Section 1: Controversies in the etiology of nAMD
Consensus Statement 1.1:
In addition to old age, the pathogenesis of nAMD involves complex interaction of both genetic and environmental risk factors.Although polymorphisms in genes such as CFH and HTRA1/ARMS2 are associated with the development of nAMD, value of routine genetic testing to evaluate the risk of nAMD is not yet certain.
Consensus Statement 1.2:
Polygenic risk scores, which consider multiple genetic variants, are likely to provide more meaningful risk stratification compared to single-gene testing for nAMD and could be the future direction for genetic testing.
Consensus Statement 1.3:
Changes in the inflammatory pathway such as activation of the complement system is involved in the etiology of nAMD.However, it remains unclear whether systemic or local inflammatory response contribute more to the pathogenesis of nAMD.
Consensus Statement 1.4:
Oxidative stress , nitrosative stress and abnormalities in lipid metabolism have been implicated in the pathogenesis of nAMD.Further studies are required to determine how these different metabolic pathways interact with cellular targets in resulting in nAMD at a systemic or local level.
Consensus Statement 1.5:
Choroidal blood flow and vascular insufficiency is associated with nAMD development, but it remains uncertain whether the changes are primary or secondary.
Consensus Statement 1.6:
Intermediate or large drusen are commonly found in eyes with nAMD and their fellow eyes. However, the absence of such drusen, particularly in Asian populations, does not preclude the diagnosis of nAMD, reflecting potential ethnic differences in disease etiology.
Consensus Statement 1.7:
Some cases of MNV may be classified as nAMD while also exhibiting features characteristic of PNV or myopic CNV. These overlapping phenotypes suggest potential comorbid or converging etiologic pathways in the development of nAMD.
Section 2: Controversies in the Diagnosis of AMD
Consensus Statement 2.1:
Based on current classification schemes, AMD can be classified as early, intermediate and late (geographic atrophy and nAMD).Recent development in multimodal imaging with enhanced imaging of the choroid has led to further classification of AMD into drusen-driven AMD and pachychoroid-driven AMD.
Consensus Statement 2.2:
According to the origin of the MNV in nAMD, the MNV can be classified as Type 1 (originating from the choroid and confirmed beneath the RPE), Type 2 (originating from the choroid and penetrates the RPE into the subretinal space) and Type 3 (originating from the retinal vasculature, also known as RAP).
Consensus Statement 2.3:
PCV is a sub-type of nAMD and is characterized by the presence of polypoidal lesions and branching neovascular network which can be diagnosed using multimodal imaging.
Consensus Statement 2.4:
Dye-based angiographies such as fluorescein angiography (FA) and indocyanine green angiography (ICGA) are routinely used for providing definitive diagnosis and evaluation of activity in nAMD in clinical trials.However, in real-world clinical practice, the role of FA and ICGA in assessing disease activity has largely been replaced by OCT.
Consensus Statement 2.5:
OCT can diagnose various subtypes of nAMD and it is highly desirable to use it routinely for evaluation and monitoring of the disease activity.OCT features of nAMD disease activity include SRF, IRF, sub-retinal RPE fluid, SHRM and hemorrhage.
Consensus Statement 2.6:
OCTA can provide non-invasive imaging of retinal and choroidal blood flow in conjunction with structural OCT data.Both en face and cross-sectional B-scan OCTA images are used to enhance the diagnostic capability of various nAMD lesions.
Consensus Statement 2.7:
In most clinical trials for nAMD, multimodal imaging should include color fundus photography, OCT and FA.ICGA should also be included as an imaging modality for nAMD clinical trials involving in Asian populations. Inclusion of OCTA as a clinical trial investigation remains a potential limitation due to variations in machines used and imaging protocol.
Consensus Statement 2.8:
Qualitative and quantitative analyses of various OCT biomarker features such as subretinal drusenoid deposits and hyperreflective foci might have a potential predictive role in nAMD prognosis and progression.
