Peer Reviewed
Evaluating Retinal Thickness During Pegaptanib
Sodium Therapy
RICHARD
B. ROSEN, MD, THOMAS O. MULDOON, MD, & PATRICIA GARCIA,
MD
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Figures 1A (top) and 1B (bottom). 1A. Location of the thickness grids relative to the fundus is demonstrated by
placement on the SLO images. Alignment is confirmed by vessels in the SLO. 1B. Retinal
thickness grids before and after treatment are shown. The red colors indicate greater
thickness, while the greens and blues represent thinner areas. A post-treatment
map on the right in 1B showed a blink artifact (gray band) This was not significant
enough to invalidate the scan. |
With the development
and refinement of imaging systems in recent years, physicians are able to diagnose
and evaluate their patients' retinal conditions more closely without having to use
invasive means. Topographic retinal thickness mapping is one example of an imaging
system measuring the progression of macular disease and the response to a variety
of therapies. Currently, the 3 commercial systems available for topographic mapping
are the Retinal Thickness Analyzer (RTA), (Talia/Marco, Jacksonville, Fla.), the
Stratus OCT3 (Carl Zeiss Meditec, Dublin, Calif.), and the OCT/SLO (OTI, Toronto,
Ontario).
The
RTA is a computerized laser slit lamp, which assembles sequences of optical cross-sections
from 5 points surrounding the fovea to generate a map that is overlaid upon a fundus
image. The Stratus OCT3 expands a sequence of 6 fixation-centered radial scans into
a free-floating thickness map. The OCT/SLO utilizes volumetric analysis for more
complete sampling and offers precise registration with macular landmarks.
This article will describe how the OCT/SLO system obtains images
and will illustrate image examples of how the technology was utilized to measure
macular thickness changes in patients treated with pegaptanib sodium (Macugen, OSI
Pharmaceuticals) for exudative age-related macular degeneration (AMD) in a small
pilot study.
A DISCUSSION OF RETINAL IMAGING SYSTEMS
The advent of extended pharmacologic therapies for exudative AMD
and diabetic macular edema (DME) has stimulated new interest in using such a technique
to monitor anatomic response to therapy quantitatively.1
Conventional approaches involving the RTA and Stratus OCT have
various limitations of the respective technologies. The RTA employs the technique
of laser slit beam triangulation to measure retinal thickness. The laser slit beam
is projected at an angle on the retina while a CCD camera records the backscattered
light. As the camera records the reflected image, a thickness algorithm identifies
the location of the anterior and posterior retinal borders. The distance between
the two light peaks determines the retinal thickness at a given point.
While this technique limits its accuracy and registration in eyes
with any media nonhomogeneity such as cataract or pseudophakia, it does offer alignment
of the thickness grid to the fundus map by merging the submaps from the 5 fixation
points used in the test.
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Figures 2A(top) and 2B (bottom). 2A. Pretreatment grid appears following automated
alignment sequence. The operator can adjust any mismatch between the two studies
that makes the grid appear tilted against the background of the SLO image and check
the placement of the grid on the SLO image. 2B. Post-treatment grid appears once
the operator confirms acceptance of the first alignment. |
The Stratus OCT3 generates nonregistered maps with minimal detail
that are intended to link to a central fixation point. Conversely, the OCT/SLO uses
one-to-one registration between high-resolution SLO fundus surface features and
the stack of OCT coronal planar images. A comparison algorithm features a user-modifiable
automated alignment of the retinal vessels from successive SLO images and coronal
OCT scans. This alignment ensures the accuracy of subtracting serial studies.
A second concern with the Stratus OCT maps is the heavy reliance
upon interpolated data from a small number of points to construct the maps. Six
radial scans, from which the fast macula maps are generated, are only 20 μm
in thickness each and do not all run through the same point of origin. Relying upon
the patient's fixation increases the likelihood of shifting of the point of origin
as the central vision improves or worsens. The interpolated wedges decrease in accuracy
as they extend into the periphery. The OCT/SLO maps are generated from a large sampling
of points (512 x 512 or 256 x 256 pixels and a stack 100 to 200 sets of C-scans)
captured within the coronal OCT stacks. This robust data set for each map helps
to ensure accurate representation of retinal thickness, which can be compared with
previous and future studies.
