Virtual Reality Enables Rapid and Multi-Faceted

Retinal Function Screening

Margarita Labkovich (  margarita.labkovich@icahn.mssm.edu )
margarita.labkovich@icahn.mssm.edu https://orcid.org/0000-0001-9500-348X
Andrew Warburton
Icahn School of Medicine at Mount Sinai
Christopher Cheng
Oluwafeyikemi Okome
Vicente Navarro
Randal Serafini
Icahn School of Medicine at Mount Sinai https://orcid.org/0000-0002-5836-3686
Aly Valliani
Icahn School of Medicine at Mount Sinai
Harsha Reddy
James Chelnis
Icahn School of Medicine at Mount Sinai

Article

Keywords:

Posted Date: October 11th, 2022

DOI: https://doi.org/10.21203/rs.3.rs-2011868/v1

License:   This work is licensed under a Creative Commons Attribution 4.0 International License.
Read Full License

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Abstract
Background: Given global population growth and aging, it is imperative to prioritize early eye disease
detection and treatment. However, the current eye specialist workforce capacity is not bridging the
growing gap, making it important to consider alternative solutions for increasing eye screening
capabilities. This study compared virtual reality (VR) vision screening exams that help evaluate retinal
health, such as 24-2 perimetry, Ishihara color blindness, and Amsler grid tests, against their in-clinic
counterparts. Methods: 86 subjects were recruited from Mount Sinai’s ophthalmology clinic for a head-to-
head comparison trial that was internally controlled across healthy controls and eyes with glaucoma and
retinal disease. Results: Perimetry results from Humphrey Visual Field Analyzer (HVFA) and VR
suprathreshold testing demonstrated a good sensitivity both overall (80% OD, 84% OS) and across control
(86% OD, 89% OS), glaucoma (69% OD, 78% OS), and retinal disease (76% OD, 80% OS) groups. A
Garway-Heath anatomical map showed an overall 70-80% agreement. Ishihara plate tests did not show a
significant difference between the two testing modalities (p = 0.12; Mann-Whitney U test), which remained
true across groups. Amsler grid testing differences were also non-significant (p = 0.81; Mann-Whitney U
test), including each subgroup. Patient time required to complete VR exams was significantly improved
(p<0.0001; Wilcoxon) compared to the gold standard tests. Conclusions: All VR tests showed high
sensitivity and percent agreement compared to in-office standards, indicating a promising potential for
VR technologies in visual function screening for early identification of prevalent diseases such as
glaucoma and retinal conditions.

Introduction
A general lack of vision specialists and a growing need for vision care that was accentuated by the
COVID-19 pandemic contributes to a rising prevalence of undiagnosed, advanced vision disorders.1–5 In
the United States alone, it is estimated that 1.5 and 2 percent of the 40 + year-old population suffers from
age-related macular degeneration (AMD) and glaucoma, respectively.6,7 In the developing world, CMV
retinitis presents a high disease burden with a 5–15% of those afflicted developing blindness.8
Furthermore, lower socioeconomic status has been associated with more advanced visual function loss
in glaucoma and AMD at the time of diagnosis.9–11 Local availability of specialized vision testing leads
to faster disease identification/awareness and successful treatment of retinal diseases like diabetic
retinopathy (DR) and AMD.12

Several studies have demonstrated the clinically meaningful benefits of empowering adult vision
screening or monitoring in a primary care or community setting, particularly in identifying irreversible
retinal diseases that could require immediate ophthalmic intervention, such as glaucoma, DR, and
AMD.13,14 The benefits of implementing each test independently of a complete eye examination in a
primary care setting have been variable. For example, mixed outcomes have been found for acuity testing
in underserved or older populations.15–18 However, screening tools that can detect functional vision
impairment to ensure early-stage treatment have shown more promise. Such tests range from relatively

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sophisticated technologies, such as tonometers, to growingly available functional technologies, such as
perimetry and Amsler grid tests.19–24 Benefits have also been observed from early treatment and
identification of AMD and DR using manual ophthalmoscopy or portable fundus photography and Amsler
grid testing.25

Given that many neurologic and endocrine conditions manifest in the eyes, multimodal vision testing
tools such as color vision and scotoma testing can enhance a screening potential for these conditions.26
As with the ophthalmic diseases discussed above, non-ocular conditions such as multiple sclerosis,
pseudotumor cerebri, cerebral neoplasms, and cerebrovascular accidents have a higher rate of treatment
success with early detection and treatment.

