide with contemporaneous imaging findings.

Conclusion: Type 3 neovascularization likely grows in response to increased cytokine levels, particularly VEGF, in a permissive environment. Elevated levels of VEGF have been shown to cause hemorrhage, edema, and telangiectasis in the macula, suggesting some of the manifestations of Type 3 neovascularization are related to increased tissue VEGF levels and not necessarily to the neovascularization alone. A proposal based on imaging and histopathologic findings and known physiologic effects of VEGF is presented.

Eyes with Type 3 disease have hemorrhage and edema not necessarily contiguous with areas of neovascularization. The macular findings such as hemorrhage, telangiectasis, and edema may be related, in part, to increased cytokine levels, particularly vascular endothelial growth factor, and not necessarily the neovascularization itself.

Vitreous, Retina, Macula Consultants of New York, New York.

Reprint requests: Richard F. Spaide, MD, Vitreous, Retina, Macula Consultants of New York, 460 Park Avenue, New York, NY 10022; e-mail: rick.spaide@gmail.com

Supported by the Macula Foundation, Inc, New York, NY, which had no control over content.

Consultant and royalties, Topcon Medical Systems, royalties, DORC, and consultant Quark Pharmaceuticals.

Our appreciation of the exudative complications of age-related macular degeneration took a giant step forward with the 1967 publication by Gass,1 elucidating the pathophysiology of neovascularization. Subsequent decades of investigation, including that done by Gass,2 refined the ideas of choroidal neovascularization and its subclassification into Type 1 and Type 2 neovascularization. In 1992, Hartnett et al3 showed retinal blood vessels could proliferate posteriorly and be associated with detachments of the retinal pigment epithelium (RPE). In a subsequent publication in 1996, Hartnett et al4 showed how these descending retinal vessels were accompanied by hemorrhage, telangiectasis, and in addition to the pigment epithelial detachment. A disciform scar occurred as an end-stage result in some patients. They called this condition “deep retinal vascular anomalous complexes in advanced age-related macular degeneration.” This exudative manifestation was incorporated into the larger framework of neovascular age-related macular degeneration, although the vessels did not originate from the choroid. Over the subsequent years, the names used to designate the disorder have grown to include retinal angiomatous proliferation (RAP),5 occult chorioretinal anastomosis,6 and Type 3 neovascularization.7

The ideas concerning the pathophysiology and the sequence of events in the development of disease have changed many times over the years, even from the same groups of authors as will be reviewed in the Discussion. In the present study, multimodal retinal imaging, including volume-rendered structural and angiographic optical coherence tomography (OCT), was evaluated to determine characteristics of disease. Some simple findings were observed and offered clues to advance the concepts of this disease and its progression.

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Methods

This study involved 10 eyes of 9 patients with early new-onset Type 3 neovascularization examined at the Vitreous, Retina, Macula Consultants of New York, a community-based retinal practice by the author over a 1-year period. The study design was approved by the Western Institutional Review Board (Puyallup, WA).

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Study Design

The entry criteria were the presentation of having intraretinal hemorrhage, edema, and fluorescein angiographic findings consistent with Type 3 disease including localized telangiectasis and intraretinal leakage and staining in the context of localized intraretinal hemorrhage in a patient older than 55 years. Patients with extension of Type 1 choroidal neovascularization into the retina, considered by some to be part of Type 3 neovascularization,7 were not included in this study. Additional exclusion criteria included those eyes with evidence of neovascularization under the RPE, any inflammatory disease involving the eye, history of treated neovascular age-related macular degeneration in the study eye, laser photocoagulation, high myopia, inability to accurate fixation, or any media opacity that reduced the imaging quality. All patients underwent a complete ophthalmologic examination, which included measurement of best-corrected visual acuity, color fundus photography, fluorescein angiography, and in some cases indocyanine green angiography, OCT, and OCT angiography.

