Current Perspectives on Type 3 Macular Neovascularization due to Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is a prevalent, chronic, and progressive retinal disease that causes central vision loss due to damage to photoreceptors, retinal pigment epithelium (RPE), and choriocapillaris (CC) [1, 2]. The neovascular phenotype of the disease accounts for almost 90% of the severe visual loss associated with AMD [3]. Progress in in vivo retinal imaging has enabled refined characterization of neovascular AMD (nAMD) lesions, underscoring the heterogeneity of the disease. Therefore, an international group of retinal specialists, imaging experts, and ocular pathologists proposed a new consensus nomenclature for nAMD in 2020, providing a more complete view of pathological changes that occur in AMD and determining common terminology for phenotypic features [4]. Among others, the proposal defines the new term “type 3 macular neovascularization” (MNV3), replacing earlier descriptions of this form of neovascularization including retinal vascular anomalous complexes, retinal angiomatous proliferation, and occult retinal-choroidal anastomosis [5‒7]. The exact characterization of this type is important as recent multimodal imaging studies have shown that the frequency of MNV3 lesions in nAMD appears to be significantly higher than previously thought. Moreover, for this macular neovascularization (MNV) type, the validity of established optical coherence tomography (OCT) biomarkers such as intraretinal (IRF) and subretinal (SRF) fluid needs to be re-evaluated [8‒12]. The current pathophysiological understanding of MNV3 and its implications for current patient care and future clinical research directions are described in detail.

The neovascular phenotype of AMD is characterized by a MNV invading the outer retina, subretinal space, or sub-RPE space. Depending on the anatomical location of the neovascularization in OCT, the lesion is classified as MNV1, MNV2, or MNV3 [4] (Table 1).

In angiographic studies, MNV3 had been estimated to occur in approximately 10–15% of newly diagnosed cases of nAMD [13‒15]. Yet, the increasing availability of OCT imaging appears to have distinctly improved the identification of MNV3 lesions. For instance, Jung et al. [16] reported the incidence of the three types of MNV in nAMD with the use of OCT. They found that MNV3 comprised 28–34% of eyes with nAMD. The authors attributed the discrepancies to the identification of a higher frequency of MNV3 and a lower frequency of MNV1 with the aid of OCT. Consistently, Mrejen et al. [17] also reported a frequency of MNV3 lesions of 34% in their cohort based on OCT and fluorescein angiography (FA). In a post hoc analysis of the phase 3 HARBOR trial of ranibizumab in nAMD, the CONAN Study Group criteria were applied for the first time to a major trial dataset and identified 37.6% of eyes with MNV1, 41.0% with MNV2 and mixed, and 21.4% with MNV3 lesions [18].

A high incidence of bilateral involvement is characteristic of MNV3 [19‒22]. Gross et al. [19] reported a risk of up to 100% of second eye involvement in MNV3 after 3 years. In fact, the annual and accumulative risk of neovascularization in the fellow eye is strikingly higher in unilateral MNV3 patients than in patients with other forms of exudative AMD. Importantly, in patients with unilateral MNV3, a longer time interval between fellow-eye examinations resulted in poorer visual acuity and greater vision loss of the fellow eye at neovascularization. Thus, the importance of regularly monitoring unaffected fellow eyes must be emphasized, and patients must be made aware of frequent fellow-eye examinations to preserve their vision.

MNV3 lesions are located between 500 and 1,500 µm from the central fovea, mainly in the temporal area [23]. Due to the origin of MNV3 in the deep retinal plexus [24‒26], MNV3 is not found within the foveal avascular zone [23]. In a recent study, one or more intraretinal flame-shaped or punctate hemorrhages were observed funduscopically in 75% of MNV3 eyes, always outside the foveal avascular zone, which can be considered pathognomonic for treatment-naive MNV3 [27]. In the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) study, even 90% of patients with MNV3 lesions showed intraretinal hemorrhages [28]. Besides, cystoid macular edema may be present. Both intraretinal hemorrhages and cystoid macular edema may appear prior to the neovascularization and must not necessarily co-localize with the neovascularization [29]. Moreover, dense exudates are seen funduscopically in 63% of MNV3 patients, which is significantly higher compared to the other types of MNV [27]. At diagnosis, an incidence of SRF is reported in 29.4–47.5% of patients [8, 9, 30]. A serous pigment epithelium detachment (PED) is present in 61.9% of patients at the time of diagnosis [31]. In a retrospective study evaluating the incidence and timing of PED and SRF development in MNV3, serous PED developed in 62.5% at a mean of 10.9 ± 5.1 months after diagnosis if PED was not present at diagnosis. Further, in patients with PED and without SRF at diagnosis, SRF developed in 28.8% at a mean of 11.2 ± 6.4 months after diagnosis [31].

