Open access peer-reviewed chapter - ONLINE FIRST

Anti-VEGF Treatment and Optical Coherence Tomography Biomarkers in Wet Age-Related Macular Degeneration

Written By

Maja Vinković, Andrijana Kopić and Tvrtka Benašić

Submitted: October 21st, 2020 Reviewed: April 12th, 2021 Published: May 19th, 2021

DOI: 10.5772/intechopen.97689

IntechOpen
Recent Advances and New Perspectives in Managing Macular Degeneration Edited by Pinakin Gunvant Davey

From the Edited Volume

Recent Advances and New Perspectives in Managing Macular Degeneration [Working Title]

Prof. Pinakin Gunvant Gunvant Davey

Chapter metrics overview

182 Chapter Downloads

View Full Metrics

Abstract

Age-related macular degeneration (AMD) is one of the most common causes of severe visual loss in middle and old-age population, and often leads to serious deterioration in quality of life. Currently, the first-line treatment for neovascular AMD (nAMD) are intravitreal injections of anti-vascular endothelial growth factor (VEGF) medications, including bevacizumab, ranibizumab, and aflibercept and also latest commercially available drug, brolucizumab. During initial examination and imaging and treatment follow-up for patients with nAMD, optical coherence tomography (OCT) is used to predict and assess the therapeutic response and guide the treatment. Several OCT-based biomarkers, including the central subfoveal thickness (CSFT), the presence of intraretinal cysts (IRCs) or subretinal fluid (SRF), and the presence of pigment epithelial detachment (PED), were found to influence baseline visual acuity or visual improvements. Recent analyses of large randomized control trials (RCTs) summarized the usefulness of these OCT-based biomarkers. However, many of these early studies relied on time-domain OCT to evaluate the retinal structures thus providing less precise evaluation of the retinal details. After introduction of spectral-domain OCT (SD-OCT) which provided high resolution images, recent studies offered new insights in specific morphological changes and their different impact on visual function in nAMD. For example, these advancement in resolution offered new classification of IRCs into degenerative and exudative which impacts treatment strategy and final outcome in the treatment of nAMD. Moreover, the recent data disclose a substantial difference between RCTs and real-world studies regarding the response to anti-VEGF therapy. In conclusions, IRCs and PED are associated with poor visual improvement in nAMD in a realworld setting. Both IRCs and SRF responded better than PED to anti-VEGF therapy. These observations mandate large longitudinal studies focusing on the usefulness of these high resolution SD-OCT biomarkers in real-world situations.

Keywords

  • Anti-VEGF treatment
  • biomarkers
  • intraretinal cysts
  • intraretinal fluid
  • neovascular AMD
  • OCT
  • pigment epithelial detachment
  • subretinal fluid

1. Introduction

Improving or maintaining visual acuity is the main target of treatment of neovascular age-related macular degeneration (nAMD). Standard nAMD care mandate frequent intravitreal (IVT) antivascular endothelial growth factor (VEGF) injections, which represents a heavy burden on patients, health systems, and physicians.

Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries, with a global prevalence of 8.69% [1]. The prevalence of AMD increases with age among all ethnicities and in all geographic regions, as a result of a growing aging population [2].

Age-related macular degeneration is a progressive, chronic, multifactorial disease of the retina that can lead to visual impairment and blindness, mostly affecting individuals aged more than 60 years [3]. The disease progresses from early to advanced stages and can be divided into 2 major advanced forms: neovascular (wet) AMD (nAMD) and geographic atrophy in dry AMD [4]. A smaller proportion of patients with AMD (20%) are diagnosed with nAMD, but it is responsible for the majority (90%) of vision loss cases and presents as acute painless loss of vision [5, 6]. Neovascular AMD is characterized by the presence of choroidal neovascularization (CNV), a pathologic form of angiogenesis resulting in leakage of fluid that accumulates in the retina, subretinally or below the retinal pigment epithelium (RPE); other features include the development of RPE tears, hard exudates, hemorrhage, or fibrous disciform scar tissue formation [7, 8, 9].

These clinical abnormalities in patients with nAMD lead to a gradual loss of retinal photoreceptors, resulting in decreased vision and even blindness if disease progression is not prevented [10].

Central vision is the key to variuos daily activities, including a person’s ability to read, drive, and recognize faces [11]. The loss of central vision that accompanies AMD greatly affects an individual’s quality of life [12].

Deleterious effect of vision loss on an individual’s quality of life mandates further development of effective treatment modalities and new molecules to treat nAMD.

Advertisement

2. Advances in nAMD treatment

Preservation of visual function is the main goal for nAMD treatment. This is achieved by inhibition of the new blood vessel growth and reduction of the fluid leakage [13]. Vascular endothelial growth factor is a major molecule which contributes to development of CNV [14]. Choroidal neovascularization can be slowed by inhibiting VEGF binding to its receptor, VEGF receptor-2, on blood vessels, which is the major proangiogenic pathway [15]. Anti-VEGF agents are antibodies which neutralize VEGF binding to its receptor and they have different mechanisms of action. They reduce fluid leakage from the CNV, stop growth, and lead to regression of CNV [16]. The introduction of the anti-VEGF drugs into clinical practice has immensely improved the prognosis for patients with nAMD, in such a way that nAMD is no longer considered an incurable disease [17]. The first anti-VEGF agent approved in 2004 by Food and Drug Administration (FDA) was pegaptanib sodium, an aptamer that binds VEGF₁₆₅ [18]. Ranibizumab, an antibody fragment that binds all VEGF-A isoforms was FDA approved in 2006 after the ANCHOR and MARINA studies [19, 20]. In the following years, from 2006 till 2013, there were 2 other anti-VEGF therapies available for nAMD treatment: aflibercept and conbercept, approved based on the results of the VIEW 1 and VIEW 2 studies, and PHOENIX study, respectively [21, 22]. Both of them are antibody fusion proteins [23].

Two other anti-VEGF agents approved for therapy in oncology are used “off-label” for nAMD: ziv-aflibercept and bevacizumab [7]. Current care standards for nAMD include regular intravitreal (IVT) injections of anti-VEGF therapy [24]. This poses a substantial burden on patients, as well as health systems worldwide [3]. For some patients, anti-VEGF treatment involves monthly injections over a long period of time, making patient adherence and monitoring difficult, which in turn has consequences for visual and anatomic outcomes [25]. Also, the cost associated with managing nAMD is substantial [26]. In an attempt to lessen the load of frequent therapy and costs associated with anti-VEGF medications, some clinicians proposed alternative dosing strategies which are different from those in the registered clinical trials (q4- or q8-weeks). These include pro re nata (PRN) and treat-and-extend (TAE) regimens [27]. They attempt to provide the same efficacy and at the same time more convenient regimen that is easier to adhere to and is taking into account individual OCT features of the patient.

