Objectives: To validate the RAPD neoscore, a simple and objective metric for detecting RAPD, by comparing its diagnostic accuracy with traditional clinical evaluations.

Methods: A cohort of 164 individuals, comprising healthy controls and patients clinically diagnosed with RAPD, underwent neuro-ophthalmic evaluation using a PRET device (machineMD, Switzerland) alongside standard clinical assessments. Diagnoses included relapsing-remitting multiple sclerosis (RRMS, n=35), primary progressive multiple sclerosis (PPMS, n=2), secondary progressive multiple sclerosis (SPMS, n=2), and other demyelinating disorders (n=5). RAPD neoscore calculations were performed independently and blinded at a separate site. Diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis to determine sensitivity, specificity, and area under the curve (AUC).

Results: ROC analysis revealed an AUC of 0.80 ± 0.02 for RAPD neoscore across all RAPD cases. When clinically ambiguous cases were excluded, the discriminative performance improved, with an AUC of 0.83 ± 0.02, indicating good diagnostic accuracy.

Conclusions: The RAPD neoscore demonstrates robust agreement with traditional clinical assessments, highlighting its strong potential as a digital biomarker. Given the proposal to include optic nerve evaluation in diagnostic criteria for multiple sclerosis (MS), RAPD neoscore’s standardized and objective measurement could fulfill the dissemination-in-space criterion. This may significantly enhance diagnostic accuracy, facilitate monitoring, and support clinical decision-making in neuro-ophthalmology and multiple sclerosis diagnostics, ultimately improving patient outcomes.

Purpose: The purpose of this study was to assess the feasibility of detecting relative afferent pupillary defects (RAPDs) using a commercial virtual reality headset equipped with an eye tracker.

Methods: This is a cross-sectional study in which we compare the new computerized RAPD test with the traditional clinical standard using the swinging flashlight test. Eighty-two participants including 20 healthy volunteers aged 10 to 88 years were enrolled in this study. We present a bright/dark stimulus alternating between the eyes every 3 seconds using a virtual reality headset, and we simultaneously record changes in pupil size. To determine the presence of an RAPD, we developed an algorithm analyzing the pupil size differences. For the assessment of the performance of the automated and the manual measurement a post hoc impression based on all available data is created. The accuracy of the manual clinical evaluation and the computerized method is compared using confusion matrices and the gold standard of the post hoc impression. The latter is based on all available clinical information.

Results: We found that the computerized method detected RAPD with a sensitivity of 90.2% and an accuracy of 84.4%, as compared to the post hoc impression. This was not significantly different from the clinical evaluation with a sensitivity of 89.1% and an accuracy of 88.3%.

Conclusions: The presented method offers an accurate, easy to use, and fast method to measure an RAPD. In contrast to today's clinical practice, the measures are quantitative and objective.

Background: Current standard methods in monitoring glaucoma progression, like optical coherence tomography (OCT) and standard automated perimetry (SAP), have limitations in certain cases. Automated relative afferent pupillary defect (RAPD) and pupillary light reflex (PLR) testing may offer more objective alternatives. This pilot study aimed to evaluate whether RAPD could sufficiently distinguish between the two eyes in asymmetrical glaucoma, and thus could lay the foundation for using the PLR of a single eye to monitor progression longitudinally.

Methods: Twenty-one patients underwent quantitative PLR measurements using a virtual reality headset. RAPD was calculated by subtracting the amplitude of PLRs between eyes. Both RAPD and relative SAP (measured using the mean defect or MD) results were correlated to the thickness of the peripapillary retinal nerve fiber layer (RNFL), as measured by OCT.

Results: Data from 18 patients was analyzed after exclusions. RAPD significantly correlated with differences between the two eyes as measured by RNFL thickness (Pearson r = 0.79, p = 0.05). MD differences correlated slightly better with RNFL differences (Pearson r = 0.87, p < 0.05). RAPD and MD combined yielded an improved prediction of RNFL differences by 5% compared to using MD only.

Conclusions: RAPD measurements reliably detected asymmetries in optic nerve damage in glaucoma patients. SAP measurements correlated better with OCT results than RAPD results. However, SAP and RAPD combined led to an improved prediction of RNFL thickness. This could possibly allow us to use PLR only over longer periods of time to monitor glaucomatous optic nerve damage in a single eye in the future.

