Automated instrument designed to determine visual photosensitivity thresholds

: The Ocular Photosensitivity Analyzer (OPA), a new automated instrument to quantify the visual photosensitivity thresholds (VPT) in healthy and light sensitive subjects, is described. The OPA generates light stimuli of varying intensities utilizing unequal ascending and descending steps to yield the VPT. The performance of the OPA was evaluated in healthy subjects, as well as light sensitive subjects with achromatopsia or traumatic brain injury (TBI). VPT in healthy, achromatopsia, and TBI subjects were 3.2 ± 0.6 log lux, 0.5 ± 0.5 log lux, and 0.4 ± 0.6 log lux, respectively. Light sensitive subjects manifested significantly lower VPT compared to healthy subjects. Longitudinal analysis revealed that the OPA reliably measured VPT in healthy subjects.

A few studies have been conducted to quantify visual photosensitivity. Wirtschafter and Bourassa [27][28][29] investigated the threshold of discomfort to bright light in normal subjects as well as subjects with neurologic and ophthalmic disorders. They positioned the subjects 50 cm from a large translucent screen marked at the center with a 6 cm fixation target. Four fluorescent lights and two incandescent spotlights aimed at the center of the screen were positioned behind the translucent screen. The luminance of the sources was modified using a motor operated transformer that directly regulated the voltage to the lamps. The subjects were instructed to look at the fixation target and to press a large red button located in front of them as soon as the light became uncomfortable. The luminance at which the subject pressed the button was considered to be the VPT for the trial. The illumination increased from its lowest to its highest value in 15 seconds. The variability of the measured VPTs prevented reliable group comparisons.
Vanagaite et al. [12] measured light discomfort thresholds in individuals with migraine, cervicogenic headache [30], cluster headache [31] and compared to control subjects. They used a high power (800 -1000 W) halogen lamp connected to a rheostat, a modified slit-lamp chin and forehead rest, and heat filters, which blocked a portion of the infrared radiation. Illuminance was measured with a photometer and the subject reported to the operator verbally when the illuminance became uncomfortable. Adams et al. [8] used a similar system and methodology to measure light sensitivity of subjects with benign essential blepharospasm, migraine and compared to control subjects. Cortez et al. [32] further modified the system from Adams et al. [8] to include recording and offline processing of pupil responses during photophobia threshold testing in migraine and non-migraine subjects. In these previous studies, non-control subjects were found to be more light sensitive than control subjects. However, these systems had limitations. They were bulky laboratory instruments requiring significant operator verbal instruction input, generated a significant amount of heat, and were subject to spectral as well as power fluctuation of thermal light sources.
These few previous studies on photosensitivity relied on rudimentary laboratory setups that are not suitable for use in the clinic, are difficult to reproduce in a consistent manner, and are therefore not appropriate for comparative, multicenter, or quantitative studies. There is currently no clinically available instrument or standard protocol to quantitatively assess visual photosensitivity. The lack of reliable, standardized testing protocols and assessment tools for evaluating visual photosensitivity have led to different definitions and criteria of what it means to be "photosensitive". A quantifiable standardized measure would allow us to better understand visual photosensitivity as it relates to different diseases and disorders.
Our goal is to design a novel compact automated computer-controlled instrument to reliably quantify VPT to facilitate assessment of disease severity and enable monitoring of both disease progression and efficacy of treatments over time. In this manuscript, the design, construction, and testing of the Ocular Photosensitivity Analyzer (OPA) and VPT measurements of both healthy and light sensitive subjects with achromatopsia or traumatic brain injury are presented.

Design of OPA
The OPA consists of a computer-controlled LED array mounted on a stand with an adjustable head-chin rest, a video camera that records infrared images of the subject's face, a push button, and a laptop computer (Fig. 1). The light source consists of 210 white light emitting diodes (LED) (COM-11118, White -10 mm, Sparkfun, Niwot, CO). The LEDs are assembled in a custom-built three-dimensional printed polymer-resin bi-cupola curved surface (BIONIKO Consulting, LLC, Miami, FL) mounted on an enclosure (WA-35, Polycase, Avon, OH). The left and right halves of the array each form a curved surface with its center of curvature located at the position of the left eye and right eye, respectively. The distance between the array and subject's eyes is 50 cm. At that distance, the entire LED array covers a field of view (angular subtense of the 23 cm wide array as seen by the subject) of 26 degrees. The LED array is viewed directly by the subject, no diffuser is used. Therefore, the retinal image is a grid of 210 individual LED images.
An additional single blinking white LED producing an illuminance of 0.14 lux (RL5-BW1520, Cool White -5 mm, Super Bright LEDs Inc., St. Louis, MO) is located in the center of the bi-cupola for visual fixation. The blink frequency is 2 Hz. A miniature nearinfrared camera (UI-5241LE, Imaging Development Systems Inc., Woburn, MA) for subject imaging and recording is integrated in the LED array enclosure with a single 850 nm infrared LED (HIR8323/C16, Everlight Americas Inc., Carrollton, TX) for illumination and a 850 nm

