Methods to Assess Ocular Motor Dysfunction in Multiple Sclerosis

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system causing the immune-mediated demyelination of the brain, optic nerve, and spinal cord and resulting in ultimate axonal loss and permanent neurological disability. Ocular motor dysfunction is commonly observed in MS but can be frequently overlooked or underappreciated by nonspecialists. Therefore, detailed and quantitative assessment of eye movement function has significant potential for optimization of patient care, especially for clinicians interested in treating visual symptoms or tracking disease progression. METHODS:: A brief history of eye tracking technology followed by a contextualized review of the methods that can be used to assess ocular motor dysfunction in MS-including a discussion of each method's strengths and limitations. We discuss the rationale for interest in this area and describe new tools capable of tracking eye movements as a possible means of monitoring disease. RESULTS/CONCLUSIONS:: This overview should inform clinicians working with patients with MS of how ocular motor deficits can best be assessed and monitored in this population. It also provides a rationale for interest in this field with insights regarding which techniques should be used for studying which classes of eye movements and related dysfunction in the disease.

Disease of the Year: Multiple Sclerosis Section Editor: Fiona Costello, MD, FRCP(C) From the Section Editor: The JNO "Disease of the Year: Multiple Sclerosis" series concludes with a focus on cutting edge techniques used to qualitatively and quantitatively evaluate ocular motility abnormalities. In their article, "Methods to Assess Ocular Motor Dysfunction in Multiple Sclerosis," Sheehy and colleagues expand on the earlier works published by Lee et al, and Nerrant et al, which provide an elegant overview of extra-ocular movement findings associated with brainstem disorders, and multiple sclerosis, respectively. The tools highlighted by Sheehy and colleagues add to our understanding of structurefunction relationships in multiple sclerosis, and further expand the role of visual system models in multiple sclerosis research and clinical trials. In the series finale, "The International Multiple Sclerosis Visual System Consortium: Advancing Visual System Research in Multiple Sclerosis," Balcer and colleagues chronicle the inception, development, and achievements of IMSVISUAL, a consortium created by clinicians and researchers committed to advancing the role of visual outcomes in the care of multiple sclerosis patients. The ingenuity and accomplishments of IMSVISUAL will serve to inspire other international collaborations, and further advance scientific discovery in the field of neuro-ophthalmology. Methods to Assess Ocular Motor Dysfunction in Multiple Sclerosis Christy K. Sheehy, MS, PhD, Alexandra Beaudry-Richard, Ethan Bensinger, Jacqueline Theis, OD, Ari J. Green, MD, MCR Background: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system causing the immunemediated demyelination of the brain, optic nerve, and spinal cord and resulting in ultimate axonal loss and permanent neurological disability. Ocular motor dysfunction is commonly observed in MS but can be frequently overlooked or underappreciated by nonspecialists. Therefore, detailed and Department of Neurology (CKS, AB-R, JHS, AJG), University of California, San Francisco, San Francisco, California; School of Medicine (ABR), University of Ottawa, Ottawa, Ontario, Canada; School of Optometry (EB, JT), University of California, Berkeley, Berkeley, California; Vision Science Graduate Group (EB), University of California, Berkeley, Berkeley, California; and Department of Ophthalmology (AJG), University of California, San Francisco, San Francisco, California C.K. Sheehy and A.J. Green hold intellectual property related to the TSLO and its methods. C.K. Sheehy has a financial interest in the TSLO technology (Founder and CEO of C. Light Technologies). E. Bensinger is a paid consultant for C. Light Technologies. A.J. Green has received research support from NMSS, HHMI, Hilton Foundation, Sherak Foundation, Fidelity Foundation and has served on the scientific advisory board for Bionure, as well as provided service as a consultant on the endpoint adjudication committee for Medimmune. He was previously a paid expert witness for Mylan Pharmaceuticals, Amneal Pharmaceuticals, received grant support from Novartis pharmaceuticals, and served as an advisor for Inception Sciences. J. Theis was a paid consultant for C. Light Technologies. The remaining author reports no conflicts of interest. Address correspondence to Christy K. Sheehy, MS, PhD, UCSF Department of Neurology, 675 Nelson Rising Lane, San Francisco, CA 94158; E-mail: [e-mail] 488 quantitative assessment of eye movement function has significant potential for optimization of patient care, especially for clinicians interested in treating visual symptoms