OCT Imaging: Advances Over the Past 5 Years and Beyond

Optical coherence technology has come a long way, and it continues to move forward.

HENRY ALEXANDER LEDER, MD · SCOTT W. COUSINS, MD

Over the past 16 years optical coherence tomography (OCT) has developed from a simple concept to a critical part of the retinal specialists' diagnostic arsenal.¹ It has supplemented, and in many instances replaced, earlier imaging modalities, making diagnosis much easier and faster for patients and clinicians alike. OCT's inherent advantages over contact lens biomicroscopy, ultrasound and fluorescein angiography include the following: It is non-invasive, it does not require contact with the globe with a coupling agent, it is more comfortable for the patient, it can be imaged through a moderately sized nondilated pupil, and it allows imaging at the 15-μm level — far beyond ultrasound, computed tomography, or magnetic resonance imaging resolution.

The technique was first demonstrated in 1991 with ~30-μm axial resolution.² The first commercially available OCT was the Carl Zeiss Meditec (CZM, Dublin, CA) OCT1. It was improved in 2001 with the introduction of wide-bandwidth (over a ~100-nm range) light sources, and submicrometer resolution was achieved. In 2003, CZM released the Stratus OCT.³ Soon new advances in image acquisition and analysis will allow much higher resolution images, and the combination of OCT with other imaging modalities will give new insights to clinical pathology.⁴

OCT has been used to image many tissues in many parts of the body.⁵ It has been most successful in the eye, due to the transparent nature of the optical system. OCT has been widely used for anterior- and posterior-segment pathology. For purposes of this article we will concentrate on retinal imaging.

OCT CONCEPT

Optical coherence tomography is often compared to an ultrasound imaging device, except that it uses light instead of sound. This is superficially correct. Light travels in a vacuum at 300 000 000 m/second, while sound travels at approximately 300 m/second.⁶ The speed of light is so great that a direct measurement of the time delay of light is not possible. Instead, OCT uses the principle of interferometry to measure indirectly distances with reflected light.

Either coherent laser light or low-coherence, conventional light is used. A beam splitter splits the light, with a fraction of the light reflecting off the retina. Most OCT systems use near-infrared light in the 600-nm to 2000-nm range.⁵ This spectrum is convenient because it has low absorption for tissue, water, and pigments. It is also more comfortable for patients and allows imaging through a nondilated pupil. The other fraction of the beam is kept as a reference traveling a known distance. The light beams are then recombined and an interference pattern created. Light of the same frequency that is out of phase interferes destructively, while light of the same frequency that is in phase interferes constructively. Thus the distance the light traveled before reflecting off the retinal surface can be calculated using the interference pattern.

In time-domain OCT (TD-OCT) a mirror is moved to vary the distance traveled by the reference beam. The interference pattern varies with the mirror's movement and the output is used to create an A-scan or 1-D output. Multiple A-scans can be combined to form a B-scan or 2-D image. In turn, multiple B-scans can be combined into a 3-D map.⁵ From this 3-D model, planes parallel to the retinal surface, called C-scans, can be imaged. This is like taking horizontal layers through a cake, unlike B-scans, which are vertical slices. The problem with TD-OCT is that the mechanical component, movement of the mirror, limits the speed of the machine. Scan speeds are approximately 400 A-scans per second.

SPECTRAL-DOMAIN OCT

A paradigm shift has occurred in OCT with the development of Fourier- or spectral-domain (SD)-OCT. SD-OCT discards the mechanical mirror completely. Instead a spectrometer and a high-resolution charged-couple device (CCD) camera are used to image low-coherence light. The signals are interpreted using a Fourier transform algorithm to electronically, rather then mechanically, separate the interference pattern into different frequencies.⁵ This permits simultaneous axial analysis, rather than the sequential analysis of TD-OCT, thus affording much greater imaging speed. (The development of this technology was dependent on advances in CCD detectors and computer processing speed.) Speeds achieved using SDOCT are approximately 26 000 axial scans per second, or 60 times faster then TD-OCT. This faster speed means less movement artifact and greater comfort to the patient, as well as the ability to generate much more detailed 3-D images. Although the theoretical axial and transverse resolutions are similar in TD-OCT and SDOCT, in practice movement artifact limits TD-OCT's resolution. With the higher scan speeds of SD-OCT, this artifact is greatly reduced.

ALL IMAGES APPEAR COURTESY OF THE AUTHORS.

