When One Becomes Two

Age-related macular degeneration (AMD) has long been studied and delineated on a straight-forward path of development; when soft drusen appear in the later decades of life and are not curbed by preventative measure, the macula deteriorates to intermediate and advanced disease. Because AMD is studied as a singular disease, correlations between AMD and other systemic diseases commonly associated with the aging population have been tenuous at best. Our new research suggests that perhaps this is where we are going wrong with AMD research – rather than studying it as one disease, we should be studying it as two.

Theodore Smith – Director of Biomolecular Retinal Imaging at the New York Eye and Ear Infirmary of Mount Sinai and a professor of ophthalmology and neuroscience at the Icahn School of Medicine at Mount Sinai – has been interested in the pathophysiology of AMD for over a decade. As a research associate in Smith’s team, I am proud to report on our findings and ongoing research.

Our recently published paper underlines a fork in the path of AMD development, describing two distinct pathways that lead to the progression of geographic atrophy (GA) (1). These two suggested routes of pathogenesis revolve around the differentiation of hallmark lesions: classical drusen and the less understood, subretinal drusenoid deposits (SDDs).

Evidence for the development of the two disease pathways in the formation and progression of intermediate AMD (iAMD) extends beyond our recent publication; we have previously reported a strong connection of SDDs, and not drusen, to varying serum and genetic risk factors, supporting the two-disease hypothesis (2). Histological evidence also links soft drusen spatially with the cone photoreceptors and SDDs with the rod photoreceptors peripherally, while further differences in laser treatment response corroborates this as well (3, 4).

Canaries in the coal mine
 

Perhaps the most unique aspect of differentiation is not within the retina at all, but instead its vasculature. We have previously revealed a strong connection of SDDs, and not drusen, to cardiovascular disease and stroke, consistent with a vascular component of the unique mechanism of pathogenesis (2). Backtracking the arterial blood supply associated with drusen and SDDs leads to the unique correlation of SDDs, choroidal thinning, and choriocapillaris insufficiency (5, 6). Therefore, we can see that a local or systemic cause that reduces the supply of nutrients to the area of drusen and SDD formation leads primarily to SDD formation and not drusen.

Smith has hypothesized a straightforward vascular mechanism for the association. He says, “We have strong evidence for what actually happens: the blood supply to the eye is directly diminished by these diseases, either by heart damage that diminishes blood supply throughout the body or from a blocked carotid artery that directly impedes blood flow to the eye [...] A poor blood supply can cause damage to any part of the body, and with these specific diseases, the destroyed retina and leftover SDDs are that damage.” SDDs may simply be the consequence for when an already under-supported choroidal perfusion cannot compensate for a reduction in arterial blood supply.

Connecting the dots
 

Our primary focus in Smith’s lab is to identify the missing link between the leading causes of blindness and death in the developed world: namely, AMD, cardiovascular disease (CVD), and stroke, respectively. New approaches to proper multi-disciplinary screening of these insidious chronic diseases in at-risk populations may serve to greatly reduce morbidity and mortality.

Our research in BMJO was the first to identify which types of systemic diseases are the key culprits (7). Out of the 200 subjects studied with intermediate stage AMD – 85 percent of whom had a history of myocardial infarction, heart failure, major valve disease, and ischemic stroke – we found that all had SDDs on multi-modal imaging. We were able to conclude that AMD patients with severe cardiovascular disease and stroke were nine times more likely to have SDDs than those without them. With this research we have reinforced existing evidence that suggest SDDs are markers for a retinal disease distinct from soft drusen, and may even be a retinal disease driven by systemic vascular disease. Smith says, “We know that the highest level of patient care occurs when we use every available form of systemic and ophthalmic imaging.”

As indicated in the findings above, patients with SDDs found at the eye clinic warrant more than standard vitamin supplementation – they need a trip to the heart or brain clinic for the evaluation of underlying disease. Standard work-up of heart function includes transthoracic echocardiogram (TTE), and standard work-up of the arterial blood supply in the neck includes computed tomography angiography (CTA). After their participation in our study, we provided many of the patients referrals for these tests and often found previously undiagnosed diseases in the neck vessels and heart. Several of these patients now have regular follow-ups and care in newly established cardiologist and neurologist relationships. Many patients were grateful for the discovery of a brewing but undetected heart disease or stroke risk – the very precursors for a life-threatening event.

A curative treatment
 

The long-established treatment options for AMD have either been preventative (multivitamins) or reactive (laser treatments and intravitreal injections). Without a localized region to address, curative treatment has long eluded ophthalmologists. Perhaps now, with an increased correlation of the SDD phenotype of AMD to vascular compromisation, a surgical operation could feasibly be developed and employed to tackle the root cause of AMD.

Although the discussion in this article has already addressed arterial blood supply to the retina at the level of the heart and the neck vessels, there is a final artery that connects systemic (the internal carotid artery) and ophthalmic vasculature (the choriocapillaris) – the ophthalmic artery (OA).

A recent, first-of-its-kind study describes the use of OA angioplasty for the treatment of AMD (8). Five subjects with advanced AMD were found eligible for “Compassionate Use” eligibility (which is to say, patients in an environment where conventional, recognized therapy is ineffective or non-existent) and volunteered for the operation. The feasibility and safety of the OA angioplasty was demonstrated, and a subjective benefit was immediately perceived in all five patients. At regularly spaced follow-ups, four out of the five patients experienced increased visual acuity, with one achieving six-month postoperative 10-line gain in the Snellen eye chart.

Although the study did not differentiate by SDD presence, the connection between SDD phenotype AMD and GA, opposed to drusen phenotype AMD and GA has already been established by Smith’s team. And this surgery represents the first step in addressing the OA as a viable target to increase blood flow to the eye, restore retinal perfusion, and perhaps disrupt AMD disease progression.

Though the screening of SDDs in several at-risk patient populations has been discussed above, the relationship between AMD and vascular disease, particularly relating to standard-of-care imaging, has never been fully evaluated. The exact parameters and cutoff needed for adequate, non-invasive, and cost-effective screening are currently being evaluated by our team. OA angioplasty is a now explored potential curative procedure to address the root cause of vascularly-derived AMD that is highly associated with the presence of SDDs.

To summarize, we believe that SDDs are strongly associated with vascular disorders. These lesions may one day be widely recognized as biomarkers of cardiovascular and neurovascular compromise, giving ophthalmologists the license to refer patients to specialists who can prevent not only blindness, but also death.