Age-related Macular Degeneration (AMD)

June 27, 2024 by Modulight Content
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Age-related Macular
Degeneration (AMD)

Age-related Macular Degeneration (AMD) is a disease causing choroidal neovascularization (CNV) and consequent irreversible damage in the macula. AMD is classified into dry (atrophic) and wet (exudative) forms, with the latter causing faster vision loss and being the leading cause of blindness in people over 65.

Introduction to AMD

Age-related Macular Degeneration (AMD) is one of the leading causes for  visual impairment. AMD is charactirized by development of Choroidal neovascularization (CNV) and consequent irreversible damage in the macula. CNV means abnormal development (angiogenesis) of blood vesseld from the choroid into Bruch’s membrane, sometimes capable of even perforating retinal pigment epithelium (RPE).

AMD is classified in two categories, dry and wet AMD.  The dry (atrophic) form of AMD is more common, but it may develop into wet AMD. Wet (exudative) AMD results in faster vision loss, and it is the leading cause for blindness in people over 65 years.

Types of AMD

Dry AMD

  • Description: The most common form, accounting for 80-90% of AMD cases. It occurs due to the thinning of macular cells.
  • Symptoms: Gradual vision loss, blurry central vision, difficulty recognizing faces.
  • Stages:
    • Early: Few symptoms, presence of drusen (yellow deposits).
    • Intermediate: Increased drusen, mild vision loss.
    • Advanced: Significant vision loss, larger drusen, geographic atrophy.

Wet AMD

  • Description: Less common but more severe, accounting for 10-20% of AMD cases. It occurs when abnormal blood vessels grow under the retina and macula, leaking blood and fluid.
  • Symptoms: Rapid vision loss, dark spots in vision, straight lines appearing wavy.
  • Types:
    • Classic Choroidal Neovascularization (CNV)
    • Occult Choroidal Neovascularization (CNV)
    • Retinal Angiomatous Proliferation (RAP)

Future increase in AMD patient numbers is expected

Significant increase in Wet AMD patients [22]

Numerous population-based studies of age-related macular degeneration have been reported around the world. Globally, the number of people with age-related macular degeneration is projected to increase to 288 millions in year 2040.

The number of Wet AMD patients in North America is expected to increase to 15.6 million in 2040, meaning a 43% increase.

These estimates indicate the substantial global burden of age-related macular degeneration.

Physiology of choroidal neovascularization in wet AMD

Choroidal neovascularization (CNV) means the growth of blood vessels in the choroidal layer of eye, located between the retina and the sclera. The figure below displays a schematic cross-section of a human eye, and an enlarged schematic cross-section of the macula with the components of the neovascular membrane.

Reproduced after 21 The Role of Photodynamic Therapy in Non-malignant and Malignant Eye Disorders, Patrycja Nowak-Sliwinska, Andrea Weiss, Michel Sickenberg, Arjan W. Griffioen, and Hubert van den Bergh, J. Anal. Bioanal. Tech., 2013, S1, http://dx.doi.org/10.4172/2155-9872.S1-007

Schematic of the eye with healthy retina, choroid and retinal pigment epithelium (RPE) cells.

Effects of AMD: presence of early drusen and neovascularization, disruption of Bruch’s membrane and Retinal Pigment Epithelium (RPE) cells, and vascular leakage.

Reproduced after 23 Experimental Models in Neovascular Age Related Macular Degeneration, Olivia Rastoin, Gilles Pagès, and Maeva Dufies, Int. J. Mol. Sci. 2020, 21(13), 4627, https://doi.org/10.3390/ijms21134627

Treatment Options for wet AMD

1. Anti-VEGF Injections

  • Description: Medications are injected into the eye to block the growth of abnormal blood vessels.
  • Medications: Bevacizumab (Avastin), Ranibizumab (Lucentis), Aflibercept (Eylea).
  • Frequency: Regular injections, often every 4-8 weeks.

2. Photodynamic Therapy (PDT)

  • Description: A two-step treatment that uses a light-sensitive drug (verteporfin) and a laser to close abnormal blood vessels.
  • Process:
    • Injection: Verteporfin is injected into the bloodstream.
    • Activation: A cold laser is shone into the eye to activate the drug, targeting and closing abnormal blood vessels.
  • Frequency: May require multiple treatments over time.

