Expanding the definition of AMD

Supplements And Featured Publications, Modern Retina Europe Summer 2021, Volume 1, Issue 1

Why investigators are recognising AMD as a disease spectrum rather than a single entity.

Reviewed by Monika Fleckenstein, MD.

A recently published review article on age-related macular degeneration (AMD) presents a comprehensive discussion of current knowledge regarding the disease state, raises important questions to be addressed in future research and underscores the idea that AMD is not a single entity but instead represents a disease spectrum with distinct phenotypes that appear to have different underlying risk factors and pathogenic pathways.

The 25-page paper1 was written by invitation from the journal’s editors and represents joint efforts by an international expert panel organised by Emily Y. Chew, MD, PhD, director of the Division of Epidemiology and Clinical Applications at the National Eye Institute at the National Institutes of Health in Bethesda, Maryland. The paper covers epidemiology; mechanisms/pathophysiology; diagnosis, screening and prevention; management; and quality of life, and it cites 280 references.

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Monika Fleckenstein, MD, a professor of ophthalmology at John A. Moran Eye Center at the University of Utah in Salt Lake City, is the first author of the work. Although there have been several recent review articles on AMD, Fleckenstein told Modern Retina™ that she believes this paper stands out for the depth and breadth of the information it contains.

“Although our paper, which is a review article, does not present new original research, we believe it highlights some important new concepts about AMD and topics for future investigations,” she said.

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Moreover, Fleckenstein added that her team believes the global overview of AMD provided in their paper will be useful for all ophthalmologists, ophthalmologists in training and physicians in other fields of medicine in addition to anyone with a special interest in AMD.

“We hope that our emphasis on the idea that AMD comprises diverse pathological conditions will be thought-provoking for basic and clinical scientists as they plan new research that ultimately will lead to improved care and better quality of life for patients with AMD,” she added.

Rethinking AMD

Fleckenstein pointed out that when the article was solicited, the journal editors asked that it describe a model of AMD. However, complying with this request challenged the writing group because the exact interactions of pathophysiological events that may culminate in different AMD types remain to be elucidated.

“We know there are different phenotypes and stages in this bucket of AMD, and because of accumulating evidence, we are more and more convinced there are different dominant mechanisms for their development,” Fleckenstein said.

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For example, she noted that current information indicates that risk factors for the development of geographic atrophy differ from those associated with progression of the atrophic lesions. Knowledge of these differences is important for investigators, as it indicates a need to focus on different targets for preventive versus therapeutic interventions.

In discussing neovascularisation in AMD, the paper highlights new concepts and terminologies that have emerged thanks to clinicopathological correlations that have been refined through advances in imaging techniques. First, the paper uses the term macular neovascularisation (MNV) rather than choroidal neovascularisation based on the fact that not all neovascularisation in the area of the macula arises from the choroid.

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In addition, the article reviews evidence of different types of MNV, some of which seem to protect against AMD progression.

“This latter concept was first put forth decades ago by histopathologists but has only recently gained full attention because newer imaging technologies have enhanced our ability to visualise different subtypes of MNV in vivo,” Fleckenstein said. “Indeed, several studies implementing high-resolution retinal imaging have shown that rates of dry AMD progression differ depending on the presence of certain MNV subtypes.”

Fleckenstein added that the observations may lead to the identification of new therapeutic targets and also argue against interventions that aim to eliminate all MNV.

Consensus on Terminologies

One goal of developing new consensus terminologies for distinct manifestations of AMD is to provide a complete view of pathological changes that occur in the disease.

Fleckenstein noted, however, that it is a task not easily done. For example, although the term MNV recognises the fact that not all AMD-related neovascularisation originates from the choroid, it does not account for the fact that AMD can also be associated with neovascularisation in the peripheral retina.

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“It became clear to me while working on this project that it is not always possible to find all-inclusive terms that also reflect the range of experts’ opinions,” she said. Even if a group comes to a consensus about a particular classification system or preferred term, other specialists in the field may not agree.

“But it is the open-minded discourse that will advance our field,” she noted. “We also have to realise that terminologies are always subject to flux as new information emerges.”

Monika Fleckenstein, MD
e: monika.fleckenstein@hsc.utah.edu
Fleckenstein receives grants from Heidelberg Engineering, Genentech/Roche, Novartis and Optos; personal fees from Bayer, Heidelberg Engineering, Genentech/Roche and Novartis; and nonfinancial support from Carl Zeiss Meditec, Heidelberg Engineering and Optos outside the submitted work.
References
1. Fleckenstein M, Keenan TDL, Guymer RH et al. Age-related macular degeneration. Nat Rev Dis Primers. 2021;7(1):31. https://doi.org/10.1038/s41572-021-00265-2
2. Fleckenstein M, Mitchell P, Freund KB, Sadda S, Holz FG, Brittain C, Henry EC, Ferrara D. The progression of geographic atrophy secondary to age-related macular degeneration. Ophthalmology. 2018;125(3):369-390. doi: 10.1016/j.ophtha.2017.08.038. Epub 2017 Oct 27. PMID: 29110945

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