or tracking disease progression. Methods: A brief history of eye tracking technology followed by a contextualized review of the methods that can be used to assess ocular motor dysfunction in MS-including a discussion of each method's strengths and limitations. We discuss the rationale for interest in this area and describe new tools capable of tracking eye movements as a possible means of monitoring disease. Results/Conclusions: This overview should inform clinicians working with patients with MS of how ocular motor deficits can best be assessed and monitored in this population. It also provides a rationale for interest in this field with insights regarding which techniques should be used for studying which classes of eye movements and related dysfunction in the disease. Journal of Neuro-Ophthalmology 2018;38:488-493 doi: 10.1097/WNO.0000000000000734 © 2018 by North American Neuro-Ophthalmology Society T here has been growing interest in using visual biomarkers for the noninvasive and quantitative assessment of dysfunction in patients with neurodegenerative disease. These approaches also have gained attention for potential monitoring of disability in patients with multiple sclerosis (MS), Alzheimer Sheehy et al: J Neuro-Ophthalmol 2018; 38: 488-493 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Multiple Sclerosis FIG. 1. Dual Purkinje (Dpi) eye tracking methods. A. As incoming light enters the eye, a reflection (or Purkinje image) is created from each optical surface: the front and back surfaces of the cornea, as well as the front and back surfaces of the lens. Dual Purkinge eye tracking measures the movement of the first and fourth Purkinje images with respect to one another. B. The first and fourth Purkinje images each demonstrate their own reflected image of the incoming light source. (i) As the eye turns away from the light source, the 2 Purkinje images get further apart. (ii) As the eye turns toward the light source, the 2 Purkinje images get closer together, each moving toward the pupil center. Modified from (49). disease, Parkinson disease, and amyotrophic lateral sclerosis with the assumption that damage in these areas precedes or at least parallels other more clinically apparent areas of dysfunction. Visual pathway injury is common during the course of MS, with approximately 80% of patients experiencing some type of subjectively notable visual symptoms during the course of their disease (1,2). The best-known and well-recognized clinical syndrome causing visual symptoms in MS is optic neuritis and resulting chronic optic neuropathy-which involves the afferent visual pathway (3). The quantitative evaluation of the afferent pathway has become increasingly routine in the management of patients with MS, including optical coherence tomography (OCT), low-contrast visual acuity and quantitative color vision testing, and visual evoked potentials. With technological advancements and validation of the clinical usefulness of these methods in the afferent system, quantitative analysis of ocular motor dysfunction has received far less attention in MS. The efferent visual pathways encompass and traverse entirely different-and significantly broader-areas and networks when compared with the afferent system. Studying eye movement dysfunction can potentially provide valuable information on a much wider area of the brain susceptible to injury, with potential relevance for monitoring of cognitive, cerebellar, and motor domains. In addition, unlike the static structural view provided by OCT and MRI, eye motion recordings provide a measure of functional preservation of the nervous system, which should be recognized to be of significant importance in assessing a disease in which disability is manifested by disruption of normal neuronal functions. The efferent visual pathways are responsible for 3 fundamental visual sensory-motor integration tasks: resolving the visual field while we are moving in space (self-motion), resolving the visual field when objects are moving in space Sheehy et al: J Neuro-Ophthalmol 2018; 38: 488-493 (object motion), and quickly shifting our eyes and attention from one object to another (saccades and retinal image stabilization) (4). To properly maintain control of these motor functions, many different parts of the brain must work together to plan, coordinate, and execute each required task. These areas include (a) the supranuclear regions of the brain, including the superior colliculus, the substantia nigra, the cerebellum, frontal and supplementary eye fields, the medial temporal visual area, the medial superior temporal visual area, the lateral intraparietal area, and the posterior parietal area; (b) the brainstem nuclei that ensure eye motion of proper amplitude, velocity, and duration; (c) third, fourth, and sixth cranial nerves; (d) the extraocular muscles responsible for translation and rotational motion of the eye (4); and (e) the white-matter tracts connecting all these areas. For retinal image