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Performance of real-world functional vision tasks by blind subjects improves after implantation with the Argus® II retinal prosthesis system: Functional vision tasks using Argus® II

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Abstract and Figures

Background: The main objective of this study was to test Argus II subjects on three real-world functional vision tasks. Design: The study was designed to be randomized and prospective. Testing was conducted in a hospital/research laboratory setting at the various participating centres. Participants: Twenty eight Argus II subjects, all profoundly blind, participated in this study. Methods: Subjects were tested on the three real-world functional vision tasks: Sock Sorting, Sidewalk Tracking and Walking Direction Discrimination task MAIN OUTCOME MEASURES: For the Sock Sorting task, percentage correct was computed based on how accurately subjects sorted the piles on a cloth-covered table and on a bare table. In the Sidewalk Tracking task, an 'out of bounds' count was recorded, signifying how often the subject veered away from the test course. During the Walking Direction Discrimination task, subjects were tested on the number of times they correctly identified the direction of testers walking across their field of view. Results: The mean percentage correct OFF versus ON for the Sock Sorting task was found to be significantly different for both testing conditions (t-test, P < 0.01). On the Sidewalk Tracking task, subjects performed significantly better with the system ON than they did with the system OFF (t-test, P < 0.05). Eighteen (18) of 27 subjects (67%) performed above chance with the system ON, and 6 (22%) did so with system OFF on the Walking Direction Discrimination task. Conclusions: Argus II subjects performed better on all three tasks with their systems ON than they did with their systems OFF.
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Original Article
Performance of real-world functional vision tasks by
blind subjects improves after implantation with the
Argus® II retinal prosthesis system
Gislin Dagnelie PhD,
1
Punita Christopher PhD,
2
Aries Arditi PhD,
3
Lyndon da Cruz MD,
4
Jacque L Duncan MD,
5
Allen C Ho MD,
6
Lisa C Olmos de Koo MD,
7
José-Alain Sahel MD,
8
Paulo E Stanga MD,
9
Gabriele Thumann MD,
10
Yizhong Wang MD,
11
Maura Arsiero PhD,
2
Jessy D Dorn PhD,
2
Robert J Greenberg MD
2
and the Argus® II Study Group
1
Lions Vision Research and Rehab Center, Johns Hopkins University, Baltimore, Maryland,
2
Second Sight Medical Products Inc, Sylmar,
5
University of California, San Francisco,
7
Department of Ophthalmology, University of Southern California, Los Angeles, California,
3
Lighthouse Guild, New York, New York,
6
Wills Eye Hospital, Philadelphia, Pennsylvania,
11
Retina Foundation of the Southwest, Dallas,
Texas, USA;
4
Moorelds Eye Hospital, London;
9
Manchester Royal Eye Hospital, Manchester, UK;
8
Quinze-Vingts National Ophthalmology
Hospital, Paris, France; and
10
Geneva University Hospital, Geneva, Switzerland
ABSTRACT
Background: The main objective of this study was to
test Argus II subjects on three real-world functional
vision tasks.
Design: The study was designed to be randomized
and prospective. Testing was conducted in a
hospital/research laboratory setting at the various
participating centres.
Participants: Twenty eight Argus II subjects, all pro-
foundly blind, participated in this study.
Methods: Subjects were tested on the three real-world
functional vision tasks: Sock Sorting, Sidewalk Track-
ing and Walking Direction Discrimination task
Main Outcome Measures: For the Sock Sorting task,
percentage correct was computed based on how ac-
curately subjects sorted the piles on a cloth-covered
table and on a bare table. In the Sidewalk Tracking
task, an out of boundscount was recorded,
signifying how often the subject veered away from
the test course. During the Walking Direction Dis-
crimination task, subjects were tested on the number
of times they correctly identied the direction of tes-
ters walking across their eld of view.
Results: The mean percentage correct OFF versus ON
for the Sock Sorting task was found to be signicantly
different for both testing conditions (t-test, P<0.01).
On the Sidewalk Tracking task, subjects performed
signicantly better with the system ON than they
did with the system OFF (t-test, P<0.05). Eighteen
(18) of 27 subjects (67%) performed above chance
with the system ON, and 6 (22%) did so with system
OFF on the Walking Direction Discrimination task.
Conclusions: Argus II subjects performed better on all
three tasks with their systems ON than they did with
their systems OFF.
Key words: activities of daily living, clinical trial, out-
come measures, retinal prosthesis, visual performance.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and
distribution in any medium, provided the original work is properly cited, the useis non-commercial and no modications or adaptations are made.
jCorrespondence: Dr Gislin Dagnelie, JHU Lions Vision Center, Wilmer Woods 358, 1800 Orleans St, Baltimore, MD 212877-0023, USA. E-mail
gdagnelie@jhmi.edu
Received 5 April 2016; accepted 31 July 2016.
Competing/conicts of interest: All authors, through their participating institutions, were supported by research funds from Second Sight Medical
Products Inc (SSMP). Punita Christopher, Maura Arsiero, Robert J. Greenberg, and Jessy Dorn are employees of and have stock options in SSMP.
Robert J. Greenberg has an equity interest in SSMP and intellectual propertyrightstotheArgus®IIretinalprosthesis system and related technology.
Funding sources: Funded by National Institutes of Health grant no. 5R01EY012893 (R.J.G., principal investigator) through the National Eye
Institute, and by Research/?Development of Articial Retinas for the Blind and National Institutes of Health grant no. 1RC3EY020778-01
(R.J.G., principal investigator). The clinical trial was sponsored by Second Sight Medical Products, Inc.
© 2016 The Authors Clinical & Experimental Ophthalmology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian
and New Zealand College of Ophthalmologists
Clinical and Experimental Ophthalmology 2017; 45: 152159 doi: 10.1111/ceo.12812
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INTRODUCTION
The Argus® II, the rst commercially available
retinal prosthesis, is intended to partially restore
useful vision in blind patients with severe to pro-
found retinitis pigmentosa. Several tests have been
developed to test subjectsimprovement in vision
with the Argus II system in a clinical trial.