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Fundus Photography

Digital fundus photographs and fluorescein angiograms were taken with a Topcon TRC-50IX retinal camera (Topcon Medical Systems, Oakland, NJ) using a 50° field of the posterior pole and recorded on a MegaPlus II ES 11000 (Redlake, Inc, Tuscon, AZ). The leakage seen in a midphase angiogram was delineated. The fluorescein angiogram was morphed to the color photograph of the same eye, and the segmented area of fluorescein leakage was overlaid on the color photograph as a white outline that contained a transparent white fill. Areas of blood were segmented by using the green channel of the color photograph and then were outlined in red and given a transparent red fill in the color photograph.

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Optical Coherence Tomography

Images were obtained with both the Heidelberg Spectralis (Heidelberg Engineering, Franklin, MA) and the Optovue RTVue XR Avanti (Optovue, Inc, Freemont, CA). The Heidelberg Spectralis is a spectral domain instrument with a scanning speed of 85,000 A-scans per second and it also has eye tracking. The Optovue has an A-scan rate of 70,000 scans per second and was used in conjunction with its angiographic capability. En face slab images through the retina were obtained and the cystoid spaces were segmented from the structural data at various levels and added together to make a composite. The corresponding angiographic image was morphed to fit the retinal color image and the demarcated segmented areas of cystoid edema fluid were overlaid onto the color image. These were outlined in cyan and filled with a transparent overlay of cyan for select images. The segmented areas of intraretinal blood were used as masks in segmenting the OCT reflectivity data for the presence of blood. These areas were colored red for select volume-rendered images.

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Optical Coherence Tomography Angiography and Subsequent Volume Rendering

The instrument used for OCT angiography images is based on the Optovue RTVue XR Avanti (Optovue, Inc) to obtain amplitude-decorrelation angiography images. Each OCT angiography 3 mm × 3 mm volume contains 304 × 304 A-scans with two consecutive B-scans captured at each fixed position before proceeding to the next sampling location. Split-spectrum amplitude-decorrelation angiography was used to extract the OCT angiography information. Exclusion criteria included a quality score of less than six as supplied by the Optovue instrument and gross eye motions not corrected by the motion control software in the Optovue system.

En face images were obtained by using the superficial segmentation algorithm in ReVue software (Version 2017.1.0.151; Optovue, Inc). The data from the en face imaging were used to create volume-rendered images as previously described,8,9 with slight modification. The vascular data were given a pseudocolor based on depth with approximately 2° in hue in the HSB (hue saturation, brightness) color model for every 10 µm in depth. This provided a color clue to the depth of the image without resorting to retinal vascular segmentation-based color schemes. The B-scan structural OCT scan information was obtained from the same source. Both the en face and the B-scan data had projection artifact removal before use. The B-scan with flow overlay data was also used for volume rendering, where the intensity of the B-scan data was reduced while the flow data were retained. The OCT angiographic data were imported into the program MIPAV (Medical Image Processing, Analysis, and Visualization, version 8.0.2; US National Institutes of Health, Bethesda, MD) for volume rendering. The opacity transfer and the look-up table functions were adjusted to improve visualization of the vasculature. Volume rendering of the B-scan image information data created images in which diaphanous remnants of the ellipsoid layer, when present, and the RPE were retained and acted as fiducial landmarks. Using the RPE layer as a landmark, the exact relationship of vessels to the RPE layer could be visualized. The resultant volume-rendered sample could be examined at any arbitrary magnification, rotated in any axis and could be sliced to reveal contents obscured by other structures.

Retina subsidence was a term used to designate the descent of the outer retina vessels toward the RPE with a lessening of the distance from the deep vascular plexus, or any potential posterior proliferation of vessels and the RPE. The extent of edema was considered to represent the outer demarcation of the region of the retina having cystoid spaces, not retinal thickening, which likely underestimated the true lateral extent of the edema.