Brolucizumab, a newly developed anti-VEGF drug for nAMD treatment, has demonstrated longer durability and improvement in visual and anatomic outcomes in clinical studies in a q12-week regimen, indicating its potential to reduce treatment burden as an important therapeutic tool in nAMD management [28].

Advertisement

3. The role of OCT + OCT-A in nAMD

3.1 Specific OCT biomarkers

Several OCT-based biomarkers, including the central subfoveal thickness (CSFT), the presence of intraretinal cysts (IRCs) or fluid (IRF), subretinal fluid (SRF), and sub-RPE fluid or pigment epithelial detachment (PED), were found to be associated with baseline visual acuity and response to the anti-VEGF treatment (Figure 1). One of the main goals in the management of nAMD has been the removal of fluid in the macular compartments [26]. The clinical significance of fluid depends on its location where it plays a major role in determining the long term success of the treatment and its presence should be recorded at baseline, according to the guidelines from the Vision Academy. Fluid segments should be assesed individually and fluid status evaluated after loading phase and throughout the course of treatment [29, 30].

Figure 1.

OCT biomarkers.

The introduction of OCT into everyday clinical practice allowed a new classification of CNV according to its location, complementing fluorescein angiography (FA) and indocyanin green angiography (ICGA) [31]. In OCT, type 1 CNV, located between Bruch membrane (BM) and RPE, corresponds to PED, often accompanied by subretinal fluid and in later stages of disease by IRC [32]. Type 2 CNV presents as subretinal hyperreflective material (SHRM) and shows concomitant IRF and SRF [33]. SHRM may be composed of exudative fluid, fibrin, blood, or scarring and its characteristics may change during treatment period [34]. According to CATT study, SHRM was present in 77% of treatment-naive eyes at baseline with the prevalence decreasing to 58% at week 4 after treatment and further to 46% after 2 years [35]. It is hypothesized to be caused probably by a dehydration and condensation of the active CNV component [36, 37].

IRC overlying PED, accompanied by SRF, are typical features commonly present in retinal angiomatous proliferation (RAP), classified as type 3 CNV by Freund et al. [38]. Mature type 3 lesions, associated with serous PEDs, are highly responsive to anti-VEGF therapy [39]. However, the development of GA has frequently been described in association with treatment of RAP lesions [40].

3.1.1 Central subfoveal thickness

The greatest importance of CSFT was actually in the research because it was used as a criterion for continued treatment in trials of various drugs and treatment protocols. If the reduction in CSFT after injection is less than 25%, this is considered a criterion for reinjection [41, 42].

Value of CSFT depends mostly on the amount of retinal fluid in the different retinal compartments, so in most cases a higher CSFT is also a sign of a worse VA. If the cause of CSFT is mostly retinal fluid, it will be reduced by treatment with anti-VEGF factors, and VA in this case will be better or not get worse. Recently there was an observation that there is a direct correlation between vision, fluid, the amount of fluid, and fluctuations in CST [28]. A new option is to look at what effect a drug has on fluctuations in CST, which may prove to be extremely important in identifying patients at risk for closer monitoring and more aggressive therapy.

The presence of an epiretinal membrane (ERM) and the accumulation of drusenoid or fibrous material may also be responsible for a higher CSFT. In this case, the prognosis for CSFT reduction with anti-VEGF treatment is usually poor [28, 41].

A certain percentage of subjects in clinical trials as well as patients in clinical practice developed geographic atrophy (GA) after treatment with anti-VEGF factors. Risk factors for such development include the presence of foveal fluid and monthly dosing of injections. In the CATT study, approximately 38% of subjects developed GA after 5 years, mainly those receiving ranibizumab rather than aflibercept. In the case of GA development, a lower CSFT will also mean a significantly lower VA [7, 43].

3.1.2 Intraretinal fluid

Intraretinal fluid appears as round or oval hyporeflective spaces – cysts, but may also present as diffuse thickening of the neurosensory retina [1]. Intraretinal cysts (IRCs) are OCT biomarkers for various retinal diseases such as nAMD, diabetic macular edema, central retinal vein occlusion, and uveitic macular edema.

Since IRCs often differ in their shape and size, and also in their response to anti-VEGF therapy, some authors have divided them into exudative and degenerative. The criteria taken into account were the size of the cyst, its shape, and the possible alteration of the continuity of the RPE below the cyst. Degenerative cysts were described as smaller than 125 μm, usually square in shape and with RPE alterations below the cyst itself, while exudative cysts are more often ovoid and larger [41, 44, 45]. Intraretinal fluid usually results from active fluid exudation, but the degenerative cysts may orginate from passive fluid accumulation due to atrophy of neurosensory elements [1]. Exudative cysts had better initial response to 3 loading monthly injections of anti-VEGF treatment whereas degenerative cysts had lower response to the therapy, persisted for a longer time and were associated with lower VA after treatment [44, 45, 46, 47].

3.1.3 Subretinal fluid

Subretinal fluid can be characterized as hyporeflective fluid accumulation overlying the RPE layer. It resolves in most eyes in response to anti-VEGF treatment, however, not as rapidly as IRF.

According to the several studies, the presence of SRF at baseline or after 1-year treatment did not significantly affect VA [44, 48, 49]. Residual SRF may not always represent ongoing neovascular activity. It may instead be dysfunction of the RPE leading to SRF accumulation, much like central serous chorioretinopathy [50, 51]. Among patients treated with a PRN regimen, those who presented with SRF achieved even higher VA gains [52]. VA was stable regardless of treatment frequency [53]. The pathomechanism for the beneficial role of SRF has not been fully explained but possible explanations suggest the preservation of photoreceptor integrity, less IRF, RPE atrophy and fibrosis [54].

3.1.4 Pigment epithelial detachment

Pigment epithelial detachment (PED) (Figure 2) the anatomical separation of the RPE from the Bruch membrane i.e. sub-RPE fluid is present in about 30–80% of nAMD patients based on the CATT, EXCITE, and VIEW studies [41, 55, 56].

Figure 2.

Pigment epithelial detachment.

PED lesions have been classified based on clinical findings, angiography and OCT assessment (height, width, greatest linear diameter, area, volume, reflectivity, progression and response to treatment of PED lesions) [57]. Three subtypes of PED may be identified based on the reflectivity of the material under the RPE: serous (primarily hyporeflective; hollow), solid (primarily hyperreflective; drusenoid), and mixed (combination of solid and serous PEDs; fibrovascular) [58, 59, 60]. The CNV membrane itself corresponds to hyperreflective material along the back surface of the PED, readily visible by enhanced-depth imaging, or a tomographic notch within the PED, identifiable by conventional OCT [61].