Purpose: In virtual reality (VR) systems that track eye movements using infra-red cameras, the precision of gaze measurement is crucial for reliable detection of eye movement disorders.

Methods: To assess gaze measurement ability and gaze precision consistency of an HMD VR-based medical device system, neos^™, under optimal conditions, we used a robotized setup that provides the advantage of mimicking human eye movements with minimal movement variability. We assessed neos^™’s gaze examination test twice for thirteen simulated conditions with different noise levels, and then assessed gaze precision and gaze consistency for each by computing the intraclass correlation coefficient (ICC), standard error of measurements (SEM) and Bland-Altman analysis.

Results: We found excellent test-retest reliability (ICC > 0.99, SEM = 0.04) for neos^™’s gaze precision, with good agreements between first and second gaze precision measurements observed via Bland-Altman analysis. The high ICC and low SEM of neos^™ in all nine cardinal directions of gaze demonstrates its eye tracking reliability and measurement consistency. This is a crucial feature for eye-tracking applications for HMD-based VR devices when used in clinical settings.

Conclusions: The use of a robotic eye to objectively validate a VR-based eye tracker can be applicable to other devices. Future research will investigate the longitudinal stability of the measurements in different human populations.

Purpose: Eye and pupil movements are critical biomarkers for assessing neurological conditions. Most functional eye exams are manually performed making them subjective and error-prone; contributing to an estimated 50% misdiagnosis referral rates for neuro-ophthalmic conditions. neos^™ (machineMD, Switzerland) is a novel virtual reality (VR) based measurement device, utilizing a head-mounted VR display and stimuli with infra-red eye tracking and proprietary algorithms to perform neuro-ophthalmological based tests in a non-invasive, automated, and quantitative way. However, validation of eye-tracking-based tools like neos^™ poses inherent challenges, particularly in separating the device’s performance characteristics from those of the examinee. This study outlines a methodology to isolate and evaluate neos’s performance independent of external influences to ensure measurement reliability and robustness.

Methods: We evaluated neos’s gaze precision and pupil size measurement outputs independently using a customized eye-robot that simulates human eye movements and in human participants. We used test-retest reliability as a robust, calibration-independent surrogate metric of gaze precision of robot data that was further analyzed using intraclass correlation coefficients (ICCs), standard error of measurements (SEM), and Bland-Altman analysis. For human participants, we assessed pupil size by comparing neos’s eye tracker measurements and infrared images to visual light images calibrated with a physical scale, using the iris diameter as a reference.

Results:  In robotic trials, neos^™ achieved excellent test-retest reliability for gaze precision (ICC > 0.99, SEM = 0.04), with high agreement between repeated measurements. Bland-Altman plots confirmed minimal bias and narrow variability across measurements, demonstrating robustness even in noisy conditions. Human trials revealed a mean pupil size difference of 0.38 ± 0.20 mm and iris size difference of 1.66 ± 0.38 mm between eye tracker and reference measurements.

Conclusions: The neos^™ device has the potential to automate functional eye movement and pupil response measurements with high precision and minimal operator dependency, which can enhance neuro-ophthalmic diagnostic accuracy in clinical settings. Future studies will investigate its performance in detecting a range of specific biomarkers.

Purpose: Current clinical measurements of strabismus angles (SAs) are manual and require a skilled examiner and active cooperation by patients. This results in high interexaminer variability, and clinical use is limited by the availability of trained examiners. An objective and automated procedure, independent of the examiner, would be useful.

Methods: This single-center, prospective, diagnostic feasibility study compared the vertical and horizontal SA of patients, as measured with a commercially available virtual reality headset (VRH) and custom software with the gold standard measurements performed manually with the Harms tangent screen (HW) and the alternate prism cover test (ACT). We implemented the ACT by showing the patient a fixation target on each eye alternatively with the VRH while recording the eye position of the patient. We then processed the data with custom written software to calculate the SA of the patients. These measurements were then compared to the SA measured with HW and the clinical ACT. Thirty-three patients took part in our study.

Results: We found good correlation between the VRH method and the HW as well as the clinical ACT. Best correlation was found for horizontal SA in the primary position, with the vertical SA in the primary position also correlating well. Peripheral gaze resulted in a slightly lower correlation due to the overestimation of horizontal SA and underestimation of vertical SA; cyclorotation was not measured with the VRH. Overall, VRH, HW, and clinical ACT correlated similarly well as the published interexaminer correlation for ACT.