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Results

There were 10 eyes of nine patients who had a mean age of 87 (range 79–93) years and seven were women. The changes in retinal vessels over time are shown in one 84-year-old patient who had established Type 3 neovascularization in the fellow eye (Figures 1−3). The patient began having manifestations in the second eye appearing as subtle cystoid collections of fluid (Figure 1A). There was a descent of retinal vessels toward the RPE and coincident alterations in the superficial vascular plexus (Figure 1, B and C). There were vessels that appeared to connect to the angiomatous lesion. Both the angiomatous lesion and the associated vessels regressed promptly with treatment, seemingly highlighting the rapidity of vascular remodeling that could occur in this disease (Figure 1D). An alternate method of viewing the imaging information is to volume render the projection artifact–removed imaging data while leaving vestiges of the structural OCT data. This produces the imaging shown in Figure 2. Note when viewed from the vitreous side, the image is similar to the en face OCT angiographic image, as it should. The image was produced from the data of imaging done when the patient had prominent edema associated with an angiomatous proliferation, and the enlarged retinal vessels are visualized. The data block can be rotated to visualize the flow structure at an angle or perpendicular to the surface. In the perpendicular view (Figure 2C), the descent of the angiomatous lesion to halfway between the deep capillary plexus and the RPE can be seen. The retinal vascular changes seen in the OCT angiographic images could be seen in ordinary fundus photographs (Figure 3), in which the feeding and draining vessels could be seen to regress.

Fig. 1

Fig. 1

Fig. 2

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Fig. 3

Fig. 3

The region involved with the neovascularization was small and not necessarily contiguous with the area of fluorescein staining as shown in Figure 4. This patient had retinal hemorrhage surrounding an area of fluorescein staining. An area of cystoid edema was located in a noncontiguous region of the macula. The areas involved with cystoid spaces could be curiously distant from observed regions of fluorescein staining, and they did not fill with dye during the relatively short course of the angiographic sequence. Figure 5 shows an eye with a small area of fluorescein staining that had a colocalizing descent of intraretinal neovascularization to the level of the RPE. Contiguous with this area was a small retinal hemorrhage. Cystoid edema, not contiguous with the observed neovascularization, was seen to arch around a small focus of geographic atrophy and was present on the antipodal side of the atrophy from where the neovascularization was imaged. Figure 6 shows a patient with intraretinal hemorrhage and edema that showed a deep plaque of fluorescein staining. There was overlying hemorrhage that blocked visualization with OCT angiography, but three larger vessels were seen to course posteriorly to a small lesion at the level of the RPE. No penetration of the RPE by vessels and no visualization of vascular flow were imaged under the RPE. In this case, areas of deeper cystoid edema were imaged in areas not contiguous with the nexus of the descending vessels.

Fig. 4

Fig. 4

Fig. 5

Fig. 5

Fig. 6

Fig. 6

Some patients had small areas of apparent neovascularization but had extensive edema. Figure 7 shows a small area of fluorescein staining surrounded by a region many times larger than that was involved with cystoid edema. Figure 8 shows an eye with a relatively large area of fluorescein leakage that was partially obscured by hemorrhage. The patient had very prominent cystoid edema. Optical coherence tomography angiography demonstrated modest evidence of the vascular presence deeper than the outer plexiform layer, but no invasion into the deepest layers of the retina. The patient showed a prompt response to injection of anti–vascular endothelial growth factor (VEGF) agents, and by the fourth injection showed no evidence of hemorrhage, edema, or perfusion of the neovascularization (Figure 9). The patient shown in Figure 10 was similar in that there was hemorrhage and prominent edema, but little evidence of vascular invasion deep into the retina in OCT angiography and there was no evidence of Type 1 neovascularization. The fluorescein angiogram shows modest and nonlocalizing hyperfluorescence from the retinal tissue against a background of drusen and adjacent geographic atrophy. Indocyanine green angiography did not demonstrate any prominent retinal vascular abnormality or Type 1 neovascularization. There was an area in the nasal macula that appeared to show vessels deeper than the outer plexiform layer in the B-scan OCT images with flow overlay, and this area is shown in the volume-rendered version (Figure 10B). The patient showed a dramatic improvement after anti-VEGF therapy. After one injection, most of the hemorrhage and edema nearly resolved and there was only a suggestion of remaining neovascularization.

