Download Optical Coherence Tomography and Advanced Fundus Imaging

Optical Coherence Tomography and Advanced Fundus Imaging
©Gillian J. McLellan, BVMS, PhD, DECVO, DACVO, DVOphthal, MRCVS
Assistant Professor in Comparative Ophthalmology
University Of Wisconsin-Madison
Objectives:
1) To provide an overview / review of the theoretical basis of confocal Laser Scanning
Ophthalmoscopy (cLSO) and Optical Coherence Tomography (OCT)
2) To evaluate and discuss the practical clinical and research applications of cLSO and
OCT in comparative ophthalmology
I.
Introduction: Advanced Imaging of the Ocular Fundus
 Confocal Laser Scanning Ophthalmoscopy (cLSO) and Optical coherence
tomography (OCT) are non-invasive, non-contact optical imaging
techniques capable of producing high resolution images of the retina and
optic nerve head.
 These images provide information that is useful for following the
progression and / or resolution of posterior segment disease longitudinally.
 Clinical investigation of disorders of the human fundus, including
maculopathies and glaucoma, increasingly utilizes a “multimodal imaging”
approach.
 While many of these advanced imaging techniques remain within the
research domain in other species, as their cost progressively declines,
veterinary ophthalmologists should be familiar with these technologies and
their limitations.
II.
Confocal laser scanning ophthalmoscopy, first described in the 1980s, provides
detailed, high resolution images of the fundus.[1]
 The laser is projected into the eye as a narrow beam, typically occupying
just 1 mm of the pupil. As this leaves a large area of the pupil available for
the reflected light from the fundus to pass through, imaging low light
intensities is possible. Capturing images through a confocal aperture,
essentially a “pinhole effect”, greatly enhances contrast. Such a narrow
illumination beam can also be positioned to minimize the detrimental, lightscattering effect of opacities in the ocular media.[2]
 The laser is typically directed in a raster pattern (i.e. an x-y matrix of
parallel lines), providing 2D images.
 The light is monochromatic and resulting images are also monochromatic,
although pseudo-color mapping may be produced by instrument software.
 By varying the wavelength of the laser used, imaging can be carried out at
those wavelengths that give most information on structures of interest, for
example, by using an infrared laser to image structures deep in the fundus.
 When cLSO laser of very specific wavelengths (e.g. blue to excite
fluorescein, or near infra-red for indocyanine green) are combined with
specific barrier filters, it becomes possible to visualize fluorescent-labelled
cells in the retina in vivo; angiographic studies are enhanced and fundus
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IV.
auto-fluorescence can be documented in vivo (e.g. lipofuscin within the RPE
or Bruch’s membrane).[3]
Various modifications of cLSO technology have led to instruments (some
combining multiple imaging modalities) that can provide different, often
complementary, information about structure or physiologic properties of the
fundus.
The Heidelberg Retinal Tomograph (HRT)
o provides detailed structural information that has been widely used to
study optic nerve head topography longitudinally in human
glaucoma patients.[4]
Fundus Autofluorescence (FAF)
o FAF imaging, first reported in the mid-1990s,[5] is now widely
utilized in the investigation of macular diseases in human patients.
o A blue laser optimally excites the autofluorescence of lipofuscin and
is combined with a broad band pass barrier filter with short
wavelength cut-off at about 520nm.
o As in conventional fluorescein angiography, intrinsic fluorescence of
the tapetum complicates cLSO imaging and auto-fluorescence
detection. Presence of this highly reflective structure also impacts
the quality of cLSO images by increasing back-scatter.
o However, fundus autofluorescence imaging is still of value in tapetal
species, as demonstrated by the ability of a prototype cLSO to
detect and track the accumulation of autofluorescent lipopigment in
dogs with vitamin E deficiency retinopathy,[6]
o Imaging of FAF has also been applied to mouse models of retinal
disease.[7]This modality is now often incorporated in commercially
available fundus imaging platforms, e.g. the Heidelberg Spectralis
HRA + OCT (see below).[8]
o
Additional modifications to cLSO technology include wide-field fundus
imaging. In addition, a number of instruments (based on both cLSO and
OCT platforms) are now available that incorporate the Doppler principle,
allowing ocular blood flow to be studied.