1,2
Most
of these tests involve computer-based tasks that are
conducted in a highly controlled, laboratory setting.
Additionally, we also use self-reported and observer
rated instruments such as the Massof Activity
Inventory,
3
VisQOL
4
and FLORA
5
to quantify the
improvements in the ability of subjects to perform
real world activities of daily living (ADL) while
using the Argus II system. However, most of these
instruments that are currently in use for low vision
testing consist of tasks that are often beyond the
scope of what subjects can do with the Argus II
system. This research study was thus developed to
test subjects on real-world functional vision tasks
that can be scored in an objective manner. These
tasks were designed to approximate everyday
activities that a totally blind individual may not be
able to do, and to measure in a less-controlled, more
real-world environment whether the Argus II
system helped the subjects successfully perform them.
These functional vision tasks encompassed several
aspects of everyday life: housekeeping chores, social
engagement, and orientation and mobility. Each of
these aspects was represented by one task developed
for this research study: sock sorting, sidewalk track-
ing, and perceived direction of walking. The sock
sorting task was designed to mimic the real-world
scenario of sorting light and dark laundry. It
represents a task that is difcult or impossible to do
without vision (i.e. through tactile cues alone). The
Sidewalk Tracking task was developed to assess
subjectsability to visually track an edge such as the
border between a sidewalk and grass in a real-world
outdoor setting, as the visual analogue of the
shoreliningtechnique commonly employed by
white cane users to follow the wall of a building or
corridor, a curb, or other tactile guidance.
6
The ability
to follow along such an edge and detect the transition
between two surfaces of different brightness levels
may be useful to blind subjects for mobility and
orientation purposes in their daily life. The Walking
Direction Discrimination (WDD) task was developed
to assess subjectsability to identify the direction of
motion of a person passing in front of them. The
ability to detect people moving nearby and identify
their direction may be useful to blind subjects in
unfamiliar environments or in social situations.
METHODS
The Argus II system consists of an implant that is
surgically placed on and in the eye and external
equipment that is worn by the subject. The implant
consists of a receiving antenna and an electronics case
that are secured to the outside of the eye using a stan-
dard scleral band and sutures, and an intraocular
electrode array that is secured to the retina over the
macula using a retinal tack (Fig. 1a). The electrode
array contains 60 electrodes arranged in a 6 × 10 grid.
The external equipment consists of the Argus II
glasses and the Argus II Video Processing Unit
(VPU) (Fig. 1b). A small video camera and transmit-
ting antenna are mounted on the glasses. The VPU
is worn by the subject on a shoulder strap or belt,
and is used to process the images from the video cam-
era and convert the images into electrical stimulation
commands that are wirelessly transmitted to the
implant. The electrodes in the array emit stimulation
pulses whose amplitude corresponds to the bright-
ness of the scene in that location. Stimulation of the
remaining retinal cells results in visual percepts that
subjects learn to interpret.
The Argus II clinical trial enrolled 30 subjects, 14
from the United States and 16 from Europe, with an
average age of 58 years (standard deviation: 10 years)
at time of implantation. All subjects had Retinitis
Pigmentosa with the exception of one subject who
had Choroideremia. Subjects were implanted with
the Argus II Retinal Prosthesis System in one eye,
typically the worse-seeing eye. All subjects were
profoundly blind and had bare light perception or
no light perception at implantation.
Figure 1. The Argus II System. (a) Implanted
components of the system. (b) External compo-
nents of the system.
© 2016 The Authors Clinical & Experimental Ophthalmology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian
and New Zealand College of Ophthalmologists
Functional vision tasks using Argus® II 153
Twenty seven subjects performed all three tests
between 1 January and 30 November 2010. Subject
S2 was not available for testing during this study
period, and S13s device was explanted before this
study commenced. Subject 25 discontinued participa-
tion after the rst test, because of intermittent prob-
lems with the implant (the external antenna could
not consistently establish a radio-frequency link with
the implanted antenna, so we could not guarantee a
continuous data and power stream to the electrode
array). Subjects performed these tests during or close
to a clinical follow-up visit. The follow-up time
varied for each subject depending on the time of
implantation (Argus II subjects were implanted over
the course of about two years), between a minimum
of 6 months and a maximum of 36 months post-
implant. The tests were conducted during subjects
regular psychophysics testing sessions (all three
tasks were not necessarily assessed during the same
session). Testing was performed by clinical site staff
and/or Second Sight Medical Products staff under
direction of the site principal investigator.
The Argus II clinical trial is a multi-centre trial and
is being conducted in accordance with the Declara-
tion of Helsinki and the national regulations for
medical device clinical trials in the countries where
the study is being conducted. The National Ministries
of Health in each of these countries have approved
this study. This study has also been approved by
the ethics committees or institutional review boards
of participating centres. All subjects consented to
participate. The clinical trial is posted on www.
clinicaltrials.gov, trial registration number
NCT00407602.
Task 1: sock sorting
Twenty-eight (28) subjects were included in this
assessment. Subjects were presented with 30 socks
jumbled together in a pile: 10 pure white socks, 10
pure black socks and 10 of an intermediate gray
colour. To avoid the presence of non-visual cues, all
socks were made of the same material, size and
shape; all socks were bought from the same manufac-
turer and were intended to be indistinguishable by
touch. The subjectstask was to sort the socks into
three piles representing the three different colours.
Some subjects counted piles and ensured that they
had 10 socks in each pile; others simply sorted
according to what colour they believed each sock to
be, resulting in some piles with more or fewer than
10 socks.
The task was performed in the clinic, in lighting
conditions that varied from site to site, but that can
all be qualied as medium to bright indoor lighting.