Fig. 7

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Discussion

This study shows features in the development of Type 3 neovascularization that expands the underlying concepts of disease pathophysiology. Edema and hemorrhage were found to occur before neovascularization. In eyes with neovascularization, there were widespread edema and hemorrhage, much greater in extent than the area of neovascularization, and were not necessarily contiguous with the new vessels. With evolution of neovascularization, there appeared to be rapid vascular remodeling of vessels associated with the lesion, including vessels supporting the lesion involving the superficial plexus. Treatment brought a rapid reduction in the amount of edema and hemorrhage and associated retinal vascular changes. Although these seem to be simple findings, they differ from what has been previously reported and they have significant implications in our understanding of Type 3 disease. To fully understand these implications, it is important to appreciate historical developments in the perception of the disease, particularly the contradictory nature of what has been reported over the past two and a half decades.

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Historical Perspectives

In 1992, Harnett et al3 reported unusual retinal pigment epithelial detachments that were associated with retinal vessels that dove down into the deep retina and formed an angiomatous lesion. In 1996, Harnett et al4 further defined what they called “deep retinal vascular anomalous complexes” as having at least one retinal arteriole dipping to a deep vascular complex and at least one draining retinal venule with an intervening angiomatous lesion. The angiographic examples showed the vascular connections to arise from the inner retina. The authors described additional characteristics, including blot and nerve fiber layer intraretinal hemorrhages, retinal telangiectasis, and microaneurysms. They proposed that outer retinal “hypoxia, angiogenic factors such as vascular endothelial growth factor released by Müller and other cells may encourage retinal vessels to proliferate in a directional manner toward the outer retina.”

In 2000, Lafaut et al10 reported the histopathologic findings of six specimens from eyes with deep retinal anomalous complexes that were obtained at the time of retinal translocation surgery. Four of the cases had angiography and showed retinal vascular vessels from the inner retina descending into the retina to the deeper angiomatous lesion. None of the cases showed vascular connections to the choroid by histology and two specimens had retained large retinal vessels attached to the excised lesion.10

In 2001, Yannuzzi et al5 published a paper covering the clinical aspects of 143 eyes of 108 patients with an entity that they called “retinal angiomatous proliferation” (RAP). The neovascularization appeared to be identical to that reported earlier by Hartnett et al, but Yannuzzi et al fleshed out what they considered to be the pathophysiologic development of neovascularization. They proposed that neovascularization originated from the deep vascular plexus and grew toward the superficial retina and deep retina simultaneously. This was Stage I RAP (see Figure 1 of the article by Yannuzzi et al). In Stage II RAP, the newly proliferating vessels extended out of the retina into the vitreous and were associated with preretinal hemorrhages. There was also a large vascular structure in the inner retina in the schematic drawings, but this structure was not defined. In addition to anterior retinal neovascularization, vessels proliferated posteriorly toward the RPE. The vessels originating from the neovascularization were capillaries, but they did not change in caliper after the development of the new vessels. The new vessels appeared to be smaller in diameter than the capillaries. In both the inner and outer neovascularization, there were dozens of new retinal vessels drawn in the schematics. Curiously, the accompanying angiographic images showed a limited number of vessels, sometimes as few as two, descending into the retina. No angiographic example of preretinal neovascularization was shown. The schematics showed cystoid collections of fluid in the retina were contiguous with individual newly growing vessels.

