Microcystic macular edema detection in retina OCT images

Emily K. Swingle
a
, Andrew Lang
b
, Aaron Carass
b
, Howard S. Ying
c
,
Peter A. Calabresi
d
, and Jerry L. Prince
b
a
Department of Biomedical Engineering, The Ohio State University
b
Department of Electrical and Computer Engineering, The Johns Hopkins University
c
Wilmer Eye Institute, The Johns Hopkins University School of Medicine
d
Department of Neurology, The Johns Hopkins University School of Medicine
ABSTRACT
Optical coherence tomography (OCT) is a powerful imaging tool that is particularly useful for exploring retinal
abnormalities in ophthalmological diseases. Recently, it has been used to track changes in the eye associated with
neurological diseases such as multiple sclerosis (MS) where certain tissue layer thicknesses have been associated
with disease progression. A small percentage of MS patients also exhibit what has been called microcystic macular
edema (MME), where uid collections that are thought to be pseudocysts appear in the inner nuclear layer. Very
little is known about the cause of this condition so it is important to be able to identify precisely where these
pseudocysts occur within the retina. This identication would be an important rst step towards furthering our
understanding. In this work, we present a detection algorithm to nd these pseudocysts and to report on their
spatial distribution. Our approach uses a random forest classier trained on manual segmentation data to classify
each voxel as pseudocyst or not. Despite having a small sample size of ve subjects, the algorithm correctly
identies 84.6% of pseudocysts as compared to manual delineation. Finally, using our method, we show that
the spatial distribution of pseudocysts within the macula are generally contained within an annulus around the
fovea.
Keywords: OCT, pseudocysts, segmentation, classication, microcystic macular edema
1. INTRODUCTION
Optical Coherence Tomography (OCT) is becoming a useful imaging tool for estimating the severity of retinal
pathology in both ophthalmology
1
and neurology.
2
Near-infrared light from the OCT scanner penetrates retinal
layers at the back of the eye, and detects backscattered light to create an image. In addition to displaying
the retinal layers, these images can be used to identify structural abnormalities within each layer. One such
abnormality is the appearance of small uid lled regions, sometimes called microcysts or pseudocysts, found
within the retinal tissue. In multiple sclerosis (MS), these pseudocysts occur in about 5% of subjects;
3, 4
a
condition that has been termed microcystic macular edema (MME). Specically, MME is most commonly found
in the inner nuclear layer (INL), see Fig. 1 for an example. Little is known about the appearance of these
pseudocysts, or their implications for disease prognosis, but they have been found to be correlated with disease
severity, a reduction of visual acuity, and thinning of the retinal nerve ber layer (RNFL).
4
It also seems that
optic neuropathy may be associated with these pseudocystic changes.
5, 6
In addition to simply exploring the appearance of these pseudocysts, tracking the longitudinal changes may
also prove to be useful to enhance our understanding of MME. In recent studies by Saidha et al.
3
and Gelfand et
al.,
4
longitudinally scanned OCT data were obtained from several patients with MME (ten patients in Ref. 3
and six patients in Ref. 4). In total, ve of the aected eyes exhibited improvement of MME, seven experienced
worsening of MME, and six showed either no apparent change or uctuations over time (noting that MME was
bilateral in two of the patients). Although these studies indicate possible dynamic characteristics of MME over
time, the volume and location of MME was not quantitatively evaluated and therefore much more can be learned
about the pseudocyst volume and location over time in relation to MS.
It is clear that studying the appearance of these pseudocysts, both cross-sectionally and longitudinally, is
necessary to better help study this condition. With so much about MME still unknown, methods for detecting
and quantifying the size and distribution of these uid-lled areas are essential. Due to the sheer amount of
Medical Imaging 2014: Biomedical Applications in Molecular, Structural, and Functional Imaging,
edited by Robert C. Molthen, John B. Weaver, Proc. of SPIE Vol. 9038, 90380G
2014 SPIE CCC code: 1605-7422/14/$18 doi: 10.1117/12.2043910
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(a)
(b)
(c) (d)
(a)
(b)
(c) (d)
(a)
(b)
(c) (d)
Figure 1: (a) Fundus image showing the location of acquired B-Scans; the red line represents the location of
the B-scan portrayed in (b). (b) B-scan image containing pseudocysts which are shown with 3 zoom below.
