Drusen characteristics of type 2 macular neovascularization in age-related macular degeneration

Early and intermediate age-related macular degeneration (AMD) are defined by the existence of drusen, pigmentary abnormalities or extrafoveal atrophy [1, 2]. Various types of drusen such as soft, hard, cuticular or subretinal drusenoid deposits (SDD) – also referred to as reticular pseudodrusen - confirm with the diagnosis of AMD [3]. Drusen are typically located between the retinal pigment epithelium (RPE) and the Bruch’s membrane, whereas SDD are found in the subretinal space [4‐7]. Small drusen (< 63 μm) are considered normal aging changes, while medium (≥63 - < 125 μm) to large drusen (≥125 μm) are associated with an increased risk for the development of late stage disease. Advanced AMD refers to either neovascular AMD (nAMD) or subfoveal geographic atrophy (GA) [1]. Spaide et al. suggested the term macular neovascularization (MNV) more adequate to sum up all neovascular entities in AMD including type 3 [8, 9]. Therefore, the author proposed a new classification system encompassing extracellular deposits as well as the subfoveal choroidal thickness (SFCT) to integrate all aspects of the disease. Type 1 MNV originates from the choroid and remains exclusively underneath the RPE. Polypoidal choroidal vasculopathy has recently been described as aneurysmal neovascularization type 1 and represents a subtype of this entity [10]. A mixed type neovascularization is composed of new choroidal vessels growing in more than one layer. A vascular network only present in the subretinal space is referred to as type 2 MNV. In contrast, type 3 neovascularization - also called retinal angiomatous proliferation (RAP) - reflects a distinct form of nAMD with an intraretinal origin and hence different pathophysiology [11].

While type 1 MNV is the most common subtype in nAMD followed by type 3 and mixed type MNV, the appearance of type 2 MNV is a rare condition [12, 13]. So far, drusen characteristics were mainly investigated in type 1 MNV [1, 2, 14‐16]. Type 2 and mixed type MNV with a preponderance towards type 2 – formerly known as classic or predominantly classic choroidal neovascularization - were observed in 11.5–24.6% in the era of FA alone [17‐20]. SD-OCT imaging led to a deeper knowledge of the neovascular anatomy as well as the aggregation of extracellular debris [11]. A combination of FA and OCT reduced the percentage of type 2 MNV to 0.8–9% according to the most recent studies with a focus on deposits and choroidal thickness in the latter one [12, 13].

Accompanying factors of type 2 MNV remain still unclear. The main purpose of this study was to gain a better understanding of the characteristics associated with type 2 MNV in AMD based on multimodal imaging.

Data records of 835 eyes in 749 consecutive patients with nAMD were reviewed for MNV distribution. Type 1 MNV was diagnosed in 658 eyes (78.8%), type 2 MNV in 27 eyes (3.2%), type 3 MNV in 75 eyes (9%), mixed type MNV in 51 eyes (6.1%) and polypoidal MNV in 24 eyes (2.8%).

27 eyes of 27 patients with type 2 MNV could be enrolled for further analysis. Type 2 MNV was present in 11 (41%) female and 16 (59%) male patients with a mean age of 73.3 ± 7.1 standard deviation (SD) years (range: 57–86 years). Overall, 17 eyes (63%) compromised by type 2 MNV presented drusen or SDD, leaving 10 eyes (37%) without any extracellular debris (Fig. 3). Drusen or SDD were present in 14 of 23 fellow eyes (60.9%). The distribution of drusen subtypes and their proportions was displayed in Table 1. Patients with drusen or SDD in the neovascular eye were significantly younger (mean 70.88 ± 6.85, p = 0.04) than patients without deposits (mean 77.40 ± 5.74). Sex was not significantly associated with the appearance of drusen or SDD. The mean SFCT was 140 ± 49 μm in the neovascular eyes and 152 ± 41 μm in the fellow eyes. It had no significant impact on the occurrence of drusen or SDD. Extrafoveal atrophy was evident in 1 fellow eye (4.3%). Four fellow eyes were excluded either due to neovascularization (1 eye with mixed type MNV) or fibrosis (3 eyes).

