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Current and Emerging Diagnostic and Therapeutic Developments in Age-Related Macular Degeneration (AMD)
By Dr Anna Tan

Introduction

Age-related macular degeneration (AMD) is characterized by aging changes in the retina, the presence of drusen and a thin choroid. AMD accounts for 8.7% of blindness worldwide and is the most common cause of blindness in developed countries in the elderly.1 Due to an increasing aging population, it is projected that AMD will affect 196 million people in 2020, increasing to 288 million in 2040.1

AMD can be broadly classified into early, intermediate and late or advanced AMD.2 Early or intermediate AMD is classified by the presence of drusen and pigmentary changes. (Figure 1)2 Advanced AMD includes either “dry” or non-neovascular AMD characterised by geographic atrophy (GA) of the macula while “wet” or neovascular AMD is characterised by the development of neovascularization in the retina or the choroid resulting in exudation, haemorrhage, pigment epithelial detachments (PEDs) and subsequent fibrosis and scarring. (Figure 2)2 Polypoidal choroidal vasculopathy, a disease more common in Asians and Africans, is a subtype of neovascular AMD and is characterised by a branching vascular network that is associated with polypoidal lesions.(Figure 3)3 Polyps, which appear as vascularized, peaked PEDs, may be seen adjacent or within larger serous PEDs.(Figure 3)3

The symbiotic advances in multi-modal imaging including optical coherence tomography (OCT) and anti-angiogenic therapies such as anti-vascular endothelial growth factor (anti-VEGF) inhibitors have revolutionised the treatment of exudative retinal diseases in particular neovascular AMD.4

Developments in multi-modal imaging for AMD

Multi-modal imaging is intrinsic to any current retinal practice and is essential for the accurate diagnosis of the various subtypes AMD as well as to monitor response to treatment. Perhaps the most significant development in multi-modal imaging in the last decade is OCT imaging. OCT imaging is based on low coherence interferometry typically employing the use of near infra-red light to create cross sectional images of the retinal and choroidal layers.5 The non-invasive nature and fast acquisition time allow this test to be repeated frequently in contrast to more conventional imaging techniques such as fundus fluorescein angiography (FA) and indo-cyanine angiography (ICGA) which have risks associated with the injection of intravenous dye.

OCT imaging has allowed high-resolution details of the retinal and choroidal structure to be imaged with depth-resolved analysis and imaging-histology correlations have provided valuable insights into the pathogenesis of AMD.6,7 Both the natural history of disease progression as well as the response to therapy can be imaged in vivo with consecutive OCT imaging in greater detail than ever before.4 Central sub-foveal thickness and the presence of exudation seen on OCT have emerged as a valuable outcome measures to assess therapeutic therapy in neovascular AMD in clinical trials.8,9

OCT angiography (OCTA) is a recent development that allows the detailed 3-dimensional study of blood flow within the vascular structures of the eye without the need to intravenously administer fluorescent dyes.10 OCTA has allowed the imaging of vascular structures in greater detail because unlike conventional angiography (FA or ICGA), no leakage obscures the vascular details (Figure 2 & 3). This new technology is still in its infancy and its interpretation and clinical application is still being established.11

Another significant advancement in imaging in advanced non-neovascular AMD is fundus autofluorescence (FAF) (Figure 1). GA has been defined as “a complete depigmentation of the RPE on the fundus photographs that had at least 2 of the following 3 characteristics: roughly round or oval shape, sharp margins, and visibility of underlying large choroidal vessels.”12 FAF imaging has been shown to demarcate distinctly the areas of GA with a homogenous hypo autofluorescent area surrounded by an abnormal hyperautofluorescent pattern at the junctional areas of the GA. (Figure 1)13 The recent development of quantitative FAF may have the potential to measure hyper- or hypofluorescence more accurately, however the clinical implication of this technology is still not established in AMD.14

Additional emerging imaging modalities include adaptive optics that allow imaging down to the cellular level of rod and cone photoreceptors, retinal pigment epithelium and white blood cells within the retina15. This technology has the potential to monitor both the in vivo cellular structure and function during disease progression. However, current limitations include the small field of view and the lack of standardised protocols for image acquisition, analysis and interpretation. Macula pigment optical density is another modality gaining interest, due to the macula pigment alterations in eyes with AMD.16 The hypothesis that dietary supplements such a lutein, zeaxanthin and meso-zeaxanthin can alter macular pigment levels within the retina and whether this can result in either functional improvements or retard disease progression is still debatable.17

