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29 Microperimetry
https://t.me/med1917
Fig. 29.4 Aligning microperimetry with a scanning laser
ophthalmoscopy (SLO) image to measure retinal sensitivity in diabetic macular edema (in decibels). The microperimetry image is superimposed onto the color fundus
image in a case of clinically signicant diabetic macular
edema. A decrease in retinal sensitivity is seen on the temporal side of the macular region (Reprinted with permission from Midena E, and Vujosevic S [35] Copyright
2011, Saudi Ophthalmological Society; Elsevier)
collect data on live eye tracking and to measure
macular sensitivity quantitatively [41]. Of these,
the Natural History of the Progression of Atrophy
Secondary to Stargardt’s Disease (ProgStar)
studies comprise the largest collection of data
evaluating the progression of this disease [42].
Macular sensitivity loss under mesopic conditions has been reported in Stargardt using data
from microperimetry [42]. Findings from the
ProgStar studies revealed a clinically signicant
annual change in macular sensitivity of −0.68dB
per year using an MP-1, [42] which was not much
lower than the −1.19dB/year change reported by
others [42]. The stability of xation remained
unchanged. Unlike previous studies that have
reported associations between early disease
onset, long duration, and increasing age with
unstable xation, lower sensitivity, and higher
scotoma count, the ProgStar 12-month follow-up
study only showed a change in the number of
deep scotomas with a decrease in macular sensitivity [42]. The mean reduction in light sensitivity was higher with increasing distance from the
fovea, considering the number of regions tested.
Following these reports, the Scotopic
Microperimetric Assessment of Rod Function in
Stargardt’s Disease (SMART) study also used
microperimetry to assess macular function loss
395
under scotopic conditions [41]. Data from this
study suggested that the loss of scotopic macular
function occurs faster (−1.42 dB/year) than
mesopic (−0.63dB/year) macular function in the
extrafoveal region, potentially making it a more
sensitive outcome measure. As rods progressively decline from the fourth decade of life,
studies on AMD have shown dark-adapted dysfunction that can be attributed to the rod system
[43]. Although AMD and STGD1 differ, overlapping pathogenic features linked to light exposure
suggest potential benets in testing scotopic
visual function using microperimetry for both
conditions. As such, specic therapies can have
selective effects on the rod versus cone system.
Other studies have continued to evaluate the progression of STGD1 using microperimetry. In
some of these, high spatial density sampling was
used for the functional evaluation of the transition zones between the centrally diseased retina
and the less diseased pericentral retina [44]. This
may allow for faster detection of the transition
zone if there is a statistically signicant
expansion.
As it most commonly affects children, microperimetry in STGD1 may be challenging to perform in less cooperative patients. However,
studies have demonstrated reliable microperimetry values in children above 9years of age [45].
Challenges with attentiveness and xation can
reduce or remove this reliability. Further studies
are needed on optimizing grids, alignment, and
eye-tracking systems for accurate co-registration
of the retinal examination modalities and
microperimetry.
29.5.4 Retinitis Pigmentosa
Retinitis pigmentosa (RP) constitutes a group of
retinal disorders that typically presents bilaterally
and is caused by mutations in the RPGR gene.
This condition clinically manifests as nyctalopia
due to rode-cone dystrophy, followed by a narrowing of visual elds. Visual acuity is typically
preserved due to its dependence on the central
fovea. Consequently, BCVA is inadequate in
monitoring the progression of this set of diseases.
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K. R. Grimes and J. Chhablani
Instead, microperimetry can be used to isolate the
function of rods versus cones by altering background luminance within the photopic (cone
function), mesopic (mostly cone function), and
scotopic (rod function) ranges. By evaluating rod
and cone function throughout the natural history
of the disease, the disease response to novel therapies can be compared under mesopic and scotopic conditions.
Data collected in the Photoreceptor Cell Death
in Retinitis Pigmentosa Retrospective (PREP-1)
study assessed visual acuity, xation stability,
and mean and regional sensitivity annually over
1–4years [46]. Although no signicant changes
were detected in visual acuity or xation stability, all retinal sensitivity parameters showed a
signicant decline in mean sensitivity of 0.4dB
per year [46]. In this study, the functional features
of test loci directly adjacent (horizontally or vertically) to the point of absolute scotoma were
measured and referred to as the “edge of scotoma” (ES).Other studies have also used MAIA
microperimetry to measure ES sensitivity in
USH2A retinopathy and have proposed that the
greater rates of decline present in ES with a
greater area of retinal coverage may require
shorter trial periods to optimize the detection of
change [28]. The USH2A-related Retinal
Degeneration (RUSH2A) study compared microperimetry with spectral domain OCT and found
that longer disease duration was correlated with
more severe retinal structure and function abnormalities such as smaller ellipsoid zone (p<0.001)
and lower mean sensitivity (p<0.01) [47].
