Short- and Long-Term Response of Choroidal Neovascularization to Anti-Angiogenic Treatment
Bruno Lumbroso, MD; Steven T. Bailey, MD; Yali Jia, PhD; Marco Rispoli, MD; and Maria Cristina Savastano, MD
Choroidal neovascularization (CNV) examination by optical coherence tomography angiography (OCTA) scans gives sharper vascular images than with fluorescein angiography (FA) or indocyanine green angiography(ICGA). Feeder vessel trunks or feeder vessel bundles are easily seen, and smaller collateral branches, loops, and peripheral anastomoses are well identified. FA or ICGA1,2 that were used till very recently in the study of CNV did not allow precise visualization of the CNV, but gave blurred images of the vascular net, due to early dye leakage.
CNV is a complex process from early onset to final fibrosis and atrophy,3,4 and is observed more easily with OCTA. Anti-vascular endothelial growth factor (VEGF) therapy is currently administered regularly for many months or years because its suspension or discontinuation may cause recurrence of neovascularization. A precise review of CNV evolution is necessary and is presently allowed by OCTA. OCTA allows faster, better, and easier visualization of CNV features without the risk of side effects. OCTA of CNV evolution after treatment, cyclic CNV recurrences, and acute sporadic recurrences are discussed in this chapter.
OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY OF CHOROIDAL NEOVASCULARIZATION EVOLUTION AFTER TREATMENT
We describe in this chapter CNV evolution in cases followed for 12 to 24 months and observation of cyclic regular CNV recurrences and acute abnormal irregular recurrences. We will then discuss the conclusions that can be drawn. We assessed by OCTA early CNV modifications occurring after intravitreal (IVT) therapy, from as short a period as 24 hours after treatment and as long a period as a 24-month follow-up. During follow-up with OCTA we observed certain CNV parts remain unchanged or do not go through significant changes while other parts undergo changes or seem to regress or disappear for some time. We describe and give an interpretation of these changes.
Three years ago, OCTA allowed for the first time the evaluation of clinically retinal circulation by a dyeless method.5 The technology we use is based on split-spectrum amplitude-decorrelation angiography (SSADA), which is able to detect flow and connectivity of retinal microvascular networks6 as reported by de Carlo et al.7
There were few studies on CNV evolution after treatment by OCTA until recently. Spaide8 reported the long-term evolution of type I CNV in 17 eyes of patients followed for years having received a mean of 47 injections. Shah and Del Priore3 reported 1 case followed for 1 week, 3 weeks, and 2 months after injection with anti-VEGF. Kuehlewein et al9 observed cases for which OCTA was performed 4 weeks after the first, and 2 and 4 weeks after the second ranibizumab injection.
Angiogenesis is the cause of vessel proliferation. As reported by Ferrara10 and then by Spaide,8 the angiogenesis process is highly anti-VEGF dependent. In the treatment of vasoproliferative diseases, VEGF is considered the main target. Two mechanisms operate in neovascularization development: the arteriogenesis that promotes dilation of the preexisting channel and the angiogenesis that provoke new vessel sprouting. Lumbroso et al11 and Huang et al12 observed and described the morphological changes on OCTA in the early evolution of the vessels, days and weeks after treatment with repeated IVT anti-VEGF injections. We recorded OCTA 24 hours after injection, and 7 days, 20 days, and 30 days later. These patients were followed for 12 to 24 months. Our 2 groups recently published their results.11,12
In an observational longitudinal study, a total of 10 eyes of 9 patients with type 2 CNV were assessed by OCTA. The CNV series comprised 8 type 2 CNV, 1 type 2 CNV in a fibrovascular formation, and 1 mixed type 1 and 2. CNV-type labeling was determined on OCT B-scans as type 2 CNV if retinal edema and subretinal fluid and no retinal pigment epithelium (RPE) elevation was observed, and as a mixed type 1 and type 2 CNV if a hyper-reflective subretinal formation anterior to an elevated disrupted RPE was seen. We recorded OCTA to closely observe the early evolution of neovascularization after IVT aflibercept or ranibizumab injection and precisely at 24 hours, 7 to 10 days, 12 to 18 days, and 28 to 35 days after the injection. The loading phase interval was about 30 days. The patients were followed for 12 to 24 months. We used the AngioVue Imaging System for OCTA (Optovue Inc) to obtain amplitude decorrelation angiography images. This instrument has an A-scan rate of 70,000 scans/second, using a light source centered on 840 nm and a bandwidth of 50 nm. Each OCTA volume contains 304 × 304 A-scans with 2 consecutive B-scans captured at each fixed position before proceeding to the next sampling location. SSADA was used to extract the OCTA information. Each OCTA volume is acquired in 3 seconds, and 2 orthogonal OCTA volumes were acquired in order to perform motion correction to minimize motion artifacts arising from microsaccades and fixation changes. Angiography information displayed is the average of the decorrelation values when viewed perpendicularly through the thickness being evaluated. The macular angiography scan protocol covered a 3 × 3 mm area. The stack of angiography selection was applied in correspondence with neovascularization visualization, and the change analysis automated protocol was applied along the follow-up.
OCTA software was used to delineate the region of interest. The inner and outer boundaries of OCT angiograms included all apparent CNV vessels. An artifact removal possibility in the software allowed the subtraction of the retinal vessel reflection (derived from the RPE reflection) from flow imaging. Two independent readers classified OCTA scans with an agreement > 92%.