In addition, the new Heidelberg (Vista, CA) SDOCT uses automatic eyetracking software to reduce movement and blink artifacts from the patient. This allows a much greater level of detail as well as simultaneous imaging with other modalities such as fluorescein, indocyanine green (ICG), autofluorescence, infrared, and red-free images. It is hoped that combining these imaging modalities will provide new insights into the structure and function of disease and enable quick and precise diagnosis for our patients.

A summary of some features of SD-OCT machines is included in the Table. The Cirrus (CZM) HD-OCT, the RTVue-100 (Optovue, Meridianville, AL), the Spectralis Family (Heidelberg), the 3D OCT-1000 (Topcon, Paramus, NJ), and the Spectral OCT/SLO (OTI, Toronto) are available now. The Bioptigen (Research Triangle Park, NC) SDOCT has been developed with research and extraocular as well as ocular applications in mind. It is available and in use in some academic centers. The Copernicus SOCT (Reichert, Depew, NY) will enter the market soon.

Another advantage of SD-OCT is its denser sampling of larger retinal areas, which makes missing small areas of pathology in "skipped regions" less likely. This is particularly important when following a patient over time and using the OCT to look for progression of the disease as a guide to treatment. Using the current generation TD-OCT can be frustrating because different images taken at different times do not necessarily correspond to the same position in the retina. Thus cystoid macular edema may appear to have improved, when in fact a smaller area of edema was sampled and the condition is stable or even progressing. This is particularly true of the global maps featured in many OCT software packages. While the maps give an idea of the thickening pattern, they are not reliable and are often offcenter, particularly in patients who have lost fixation.

Likewise, many physicians have adopted OCT as a quick, easy, and noninvasive way to follow patients with macular degeneration.¹⁴ In our practice, patients with neovascular age-related macular degeneration with new subretinal subretinal fluid are generally treated with anti-vascular endothelial growth factor injections, while those whose eyes are stable are observed. Unfortunately, small areas of subretinal fluid can easily be missed with the current sampling algorithms of OCT. It is hoped that the larger sampling of SD-OCT and improved imaging will translate into better treatment outcomes for our patients.

Figures 1, 2, 3 and 4 are horizontal OCT images taken from the right eye of a healthy 33-year-old volunteer. They were produced using Bioptigen, Spectralis, and CZM's Cirrus and Stratus machines.

FUTURE PROGRESS

In medicine and especially in ophthalmology, we are highly dependent on imaging modalities for accurate diagnosis and as a guide to treatment. With the new generation of SD-OCT, we have the ability to accurately quantify specific changes such as volume, central thickness, and fluid composition over time. In addition, the greater resolution and ability to combine multiple imaging techniques such as autofluorescence and ICG will allow us to image the choroid and retinal pigment epithelium (RPE) as never before. We can foresee a time when RPE height and thickness are followed as macular edema and subretinal fluid are today. This technology's improved resolution and detail will help us diagnose disease earlier and monitor disease progression more effectively. Ultimately, this will mean earlier and more effective interventions with better patient outcomes.

Figure 1. A horizontal OCT image taken with the Bioptigen SD-OCT.

In the future, other advances will greatly improve the usefulness of OCT to clinical practice. For example, the use of OCT contrasts may allow for better imaging of retinal lesions. Coordinating ultrasound with OCT and photography could greatly help in the diagnosis and treatment of retinal tumors like melanoma and retinoblastoma. Currently, optical aberrations from the cornea and lens limits focus to 10 to 15 μm; it is possible that adaptive optics could reduce this limit to 2.5 μm or lower.¹⁵ OCT can also be used to measure oxygenation in retinal tissue.⁵ When perfected, this would allow targeted therapy, such as scatter laser, to be directed only at ischemic areas of the retina, sparing the majority of the retina and insuring a more effective treatment for ischemic retinal disease.

Figure 2. OCT imaging as performed by Spectralis.

Researchers are also investigating contrast to enhance OCT. ICG has been used, as well as other dyes. Beyond its clinical application, this could be a great adjunct to research. If drugs could be attached to dyes, OCT could be used to demonstrate distribution within the eye, aiding in the development of new drugs as well as determining the best method for delivery. Other work is being done on measuring neuronal activity with OCT. Areas of the retina are simultaneously stimulated with light while being imaged on OCT.