MNV3 lesions arising from cilioretinal arteries represent a subtype named cilioretinal MNV3 (cMNV3), first described in 2005 [32]. The cMNV3 subtype is defined by a cilioretinal artery as the feeding arteriole, which, in contrast to the classic MNV3 lesion, originates from the choroidal vasculature rather than the retinal [32, 33]. Based on current multimodal imaging, cMNV3 was reported to account for 12% of all MNV3 lesions [33]. Lately, the interesting finding of multifocal MNV3 (mMNV3) lesions has been reported [33, 34]. In a study cohort of 22 eyes with mMNV3, Haj Najeeb found bifocal lesions in 73%, trifocal in 23%, and quadrifocal in 4% [34].

In the last 3 decades, there has been a debate on the pathogenesis of MNV3. In 1992, Hartnett first reported lesions studied by FA that were associated with unusual RPE detachments and retinal vessels that dove down into the deep retina and formed an angiomatous lesion [35, 36]. Later, in a follow-up study with FA and indocyanine green angiography (ICGA), it was also referred to as deep retinal vascular anomalous complexes [5]. In 2001, Yannuzzi et al. [6] published a large series of 143 eyes examined with FA and ICGA and named this phenotype retinal angiomatous proliferation to suggest an intraretinal origin and proposed a three-stage model of progression including intraretinal neovascularization (stage 1), subretinal neovascularization (stage 2), and choroidal neovascularization (stage 3). In contrast, Gass et al. [7] suggested, based on FA and ICGA studies, the term occult chorioretinal anastomosis, emphasizing the choroidal origin of the disease. In 2008, Freund et al. [37] were already able to use OCT to complement FA and ICGA and proposed the more descriptive term “type 3 neovascularization” to emphasize the intraretinal location of vascularization and to distinguish this type from type 1 and type 2 choroidal neovascularization previously described by Gass in 1997 [37, 38].

There is evidence that ischemia of the outer retina due to CC insufficiency may be a component in the pathomechanism of MNV3 [39]. Therefore, Borelli et al. and Le et al. [40, 41] used optical coherence tomography angiography (OCTA) to investigate the CC in eyes with MNV3. CC was compared between eyes affected by MNV3 and fellow eyes without MNV, and the latter fellow eyes were compared with the fellow eyes of AMD patients with unilateral type 1 or 2 MNV. Interestingly, eyes with MNV3 had an overall reduction in CC perfusion, and also the fellow non-neovascular eyes with MNV3 in the other eye had a greater CC impairment than non-nAMD fellow eyes from patients with unilateral type 1 or type 2 MNV [40]. Le and colleagues [41] quantitatively analyzed CC flow deficits (FD) in MNV3 eyes in comparison to intermediate AMD eyes. They found that MNV3 eyes showed reduced CC perfusion with a greater total area of FDs and a greater average size of FDs compared with intermediate AMD eyes.

Several authors postulated that an imbalance between vascular endothelial growth factor (VEGF) and other RPE-derived angiogenic factors arising from the apical side of the RPE cells may promote MNV3 development [42, 43]. Notably, it was demonstrated that in eyes with untreated nAMD, aqueous humor VEGF levels were more elevated in eyes with MNV3 versus eyes with MNV1 or MNV2 [44]. Possibly, CC malperfusion triggers biochemical processes in the RPE that lead to the development of MNV3. OCTA findings, as reported by Borelli and Le [36], underscore the hypothesis of choroidal hypoperfusion having a key role in the pathogenesis of MNV3. Besides, mouse models directly related to the hypoxia pathway support the idea that outer retinal hypoxia is an initiation factor for MNV3 development.