Subjects sorted the socks four times: once each with
the Argus II system ON and OFF and the surface of
the table covered in a known-colour of cloth (either
black or white, as preferred by the subject), and once
each with the system ON and OFF on a bare table.
Only one subject chose to use a white-coloured cloth;
all other subjects used a black-coloured cloth. Bare
tables were as-found in the clinical site testing
rooms; they were various types of desks and tables
of various colours of wood or laminate. This condi-
tion was intended to produce a more real-worldtest,
as blind Argus II users will not always have control
over the level of contrast available in the environ-
ment where they use the system. Subjects performed
all tests binocularly. All test conditions comprising
the task were assessed in the same session with the
exception of subject S4, who completed some condi-
tions in a second session less than a month after the
rst session.
After the subjects had nished sorting the socks
and identied which pile was which (i.e. white
pile,’‘gray pile,’‘black pile), the number of each
colour in each pile of socks was counted. Results
were thereafter recorded as the number of
correctly-sorted white, gray and black socks. For
some analyses, results were further compiled to
yield a total percent correct across all colours.
T-tests (assuming unequal variance) were used to
test for signicant differences between the means
for various conditions. Figure 2 shows a subject
performing the sock-sorting test.
Figure 2. Photograph of an Argus II subject performing the
Sock Sorting task.
© 2016 The Authors Clinical & Experimental Ophthalmology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian
and New Zealand College of Ophthalmologists
154 Dagnelie et al.
Task 2: sidewalk tracking
Twenty-seven (27) subjects were tested on the
Sidewalk Tracking task. For this task, the tester
identied three different 20-foot (6-m) stretches of
grass or low shrubbery bordered by concrete or
asphalt such as a sidewalk, driveway, parking lot,
etc. Some edges were straight; others were curved
or angled. The subject was asked to walk along
each of the three paths on the pavement within
1 m of the edge without stepping off the pavement,
as shown schematically in Figure 3. The subject did
not use any mobility aid such as a cane or a guide
dog during the test. The test consisted of three trials
with the system ON and three trials with the
system OFF. The order of trials was varied by the
tester. All six trials were completed on the same day
with the exception of subject S22, who completed
the trials with the System ON a week after the trials
with the System OFF, in the same location.
Performance was measured by the number of times
the subject moved out of bounds, that is, when they
stepped off the pavement or when they moved farther
than 1 m away from the edge. If subjects moved out of
bounds during the trial, the tester corrected their posi-
tion accordingly, and subjects continued to complete
the trial. A video of a subject performing this task is
included as supplemental material online (Video S1).
Task 3 Walking Direction Discrimination
(WDD)
Twenty-seven (27) subjects were included in this
activity. For this task, the subject was seated, and
markers were placed 10 feet away. The test began
with two testers positioned on the markers, on either
side of the subject, as shown in Figure 4. Every 15 s,
prompted by an audible beep, one of the testers
crossed the subjectseld of view by walking from
one side to the other. A few seconds after the audio
prompt, the subject identied in what direction the
tester was moving.
This was a two-alternative forced-choice test; if the
subject did not see movement he/she was required to
guess. The test consisted of 40 trials. Some care was
taken to reduce the possibility of auditory cues for
example, testers may have removed their shoes if
the oor material was hard. As the task was intended
to represent real-world conditions, however, no
masking noise or noise-cancelling headphones were
used. The task was performed with the system ON
and OFF. Performance was measured by the number
of correct answers, that is, the trials in which the
subject correctly identied the direction of the person
passing in front of him/her.
RESULTS
Task 1: sock sorting
Figure 5 shows the mean percent correct and stan-
dard deviation for all four testing conditions (system
ON and system OFF, felt-covered table and bare
table). As indicated by the stars in Figure 5, the mean
percentages correct OFF versus ON conditions are
signicantly different for both the felt-covered table
Figure 3. Schematic of the Sidewalk Tracking task.
Figure 4. Schematic of the Walking Direction
Discrimination task.
© 2016 The Authors Clinical & Experimental Ophthalmology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian
and New Zealand College of Ophthalmologists
Functional vision tasks using Argus® II 155
and the bare table (t-test assuming unequal
variances, P<0.01). We also found that the mean
percentage correct was signicantly greater for the
felt-covered table versus the bare table with the system
ON (t-test assuming unequal variances, P<0.01); this
suggests that subjects can more reliably identify the
colour of the socks against the felt-covered table.
A large majority of subjects perform better on this
task with the system ON than with it OFF (27 of 28
with the felt-covered table, and 21 out of 28 with the
bare table). Subject S8 is an exception; this subject
performed noticeably better with the system OFF in
both conditions. The subject noted during testing that
it was possible for him to feel the difference between
the white socks and the other colours with no visual
information, which likely explains the outlier results.
To investigate whether there was a difference in
performance for different colours of socks, the aver-
age percent correct was calculated for each colour
over all subjects when using the felt-covered table
and bare table (system ON). In other words, for
white, the number correct for white socks divided
by the total number of white socks was calculated.
Means and standard deviations are shown in Figures
6 and 7 for the felt-covered table and bare table
conditions, respectively. There is no signicant
difference in mean percentage correct between white
and gray socks when using the felt-covered table
(t-test, P>0.05); however, mean percentages correct
for black and gray socks are signicantly different
(P<0.01), as are those for white and black socks
(P<0.01), when using the felt-covered table, as
indicated by stars on the gure. This suggests that
subjects can more reliably identify black socks than
white or gray socks. There is no signicant difference
in mean percentages correct between white and gray
socks, white and black socks, and black and gray
socks, when using the bare table. This suggests that
subjects have equal difculty identifying the black,
white or gray socks on the bare table.
Task 2: sidewalk task
Figure 8 shows a comparison between the system
ON and OFF performance for all tested subjects.
Eighteen (18) of 27 subjects (67%) performed better
(i.e. fewer out of bounds) with the system ON
when compared to system OFF, and seven (27%)
performed better with the system OFF (two sub-
jects had equal performance ON and OFF). Mean
Figure 5. Mean percent correct, sock sorting,
all conditions. Stars indicate signicant differ-
ence, t-test assuming unequal variances,
P<0.01.