In 2003, Spaide11 reported a significant association of focal hyperpigmentation with RAP in the fellow eye; both of these conditions showed bilateral symmetry. Spaide et al12 proposed the focal hyperpigmentation was caused by detached retinal pigment epithelial cells that migrated into the retina but retained their ability to secrete VEGF. This caused a VEGF gradient that helped induce the posterior growth of vessels in the disease. In 2003, Gass et al6 proposed a different explanation than what was proposed by Hartnett et al4 and Yannuzzi et al.5 Gass et al believed there was preexisting occult neovascularization with coexistent atrophy of the outer retina. With subsidence of the retina, the retinal blood vessels came near the occult neovascularization, which eventually resulted in chorioretinal anastomoses and associated intraretinal hemorrhage. The superficial hemorrhage was a sign of occult chorioretinal anastomosis in occult choroidal neovascularization, thus two uses of the word occult in a one-phrase disease description.

Shimada et al13 reported the histopathologic findings of specimens obtained by surgical excision of RAP in nine eyes of eight patients in 2007. The neovascular masses expressed VEGF and included macrophages and RPE cells. Hypoxia-inducible factors (HIF-1 alpha and HIF-2 alpha) were also expressed.13 Histologic examination by Monson et al, and Klein and Wilson showed prominent intraretinal hemorrhages could be found in the superficial retina, even the nerve fiber layer, well away from the neovascularization. Intraretinal RPE cells were observed to be contiguous with the neovascular lesion.14,15 Like the Lafaut et al's paper, none of these publications showed any vascular connection to the choroid.

In 2008, Krebs et al16 had a schematic progression of RAP (shown in Figure 1 of the article), and like Yannuzzi et al, they showed the vessels started in the deep plexus and proliferated anteriorly and posteriorly in the retina. The newly growing vessels were proposed to penetrate the internal limiting membrane to enter the vitreous cavity anteriorly, whereas the posteriorly proliferating vessels reached and then penetrated the RPE layer. There were hundreds of proliferating vessels shown. The two supporting angiographic cases shown in Figures 2 and 3 of the article, nevertheless, showed two vessels connecting the superficial retinal plexus to an angiomatous lesion in one figure and no visible connection from any layer vessels in the other, respectively.

In 2008, Freund et al reported five eyes of four patients with early Stage 1 RAP lesions. They stated the analysis of selected cases suggested a choroidal origin of the neovascular complex with early retinal choroidal anastomosis and evidence of early Type 1 neovascularization.7 They did not state how this would be differentiated from a mixed Type and Type 2 lesion. They specifically stated that because RAP may originate not only from deep retinal capillaries but also from the choroid, the term “Type 3 neovascularization” should be used instead of RAP. They updated the drawings from Yannuzzi et al's three-stage classification to include the theory of choroidal origin while retaining the preretinal neovascularization and large superficial intraretinal vessels. They showed the cystoid edema and individual hemorrhages being closely associated individual vascular segments in the neovascular growth. The new vessels were shown to arise from the capillaries in the retina. With the advent of neovascularization, the originating vessels did not change in diameter and the new vessels were smaller in diameter than the capillaries.

Querques et al17 reported in 2013 that the precursors to Type 3 neovascularization were baseline hyperautofluorescence that turned to focal hypoautofluorescence over time. They also reported that there was localized RPE elevation with focal disruption of the RPE and photoreceptors and “the overlying outer plexiform layer that progressively took contact with the RPE.” It is not clear if the contact was with the RPE or the RPE defect.17 In the same year, Querques et al18 reported 19 eyes of 19 patients with Type 3 neovascularization with simultaneous OCT and angiography. They stated all eyes had focal discontinuity of the RPE monolayer, there was a single retinal arteriole feeding into the lesion, and choroidal contributions to the neovascular process could not be visualized.