Conclusions: The automated measurement of strabismus with a VRH is feasible, easily applicable, fast, accurate, and can be run on consumer hardware that is affordable and increasingly available.

Eye and pupil movements are sensitive biomarkers for brain disorders affecting the visual- and the oculomotor pathways. Today, neuro-ophthalmological examinations are usually performed manually. They are time-consuming, require well-trained specialists and the results are mostly qualitative. A new generation of diagnostic tools is need- ed to perform a fast, high-quality, automated, and easy-to-use examination of brain function that provides quantifiable and reproducible data. machineMD, a Swiss medical device company, is developing neos^™, a non-invasive diagnostic device intended to provide an automatic and quantitative full neuro-ophthalmic work-up. It includes eight measures: visual field, efferent pupillary function, afferent pupillary function, ocular alignment, smooth pursuit, saccades, gaze holding, and fusional amplitudes.

Introduction: Although frequently reported by Multiple Sclerosis patients (MS), it is hard to objectify subtle changes in oculomotor function. An objective measure of oculomotor involvement might represent a biomarker alleviating lesion localization, assessing disease progression and response to treatment. We applied a novel eye-tracking tool (PRET™, machineMD AG, Switzerland) to objectively assess a quantitative neuroophthalmological status in moderately to severely disabled MS and healthy controls (HC).

Objectives: We aim to i) demonstrate feasibility of PRET™ in neurological conditions and ii) provide an objective measure of deviations in primary gaze and horizontal/vertical saccades.

Methods: MS and HC were recruited for a pilot study using PRET™, a virtual reality (VR-)headset-based oculography tool (ethics approval no. 23-7934-BR, Ruhr-University Bochum). We examined MS with an expanded disability status scale (EDSS) of ⩾3.0 and sex- and age-matched HC. PRET™ runs an automated programme examining gaze holding and horizontal and vertical saccades, among other parameters not evaluated, here.
Descriptive statistics include median [interquartile range, IQR] and absolute frequencies. Fisher’s exact and Mann-Whitney test were used for comparisons. Exact p-values are given.

Results: We examined 17 MS (47.1 [41.2-56.6] years; n=12 female, n=5 male; n=12 relapsing-remitting MS (RRMS), n=4 secondary progressive MS (SPMS), n=1 primary progressive MS (PPMS); EDSS 4.0 [3.0-5.5]) and 17 HC (47.4 [40.5-56.1] years; n=12 female, n=5 male). None of HC and 8/17 MS reported subjective ocular complaints. All participants underwent PRET™ examination without patient-sided abortion due to discomfort or motion sickness. Primary gaze abnormalities were detected in 7/16 MS and 2/16 HC (data missing in n=1 each, p=0.1134). Saccadic abnormalities were present in 10/17 MS and 3/17 HC (p=0.0324), mostly driven by horizontal saccadic abnormalities, such as subtle internuclear ophthalmoplegia (INO; 8/17 MS, 1/17 HC, p=0.0167; vertical: 5/17 MS, 3/17 HC, p=0.6880). In HC, presence of saccadic abnormalities was not associated with age (p=0.5088).

Conclusions: VR-examination was feasible and well-tolerated by all MS and HC. Primary gaze and saccadic abnormalities were detected in a higher proportion of MS with moderate to severe disability than HC with some specific patterns such as INO not detected during routine clinical examination. VR-based oculography may serve as an outcome tool if further confirmed during our study in different MS stages.

Background: Internuclear ophthalmoplegia (INO) is an eye movement disorder that occurs in approximately one-third of people with multiple sclerosis (MS).

Methods: We used a novel, head-mounted, virtual reality (VR)-based oculography device (PRET™, machineMD AG, Switzerland) to objectively measure oculomotor symptoms reported by a patient with MS to aid in the clinical diagnosis confirmation of INO.

Conclusions: The patient’s symptoms, primarily diplopia, were managed successfully with 4-aminopyridine. The VR-based eye-tracking tool documented the subjective improvement in oculomotor function tracking treatment effects.