3. Laser Therapy

  • Description: Uses a high-energy laser beam to destroy abnormal blood vessels.
  • Usage: Less common due to potential damage to surrounding retinal tissue.
  • Frequency: Usually a one-time treatment, but may need repetition.

Photodynamic Therapy Working Principles

Photodynamic Therapy (PDT) involves the use of a light-sensitive drug, known as a photosensitizer (PS), which is activated by non-ionizing energy, typically light. In retinal therapies for Choroidal Neovascularization (CNV) due to Age-related Macular Degeneration (AMD), Verteporfin is commonly used as a photosensitizer.   

The process begins with intravenous (i.v.) injection of the PS, which then metabolically distributes throughout the body, including the abnormal blood vessels in cases of exudative AMD. Once the PS has accumulated in the target area, a specific wavelength of laser light is used to activate it. For Verteporfin, 689 nm laser is employed to match its absorption peak. 

The laser light is precisely directed to the patient’s retina using an aiming beam of different wavelength that is not absorbed by the PS. The ophthalmologist adjusts the laser spot size and determines the laser irradiance and dose for the specific case. 

When the PS absorbs the laser light, it becomes excited to a higher energy state. With the subsequent state relaxation, the released energy is transferred to the surrounding oxygen in the tissue, creating reactive oxygen species (ROS). The ROS then attacks the vascular tissue, helping to treat the condition. 

Vascular effects of PDT in CNV

  • Drug remains inactive in the vessels until illuminated
  • Light exposure in the choroidal neovessels locally activates the drug (verteporfin)
  • Vasoconstriction, blood flow stasis, thrombus formation lead to vessel occlusion
  • Also novel drugs being developed for ocular oncology with direct tumor targeting mechanism (bel-sar)
Reproduced after 21 The Role of Photodynamic Therapy in Non-malignant and Malignant Eye Disorders, Patrycja Nowak-Sliwinska, Andrea Weiss, Michel Sickenberg, Arjan W. Griffioen, and Hubert van den Bergh, J. Anal. Bioanal. Tech., 2013, S1, http://dx.doi.org/10.4172/2155-9872.S1-007

Which patient groups benefit most from PDT?

  • Patients for whom anti-VEGF therapy cannot be performed such as hypersensitivity/reaction to anti-VEGF agents, acute inflamed or infected eye or increased ocular pressure [1-2]
  • Patients with subfoveal refractory AMD (poor or no response to anti-VEGF monotherapy (up to 25% of patients) [3-8]
  • Subfoveal CNV patients who cannot extend, refuse ocular injections or wish to reduce injection burden [9-19]
  • Patients who have had a stroke in the last 90 days [20]

The main potential of PDT in treating CNV is combination therapy with anti-VEGF

  • Combination therapy is biologically justifiable: disease is targeted through multiple mechanisms/pathways, accomplishing synergies [3, 21]
    • Anti-VEGF agents and PDT inhibit different parts of the angiogenic process: anti-VEGF agents target the process of angiogenesis, inhibiting the formation of new vessels, while PDT destroys existing neovessels acting as a “CNV eraser” [21]
    • PDT is very effective in the initial control of CNV, achieving almost 100 % closure of the neovessels in a period of 7 days to one month, since it targets the existing neovessels but does not inhibit the process of formation new vessels [3]
    • Anti-VEGF alone does not decrease existing CNV size, despite improving visual acuity [3]
  • Combination may not only increase overall efficacy but also reduce the potential for side effects by allowing use of lower doses of a single agent [3]
  • By decreasing the number of anti-VEGF injections by PDT several problems can be tackled:
  1. There is significant tachyphylaxis with anti-VEGF agents alone: decrease or lack of beneficial effects after repeated treatments, potentially related to autoimmunity mechanisms that can trigger formation of autoantibodies against anti-VEGF agents
  2. Prolonged suppression of VEGF can cause undesired side effects on the beneficial biological functions it controls, such as important role of VEGF as a neuroprotectant in the mature retina
  3. Non-biological aspects like significant difficulties in terms of clinical management and patient convenience
  • Combination Therapy: Popularized by Dr. Nelson and Dr. Scott Cousins, combining anti-VEGF, half-fluence PDT, and steroids for conditions like exudative age-related macular degeneration (AMD) and chronic CSC.
  • Patients generally have a positive acceptance of PDT, appreciating the reduced treatment burden compared to frequent injections.