Spaide proposed a series of pathophysiologic events starting with a pre-proliferative stage with elevated levels of VEGF leading to retinal vascular leakage, telangiectasia, and hemorrhage. In his study, areas of hemorrhage and edema were not necessarily contiguous and possibly appeared before the advent of actual neovascularization [29]. Choroidal hypoxia may be a factor in causing RPE cells to detach from the RPE monolayer and migrate into the more vascularized inner retina [45]. Such detached RPE cells have been proposed as a source of elevated intraretinal levels of VEGF. Increasing VEGF levels in a permissive cytokine environment leads to a downgrowth of vessels. IRF may originate from VEGF-driven leakage or from the neovessels. Subsequently, vascular remodeling leads to larger descending vessels. A RPE detachment develops near the neovascularization [29]. Contrary to this hypothesis proposing a local effect of VEGF as a cause for the development of retinal hemorrhages, Haj Najeeb et al. [27] suggest a mechanical cause of retinal hemorrhages in MNV3. In their multimodal imaging study involving eighty-three eyes of 83 treatment-naıve patients with stage 3 MNV3, they found that these hemorrhages occur in edematous retinal tissue and typically fill pre-existing cystoid formations. They postulate that the increasing retinal edema stresses the vertically oriented fragile neovessels which have a limited ability to stretch and therefore are more susceptible to bleed in the inner retina.

MNV3 often develops over a large druse or a drusenoid PED [46]. In a multicenter cohort study of 31 patients with treatment-naïve MNV3, Bousquet et al. [47] found a progressive increase in drusen size/PED height prior to the MNV3 development. Further, they reported a MNV3 location at the apex of the druse/drusenoid PED in 95% of cases. The authors point out that the distance between the RPE and the underlying CC is greatest at the apex. This could lead to progressive dysfunction of the RPE, especially at this point, and contribute to the frequent MNV3 development at the apex.

Since their first description over 3 decades ago, reticular pseudodrusen (RPD) has become an increasingly recognized characteristic in AMD patients [48‒55]. In 2007, Cohen and co-workers [56] reported for the first time that RPD is significantly more prevalent in eyes with MNV3 than in other types of MNV in nAMD using blue light photography. Many studies that followed confirmed this observation using increasingly improved imaging modalities, and all of them highlighted a strong association between RPD and MNV3 [46, 57‒60]. With regard to RPD, interesting findings have also been reported for the fellow eyes of unilateral MNV3 patients. In a cohort of 81 unilateral MNV3 patients, fellow-eye neovascularization was noted in 38.3% in 27.8 months. However, the period between MNV3 diagnosis and fellow-eye neovascularization was significantly shorter in eyes with RPD than in eyes without [61]. Both RPD and MNV3 patients reportedly share common features such as a high rate of bilaterality, associations with older age and arterial hypertension, a decreased choroidal thickness, and possibly altered CC flow characteristics [62‒67]. In summary, RPD is a striking phenomenon in MNV3 patients, but its cause remains largely unexplained to date. A better understanding of RPD will probably contribute to a deeper insight into MNV3 pathogenesis. Figure 1 shows the development of RPD over a 7-year period before the formation of an MNV3 lesion.

As mentioned, the subtype of mMNV3 lesions was lately reported [33, 34]. Notably, no concurrent MNV1 or 2 lesions elsewhere in the macula were found in these patients. Besides, there is still no report about a concurrent development of MNV1 or 2 lesions with MNV3 in the literature, both strengthening the hypothesis of different underlying pathophysiologic pathways in MNV types [34].

Histopathological studies have contributed substantially to today’s understanding of the pathophysiology of MNV3. Several clinicopathologic correlations of MNV3 using either surgically excised membranes or intact postmortem eyes addressed the question regarding the origin of neovascularisation. Studies mainly support a retinal origin for initial lesion stages, with a choroidal component joining the neovascular complex at later stages [69‒72].

In a clinicopathological correlation of a postmortem eye of a patient with MNV3, Skalet et al. [73] presented for the first time corresponding OCT imaging 7 weeks before the patient’s death. The patient had received serial injections of ranibizumab over a period of 50 months. Histology revealed a thick-walled vascular complex adjacent to the inner portion of the Bruch’s membrane with a continuous layer of basophilic basal laminar deposits and without evidence of choroidal anastomosis.

Later, the group of Curcio et al. [51] contributed important data on several clinicopathologic correlations of MNV3 lesions [74‒76]. They reported a direct clinicopathologic correlation of an early, treated MNV3 lesion without evidence for choroidal involvement. They found vascular elements of retinal origin associated with collagenous material and Müller cell processes implanting into the sub-RPE basal laminar deposit in proximity to inflammatory cells [74].