Figure 6. Mean percent correct, sock sorting,
by colour (felt-covered table). Stars indicate sig-
nicant difference, t-test assuming unequal vari-
ances, P<0.01.
© 2016 The Authors Clinical & Experimental Ophthalmology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian
and New Zealand College of Ophthalmologists
156 Dagnelie et al.
and standard deviation for ON and OFF are shown
in Table 1. A paired t-test was used to compare the
number of out of bounds errors with system ON
and system OFF for all subjects. Results indicate
that subjects performed signicantly better with
the system ON than they did with the System
OFF (two-tailed t-test, P<0.05).
Task 3: Walking Direction Discrimination
Figure 9 shows a comparison between system ON
and OFF performance for all tested subjects. Accord-
ing to the binomial distribution (one-tailed), scoring
26 or more correct answers out of 40 is signicantly
above chance. Eighteen (18) subjects performed
above chance with the system ON, and six subjects
performed above chance with the system OFF. (One
of these performed signicantly above chance only
with the system OFF, and the other three performed
signicantly above chance in both conditions.)
DISCUSSION
Task 1 sock sorting
The task of sorting laundry by colour was suggested
by Argus II subjects as a task they would like to be
able to do without help but cannot perform without
sight. Based on that suggestion, an objectively scored
sock sorting task was developed to be performed in
real-world conditions (i.e. with varying lighting and
table surface colour across the different clinical sites).
This study demonstrated that Argus II subjects were
able to sort white, gray and black socks by colour
signicantly better with their systems ON than they
were with their systems OFF. This held true whether
the background colour was controlled (either white
or black, according to the subjects preference) or
uncontrolled (a bare table). However, performance
Figure 7. Mean percent correct, sock sorting,
by colour (bare table). Stars indicate signicant
difference, t-test assuming unequal variances,
P<0.01.
Figure 8. Number of out-of-bounds, sidewalk
tracking task. Stars indicate signicant differ-
ence, paired t-test, P<0.05.
Table 1. Sidewalk task summary results
Out of bound counts
system ON
(Mean ± SD)
Out of bound counts
system OFF
(Mean ± SD)
P-value
(paired
t-test)
4.93 ± 2.62 6.85 ± 3.03 P<0.05
© 2016 The Authors Clinical & Experimental Ophthalmology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian
and New Zealand College of Ophthalmologists
Functional vision tasks using Argus® II 157
was better with the felt-covered table; this is not
surprising, as the felt cover held two important
advantages: it likely increased the contrast between
the socks and the table (compared to intermediate
shades of the bare tabletops), and it was a known
colour subjects knew whether the felt was black
or white, so perhaps had an easier comparison for
the sock colour. Subjects were generally aware of
the colour of the bare table, but may not have had a
precise mental image of the table colour.
Task 2 sidewalk task
This task was developed to test blind subjectsability
to detect and track edges in a real-world outdoor
situation where lighting and contrast conditions are
uncontrolled, a task that subjects had previously
reported as difcult. It is thus encouraging that these
results demonstrated that Argus II subjects, as a
group, performed signicantly better on this
uncontrolled task with their system ON versus OFF.
Moreover, a quarter of the subjects performed at least
50% better with system ON versus OFF, that is, the
number of errors with the system ON was less than
67% of that with the system OFF.
Time to complete this task was not measured, as
the test was stopped each time a subject strayed out
of bounds. It has been shown, however, that System
ON tasks tend to take longer than performing the
same task System OFF.
7
We would expect the case
to be the same here sidewalk tracking with the
System ON is slower, but more accurate.
One may object to the notion that the Sidewalk
Tracking task is representative of daily activities:
Blind people travelling alone will use either a guide
dog or a white cane, and an unaccompanied Argus
II wearer should still use a white cane for reasons of
safety, both to avoid obstacles and changes in ground
level, such as steps, and to signal their blindness to
other pedestrians and to motorists. One should real-
ize, however, that certain visible markings, such as
paint lines on pavement, may not lend themselves
to tactile detection. As an example, an Argus II
wearer can use the crosswalk lines to safely cross
the street, but the cane she is using will not protect
her from veering out of the crosswalk before reaching
the other side of the street.
Task 3 Walking Direction Discrimination
This task was developed to mimic a real-world situa-
tion in which a blind subject, sitting in a stationary
position, identies the walking direction of people
passing in front of him or her (as might be useful
while sitting on an outdoor bench or in a social situ-
ation). Argus II subjects, as a group, have signi-
cantly better performance on this task with their
systems ON than OFF (two-tailed t-test, P<0.05).
Although 15 subjects were able to perform signi-
cantly above chance with their systems ON, only four
were able to reach this performance with the system
OFF. Those four were likely using auditory cues to
perform the task without the system. Although this
task could be controlled to eliminate auditory cues,
it is believed to be more valuable to present a real-
world environment (while still controlling enough
factors to allow for objective measurement of perfor-
mance). In this way, the results shown here represent
actual benet of the system and other sensory infor-
mation, compared with use of only residual vision
and other sensory information.
The tasks are representative of ADL tasks and
were developed as a complementary assessment for
Argus II subjects; they mimicked activities that sub-
jects perform in their daily lives, but were objectively
scored. They provided information about how
subjects can use their systems for complex tasks in
different uncontrolled environments.
Figure 9. Walking Direction Discrimination re-
sults for each subject. Dotted line indicates per-
formance signicantly above chance according
to the binomial distribution, P<0.05.
© 2016 The Authors Clinical & Experimental Ophthalmology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian
and New Zealand College of Ophthalmologists
158 Dagnelie et al.
The results indicated that performance on these
tasks varied across subjects, but that as a group,
Argus II subjects performed better on all three tasks
(Sock Sorting, Sidewalk Tracing and WDD) with
their systems ON than they did with their systems
OFF.
