Japanese clinical guidelines for neovascular age-related macular degeneration

Abstract

Recent advances in imaging technology and increased options of pharmaceutical therapy require that guidelines on the diagnostic criteria and treatment of neovascular age-related macular degeneration (AMD) be updated at regular intervals. These guidelines aim to standardize the management of neovascular AMD based on the latest understanding of its pathophysiology, advancements in diagnostic imaging modalities, and treatment options. The key updates include: (1) a revision of terminology and stage classification, adopting the AMD classifications of atrophic and neovascular, and adding end-stage AMD to the existing early, intermediate, and late stages; (2) the inclusion of pachychoroid in addition to drusen in the initial pathophysiology and pathogenic background; (3) diagnostic criteria defined by the presence of macular neovascularization based on multimodal imaging, including optical coherence tomography (OCT) and OCT angiography; (4) assessment of disease activity based on OCT; and (5) treatment guidance, including prophylaxis and low vision care as well as loading and maintenance phases by use of anti-vascular endothelial growth factor therapy and adjunctive therapies. We hope that these guidelines will be useful for those working in clinical practice in Japan, in other Asian countries, and in countries outside Asia.

Keywords: Guideline; Macular neovascularization; Neovascular AMD; Pachychoroid; Polypoidal choroidal vasculopathy.

Fig. 1

Diagnostic flowchart for neovascular age-related macular degeneration. *1: Medium drusen: ≥63 µm and <125 µm; large drusen: ≥125 µm. *2 Retinal pigment epithelial detachment (PED) without MNV.*3: Not suitable for MNV close to the fovea because of irreversible damage to the outer retina and RPE. *4 Treatment regimens include treat-and-extend, fixed dosing, or pro re nata (PRN). *5: For patients with inadequate or no response to treatment, consider switching anti-VEGF drugs or combining anti-VEGF therapy with PDT. *6 Observation of fibrotic scars with low disease activity, cystoid macular degeneration, and atrophy. *7: Provides low-vision care for patients with poor visual acuity in both eyes. *8 Submacular hemorrhage, vitreous hemorrhage, and endophthalmitis. RPE, retinal pigment epithelium; VEGF, vascular endothelial growth factor; PDT, photodynamic therapy

Fig. 2

Type 1 macular neovascularization (MNV). a Hard exudates and serous retinal detachment (arrowhead) are observed in the fundus. b Late-phase fluorescein angiography (FA) shows mild leakage of fluorescence. Scale bar, 200 μm. c Indocyanine green angiography (ICGA) shows hyperfluorescence indicative of MNV (arrow). Scale bar, 200 μm. d Optical coherence tomography (OCT) corresponding to the dashed arrow in A shows subretinal fluid and a shallow elevation of the retinal pigment epithelium (RPE) with a double layer sign (arrowhead). e The en face OCT angiography (OCTA) image from the outer retina to the choriocapillaris, corresponding to the area indicated by the white square in C, shows MNV (arrow)

Fig. 3

Polypoidal choroidal vasculopathy. a Fundus photo shows orange-red elevated lesions with subretinal hemorrhage (arrow). b ICGA shows nodular polypoidal lesions (arrow) continuous with type 1 MNV. Scale bar, 200 μm. c OCT corresponding to the site indicated by the dashed arrow in b shows a steep elevation of the RPE. Scale bar, 200 μm. d The en face OCTA image from the outer retina to the choriocapillaris, corresponding to the area indicated by the white square in b, shows MNV. e B-scan OCTA image corresponding to the site indicated in d shows blood flow signals (red) within the PED

Fig. 4

Polypoidal choroidal vasculopathy. a Fundus photo shows round PED. b FA shows dye pooling in the area of PED. Scale bar, 200 μm. c ICGA shows PED as a fluorescence block, with type 1 MNV (arrowhead) and polypoidal lesions (arrow). Scale bar, 200 μm. d OCT corresponding to the site indicated by the dashed arrow in c shows a serous PED with a notch (arrow) and a shallow elevation of the RPE with a double layer sign. e B-scan OCTA image shows blood flow signals (pink) at the site of the notch

Fig. 5

Massive subretinal and sub-RPE hemorrhage. a Fundus photo shows massive subretinal hemorrhage. b OCT shows hyperreflective subretinal hemorrhage and PED. c ICGA does not show MNV due to fluorescence blockage by hemorrhage. Scale bar, 200 μm

