Optical coherence tomography entered clinical use during the late 1990s. At the turn of the century, advances in OCT technology, namely the application of Fourier domain algorithms as well as more advanced light sources, improved output images to the point that retinal specialists could appreciate subtle architectural changes as never before possible.

Today, commercially available OCT devices are capable of axial resolution of up to 4 µm. Research laboratories have constructed investigational OCT devices capable of even finer resolution that can image individual photoreceptors. Yet, the applicability of ultrahigh-resolution OCT in the clinical setting seems a distant possibility.

However, devices being explored in the research and clinical setting employing adaptive optics — capable in some instances of producing images of individual photoreceptors — are already nearing commercial viability.

Naturally occurring irregularities within the eye create aberrations that distort light waves entering and leaving the eye. As a result, light sources used to create retinal images are naturally distorted, affecting final resolution. Adaptive optics systems use wavefront scanning to detect relevant aberrations, as well as a deformable mirror that adjusts to the returning light waves so that the returned waves are parallel to those entering the eye.

“Irregularities in the eye create aberrations, such that images we see with standard clinical instruments are limited in their resolution. We cannot image individual photoreceptors routinely,” Jacque L. Duncan, MD, professor of clinical ophthalmology at the University of California, San Francisco, School of Medicine, said. “But if you use a scanning laser ophthalmoscope with correction of those aberrations using a deformable mirror, we can actually see individual cellular details.”

Clinical applications

Adaptive optics systems offer the potential for retinal specialists to see at a cellular level how a disease state is affecting the eye. One such application of adaptive optics that is relatively close to commercial viability, according to Dr. Duncan, is the rtx1 Adaptive Optics Retinal Camera (Imagine Eyes). According to information on the company’s website, the device is in the late stage of prototyping, and studies are ongoing to develop both research and clinical applications.

Early indications are that the device will alert ophthalmologists when individual cones have been lost. This information, when combined with images from an OCT scan, might return a more accurate depiction of the health of the retina in a given area.

“What it allows you to image very well is the cone inner segments. In conjunction with spectral-domain OCT, which gives you cross-sectional information about the photoreceptors, it gives us information about when the cone photoreceptors are intact,” Dr. Duncan said.

Adaptive optics have also been used in the setting of scanning laser ophthalmoscopy, a modality that Dr. Duncan has used in her own research to measure individual cone photoreceptors in slowly progressing retinal diseases. In this setting, adaptive optics scanning laser ophthalmoscopy can be used to measure cone density or average cone spacing in an affected area to assess structural integrity long before visual disruption occurs.

At the present time, information on the viability of cone photoreceptors may have little impact on clinical decision-making, especially given the dearth of available treatment options. But adaptive optics scanning laser ophthalmoscopy is already finding its way into use in clinical trials.

A recent phase 2 trial, for instance, employed the scanning technology to study average cone spacing in eyes with slowly progressing diseases such as retinitis pigmentosa, Usher syndrome or choroideremia that were treated with ciliary neurotrophic factor (NT-501, Neurotech).

The rationale for using the device was that cone spacing could provide a measure of disease progression and treatment effect on a high-resolution scale. Increased average cone spacing over time would indicate that those eyes were losing cone photoreceptors to cell death, thus losing potential for vision. The imaging device would, therefore, be capable of detecting a surrogate of visual function over a short time frame instead of actual functional vision loss that would take years to measure reliably.

“The time course of retinal degeneration, the progression, tends to be very slow, and by the time people have experienced measurable changes in visual function, which is what the FDA currently requires, several years have gone by, and probably many, many more cones have been lost,” Dr. Duncan said.

Alternatively, if information about the health of individual photoreceptor cells and/or their response to treatment were obtained before the irreversible damage had occurred, “then we would have, one, a way to measure safety and efficacy in a shorter time frame, and, two, potential to intervene before irreversible changes had gone on,” she said.

Clinical diagnostics role

Although clinical application of adaptive optics is not yet widely available, in the future, average cone spacing might have several potential applications. For instance, imaging of individual cone cells may be useful in tracking patients taking retinotoxic medications, such as the antimalarial drug Plaquenil (hydroxychloroquine).

Beyond that specialized use, though, understanding the cellular health of an eye suffering vision loss can be informative.

“If you’re wondering whether it’s a cone photoreceptor problem in the macula vs. some inner retinal problem, it’s helpful to know whether the cones are intact in that area, structurally,” Dr. Duncan said.

Adaptive optics scanning laser ophthalmoscopy can also be used to provide high-resolution images of the retinal vasculature, in particular the capillary flow around the fovea.

“If you’re wondering about macular nonperfusion in patients who have diabetic retinopathy or maculopathy, or macular nonperfusion after a retinal vein occlusion, it’s really good for looking at perfusion of small capillaries near the fovea,” Dr. Duncan said.

Images of individual cone cells may be useful for explaining why some patients may, for example, have thinning of the macula after steroid treatment of diabetic macular edema but no resulting gain in visual function. However, Dr. Duncan said, even though adaptive optics may reveal fine cellular architecture, adaptive optics scanning laser ophthalmoscopy images do not provide any information about function of those cells.

Because of the limitations involved in cellular level imaging, adaptive optics devices will most likely serve a complementary role in clinical diagnostics.

“I think it provides an en face, very high-resolution way to image the retina, and we use it in combination with cross-sectional measures like [spectral-domain] OCT and also with functional measures like visual acuity and fundus-guided microperimetry,” Dr. Duncan said.

• Jacque L. Duncan, MD, can be reached at University of California, San Francisco, School of Medicine, Box 0730, 10 Koret Way, Room K129, San Francisco, CA 94143-0730; 415-514-4241; fax: 415-476-0336; e-mail: duncanj@vision.ucsf.edu.

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