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Methods and systems for diagnosis of ocular disease
Michael Kalloniatis Sieu Khuu Noha Al Saleem

Centre for Eye Health, School of Optometry and Vision Science, University of New South Wales,
Kensington, NSW, Australia.
Department of Optometry and Vision Science, King Saud University, Kingdom of Saudi Arabia.

Introduction
An aspect of the present invention provides a method for
early detection of ocular disease in a subject. The method
comprises the steps of: successively applying a plurality of
test stimuli at different eccentricities to the subject's
retina, wherein each of the test stimuli is adjusted for
differences in spatial or temporal summation resulting
from application of the test stimuli; determining visual
field capability loss of the subject in response to each of
the plurality of test stimuli; and diagnosing ocular disease
in the subject if the subject's visual field capability loss in
response to each of the test stimuli is substantially equal.
Another aspect of the present invention provides a visual
field analysis system comprising: at least one processor;
memory coupled to the at least one processor for storing
program instructions and data; a visual stimuli generator
coupled to the at least one processor for generating and
applying visual stimuli to a subject's retina; a visual
analyser coupled to the at least one processor for
determining visual field capability loss in the subject; and
a visual display coupled to the at least one processor for
outputting information. The at least one processor is
programmed to: apply, using the visual stimuli generator,
a plurality of different test stimuli at different eccentricities
to a subject's retina, wherein each of the test stimuli is
adjusted for differences in spatial or temporal summation
resulting from application of the test stimuli; identify,
using the visual analyser, visual field capability loss of the
subject in response to each of the plurality of test stimuli;
determine whether the visual field capability loss in
response to each of the test stimuli is substantially equal;
and output, using the display, a result of the
determination.
Another aspect of the present invention provides a method
for early detection of ocular disease in a subject. The
method comprises the steps of: successively applying a
plurality of test stimuli at different eccentricities to the
subject's retina, wherein one or more of the test stimuli fall
within Ricco's law and one or more of the test stimuli fall
outside Ricco's law; comparing threshold response of the
subject to the test stimuli at various eccentricities; and
determining visual field capability loss of the subject due
to ocular disease based on the threshold response
comparison.
Another aspect of the present invention provides a visual
field analysis system comprising: at least one processor;
memory coupled to the at least one processor for storing
program instructions and data; a visual stimuli generator
coupled to the at least one processor for generating and
applying visual stimuli to a subject's retina; a visual
analyser coupled to the at least one processor for
determining visual field capability loss in the subject; and
a visual display coupled to the at least one processor for
outputting information. The at least one processor is
programmed to: deliver, using the visual stimulator, a
plurality of different test stimuli at different eccentricities
to a subject's retina, wherein one or more of the test
Material
&and
Methods
stimuli fall within
Ricco's law
one or more of the test
stimuli fall outside Ricco's law; compare, using the visual
The
methods threshold
and systems described
herein
relate subject
to automated
field
analyser,
response
of the
to visual
the test
testing
for at
the various
detection and/or
diagnosis of ocular
diseases.visual
The methods
stimuli
eccentricities;
determine
field
and
systems loss
are described
with specific
to early
detection
of
capability
of the subject
duereference
to ocular
disease
based
glaucoma,
however, it response
is not intended
that the present
invention
be limited
on the threshold
comparison;
and
output,
using
to
thisvideo
specific
application
as theof
principles
of the present invention have
the
display,
a result
the determination.
general applicability to the diagnosis and/or detection of other ocular
diseases.
The average human retina is approximately 0.5 mm thick and has a
diameter of 30-40 mm. The central retina comprises the macula and fovea
(approximately 6 mm). Beyond the central retina is the peripheral retina,
which extends to 21 mm and ends at the ora-serrata. The human retina
comprises different kinds of cells on different layers. The main cells of
interest are the ganglion cells, which send stimuli from photoreceptors
through the optic nerve to the central visual pathways. Ganglion cells are
connected to the photoreceptors via bipolar cells. This connection differs
between the central retina and the periphery.
Changes in sensitivity between the fovea and eccentric locations of the
retina are affected by the numbers of cone and rod detectors and their
associated circuitry. Under phototropic conditions, where thresholds are
measured to establish sensitivity of visual field, cone photoreceptors
mediate detection. The change in visual sensitivity as a function of
eccentricity is dependent on cone density and circuitry, as shown in FIGS.
1A and 1B, hereinafter. FIG. 1A shows receptor density as a function of
eccentricity and FIG. 1B shows sensitivity and threshold (log scales) as a
function of eccentricity for different test size stimuli under photopic
conditions.
In the fovea, which is dominated by a massive number of closely spaced
cones, the connection is almost one to one. Away from the macula,
however, the retina becomes dominated by rods with fewer cones, and
cone pathway connections are also reduced. The modification in cone
circuitry is reflected by a change of one-to-one (photoreceptor-to-ganglion
cell) to many (10-20 photoreceptors-to-one ganglion cell).
This difference is a reason for differing central and peripheral retinal
thickness and vision sensitivity under photopic conditions. In other words,
this difference explains the fact that critical area varies with eccentricity
because receptive field size varies with eccentricity and resolution
capability is limited by the size of spatial summation.
Poster template by ResearchPosters.co.za