Fig. 6

Type 2 MNV. a Fundus photo shows a gray-white lesion with hemorrhage and fibrinous exudates (arrowhead). b, c Early-phase FA (b) and late-phase ICGA (c) show hyperfluorescence indicating MNV. d OCT corresponding to the dashed arrow in (a) shows subretinal hyperreflective material under the retina. Scale bar, 200 μm. e The en face OCTA image from the outer retina to the choriocapillaris, corresponding to the area indicated by the white square in c, shows MNV

Fig. 7

Type 3 MNV. a Fundus photo shows soft drusen and intraretinal hemorrhage. b OCT shows macular edema and a serous PED with a bump sign (arrow). c OCTA shows continuous blood flow signals (red) from the superficial retina to the bump sign, indicating intraretinal neovascularization. d, e Early-phase FA (d) and ICGA (e) show anastomosis between superficial retinal vessels and punctate hyperfluorescence (arrow). Scale bar, 200 μm. f, g Late-phase FA (f) shows progressive leakage, and ICGA (g) shows a hot spot (arrow). Scale bar, 200 μm

Fig. 8

Drusen. a Fundus photo shows multiple drusen. b OCT shows large soft drusen (arrow) and subretinal drusenoid deposits (arrowhead). Scale bar, 200 μm

Fig. 9

Pachychoroid neovasculopathy. a Fundus photo shows serous retinal detachment and attenuated fundus tessellation. b OCT shows dilated large choroidal vessels, thinning of the choroidal inner layer, subretinal fluid, and a shallow elevation of the RPE with a double layer sign. Scale bar, 200 μm. c The en face OCT image shows dilated large choroidal vessels. d Mid-phase ICGA shows choroidal vascular hyperpermeability, but MNV is difficult to determine. Scale bar, 200 μm. e: The en face OCTA image from the RPE to the choriocapillaris, corresponding to the area indicated by the white square in (d) shows MNV (arrow)

Fig. 10

Type 2 MNV. a Fundus photo shows a gray-white lesion with subretinal hemorrhage and fibrinous exudates. b OCT corresponding to the dashed arrow in (a) shows subretinal hemorrhage (arrow) as well as fibrin and MNV (arrowhead) observed as subretinal hyperreflective materials. Scale bar, 200 μm

Fig. 11

Retinal pigment epithelium tear. a Fundus photo shows choroid visible through the RPE defect (arrowhead). b Fundus autofluorescence shows hypofluorescence, indicating the RPE defect (arrowhead). Scale bar, 200 μm. c Near-infrared image shows the RPE tear area as a hyperreflective area (arrowhead). Scale bar, 200 μm. d OCT corresponding to the green arrow in (c) shows RPE shrinkage (rolling, arrow) and RPE defect (arrowhead). Scale bar, 200 μm

Fig. 12

Fibrotic scar with cystoid macular degeneration. a Fundus photo shows a white to yellow-white fibrotic scar (arrow). b OCT shows a hyperreflective area under the retina indicating fibrotic scar and cystoid spaces (*) within the retina. Scale bar, 200 μm

Fig. 13

Type 3 MNV treated with anti-VEGF drugs. a Pre-treatment fundus photo shows punctate intraretinal hemorrhage (arrow). b OCT shows retinal edema and RPE disruption (arrow). c OCTA corresponding to B shows blood flow signals (red) indicating intraretinal neovascularization from the retina to the RPE disruption site (arrow). d One month after anti-VEGF treatment, the intraretinal edema has resolved

Fig. 14

Polypoidal choroidal vasculopathy with polypoidal lesions regressed following PDT combined with anti-VEGF drug. a Pre-treatment fundus photo shows orange-red lesions at the fovea (arrow). b Pre-treatment OCT shows subretinal hyperreflective material (arrow) and protruded RPE elevation with hyporeflective spaces within (arrowhead). c ICGA shows type 1 MNV (arrow) and nodular polypoidal lesions (arrowhead). Scale bar, 200 μm. d, e After PDT combined with anti-VEGF drug, OCT shows the resolution of the protruded RPE elevation (d), and ICGA confirms the regression of polypoidal lesions (e). Scale bar, 200 μm

Fig. 15

Displacement of submacular hemorrhage by intravitreal gas injection. a Fundus photo shows massive subretinal hemorrhage. b OCT shows hyperreflective subretinal hemorrhage (arrow) and PED (arrowhead). c ICGA shows a nodular hyperfluorescence indicative of polypoidal lesions (arrow), but the overall extent of MNV is unclear due to fluorescence blockage by hemorrhage. d The submacular hemorrhage is displaced from the macula following intravitreal gas injection. e OCT shows the resolution of submacular hemorrhage, although PED remains (arrowhead)