OCT/SLO
METHODOLOGY
OCT/SLO imaging employs a single illumination source and multiple
detectors designed to integrate the raster scanning technology of the confocal scanning
laser ophthalmoscope with the high-resolution capabilities of OCT interferometry.
Utilizing transverse raster scans
(T-scans) that run parallel to the retinal
surface, the device generates both coronal OCT slices (C-scans) and conventional
saggital OCT cross-section (B-scans).2
Rapidly acquired stacks of C-scans are aligned looking at retinal vessels and are
reconstructed into 3-D volumes for thickness mapping. Scanning at a rate of 100
slices per second, each OCT/SLO slice samples a 512 x 512 or 256 x 256 pixel matrix.
Multiple bursts of slices are used to compare sample sets and discard ones with
movement artifacts, which are often generated by the cardiac pulse.
METHODS FOR PILOT STUDY
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Figure
3. Subtraction of the topographic maps. A map of the subtracted aligned images reveals
the differences between corresponding points and shows the overlap between scans.
Average thickness change and standard deviation is calculated for the overlapping
points. Unchanged areas remain gray and do not affect the average change or standard
deviation. |
To evaluate the utility of this approach we followed the progress
of 20 patients undergoing pegaptanib sodium therapy in the spring of 2005 shortly
after it became commercially available. The study was designed as a retrospect case
series. Patients were imaged before and after treatments and topographic maps were
generated. Automated comparative analysis was performed following alignment of serial
maps to evaluate the thickness changes. Here is a discussion of 2 cases from the
study.
STUDY DISCUSSION
In this small pilot study of topographic mapping of pegaptanib
sodium therapy, several observations were evident. First, OCT B-scan cross-sections
frequently do not portray the effectiveness of the therapeutic response accurately.
Since each slice is only 20 μm wide, the response seen in one slice often does
not represent the response of the larger 10 x 10 area of the macula. This was evident
in Case 2, where the OCT slices looked similar but the topography revealed a more
extensive response.
Richard
B. Rosen, MD, is director of the New York Eye and Ear Infirmary (NYEE) Advanced
Retinal Imaging Center, and Thomas O. Muldoon, MD, is director of its vitreo-retinal
service. Patricia Garcia, MD, is a research associate. Dr. Rosen can be e-mailed
at RRosen@NYEE.EDU. Dr. Rosen has received travel reimbursements from OTI; Dr. Garcia
is a consultant for OTI; and Dr. Muldoon does not have any financial interest in
the technology discussed in this article.
CASE 1
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Figure
4. Serial B-scan OCT slices during pegaptanib sodium therapy. Images taken at 6-week
intervals preceding injections are seen in the upper row and in the lower left,
and large cystic spaces appeared unresponsive to the therapy. The lower right frame
shows resolution of the cystoid spaces and retinal thickening following intravitreal
triamcinolone acetonide. |
A
74-year-old woman who had a history of choroidal neovascular membrane in her right
eye had been treated with verteporfin (Visudyne, Novartis)
1 year prior to presentation.
Her visual acuity (VA) was 20/400 in the right eye and 20/30 in the left eye. The
patient presented after 2 days of visual disturbance in her left eye with visual
acuity reduced to 20/150. Fundus exam revealed a macular hemorrhage. Fluorescein
angiogram confirmed the presence of a poorly defined choroidal neovascular membrane
and indocyanine green (ICG) angiography showed a hot spot in the same region. Following
pegaptanib sodium therapy, performed on the day of presentation, the patient experienced
a return of visual acuity to the level of 20/50 measured at 2 weeks post treatment.
OCT/SLO was performed pre treatment and two weeks posttreatment with pegaptanib
sodium. Figure 3 shows a representative B-scan OCT slice beneath topographic maps
taken during the same session. The B-scan OCT images demonstrate significant decrease
in cystoid edema and thickness, which is described quantitatively by the topographic
maps. In this case the B-scan OCT, topographic map, and VA all demonstrated a positive
therapeutic response. This was, in fact, unusual since often there was a disconnect
with functional response preceding or lagging behind anatomic change.