The Bioptigen OCT has been developed with the academic center and research market primarily in mind. Bioptigen is hoping to apply their technology to animal research and nonophthalmic applications. To this end, it has developed a hand-held OCT probe that allows easier imaging of animals, as well as children and nonambulatory patients. It can also be taken into the operating room. OCT probes have also been developed for cardiac catheterization, endoscopy, and cystoscopy. These images could allow surgeons to make better decisions and ultimately produce superior surgical outcomes for their patients. Tumor resection could be guided with real time OCT "biopsy," thereby ensuring full removal of malignant tissue while sparing the maximum healthy tissue possible. We are still in the very beginning of this technology.

Figure 3. Horizontal OCT as performed by Carl Zeiss Meditec's Cirrus TD-OCT.

Figure 4. Horizontal OCT as performed by Carl Zeiss Meditec's Stratus OCT machine.

CONCLUSION

When OCT was first introduced to ophthalmology, it was largely viewed as a research tool. Since the time of its first use, clinicians have continued to find innovative ways to utilize this technology, and it has contributed to advances not only in imaging the retina, but in guiding drug-treatment patterns. The interest in OCT technology is great, as evidenced by the investments made by multiple manufacturers in the realm of spectral domain. We are still in the early stages of this technology, and it is with eager anticipation that we await its continued development. RP

REFERENCES

1. Congdon N, O'Colmain B, Klaver CC, et al. Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol. 2004;122:477-485.
2. Buch H, Vinding T, La Cour M, Appleyard M, Jensen GB, Nielsen NV. Prevalence and causes of visual impairment and blindness among 9980 Scandinavian adults: the Copenhagen City Eye Study. Ophthalmology. 2004;111:53-61.
3. Polito A, Isola M, Lanzetta P, et al. The natural history of occult choroidal neovascularisation associated with age-related macular degeneration: a systematic review. Ann Acad Med Singapore. 2006;35:145-150.
4. Macular Photocoagulation Study Group. Argon laser photocoagulation for neovascular maculopathy. Five-year results from randomized clinical trials. Arch Ophthalmol. 1991;109:1109-1114.
5. Macular Photocoagulation Study Group. Laser photocoagulation of subfoveal neovascular lesions of age-related macular degeneration. Updated findings from two clinical trials. Arch Ophthalmol. 1993;111:1200-1209.
6. Macular Photocoagulation Study Group. Laser photocoagulation for juxtafoveal choroidal neovascularization. Five-year results from randomized clinical trials. Arch Ophthalmol. 1994;112:500-509.
7. Penfold PL, Wen L, Madigan MC, Gillies MC, King NJ, Provis JM. Triamcinolone acetonide modulates permeability and intercellular adhesion molecule-1 (ICAM-1) expression of the ECV304 cell line: implications for macular degeneration. Clin Exp Immunol. 2000;121:458-465.
8. Penfold PL, Wen L, Madigan MC, King NJ, Provis JM. Modulation of permeability and adhesion molecule expression by human choroidal endothelial cells. Invest Ophthalmol Vis Sci. 2002;43:3125-3130.
9. Lewis GD, Campbell WB, Johnson AR. Inhibition of prostaglandin synthesis by glucocorticoids in human endothelial cells. Endocrinology. 1986;119:62-69.
10. Umland SP, Nahrebne DK, Razac S, et al. The inhibitory effects of topically active glucocorticoids on IL-4, IL-5, and interferon-gamma production by cultured primary CD4+ T cells. J Allergy Clin Immunol. 1997;100:511-519.
11. Bhattacherjee P, Williams RN, Eakins KE. A comparison of the ocular antiinflammatory activity of steroidal and nonsteroidal compounds in the rat. Invest Ophthalmol Vis Sci. 1983;24:1143-1146.
12. Ciulla TA, Criswell MH, Danis RP, Hill TE. Intravitreal triamcinolone acetonide inhibits choroidal neovascularization in a laser-treated rat model. Arch Ophthalmol. 2001;119:399-404.
13. Danis RP, Bingaman DP, Yang Y, Ladd B. Inhibition of preretinal and optic nerve head neovascularization in pigs by intravitreal triamcinolone acetonide. Ophthalmology. 1996;103:2099-2104.
14. Antoszyk AN, Gottlieb JL, Machemer R, Hatchell DL. The effects of intravitreal triamcinolone acetonide on experimental pre-retinal neovascularization. Graefes Arch Clin Exp Ophthalmol. 1993;231:34-40.
15. Jonas JB, Akkoyun I, Budde WM, Kreissig I, Degenring RF. Intravitreal reinjection of triamcinolone for exudative age-related macular degeneration. Arch Ophthalmol. 2004;122:218-222.