Performing rapid vision testing across various clinical environments requires a portable, fast, and easy-to-
use technology that allows administration of several vision function exams from the same device.12
Integrating a series of retinal health screening exams into one platform would allow for multimodal
functional testing that can localize abnormalities to a specific anatomical area of the retina while
allowing for improved user feasibility within a single device platform.

Ophthalmic tests have successfully been adopted on portable devices such as tablets and virtual reality
(VR) headsets.27–32 To contribute to this progress, our group developed a platform that provides a more
comprehensive vision screening method to evaluate retinal health by developing a battery of VR vision
tests that are analogous to ophthalmic in-office tests. This study compares the performance of VR
analogues (24 − 2 suprathreshold perimetry, Ishihara Tiles, and Amsler Grid tests) against their in-office
standards. The primary outcome measure of this study was evaluating outcome similarities between
each modality in healthy eyes and those with glaucoma and retinal abnormalities. Secondary outcome
was the test time to complete perimetry exam.

Methods
Overall Study Design
This study was approved by the Institutional Review Board (IRB) of the Icahn School of Medicine at
Mount Sinai (IRB #19–00679). Patient recruitment was conducted at the Mount Sinai 102nd Street
ophthalmology clinic on a voluntary basis with randomization of either the clinical gold standard exams
followed by the VR counterpart or vice versa. Patients were then stratified into either healthy controls or
disease groups for a glaucoma or retinal disease diagnosis. Glaucoma group consists of mild, moderate,
and severe stages of primary open angle glaucoma. Retinal group has patients with many posterior
chamber diagnoses, including macular degeneration, diabetic retinopathy, retinal tears, detachments,
scars, macular changes with drusen, optic nerve head drusen, optic atrophy. Patients with both glaucoma
and retinal disease diagnoses (N = 6 patients) were included in each disease group. Table 1 breaks these
groups down by age, gender and ethnicity.

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Due to factors such as time-restraints or workflow restrictions, not all patients completed all three exams
(both in-clinic and VR analogues), resulting in different numbers of participants per test. A comprehensive
diagram of the patient data funnel is shown in Fig. 1. Patients’ data were only included for a particular
test if they completed both the in-office and VR versions. The time taken to complete perimetry testing
was recorded automatically by the Humphrey and VR devices.

VR Hardware and Software

A PICO Neo Eye 2 commercial VR headset was used to demonstrate the hardware-agnostic performance
of the three VR tests. This headset has a 4K screen resolution, controllers, and Tobii eye tracking. Eye
tracking capabilities are essential for ensuring that the patient’s gaze stays focused on the central target,
thereby producing reliable visual field perimetry results. Software was written in Unity Version 2020.3.2.f1
with SDKs on software websites. Tobii Eye tracking technology and SDKs were implemented. Steam VR
was used to monitor the progress of the patient during VR testing. At any time, the patient could terminate
the exam if they experienced any discomfort.
In-Office Standard Tests
A 24 − 2 perimetry test was conducted on a Humphrey Visual Field Analyzer (HVFA) by trained
technicians. A full-threshold 24 − 2 HVFA test was used for increased rigor in comparison to our
suprathreshold VR exam, as our group prioritized the effect of increased speed during examinations. For
red-green color deficit testing, red-green color and control tiles from a physical Ishihara book were used.
For the Amsler Grid, a paper form and pen were given to a participant to draw or circle any abnormalities,
such as distortions, holes, vision gaps, and wavy lines. All results were securely uploaded and encrypted
on a folder with patients de-identified.