In another clinicopathologic study, they were able to correlate the OCTA decorrelation signal of a MNV3 lesion with intraretinal neovascularizations in histology. A vascular connection between the sub-RPE space and CC was not found in this case either [75]. Shortly thereafter, Curcio and colleagues [51] compared the longitudinal multimodal clinical imaging and histology of three MNV3 lesions in two anti-VEGF-treated eyes of 1 patient. All three lesions originate at the deep capillary plexus and extend posteriorly without entering the sub-RPE space. The authors differentiate two morphologic phenotypes: “pyramidal MNV3,” defined as a focal, vertically extending neovessel complex, and “tangled MNV3,” defined as a horizontally extending neovessel complex with a thinner collagenous sheath [76]. It remains to be determined whether pyramidal and tangled lesions differ in frequency, distribution, and time of appearance.

Recently, Cabral et al. [77] proposed the term deep retinal age-related microvascular anomalies (DRAMA) to distinguish non-neovascular microvascular alterations in the setting of AMD findings, such as soft drusen and HRF, from MNV3 lesions. The authors identified two types of DRAMA: round-shaped dilations at the inner nuclear layer or outer plexiform layer level and outpouchings below the outer plexiform layer. Notably, DRAMA occurs in the absence of any vascular remodeling of the surrounding network. According to the authors, this phenotype may be triggered by ischemia of the outer retina in patients with AMD, and in a favorable cytokine environment, some forms of DRAMA may progress to MNV3 [77]. Comparing the histologic characteristics of MNV3 and DRAMA, Berlin et al. [76] found that DRAMAs lacked a collagenous sheath and, unlike MNV3, the vessels do not extend beyond the Henle fiber layer, with the ELM remaining unaffected. The authors hypothesize that the presence of a collagenous sheath may represent a stage in the evolution of DRAMA toward type 3 MNV.

FA demonstrates intraretinal leakage of fluorescein; ICGA shows a small hyperfluorescent lesion, which represents descending vessels viewed axially [4]. ICGA is not mandatory to validate the diagnosis of every MNV3 lesion; however, it is still a useful tool to confirm the diagnosis of MNV3 where no clear vascular shunt is seen in FA [33]. OCT shows varying amounts of IRF according to the stage of the lesion [25]. Furthermore, a PED may be present with or without RPE disruption in close association with a hyperreflective complex above the RPE. OCTA illustrates a flow signal originating from the deep vascular plexus with progressive downgrowth of vessels into the deeper portions of the retina [4, 8]. Figures 2 and 3a show exemplarily the characteristics of a MNV3 lesion in multimodal imaging.

In 2013, Querques et al. [78] observed intraretinal hyperreflective foci (HRF) in OCT in the early stages of MNV3. Later, Su et al. [25] proposed a MNV3 classification system based on SD-OCT including this observation of HRF in the outer retina as a precursor lesion. They hypothesized that such HRF represents migrated RPE cells, which was subsequently supported by the findings of histologic studies [45, 74]. Stage 1 is defined as intraretinal HRF associated with cystoid macular edema without outer retinal disruption. In stage 2, there is an intraretinal HRF with cystoid macular edema and outer retinal disruption with or without RPE disruption. Stage 3 represents a progressive downward growth of the MNV3 lesion, proliferating through the RPE and creating a vascularized serous PED [25]. Figure 4 schematically depicts the stages of MNV3 with corresponding OCT images.

Using OCTA, Sacconi et al. [8] described a condition they termed “nascent Type 3 neovascularization.” They found that, previously described by other authors, intraretinal HRF had flow signal on OCTA, suggesting that these foci may represent new vessels instead of migrated RPE cells. Of note, no signs of active neovascularization such as IRF or SRF, hemorrhage, or serous PED were noted in their study. Nascent type 3 MNV may progress to an active form of type 3 MNV or, more rarely, may regress without clinical manifestations.

The natural history of MNV3 is characterized by exudative maculopathy, leading to severe and rapid visual loss in a large proportion of patients [79]. Before the introduction of intravitreal anti-VEGF for the treatment of MNV3, various approaches of laser photocoagulation were pursued, as well as photodynamic therapy, transpupillary thermotherapy, and intravitreal triamcinolone acetonide, each of which resulted in only modest improvement and/or short-term improvement in visual acuity [80, 81]. Better visual outcomes were achieved with intravitreal anti-VEGF injections [82‒85]. When treated in time, MNV3 lesions are very responsive to anti-VEGF therapy [28, 46, 86].