PED has a negative effect on VA only in combination with additional components, mostly IRF [47, 62]. In VIEW studies, the baseline presence of PED, disrupted external limiting membrane (ELM) and ellipsoid zone (EZ), and greater CSFT were associated with poor baseline VA [46]. However there are some controversial data by real-world study where initial VA was worse and visual improvement poorer if PED was present before treatment regardless of IRC or SRF presence [44]. Microperimetry analysis has shown higher retinal sensitivity for SRF and serous PED (sPED) than for IRF and fibrovascular PED (fvPED) [63]. The volume of fvPED at baseline was associated with impaired VA and PED growth seemed to precede fluid recurrence [64, 65, 66].

When SRF is located on the top of a PED (rather than on its edge), without associated IRF, hemorrhage, then probably the PED is not vascularized and will response poorely to anti-VEGF therapy [67]. PEDs are also less responsive to anti-VEGF treatment than SRF or IRC in nAMD [41, 46]. Serous PEDs showed better response to IVIs than fibrovascular ones which may suggest that they are possible signs of lesion activity. Serous PEDs showed most improvement in VA whereas fvPEDs showed most reduction in PED height, especially with aflibercept [50, 57, 68, 69, 70]. Fibrovascular PEDs may be difficult to treat, but even these eyes can gain vision with anti-VEGF therapy. The IVIs change PED morphology in such way that their content becomes more hyperreflective, suggesting an increasing fibrovascular maturization of the CNV [71]. PEDs behavior and functional outcomes are influenced by the treatment regimen. VIEW trials found that the switch from a monthly to an as-needed regimen led to reactivation of PED with a resultant decline in visual outcome, especially in patients who developed secondary IRC following that change [46]. The recurrence of PED is the primary event of neovascular activation [47].

Treatment should focus on vision gains rather than PED resolution because there is no apparent correlation between anatomical and functional improvement in most eyes with PED and nAMD. More frequent anti-VEGF doses may improve anatomical response, without correlation with vision improvement [29]. Atrophy may complicate eyes with PED and nAMD after anti-VEGF therapy, especially in association with complete PED resolution [29].

In 15–20% of eyes with PEDs a RPE tear that may lead to decline or loss of vision spontaneously but also as a serious complication of anti-VEGF therapy. Hyperreflective lines in near-infrared (NIR) images and PEDs greater than 500 μm to 600 μm in height on OCT present an indicator of an increased risk in developing an RPE tear in eyes where the sub-RPE CNV has created contractile folds in response to the treatment [72, 73]. RPE tears after anti-VEGF therapy only developed in patients with serous PED (14.6%) [74].

In conclusion, the presence or persistence of a PED may still be compatible with relatively good visual acuity, but may require more regular treatment.

3.2 Specific OCT-A biomarkers

Noninvasive OCT angiography (OCT-A) generates images of the retinal and choroidal vessels, with the excellent sensibility and specificity for detection of the CNV compared to FA and ICGA [75, 76]. OCT-A provides detailed visualization of the CNV complex in patients with nAMD and its evolution in response to anti-VEGF treatment, disclose a perfused vascular network in nonexudative stage of CNV and also in advanced cases of evident nAMD with fibrotic scars and history of prior treatment with anti-VEGF therapies [77]. CNV type 1 and 2 seem to be more easily visualised on OCT-A compared with retinal angiomatous proliferation (RAP) or polypoidal lesions [78].

Current studies evaluate the association between OCT-A parameters, structural OCT changes and functional response on anti-VEGF therapies. Five qualitative criteria have been recognized on OCT-A: (1) Numerous branching capillaries between major vessels separating the lesion area into fractals, (2) end-to-end anastomoses or intervascular anastomoses within the lesion, (3) arcades or vascular loops at the vessel termini, (4) major, well-defined filamentous vessels, and (5) peri- or intralesional nonvascularized hypointense halos surrounding or embedding the CNV membrane [75]. Greater rate of small branching vessels and peripheral arcades have been detected in immature lesions and a dead-tree appearance in hypermature lesions [79]. A qualitative classification algorithm has been developed based on neovascular density as a predictive factor for clinical activity [80]. Recently, some authors have demonstrated quantitative biomarkers for nAMD disease activity: (1) CNV’s blood flow surface area (SA), (2) vessel density (VD), (3) fractal dimension (FD), and (4) lacunarity index (LAC) [81].

Blood flow SA is a readily available and well-studied OCT-A parameter. Previous qualitative assessments of OCT-A images in CNV networks showed that most of the lesions demonstrated shrinkage of fine peripheral vessels and arteriogenesis of the remaining vessels after anti-VEGF treatment [82]. The branching complexity and blood flow area decrease after the loading doses then regrow and return to the original size at 12 months irrespective of the treatment protocol. The same modifications of blood flow area in patients followed under PRN and TAE regimens [83]. SA also seems to have a weak association with functional outcomes (i.e. VA), highlighting the need to assess other parameters. Finally, the baseline blood flow area had an inverse association with the number of IVIs concerning baseline FD [83].

FD quantifies branching pattern complexity and organization of the vascular structure. It varies according to the number of secondary divisions of the CNV: the higher the number of discernible secondary divisions, the higher the FD value [84]. Many authors demonstrated attenuation and pruning of secondary ramifications after anti-VEGF treatments, with subsequent decrease of the FD value. A FD values is lower in the inactive stage than in the active stage [83, 84]. A weak association between blood flow aspect (FD) and retinal fluid suggests that factors other than CNV morphology are responsible for retinal exudation [79]. There is a poor association between the most studied quantitative OCT-A parameters and functional outcomes at 12 months’ follow-up. FD did not differ between good and bad responders [83].

Lacunarity (LAC) is a measure of the size of gaps within a structure. Higher values reflect heterogenic texture of vascular networks and lower values reflect a more homogeneity of vascular skeleton. The results showed that arrangement of lacunas of the vascular plexus do not change after anti-VEGF, therefore lacunarity may be an OCT-A parameter for nAMD follow-up [85].

According to some investigators, patients with a lower baseline FD and a lower SA have higher odds of having 8 or more IVI injection during the first year. Typical examples of patients that required less than 8 IVI in the first year of treatment are large and complex CNVs. On the other hand, typical examples of patients that required more than eight IVI in the first year of treatments are small lesions with a disorganized architecture [83]. A hypothesis is that in the presence of high VEGF levels, CNVs would have numerous tiny branches and a disorganized architecture, reflecting an aggressive angiogenic process with greater exudation and a heavier treatment burden. In eyes with lower VEGF availability, CNV would grow without leakage maturing their branching architecture toward a complicated network before exudation becomes overly symptomatic [86]. In conclusion, it seems that all evaluated OCT-A parameters were poor biomarkers in predicting anatomic and functional response but baseline FD and SA were the best biomarkers regarding treatment burden.

Advertisement

4. The role of visual acuity on long term prognosis

Early response to anti-VEGF therapy has been shown to be an important predictor of VA recovery in nAMD treatment. VA after 3 months of consecutive intravitreal injections is a better prognostic factor than baseline VA [87]. Likewise, early morphological change of the described OCT biomarkers is a very important prognostic factor for overall treatment outcome.