(c) and (d) shows areas with small and large pseudocysts, respectively.
data output from OCT, this analysis is only feasible with an automatic detection method. To the best of our
knowledge, there has been no previous research to automatically detect and analyze the spatial conguration of
these pseudocysts within the retina for MME patients. Although a method for identifying closed-contour features
in the retina has been investigated,
7
and a 3D process has been analyzed to locate retinal abnormalities,
8
this
research was not done to identify and analyze the types of cystic areas found in MME, specically.
In this work, we created an algorithm to automatically identify pseudocysts in the retina. The algorithm
uses a simple classication approach where each voxel is classied as pseudocyst or not based on the output
of a trained classier. This detection allows us to both quantify the number of pseudocysts, and display their
spatial distribution across the retina. Overall, our method could be used to give more insight on the cause and
progression of these pseudocysts.
2. METHODS
In our analysis, we used OCT images of the retina acquired over the macular cube. A fundus image, illustrated
in Fig. 1(a), displays the anterior portion of the retina where these images were obtained. The overall volume
comprises 49 OCT images, called B-scans (Fig. 1(b)). Each column of a B-scan is called an A-scan. These B-scans
are acquired over the macula as shown in Fig. 1(a), with the horizontal blue lines representing the location of
each B-scan. Each 2D image portrays details of the retinal layers, as well as abnormalities that may be located
within these layers. Examples of small and large pseudocysts in the INL are shown in Figs. 1(c) and (d).
Our pseudocyst detection algorithm uses a pixel classication approach. Before the classication stage, we
use two preprocessing steps, which are summarized here and described in detail in Lang et al.
9
In the rst step,
we normalize the intensities of the images; the intensity range of each B-scan is clamped and rescaled based on
a robust estimate of the maximum intensity. The purpose of this step is to obtain a more consistent intensity
distribution to improve the performance of the classier. Second, we estimate the location of the inner and outer
retina boundaries, the inner limiting membrane (ILM) and Bruchs membrane (BM), respectively. Knowledge of
these boundaries allows us to restrict the search area for the pseudocysts and also to incorporate the relative
distance of pseudocysts from the retina boundaries as a feature, as we only expect to see them in or near the INL.
Briey, these boundaries are found by looking for large vertical gradients in each image. The inner and outer
boundaries are roughly estimated from the largest positive and negative gradients along each A-scan, respectively.
Final boundary positions were constrained by an estimated position of the photoreceptor junction (a large positive
gradient near the bottom of the retina), median ltered to remove outliers, and nally smoothed using a Gaussian
kernel.
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With knowledge of where the retinal boundaries are, our pseudocyst detection algorithm uses a random
forest (RF) classier.
10
We use the RF classier since it has a small number of parameters, is ecient, can extract
highly nonlinear correlations, and its performance is as good or better than other state-of-the-art methods. A RF
works by constructing a forest of multiple decision trees. Each tree is independently trained using a random
sample of the training data and, given an input feature vector, provides a decision about what class the input
belongs to. By aggregating the classication result of each tree and using a majority vote rule, a nal classication
estimate is obtained.
To use RF for our problem, we look at each pixel independently, using a set of 14 features to classify whether
or not each pixel is pseudocyst or non-pseudocyst. As the pseudocysts appear darker than the surrounding retinal
tissue, we primarily use intensity-based features. For the rst two features, we use the voxel intensity and voxel
intensity after a gray-scale morphological closing operation (using a disk structuring element with a radius of
5 pixels). Closing acts to remove the pseudocysts providing a contrast to the original intensity. The next nine
features are the voxel intensity after Gaussian ltering at various scales. The next two features are the Laplacian
and Laplacian of Gaussian of the image as ways to enhance the smaller, narrow pseudocysts. Finally, we use the
relative distance to the retina boundaries as a spatial feature to localize the position of the pseudocysts within
the retina. Specically, we look at the proportional distance of a pixel along each A-scan; for instance, looking at
Fig. 1(b), we might generally expect to nd the pseudocysts at around 30% of the distance from the ILM to the
BM.