Based on the data of the CATT study, eyes with MNV3 lesions and eyes with non-MNV3 lesions were compared in terms of baseline characteristics, 2-year visual and morphological outcomes. Greater BCVA improvement from baseline to year one was seen in eyes with MNV3 (10.6 letters vs. 6.9 letters, p = 0.01) than in eyes with other types, and more eyes with MNV3 had a ≥15 letter increase from baseline (41% vs. 28%, p = 0.005). At 2 years, these differences could no longer be detected. Compared to other types, MNV3 eyes were more likely to have no fluid on OCT, no leakage on FA, and greater reduction in foveal thickness. Besides, they were more likely to develop atrophy and less likely to develop scars or subretinal hyperreflective material [28]. Mrejen et al. [86] similarly observed a clear increase in BCVA in MNV3 between baseline and 1 year and then a slight decrease in the further course of treatment. The loss of initial visual benefits is presumably due to the development of atrophy or the central progression of pre-existing atrophy. Further real-world data support the findings from the CATT sub-analysis. In a study including 157 MNV3 eyes and 469 controls, Invernizzi et al. [87] found that MNV3 lesions treated with anti-VEGF agents in a real-world setting responded very well to treatment and they had better visual outcomes at 12 and 24 months than other types of MNV. The authors hypothesize that the smaller lesion size that characterizes MNV3 lesions may partially explain the better visual outcomes as small lesions may cause less damage to the overlaying retinal structures. Besides, due to the intraretinal location, lesions may tend to become symptomatic earlier than other types, resulting in less mature vessels responding better to earlier treatment.

The effectiveness of anti-VEGF therapy is not only reflected in the visual acuity gains but can also be morphologically demonstrated by the change in the MNV3 lesion detectable in OCTA. Interestingly, 1 year after the beginning of anti-VEGF therapy, the communication between deep retinal capillaries and the RPE/sub-RPE space disappeared, while the neovessel could still be localized at the level of the deep retinal capillaries using OCTA. However, at the time of recurrence, all MNV3 lesions showed a restoration of flow deepening from the deep vascular complex to the RPE/sub-RPE space [88]. In contrast, patients with MNV3 who had no lesion on an OCTA scan after anti-VEGF treatment showed a lower recurrence rate and maintained visual acuity with fewer injections than those with persistent high-flow lesions [89].

In addition to the improved visual acuity, the lower prevalence of fibrosis also demonstrates the success of anti-VEGF therapy. In a study by Haj Najeeb et al. [90], the contralateral eyes of 94 patients with MNV3 were analyzed with respect to MNV3 stage and the development of fibrosis and retinal-choroidal anastomosis over 24 months. Fibrosis was found in 16% of contralateral eyes, a considerable decrease compared to 37% in a 2001 study [6, 90].

The development of atrophy during the course of therapy often has a visually limiting effect on patients with MNV3. Unfavorably, 86% of eyes with MNV3 lesions developed de novo atrophy or enlargement of pre-existing atrophy areas during the median follow-up period of 17 months after treatment [91]. In a large 4-year, multicenter, retrospective comparative study, the incidence and progression of macular atrophy varied among different MNV types. Particularly, MNV3 demonstrated the greatest increase in macular atrophy size, while atrophy progression rates were the smallest in MNV1 [92].

Understanding and interpreting fluid compartments has been a particular focus in clinical nAMD research. Major conclusions were drawn from the Comparison of Age-Related Macular Degeneration Treatment Trials, VIEW 2 trials, and the FLUID trial, namely that IRF is associated with poor BCVA and unfavorable visual prognosis, whereas the presence of SRF is linked with better BCVA and favorable visual prognosis [93‒96]. Interestingly, several lately published studies disagree with this principle in the type of MNV3 [8‒10]. In a retrospective study of exclusively MNV3 lesions, Sacconi et al. [8] analyzed structural OCT characteristics associated with BCVA outcome after 3-year anti-VEGF therapy. Among numerous OCT characteristics, however, the IRF was not included in the analysis. In contrast to previous studies on nAMD, SRF was the strongest independent negative predictor for BCVA outcome. The authors hypothesize that the presence of SRF characterizes a more aggressive and advanced stage of MNV3. In fact, the development of IRF always proceeds with the development of SRF in MNV3 as the origin of neovascularization is the retina [25].