Thus, early accurate monitoring of treatment responses by analysis of OCT findings and VA is of great importance to optimize the number of injections during treatment in achieving the goal of vision function recovery.

Advertisement

5. Conclusions

Introduction of OCT into everyday clinical practice has revolutionized diagnosis and management of nAMD. This diagnostic tool has pivotal role in terms of disease monitoring and evaluation of treatment efficacy. Many studies give hope that in the future we will be able to offer a better or possibly individual approach to the anti-VEGF treatment that will give the optimal morphological recovery of the macula and VA. The risk factors identified for persistent CNV activity may help clinicians to identify patients for closer monitoring and more aggressive therapy.

The main OCT features predictive of persistent disease activity are IRCs, SRF, sPED recurrence, and those indicative of poorer VA outcome are IRCs, large extent of SHRM damage to the photoreceptor or RPE layer [35]. Exudative IRCs have been shown to require monthly treatment, in particular after recurrence of PED [37, 88]. Patients with IRC after 12 monthly IVIs have shown a higher risk for fibrosis and RPE atrophy compared with patients presenting refractory SRF [89]. By contrast, SRF is associated with stable VA, regardless of treatment frequency, and with better visual gain [50, 51, 90, 91]. Consequently, SRF is an ideal feature for identifying patients suitable for flexible or treat and extend regimens.

By contrast, SRF is associated with stable VA, regardless of treatment frequency, and with better visual gain, and consequently, is an ideal for flexible or treat and extend regimens [50, 51, 90, 91]. In conclusion, these subtypes tell us what outcomes we are hoping to achieve. We can personalize the treatment to some extent – treatment intervals can be maintained or extended where disease inactivity is achieved, i.e. IRF is improving or SRF is stable, or more agressive or in shortened intervals in patients with new and/or increased fluid. It is postulated that persistent IRF should never be tolerated whereas with persistent SRF we are less likely to treat until dry [92]. Advisably is also identifying patients with fluctuations in CSFT, who are convenient for closer monitoring and more aggressive therapy [28].

OCT-A may differentiate active CNV lesions from stable fibrous complexes which could be relevant for treatment decisions. Quantitative OCT-A parameters have shown as poor biomarkers in predicting anatomic and functional response although blood flow area and FD are slightly better than the others.

Recently, automated quantification algorithms have been proposed for the analysis of OCT images with CNV, namely multi-resolution graph-theoretic-based surface detection for PED segmentation and machine learning-based pixel classification for IRC and SRF segmentations [93]. Machine learning algorithms are particularly suitable for determining treatment effect after the loading phase [94]. Computational analysis of OCT images is expected to become even more widespread in the clinical treatment strategies. This will hopefully establish a set of standardized protocols that will allow personalized anti-VEGF treatments based on identifying important differences in retinal responses between patients.

Advertisement

Conflict of interest

The authors declare no conflict of interest.

Advertisement

Abbreviations

VEGFvascular endothelial growth factor
AMDage-related macular degeneration
nAMDneovascular age-related macular degeneration
OCToptical coherence tomography
CSFTcentral subfoveal thickness
IRCintraretinal cysts
SRFsubretinal fluid
PEDpigment epithelial detachment
sPEDserous
fvPEDfibrovascular
ELMexternal limiting membrane
EZellipsoid zone
RCTrandomized control trials
SD-OCTspectral domain optical coherence tomography
IVTintravitreal
IVIintravitreal injection
CNVchoroidal neovascularization
RPEretinal pigment epithelium
PRNpro re nata (as needed)
TAEtreat-and-extend
ERMepiretinal membrane
GAgeographic atrophy
RAPretinal angiomatous proliferation
SHRMsubretinal hyperreflective material
NIRnear-infrared
OCT-Aoptical coherence tomography angiography
SAsurface area
VDvessel density
FDfractal dimension
LAClacunarity index
FAZfoveal avascular zone
FAfluorescein angiography
IVGAindocyanin green angiography
BMBruch membrane