29.5.5 Other Clinical Applications
ofMicroperimetry
Microperimetry has been widely used to study
many retinal disorders in addition to those mentioned in this chapter. This technique has been
used to characterize scotoma features in a large
cohort with macular telangectasia type 2
(MacTel) as a part of the MacTel Project [48].
Additional studies have used microperimetry to
detect anatomical and functional changes in
patients with macular epiretinal membrane, mac-
ular hole, choroideremia, retinal detachment,
retinal vein occlusion, and vitreomacular traction, among others.
29.6 Conclusion
In summary, continuous visualization of the retina
using microperimetry allows for (1) the detection
of retinal sensitivity in people without stable xation, (2) the relationship between structure and
function, and (3) improved retest reliability at the
same location [7]. As a precise diagnostic technique, microperimetry allows the visualization of
the 5mm diameter of the central area of the retina,
and small scotomas can be detected. These “blind
spots” would otherwise go unnoticed if the retina
was visualized using conventional tests.
Microperimetry can be a valuable tool for evaluating retinal and macular function, and the eld has
made great progress over the past 50 years.
Current studies have demonstrated the practical
applications of this tool in detecting disease onset
and progression. However, further research is
needed to address present challenges before it
becomes a part of routine clinical examinations.
Funding None.
Disclosure None.
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Adaptive Optics
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30
KaraR.Grimes andJayChhablani
30.1 Introduction
Adaptive optics (AO) is used for invivo visualization of individual cells in the retina; historically, this was only possible using in vitro
histological methods. Today, AO imaging systems use active optical elements to correct wavefront aberrations in retinal technologies such as
the ood-illumination fundus camera, scanning
laser ophthalmoscopy (SLO), and optical coherence tomography (OCT). This tool also provides
advanced lateral resolution, which facilitates the
visualization of photoreceptors, retinal vasculature, and the optic nerve head. This chapter will
highlight the history, technology, techniques, and
application of AO, as well as the advantages and
limitations of implementing AO imaging in a
clinical setting.
30.2 Brief History ofAdaptive
Optics
The principles of AO were devised by the astronomer Horace Babcock in 1953. This wavefront
technology was rst applied to astronomy to
K. R. Grimes
New York Medical College, New York, USA
J. Chhablani (*)
Department of Ophthalmology, University
of Pittsburgh, Pittsburgh, PA, USA
measure distortions in atmospheric light that
caused a severe blurring of the images of distant
stars captured by the telescope. Images of stars
could be rened with diffraction-limited performance through AO [1]. These principles were
then used later to correct imperfections in ocular
imaging.
In the early 1980s, AO systems were developed to study the human eye with closed-loop
controls. These systems helped eliminate aberrations from the eye—such as astigmatisms of
the cornea—and made it possible to resolve
individual receptors on the fovea. Further
research and investigations in the following
decade led Liang et al. (1997) to apply these
principles to retinal imaging and overcome
higher order aberrations, thereby “providing
normal eyes with supernormal optical quality.”
[2] Using AO with Shack- Hartmann wavefront
sensors and deformable mirrors, Liang et al.
(1997) could visualize single cells in a living
human retina [2]. Soon after, AO was used to
visualize retinal blood vessels by Burns et al.
(2002) and assess cone-rod dystrophy by Roorda
(2000) [3, 4]. Currently, AO technology is used
to visualize and understand the pathophysiology
of diseases that affect the retinal vasculature,
individual photoreceptors, retinal pigment epithelial cells, and ganglion cells; it is also used to
monitor cellular-level responses to therapeutic
interventions.
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2024
T. Das, P. Satgunam (eds.), Ophthalmic Diagnostics, https://doi.org/10.1007/978-981-97-0138-4_30
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30.3 Technology
Optical or wavefront aberrations are irregularities
in the eye that can lead to distorted images and
decreased visual performance. In recent years, AO
has been used to create various measurement
devices to assess the refractive properties of the eye
[5]. To obtain images with improved resolution and
sensitivity, most AO-based devices must contain
three main components (Fig.30.1), namely,
1. Wavefront sensor—It is required to measure
ocular aberrations. The apparatus will direct a
small beam of light into the eye that backscatters off the retina. The resulting light that leaves
the eye will be aberrated by the optics of the
eye and measured by the wavefront sensor. The
most common method for measuring ocular
aberrations is with the Shack- Hartmann wavefront sensor, which uses a microlenslet array.