Optical Coherence Tomography
 (OCT) technology, first developed in the 1990s, now allows the acquisition
of 3D data sets that provide exquisitely detailed cross-sectional images,
approaching in vivo histopathology. [9-12]
Modifications in OCT technology allow high resolution imaging of anterior
segment structures as well, including the cornea and anterior chamber angle.[13-17]
OCT Technology:
 The principle of operation of OCT, low coherence interferometry, is broadly
comparable to ultrasonography, except that it uses light rather than sound.
OCT uses the reflectivity of light waves to produce detailed cross-sectional
images of ocular tissues.
 Unlike ultrasonography, which requires direct contact between probe and
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tissues or between probe, coupling medium and tissues, OCT does not
require any contact with the eye (thus avoiding the potential for tissue
compression and/or distortion) and it allows measurement of structures and
distances on the sub- 10 micron scale, versus the 100micron scale of all but
the highest-resolution ultrasonography.
OCT systems combine an interferometer with a low coherence light source.
The optical beam is split and sent to both the sample (i.e. tissue of interest)
and a reference arm (typically a mirror). The light reflected by sub-surface
features of the tissue is collected by an interferometer. Low coherence
optical interferometry involves detection and evaluation of the interference
pattern of light reflected from the reference arm interacting with
backscattered, reflected light from the tissues of interest. The information
obtained about depth and intensity of light reflected from a sub-surface
feature is, in turn, utilized to determine spatial dimensions and location of
structures within the tissue of interest. These intensity profiles (the axial or
A-scans) are then laterally combined to create a transverse, detailed crosssectional image. [9, 11]
The first widely used commercial OCT system was the Stratus OCT 3 (Carl
Zeiss Meditec, Inc.). This system uses time domain (TD-OCT) technology
in which the position of the reference mirror is changed and reflected
intensity signals are detected from the sample at different depths,
sequentially, based on “time of flight” / echo time delay. Since the signals
gathered are time-encoded, the system is referred to as a time domain.
Newer systems use broadband light sources and gather all backscattered
frequencies simultaneously, using a spectrometer as the reference mirror
remains stationary.[18-20]. The signal is then analyzed using Fourier
analysis, a mathematical transformation in which spatial frequencies are
processed to isolate individual components of compound waveforms. This
method enables recognition of patterns and mapping of the form of objects,
essentially expressing data as a frequency spectrum, with each frequency
corresponding to a different tissue depth. These systems are referred to as
spectral domain (SD-OCT) or Fourier domain (FD-OCT).
Axial resolution and scan acquisition speed are both dramatically improved
with SD-OCT. For example, TD-OCT systems may capture 512 A-scans in
1.28 seconds and provide an axial resolution of 10 microns. In contrast SDOCT systems generally capture many more A-scans in a fraction of a second
(a rate of 20,000 - >70, 000 per second in the latest instruments) and have an
axial resolution of ~ 2-5µm (transverse resolution is “only” ~ 10-15µm).
The higher resolution and denser sampling of SD-OCT increase its
diagnostic utility, allowing detection of smaller, more subtle morphologic
changes and rapid collection of 3D data sets.
The longer scan acquisition time of TD-OCT means that motion artifact can
be a problem, even with relatively small ocular movements. Motion artifacts
are still possible with SD-OCT but the faster scan time can reduce their
frequency. In animal subjects, if quantitative measurement of tissue
thicknesses are needed, heavy sedation or general anesthesia are generally
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required to ensure that the subject is adequately immobilized to limit motion
artifact.