Interestingly, high performance on these tasks did
not always correspond to high performance on other
tasks such as character recognition
8
or grating visual
acuity (data not shown). However, more importantly,
some subjects performed very well on these func-
tional vision tasks but not as well on other assess-
ments. This suggests that when assessing the benet
that subjects have received from use of the Argus II
system, certain daily activities may show benets
that cannot easily be demonstrated in standardized
laboratory tests.
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SUPPORTING INFORMATION
Additional Supporting Information may be found in
the online version of this article at the publisher's
web-site:
Video S1. Sidewalk tracking task.
© 2016 The Authors Clinical & Experimental Ophthalmology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian
and New Zealand College of Ophthalmologists
Functional vision tasks using Argus® II 159
... For example, these implants require invasive surgery and rely on the extracellular electrical stimulation of the RGC, which can be cytotoxic at high stimulation intensities [265]. The spatial acuity of retinal implants is limited by the number of stimulating electrodes [266]. Moreover, adverse events in early clinical trials, such as retinal ruptures in subjects during implant positioning, conjunctival complications during implant residence, and the disruption of the blood retinal barrier, have led to the discontinuation of some retinal implant clinical trials. ...
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... Until now, retinal prostheses have been implanted in over 500 people (Ayton et al., 2020) and have shown great potential in restoring partial visual function in advanced outer retinal degenerative diseases, such as retinitis pigmentosa and age-related macular degeneration patients (Weiland and Humayun, 2014;Yue et al., 2016). Clinical trials with these implants have been proven to produce functional vision (Dagnelie et al., 2017;Stingl et al., 2015). In comparison, TES is a less invasive therapeutic approach that is utilized in the clinical selection of candidates for retinal prosthesis implantation. ...
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Retinal stimulation has become a widely utilized approach to restore visual function for individuals with retinal degenerative diseases. Although the rectangular electrical pulse is the primary stimulus waveform used in retinal neuromodulation, it remains unclear whether alternate waveforms may be more effective. Here, we used the optical intrinsic signal imaging system to assess the responses of cats’ visual cortex to sinusoidal electrical stimulation through contact lens electrode, analyzing the response to various stimulus parameters (frequency, intensity, pulse width). A comparison between sinusoidal and rectangular stimulus waveform was also investigated. The results indicated that the optimal stimulation frequency for sinusoidal electrical stimulation was approximately 20 Hz, supporting the hypothesis that low-frequency electrostimulation induces more responsiveness in retinal neurons than high-frequency electrostimulation in case of sinusoidal stimulation. We also demonstrated that for low-frequency retinal neuromodulation, sinusoidal pulses are more effective than rectangular ones. In addition, we found that compared to current intensity, the effect of the sinusoidal pulse width on cortical responses was more prominent. These results suggested that sinusoidal electrical stimulation may provide a promising strategy for improved retinal neuromodulation in clinical settings.
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Causes of blindness differ across the globe; in higher-income countries, most blindness results from the degeneration of specific classes of cells in the retina, including retinal pigment epithelium (RPE), photoreceptors, and retinal ganglion cells. Advances over the past decade in retinal regenerative medicine have allowed each of these cell types to be produced ex vivo from progenitor stem cells. Here, we review progress in applying these technologies to cell replacement — with the goal of vision restoration in degenerative disease. We discuss the landscape of human clinical trials for RPE transplantation and advanced preclinical studies for other cell types. We also review progress toward in situ repair of retinal degeneration using endogenous progenitor cells. Finally, we provide a high-level overview of progress toward prosthetic ocular vision restoration, including advanced photovoltaic devices, opsin-based gene therapy, and small-molecule photoswitches. Progress in each of these domains is at or near the human clinical-trial stage, bringing the audacious goal of vision restoration within sight. Restoration of visual function in degenerative retinal disease may be an attainable goal, thanks to advances in cell-based therapy, gene therapy, and prosthetics. This Review discusses the most promising strategies that will probably reach clinical use in the next decade.
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Introduction Various retinal implants are being developed and appear to be a promising option for improving the visual capacities of individuals with retinal dystrophy. A multidisciplinary approach to both assessment of a candidate’s factors and rehabilitation could contribute to improved activity and participation. The purpose of this study was (i) to document the approach taken by a multidisciplinary team in the candidate selection process and in training in the use of the Argus II retinal prosthesis system (RPS), and (ii) to examine the effects of the RPS on sensory and mental functions and on activity and participation. Methods An A1-B1-A2-B2 experimental case report was used, with repeated measures pre- and post-rehabilitation program design. The A phases represent the periods with the system off, whereas the B phases represent the periods with the system on. A 65-year-old man with retinitis pigmentosa and total blindness was followed by a multidisciplinary team for over 18 months. After receiving the retinal implant, he benefited from a 10-week rehabilitation program (twice per week; B1 phase). Results Globally, the RPS improved vision in the B phases when the system was on and visual acuity was stable at 2.3 logMAR (functional blindness). The participant’s mental and neuromusculoskeletal function scores were generally stable throughout the data collection periods. Lower performance on some measures at the end of phase B2 coincided with a negative mood. Discussion Use of the RPS improved activity, but this did not transfer into greater participation in the living environment. Despite efforts made by the rehabilitation team to manage the user’s expectations concerning the RPS, the interventions reactivated his grieving over his vision loss. Implications for Practitioners New technologies can make users dream of unrealistic possibilities, and managing their expectations requires problem solving supported by a multidisciplinary team.