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Subject testing protocol
The study was approved by the University of Miami Institutional Review Board. Informed consent was obtained from all subjects. Exam room lighting was adjusted to 4 lux (Mesopic illumination [38]) prior to subject arrival and a five minute adaptation period at minimum was implemented for all subjects. Spectacles and contact lenses were removed prior to testing to avoid optical interference due to tint, anti-reflective coatings, etc. Both eyes were tested simultaneously without pupil dilatation or ophthalmic medication.
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Discussion
To the best of our knowledge, the OPA is the first instrument designed to provide a reliable and quantifiable measure of VPT in a clinical setting. The device will facilitate quantitative assessment of the efficacy of treatments for conditions associated with visual photosensitivity. The instrument design focused on reproducibility and scalability to enable longitudinal and multicenter studies. In addition to VPT, the system provides pupil diameter, palpebral fissure height, and inter-blink interval. These physiologic parameters will help provide a better understanding of the factors associated with visual photosensitivity. The performance of the OPA was evaluated in healthy and light sensitive (achromatopsia or traumatic brain injury) subjects. Light sensitive subjects manifested significantly lower VPT compared to healthy subjects. A longitudinal study revealed that the OPA reliably measured VPT in healthy subjects over one year. Another potential application of the OPA is to quantify light perception thresholds in subjects with vision in the bare light perception range.
The OPA presented in this study differs from the systems used in previous studies in that the determination of VPT is entirely automated and under subject's control. The synthesized speech provides instructions that reduce undesired operator bias and vocal cues, hence producing a more reliable measure. Also, unlike the halogen based system previously described [8,12,30,31] which provided a stimulus starting at an illuminance of 50.0 lux, the OPA can produce a stimulus starting at 1.5 lux allowing for more sensitive VPT measurements. Furthermore, by utilizing LEDs, the OPA produces a more stable output when compared to the halogen light source used in previous studies (Fig. 2) [8,12,[30][31][32]. Lowering the voltage on tungsten halogen lamp produces changes in the spectra. The increased reliability and light output stability of the LEDs may enable more accurate testing in longitudinal studies. The spectral stability is especially important because visual photosensitivity is dependent on the light spectral input [42]. Further research is needed to investigate the relationship between light source spectrum and visual photosensitivity. Additionally, the effect of other parameters including age-related changes in spectral transmission of the crystalline lens as well as lens status (presence of cataract or intraocular lens), may impact the OPA VPT measurements and remain to be studied [43].
The ability to measure pupil diameter, palpebral fissure height and inter-blink interval will help provide deeper insight into the factors that contribute to visual photosensitivity and its variations across individuals or pathologies. For instance, our preliminary studies suggest that subjects with achromatopsia have a larger baseline pupil diameter than healthy subjects. On the other hand, the relative change in pupil diameter increases with the VPT in a manner that seems to be consistent in healthy and achromatopsia subjects. Eventually, we hope that the pupil diameter measurement will also enable predictions of the retinal irradiance at the VPT. Expressing the VPT in terms of retinal irradiance instead of illuminance may help eliminate confounding factors, such as the effects of variations in the pupil response. Furthermore, the relative change in palpebral fissure height remains mostly constant in healthy subjects whereas the achromatopsia subjects showed an increase in range.
One limitation of the present study is that refractive error was not taken into account in the analysis. All subjects wearing spectacles were tested without correction. Since each individual LED of the array forms its own separate small image on the retina, blur due to defocus could significantly reduce retinal irradiance. Therefore, uncorrected refractive error could be one of the factors that contributed to the inter-individual variability in VPT observed in our study. In principle, the measurements can be performed with untinted non-polarizing spectacles or contact lens correction.
Future studies with a larger sample size are warranted to determine the visual photosensitivity threshold differences between healthy subjects and subjects with conditions that affect light sensitivity such as dry eye, blepharospasm, migraine, traumatic brain injury, and retinal genetic disorders (achromatopsia and retinitis pigmentosa) and other retinal dysfunctions. Quantifying the visual photosensitivity thresholds of these individuals may help differentiate these different pathologies. Assessment tools for diagnosing visual photosensitivity have been limited [5]. Improving diagnostic measures and earlier detection criteria has the potential to improve treatment options especially assessing the effectiveness of novel gene therapies. The connection between visual photosensitivity and these pathologies is not clearly understood [19], in part because previous studies have reported visual changes in subjective terms which vary between fields and are not standardized. The OPA provides a reproducible and scalable method of measurement that will allow for a standardized measure of visual photosensitivity across studies.