Design of VR Tests Compared to Clinical Standards

The VR analogue for the 24 − 2 perimetry test (VR 24 − 2) was designed with an unchanging stimulus
intensity at 25 Apostilibs with 15 non-stimulus points (a point is not shown), testing each point only once.
The points were mapped in accordance with the 24 − 2 degrees from the center to minimize the time
required to complete the exam. The results of VR 24 − 2 were compared to Humphrey results on a point-
by-point analysis to determine % agreement. Eye tracking deviation calibration was performed to
equivocate Unity meters to degrees. The four cardinal positions of gaze (left, right, top, bottom) were
determined to be 0.4 Unity meters in each direction of the 24-degree field, and thus each 0.1 Unity meter is
about 6 degrees, which is an approximate area of the blind spot. Thus, any gaze deviation > 0.1 Unity
meters was considered a true deviation. A Garway-Heath Analysis was applied to both 24 − 2 perimetry
results to further characterize the VR analogue’s performance based on optical nerve fibers and its
percent agreement with Humphrey 24 − 2 results. Patients were encouraged to undergo perimetry testing
on both eyes; however, due to time constraints or workflow restrictions, many patients could only perform
the test on one eye.

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For color deficit testing, a standard red-green/control 12-tile screening was implemented under pre-set VR
illumination conditions similar to an office setting were quantified using a light meter. Both the PICO and
the VIVE headsets at white-light settings on maximum brightness outputted around 250 nits. Specific tiles
testing for red-green color blindness were the focus of analysis rather than magenta-grey controls for a
diseased state. Numeric answer choices were presented in a multiple-choice format.

A virtual pen and standard Amsler grid were provided in a virtual environment, with any dysmorphia
counted as a “pathologic” result. The patients were asked to color in or circle areas with wavy lines,
distortions or spots. The total amount of visible squares in a 20x20 grid was calculated for comparison.

Statistical Analysis
All statistical analyses were conducted in R-4.0.4. Perimetry percent agreement graphs were made with
the ggplot2 package and qplot function in R, with sensitivity and specificity calculations used to assess
statistical differences in perimetry results between modalities. Mann-Whitney-U (with an alpha value set
to 0.05), sensitivity, specificity and accuracy calculations were used to determine the statistical
differences for color blindness and Amsler grids tests. Welch’s t-tests were used to compare HVFA testing
times against those of VR 24 − 2 and a Wilcoxon signed-rank test compared patient satisfaction between
the two testing modalities.

Results
Perimetry
A total of 86 patients were recruited from the Mount Sinai 102nd Street Ophthalmology Clinic. N = 102
eyes completed VR 24 − 2 perimetry and gold standard testing; their results showed 80% sensitivity, 42%
specificity in the right eye (n = 43 eyes) and 84% sensitivity, 59% specificity in the left eye (n = 41 eyes)
compared with HVFA results (Table 2). When stratified by control (86% OD, n = 16 eyes; 89% OS, n = 15
eyes), glaucoma (69% OD, n = 11 eyes; 78% OS, n = 11 eyes), and retinal disease (76% OD, n = 16 eyes;
80% OS, n = 15 eyes) groups, the sensitivity remained high (Table 2).

VR results underwent Garway-Health analysis. Sensitivity varies by structural region, with all the
outcomes listed in Table 2. It is important to note that the quadrant with highest percent sensitivity at a
25 Apostilib threshold is the central part of the retina for the overall (92% OD, 96% OS), control (96% OD,
99% OS), glaucoma (82% OD, 93% OS), and retinal disease (94% OD, 96% OS) groups.

When looking at the percent agreement heat map in Fig. 2, the central retina has the highest agreement
percentage. Overall (n = 43 OD, n = 41 OS), patients exhibited > 80% agreement for both eyes, with superior
arcuate fibers being the weakest region. For controls (n = 16 OD, n = 15 OS) the central field agreement
was generally > 90%, while the superior and inferior arcuate fibers of the outer rim showed the most
disagreement in the right eye (60–80%); only superior arcuate fibers showed disagreement on the left eye
(40–80%). Eyes with glaucoma (n = 11 OD, n = 11 OS) showed high agreement centrally, ranging from

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60–90%. The weakest areas were the superior outer rim for the right eye (40–80%) and the inferior outer
rim for the left eye (30–80%). Eyes with retinal disease (n = 16 OD, n = 15 OS) followed a pattern similar to
other groups, with the central fields showing 80–100% agreement and peripheral fields displaying 40–
70% agreement of the right eye and 60–80% of the left. Notably, disagreement in left eye field was more
pronounced than the right.