References

  1. 1. Keane PA, Patel PJ, Liakopoulos S, Heussen FM, Sadda SR, Tufail A. Evaluation of age-related macular degeneration with optical coherence tomography. Surv Ophthalmol. 2012 Sep;57(5):389-414. doi: 10.1016/j.survophthal.2012.01.006.
  2. 2. Mitchell P, Liew G, Gopinath B, Wong TY. Age-related macular degeneration. Lancet. 2018 Sep 29;392(10153):1147-1159. doi: 10.1016/S0140-6736(18)31550-2.
  3. 3. Wong WL, Su X, Li X, Cheung CM, Klein R, Cheng CY, Wong TY. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014 Feb;2(2):e106-16. doi: 10.1016/S2214-109X(13)70145-1.
  4. 4. Holz FG, Schmitz-Valckenberg S, Fleckenstein M. Recent developments in the treatment of age-related macular degeneration. J Clin Invest. 2014 Apr;124(4):1430-8. doi: 10.1172/JCI71029.
  5. 5. Wykoff CC, Clark WL, Nielsen JS, Brill JV, Greene LS, Heggen CL. Optimizing Anti-VEGF Treatment Outcomes for Patients with Neovascular Age-Related Macular Degeneration. J Manag Care Spec Pharm. 2018 Feb;24(2-a Suppl):S3-S15. doi: 10.18553/jmcp.2018.24.2-a.s3.
  6. 6. Bakri SJ, Thorne JE, Ho AC, Ehlers JP, Schoenberger SD, Yeh S, Kim SJ. Safety and Efficacy of Anti-Vascular Endothelial Growth Factor Therapies for Neovascular Age-Related Macular Degeneration: A Report by the American Academy of Ophthalmology. Ophthalmology. 2019 Jan;126(1):55-63. doi: 10.1016/j.ophtha.2018.07.028.
  7. 7. Maguire MG, Martin DF, Ying GS, et al. Five-year outcomes with anti-vascular endothelial growth factor treatment of neovascular age-related macular degeneration: the Comparison of Age-Related Macular Degeneration Treatments Trials. Ophthalmology. 2016;123:1751e1761. doi: 10.1016/j.ophtha.2016.03.045
  8. 8. Daniel E, Grunwald JE, Kim BJ, et al. Visual and morphologic outcomes in eyes with hard exudate in the comparison of agerelated macular degeneration treatments trials. Ophthalmol Retina. 2017;1:25-33. doi: 10.1016/j.oret.2016.09.001
  9. 9. Ersoz MG, Karacorlu M, Arf S, et al. Retinal pigment epithelium tears: classification, pathogenesis, predictors, and management. Surv Ophthalmol. 2017;62:493-505. doi: 10.1016/j.survophthal.2017.03.004.
  10. 10. Bhutto I, Lutty G. Understanding age-related macular degeneration (AMD): relationships between the photoreceptor/retinal pigment epithelium/Bruch’s membrane/choriocapillaris complex. Mol Aspects Med. 2012;33:295-317. doi: 10.1016/j.mam.2012.04.005
  11. 11. Roh M, Selivanova A, Shin HJ, et al. Visual acuity and contrast sensitivity are two important factors affecting visionrelated quality of life in advanced age-related macular degeneration. PLoS One. 2018;13:e0196481. doi: 10.1371/journal.pone.0196481.
  12. 12. Mitchell J, Bradley C. Quality of life in age-related macular degeneration: a review of the literature. Health Qual Life Outcomes. 2006;4:97. doi: 10.1186/1477-7525-4-97.
  13. 13. Mitchell P, Liew G, Gopinath B, Wong TY. Age-related macular degeneration. Lancet. 2018;392(10153):1147-1159. doi: 10.1016/S0140-6736(18)31550-2.
  14. 14. Ferris FL, Wilkinson CP, Bird A, et al. Clinical classification of age-related macular degeneration. Ophthalmol. 2013;120(4):844-851. doi: 10.1016/j.ophtha.2012.10.036.
  15. 15. Shibuya M. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: a crucial target for anti- and pro-angiogenic therapies. Genes Cancer. 2011;2:1097-1105. doi: 10.1177/1947601911423031.
  16. 16. Campochiaro PA, Aiello LP, Rosenfeld PJ. Anti-vascular endothelial growth factor agents in the treatment of retinal disease: from bench to bedside. Ophthalmology. 2016;123(10S):S78-S88. doi: 10.1016/j.ophtha.2016.04.056.
  17. 17. Schmidt-Erfurth U, Chong V, Loewenstein A, et al. Guidelines for the management of neovascular age-related macular degeneration by the European Society of Retina Specialists (EURETINA). Br J Ophthalmol. 2014;98:1144-1167. doi: 10.1136/bjophthalmol-2014-305702.
  18. 18. Gragoudas ES, Adamis AP, Cunningham Jr ET, et al. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004;351:2805-2816. doi: 10.1056/NEJMoa042760.
  19. 19. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1432-1444. doi: 10.1056/NEJMoa062655.
  20. 20. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419-1431. doi: 10.1056/NEJMoa054481.
  21. 21. Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012;119:2537-2548. doi: 10.1016/j.ophtha.2012.09.006.
  22. 22. Liu K, Song Y, Xu G, et al. Conbercept for treatment of neovascular age-related macular degeneration: results of the randomized phase 3 PHOENIX study. Am J Ophthalmol. 2019;197:156-167. doi: 10.1016/j.ajo.2018.08.026.
  23. 23. de Oliveira Dias JR, de Andrade GC, Novais EA, et al. Fusion proteins for treatment of retinal diseases: aflibercept, ivaflibercept, and conbercept. Int J Retina Vitreous. 2016;2:3. doi: 10.1186/s40942-016-0026-y.
  24. 24. Jaffe DH, Chan W, Bezlyak V, Skelly A. The economic and humanistic burden of patients in receipt of current available therapies for nAMD. J Comp Eff Res. 2018;7:1125-1132. doi: 10.2217/cer-2018-0058.
  25. 25. Lanzetta P, Loewenstein A. Fundamental principles of an anti-VEGF treatment regimen: optimal application of intravitreal anti-vascular endothelial growth factor therapy of macular diseases. Graefes Arch Clin Exp Ophthalmol. 2017;255: 1259-1273. doi: 10.1007/s00417-017-3647-4.
  26. 26. Ehlken C, Helms M, Bohringer D, et al. Association of treatment adherence with real-life VA outcomes in AMD, DME, and BRVO patients. Clin Ophthalmol. 2018;12:13-20. doi: 10.2147/OPTH.S151611.
  27. 27. Wykoff CC, Croft DE, Brown DM, et al. Prospective trial of treat-and-extend versus monthly dosing for neovascular agerelated macular degeneration: TREX-AMD 1-year results. Ophthalmology. 2015;122:2514-2522. doi: 10.1016/j.ophtha.2015.08.009.
  28. 28. Dugel PU, Koh A, Ogura Y, et al. HAWK and HARRIER: phase 3, multicenter, randomized, double-masked trials of brolucizumab for neovascular age-related macular degeneration. Ophthalmology. 2020;127(1):72e84. doi: 10.1016/j.ophtha.2019.04.017.