Therapeutic developments in AMD

Therapeutic strategies for AMD have largely been focussed on treatment of neovascular AMD. Before the introduction of intravitreal anti-VEGF therapy, the mainstay of therapy was argon laser photocoagulation for extra-foveal lesions and photodynamic therapy (PDT) for peri- and subfoveal lesions.18 In general with PDT treatment, visual acuity outcomes did not improve but only prevented vision loss. At 12 months follow up, less eyes treated with PDT had a more than 15 letters lost compared with placebo controls (61% versus 46%).19

The advent of intravitreal anti-VEGF therapy, revolutionised the treatment of neovascular AMD. Treatment with ranibizumab, a recombinant, humanized, monoclonal antibody Fab against VEGF-A, compared to either sham injection or PDT was shown in early studies at 12 months to prevent a more than 15 letter loss in over 90% of treated patients and improved vision by more than 15 letters in more than 30% of patients receiving monthly ranibizumab injections.20,21 Limitations of intravitreal monthly injections were the high costs, high burden of care on the patient as well as the ocular and systemic risks associated with frequent intra-vitreal injections. Bevacizumab, a similar recombinant humanized monoclonal antibody that blocks angiogenesis by inhibiting vascular endothelial growth factor A (VEGF-A) used for the systemic treatment of cancer has been used widely by ophthalmologist as an off-label treatment alternative due to the lower cost.22 Aflibercept, the most recently approved anti-VEGF agent, is a recombinant fusion protein inhibits the activity of the vascular endothelial growth factor subtypes VEGF-A and VEGF-B, as well as to placental growth factor (PGF).8 A meta-analysis comparing the efficacy and safety of these 3 agents showed modest superiority of both ranibizumab and aflibercept over bevacizumab, however bevacizumab is significantly cheaper. (Figure 4)23 In terms of safety, ranibizumab and aflibercept have a similar safety profiles with bevacizumab being associated with a small increased risk of serious side effects. (Figure 4)23

Clinical trials have shown that monthly intravitreal injections result in superior visual and anatomical outcomes when compared to other regimes such as “treatment as needed”.24,25 However, real world clinical practice outcomes with a similar treatment regimes have been shown to be inferior to clinical trial outcomes due to constraints such as co-morbidities, injection fatigue and financial barriers.26 A pro-active treat and extend treatment regime has recently gained popularity because it showed comparable results to a fixed monthly dosing regime with significantly less visits.27

Combined therapy with anti-VEGF injections and PDT versus monotherapy with anti-VEGF injections has not found to be beneficial in typical AMD. However, in patients with PCV, combination therapy has been associated with superior visual outcomes, a higher rate of polyp closur e and less overall number of injections.28

Emerging treatments for the treatment neovascular AMD can be classified into novel pharmacotherapeutic agents targeting the different pathways of neovascular AMD pathogenesis, longer acting agents that may reduce the number of injections, novel drug delivery systems to improve the half-life of intra-vitreal injections and combination therapies.29

No treatment currently exists for non-neovascular AMD, and emerging therapeutic strategies have focussed on novel pharmocotherapies targeting the different pathways of non-neovascular AMD such as inhibiting the complement pathway, other inflammatory pathways and reducing oxidative stress.30 Neuro-protection, protecting retinal pigment epithelial (RPE) cells, inhibiting lipofuscin, altering the visual cycle, regenerating RPE cells from stem cells and restoring choroidal blood flow are other strategies that are currently being studied with variable success.30 Currently, the only prevention option for AMD is the age related eye disease study (AREDS) formulation that reduces the progression of dry AMD in certain patients. More therapies such a micropulse laser and gene therapy are currently being tested for the effectiveness in reducing AMD progression in high risk individuals.30