In 2015, Kuehlewein et al19 reported the OCT angiographic findings of Type 3 neovascularization in 29 eyes of 24 patients. They believed the neovascular complex appeared as a “small tuft of bright, high-flow tiny vessels with curvilinear morphology located in the outer retinal layers with a feeder vessel communicating with the inner retinal circulation (i.e., deep retinal capillary plexus).” This is difficult to understand because the deep capillary plexus is separate from the inner, or superficial, vascular circulation. Of the 29 eyes, 16 were active and in 10 of these vessels could be visualized, whereas in the 13 inactive eyes no vessels could be visualized. In 2015, Miere et al20 reported 18 treatment-naive eyes of 18 consecutive patients; OCT angiography reportedly showed lesions characterized by retinal–retinal anastomosis that emerged from the deep capillary plexus and descended down to abut the RPE.

In 2015, Querques et al21 (the same authors as Ref. 18) published an editorial, which also contained supporting clinical imaging information. They stated that “in many cases, the early appearance of Type 3 neovascularization is characterized by an intraretinal vascular complex emanating from the deep capillary plexus often associated with adjoining telangiectatic vessels.” The lesions were said to be retinal–retinal anastomoses. In their schematics, they showed Type 3 neovascularization arising as a multitude of vessels (unlike their 2013 paper)18 from the deep capillary plexus. The drawings did not show extension of the neovascularization into the inner retina until late in the disease, but when it happened, the extension was by numerous vessels. This suggests there must be a VEGF gradient to the inner retina. Cystoid spaces were shown to be directly contiguous with the new vessel elements. Unlike the 2013 paper, many cases shown did not have subsidence of the inner and middle retina, and high-resolution OCT scanning did not show any apparent defect in the RPE. The authors retained the idea that Type 3 neovascularization could arise from the choroid, in a process where many vessels broke through the RPE and connected to the deep plexus with no change in the diameter of the deep plexus capillaries.21

Su et al22 reported 34 eyes with new-onset Type 3 neovascularization in 2016. Some eyes had what the authors considered to be a preonset OCT; the majority of these, 77.8%, had hyperreflective foci. With initiation of neovascularization, which grew toward the deep retina, there was also neighboring cystoid edema in the retina. As the neovascularization descended, the associated cystoid spaces became larger. The neovascularization originated from the deep vascular plexus and did not involve any more superficial layers with maturation of the lesion, which contained what appeared to be dozens of small vessels (see Figure 1 in Su et al22). They showed one angiographic image, which demonstrated two vessels from the superficial vascular plexus descending to a deeper lesion and no apparent deeper vascular contributions. In 2018, Sacconi et al23 reported a condition they termed “nascent Type 3 neovascularization.” Hyperreflective foci were found to have flow signal, suggesting to the authors these foci, as opposed to previous proposals, may represent new vessels. The authors did not use projection artifact removal in their imaging. They stated the neovascularization did not show leakage until the vessels progressed into the RPE and sub-RPE space.23

There are many common elements to previously reported schema for the development of Type 3 neovascularization. The first steps involve vessels originating from the deep plexus. The main vector for growth of these vessels appeared to be posteriorly, in which a diffusely distributed multitude of vessels, dozens in number, descended toward the RPE. The deep vascular plexus is composed of capillary-sized vessels,24 but each of these capillaries was shown to sprout many smaller-sized vessels and so were vessels smaller than capillaries. In none of the published models do the vessels in the deep plexus enlarge after this occurs, so it is difficult to know how the increased blood flow of the lesion was delivered. A choroidal connection or origin is shown in these schemas, and the many capillaries proposed to be involved sprout from a few capillaries in the choriocapillaris. The sprouting vessels were a fraction of the diameter of the choroidal capillaries, and the choriocapillaries do not change in diameter once this occurs (note that vessels have a lower limit in terms of size, given the dimensions of the cellular elements in blood). Either initially or in some models later, a myriad of small vessels grew into and connected with the superficial vascular plexus, but the inner vessels did not change in diameter. In addition, the direction of growth appears to be directed anteriorly, which is running counter to the vector of the previously growing vessels. In several papers, vessels are shown to enter the vitreous cavity, but corresponding clinical evidence for this has not been published. Any associated hemorrhage or cystoid spaces were shown to be contiguous with specific vessels in the neovascular complex. These models did not agree with the observed vascular growth contemporaneously imaged with fluorescein and indocyanine green angiography, which generally showed only one or a few feeding and draining vessels that connected directly to the superficial vascular plexus. These models did not agree with contemporaneous histopathologic studies.