In this retrospective cohort analysis of 835 eyes complicated by nAMD, only 27 (3.2%) were compromised by type 2 MNV. Drusen or SDD - the hallmark of AMD - were absent in a representative number of 10 (37%) neovascular eyes and 9 (39.1%) fellow eyes. Interestingly, age was the only accompanying factor in a substantial part of patients with pure type 2 lesions. Eyes compromised by this subtype and co-existing deposits were significantly related to younger age in contrast to eyes without additional signs of AMD. It is considered a typical neovascular subtype in entities such as high myopia, inflammatory chorioretinopathies or angioid streaks. Idiopathic choroidal neovascularization was originally described as a focal or type 2 lesion in patients younger than 50 years by Hu et al. in 1995 [30]. These findings suggest a more heterogenic picture of patients compromised by this phenotype of AMD.

Spaide recently proposed a new classification of AMD based on soft drusen, pachydrusen and SDD with predictive capabilities regarding a further development to late stage disease [8]. The appearance of soft drusen might lead to any type of MNV as well as GA. Eyes with SDD - particularly these with dot SDD - could progress to type 3 or type 2 MNV, whereas GA is typically associated with confluent SDD. We were not able to relate SDD subtypes to type 2 MNV. Only one other group focused primarily on clinical characteristics of type 2 lesions in nAMD [13]. 8 of 694 patients expressed this type of neovascularization with 7 of them (88%) possessing SDD and thin choroids. Deposits must have been documented by multimodal imaging before the development of MNV. The authors concluded that the low incidence of type 2 MNV could be attributed to the strict inclusion criteria. Drusen regression with subsequent formation of MNV or GA has already been described [31, 32]. Also, SDD might regress and convert into atrophy over time [33]. We were looking for extracellular material at the onset of neovascular changes and initially excluded eyes with subfoveal atrophy. In concordance to our data, Wilde et al. found no difference in the occurrence of nAMD subtypes and SDD [34]. Another paper published by Marsiglia et al. could not correlate SDD with type 2 MNV significantly 1 year earlier [35]. They investigated the association between MNV subtypes and clinical findings of the non-neovascular fellow eye in patients with unilateral nAMD. SDD and thin SFCT were more frequently seen in fellow eyes of patients with type 3 MNV, whereas type 1 MNV was associated with a decreased odds ratio for SDD and a thin SFCT. We carefully monitored the SFCT of both the affected and the fellow eyes of patients with type 2 MNV and compared eyes with drusen and SDD to eyes without retinal deposits. The term pachydrusen referred to pachychoroid according to Spaide and evolved preferentially into type 1 MNV or polypoidal choroidal vasculopathy [8]. Choroidal thickness measured max. 259 μm in eyes with type 2 MNV, as per definition pachychoroid-associated drusen could not be detected. Moreover, SFCT was not significantly related to extracellular material in the fellow eye. SDD were classified as visible in OCT B-scans but no significant pattern could be assessed in either eye. Drusen or SDD were absent in 9 of 23 fellow eyes (39.1%). Abugreen et al. related neovascular subtypes to AMD severity of the fellow eye and found comparable numbers [36]. No features of AMD were exhibited in 10 of 23 fellow eyes (43.5%) in patients compromised by classic lesions in 2003.

Limitations of this study include the retrospective evaluation of deposits in previously acquired images and their available information. Peripheral SDD or drusen could have been missed as the primary focus of interest was the macular area pictured by Heidelberg’s Spectralis 30° images. Certain questionnaires would be more likely to be answered in a prospective study design. Other MNV subtypes were not analyzed in detail, which impaired the study’s comparative nature. On the other hand, MNV anatomy was examined by multimodal imaging in a large cohort of 835 consecutive patients. Twenty-seven eyes with type 2 MNV in AMD are considered as this study’s strengths. Two thirds of type 2 MNV were found in the presence of soft or hard drusen and SDD. One third of eyes without deposits was frequently related to older age, suggesting a more heterogenic picture of this phenotype.

The herein presented data contribute to a better understanding of the anatomical features in this rarely found nAMD subtype. AMD is not necessarily confined to the existence of extracellular deposits. Other biological pathways in AMD may lead to the development of a neovascularization limited to the subretinal space.