References

  1. Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. The Lancet. Global health. 2014;2(2):e106-116.
  2. Bird AC, Bressler NM, Bressler SB, et al. An international classification and grading system for age-related maculopathy and age-related macular degeneration. The International ARM Epidemiological Study Group. Surv Ophthalmol. 1995;39(5):367-374.
  3. Wong CW, Yanagi Y, Lee WK, et al. Age-related macular degeneration and polypoidal choroidal vasculopathy in Asians. Progress in retinal and eye research. 2016;53:107-139.
  4. Rosenfeld PJ. Optical Coherence Tomography and the Development of Antiangiogenic Therapies in Neovascular Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci. 2016;57(9):OCT14-26.
  5. Huang D, Swanson EA, Lin CP, et al. Optical coherence tomography. Science. 1991;254(5035):1178-1181.
  6. Ooto S, Vongkulsiri S, Sato T, Suzuki M, Curcio CA, Spaide RF. Outer retinal corrugations in age-related macular degeneration. JAMA Ophthalmol. 2014;132(7):806-813.
  7. Tan ACS, Astroz P, Dansingani KK, et al. The Evolution of the Plateau, an Optical Coherence Tomography Signature Seen in Geographic Atrophy. Investigative ophthalmology & visual science. 2017;58(4):2349-2358.
  8. Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, et al. Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies. Ophthalmology. 2014;121(1):193-201.
  9. Ho AC, Busbee BG, Regillo CD, et al. Twenty-four-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration. Ophthalmology. 2014;121(11):2181-2192.
  10. Gao SS, Jia Y, Zhang M, et al. Optical Coherence Tomography Angiography. Investigative ophthalmology & visual science. 2016;57(9):OCT27-36.
  11. Cole ED, Ferrara D, Novais EA, Louzada RN, Waheed NK. Clinical Trial Endpoints for Optical Coherence Tomography Angiography in Neovascular Age-Related Macular Degeneration. Retina. 2016.
  12. Davis MD, Gangnon RE, Lee LY, et al. The Age-Related Eye Disease Study severity scale for age-related macular degeneration: AREDS Report No. 17. Archives of ophthalmology. 2005;123(11):1484-1498.
  13. Schmitz-Valckenberg S, Fleckenstein M, Scholl HP, Holz FG. Fundus autofluorescence and progression of age-related macular degeneration. Surv Ophthalmol. 2009;54(1):96-117.
  14. Jolly JK, Wagner SK, Moules J, et al. A Novel Method for Quantitative Serial Autofluorescence Analysis in Retinitis Pigmentosa Using Image Characteristics. Translational vision science & technology. 2016;5(6):10.
  15. Godara P, Dubis AM, Roorda A, Duncan JL, Carroll J. Adaptive optics retinal imaging: emerging clinical applications. Optom Vis Sci. 2010;87(12):930-941.
  16. Velaga SB, Nittala MG, Konduru RK, Heussen F, Keane PA, Sadda SR. Impact of optical coherence tomography scanning density on quantitative analyses in neovascular age-related macular degeneration. Eye (Lond). 2017;31(1):53-61.
  17. Azar G, Quaranta-El Maftouhi M, Masella JJ, Mauget-Faysse M. Macular pigment density variation after supplementation of lutein and zeaxanthin using the Visucam(R) 200 pigment module: Impact of age-related macular degeneration and lens status. J Fr Ophtalmol. 2017;40(4):303-313.
  18. Verteporfin R, Participants, Treatment of age-related macular degeneration with photodynamic therapy study group principal i, Verteporfin in photodynamic therapy study group principal i. Guidelines for using verteporfin (visudyne) in photodynamic therapy to treat choroidal neovascularization due to age-related macular degeneration and other causes. Retina. 2002;22(1):6-18.
  19. Photodynamic therapy for subfoveal choroidal neovascularization. Tecnologica. MAP supplement. Blue Cross and Blue Shield Association. Medical Advisory Panel. 2000:21-25.
  20. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. The New England journal of medicine. 2006;355(14):1432-1444.
  21. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. The New England journal of medicine. 2006;355(14):1419-1431.
  22. Solomon SD, Lindsley KB, Krzystolik MG, Vedula SS, Hawkins BS. Intravitreal Bevacizumab Versus Ranibizumab for Treatment of Neovascular Age-Related Macular Degeneration: Findings from a Cochrane Systematic Review. Ophthalmology. 2016;123(1):70-77 e71.
  23. Schmid MK, Bachmann LM, Fas L, Kessels AG, Job OM, Thiel MA. Efficacy and adverse events of aflibercept, ranibizumab and bevacizumab in age-related macular degeneration: a trade-off analysis. The British journal of ophthalmology. 2015;99(2):141-146.
  24. Investigators IS, Chakravarthy U, Harding SP, et al. Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial. Ophthalmology. 2012;119(7):1399-1411.
  25. Yeh S, Albini TA, Moshfeghi AA, Nussenblatt RB. Uveitis, the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT), and intravitreal biologics for ocular inflammation. Am J Ophthalmol. 2012;154(3):429-435 e422.
  26. Chong V. Ranibizumab for the treatment of wet AMD: a summary of real-world studies. Eye (Lond). 2016;30(2):270-286.
  27. Berg K, Pedersen TR, Sandvik L, Bragadottir R. Comparison of ranibizumab and bevacizumab for neovascular age-related macular degeneration according to LUCAS treat-and-extend protocol. Ophthalmology. 2015;122(1):146-152.
  28. Koh A, Lee WK, Chen LJ, et al. EVEREST study: efficacy and safety of verteporfin photodynamic therapy in combination with ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy. Retina. 2012;32(8):1453-1464.
  29. Smith AG, Kaiser PK. Emerging treatments for wet age-related macular degeneration. Expert opinion on emerging drugs. 2014;19(1):157-164.
  30. Hanus J, Zhao F, Wang S. Current therapeutic developments in atrophic age-related macular degeneration. The British journal of ophthalmology. 2016;100(1):122-127.
About the Author