CASE 2
A
78-year-old woman with a history of unsuccessful treatment with photodynamic therapy
(VA=20/400) in her left eye presented with a new onset of macular hemorrhage and
decreased VA to 20/70 due to an occult choroidal neovascular membrane in her right
eye. She received pegaptanib sodium as part of an open label trial and her visual
acuity stabilized in the range of 20/100 to 20/150 on a standard treatment regimen.
OCT /SLO B-scans taken in August, October, and December showed persistence of cystoid
changes in the macula despite apparent stabilization.
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Figure
5. Comparison of topographic maps. The thickness grid pre and post first pegaptanib
sodium treatment showed a small reduction in the size of the thickened area. The
version of the software at this point did not allow subtraction
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Permission for study monitors was granted for the patient to receive
an intravitreal injection of 4 mg of triamcinolone acetonide (Kenalog, Bristol-Myers
Squibb). B-scan OCT (Figure 4) revealed a dramatic reduction, but not elimination,
of the cystic edema. Topographic map comparison documented the full extent of the
marked reduction in the thickened area, which is seen in Figure 7B. As impressive
as the anatomic and quantitative changes were with the addition of the steroid,
the VA improvement was modest to the level of 20/80 and subjectively the patient
was not able to notice the improvement.
Second, comparison of OCT changes over time can only be accurately
performed if registration between studies can be assured. Even with scans and topographic
maps centered on fixation, alignment of blood vessels between corresponding SLO
images revealed that fixation-centered scans demonstrated considerable shifts and
rotation that were only evident in subtraction overlays. This was seen in Figures
3 and 7 and to a lesser extent in Figure 6. Third, with regard to the relationship
between OCT anatomy and VA, topographic maps may be able to define the relationship
better. This study, however, was too small and was not designed to answer that question.
Finally, the variability of response to treatment even in the same patient contains
a variability component. This is encouraging since the risk of choroidal neovascular
membranes in the fellow eye is significant, and patients having limited response
in the first eye may respond more favorably in the second eye.
SUMMARY
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Figures 6A and 6B. Comparison and subtraction
of maps shows the changes before the second injection vs. before the third injection.
Subtraction reveals some reduction and some increased thickening. |
The OCT/SLO retinal topographic mapping offers a potentially more
accurate imaging system for measuring anatomic response to treatment with anti-VEGF
drugs. The point-to-point registration of OCT/SLO ensures accurate assessment of
topographic changes over time. Analysis of patterns of thickness changes may be
helpful in predicting which eye will respond more favorably to treatment. Patterns
of change also may help with decisions as to when therapy may be discontinued.
The OCT/SLO approach of linking surface anatomy to internal features
and thickness changes is a major advance in retinal monitoring since it ensures
that measurements used for therapy decisions reflect the changes being monitored.
Since this study, other anti-angiogenic agents have been made available and the
concept of discontinuing therapy as soon as stability is demonstrated has become
increasingly popular. retinal topographic maps may serve as an important tool for
documenting a clinical stability.
Having a technology like the OCT/SLO that employs a more comprehensive
scanning pattern and a larger field of view can potentially assist physicians in
gauging the condition of the macula in response to therapies, and may influence
treatment patterns. However, further studies are warranted to confirm these possibilities. RP
REFERENCES
1. Rosen RB, Will D, Garcia P, et al. OCT ophthalmoscope. In:
Alfaro DV, Liggett PE, Mieler WF, et al. Age-Related Macular Degeneration: A
Comprehensive Textbook. Philadelphia, Pa: Lippincott Williams & Wilkins;
2005.
2. Rosen RB, Dunne S, Podoleanu AG, Garcia PM. OCT ophthalmoscopy.
Posterior Segment Imaging of the Eye. Philadelphia, Pa: Elsevier; 2006.
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Figures 7A and 7B. Subtraction of topographic
maps showing the differences before the third injection and 6 weeks following triamcinolone.
Registered subtraction reveals a dramatic response to treatment with marked reduction
of thickness.
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Retinal Physician, Issue: September 2006