  29. 29. Leuschen JN, Schuman SG, Winter KP, McCall MN, Wong WT, Chew EY et al. Spectral-domain optical coherence tomography characteristics of intermediate age-related macular degeneration. Ophthalmology 2013; 120(1): 140-150. doi: 10.1016/j.ophtha.2012.07.004.
  30. 30. Mcneil R. Considering the presence of retinal fluid when treating nAMD patients. Ophthalmology Times Europe. 2020. Vol. 16 No 6 6-9.
  31. 31. Ma J, Desai R, Nesper P, Gill M, Fawzi A, Skondra D. Optical Coherence Tomographic Angiography Imaging in Age-Related Macular Degeneration. Ophthalmol Eye Dis. 2017;9:1179172116686075. Published 2017 Mar 20. doi:10.1177/1179172116686075
  32. 32. Nagiel A, Sadda SR, Sarraf D. A promising future for optical coherence tomography angiography. JAMA Ophthalmol. 2015;133:629-630. doi: 10.1001/jamaophthalmol.2015.0668.
  33. 33. Fang PP, Lindner M, Steinberg JS, et al. Clinical applications of OCT angiography. Ophthalmologe. 2016;113:14-22.
  34. 34. Cheung CMG, Grewal DS, Teo KYC, Gan A, Mohla A, Chakravarthy U, Wong TY, Jaffe GJ. The Evolution of Fibrosis and Atrophy and Their Relationship with Visual Outcomes in Asian Persons with Neovascular Age-Related Macular Degeneration. Ophthalmol Retina. 2019 Dec;3(12):1045-1055. doi: 10.1016/j.oret.2019.06.002.
  35. 35. Willoughby AS, Ying GS, Toth CA, Maguire MG, Burns RE, Grunwald JE, Daniel E, Jaffe GJ; Comparison of Age-Related Macular Degeneration Treatments Trials Research Group. Subretinal Hyperreflective Material in the Comparison of Age-Related Macular Degeneration Treatments Trials. Ophthalmology. 2015 Sep;122(9):1846-53.e5. doi: 10.1016/j.ophtha.2015.05.042.
  36. 36. Daniel E, Shaffer J, Ying GS, Grunwald JE, Martin DF, Jaffe GJ, Maguire MG; Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) Research Group. Outcomes in Eyes with Retinal Angiomatous Proliferation in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT). Ophthalmology. 2016 Mar;123(3):609-16. doi: 10.1016/j.ophtha.2015.10.034
  37. 37. Daniel E, Toth CA, Grunwald JE, Jaffe GJ, Martin DF, Fine SL, Huang J, Ying GS, Hagstrom SA, Winter K, Maguire MG; Comparison of Age-related Macular Degeneration Treatments Trials Research Group. Risk of scar in the comparison of age-related macular degeneration treatments trials. Ophthalmology. 2014 Mar;121(3):656-66. doi: 10.1016/j.ophtha.2013.10.019.
  38. 38. Freund KB, Ho IV, Barbazetto IA et al. Type 3 neovascularization: the expanded spectrum of retinal angiomatous proliferation. Retina. 2008 Feb;28(2):201-11. doi: 10.1097/IAE.0b013e3181669504.
  39. 39. Yanuzzi LA, Negrao S, Iida T, et al. Retinal angiomatous proliferation in age-related macular degeneration. Retina 2012;32(Suppl 1):416-34. doi: 10.1097/iae.0b013e31823f9b3b
  40. 40. Browning AC, O'Brien JM, Vieira RV, Gupta R, Nenova K. Intravitreal Aflibercept for Retinal Angiomatous Proliferation: Results of a Prospective Case Series at 96 Weeks. Ophthalmologica. 2019;242(4):239-246. doi: 10.1159/000500203
  41. 41. Schmidt-Erfurth U, Waldstein SM. A paradigm shift in imaging biomarkers in neovascular age-related macular degeneration. Prog Retin Eye Res. 2016;50:1-24. doi: 10.1016/j.preteyeres.2015.07.007.
  42. 42. Amoaku WM, Chakravarthy U, Gale R, Gavin M, Ghanchi F, Gibson J, Harding S, Johnston RL, Kelly SP, Lotery A, Mahmood S, Menon G, Sivaprasad S, Talks J, Tufail A, Yang Y. Defining response to anti-VEGF therapies in neovascular AMD. Eye (Lond). 2015 Jun;29(6):721-31. doi: 10.1038/eye.2015.48.
  43. 43. Grunwald JE, Pistilli M, Daniel E, Ying GS, Pan W, Jaffe GJ, Toth CA, Hagstrom SA, Maguire MG, Martin DF; Comparison of Age-Related Macular Degeneration Treatments Trials Research Group. Incidence and Growth of Geographic Atrophy during 5 Years of Comparison of Age-Related Macular Degeneration Treatments Trials. Ophthalmology. 2017 Jan;124(1):97-104. doi: 10.1016/j.ophtha.2016.09.012.
  44. 44. Lai TT, Hsieh YT, Yang CM, Ho TC, Yang CH. Biomarkers of optical coherence tomography in evaluating the treatment outcomes of neovascular age-related macular degeneration: a real-world study. Sci Rep. 2019 Jan 24;9(1):529. doi: 10.1038/s41598-018-36704-6.
  45. 45. Schmidt-Erfurth U, Eldem B, Guymer R, Korobelnik JF, Schlingemann RO, Axer-Siegel R, Wiedemann P, Simader C, Gekkieva M, Weichselberger A; EXCITE Study Group. Efficacy and safety of monthly versus quarterly ranibizumab treatment in neovascular age-related macular degeneration: the EXCITE study. Ophthalmology. 2011 May;118(5):831-9. doi: 10.1016/j.ophtha.2010.09.004.
  46. 46. Waldstein, S. M. et al. Morphology and Visual Acuity in Aflibercept and Ranibizumab Therapy for Neovascular Age-Related Macular Degeneration in the VIEW Trials. Ophthalmology 123, 1521-1529 (2016) doi: 10.1016/j.ophtha.2016.03.037
  47. 47. Simader C, Ritter M, Bolz M, Deák GG, Mayr-Sponer U, Golbaz I, Kundi M, Schmidt-Erfurth UM. Morphologic parameters relevant for visual outcome during anti-angiogenic therapy of neovascular age-related macular degeneration. Ophthalmology. 2014 Jun;121(6):1237-45. doi: 10.1016/j.ophtha.2013.12.029.
  48. 48. Tan CS, Lim LW, Ngo WK, et al. Predictors of persistent disease activity following anti-VEGF loading dose for nAMD patients in Singapore: the DIALS study. BMC Ophthalmol. 2020;20(1):324. Published 2020 Aug 6. doi:10.1186/s12886-020-01582-y
  49. 49. Clemens CR, Alten F, Termühlen J, et al. Prospective PED-study of intravitreal aflibercept for refractory vascularized pigment epithelium detachment due to age-related macular degeneration: morphologic characteristics of non-responders in optical coherence tomography. Graefes Arch Clin Exp Ophthalmol. 2020;258(7):1411-1417. doi:10.1007/s00417-020-04675-y
  50. 50. Arnold JJ, Markey CM, Kurstjens NP, Guymer RH. The role of sub-retinal fluid in determining treatment outcomes in patients with neovascular age-related macular degeneration--a phase IV randomised clinical trial with ranibizumab: the FLUID study. BMC Ophthalmol. 2016 Mar 24;16:31. doi: 10.1186/s12886-016-0207-3.
  51. 51. Veritti D, Sarao V, Missiroli F, Ricci F, Lanzetta P. TWELVE-MONTH OUTCOMES OF INTRAVITREAL AFLIBERCEPT FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: Fixed Versus As-needed Dosing. Retina. 2019 Nov;39(11):2077-2083. doi: 10.1097/IAE.0000000000002299