2. Wavefront corrector—Typically, it is a
deformable mirror based on electromagnetic
actuation that can alter its shape to compensate for the measured aberration.
3. Controller—The control system is a computer
that regulates the interaction between the
wavefront sensor and the wavefront collector.
The controller can measure and compute signals for the wavefront corrector using the
appropriate software.
30.3.1 Quantitative Measurement
ofOcular Aberrations
The angular resolution and efciency of light collection of the optical system are improved with
AO.Mathematically, the wavefront aberrations in
human eyes are dened by Zernike polynomials.
This method classies the shape of aberration
Fig. 30.1 Schematic diagram of an optics-assisted retinal
imaging system. The aberrated wavefront is measured
using the wavefront sensor (a), and the system compensates for the aberration using a wavefront corrector (c).
a
c
b
The wavefront sensor and corrector are connected by a
control system (b). (Reprinted with permission from Gill
etal. [6] Copyright 2022, Springer Nature)
R
A
RMS
=−
−
()
1
NA nsin=
()
θ
rNA=
./
λ
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401
maps as the sum of fundamental shapes or basic
functions and can be further classied into lower
order or higher order aberrations. Lower order
aberrations make up a majority of aberrations
that can be corrected with glasses, contact lenses,
or refractive surgery (e.g., myopia, hyperopia,
and astigmatism). Higher order aberrations are
more complex and can contribute to nyctalopia,
glare, and halos. This phenomenon of aberration
is simplied into a single number using AO
through the calculation of root mean squares
(RMS), as described by Jayabalan et al. (2019)
[1]. The RMS wavefront error is calculated
directly from the Zernike polynomials to nd the
mean squared value of the wavefront over the
pupil. In this equation, A is the area of the pupil,
and
is the mean wavefront optical path differ-
ence to dene RMS:
WxyWdx dy
,
()
MS
∫∫
=
2
−
Additionally, the optical aberration index
(OAI) is calculated to determine if the optical
system is perfect (OAI=0) or has innite aberrations (OAI=1). The OAI is calculated using the
RMS value and is dened as:
The point spread function and modulation
transfer function are also calculated to measure
imaging waves from a point source and to characterize the resolution of an imaging system,
respectively [6]. AO can resolve rods and cones
in the retina to 2μm, but there is a substantial difference in determining cones over rods; cones are
better resolved, while rods are not, likely due to
their smaller size [7]. Typically, the resolution of
an imaging system is set by the numerical aperture (NA) of the system, which is dened as:
Where n is the index of refraction of the
medium and θ is the angle viewed from the retina
subtended by distance from the center of the
pupil to the pupil margin [8]. The resolution (r)
of AO imaging systems is determined using
wavelength (λ) and numerical aperture (NA) and
is dened as:
061
The numerical aperture is about 0.23 for a
maximally dilated pupil.
30.4 Technique
30.4.1 Retinal Imaging
Imaging the retina using AO is non-invasive but
requires a pupillary diameter of at least 4 mm.
Most systems require the patient to be positioned
comfortably on a conventional chin rest and
focus on an internal xation target. The target can
be moved according to the area of interest. Using
combined software approaches, this area will
then appear on the graphic display, and microscopic structures, such as photoreceptors, may be
brought into focus. A template image is used to
track relative ne-scale motions of the eye that
are captured in each frame of the video [9]. The
software will acquire multiple images, of which
those with the best contrast are selected and
summed together using an auto-correlation algorithm to generate one image [10]. Images with a
high signal-to-noise ratio tend to stabilize best
[8]. The nal image will remove the computed
image from the background and be adjusted for
brightness and contrast.
30.4.2 Types ofAO Imaging Systems
An AO system does not work as a standalone system but operates as a subsystem that must be
incorporated into an imaging device. Devices
such as SLOs, fundus cameras, and techniques
such as OCT have revolutionized invivo retinal
diagnostics to provide a macroscopic view of the
retina; this has been invaluable in diagnosing and
monitoring the progression of retinal diseases.
However, these technologies lack the transverse
resolution required to view microscopic retinal
structures. Multi-modal imaging combining AO
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K. R. Grimes and J. Chhablani
technology with SLO, OCT, and fundus camera
systems enables high-delity correction of ocular
aberration.