In the multicenter, retrospective FLIP-3 study, Sharma et al. [9] included 56 eyes with treatment-naïve MNV3. Eyes that had IRF alone at baseline had better visual acuity compared with the patients who had both IRF and SRF/sub-RPE fluid. The authors postulate the need for an isolated analysis of MNV3 in the future. However, the actual effect of SRF on visual function in MNV3 remains questionable, as Su et al. [25] reported that SRF occurs eccentrically at the border of the PED and only in eyes with pronounced IRF. With respect to the quantitative and topographic changes of the IRF in relation to the progression of the lesion in the study of Sharma et al. [12], there is ongoing debate about a better visual prognosis of the isolated IRF in type 3 eyes [11, 12].

In a retrospective study including 95 patients, Kim et al. [10] compared lesion reactivation after initial treatment between MNV3 eyes with and without SRF. A reactivation was more frequent in the SRF group than in the non-SRF group. Moreover, the incidence of focal retinal hemorrhages was markedly higher in the SRF group than in the non-SRF group. According to Spaide’s hypothesis of hemorrhages being driven by elevated VEGF levels, this could indicate that eyes with MNV3 lesions and SRF have more elevated VEGF levels than those without SRF [29]. Due to greater reactivation rates and the more frequent occurrence of retinal hemorrhages, the authors suggest implementing a treat-and-extend regimen immediately after the initial loading injection in MNV3 patients with baseline SRF. With regards to the risk of RPE atrophy in MNV3 eyes, the authors prefer an as-needed regimen requiring fewer anti-VEGF injections than treat-and-extend regimens in MNV3 eyes without SRF [10]. In a more recent paper by the same group, the authors recommend switching to a treat-and-extend regimen no later than after the first lesion reactivation [31].

A lesion-specific therapeutic regimen also appears reasonable for the subtype of mMNV3. Haj Najeeb et al. [97] hypothesized that the development of multiple lesions may indicate that VEGF levels are more elevated and the stimulus of angiogenesis is more pronounced than in solitary MNV3. They conclude that further studies are needed to explore the response of mMNV3 to anti-VEGF and whether mMNV3 needs higher dosages or shorter treatment intervals.

Of note, the neovascular type of MNV3 has rarely been analyzed as a distinct group in the large trials of nAMD treatment, and these lesions may have been classified as MNV1 or MNV2, so the data on anti-VEGF therapy for MNV3 remains limited to date. Considering the numerous clinical and pathomorphological features that set MNV3 apart from MNV1 and 2, Haj Najeeb et al. [97] raised the question of whether AREDS formula can in fact reduce the incidence of advanced AMD in the fellow eyes of patients with unilateral MNV3. In AREDS reports, all patients were pooled together for data analysis without a predetermination of their type of MNV. Therefore, the authors support a reevaluation of the effect of AREDS supplements on patients with MNV3 in light of today’s knowledge.

MNV3 is characterized by typical clinical and pathomorphological features, clearly setting it apart from the other MNV types in nAMD. OCTA imaging has not only made an important contribution to the pathophysiological characterization of MNV3 but also provides an additional biomarker for practical guidance in the treatment and monitoring of MNV3 lesions. Due to the high incidence of bilateral involvement, patients with MNV3 in one eye must be made aware of regularly monitoring unaffected fellow eyes. Further research shall elucidate the relationship between OCTA flow, hyperreflective foci, and retinal edema in the context of MNV3 to understand the chronology and correlations of such pathophysiologic observations. In addition, a better understanding of RPD could answer the question of how far the presence of RPD contributes to an MNV3-permissive environment. With regard to the interpretation of OCT biomarkers such as IRF and SRF, MNV3 seems to need to be considered in clear distinction to the other MNV types in nAMD. Such new OCT findings must be verified in future studies and should also be included in the consideration of optimal type-specific treatment strategies.

Christoph R. Clemens: Speaker’s fee from Heidelberg Engineering, Novartis, and Bayer. Nicole Eter: grants or contracts from any entity: Novartis and Bayer to department; consulting fees from Novartis, Bayer, Roche, Apellis, Allergan, and Alcon; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Novartis, Bayer, Roche, Apellis, and Allergan; support for attending meetings and/or travel from Roche. Florian Alten: speaker’s fee from Bayer.

No funding was obtained for this study.

Christoph Roman Clemens, Nicole Eter, and Florian Alten were involved in the conceptual design of the manuscript, drafting, and development, and read and approved the final manuscript.