In recent years, a number of different commercially available instruments
have entered (and left) the market. These instruments are reviewed
elsewhere [11, 12, 21]. Rapid developments in OCT technology mean that
the list of available instruments is likely to change markedly over a
relatively short span of just a few years. This rapid evolution may work in
favor of veterinary clinicians!
V. Pathology, Longitudinal studies and Reproducibility/ Reliability
The distinct layers, visible as alternating bright-dark signals, in cross-sectional images of
the retina obtained by OCT in vivo, can be correlated with retinal layers that are
histologically identifiable on light microscopy.[12, 22-27] The number of distinct retinal
“layers” that are routinely detectable on OCT images varies with species and instrument
(cat retina shown below).
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Optical coherence tomography can provide valuable information regarding
progression or resolution of diseases or injuries. The location, progression
and/or resolution of retinal pathology can be followed longitudinally.
Posterior segment lesions identified on ophthalmoscopy and/or fundus
photography can be better characterized with OCT, which more clearly
identifies which retinal layers are involved[28, 29].
Reproducibility and reliability are central to the use of OCT in
longitudinal studies and have been demonstrated in a variety of macular and
optic nerve indications in humans and in animal models [30-34]
Reproducibility of results depends on understanding the nature of artifacts
that can affect quantitative and qualitative assessment of the OCT data .[35]
It is possible to acquire high quality scans in most species but the range of
normal variation within differing species has not been well-defined and
reproducibility of measurements must be determined for each subject
population and instrument.
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In longitudinal studies, the effects of age on thickness values must be taken
into consideration. For example, in humans, RNFL thickness parameters
decreased significantly with increasing age.[36] This effect of age may be
less of a concern in short term studies in laboratory animals. However, in
clinical practice, as many of the animals that present with retinal or optic
nerve disease are middle aged or order, age-matched control animals should
be evaluated concurrently, if possible. Although no significant age-related
decline in mean RNFL thickness value was identified within a cohort of 16
normal cats ranging in age from 6 months to 6 years,[37] the potential for an
effect of aging should still be considered when conducting long-term
longitudinal studies.
Deriving quantitative measurements from OCT instruments is hindered by
software algorithm errors in detecting the edges of the distinct retinal layers
(segmentation). These segmentation errors occur in scans of human eyes as
well in other species and arise with similar frequency with each of the
different OCT instruments. Fortunately, most instruments have software
features that allow these manual corrections to be made and several also
have 3-D and en face visualization features to facilitate qualitative
assessments. Manual segmentation methods to derive optic nerve head and
other structural indices have been developed for several species, as have
custom segmentation algorithms.
Practicalities of Image Acquisition in Animals:
 Globe immobilization, alignment and pupil dilation
o Movement artifact should be minimized. In addition, angle of
scanning can impact scan quality and quantitative measures. Options
to help maintain a central, immobile eye for scanning include
neuromuscular blockade,[38] retrobulbar saline injections, or
retrobulbar local anesthetic block. [39] Manual rotation and fixation
of the globe to facilitate scanning may be achieved with forceps or
atraumatic conjunctival clip electrodes. [40] A combination of
ketamine and xylazine provides optimal scanning conditions in cats.
o Some instruments’ software packages offer an “alignment tool” that
can compensate for changes in blood vessel orientation. The latter is
of great importance during longitudinal studies to detect changes in
RNFL thickness values for different quadrants or sectors of the peripapillary region, particularly as retinal blood vessels tend to be colocalized with thicker bundles of ganglion cell axons.[41]
o Although it may not be necessary for scanning in larger species,
application of a mydriatic, such as 0.5-1% tropicamide, is generally
recommended (and is necessary for rodents)
 Clear ocular Media
o Even minimal cataract, corneal opacity, inflammatory cells, flare or
hemorrhage within aqueous or vitreous can compromise the image
quality, resulting in areas of signal drop-out. Remember that OCT
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is an optical imaging technique, and opacity may even preclude
image acquisition.