Changes in sensitivity from the fovea to eccentric locations are described
by certain relevant psychophysical laws. Ricco's law (of spatial
summation) and Bloch's law (of temporal summation) relate to different
perceptual attributes, which explain the threshold response of size and
duration of exposure to stimuli, respectively. These two laws are similar
in that if the size or the duration of a stimulus is increasing, a reciprocal
relationship with luminance must be considered to have a constant value
of threshold, which is called critical area (Ac) or critical time (tc). Ac and
tc vary for the rod (scotopic) and cone (photopic) visual system. The
description here relates to photopic conditionsreflecting the light levels
used to measure sensitivity in standard visual fields investigations.

Results
Different retinal positions have different critical areas. In
particular, the critical area described by Ricco's law and
the critical duration described by Bloch's law both vary
with eccentricity. However,
critical area at different
retinal eccentricities has not been well explored to date.
Bloch's law has been characterised for differing
eccentricities and the maximum duration has been found
to be 100 ms away from
the fovea (for photopic vision).
Accordingly, any stimulus durations that exceed 100 ms
will be
under complete temporal summation for any
eccentricity.

Table 1: Shows standard size test targets (known as the Goldmann test targets),
which are available on typical automated visual field analyzers such as the
Humphrey Visual Field Analyzer (HVFA).
Goldmann test targets (I through V available on the HVFA)
diam
Area
TEST
mm(diam) mm2
log Area
(deg)
(deg2)
0
0.28
1/16th
0.05375 0.00227
2.64
I
0.56
th
0.1075
0.00908
2.04
II
1.13
1
0.215
0.0363
1.44
III
2.26
4
0.43
0.145
0.838
IV
4.51
16
0.86
0.581
0.236
V
9.03
64
1.72
2.32
0.366
Table 2: Shows a comparison between retinal measurement of critical area and
duration and test size III of the HVFA.
Visual psychophysics

Eccentrici
ty

Critical area

Critical
duration

HVFA***

(degree2)*

calculated
from critical
flicker
frequency
(CFF)
(millisecond)*
*

Stimulus size
III = 0.43
diameter
=(degree2)

Stimulus
duration
(millisecond)

5
0.05
29
0.145
200
10
0.08
n/a
0.145
200
15
0.13
56
0.145
200
summation
lead to n/a
different 0.145
sensitivity200measures
20 may0.18
compared
the use of stimuli that probe the system when
*(Sloan,to
1961)
it is **(Kolb
operating
under incomplete spatial summation
et al., 2005)
conditions.
stimuli
falling
***From: Thus,
(Codicil, 1990)
(Zeiss,
2010) within Ricco's law (i.e.,

stimuli smaller than the critical area) will be relatively
more sensitive to detect a loss of visual function.

Figure 1: 3A -3D shows the relation between various test stimuli and critical
area at various eccentricities on the same meridian on a log-log plot of
threshold as a function of area;

Figure 2: 4A and 4B shows the relation between various test stimuli and critical
area at different locations (nasal steps) for the same eccentricity on a log-log
plot of threshold as a function of area;

Discussion
Various existing techniques correlate function with
structure for the evaluation of ocular health. Two such
tests include: Standard Automated Perimetry (SAP) for
testing vision sensitivity; and Optical Coherence
Tomography (OCT) for measuring retinal nerve fiber layer
thickness anywhere in the retina.
The visual field (white-on-white) Standard Automated
Perimetry (SAP) test is one of the gold standard tests for
the diagnosis and progression of glaucoma. However, the
SAP test is considered to be late in predicting functional
loss compared with structural damage with poor overall
correlation between function (visual field results) and
structure (anatomy). The reason for this discrepancy is the
use of test stimuli that are within or outside Ricco's law at
the different retinal eccentricities. The belief that
structural damage occurs ahead of functional loss is a
common misconception.
The present inventors realized that a different retinal
stimulus is needed for early detection of ocular disease
such as glaucomatous damage. Put differently, the spatial
and temporal measurements used in the SAP test are not
the ideal parameters for identifying early defects and
providing a good measure to match with anatomical
changes for detection of the early stages of glaucoma and
other ocular diseases.
The Humphrey Visual Field Analyzer (HVFA) standard III
target is 0.43 degrees in diameter (area=0.145 degree2)
and is presented for a 200 millisecond duration for all
eccentricities. Such a presentation strategy does not take
into account differences in critical area and duration for
the human visual system for different eccentricities.
If a comparison is made between the stimulus size of the
HVFA and known critical areas levels, the HVFA stimulus is
larger than the critical area for 5, 10 and 15 degrees of
eccentricity, but falls within critical area for larger
eccentricities (see Table 2). Furthermore, the test stimulus
duration (200 milliseconds) always places the test outside
the critical duration for all eccentricities (see Table 2).
The HFVA presents one stimulus size at all eccentricities.
Given that the two approaches, static versus kinetic
perimetry employ different strategies, the use of one test
size may result in probing of different mechanisms at