Dr Anna Tan
Singapore National Eye Centre
Medical Retina Department
Consultant
MBBS, MMed(Ophth)

Dr Anna Tan graduated from the University of Melbourne in 2004 after completing her basic medical degree. In addition she graduated with first class honours with an additional Advanced Medical Science degree conjoint with Imperial College, London. She then returned to Singapore to complete her ophthalmology subspecialty training (Fellowship of the Academy of Medicine Singapore) in 2013. In addition, she has also obtained her Fellowship of the Royal College of Surgeons in Edinburgh in December 2013. As further sub-specialty training, she has completed multiple medical retina fellowships at the Singapore National Eye Centre, the Opthalmology Department at the University of Bonn under Prof Frank Holz and the Vitreous Retina Macula New York (VRMNY) under Dr. Lawrence Yannuzzi and Dr. K Bailey Freund.

Dr Anna Tan has had many leadership roles in SNEC including chief resident and chief registrar. She has lead many committees that have organized various health initiatives and quality improvement projects. She is also dedicated to education and has organised many teaching courses for ophthalmology residents, general practitioners, allied health staff and the public. She is an avid researcher and has authored 31 peer reviewed articles and 3 book chapters. She has represented SNEC at many local and international conferences with various poster and oral presentations. She has been awarded 4 grants including the Khoo Clinical Scholarship Award aimed at developing research among clinicians and recently the Academic Clinical Program Grant for Clinician Scientists. Her subspecialty research interests include retinal inherited diseases, age-related macular degeneration, low vision and visual rehabilitation. She is currently involved in developing multi-disciplinary teams that would further the visual rehabilitation department at SNEC.

Recent publications

  1. Tan ACS, Dansingani K, Yannuzzi L, Sarraf D, Freund KB. Type 3 neovascularization imaged with cross-sectional and en face optical coherence tomography angiography Retina 2016 in press
  2. Tan AC, Simhaee D, Balaratnasingam C, Dansingani KK, Yannuzzi LA. A Perspective on the Nature and Frequency of Pigment Epithelial Detachments. Am J Ophthalmol. 2016 Sep 13.
  3. Tan AC, Chen L, Png R, Chia A. The diagnosis and assessment of visual function in Singaporean children with electrophysiology: 10-year results. Doc Ophthalmol. 2016 Jun;132(3):189-99. doi: 10.1007/s10633-016-9539-9. IF:1.631
  4. Tan AC, Balaratnasingam C, Yannuzzi LA. Treatment of Macular Telangiectasia Type 2 With Carotenoid Supplements Containing Meso-Zeaxanthin: A Pilot Study.Ophthalmic Surg Lasers Imaging Retina. 2016 Jun 1;47(6):528-35.
  5. Tan AC, Fleckenstein M, Schmitz-Valckenberg S, Holz FG. Clinical Application of Multicolor Imaging Technology. Ophthalmologica. 2016;236(1):8-18.

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