Dr. Mark H. Nelson Discusses PDT in Retinal Conditions

Dr. Mark Nelson, a retinal specialist from Winston-Salem, North Carolina, provides an in-depth discussion on Photodynamic Therapy (PDT) and its applications in treating retinal diseases. With over 20 years of experience and more than 25,000 laser treatments performed, Dr. Nelson shares valuable insights into the efficacy and operational aspects of PDT.

The thoughts and recommendations on the video are based on the speaker’s personal clinical experience. Modulight disclaims any responsibility for their clinical relevance or efficacy.

What the Key Opinion Leaders have to say about Retinal PDT? [20]

“Even though PDT isn’t utilized very often in my practice, it is important to have at your disposal. — PDT is the best treatment option for CSR. It’s also an important treatment option for polypoidal patients. It’s a viable, supplemental treatment or combination treatment in patients with unresponsive AMD patients. — Several studies have shown that the use of PDT in juxtafoveal and extrafoveal CNV can achieve long-term stabilization and an improvement of visual acuity.”

– David S. Dyer, MD, FACS

“There’s a definite role for PDT, and every practice should have at least one laser. We see a lot of patients with CSR and refractory AMD who can benefit from PDT.”

– Vivek Chaturvedi, MD

“Up to one-fourth of all treated patients do not benefit from intravitreal injections and visual acuity deteriorates even under treatment. This group has been described as nonresponders.”

– Christoph Ehlken, MD

“PDT is used in practice more than people realize. It provides an extra benefit to those patients who can’t extend when we’re treating with anti-VEGF therapy or who have CSR that’s not responding treatment. — PDT is a great option for those high-strung, high-energy patients who are very nervous. It gives them an excellent outcome.”

– Amani Fawzi, MD

“PDT has many advantages: it is the standard of care for PCV and Acute CSR, and in wet AMD it can significantly reduce the treatment burden. There is a group of AMD patients for which the combination of PDT, anti-VEGF and steroids is superior.”

– Mark H. Nelson, MD, MBA

Modulight Solution for PDT treatments of AMD

Designed specifically for retinal PDT treatments, ML6710i laser is well-suited for indications such as CNV and ophthalmic tumors. The laser is controlled intuitively from iPad app: the wireless connection allows flexibility for the treatment setup. ML6710i is a must-have tool for anyone ophthalmic PDT. ML6710i has the standard wavelength of 689 nm matching the Verteporfin absorption maximum.

Learn more about ML6710i

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    References

    1. Intravitreal Injections, Kamjoo, S., et al. (n.d.), AAO EyeWiki https://eyewiki.aao.org/Intravitreal_Injections

    2. Intravitreal Injection for Wet (Exudative) Age-Related Macular Degeneration (AMD), Tsui Jonathan C., et al. (n.d.), Medscape https://emedicine.medscape.com/article/1844351-overview

    3. Combined Therapies to Treat CNV in AMD: PDT + Anti-VEGF, Mataix, J., et al. (2012), Age Related Macular Degeneration – The Recent Advances in Basic Research and Clinical Care https://www.intechopen.com/chapters/26336  

    4. Switch of anti-VEGF agents is an option for nonresponders in the treatment of AMD, Ehlken, C., et al. (2014), Eye, May;28(5) https://pubmed.ncbi.nlm.nih.gov/24722504/

    5. Resistance to anti-VEGF therapy in neovascular age-related macular degeneration: a comprehensive review, Yang, S., et al. (2016), Drug Design, Development and Therapy, Jun 2(10). https://pubmed.ncbi.nlm.nih.gov/27330279/

    6. Anti-VEGF-Resistant Retinal Diseases: A Review of the Latest Treatment Options, Wallsh, J. O., et al. (2021), Cells, Apr 29;10(5):1049. https://pubmed.ncbi.nlm.nih.gov/33946803/

    7. Combination Therapy for Neovascular Age-related Macular Degeneration Refractory to Anti-Vascular Endothelial Growth Factor Agents, Tozer, K., et al (2013), Ophthalmology 120(10). https://www.aaojournal.org/article/S0161-6420(13)00240-6/fulltext 

    8. Resistance to anti-VEGF therapy in neovascular age-related macular degeneration: a comprehensive review, Yang, S., et al. (2016), Drug Design, Development and Therapy, Jun 10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4898027/