This accords firstly with the present inventors' observation,
from results of work performed by Harwerth et al. in a
paper entitled Scaling the structure-function relationship
for clinical perimetry, published in ActaOphthalmol Scand.
2005 83(4):448-55, that structure function correlation
performed at different eccentricities displays a significantly
different slope for different eccentricities. Such a
relationship would be experienced if functional measures
were not reflecting visual mechanisms operating under the
same conditions.
Secondly, Redmond et al., in a paper entitled Sensitivity
Loss in Early Glaucoma Can be Mapped to and
Enlargement of the Area of Complete Spatial Summation,
Investigative Ophthalmology & Visual Science 51(12):
6540-6548, showed a significantly larger loss in glaucoma
subjects for stimuli within Ricco's critical area compared to
larger stimuli test. The present inventors concluded, from
the results of Redmond et al., that the use of stimuli under
incomplete summation (i.e., smaller stimuli) will lead to
larger threshold elevations in the early stages of glaucoma.
Given the available data, the present inventors predicted
The present
inventors
experiments
determine
that
the seminal
sign conducted
of early glaucoma,
thetonasal
step,
critical show
area different
as a function
of eccentricity
different
should
Ac values
for the sameand
eccentricity
orientations
in subjects
having normal
visual and
field just
capability.
(at
10-25 degrees
temporally)
just above
below
The horizontal
subjects were
subjected to visual psychophysical testing
the
meridian.
and the collected data was processed or analyzed using a nonparametric bootstrap paradigm to determine various
parameters, including critical area (Ac). The results are
presented hereinafter with reference to FIGS. 3A-3D and FIGS.
4A-4B.

FIGS. 3A-3D show the relation between various test stimuli and
critical area at various eccentricities on the same meridian. In
each of FIGS. 3A-3D, the vertical dashed line 300 represents the
area tested by the Goldmann standard size III. The test size III is
clearly not compatible for all eccentricities as it lies within the
linear region for the foveal data and just within Ricco's law at
E15. The vertical arrow 310 in FIG. 3A identifies the critical area
when the stimulus is applied to the fovea. The vertical arrow
320 in FIG. 3B identifies the critical area when the stimulus is
applied at an eccentricity of 5. The vertical arrow 330 in FIG.
3C identifies the critical area when the stimulus is applied at an
eccentricity of 10. The vertical arrow 340 in FIG. 3D identifies
the critical area when the stimulus is applied at an eccentricity
of 15. As shown in FIGS. 3A-3D, critical area increases in size
with eccentricity. FIGS. 4A and 4B shows the relation between
various test stimuli and critical area at different locations (the
nasal step region) for the same eccentricity. In each of FIGS. 4AB, the vertical dashed line 400 represents the area tested by
the Goldmann standard size III.
The vertical arrow 410 in FIG. 4A identifies the critical area
when the stimulus is applied at an eccentricity of 10 and a
nasal step of 165. The vertical arrow 420 in FIG. 4B identifies
the critical area when the stimulus is applied at an eccentricity
of 10 and a nasal step of 195. As shown in FIGS. 4A-4B,
critical area differs at different locations for the same
eccentricity. Given the study of Redmond et al, the present
inventors
the 195
meridian,
will in
ona average
A methodpredicted
for early that
detection
of ocular
disease
subject,
display
a larger
loss that the
165 meridian
resulting
in a nasal
the method
comprising:
successively
applying
a plurality
of
step
test sensitivity
stimuli atdifference.
different eccentricities to a retina of the

Conclusion

subject, wherein each of said test stimuli is adjusted for
differences in spatial or temporal summation resulting from
application of said test stimuli; determining visual field
capability loss of said subject in response to each of said
plurality of test stimuli; and diagnosing ocular disease in
said subject if said visual field capability loss in response to
each of said test stimuli is substantially equal.

References

https://patentimages.storage.googleapis.com/5d/4a/bd/
436cbaeb28f8c9/US20150313457A1.pdf

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