Ishihara
N = 116 eyes underwent both in-office and VR test versions of color testing. No significant difference was
observed between the two modalities overall (p = 0.12, U = 1253.5), with sensitivity = 100%, specificity =
79%, and test accuracy = 82% (Table 3). Differences between results were also non-significant among the
control and disease groups, including eyes with glaucoma and retinal abnormalities. Control eyes showed
100% sensitivity and 89% specificity with 89% accuracy and non-inferior testing (p = 0.49, U = 324).
Glaucomatous eyes displayed 100% sensitivity, 45% specificity, and 57% accuracy, while also
demonstrating inter-test comparability (p = 0.051, U = 55). The retinal disease group showed 100%
sensitivity, 89% specificity and 93% accuracy (p = 0.8, U = 92).

Amsler grid
Amsler grid testing of N = 108 eyes showed no significant difference between the two tests (p = 0.81, U =
4514.5); sensitivity = 100%, specificity = 98%, and accuracy = 98%) as shown in Table 4. When comparing
the controls and disease groups, the VR test remains non-inferior for the control (p = 0.74, U = 1352.5),
glaucoma (p = 1, U = 264), and retinal disease groups (p = 0.99, U = 200). The sensitivities were 100% for
each respective group while specificity varied slightly with 96% for control and 100% for diseased groups.
Accuracy was 96% for the control group and 100% for the glaucoma and retina groups.

Exam Efficiency Measured

When asked to testing speed, the time required to complete the HVFA was 336.2 seconds per eye and was
significantly longer compared to the VR perimetry time of 86.7 seconds, as expected with a
suprathreshold examination (p < 0.0001; Welch’s t-test). Given that the HVFA used in this study was a full
field perimetry exam, the threshold version takes approximately half the time, which would be 168.1
seconds per eye. The time difference between each test remains significant (p < 0.001; Welch’s t-test).

Discussion
Global vision testing disparities necessitate the introduction of validated, affordable screening and
diagnostic technologies that are developed or adapted for ocular testing, such as VR headsets, to address
the problem. To-date, few groups have performed direct comparison using several VR vision screening
tests against in-office standards within a single clinical trial. In the present study, our group performed a
non-inferiority trial between in-office and VR analogues of 24 − 2 perimetry (HVFA vs. suprathreshold
single contrast value), Ishihara (book vs. multiple choice), and Amsler grid (paper vs. digital free-handing)
tests.
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All three VR tests showed high sensitivity compared to in-office tests, although VR perimetry performance
showed some level of geographical dependence on a Garway-Heath map. The central field showed the
highest percentage sensitivity and agreement between the VR and HVFA results at a 25 Apostilb
threshold. Overall, perimetry VR results have a moderately high sensitivity that remained after patients
were stratified into control and disease groups for glaucoma and retinal diseases. It is important to note
that control eyes had higher sensitivity than glaucoma and retinal disease eyes, suggesting that this
technology can serve as a screening device. Additionally, in the glaucoma group, the superior and inferior
nasal regions that are known to provide a characteristic pattern of glaucomatous field loss have the
highest overall sensitivity.33 On the other hand, the retina group had a high percent sensitivity in the
central region of the field that is known to be most at-risk in conditions such as macular degeneration.34

VR analogues of Ishihara and Amsler tests also proved comparable to gold standards in overall and
within both healthy control and disease groups. Of note, while each group had high sensitivity, the
specificity and accuracy did vary, with the glaucoma group having the lowest figures. This could be due
to peripheral vision field loss interfering with answer selection since each answer choice is positioned
inferior to the Ishihara letter on the screen.

The transition to value-based care in the United States has emphasized empowering as well as financially
and technically supporting primary care providers. Recent advancements in portable imaging and
machine learning have enabled the adoption of handheld retinal cameras, with diabetic retinopathy
diagnostic algorithms, in primary care settings. While studies on vision screening for various conditions
with different testing modalities present mixed conclusions, the literature largely supports increasing
vision testing capabilities in rural and under-resourced populations, as well as for populations at risk of
progressive diseases such as glaucoma, AMD, and DR.13,14