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Rod and cone photoreceptors degenerate in retinitis pigmentosa (RP). While downstream neurons survive, they undergo physiological changes, including accelerated spontaneous firing in retinal ganglion cells (RGCs). Retinoic acid (RA) is the molecular trigger of RGC hyperactivity, but whether this interferes with visual perception is unknown. Here, we show that inhibiting RA synthesis with disulfiram, a deterrent of human alcohol abuse, improves behavioral image detection in vision-impaired mice. In vivo Ca2+ imaging shows that disulfiram sharpens orientation tuning of visual cortical neurons and strengthens fidelity of responses to natural scenes. An RA receptor inhibitor also reduces RGC hyperactivity, sharpens cortical representations, and improves image detection. These findings suggest that photoreceptor degeneration is not the only cause of vision loss in RP. RA-induced corruption of retinal information processing also degrades vision, pointing to RA synthesis and signaling inhibitors as potential therapeutic tools for improving sight in RP and other retinal degenerative disorders.
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Late-stage retinal degenerative disease involving photoreceptor loss can be treated by optogenetic therapy, cell transplantation and retinal prostheses. These approaches aim to restore light sensitivity to the retina as well as visual perception by integrating neuronal responses for transmission to the cortex. In age-related macular degeneration, some cell-based therapies also aim to restore photoreceptor-supporting tissue to prevent complete photoreceptor loss. In the earlier stages of degeneration, gene-replacement therapy could attenuate retinal-disease progression and reverse loss of function. And gene-editing strategies aim to correct the underlying genetic defects. In this Review, we highlight the most promising gene therapies, cell therapies and retinal prostheses for the treatment of retinal disease, discuss the benefits and drawbacks of each treatment strategy and the factors influencing whether functional tissue is reconstructed and repaired or replaced with an electronic device, and summarize upcoming technologies for enhancing the restoration of vision. This Review discusses the most promising gene therapies, cell therapies and retinal prostheses for the treatment of retinal degeneration, as well as upcoming technologies for enhancing vision restoration.
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In February 2013, the Argus® II Retinal Prosthesis System (Second Sight Medical Products, Inc., Sylmar, CA, US) became the first "bionic eye" approved by the FDA to restore useful vision in patients previously blinded by end-stage retinitis pigmentosa, a hereditary, progressive degeneration of the outer retinal photoreceptor cells. The system captures and converts an external optical input into an electrical signal that activates an epiretinal electrode array on the inner surface of the retina. This signal bypasses dysfunctional photoreceptors and directly stimulates the functional inner retina, thus transmitting information to the visual cortex and creating artificial vision. This article describes the first implantation of the Argus II Retinal Prosthesis System in the Asia-Pacific region, which occurred in a deaf and blind 72-year-old Japanese American woman with Usher syndrome. At 57 months after her operation, the patient uses the device daily to perform visual tasks, and the microelectrode array remains in the proper position on the macula. This case demonstrates the long-term safety and efficacy of the Argus II epiretinal implant, which allowed a functionally blind patient to gain meaningful vision.
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Purpose: To report the initial safety and efficacy results of a second-generation (44-channel) suprachoroidal retinal prosthesis at 56 weeks after device activation. Methods: Four subjects, with advanced retinitis pigmentosa and bare-light perception only, enrolled in a phase II trial (NCT03406416). A 44-channel electrode array was implanted in a suprachoroidal pocket. Device stability, efficacy, and adverse events were investigated at 12-week intervals. Results: All four subjects were implanted successfully and there were no device-related serious adverse events. Color fundus photography indicated a mild postoperative subretinal hemorrhage in two recipients, which cleared spontaneously within 2 weeks. Optical coherence tomography confirmed device stability and position under the macula. Screen-based localization accuracy was significantly better for all subjects with device on versus device off. Two subjects were significantly better with the device on in a motion discrimination task at 7, 15, and 30°/s and in a spatial discrimination task at 0.033 cycles per degree. All subjects were more accurate with the device on than device off at walking toward a target on a modified door task, localizing and touching tabletop objects, and detecting obstacles in an obstacle avoidance task. A positive effect of the implant on subjects' daily lives was confirmed by an orientation and mobility assessor and subject self-report. Conclusions: These interim study data demonstrate that the suprachoroidal prosthesis is safe and provides significant improvements in functional vision, activities of daily living, and observer-rated quality of life. Translational relevance: A suprachoroidal prosthesis can provide clinically useful artificial vision while maintaining a safe surgical profile.
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Purpose: Retinitis pigmentosa (RP) is a hereditary disease causing photoreceptor degeneration and permanent vision loss. Retinal implantation of a stimulating electrode array is a new treatment for RP, but quantification of its efficacy is the subject of ongoing work. This review evaluates vision-related outcomes resulting from retinal implantation in participants with RP. Methods: We searched MEDLINE and Embase for journal articles published since January 1, 2015. We selected articles describing studies of implanted participants that reported the postimplantation measurement of vision. We extracted study information including design, participants' residual vision, comparators, and assessed outcomes. To assess the risk of bias, we used signaling questions and a target trial. Results: Our search returned 425 abstracts. We reviewed the full text of 34 articles. We judged all studies to be at high risk of bias owing to the study design or experimental conduct. Regarding design, studies lacked the measures that typical clinical trials take to protect against bias (e.g., control groups and masking). Regarding experimental conduct, outcome measures were rarely comparable before and after implantation, and psychophysical methods were prone to bias (subjective, not forced choice, methods). The most common comparison found was between postimplantation visual function with the device powered off versus on. This comparison is at high risk of bias. Conclusions: There is a need for high-quality evidence of efficacy of retinal implantation to treat RP. Translational relevance: For patients and clinicians to make informed choices about RP treatment, visual function restored by retinal implantation must be properly quantified and reported.