Corneal Hydration
o Corneal desiccation should be avoided as this will negatively impact
optical clarity of the cornea and scan quality.[42]
o Frequent application of a topical wetting agent (e.g. balanced salt
solution, or 0.5% carboxymethylcellulose) is helpful.
o When imaging multiple subjects of the same species, perhaps the
best solution is to use plano, rigid gas permeable contact lenses that
have been manufactured to conform to the approximate corneal
curvature and diameter of the particular species to be imaged.
Combination with other Test Procedures:
o In studies that collect multiple structural and functional measures,
e.g. ultrasonography, fundus or gonio- photography and
electrophysiology, care should be taken during and between
procedures to avoid any corneal drying or epithelial surface damage
(see above).
o Consider separating studies into different sessions depending on the
compatibility of procedures. For example, as this is an optical
imaging technique, any electrophysiological tests should be
conducted prior to OCT imaging. However, the corneas could
potentially be compromised by prior application of ERG contact lens
electrodes or drying during the ERG procedure, and image quality
can suffer.
o When evaluating ONH parameters in glaucoma subjects, intraocular
pressure (IOP) should be measured prior to and at the conclusion of
the scanning session, taking into potential effects of mydriatics on
IOP. [43] If possible, IOP should be within the normal range when
scans are acquired to limit corneal edema and reversible “cupping”
due to tissue compliance that can both confound quantification of
ONH morphologic parameters. [44]
Species-specific considerations:
OCT scanning can be accomplished in a wide variety of animal species. However,
each species presents its own challenges [12]:
 Dogs and cats
o The presence of the reflective tapetum lucidum in these species may
require adjustment of scan acquisition parameters to achieve even
illumination, especially of the fundus reflectance image.
o If a calm, quiet scanning environment is created, minimal use of
sedation may be possible, limiting globe rotation. Anterior segment
scans – e.g. for corneal pachymetry - may be acquired in unsedated
dogs and cats but generally sedation or general anesthesia is
required.[45-49] We have found that heavy sedation or general
anesthesia has been necessary to acquire good quality fundus scans,
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free from motion artifact. Various strategies to maintain a stable,
central eye position have been discussed previously.
o Previous studies in dogs show that whole retinal thickness, RNFL
thickness and photoreceptor layer thickness were all greater in the
superior (tapetal) than in the inferior (non-tapetal) retina.[38] These
authors reported that the thickness measurements on the linear scans
often required manual correction and although the RNFL was
correctly delineated in approximately 60% of the peri-papillary scans
with the automatic software algorithm, the remaining 40% of these
scans had inadequate RNFL delineation. The most common clinical
application for posterior segment OCT with companion animal
species is to assist in the diagnosis and documentation of treatment
efficacy or progression of spontaneous or genetic retinal disease, as
well as glaucoma. Optical coherence tomography has been used in
both dogs and cats in a clinical and research setting to visualize
subretinal implants [50-52]; evaluate disease progression and
response to therapies in retinal degeneration models and patients ,
[53-56] and to evaluate the retina and optic nerve head in glaucoma
models. [37, 57, 58]
Rabbits
o The unique ocular anatomy of rabbits poses a challenge in
positioning, as the optic nerve head and medullary ray are both
situated superiorly.
o The rabbit optic nerve head is quite wide and has a very deep central
cup. Both can be at or near the maximum size capable of fitting in
the scan axial and lateral field of view.
o Using software programs designed for human eye structures will
likely result in unreliable quantitative values, especially for the
RNFL, but most instruments have software features that allow
adjustment of segmentation lines and scan circle placement. [44]
o Custom measurements can be made using caliper features.
o Fewer retinal structures / layers are demarcated by OCT in rabbits,
which may in part relate to optical aberration.
o The merangiotic vascular pattern of the rabbit fundus limits the
number of available landmarks to assist in location of sequential
scans in longitudinal studies, [45] due to an absence of retinal blood
vessels, except for within the region of the medullary rays. [46]
Horses
o The equine subject presents many practical challenges to scanning.