  52. 52. Pron G. Optical Coherence Tomography Monitoring Strategies for A-VEGF-Treated Age-Related Macular Degeneration: An Evidence-Based Analysis. Ont Health Technol Assess Ser. 2014;14(10):1-64. Published 2014 Aug 1.
  53. 53. Inan S, Polat O, Karadas M, Inan UU. The association of exudation pattern with anatomical and functional outcomes in patients with Neovascular Age-Related Macular Degeneration. Rom J Ophthalmol. 2019;63(3):238-244.
  54. 54. Mantel I, Niderprim SA, Gianniou C, Deli A, Ambresin A. Reducing the clinical burden of ranibizumab treatment for neovascular age-related macular degeneration using an individually planned regimen. Br J Ophthalmol. 2014;98(9):1192-1196. doi:10.1136/bjophthalmol-2013-304556
  55. 55. Ashraf, M., Souka, A. & Adelman, R. A. Age-related macular degeneration: using morphological predictors to modify current treatment protocols. Acta Ophthalmol. 96, 120-133 (2018). doi: 10.1111/aos.13565.
  56. 56. Cheong KX, Teo KYC, Cheung CMG. Influence of pigment epithelial detachment on visual acuity in neovascular age-related macular degeneration. Surv Ophthalmol. 2021 Jan-Feb;66(1):68-97. doi: 10.1016/j.survophthal.2020.05.003.
  57. 57. Balaskas K, Karampelas M, Horani M, et al. Quantitative analysis of pigment epithelial detachment response to different anti-vascular endothelial growth factor agents in wet age-related macular degeneration. Retina. 2017 Jul;37(7):1297-304. doi: 10.1097/IAE.0000000000001342.
  58. 58. Tyagi, P., Juma, Z., Hor, Y.K. et al. Clinical response of pigment epithelial detachment associated with neovascular age-related macular degeneration in switching treatment from Ranibizumab to Aflibercept. BMC Ophthalmol 18, 148 (2018). doi: 10.1186/s12886-018-0824-0.
  59. 59. Karampelas M, Malamos P, Petrou P, Georgalas I, Papaconstantinou D, Brouzas D. Retinal Pigment Epithelial Detachment in Age-Related Macular Degeneration. Ophthalmol Ther. 2020;9(4):739-756. doi:10.1007/s40123-020-00291-5
  60. 60. Nagai N, Suzuki M, Uchida A, et al. Non-responsiveness to intravitreal aflibercept treatment in neovascular age-related macular degeneration: implications of serous pigment epithelial detachment. Sci Rep. 2016;6:29619. Published 2016 Jul 11. doi:10.1038/srep29619
  61. 61. Malihi M, Jia Y, Gao SS, et al. Optical coherence tomographic angiography of choroidal neovascularization ill-defined with fluorescein angiography. Br J Ophthalmol. 2017;101(1):45-50. doi:10.1136/bjophthalmol-2016-309094
  62. 62. Khanani AM, Eichenbaum D, Schlottmann PG, Tuomi L, Sarraf D. OPTIMAL MANAGEMENT OF PIGMENT EPITHELIAL DETACHMENTS IN EYES WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION. Retina. 2018;38(11):2103-2117. doi:10.1097/IAE.0000000000002195
  63. 63. Laishram M, Srikanth K, Rajalakshmi AR, Nagarajan S, Ezhumalai G. Microperimetry - A New Tool for Assessing Retinal Sensitivity in Macular Diseases. J Clin Diagn Res. 2017;11(7):NC08-NC11. doi:10.7860/JCDR/2017/25799.10213
  64. 64. Suzuki M, Nagai N, Izumi-Nagai K, Shinoda H, Koto T, Uchida A, Mochimaru H, Yuki K, Sasaki M, Tsubota K, Ozawa Y. Predictive factors for non-response to intravitreal ranibizumab treatment in age-related macular degeneration. Br J Ophthalmol. 2014 Sep;98(9):1186-91. doi: 10.1136/bjophthalmol-2013-304670
  65. 65. Hoerster, R., Muether, P. S., Sitnilska, V., Kirchhof, B. & Fauser, S. Fibrovascular pigment epithelial detachment is a risk factor for long-term visual decay in neovascular age-related macular degeneretion. Retina 34, 1767-1773 (2014). doi: 10.1097/IAE.0000000000000188.
  66. 66. Au A, Hou K, Dávila JP, Gunnemann F, Fragiotta S, Arya M, Sacconi R, Pauleikhoff D, Querques G, Waheed N, Freund KB, Sadda S, Sarraf D. Volumetric Analysis of Vascularized Serous Pigment Epithelial Detachment Progression in Neovascular Age-Related Macular Degeneration Using Optical Coherence Tomography Angiography. Invest Ophthalmol Vis Sci. 2019 Aug 1;60(10):3310-3319. doi: 10.1167/iovs.18-26478
  67. 67. Juma Z, Hor YK, Scott NW, Ionean A, Santiago C. Clinical response of pigment epithelial detachment associated with neovascular age-related macular degeneration in switching treatment from Ranibizumab to Aflibercept. BMC Ophthalmol. 2018;18(1):148. Published 2018 Jun 22. doi:10.1186/s12886-018-0824-0
  68. 68. Punjabi OS, Huang J, Rodriguez L, Lyon AT, Jampol LM, Mirza RG. Imaging characteristics of neovascular pigment epithelial detachments and their response to anti-vascular endothelial growth factor therapy. Br J Ophthalmol. 2013 Aug;97(8):1024-31. doi: 10.1136/bjophthalmol-2013-303155
  69. 69. Tarakcioglu HN, Ozkaya A, Kemer B, Taskapili M. Multimodal imaging based biomarkers predictive of early and late response to anti-VEGFs during the first year of treatment for neovascular age-related macular degeneration. J Fr Ophtalmol. 2019 Jan;42(1):22-31. doi: 10.1016/j.jfo.2018.06.005.
  70. 70. de Massougnes S, Dirani A, Mantel I. GOOD VISUAL OUTCOME AT 1 YEAR IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION WITH PIGMENT EPITHELIUM DETACHMENT: Factors Influencing the Treatment Response. Retina. 2018 Apr;38(4):717-724. doi: 10.1097/IAE.0000000000001613.
  71. 71. Clemens CR, Krohne TU, Charbel Issa P, Helb HM, Kosanetzky N, Lommatzsch A, Holz FG, Eter N. High-resolution optical coherence tomography of subpigment epithelial structures in patients with pigment epithelium detachment secondary to age-related macular degeneration. Br J Ophthalmol. 2012 Aug;96(8):1088-91. doi: 10.1136/bjophthalmol-2011-301415.
  72. 72. Leitritz M, Gelisken F, Inhoffen W, Voelker M, Ziemssen F. Can the risk of retinal pigment epithelium tears after bevacizumab treatment be predicted? An optical coherence tomography study. Eye (Lond). 2008 Dec;22(12):1504-7. doi: 10.1038/eye.2008.145.
  73. 73. Faatz H, Farecki ML, Rothaus K, Gutfleisch M, Pauleikhoff D, Lommatzsch A. Changes in the OCT angiographic appearance of type 1 and type 2 CNV in exudative AMD during anti-VEGF treatment. BMJ Open Ophthalmol. 2019 Dec 10;4(1):e000369. doi: 10.1136/bmjophth-2019-000369.