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Purpose: In a clinical trial (NCT03406416) of a second-generation (44-channel) suprachoroidal retinal prosthesis implanted in subjects with late-stage retinitis pigmentosa (RP), we assessed performance in real-world functional visual tasks and emotional well-being. Methods: The Functional Low-Vision Observer Rated Assessment (FLORA) and Impact of Vision Impairment-Very Low Vision (IVI-VLV) instruments were administered to four subjects before implantation and after device fitting. The FLORA contains 13 self-reported and 35 observer-reported items ranked for ease of conducting task (impossible-easy, central tendency given as mode). The IVI-VLV instrument quantified the impact of low vision on daily activities and emotional well-being. Results: Three subjects completed the FLORA for two years after device fitting; the fourth subject ceased participation in the FLORA after fitting for reasons unrelated to the device. For all subjects at each post-fitting visit, the mode ease of task with device ON was better or equal to device OFF. Ease of task improved over the first six months with device ON, then remained stable. Subjects reported improvements in mobility, functional vision, and quality of life with device ON. The IVI-VLV suggested self-assessed vision-related quality of life was not impacted by device implantation or usage. Conclusions: Subjects demonstrated sustained improved ease of task scores with device ON compared to OFF, indicating the device has a positive impact in the real-world setting. Translational relevance: Our suprachoroidal retinal prosthesis shows potential utility in everyday life, by enabling an increased environmental awareness and improving access to sensory information for people with end-stage RP.
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Purpose: Retinitis pigmentosa (RP) is a group of inherited retinal degenerations leading to blindness due to photoreceptor loss. Retinitis pigmentosa is a rare disease, affecting only approximately 100 000 people in the United States. There is no cure and no approved medical therapy to slow or reverse RP. The purpose of this clinical trial was to evaluate the safety, reliability, and benefit of the Argus II Retinal Prosthesis System (Second Sight Medical Products, Inc, Sylmar, CA) in restoring some visual function to subjects completely blind from RP. We report clinical trial results at 1 and 3 years after implantation. Design: The study is a multicenter, single-arm, prospective clinical trial. Participants: There were 30 subjects in 10 centers in the United States and Europe. Subjects served as their own controls, that is, implanted eye versus fellow eye, and system on versus system off (native residual vision). Methods: The Argus II System was implanted on and in a single eye (typically the worse-seeing eye) of blind subjects. Subjects wore glasses mounted with a small camera and a video processor that converted images into stimulation patterns sent to the electrode array on the retina. Main outcome measures: The primary outcome measures were safety (the number, seriousness, and relatedness of adverse events) and visual function, as measured by 3 computer-based, objective tests. Results: A total of 29 of 30 subjects had functioning Argus II Systems implants 3 years after implantation. Eleven subjects experienced a total of 23 serious device- or surgery-related adverse events. All were treated with standard ophthalmic care. As a group, subjects performed significantly better with the system on than off on all visual function tests and functional vision assessments. Conclusions: The 3-year results of the Argus II trial support the long-term safety profile and benefit of the Argus II System for patients blind from RP. Earlier results from this trial were used to gain approval of the Argus II by the Food and Drug Administration and a CE mark in Europe. The Argus II System is the first and only retinal implant to have both approvals.
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Background Research groups and funding agencies need a functional assessment suitable for an ultra-low vision population to evaluate the impact of new vision-restoration treatments. The purpose of this study was to develop a pilot assessment to capture the functional visual ability and well-being of subjects whose vision has been partially restored with the Argus II Retinal Prosthesis System.Methods The Functional Low-Vision Observer Rated Assessment (FLORA) pilot assessment involved a self-report section, a list of functional visual tasks for observation of performance and a case narrative summary. Results were analysed to determine whether the interview questions and functional visual tasks were appropriate for this ultra-low vision population and whether the ratings suffered from floor or ceiling effects. Thirty subjects with severe to profound retinitis pigmentosa (bare light perception or worse in both eyes) were enrolled in a clinical trial and implanted with the Argus II System. From this population, 26 subjects were assessed with the FLORA. Seven different evaluators administered the assessment.ResultsAll 14 interview questions were asked. All 35 tasks for functional vision were selected for evaluation at least once, with an average of 20 subjects being evaluated for each test item. All four rating options—impossible (33 per cent), difficult (23 per cent), moderate (24 per cent) and easy (19 per cent)—were used by the evaluators. Evaluators also judged the amount of vision they observed the subjects using to complete the various tasks, with ‘vision only’ occurring 75 per cent on average with the System ON, and 29 per cent with the System OFF.Conclusion The first version of the FLORA was found to contain useful elements for evaluation and to avoid floor and ceiling effects. The next phase of development will be to refine the assessment and to establish reliability and validity to increase its value as an assessment tool for functional vision and well-being.
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Background Retinal prosthesis systems (RPS) are a novel treatment for profound vision loss in outer retinal dystrophies. Ideal prostheses would offer stable, long-term retinal stimulation and reproducible spatial resolution in a portable form appropriate for daily life. Methods We report a prospective, internally controlled, multicentre trial of the Argus II system. Twenty-eight subjects with light perception vision received a retinal implant. Controlled, closed-group, forced-choice letter identification, and, open-choice two-, three- and four-letter word identification tests were carried out. Results The mean±SD percentage correct letter identification for 21 subjects tested were: letters L, T, E, J, F, H, I, U, 72.3±24.6% system on and 17.7±12.9% system off; letters A, Z, Q, V, N, W, O, C, D, M, 55.0±27.4% system on and 11.8%±10.7% system off, and letters K, R, G, X, B, Y, S, P, 51.7±28.9% system on and 15.3±7.4% system off. (p<0.001 for all groups). A subgroup of six subjects was able to consistently read letters of reduced size, the smallest measuring 0.9 cm (1.7°) at 30 cm, and four subjects correctly identify unrehearsed two-, three- and four-letter words. Average implant duration was 19.9 months. Conclusions Multiple blind subjects fitted with the Argus II system consistently identified letters and words using the device, indicating reproducible spatial resolution. This, in combination with stable, long-term function, represents significant progress in the evolution of artificial sight.