In this observational longitudinal study on 10 eyes of 9 patients, the morphology of the CNV was assessed in all eyes followed from 12 to 24 months (about 22 cycles), with OCTA 24 hours, 7 to 10 days, 12 to 18 days, and 28 to 35 days after the injection treatment: from 3 to 4 controls per month.13
The morphology of the CNV after injection followed a periodicity involving the following:
Twenty-four hours after treatment: Decrease of visible vessels, with apparent vessel fragmentation. The CNV area decreased with loss of thinner anastomoses and of small vessels. Residual uneven flow, more evident close to the afferent trunk with important microvascular rarefaction, decreased caliber, and vessel narrowing. The CNV area and vessel density decreased because of the loss of smaller vessels.
Seven to 10 days after injection: Continuing decrease of visible vessels and CNV area dimensions. Remaining surviving vessels were grouped around feeder trunk.
Twelve to 18 days after injection: Maximum vessel decrease.
Twenty-eight to 35 days after injection: Reproliferation. The vessels seemed approximately the same vessels seen before treatment and collapse, with their caliber greater, and CNV area smaller. Thinner capillaries decreased but some anastomoses and loops reappeared.
After 5 to 8 cycles of 60 to 70 days, vessels are thicker and straighter with increased flow and arterialization features.
PERIODIC EVOLUTION
In the loading phase, we performed 3 IVT injections at 30-day intervals. While in real life it is not possible to adhere strictly to this protocol, the real-life mean interval was reasonably close to this, with a mean of 39 days while excluding one patient who came back after 70 days. After the loading phase we followed a pro re nata (PRN; as-needed) treatment regimen. Retreatment was applied in case of reoccurrence of fluid accumulation, before recurrence of metamorphopsia, and before further visual acuity decrease. Here too, in our clinic, in real life it was not possible to strictly follow this protocol. In this short observation period we did not observe retinal bleeding. In a few cases where the injection was implemented later than a few days from the initial observation of activity, patients experienced metamorphopsia and a change in visual acuity.
Figure 13-1. CNV evolution in type 2 CNV in age-related macular degeneration. (A) OCTA type 2 CNV, located in the foveal zone with central afferent trunk and dense capillary foliage. A large dark halo surrounds the CNV. (B) Twenty-four hours after treatment: CNV area is smaller with loss of smaller vessels, and thinner vessels. (C) Ten days after injection: further vascular decrease around feeder trunk. (D) Forty days after injection: CNV area is smaller than before treatment. Vessels reopening are thicker, with loss of smaller vessels.
The mean cycle duration after the loading phase was 62.3 days.11,13 After 5 to 8 cycles of 60 to 70 days, vessels appear rarer, thicker, straighter, and with increased flow. The apparent result is arterialization with decreased CNV area, decreased vessel density, loss of smaller vessels, and anastomoses reduced in number. Vessel diameter is increased and larger.
Typical Choroidal Neovascularization Cases Evolution
We describe 2 different typical case evolutions.
Typical Case Evolution 1: Type 2 Choroidal Neovascularization in Age-Related Macular Degeneration
In Figure 13-1 we show the typical case evolution of a type 2 CNV in age-related macular degeneration (AMD). The slit-lamp examination shows a small, well-demarcated, gray, roundish dark lesion at the fovea. FA and OCT show type 2 CNV. OCTA shows a central afferent trunk vessel and dense capillary arborescence. A dark area is seen around the CNV.
First Treatment: First Cycle
Twenty-four hours after treatment: OCTA shows a decrease of visible vessels. The CNV area is smaller. Vessels are decreased in number and density, with pruning of thinner anastomoses and of smaller vessels. The network density decreases, highlighting only some rare major preexisting vessels. Residual flow is uneven and more visible close to the afferent trunk. There is an important loss of smaller vessels, a microvascular rarefaction, decreased caliber, and vessels narrowing.
Seven days after injection: Remaining surviving vessels decrease even more and are grouped together around the feeder vessel.
Thirty-two days after injection: The CNV area is smaller. The visible vessels on OCTA are thicker, straighter course, with loss of smaller vessels. Decreased dimensions of CNV area and vessel density are due to the loss of smaller capillaries. Some vessels reopen.
Forty to 45 days after injection: Vessel reproliferation. Some pre-existing main vessels reappear, thicker and straighter with increased flow.
Second Treatment 45 Days After First Treatment: Second Cycle
Second cycle (24 hours after treatment): decrease of visible vessels, and pruning of thinner anastomoses. Residual flow is more visible close to the feeder vessel.
Second cycle (30 to 40 days after the injection): reproliferating vessels appear; their caliber is greater with loss of smaller vessels. They are thicker and straighter with increased flow.
After the third and fourth injection, the CNV area is smaller but denser with higher flow. Fewer vessels reappear, with larger diameter, straighter course, and increased loss of smaller vessels. Mean area of the CNV and vessel density was smaller but some anastomoses reappear.
After each new treatment the same main vessels seem to reappear with increased flow and decreased branch density. The CNV area is smaller. Some main branches do not seem affected by treatment. Some new sprouting grows in new areas and in other areas small capillaries reopen. This evolution follows Spaide’s8 description and seems to confirm his theory of CNV abnormalization after treatment. The same vessels seem to reappear with increased flow and decreased branch density. Some new sprouting has originated from the main branches.
The dark choriocapillaris area around the CNV remains unchanged during the evolution (see Figure 13-1).
Figure 13-2. CNV in fibrovascular formation in AMD. (A) OCTA before treatment shows CNV inside a fibrovascular formation with a large dark halo around the fibrotic formation. A dense irregular neovascular network is seen inside the fibrotic tissue without a peculiar pattern. (B) Seven days after injection: the fibrotic formation is unchanged, and smaller vessels decrease and are more irregular. Network density decreases. (C) Twenty days after injection: residual flow is irregular. Anastomoses and smaller vessels reappear. CNV area smaller. (D) Forty days after injection: residual flow is irregular but denser. Anastomoses and smaller vessels reappear with increased caliber and flow. CNV area is a little larger with anastomoses forming sharper boundaries.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