Consensus Statement 2.9:
Assessment with visual physiological tests like microperimetry might provide functional measurement in eyes with nAMD.Their roles of routine clinical use are less certain due to relatively time-consuming examination and limited availability.
Consensus Statement 2.10:
Application of artificial intelligence (AI) systems might help in the diagnosis and assessment of nAMD.However, there are still challenges to be tackled before widespread application of AI such as validity of findings in various ethnic groups, cross-platform application among different manufacturers and fulfilling specific regulatory requirements of the healthcare system.
Section 3: Treatment controversies in nAMD
Consensus statement 3.1:
The first-line initial treatment for patients with newly diagnosed nAMD should consist of at least 3 loading doses of intravitreal anti-VEGF therapy as soon as possible in order to prevent further visual loss and to maximize the potential visual acuity gain.
Consensus statement 3.2:
Following initial loading doses of anti-VEGF therapy, subsequent treatment regimen should consist of personalized treat-and-extend (T&E) injections of anti-VEGF agents as T&E regimen allows for similar visual acuity gain compared to fixed-dosing, with a substantially reduced number of injections.
Consensus Statement 3.3:
During the maintenance phase of anti-VEGF treatment, serial optical coherence tomography (OCT) should be performed at all treatment visits in order to allow quantitative and qualitative assessments of the macular status for evaluating the treatment response for guiding subsequent treatment interval decisions.
Consensus Statement 3.4:
The T&E treatment interval should be adjusted by 2 to 4 weeks based on the patients’ changes in visual acuity, OCT findings, presence or absence of new macular hemorrhage, and the anti-VEGF agents used.The maximal treatment interval should be 16 to 24 weeks depending on the anti-VEGF agent used.
Consensus Statement 3.5:
In nAMD eyes with suboptimal treatment response following eg. requiring high-injection frequency to control the disease activity (every 4-7 weeks) or persistent or increasing SRF or IRF, switching to an alternative anti-VEGF agent such as brolucizumab, faricimab or aflibercept 8mg may be considered for optimizing the treatment response and disease control.
Consensus Statement 3.6:
In eyes with typical nAMD, there is limited role for verteporfin photodynamic therapy (vPDT) either as a monotherapy or as a combination therapy with anti-VEGF therapy as the long-term visual outcome following vPDT is generally worse than anti-VEGF monotherapy.
Section 4: Controversies in future development in the management of nAMD
Consensus Statement 4.1:
Implantation of port-delivery system (PDS) with ranibizumab may provide sustained release of anti-VEGF at therapeutic level over several months after each refill-exchange procedure and can be a treatment option to reduce the injection burden while maintaining the patient’s visual acuity.
Consensus Statement 4.2:
Gene therapy enabling production of proteins which inhibits the pro-angiogenesis pathway may have the potential to reduce treatment burden and enable long-term disease control in nAMD.
Consensus Statement 4.3:
One of the future potential treatment options for nAMD is the use of new pharmacological agents like tyrosine kinase inhibitor to target pathogenic pathways other than VEGF.
Section 5: Controversies in Healthcare Delivery and Public Health
Consensus Statement 5.1:
Anti-VEGF therapy has been shown to be a cost-effective therapy for nAMD as it can reduce the risk of irreversible visual impairment.Newer more durable ant-VEGF agents and biosimilar anti-VEGF agents might further improve the cost-effectiveness of the drugs.
Consensus Statement 5.2:
Self-operated home telemonitoring with device testing visual function with preferential hyperacuity perimetry or home-based OCT may be useful for early detection of nAMD disease activity and may improve the treatment outcome. However, the cost involved could be a major barrier for its widespread use.
Consensus Statement 5.3:
Screening for AMD, especially in high-risk populations such as in elderly and in smokers, might be cost-effective in selective countries but further regional specific healthcare economics studies are required to determine the cost-effectiveness of the screening programs.