A novel way to use an old technology

Clinicians, researchers look at early clinical implications of DME using fundus autofluorescence.

By Vanessa Caceres, Contributing Editor

Fundus autofluorescence (FAF) is already a major imaging modality used to diagnose and monitor diseases such as age-related macular degeneration (AMD) and hydroxychloroquine toxicity — yet the technology could prove useful with diabetic macular edema (DME).

Although studies are still limited, clinicians are beginning to investigate how FAF could serve as a diagnostic tool to detect early maculopathy and to make better treatment decisions for diabetics, says Nalin J. Mehta, MD, Colorado Retina Center, Lakewood, Colo.

The full potential of FAF in diabetes, however, is unclear. “The technology shows us interesting things, but we’re still trying to discover its place in terms of our clinical algorithm as opposed to being delegated as simply a study tool,” Dr. Mehta says.

Figure. FAF findings in DME and the correlation with visual prognosis.

How FAF is already used

As a noninvasive imaging modality, FAF uses the fluorescent properties of lipofuscin in the retinal pigment epithelium (RPE), providing images with unique information not readily discernable with fundus photography, fluorescein angiography, or optical coherence tomography (OCT).

Researchers noted last year that although the technology has been around for more than 40 years, it only recently has become more clinically relevant due to technological advances, particularly in digital imaging.¹ “Fundus autofluorescence has prove[n] to be helpful in understanding the pathophysiological mechanisms, diagnostics, and identification of predictive markers for disease progression, and for monitoring of novel therapies,” the researchers wrote.

The use of FAF in AMD is already well documented, says Dr. Mehta, who uses it to evaluate geographic atrophy and monitor the status of macular RPE dysfunction, which can help to differentiate anatomic from optical etiologies of progressive visual loss.

Dr. Mehta also uses fundus autofluorescence in patients prescribed the drug hydroxychloroquine (Plaquenil) who undergo regular screening for assessment of hydroxychloroquine-associated toxicity. The technology also plays a diagnostic role in retinal artery occlusion and white dot syndromes, and has an emerging role with diabetic retinopathy.

Green light, red light?

With green-light FAF, the technology has even more potential, says Sam E. Mansour, MSc, MD, medical director, Virginia Retina Center, Warrenton, Va., and clinical professor of ophthalmology, George Washington University, Washington, D.C. “[FAF] can highlight pathology not as evident on blue light as it is on green light,” says Dr. Mansour, who commonly uses FAF for AMD.

However, a 2013 study from German researchers who focused on central green-light FAF in DME found poor correlation with central retinal thickness, inner/outer segment layer integrity, and retinal pigmentary epithelium inner/outer segment layer thickness.² They concluded that central green-light FAF was not suitable in detecting retinal thickening in DME.

“Although theoretically intriguing, green-light FAF yields controversial results in some studies and needs to be investigated further,” Dr. Mehta says.

Dr. Mansour believes FAF has become a more prominent tool in clinical studies. “We’re involved in several AMD trials, and many of the major ones now require FAF. That wasn’t the case four years ago. It’s becoming recognized as another imaging modality that was previously underappreciated.”

FAF and DME: Research, clinical implications

Neither Dr. Mehta nor Dr. Mansour are routinely using FAF in DME patients, although they both believe that with further investigation, retina specialists will increasingly consider this modality in the future.

“I think that it can be a useful tool to compare the microstructure of the macula to best corrected visual acuity [BCVA],” says retinal specialist Ameen Marashi, MD, Marashi Eye Clinic, Aleppo, Syria. Use of FAF could help identify patterns common in chronic DME that would indicate the need to shift treatment from antivascular endothelial growth factor (anti-VEGF) agents to steroids, Dr. Marashi adds. “[FAF] may save the patient from multiple anti-VEGF injections and make us choose steroids as first-line therapy, especially in pseudophakic patients where we are suspicious of chronic DME.”

Use of FAF can also help classify different patterns seen via OCT, such as diffuse versus focal or cystoid versus non-cystoid, Dr. Marashi says. This provides additional clinical information and results in diverging retinal and possibly also choroidal tissue characteristics with various FAF properties, he explains.

Another possible use of the technology is for earlier detection of DME, Dr. Mansour says. “We often say the eyes are the windows to the soul, but they are also windows to metabolic abnormalities. The earlier you can see the abnormalities, the better,” he says. Earlier detection could help curb the severe visual loss associated with DME in patients with diabetic retinopathy.

If proven effective, FAF for diabetic macular edema could spot disease-related abnormalities years earlier than the obvious clinical signs, he believes. Many clinicians are not focused on such early detection of disease — Dr. Mansour includes himself in that category — but he thinks it would be valuable to do this more often.

Emerging studies

Research focused on this area is still emerging. One key study from Italian researchers published in 2011 found that FAF correlated better with OCT patterns and central field microperimetry than visual acuity.³ The study included 151 eyes from 92 diabetic patients with untreated clinically significant macular edema, correlated with BCVA. They also had slit-lamp biomicroscopy, fluorescein angiography, OCT, FAF and microperimetry performed. In the study, cystoid OCT patterns and edema patterns as seen with fluorescein angiography correlated with increased FAF. The researchers concluded that FAF may provide insights into DME evaluation, but the validity of FAF in follow-up and treatment outcomes needed further analysis.

A 2014 study out of Shanghai involving 30 eyes with clinically significant macular edema concluded that FAF might show retinal damage and could correlate with visual function and photoreceptor integrity, providing new insight into DME evaluation. The researchers concluded that a better understanding of FAF characteristics and their role in DME should also be part of the future research.⁴

Furthermore, a strong association of FAF with SD-OCT parameters and VA was demonstrated in patients with severe DME, in whom photoreceptor integrity before treatment could not be adequately evaluated, even with SD-OCT.⁵

Drawbacks, research avenues

On the surface, FAF for DME has almost no drawbacks, Dr. Mansour says. “It’s one of those safe technologies, and it has a track record. It’s not invasive like fluorescein angiography, and it’s an easy, inexpensive thing to do.”

But, while FAF adds potential clinical value for DME patients, obtaining reimbursement for this indication could be challenging, Dr. Mehta says, especially in this era of tightening reimbursements and cost control. “You have to factor in the rationale,” he says. The same concern emerges in developing countries, he continues, where the technology would add a cost burden on patients. Many centers could not afford FAF, which is why research is needed to show that FAF makes a clinical impact—such as differentiating chronic DME from non-chronic DME, he adds.

The financial concern extends to individual practices. While OCT is virtually ubiquitous, for example, and professionals can justify its cost given the diagnostic information obtained, they couldn’t readily justify an increase associated with integrating FAF and/or fluorescein angiography.

What would help getting that justification? Studies that evaluate the use of FAF to determine which DME patients may benefit from laser treatment—particularly the newer MicroPulse lasers, which offer lower bursts of energy as an alternative to monthly or bimonthly anti-VEGF injections, Dr. Mehta says. “If you’re trying to titrate your powers to maximize efficacy, FAF may be important in confirming the lack of damage to the retinal pigment epithelium,” he says.

A better understanding of FAF characteristics and their role in DME should also be part of the future research, according to Chinese researchers.⁴ OM

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