To compute a nal pseudocyst segmentation, we simply compute these features at each pixel and evaluate
them using the trained RF classier. Since classication in this manner will produce several spurious pixels
classied as pseudocyst, we simply remove all connected components below a specied threshold. The best value
of this threshold is explored in the next section.
3. EXPERIMENTS AND RESULTS
We used available data with pseudocysts from ve MS subjects having MME. Additionally, we used two
pseudocyst-free healthy controls to aid in training. The OCT scans (20

20

) were imaged on a Spectralis

scanner (Heidelberg Engineering, Heidelberg, Germany). The scans consisted of 49 B-scans with 1024 A-scans
each, imaging approximately 6 6 mm of the macula. Manual delineation of the pseudocysts in each subject was
performed by two raters. Both raters independently delineated the scan with the most pseudocysts present, and
then separately delineated the remainder of the MS data.
To test our approach, the RF classier was tested using a leave-one-out strategy on each of the ve MS
subjects. Thus, one classier was trained to evaluate each MME subject. Each classier was trained on the data
from four MME subjects and two healthy control subjects. From each training subject, we included ten randomly
selected B-scans from the MS subjects and twelve B-scans from the healthy controls. We used only a fraction of
the training data because, at the resolution of the data, using the entire volume results in an excessive amount of
data, both in terms of training time and memory requirements. All pseudocyst pixels and 75% of the background
pixels within the estimated retinal boundaries of the respective B-scan were included. We used 75 trees to build
the RF, with the split decision at each node based on two randomly selected features.
Fig. 2 shows a comparison between the size of pseudocysts detected by our algorithm and those delineated by
our human raters on the entire cohort of ve MS subjects with MME. From this gure, it is clear that there
was broad agreement between the manual and automated segmentation for pseudocysts larger than 15 pixels,
although below that level the algorithm detected vastly more pseudocysts. For purposes of this analysis, we
consider a single pseudocyst as a single connected component area.
In Table 1, we provide a direct comparison of the number of pseudocysts found by our algorithm and the
number found by the manual raters. Listed are the number of pseudocysts found having an area above the stated
pseudocyst threshold, with the area simply being the number of pixels within the connected component. Five
dierent threshold values were compared. As we also see in Fig. 2, the performance of the algorithm improves
with a larger pseudocyst threshold. One explanation for this result is that the larger pseudocysts contain more
dark intensities making the classication task simpler. Smaller pseudocysts generally have variable levels of
dark-to-bright intensities making them more dicult to classify.
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M a n u a l S e g m e n t a t i o n
A l g o r i t h m
T o g e t h e r
1 1 L , n
Size of pseudocysts (pixels)
N
u
m
b
e
r

o
f

p
s
e
u
d
o
c
y
s
t
s
0 10 20 30 40 50 60 70 80 90 100 110
0
100
200
300
400
Manual Segmentation
Algorithm
Together
Figure 2: Histogram comparison of pseudocyst sizes for manual segmentation and algorithm identication.
Table 1: A comparison of pseudocysts segmented and correctly identied for dierent size thresholds of manual
segmentation. Values represent totals across all ve MS patients.
Pseudocyst Size # Manual # Correctly % Correctly
Threshold Segmented Segmented Detected
10 1869 1280 68.5
20 1325 1035 78.1
30 876 741 84.6
40 522 459 87.9
50 316 291 92.1
In Fig. 3, we show the result of our algorithm overlaid on a B-scan image. Looking closely at the results
(Figs. 3(d) and 3(e)), we see good overall agreement in the larger pseudocysts, as well as the slight dierences
in the boundaries when comparing the algorithm to our raters. Smaller pseudocysts show less agreement, with
several pseudocysts found by the human rater and not by the algorithm (displayed in red). It should be noted,
however, that manual delineation of these smaller pseudocysts is subjective due to the denition of what is and is
not a pseudocyst.
Next, we evaluated our algorithm on data that has no pseudocysts. To do this, we selected ve healthy control
subjects and ve additional MS patients, which were all inspected and found to not have pseudocysts. The results
of running our algorithm on this data are presented in Table 2. For this comparison, we removed all pseudocysts
below a size threshold of 30 pixels. In this table, we see that the algorithm performs particularly well on the
control subjects, with a maximum of one pseudocyst detected in each subject. The same can be said for the MS
subjects without pseudocysts, having a maximum of two detected pseudocysts.