    9. Ranibizumab combined with verteporfin photodynamic therapy in neovascular age-related macular degeneration (FOCUS): year 2 results, Antoszyk, A. N., et al. (2008), American Journal of Ophthalmology May 145(5). https://pubmed.ncbi.nlm.nih.gov/18321465/

    10. Verteporfin photodynamic therapy combined with intravitreal bevacizumab for neovascular age-related macular degeneration, Kaiser, P. K., et al. (2009), Ophthalmology Apr 116(4). https://pubmed.ncbi.nlm.nih.gov/19243834/

    11. Combination therapy in exudative age-related macular degeneration: visual outcomes following combined treatment with photodynamic therapy and intravitreal bevacizumab, Wan, M. J., et al. (2010), Canadian Journal of Ophthalmology, Aug 45(4). https://pubmed.ncbi.nlm.nih.gov/20648087/

    12. Combined ranibizumab and photodynamic therapy to treat exudative age-related macular degeneration: an option for improving treatment efficiency, Mataix, J., et al. (2010), Retina Sep 30(8). https://pubmed.ncbi.nlm.nih.gov/20539256/

    13. One-year follow-up of combined customized therapy. Photodynamic therapy and bevacizumab for exudative age-related macular degeneration, Navea, A., et al. (2009), Retina Jan 29(1). https://pubmed.ncbi.nlm.nih.gov/18854782/

    14. Intravitreal injection of bevacizumab combined with verteporfin photodynamic therapy for choroidal neovascularization in age-related macular degeneration, Smith, B. T., et al. (2008), Retina May 28(5). https://pubmed.ncbi.nlm.nih.gov/18463509/

    15. Combined treatment modalities for age related macular degeneration, Das, R. A., et al. (2011), Current Drug Targets Feb 12(2). https://pubmed.ncbi.nlm.nih.gov/20887244/

    16. Intravitreal ranibizumab and bevacizumab in combination with full-fluence verteporfin therapy and dexamethasone for exudative age-related macular degeneration, Forte, R., et al. (2011), Ophthalmic Research 45(3). https://pubmed.ncbi.nlm.nih.gov/20847575/

    17. Low fluence rate photodynamic therapy combined with intravitreal bevacizumab for neovascular age-related macular degeneration, Costagliola, C., et al. (2010), The British Journal of Ophthalmology Feb 94(2). https://pubmed.ncbi.nlm.nih.gov/19965822/

    18. A retrospective analysis of triple combination therapy with intravitreal bevacizumab, posterior sub-tenon’s triamcinolone acetonide, and low-fluence verteporfin photodynamic therapy in patients with neovascular age-related macular degeneration, Kovacs, K. D., et al. (2011), Retina Mar 31(3). https://pubmed.ncbi.nlm.nih.gov/21336068/

    19. Treatment of neovascular age-related macular degeneration with a variable ranibizumab dosing regimen and one-time reduced-fluence photodynamic therapy: the TORPEDO trial at 2 years, Spielberg, L., Leys, A. (2010), Graefes Arch Clin Exp Ophthalmol. Jul 248(7). https://pubmed.ncbi.nlm.nih.gov/20204659/

    20. Using Photodynamic Therapy in 2019:  Current Concepts for Real-World Use, Singh, R. P., et al. (2019), Retina Today suppl. May/June. https://assets.bmctoday.net/retinatoday/pdfs/0619_supp2.pdf

    21. The Role of Photodynamic Therapy in Non-malignant and Malignant Eye Disorders, Nowak-Sliwinska, P., et al. (2013), Journal of Analytical & Bioanalytical Techniques, S1:007.  https://www.omicsonline.org/the-role-of-photodynamic-therapy-in-non-malignant-and-malignant-eye-disorders-2155-9872.S1-007.php?aid=19018 

    22. Global prevalence of age-related macular degeneration, Wong, W. L., Su, X., Li, X., Cheung, C. M. G., Klein, R., Cheng, C-Y., Wong, T. Y.,  Lancet Glob Health 2014; 2: e106–16.  http://dx.doi.org/10.1016/S2214-109X(13)70145-1

    23. Experimental Models in Neovascular Age Related Macular Degeneration, Olivia Rastoin, Gilles Pagès, and Maeva Dufies, Int. J. Mol. Sci. 2020, 21(13), 4627, https://doi.org/10.3390/ijms21134627