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New Proposal

Tolentino et al injected VEGF into the vitreous cavity of monkeys.25–27 Elevated levels of VEGF were found to cause retinal vascular leakage, hemorrhage, and telangiectasis. Curiously, most eyes did not develop retinal neovascularization, but a few did produce minimal peripheral neovascularization.25,26 Vascular endothelial growth factor helps initiate the early stages of angiogenesis in which there is vascular leakage and proliferation of capillary tubes.28 From animal models of ischemia and data obtained from treating humans, we know VEGF blockade is effective in causing neovascularization to regress.29–31 This implies VEGF is necessary, but may not be sufficient in all disease states, to cause pathologic retinal neovascularization, although it is sufficient to cause iris neovascularization.27 We see VEGF-driven leakage and edema in diabetic retinopathy and veno-occlusive disease, but these patients do not develop intraretinal neovascularization in the macula. This suggests that in diseases where vessels do grow, such as Type 3 neovascularization, there must be a permissive local environment. If there is enough VEGF in the retina to elicit neovascularization, there is reason to expect vascular leakage, telangiectasis and hemorrhage would also occur independent of the new vessel growth. The new vessels also have the potential to contribute to the observed edema and hemorrhage.

Vascular remodeling is expected to occur with demands to deliver blood flow to the newly growing complex, with enlargement of a limited number of retinal vessels feeding and draining the lesion. Vascular enlargement in vessels is dependent on shear stress on the vascular endothelial cells and is not dependent on VEGF.32 Vascular enlargement can occur in newly proliferated or in established vessels. Ultimately the flow in the lesion is derived from the superficial vascular plexus. Efficient remodeling would create feeder and draining vessels connecting to the superficial plexus instead of dozens of small vessels connecting to the deep plexus, which in turn would require some method of conducting increased blood flow to and from the superficial plexus. Treatment with anti-VEGF agents causes a regression of the newly growing vascular sprouts. It is possible that older, arteriolized components of the neovascularization may not regress with VEGF withdrawal. Even so, if the lesion is sufficiently suppressed, there could be vascular remodeling leading to vascular regression. Histopathologic evaluation has shown there is a vascular network of small capillary-sized vessels in the angiomatous proliferation between the larger feeding and draining vessels, as would be expected in an acquired angiomatous growth of vessels proliferating because of a stimulus. Therefore, the term “retinal–retinal anastomosis” is not accurate as a primary descriptor for Type 3 disease.

The source of the VEGF is likely to be multifactorial. The choriocapillaris is attenuated under areas of drusen and subretinal drusenoid deposits.33 Optical coherence tomography angiography shows signal voids in eyes with pseudodrusen and drusen.34,35 This loss could lead to outer retinal ischemia. Estimates of the oxygen diffusion over drusen are limited by the lack of knowledge of the diffusion coefficient for drusen material. Assuming a solitary drusen 200 µm in diameter, 70 µm in height, and a diffusion coefficient the same as the retina, Linsenmeier and Zhang36 calculated there would be a greater than 40% drop in photoreceptor pO2. In age-related macular degeneration eyes, the choriocapillaris is compromised, there are often confluent drusen and basal laminar deposit, so the actual pO2 reduction is likely to be much worse. Hypoxia may be a factor in causing the RPE cells to detach from the RPE monolayer to migrate up to the more vascularized retina. When the RPE cells depart, one would expect a defect to occur in the monolayer. To what extent the defect persists, how much is filled with Müller cell processes, or is covered by cellular extensions of neighboring RPE cells is not known at present. Inherent in these possibilities is the likelihood that altered diffusion of material, and potentially cytokines, could occur from the choroid. Increased levels of VEGF can contribute to vessel growth, but for it to do so there has to be concomitant changes in cytokine levels produced by other cells, such as Müller cells, which can produce angiogenic and antiangiogenic37–39 cytokines. The total balance of forces exerted by proangiogenic and antiangiogenic forces would ultimately control the proliferation of vessels, but the presence of VEGF, by itself, could cause retinal vascular abnormalities (Figure 11). A gathering storm leads to increased risk of lightning strikes, which may occur in a stochastic fashion. The risk factors associated with the advent of Type 3 neovascularization, such as drusen and focal hyperpigmentation, could lead to a VEGF storm in the retina, potentially leading to increased risk of proliferation and descent of new vessels somewhere in the region involved.