stabilization, or fixation in particular, all 3 degrees of freedom of the extraocular muscles are used, requiring the full coordination of the ocular motor pathways. If any one part of these areas develop a lesion due to MS, gaze holding will be directly impacted (even without the conscious perception of the patient, beyond perhaps feeling "unsteady" or "not quite right"-both of which are commonly reported complaints from patients with MS). In addition, eye movement, both the voluntary and involuntary types, requires attention and cognitive function to perform optimally. MS patients with abnormal eye movements become more disabled than those with normal eye movements (5). Using clues provided directly from the motion of the eye could allow the clinician important information to monitor and assess prognosis of their patients with MS. Current tools for assessing ocular motor dysfunction within the clinic are lacking, rather relying on bedside visual examinations and the astute observations of experienced physicians. Several ocular motor abnormalities are common 489 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Multiple Sclerosis FIG. 2. Fixational eye motion abnormalities in central position recorded with the tracking scanning laser ophthalmoscope (TSLO). A. An asymptomatic, subclinical downbeat nystagmus of a patient with MS during a 10-second TSLO recording. Note the rhythmic slow-phase drifts, followed by corrective fast-phase microsaccades. This downbeat nystagmus has an amplitude ranging from 0.15° to 0.5°. B. A subclinical square-wave jerk train in the horizontal direction of a MS patient reporting oscillopsia, with an amplitude ranging from 0.2° to 0.5°. A square-wave jerk contains 2 microsaccades in the opposite direction separated by a refractory period (w200 ms). during the course of MS, with the most well recognized of them being internuclear ophthalmoplegia (INO) (5,6). However, there are many other eye movement abnormalities including saccadic dysmetria, saccadic intrusions, nystagmus, fixational deficits, smooth pursuit impairment, skew deviation, and optokinetic and vestibulo-ocular reflex impairments. It is often underappreciated, but should be noted, that the frequency reported for any of these deficits in the MS population is dependent on the stage of disease for the population studied and the tools used for assessment. The clinical examination often has the lowest rate of detection suggesting that some patients may have subjective deficits that escape beside evaluation and require more sophisticated testing techniques. Within this review, we will briefly describe the history of eye movement recordings and then describe the current clinical and research methods available to assess ocular motor dysfunction in patients with MS. CLINICAL METHODS TO ASSESS EFFERENT PATHWAY DEFICITS Clinicians evaluating patients with MS should be armed with specific tests for each ocular motor disorder, helping them to localize the lesion, assess its severity, and stage the disease. A thorough bedside examination should include (a) examining eye stability in primary position and in the 9 cardinal fields of gaze; (b) evaluating horizontal and vertical conjugate eye movements using the physiological H test; (c) testing smooth pursuit; (d) measuring horizontal and vertical saccades; (e) observing the efficiency of the vestibulo-ocular reflex; and (f) evaluating convergence. A comprehensive bedside examination of ocular motor function is important to detect deficits that may be asymptomatic or may cause symptoms that the patient does not immediately tie to eye motion (including "blurring" 490 and "dizziness"). However, the major limitations of bedside examination techniques are their qualitative nature and subjectivity. Inclusion of quantitative, noninvasive eye movement testing in the evaluation of patients with MS could help support clinical decisions and potentially reduce misdiagnoses (7). CURRENT AND EMERGING OCULAR MOTOR RESEARCH TOOLS Contact Lens Recording Methods The first attempts at recording eye movements were performed at the end of the 19th century using a physical lever attached to a plaster eye cup. However, this invasive approach posed risks related to corneal damage and extraocular muscle injury (8,9). The optical lever method was developed to overcome these obstacles; accuracy is attained by attaching a small mirror to a contact lens and recording the reflection of a collimated beam of light on a mirror (10). This method is limited to small eye movements because of the slippage of the contact lens during larger ocular excursions. It can be extremely accurate, recording motion as small as 3 arcseconds (11). The popularity of this method has waned in recent years with advancing technologies due to the extremely invasive nature of the mirror upon the contact lens, the inability to blink during usage and recording, and the risk of injury to subjects with large eye movements. Fixational eye motion, as well