  74. 74. Clemens CR, Bastian N, Alten F, Milojcic C, Heiduschka P, Eter N. Prediction of retinal pigment epithelial tear in serous vascularized pigment epithelium detachment. Acta Ophthalmol. 2014 Feb;92(1):e50-6. doi: 10.1111/aos.12234.
  75. 75. Coscas GJ, Lupidi M, Coscas F, Cagini C, Souied EH. OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY VERSUS TRADITIONAL MULTIMODAL IMAGING IN ASSESSING THE ACTIVITY OF EXUDATIVE AGE-RELATED MACULAR DEGENERATION: A New Diagnostic Challenge. Retina. 2015 Nov;35(11):2219-28. doi: 10.1097/IAE.0000000000000766.
  76. 76. Nikolopoulou E, Lorusso M, Micelli Ferrari L, Cicinelli MV, Bandello F, Querques G, Micelli Ferrari T. Optical Coherence Tomography Angiography versus Dye Angiography in Age-Related Macular Degeneration: Sensitivity and Specificity Analysis. Biomed Res Int. 2018 Mar 7;2018:6724818. doi: 10.1155/2018/6724818.
  77. 77. Huang D, Jia Y, Rispoli M, Tan O, Lumbroso B. OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY OF TIME COURSE OF CHOROIDAL NEOVASCULARIZATION IN RESPONSE TO ANTI-ANGIOGENIC TREATMENT. Retina. 2015 Nov;35(11):2260-4. doi: 10.1097/IAE.0000000000000846.
  78. 78. Perrott-Reynolds R, Cann R, Cronbach N, Neo YN, Ho V, McNally O, Madi HA, Cochran C, Chakravarthy U. The diagnostic accuracy of OCT angiography in naive and treated neovascular age-related macular degeneration: a review. Eye (Lond). 2019 Feb;33(2):274-282. doi: 10.1038/s41433-018-0229-6.
  79. 79. Coscas F, Lupidi M, Boulet JF, et al. Optical coherence tomography angiography in exudative age-related macular degeneration: a predictive model for treatment decisions. Br J Ophthalmol. 2019;103: 1342-1346. doi:10.1136/bjophthalmol-2018-313065
  80. 80. Stattin M, Forster J, Daniel A, Graf A, Krepler K, Ansari-Shahrezaei S. Relationship between Neovascular Density in Swept Source-Optical Coherence Tomography Angiography and Signs of Activity in Exudative Age-Related Macular Degeneration. J Ophthalmol. 2019;2019:4806061. Published 2019 Jul 9. doi:10.1155/2019/4806061
  81. 81. McClintic SM, Gao S, Wang J, Hagag A, Lauer AK, Flaxel CJ, Bhavsar K, Hwang TS, Huang D, Jia Y, Bailey ST. Quantitative Evaluation of Choroidal Neovascularization under Pro Re Nata Anti-Vascular Endothelial Growth Factor Therapy with OCT Angiography. Ophthalmol Retina. 2018 Sep;2(9):931-941. doi: 10.1016/j.oret.2018.01.014.
  82. 82. Spaide RF, Fujimoto JG, Waheed NK. IMAGE ARTIFACTS IN OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY. Retina. 2015 Nov; 35(11):2163-80. doi: 10.1097/IAE.0000000000000765.
  83. 83. Cabral D, Coscas F, Pereira T, Français C, Geraldes C, Laiginhas R, Rodrigues C, Kashi AK, Nogueira V, Falcão M, Papoila AL, Lupidi M, 19.Coscas G, Cohen SY, Souied E. Quantitative Optical Coherence Tomography Angiography Biomarkers in a Treat-and-Extend Dosing Regimen in Neovascular Age-Related Macular Degeneration. Transl Vis Sci Technol. 2020 Feb 14;9(3):18. doi: 10.1167/tvst.9.3.18.
  84. 84. Al-Sheikh M, Iafe NA, Phasukkijwatana N, Sadda SR, Sarraf D. Biomarkers of neovascular activity in age-related macular degeneration using OCT angiography. Retina. 2018; 38: 220-230. doi:10.1097/IAE.0000000000001628
  85. 85. Roberts PK, Nesper PL, Gill MK, Fawzi AA. SEMIAUTOMATED QUANTITATIVE APPROACH TO CHARACTERIZE TREATMENT RESPONSE IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Real-World Study. Retina. 2017 Aug; 37(8):1492-1498. doi: 10.1097/IAE.0000000000001400
  86. 86. Corvi F, Pellegrini M, Erba S, Cozzi M, Staurenghi G, Giani A. Reproducibility of Vessel Density, Fractal Dimension, and Foveal Avascular Zone Using 7 Different Optical Coherence Tomography Angiography Devices. Am J Ophthalmol. 2018 Feb;186:25-31. doi: 10.1016/j.ajo.2017.11.011.
  87. 87. Nguyen V, Daien V, Guymer R, Young S, Hunyor A, Fraser-Bell S, Hunt A, Gillies MC, Barthelmes D; Fight Retinal Blindness! Study Group. Projection of Long-Term Visual Acuity Outcomes Based on Initial Treatment Response in Neovascular Age-Related Macular Degeneration. Ophthalmology. 2019 Jan;126(1):64-74. doi: 10.1016/j.ophtha.2018.08.023. Epub 2018 Aug 24. PMID: 30149035.
  88. 88. de Moura J, L Vidal P, Novo J, Rouco J, G Penedo M, Ortega M. Intraretinal Fluid Pattern Characterization in Optical Coherence Tomography Images. Sensors (Basel). 2020 Apr 3;20(7):2004. doi: 10.3390/s20072004.
  89. 89. Mitchell P, Korobelnik JF, Lanzetta P, Holz FG, Prünte C, Schmidt-Erfurth U, Tano Y, Wolf S. Ranibizumab (Lucentis) in neovascular age-related macular degeneration: evidence from clinical trials. Br J Ophthalmol. 2010 Jan;94(1):2-13. doi: 10.1136/bjo.2009.159160.
  90. 90. Penha FM, Gregori G, Garcia Filho CA, Yehoshua Z, Feuer WJ, Rosenfeld PJ. Quantitative changes in retinal pigment epithelial detachments as a predictor for retreatment with anti-VEGF therapy. Retina. 2013 Mar;33(3):459-66. doi: 10.1097/IAE.0b013e31827d2657
  91. 91. Akagi-Kurashige Y, Tsujikawa A, Oishi A, Ooto S, Yamashiro K, Tamura H, Nakata I, Ueda-Arakawa N, Yoshimura N. Relationship between retinal morphological findings and visual function in age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. 2012 Aug;250(8):1129-36. doi: 10.1007/s00417-012-1928-5.
  92. 92. Sharma S, Toth CA, Daniel E, Grunwald JE, Maguire MG, Ying GS, et al. Macular morphology and visual acuity in the second year of the comparison of age-related macular degeneration treatments trials. Ophthalmology. 2016;123:865-75. doi: 10.1016/j.ophtha.2015.12.002.
  93. 93. Xiayu Xu, Kyungmoo Lee, Li Zhang, Sonka M, Abramoff MD. Stratified Sampling Voxel Classification for Segmentation of Intraretinal and Subretinal Fluid in Longitudinal Clinical OCT Data. IEEE Trans Med Imaging. 2015 Jul;34(7):1616-1623. doi: 10.1109/TMI.2015.2408632
  94. 94. Bogunovic H, Abramoff M, Zhang L, Sonka M. Prediction of Treatment Response from Retinal OCT in Patients with Exudative Age-Related Macular Degeneration. International Workshop on Ophthalmic Medical Image Analysis of MICCAI: Boston,MA, USA, 2014.

Written By

Maja Vinković, Andrijana Kopić and Tvrtka Benašić

Submitted: October 21st, 2020 Reviewed: April 12th, 2021 Published: May 19th, 2021