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To describe the methods and innovations used in constructing the VisQoL, a vision-related utility instrument for the health economic evaluation of eye care and rehabilitation programs. The VisQoL disaggregates vision into six items. Utilities were estimated for item worst responses (the worst level for each item, with all other items at their best level) and VisQoL all-worst responses (all items at their worst level) using the time trade-off procedure. Time trade-off questions require people to imagine living a fixed number of years with a particular health condition and then indicate how many of those years of life they would be willing to trade to have perfect health. Where respondents indicated a health state was "worse than death" negative utilities were estimated. Time trade-off questions minimized the "focusing effect," which occurs if respondents discount the fact that all other aspects of health are at their best when answering questions, by using pictorial and verbal aids. Item utilities were combined using a multiplicative model, and VisQoL model utilities placed on a scale where 0.00 and 1.00 represent full health and death, respectively. The VisQoL allows utilities to be calculated for a wide range of vision-related conditions. The 6-item VisQoL has excellent psychometric properties and is specifically designed to be sensitive to vision-related quality of life. It is the first instrument to permit the rapid estimation of utility values for use in economic evaluations of vision-related programs.
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We studied the capabilities of the Argus II retinal prosthesis for guiding fine hand movement, and demonstrated and quantified guidance improvement when using the device over when not using the device for progressively less predictable trajectories. A total of 21 patients with retinitis pigmentosa (RP), remaining vision no more than bare light perception, and an implanted Argus II epiretinal prostheses used a touchscreen to trace white paths on black backgrounds. Sets of paths were divided into three categories: right-angle/single-turn, mixed-angle/single-turn, and mixed-angle/two-turn. Subjects trained on paths by using prosthetic vision and auditory feedback, and then were tested without auditory feedback, with and without prosthetic vision. Custom software recorded position and timing information for any contact that subjects made with the screen. The area between the correct path and the trace, and the elapsed time to trace a path were used to evaluate subject performance. For right-angle/single-turn sets, average tracing error was reduced by 63% and tracing time increased by 156% when using the prosthesis, relative to residual vision. With mixed-angle/single-turn sets, error was reduced by 53% and time to complete tracing increased by 184%. Prosthesis use decreased error by 38% and increased tracing time by 252% for paths that incorporated two turns. Use of an epiretinal visual prosthesis can allow RP patients with no more than bare light perception to guide fine hand movement visually. Further, prosthetic input tends to make subjects slower when performing tracing tasks, presumably reflecting greater effort. (ClinicalTrials.gov number, NCT01123928.)
Article
This study evaluated the Argus II Retinal Prosthesis System (Second Sight Medical Products, Inc., Sylmar, CA) in blind subjects with severe outer retinal degeneration. Single-arm, prospective, multicenter clinical trial. Thirty subjects were enrolled in the United States and Europe between June 6, 2007, and August 11, 2009. All subjects were followed up for a minimum of 6 months and up to 2.7 years. The electronic stimulator and antenna of the implant were sutured onto the sclera using an encircling silicone band. Next, a pars plana vitrectomy was performed, and the electrode array and cable were introduced into the eye via a pars plana sclerotomy. The microelectrode array then was tacked to the epiretinal surface. The primary safety end points for the trial were the number, severity, and relation of adverse events. Principal performance end points were assessments of visual function as well as performance on orientation and mobility tasks. Subjects performed statistically better with the system on versus off in the following tasks: object localization (96% of subjects), motion discrimination (57%), and discrimination of oriented gratings (23%). The best recorded visual acuity to date is 20/1260. Subjects' mean performance on orientation and mobility tasks was significantly better when the system was on versus off. Seventy percent of the patients did not have any serious adverse events (SAEs). The most common SAE reported was either conjunctival erosion or dehiscence over the extraocular implant and was treated successfully in all subjects except in one, who required explantation of the device without further complications. The long-term safety results of Second Sight's retinal prosthesis system are acceptable, and most subjects with profound visual loss perform better on visual tasks with system than without it.
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The Activity Inventory (AI) is an adaptive visual function questionnaire that consists of 459 Tasks nested under 50 Goals that in turn are nested under three Objectives. Visually impaired patients are asked to rate the importance of each Goal, the difficulty of Goals that have at least some importance, and the difficulty of Tasks that serve Goals that have both some importance and some difficulty. Consequently, each patient responds to an individually tailored set of questions that provides both a functional history and the data needed to estimate the patient's visual ability. The purpose of the present article is to test the hypothesis that all combinations of items in the AI, and by extension all visual function questionnaires, measure the same visual ability variable. The AI was administered to 1880 consecutively-recruited low vision patients before their first visit to the low vision rehabilitation service. Of this group, 407 were also administered two other visual function questionnaires randomly chosen from among the Activities of Daily Living Scale (ADVS), National Eye Institute Visual Functioning Questionnaire (NEI VFQ), 14-item Visual Functioning Index (VF-14), and Visual Activities Questionnaire (VAQ). Rasch analyses were performed on the responses to each VFQ, on all responses to the AI, and on responses to various subsets of items from the AI. The pattern of fit statistics for AI item and person measures suggested that the estimated visual ability variable is not unidimensional. Reading-related and other items requiring high visual resolution had smaller residual errors than expected and mobility-related items had larger residual errors than expected. The pattern of person measure residual errors could not be explained by the disorder diagnosis. When items were grouped into subsets representing four visual function domains (reading, mobility, visual motor, visual information), and separate person measures were estimated for each domain as well as for all items combined, visual ability was observed to be equivalent to the first principal component and accounted for 79% of the variance. However, confirmatory factor analysis showed that visual ability is a composite variable with at least two factors: one upon which mobility loads most heavily and the other upon which reading loads most heavily. These two factors can account for the pattern of residual errors. High product moment and intraclass correlations were observed when comparing different subsets of items within the AI and when comparing different VFQs. Visual ability is a composite variable with two factors; one most heavily influences reading function and the other most heavily influences mobility function. Subsets of items within the AI and different VFQs all measure the same visual ability variable.
Foundations of Orientation and Mobility, Third Edition: Volume 2, Instructional Strategies and Practical Applications
  • Wiener WR
  • Welsh RL
  • Blasch BB