as small voluntary saccades, can be recorded accurately using this technique. The magnetic search coil method was developed to allow for the simultaneous recording of torsional and translational eye movements by using 2 orthogonal search coils embedded in to a scleral contact lens (12). A current is induced in the coils by a surrounding magnetic field, and the voltages from the coils Sheehy et al: J Neuro-Ophthalmol 2018; 38: 488-493 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Multiple Sclerosis TABLE 1. Summary of the main features of eye movement recording methods System performance Tracking accuracy (arcminutes) Largest eye movements recordable Temporal frequency (Hz) Field of view (°) System limitations Direct retinal measurement of gaze position Head stabilization required Invasiveness Optical Lever (11,47) Magnetic Search Coils (10) EOG (10) Dpi V (26,27) Tobii Pro Spectrum (48) TSLO (46) 0.05 0.5* 30 1† 18† 0.2 #5° accurately before lens slippage ,±30° (.10° accuracy compromised by lens slippage) ,±25° 150 500-1,000 40 Full field Full field Full field No† No† No† Yes (dental impression board) Direct contact with eye, physical mirror mounted onto contact lens Yes (dental impression board) Direct contact with eye ,±30° #2.5°-5°, dependent on field size 1,200 480-960 20 (30 when dilated) 30 1-10 (model dependent) No† No† Yes No Yes (chin rest and temple pads) None ,±45° (without stimulator optics) 500 No Yes (dental impression board) Electrodes None on skin near eyes None Eye tracking methodologies reviewed here include optical lever, magnetic search coils, EOG, dual Purkinje eye tracking (Dpi), Tobil Pro Spectrum (video-oculography example), and the TSLO (46). *Coils with 2 magnetic fields rely on fixation accuracy for screen calibration; coils with 3 magnetic fields can be calibrated objectively. † Requires screen calibration of fixation targets (accuracy depends on this). DPi V, dual Purkinje generation 5 eye tracker; EOG, electrooculography; Tobii Pro Spectrum, commonly published video-oculography system; TSLO, tracking scanning laser ophthalmoscope. are recorded. This method can be accurate to within 25 arcseconds and has a temporal resolution of 500 Hz (10). The subject's head is held steady with a dental impression plate for best results. Magnetic search coils mainly have been used in primate experiments using rigorous head stabilization and by embedding the search coil directly into the conjunctiva, which removes the error caused by contact lens slippage (13). It also is possible for scleral search coils to affect the eye movements themselves; saccades were found to be slower and take longer when the search coils were used (14). Generally, the magnetic search coil method is believed to be the gold standard for measuring both small fixational eye motions, as well as large voluntary saccades and smooth pursuit measurements. The drawbacks of these contact lens-based tracking systems are their invasiveness; the scleral search coil has been shown to cause corneal deformations and reduced acuity during use for as little as 15 minutes (15). However, magnetic search coils have been used in studying eye movements in MS studies largely focusing on the conjugacy between the 2 eyes during saccadic eye movement (16,17) and vergence eye movements (18-20). Electro-oculography Electro-oculography (EOG) is a method of recording horizontal and vertical eye motion without having any Sheehy et al: J Neuro-Ophthalmol 2018; 38: 488-493 contact with the eye or even requiring the eyes open. To record both horizontal and vertical eye binocular motions, electrodes must be placed bitemporally, as well as above and below the eyes. EOG measures electrical potentials with skin electrodes that are used to measure the change in the rotation of the dipole axis due to eye motion (21). EOG is not well suited to measure fixation or saccades less than 5° due to its accuracy down to only 0.5° (10). EOG is well suited for measuring eye movements for sleep studies because it is the only measurement technique that can be performed with the eyes closed and for measuring eye movements in infants. EOG has been used to measure evoked saccadic (22,23) and vestibulo-ocular (24) eye movements in patients with MS, but its utility is highly constrained by its limited accuracy. Dual Purkinje Eye Tracking The dual Purkinje (Dpi) system tracks the eye using the first Purkinje image from the anterior surface of the cornea and fourth Purkinje image from the posterior surface of the lens (Fig. 1) (25). The 2 reflections move together, but by different amplitudes, and this difference can be used to measure the rotation of the eye down to an accuracy of 1 arcminute with a temporal resolution of 500 Hz (26). 