Several studies have now documented VR-mediated perimetry examinations.29,35,36 Most of these tests,
however, are direct analogues of existing perimetry tests that modify visual stimulus signal intensity and
some measure intratest outcomes to demonstrate reproducibility. Furthermore, some studies that have
tested directly against HVFA report poor inter-device agreement.35 32 Those that do correlate strongly with
HVFA outputs do not show improvement in test time.29,36 To our knowledge, this is a unique advantage of
the accelerated analogue presented here. While uneven sensitivities across Garway-Heath geographic
retinal regions were observed to a certain degree, the lowest sensitivities were comparable to those of
other studies. This result can be improved in the future by moderately increasing the number of stimuli
presented or adding another stimulus intensity threshold, while still keeping the exam substantially
shorter than the HVFA version. When comparing speed of the current analogue exam, the VR 24 − 2
perimetry was approximately 2x faster than the HVFA suprathreshold time.

The use cases for color vision deficit testing are growing every year, with its indications including
Alzheimer’s, Parkinson’s, stroke, multiple sclerosis, AMD, glaucoma, and diabetes.29,37−43 Specifically,
several studies have documented the usefulness of Ishihara tile implementation in characterizing
neurodegenerative disorders, supporting its use as a readily available screening technology.44–46 A
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limitation of the multiple-choice approach presented here is the increased probability of a false positive.
While alternative methods, such as verbal response recording, can be implemented within existing VR
systems, there is a higher risk of technical complications due to factors obstructing communication such
as language barriers. Future studies with this test will involve performance of this VR analogue among
patients with specific neurodegenerative disorders to assess the viability of multiple-choice testing,
particularly in patients with declining mental status.

The Amsler grid has been an essential tool for measuring chronic ophthalmic disease progression,
including AMD.47 Metamorphopsia also presents as a prevalent symptom of neurodegenerative and
demyelinating conditions such as optic neuritis in multiple sclerosis.48,49 The Amsler grid has also been
effective at characterizing stroke-induced visual field deficits.50 These functionalities warrant its presence
on a retinal VR platform.

Altogether, the delivery of a multi-faceted retinal function examination on a single device, such as a VR
headset, can improve the accessibility of vision screening as well as clinical decision-making in
specialties such as neurology, neurosurgery and endocrinology, while also providing the patient with more
comfort than that afforded by standard in-office retinal examinations. Future work will include continued
adaptation of existing tests as well as the development of novel tests that will improve the adoption of
VR technologies in spaces beyond vision specialist practices.

Conclusion
A head-to-head comparison between traditional and VR-based 24 − 2 suprathreshold perimetry, Ishihara
and Amsler grid testing showed good agreement across testing methods for both healthy patients and
those with previously diagnosed glaucoma and retinal pathologies. Improving vision screening
accessibility can help achieve earlier diagnoses, promoting value-based treatments and ameliorating
population health. VR-based screening allows for a more comfortable and speedy testing experience.

Declarations
Acknowledgements

We would like to thank our statistician, Nicholas Kissel, for his help with representing the data in this
manuscript. This research was supported (in part) by an Alpha Omega Alpha Carolyn L. Kuckein Student
Research Fellowship.

Conflict of Interests Statement

Margarita Labkovich, MS, Andrew J. Warburton, MD, Randal A. Serafini, MS, and Aly A.A. Valliani, BA are
co-founders of Retina Technologies. Their involvement has been declared as a Conflict of Interest to the
Institutional Review Board at Mount Sinai.

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Funding

This study has been supported by the Icahn School of Medicine CTSA grant, number UL1TR001433. The
grant was provided by the National Center for Advancing Translational Sciences, National Institutes of
Health.

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Tables 1 To 4
Tables 1 to 4 are available in the Supplementary Files section.

Figures

Figure 1

A breakdown of patients recruited and the data collected for perimetry, Ishihara, Amsler tests. Boxes on
the right summarize data gaps that were mostly due to lack of clinical indication for binocular testing.

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Figure 2

a: Agreement percentage for each point tested on the 24-2 exam coordinate plane with 25 Apostilibsset
as a visibility threshold for total average (top) and control eyes (bottom). b: Point by point agreement of
24-2 exam based on 25 Apostilib threshold in eyes with glaucoma (top) and retinal (bottom) diseases.

Supplementary Files
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This is a list of supplementary files associated with this preprint. Click to download.

Table1To4.docx

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