As a nal comparison between the manual and automatic segmentation, we compared the spatial distribution
of the pseudocysts within the macula. This was accomplished by projecting and smoothing the number of
pseudocysts found by both our algorithm and our human raters onto a fundus image of a retina, see Fig. 4. We
again see good agreement between our algorithm and the manual segmentation, even when only a few pseudocysts
are present, as shown in Figs. 4(c) and 3(d). We also notice a pattern in the distribution of the location of the
pseudocysts around the fovea. Note that again, a pseudocyst size threshold of 30 pixels was used in these images.
It is interesting to note that the distribution of these pseudocysts forms in an annulus around the fovea at the
center of the macula.
4. DISCUSSION AND CONCLUSIONS
We have developed an algorithm for the detection of MME and the related pseudocysts in retinal OCT images.
Our segmentation agrees closely with the results of manual raters on pseudocysts larger than 15 pixels in size,
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P i g o r i t h m C y s t I d e n l i f i c a t i o n
M a n u a l v s . A l g o r i t h m C y s t I d e n t i f i c a t i o n
. .
t
L 1 4
a , _
y + 1
(a)
(b)
(c)
(d) (e)
(f) (g)
Figure 3: Performance of the pseudocyst segmentation algorithm on one B-scan, for pseudocysts above the 30
pixel threshold. From top to bottom shows (a) the original B-scan, (b) the result of the algorithm overlaid in
green, and (c) the ground truth and algorithm overlaid together (red = false negative, green = false positive, and
blue = positive). The images in (d-g) show zoomed in portions of the images in (a) and (c).
with even better performance with a threshold of larger than 30 pixels. We believe that the errors below this level
represent the diculty that human raters have in identifying small pseudocysts. This is evidenced by the fact
that the raters had an overlap agreement (Dice score) of just 0.75 on the volume they both segmented. Despite
the small sample size for training and evaluation, our approach is able to locate 85% of the pseudocysts larger
than 30 pixels. Our method also did not identify pseudocysts in pseudocyst-free subjects, suggesting its specicity
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Table 2: Comparison of pseudocyst detection of our algorithm on three cohorts: healthy controls, MS patients
without pseudocysts, and MS patients with pseudocysts. Each cohort consisted of ve subjects. The mean, min,
and max number of cysts per subject, and the mean number of cyst pixels identied per subject are reported by
cohort.
Pseudocysts detected Pseudocyst Pixels
Mean Min Max Mean
Healthy Control 0.2 0 1 6.8
MS Patients without Pseudocysts 0.6 0 2 24.8
MS Patients with Pseudocysts 118.2 7 305 6288.6
Subject #1
(a) (b) (c)
Subject #2
(d) (e) (f )
Figure 4: (a, d) Fundus image for two subjects with the black lines indicating the extents of the OCT volume.
Spatial distribution of pseudocysts overlaid on the fundus images of two subjects for (b, e) a manual rater,
and (c, f ) our algorithm. Similar annulus patterns and accuracy could be seen in all ve MS subjects with
pseudocysts.
is well suited for dierentiating MME and non-MME patients. This detection capability would also be benecial
in improving layer segmentation algorithms
9
which have diculty when run on these MME patients. The spatial
distribution of the pseudocysts (Fig. 4) as an annulus around the fovea was unexpected and represents an exciting
step forward in our understanding of MME. This is a result that has only recently been found by others.
6, 11
Our approach could be improved in several ways including increasing the size of the training data and
improving the quality of the human rater segmentations. While the features we used worked well, incorporating
more local information can help reduce the identication of smaller pseudocysts. However, there is some debate
as to whether these are false positives or failures on the part of our raters. In addition, the apparent spatial
distribution of the pseudocysts (Fig. 4) informs us that we do not expect to nd pseudocysts outside of an annulus
around the fovea. This information could be included in the classication.
Future work includes expanding our algorithm to other scanner manufacturers and a comprehensive study of
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the longitudinal behavior of MME. From this future work, a better understanding could be provided about these
pseudocysts; we will be able to learn more about the mechanisms by which these pseudocysts appear in addition
to their changes with disease progression and severity.
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