30.4.2.1 Adaptive Optics andFlood-
Illumination
Ophthalmoscopy (AO-FIO)
Fundus photography captures images of the retina in which the illumination and reectance of
the retina occur through the pupil. When combined with AO, ood-illumination ophthalmoscopy (AO-FIO) enables detailed retinal imaging
by illuminating the retinal layers with backscattered light. In this technique, a light-emitting
diode (LED) is used to illuminate the pupil uniformly, and a guide star (typically a super luminescent diode or SLD) is used to measure and
correct aberrations, which are then imaged with a
retinal camera.
Using AO-FIO, the contrast is improved, and
scanning mirrors are not required to obtain
images of retinal microstructures. These images
are also acquired in a relatively short time (<10s),
which minimizes the effects of eye movement
and operates much faster than the AO-OCT technique. This is especially important when xation
capacity is reduced by retinal disease.
Additionally, changing the focus of the camera
allows imaging of different layers of the retina by
introducing a quadratic phase shift on the deformable mirror [11]. The focus can be calibrated by
calculating the average distance between the photoreceptors and the retinal layer of interest [12].
30.4.2.2 Adaptive Optics
andScanning Laser
Ophthalmoscopy (AO-SLO)
The AO-SLO system uses confocal laser scanning microscopy to reduce artifacts due to eye
motion. In doing so, AO-SLO captures highresolution motion video of the posterior chamber
of the eye using a fast-scanning ophthalmoscope.
The advantage of AO-SLO over conventional
fundus imaging methods is that it provides a noninvasive method to obtain higher transverse resolution and closer observation of the retina [13].
This technique uses two scanners (one horizontal and one vertical) that are directed to the
eye with a photodiode used as the wavefront
sensing source. A Shack-Hartmann wavefront
sensor and deformable mirror are also present in
the optical path for optical aberration correction.
Due to its high transverse resolution, this technique can identify/image microscopic structures
such as individual photoreceptors, the ganglion
cell layer, micro capillaries, and blood ow.
AO-SLO systems can be combined with
AO-OCT systems, which obtain images at slower
rates (typically several seconds) to create a threedimensional image. These techniques can be combined with fast-motion videography to capture any
eye motion that can be processed post- capture to
stabilize the blurring effects that arise during the
slower process of capturing AO-OCT images.
30.4.2.3 Adaptive Optics andOptical
Coherence Tomography
(AO-OCT)
Since OCT provides a scan of the volume of the
retina, the combination of AO and optical coherence tomography (AO-OCT) leads to a high
transverse and axial resolution. This enables
invivo three-dimensional imaging of cells within
the retina with both transverse and axial resolution as small as 2–3μm, allowing the imaging of
individual retina layers [13].
The technique used in AO-OCT is known as
low-coherence interferometry, in which a beam of
low-coherence light directed at a surface sends
reected light to an interferometer. The major
advantage of AO-OCT, when compared to
AO-FIO and AO-SLO, is that the axial resolution
is determined by the coherence length of the light
source and is independent of the system’s NA
[14]. Additionally, OCT can detect subwavelength
changes in the optical path length in the retina that
are orders of magnitude smaller than the axial
resolution [14]. The benets of this technique are
valuable in studying the pathophysiological process of retinal diseases at the cellular level.
30.4.2.4 Wavefront Sensorless
Adaptive Optics (SAO)
In the SAO system, the deformable mirror is not
controlled by the measurements of a wavefront
sensor; this technique was created to simplify the
AO setup. Therefore, SAO uses an adaptive control method of the deformable mirror to determine
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the aberration and correct turbulence-degraded
imaging. Using SAO, the image quality is directly
optimized based on the modal deformation of the
deformable mirror. The adaptive element is controlled by the image quality metric and search
algorithm to change the shape of the mirror [15].
As a result, a compensated wavefront image and
fast-adaptive wavefront correction are generated.
The SAO systems have been widely researched
in recent years and have been used to study free-
space optical communication, inertial connement
fusion, and microscopy. This technique simplies
the optical hardware in AO and reduces equipment
costs since the sensor, coupler, and many relay mirrors are not required. However, it requires rapid
estimation of the objective function to focus on
specic tissue layers. Further applications of SAO
have led to the development of handheld AO-SLO
systems that enable invivo imaging of cone photoreceptors (Fig. 30.2) [16]. Handheld systems can
also capture retinal images in infants, whereas conventional AO-SLO systems are limited to patients
sitting upright and xating for several minutes.
30.5 Clinical Application
andInterpretation
Retinal imaging using AO systems allows the
direct observation of microscopic structures in
the retina. En-face images of the retinal layers
show the photoreceptor, retinal vasculature, and
retinal nerve ber layers (Fig.30.3). Additional
image processing methods can be used to improve
the quality of these images, and automated routines are continuously being researched to rene
the efciency of these systems.