491 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Multiple Sclerosis The Dpi system suffers from an artifact known as "lens wobble;" high accelerations from saccades cause shifts in the location because of the elasticity of the zonules of the lens (27). When dual Purkinje and magnetic search coil method are compared, the difference in eye position during saccades could be as large as half a degree (27), though generally the methods are comparable. Dpi eye tracking has been used in studies focused on MS (28). Dpi eye tracking is suitable for the study of fixational motion as well as saccades and smooth pursuits up to 45°, although larger saccades will cause significant lens wobble artifacts (29). Pupil-Based Eye Tracking Video-oculography, using the reflection of light (typically infrared) off of the cornea to track where the pupil has shifted, has gained a lot of traction in eye movement research over the past few decades because of its noninvasive recording nature. Screen-based oculography devices, as well as goggles and VR headsets, are available for use. The top research-grade pupilbased eye trackers are made by Tobii (9,230 publications in 2017), SMI (6,040 publications in 2017), EyeLink (5,530 publications in 2017), ISCAN (2,650 publications in 2017), and LC Technologies (1,130 publications in 2017) (30). Video-oculography has been used to study eye motion in MS, focusing mainly on saccades, INO, and the conjugacy between eyes (31-40). The pupil-tracking method is best suited for saccades and smooth pursuit. Depending on the device and the machine's calibration accuracy (all pupiltracking systems require screen calibration before the start of recording), some video-oculography systems may be able to measure microsaccades during fixation. It is important to note that pupil tracking performed during tasks with changing luminance values, such as viewing a movie, can result in an error of reported pupil location up to 2.5° if changes in pupil size are not compensated for (41-43). Pupil tracking is best suited for larger voluntary saccades, smooth pursuit, and vergence measurements. As stated, certain research-grade systems may have the accuracy to detect microsaccades of particular amplitude; consult the vendor and calibration procedures before use. Scanning Laser Ophthalmoscopy The scanning laser ophthalmoscope (SLO) was first developed by Webb et al in 1981 (44). The SLO relays laser light through an optical system onto the pupil of the eye and then focuses light on the retina. The light that hits the eye is raster scanned at the retina, recording retinal structure pixel by pixel over time and creating a real-time movie of retinal structure. This light is then reflected back out of the eye and onto a camera. These images can then be used for image-based retinal eye tracking. SLO systems are just starting to make their mark on MS ocular motor research in the area of fixational eye motion recordings. Mallery et al (45) studied fixational eye motion stability/instability using the SLO provided within a Heidelberg OCT device (Heidelberg, Germany). 492 Typically these SLO-OCT-based systems will have a lower temporal resolution, providing roughly only a w4-8 Hz tracking bandwidth (45). Although this temporal resolution does not allow for accurate recording of the specific types of eye movements that occurs during fixation, microsaccades, and drift, it does offer a coarse estimate of where the eye has traversed during fixation. This can provide a stability/ instability road map for physicians. The tracking SLO (TSLO) (46) provides noninvasive eye tracking for fixational eye motion with a tracking accuracy down to 1 mm. A TSLO from C. Light Technologies was used to compare 111 patients with MS to 100 healthy controls, and clear changes in the microsaccadic velocity, amplitude, and frequency were seen between patients and controls. In addition, the number of microsaccadic occurrences during a 10-second recording increased with increasing disability as defined the expanded disability status scale score (Sheehy et al, submitted, 2018). This device allows for the accurate recording of both the microsaccades and drift of the eye noninvasively, as well as small voluntary saccades ,2.5° for the 5° field of view (FOV) system and saccades ,5° for their 10° FOV system. Figure 2 showcases one MS patient with a subclinical jerk nystagmus and one with a micro square-wave jerk, both recorded during fixation with the TSLO device. This device is not suited for studies with large voluntary motion of the eye. Comparison of the methods available to researchers to record eye movements in patients with MS is listed in Table 1. The optimal method will vary depending on the type of eye motion to record, the necessary temporal frequency, the invasiveness, and the accuracy of the measurement desired. Summary Eye movement abnormalities are exceptionally common in MS. Bedside techniques for measuring these abnormalities are valuable but are limited by their subjectivity and lack of sensitivity. Many patients may have symptoms that are not adequately assessed without quantitative, highly reliable means to assess ocular motor performance. 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