Tips for Recognizing and Understanding OCT Biomarkers

You may have noticed the word biomarker making headlines recently at continuing education events and throughout ophthalmic publications. But what is a biomarker? Although its definition varies based on the source, a biomarker, short for biological marker, is considered any assessable substance, finding, or sign that can characterize or predict incidents or outcomes of a disease process.¹

Within the retina, numerous signs can be identified and/or quantified on OCT to give us clues about visual function, likelihood of disease progression, and systemic health across a wide variety of ocular and systemic conditions. The wealth of information that is obtainable when we properly analyze the results of an OCT scan is truly incredible. Just keep in mind that in order to identify OCT biomarkers, it is imperative to have a firm knowledge of normal retinal anatomy and normal retinal layers on OCT. This will help you detect abnormalities and understand anatomic landmarks when discussing where biomarkers occur (Figure 1).

This article dives into OCT biomarkers seen in two of the most commonly encountered retinal pathologies: age-related macular degeneration (AMD) and diabetic retinopathy (DR).

AMD

With new and emerging treatments for advanced AMD (both exudative and nonexudative), it becomes increasingly important not only to identify individuals who have advanced stages of AMD, but also to be on high alert for those who have increased risk of developing advanced AMD. Two classic biomarkers seen on clinical examination, large-sized drusen and pigmentary changes, have been used for decades to gauge the risk of developing advanced AMD.²

With widespread use of OCT, a variety of additional biomarkers have been uncovered to better understand who is most at risk for progression. These include reticular pseudodrusen (RPD), hyperreflective columns, hyperreflective foci, and choroidal thickness.

RPD

RPD, also known as subretinal drusenoid deposits, are a phenotype of drusen that, while difficult to detect clinically, can be easily detected using OCT alongside fundus autofluorescent imaging and near infrared reflectance imaging. On OCT, run-of-the-mill drusen deposits collect beneath the retinal pigment epithelium (RPE). The internal contents of these drusen deposits may be homogenous and uniformly moderately reflective, but they can also become heterogenous and hyperreflective and/or hyporeflective. RPD are small, moderately reflective deposits that sit on top of the RPE and can project upward through the photoreceptor integrity line. The reticular pattern of RPD can also be picked up on when viewing fundus autofluorescent and near infrared imaging (Figure 2).³

Patients with RPD have increased risk of developing geographic atrophy (GA)⁴; thus, it is important to identify this finding. In addition, those with GA may have faster rates of progression when RPD are present.⁵ Patients with RPD tend to have thinner choroids.⁶ They also have worse visual function, which can be quantifiable with measurements such as decreased contrast sensitivity and delayed dark adaptation.^7,8

Hyperreflective Columns

On a normal OCT, the RPE is an optically dense layer that decreases the amount of light that can penetrate into the choroid and beyond. As the RPE becomes atrophic, light begins to cascade easily through the RPE, into the choroid and beyond. These OCT findings are called hyperreflective columns or hypertransmission defects. They are indicative of a more diseased RPE and are a risk factor for the development of GA. In patients who have GA, hyperreflective columns are present in the areas of GA (Figure 3).⁴

Hyperreflective Foci

Hyperreflective foci are small, round, brightly reflective deposits that often sit in the neurosensory retina above large-sized drusenoid persistent epithelial defects, either clustered or isolated. They are thought to be pigment granules, outer segment debris, or degenerating RPE cells that are migrating anteriorly. They may be related to areas of pigmentary changes seen clinically. Hyperreflective foci are indicative of a more diseased outer retina and RPE and, therefore, are highly associated with the development of GA. Patients with hyperreflective foci have a five-times increased risk of developing GA in 2 years compared with those who do not have hyperreflective foci (Figure 4).⁴

Choroidal Thickness

It is important to take note of the characteristics and thickness of the choroid in patients who present with outer retinal disease. Average choroidal thickness varies based on many factors, such as age and refractive error, but typically ranges from 250 µm to 300 µm.⁹

In general, patients with AMD tend to have thinner choroidal thicknesses.¹⁰ This is opposed to a group of conditions known as the pachychoroidal disease spectrum, which may masquerade as AMD by causing pigmentary abnormalities, RPE atrophy, and chroroidal neovascularization. Those within this spectrum of disease tend to have an abnormally thick choroid or pachychoroid (not definitively established but greater than 350 - 400 µm) and large choroidal vessels called pachyvessels (Figure 5).^11,12 Thus, evaluating the choroidal thickness and quality may help identify AMD and rule out AMD masqueraders.

In addition, those with particularly thin choroids may be at the highest risk for GA. In those who have GA, a thinner choroid may indicate a higher rate of GA progression (Figure 6).¹⁰

Because choroidal thickness varies with age and refractive error, it is difficult to define a “normal” choroidal thickness. This is why there is also no definitively established cutoff for a pachychoroid. Keep in mind, a patient can also have a relatively thick or thin choroid and not be pathologic, and ultimately, a patient with a fairly normal choroidal thickness may be deemed to have AMD. However, these principles of evaluating choroidal thickness and quality can help you avoid some of the AMD masqueraders.

DR

We most commonly think of using OCT to detect or rule out diabetic macular edema (DME). Although DME is clearly an important finding in those with DR, there is more to look for on OCT than just DME. We know that diabetes is a small vessel disease. In the retina, this disease can ruthlessly attack and even obliterate the capillary beds that supply the inner two-thirds of the retina. As the blood supply to these retinal layers is compromised, ischemia can cause the inner retinal layers on OCT to become thin or disorganized.¹³

Inner Retinal Thinning

Thinning of the inner retinal layers affects the overall macular thickness and, therefore, may be observable on retinal thickness plots. In addition, ganglion cell complex or ganglion cell thickness analysis of the macula will be affected by areas of retinal ischemia. This can also be observed while viewing the cross-sectional OCT (Figure 7).¹⁴

Disorganized Retinal Inner Layers

In the normal retina, the retinal layers are stacked neatly and cleanly one on top of the other. In areas of ischemia, not only is the inner retina quantitively thinned, but qualitatively, it loses this normal, regular organization, making it more difficult to easily identify the boundaries between the inner retinal layers. This has been given the name disorganized inner retinal layers, or DRIL (Figure 8).¹⁵

Inner retinal thinning and DRIL are associated with areas of capillary nonperfusion or ischemia, which can be confirmed using fluorescein angiography and OCT angiography. These findings are associated with poorer visual function, worse stages of DR, longer duration of diabetes, worse diabetic control, and increased likelihood of systemic comorbidities of diabetes, such as kidney disease.^14-19 In addition, patients with diabetes may have thinning of the inner retinal layers before any clinical signs of DR are even present.²⁰

It is important to be aware of these features, because when they are identified, you are likely managing a patient who has diabetic macular ischemia, worse visual function, more severe stages of retinopathy, and systemically more illness. If you are managing or comanaging a patient who is being treated for macular edema, the visual prognosis is poorer in those with inner retinal thinning and DRIL, because even with resolution of edema, the visual function may be limited by ischemia. Unfortunately, there is no ocular treatment for macular ischemia at this time.

KNOW WHAT TO LOOK FOR

OCT biomarkers can give us information about the ocular and systemic health of our patients. We must be on the look out for these subtle signs so we can deliver optimal patient management.