Background: Oculomotor symptoms are frequent in Myasthenia Gravis (MG) and significantly contribute to the burden of disease in affected patients. Nevertheless, reporting of performance-dependent occurrence of double vision can often not directly be reproduced during short-term clinical examination. Here, we applied a novel AI-supported tool (PRET™) to objectively assess a quantitative neuroophthalmological status in patients with severe generalized MG and to demonstrate feasibility of PRET™ in neurological conditions affecting the oculomotor system.

Methods: Patients with different neurological conditions and healthy controls are currently recruited for a prospective pilot study using PRET™, a novel virtual reality (VR-) headset-based oculography tool (ethics approval no. 23-7934-BR, 15-Nov-2023, ethics committee of the Medical Faculty of Ruhr-University Bochum). Within this framework, patients with severe generalized MG have been examined clinically and using PRET™ and scored (activities of daily living MG-ADL, quality of life MG-QoL). PRET™ runs an automated programme examining gaze holding and eye movements including horizontal and vertical saccades and horizontal smooth pursuit as well as ocular alignment, fusional amplitudes, visual fields and pupillary function (the latter not evaluated, here) within less than 12 minutes. We qualitatively summarize the data of the first three patients.

Results: We present the baseline data of three MG patients prior to their first infusion of an ongoing efgartigimod treatment, all of whom reporting end-of-dose symptom worsening before reinfusion (Pat. 1: male, 63 years; Pat. 2: male, 43 years; Pat. 3: female, 21 years). All patients reported double vision of varying degrees. They fully underwent PRET™ examination without patient-sided interruption or abortion due to discomfort or motion sickness.

As compared to three healthy participants with only few, patients 1 and 2 showed several saccadic intrusions during gaze holding, yet still being able to fixate with only minor intereye horizontal gaze position difference (below 2°). Patient 3 complaining constant double vision was not able to binocularly fixate in all positions except for right-up gaze (intereye horizontal gaze position difference ranging from 5 to 10° except for right-up gaze with 0-3°).

During smooth horizontal pursuit, performed approximately 7 minutes after start of the examination, the intereye difference is higher as compared to the initial phase of the examination in all three patients hampering binocular fixation. This phenomenon of exhaustion is not seen in either of the healthy participants.

Conclusions: The automated neuroophthalmological examination was feasible in all three patients and informed objectively about performance-dependent worsening of MG-associated oculomotor symptoms during the 12-minute examination. It clearly outperformed sole clinical examination and may serve as a novel outcome tool if further confirmed during our ongoing study.

Background: PRET: (neos) is a novel diagnostic device based on a commercially available virtual reality goggle and has been recently introduced by the company machineMD to serve as a neuro-ophthalmological assessment tool. Although the introduction of innovative devices such as PRET has the potential to improve ophthalmological practice, their clinical practicability and tolerability is not always guaranteed. The aim of this study was therefore to assess the usability and tolerability of PRET.

Methods: A 6-week, prospective study was conducted at our institution in 2024. We included both healthy subjects from our institution and patients from the neuro-ophthalmological clinic. Data on demographics, participants' perception, and evaluation of the assessment (measured using a visual analog scale [good, mediocre, poor]), the technician's impression of the device's technical performance, as well as the need for surveillance over the assessment, were obtained via a standardized questionnaire by the same technician. The study was approved by the ETH Zurich Ethics Commission (EK 2024-N-177) and informed consent was obtained.

Results: There were 43 participants included in the study, of whom 39 were healthy subjects from our institution and 4 patients from our neuro-ophthalmological practice. Of the total cohort, 20 were women and the median age was 37 years (range 20 - 84). Overall, 86% of participants rated the device as good. Approximately 70% of participants reported no issues with the assessment, 6.2% perceived the exam as strenuous, and only one felt dizzy (without nausea) during the assessment. From a technician's perspective, PRET performed very well in most cases, with technical difficulties occurring during testing in 16% of cases and either before or after testing in 4% of cases. Of the participants, 49% were left with transient goggle marks after the examination, which was considered an acceptable adverse effect.

Conclusions: In this study, neuro-ophthalmological assessment with PRET demonstrated promising results in terms of clinical practicability and patient tolerance. However, in its current form, PRET is not self-explanatory and requires supervised care by a technician. Further studies are needed to corroborate our findings in a patient-based cohort.