MacTel and neovascular conversion: Majda Hadziahmetovic, MD, on early warning signs

Macular telangiectasia type 2 (MacTel) is generally described as a slowly progressive, neurodegenerative retinal disease, but a subset of patients develop neovascular complications that change the urgency of care—a distinction that has drawn renewed attention since the FDA approval of revakinagene taroretcel-lwey (Encelto; Neurotech Pharmaceuticals) for the disease's non-neovascular, atrophic form. Modern Retina spoke with Majda Hadziahmetovic, MD, associate professor of ophthalmology and a medical retina specialist at Duke Eye Center, who completed her medical retina fellowship at Duke and focuses her research on early detection of retinal and macular disease.

In the following Q&A, Hadziahmetovic discusses the warning signs of neovascular conversion in MacTel, how urgently patients need to reach a retina specialist, how the Encelto approval affects screening for the neovascular subtype, the evidence gaps guiding anti-VEGF use, and how she distinguishes MacTel from neovascular age-related macular degeneration (AMD) when the two overlap.

The Q&A

Editor’s note: Transcript lightly edited for clarity.

MacTel is typically described as a slowly progressive disease, but neovascular complications change that trajectory. How might a clinician explain to patients and referring clinicians what's happening when a MacTel eye develops a neovascular membrane?

Majda Hadziahmetovic, MD: MacTel type 2 is a slowly progressive disease. The hallmark of the disease is chronic neurodegeneration of the outer retina, including Müller cell dysfunction, photoreceptor loss, and disruption of the ellipsoid zone, often accompanied by cystic-like cavitations in both the outer and inner retinal layers.

Over time, vascular remodeling can build on neurodegenerative changes, and in a subset of patients, the disease may enter a proliferative or neovascular phase. During this phase, patients may develop exudation, intraretinal and subretinal hemorrhage, and disciform scarring.

Although MacTel does not share the pathophysiology of neovascular age-related macular degeneration (AMD), eyes with neovascular complications may require anti-VEGF therapy and often respond well to it.

Sudden vision change is the classic red flag for neovascular conversion. What specifically should an ophthalmologist or optometrist be listening and looking for at that visit, and how quickly does that patient need to get to a retina specialist?

Hadziahmetovic: With neovascularization, exudative changes can progress rapidly, and without timely treatment, they may lead to permanent visual decline from fibrovascular tissue consolidation and scarring.

I counsel patients that the window of opportunity is relatively short, about 2 weeks, so new symptoms should be taken seriously. I ask them to test one eye at a time, which patients often do not do unless specifically instructed, and to watch for a new central smudge, a brown or gray spot, missing or crowded letters, or any worsening of metamorphopsia. If any of these changes occur, they should contact us promptly rather than waiting for the next scheduled visit.

With revakinagene taroretcel-lwey now approved for MacTel, retina specialists have a treatment aimed at the non-neovascular, atrophic side of the disease. Does that approval change how aggressively clinicians should screen for or think about the neovascular subtype, and could a patient ever need both approaches?

Hadziahmetovic: Absolutely. Specific clinical and payer requirements must be considered to ensure that treatment of MacTel type 2 with revakinagene taroretcel-lwey is appropriately approved and covered. This requires a careful, well-documented evaluation.

In addition to clinical examination and OCT, multimodal imaging may be very helpful, including fluorescein angiography, OCTA, and, when appropriate, indocyanine green (ICG) angiography. These imaging modalities help distinguish the non-proliferative phase from the proliferative or neovascular phase of the disease.

The evidence base for anti-VEGF in neovascular MacTel is far thinner than in AMD—small case series, not large randomized trials. How does that evidence gap affect day-to-day decision-making, and where does clinical judgment take precedence over data?

Hadziahmetovic: Several diseases are associated with neovascular membranes that have pathophysiology distinct from neovascular AMD yet still respond well to anti-VEGF therapy. I do think we need a stronger evidence base to guide the use of anti-VEGF in complex cases of proliferative MacTel type 2.

Given the nature and prevalence of MacTel type 2, large-scale clinical trials may not be feasible. Also, as is often the case in medicine, we have to rely on our clinical experience. Additionally, I find my colleagues' case series and case reports very valuable, as they can help with decision-making when prospective trial data are limited.

How should a clinician counsel a patient who presents late, and how is that decision made about when treatment is still worth attempting versus when expectations need to be managed instead?

Hadziahmetovic: I am reluctant to give up on an eye if there remains a meaningful chance to preserve or improve vision and to positively impact someone's quality of life.

The decision to treat depends on several factors. We begin by assessing subjective symptoms and visual acuity, then use careful multimodal imaging to determine whether there is treatable disease activity or end-stage disease. If we identify an active neovascular membrane, exudation, hemorrhage, or another potentially modifiable finding, or if there is a reasonable opportunity to slow progression and preserve morphology, I would generally favor treatment.

In cases of end-stage disease, it is important to recognize when continued treatment is unlikely to provide meaningful benefit and may only add burden for the patient. Also, we always have to take into consideration the patient's overall health, access to a good support system, etc.

MacTel and AMD are both age-related, both can produce macular neovascularization, and there are documented cases of the two coexisting in the same patient, sometimes the same eye. How can a clinician avoid anchoring on one diagnosis and missing that the other disease, or both, may be present?

Hadziahmetovic: I usually rely on a battery of tests to arrive at the correct diagnosis. OCT often serves as the first diagnostic tool, followed by fundus autofluorescence (FAF). These imaging modalities are widely available and fast, but in some cases they may not be sufficient. In my clinic, I frequently use fluorescein angiography and indocyanine green angiography, especially in patients with neovascular AMD. I do not have OCTA readily available in my office, but needless to say, it can also be very helpful in establishing the correct diagnosis.

Although MacTel type 2 and neovascular AMD can both affect older patients, they have very different underlying pathophysiology. However, as mentioned earlier, when neovascularization develops, anti-VEGF therapy can be helpful in both conditions. Looking ahead, I am excited about precision medicine and the development of more patient-tailored treatments.

Majda Hadziahmetovic, MD, is an Associate Professor of Ophthalmology at Duke University, with a secondary appointment as Associate Professor of Electrical and Computer Engineering. She is a medical retina specialist at Duke Eye Center, where she cares for patients with MacTel and other retinal diseases. Her research bridges ophthalmology, imaging, and engineering, with a focus on early retinal disease detection through teleophthalmology and on predicting retinal disease progression using machine learning and artificial intelligence.