Fig. 11

Fig. 11

A proposed series of pathophysiologic events is schematically shown in Figure 12. Consistent with previous reports, there are drusen with overlying detachment and migration of RPE cells into the retina. At present, there are not enough data to model how subretinal drusenoid deposits, appearing as pseudodrusen, affect development of disease. Initial stages include release of VEGF leading to edema and small hemorrhages in the retina. Given the lack of visualization of vessels in early cases, it is likely that there is a preproliferative stage in which VEGF-mediated changes occur in the retina before the advent of neovascularization. Therefore, a suggested naming scheme is that the process is Type 3 disease (or alternatively Type 3 vasculopathy) and this stage is called preproliferative Type 3 disease. Over time, in a permissive environment, there is the development of new vessels that grow along a VEGF gradient that increases posteriorly. This phase is called Type 3 neovascularization. Leakage and hemorrhage present could be related to the continued levels of VEGF and from the neovascularization. Vascular remodeling would lead to the evolution of larger feeding and draining vessels, ultimately connecting to the superficial plexus. It is not necessary to posit blood vessel growing into the inner retina, as this would require another VEGF gradient. Inherent in the definition is that Type 3 vessels originate from the retina and not from underlying Type 1 neovascularization or the choroid as was proposed in Refs. 6, 7, and 21.

Fig. 12

Fig. 12

This study found that areas of hemorrhage and edema were far larger, and not necessarily contiguous, with hyperfluorescence seen during fluorescein angiography in eyes with Type 3 neovascularization. These areas could appear before the advent of actual neovascularization. These findings, in part, may be attributed to increased cytokines, such as VEGF, in the retina because the known physiologic effects of VEGF on the retinal vasculature includes leakage, hemorrhage, and telangiectasis even without the production of neovascularization. These findings mark the preproliferative stage of Type 3 disease. Proliferation and remodeling of associated retinal vasculature is proposed to lead to feeding and draining vessels with an intervening mass of new capillaries. Although the initiation of the neovascularization could be from the deep capillary plexus, after remodeling the connections would likely appear to be from the superficial vascular plexus, as has been shown in many past reports. Lack of prominent fluorescein pooling in the cystoid spaces in the present series is intriguing. In a similar manner, poorly evident pooling of dye in cystoid spaces occurs in retinovascular cystoid macular edema secondary to diabetes or veno-occlusive disease, other forms of macular neovascularization. The various possibilities for this observation could include intraretinal diffusion of fluorescein in the retina occurring at a much slower rate than the aqueous component in edema, the susceptibility to light scattering inherent in fundus camera angiography, and not enough contrast between the amount of dye in the cystoid spaces compared with the surrounding tissue at the time of image acquisition in the angiographic sequence. This study has salient weaknesses, the largest being the limited number of cases evaluated. This has been a weakness of most studies published to date and may be an explanation for the large variability in the findings attributed to Type 3 disease.

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References

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Keywords:

age-related macular degeneration; optical coherence tomography; type 3 neovascularization; volume rendering

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