Fig. 30.2 Rendering of the internal skeleton of a handheld sensorless adaptive optics (SAO) system.
Dimensions: 10.3cm×5.3cm×14.4cm (Reprinted with
permission from DuBose etal. [16] Copyright 2018, The
Optical Society)
a
Fig. 30.3 Retinal images obtained using an adaptive
optics (AO) system with adaptive compensation of the
photoreceptor layer (a), vasculature (b), and retinal nerve
ber layer (c). Scale bars represent 50μm. Images were
30.5.1 Healthy Eyes
The early uses of healthy eyes visualized with
AO systems included generating a standardized
captured using a ood-illumination AO retinal camera.
(Reprinted with permission from Lombardo et al. [24]
Copyright 2013, used under the Creative Commons
Attribution 3.0 license)
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K. R. Grimes and J. Chhablani
or normative database. Therefore, any deviations
from the norm can be used in clinical practice to
describe pathologies. As the techniques using AO
continue to improve, additional imaging of
healthy eyes is needed to dene the evolving
norm. Data from healthy eyes are fundamental
for characterizing the density, spacing, and
brightness of healthy photoreceptor cells invivo
and have been extensively studied in recent years
[17, 18]. The AO-OCT system has been used to
compare rod and cone morphology in healthy and
pathologically aged eyes, revealing the differences in the photoreceptor mosaic. Other studies
have used AO-SLO due to its superior spatial
resolution compared with perimetry or OCT, to
compare retinal nerve ber bundles in healthy
and glaucomatous eyes and the density of foveal
cones in healthy eyes and eyes with central serous
chorioretinopathy [19]. The following section
will discuss some of these.
30.5.2 Age-Related Macular
Degeneration (AMD)
Age-related macular degeneration, or AMD, is
characterized by the progressive degeneration of
photoreceptors and adjacent tissue and the accumulation of extracellular deposits known as drusen bodies in the retinal layers. These
characteristics of AMD, in addition to changes in
the retinal pigmented epithelium (RPE), can be
monitored using AO systems. The promising
contributions of AO systems to the diagnosis,
monitoring, and research on AMD have helped in
exploring the pathophysiology of this condition,
identifying novel features in AMD, studying the
progression of atrophy, and examining responses
to new treatments, particularly for dry AMD.
The AO-FIO system has been used to detect
differences in the four main drusen phenotypes:
soft drusen, hard drusen, cuticular drusen, and
reticular pseudodrusen [20]. Although these drusen bodies are composed of similar components,
they are distinguishable through AO imaging due
to differences in optical ltering effects, location,
and morphology. Research on drusen bodies has
also demonstrated that smaller drusen bodies
(<30 μm) were more readily detected in gazedependent AO images [20] than larger drusen
deposits (>30μm) that could only be seen clinically in fundus photographs. In addition to
AO-FIO, AO-SLO has also been used to visualize
cone photoreceptors, and these techniques have
been used to monitor changes in cone reectivity
with AMD progression [21]. These systems can
therefore be used as additional imaging modalities to study visual function in AMD in clinical
trials.
Foveal sparing is often observed in AMD
when an “island” of intact RPE persists under the
fovea amid RPE atrophy. In these cases, slight
progression of RPE atrophy towards the fovea
can cause severe vision loss. Using AO-FIO,
these sensitive areas can be delineated by identifying differences in reectivity between regions
of atrophy and foveal sparing.
The late stage of dry AMD, during which geographic atrophy occurs, is characterized by the
degeneration of RPE cells and photoreceptors. As
AMD progresses, hyporeective foci and extensive melanin redistribution occur on OCT angiography (OCTA) and fundoscopic examination,
respectively [22]. In AMD, hyporeective foci
are located in atrophic areas and are dispersed
along the RPE monolayer. Although functionally
and phenotypically normal RPE mosaics can be
visualized with current cell culture technology,
AO imaging offers useful support in colocalizing
lipofuscin and melanin in the transition to
geographic atrophy in AMD [23]. The AO system
is not yet routinely used to study AMD, but it is
useful for visualizing the fate and morphology of
individual RPE cells. This can be useful for identifying the origin of hyporeective foci. However,
neovascular (wet) AMD is more difcult to
examine with AO systems due to the complex
arrangement of lesions and retinal transparency.
30.5.3 Diabetic Retinopathy
The most common and severe complication of
uncontrolled diabetes is diabetic retinopathy
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