A portable instrument with a hand-held scan-head will enable scan
acquisition in standing, sedated horses. [59, 60]
o Globe size may preclude high quality image acquisition using some
instruments
o At the time of writing, proprietary segmentation algorithms have not
yet permitted automated segmentation of equine OCT scans and
measurements of anterior and posterior tissue thicknesses have been
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conducted manually using the OCT-software caliper function, which
can prove very laborious.
o Qualitative evaluation of ocular lesions may be valuable in a clinical
setting.
 Rodents
o While challenging to scan, the proliferation of mouse models of ocular
disease dictates an increasing need for documentation of retinal and optic
nerve disease and drug effects in the mouse and rat eye.
o The small size of mouse eyes may require use of a corrective lens to
compensate for the small eye and extremely short focal length. Several
commercially available instruments have specific rodent attachments for just
this purpose. For other instruments, a +ve Diopter trial lens can be affixed in
front of the scan head, although this may not prove necessary for rats.
o Rodents should be anesthetized and positioned in a tube (mice) or on a
customized platform or microscope stage.
o Duration of the scanning procedure should be minimized as safety of
anesthesia may be a concern. Reversible cataract formation may impact
outcome if the animal is hypothermic and corneal hydration not diligently
maintained by very frequent irrigation with balanced salt solution, or
application of a methylcellulose based ophthalmic demulcent together with
an appropriately sized plano contact lens or coverslip. [24, 25, 34]
Pigs
o Use of OCT has been reported previously in this species. [61]
o Positioning can be particularly difficult with pigs, including minipigs, given
their size, limited neck mobility and ocular conformation, that includes
small, deep-set eyes and thick eyelids. However, high quality scans for
diagnostic purposes can be acquired.
o As with rabbits, the anatomy of the pig eye is sufficiently different from that
of humans that instrument analysis software may not accurately detect
retinal layers, in ONH scans in particular. Scans must be carefully
examined for errors before tabulating quantitative data.
Challenges/limitations of OCT
 Segmentation
o Recognition and segmentation of retinal layers is an ongoing issue in
OCT image analysis. Each instrument comes with a proprietary
segmentation algorithm that delineates retinal layers in a slightly
different way and uses different layers to calculate macular thickness
values. Thus, instruments cannot necessarily be used
interchangeably. Thickness values generated by the software cannot
often be compared across instruments or even between different
iterations of OCT instruments made by the same company.[35, 6266]
 Segmentation errors and other errors impacting thickness calculations
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o The most common segmentation error in animal models is
misidentification of the outer retinal layers, whereby the softwaregenerated segmentation line does not follow the contour of the RPE.
o Inner retina misidentification is much less common but can occur
when debris in the vitreous is reflective enough to be identified as
the inner limiting membrane (ILM).
o The percentage of scans with segmentation errors is likely to be
greater in subjects with a relative lack of pigment in their RPE and
choroid. These errors seem to occur with greater frequency in
macular cube scans and are an important consideration as subalbinotic and albino animals are commonly utilized in laboratory
studies. These errors may in part be due to enhanced visualization of
choroidal structure (leading to visualization of additional surfaces) or
to increased back-scatter of light. [67]
o Off -center fixation, a source of segmentation artifact in humans
[35], can occur in animal imaging as a byproduct of eye movement
and often results in inaccurate thickness measurements of the area
centralis or fovea. In animal subjects operator skill is required to
compensate for lack of fixation.
o In addition, the circle defining the optic nerve head may not be
centered and the line signifying the RNFL layer may be inaccurately
drawn.
o Different instruments also have different methods of compensating
for segmentation errors and other software inaccuracies. While most
instruments allow manual segmentation of the line delineating the
RPE and RNFL, the time required might be prohibitive.
The scan angle should also be evaluated, as tilted rather than “flat” scans
indicate that the retinal or ONH surface was not perpendicular to the
scanning beam, as is assumed in thickness calculations. [68]
All of these image problems affect the numeric thickness values, so if
quantitative data is important, inclusion / exclusion criteria need to be
defined and each scan carefully evaluated.
o While artifacts such as RPE and ILM layer segmentation errors and
decentration can often be overcome using the manual adjustment
features present in most SD-OCT software, artifacts such as scan
registration errors still demand operator skill to identify so that scans
can be re-acquired.[69]
 Most OCT instruments have a circular scan designed to measure RNFL
thickness around the optic nerve head. The fixed size (3.4-3.5mm
diameter) and round shape of the circle scan is designed for humans and
it may not accurately reflect the RNFL anatomy of other species.
o Even if the circle is not sized appropriately for the subject species,
the images may still allow qualitative assessment and may still be
useful for assessing longitudinal change.
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o Thickness values for the RNFL are dependent on the location of the
OCT scan circle so registration of scans is essential for thickness
measurement reproducibility and longitudinal examination.[70, 71]
Opacities in the ocular media, including cataract and corneal lesions can
have a profound effect on signal strength and contribute to areas of signal
dropout that are often associated with errors in segmentation.
Myopia and globe axial length can also affect the incidence of scan artifacts
as well as reducing RNFL thickness values and altering thickness sectoral
distribution in humans. [72-74]
General scan quality, reproducibility and segmentation accuracy may be
negatively impacted by ocular diseases such as glaucoma or uveitis. [75]
Although in many cases this impact is minor and can be overcome by
operator skill so that OCT images of diagnostic quality may still be
obtainable, the resulting images should be evaluated carefully for the
presence of artifacts and segmentation errors before accepting quantitative
data derived from them.
Segmentation algorithms
o Proprietary segmentation algorithms are subject to ongoing
refinement for all of the OCT instruments and a number of research
groups are also working on enhancing segmentation algorithm
accuracy and thus quantitative analysis via computer-aided grading/
retinal boundary detection methodologies. [76-78]
o In some situations, the implications/nuances of the data are better
captured by creation of a unique, custom algorithm or manual system
of measurement. [79-82]
o Manual segmentation, although more subjective and laborious, can
be carried out using freely available image analysis software.
Significant inter-observer variability generally mandates evaluation
of scans by a single, consistent observer.
Scan quality
o Each OCT instrument has a unique method of assessing scan quality.
o Most use a combination of intensity level of the signal along with the
uniformity of the signal within a scan.
o Scans should be evaluated by the operator during the scanning
session, to ensure that scans at least meet pre-determined
requirements for signal strength and absence of areas of signal drop
out.
o Similar to the situation in human glaucoma patients, we have found
that mean RNFL thickness in cats is significantly affected by scan
signal strength, and this effect should be taken into account when
comparing numeric values between scans of different quality.[83,
84]
Adaptive Optics
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Adaptive optics systems, first applied to retinal imaging in the late 1990s,[85] provide
the highest resolution images of fundus structures.
Using wavefront sensing techniques, similar to that used in astronomy, the
aberrations of the eye are measured and can be corrected for using a complex system
of lenses and deformable mirrors.
With <2µm lateral resolution, these systems make it possible to visualize, in vivo, the
photoreceptor mosaic, nerve fibers and flow of blood cells within retinal capillaries.
With the use of adaptive optics, it is possible to improve the resolution of a scanning
laser ophthalmoscope. Roorda et al (2002) described the first SLO to use adaptive
optics to measure and correct the higher order aberrations of the eye.[86]
Although mainly restricted to research applications, adaptive optics systems are now
available commercially and applicability of a flood-illumination, fundus camera
adaptive optics system in cats has been reported in the veterinary literature. [40]
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