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We successfully used a LATER (linear approach to threshold with ergodic rate) analysis of the latencies of corrective saccades in patients with acute vestibular neuritis. We found two types of covert saccades: early (90 ms) covert saccades. Predictability led to an increase in VOR gain and a decrease in saccade latency.

Vertical pendular nystagmus (PN) rarely occurs with acute pontine lesions. To hypothesize a pathophysiology for acute vertical PN, we analyzed the clinical characteristics and quantitative eye-movement recordings of one new case with acute vertical PN and an additional 11 patients from the literature. Most patients had extensive pontine lesions causing either the locked-in syndrome or unresponsiveness, but two conscious patients had focal lesions restricted to the paramedian caudal pontine tegmentum. All patients presented a complete or partial horizontal gaze palsy, and about half showed ocular bobbing before or during the appearance of vertical PN. The vertical oscillations were conjugate at a frequency of 1-5 Hz, and the amplitudes were variable, ranging from 0.2° to 40°. The peak velocities were asymmetric in some patients, faster with downward movements. About half of the patients developed palatal tremor several weeks or months after presenting with acute vertical PN. Based on the location of the lesions and results of eye-movement recordings, we suggest two possible mechanisms for acute vertical PN; oscillations originating in the inferior olives due to disruption of the central tegmental tract or low-velocity saccadic oscillations caused by omnipause neuron damage.

We report a patient with spontaneous upbeat nystagmus (UBN) due to an ischemic lesion involving the paramedian tract (PMT) in the medulla. Eye movement recordings, using an infrared video-oculography (VOG) system, showed that the slow phase of the nystagmus was initially velocity-decreasing but gradually became velocity-increasing. Simulation of the nystagmus with a mathematical model supports a role for the PMT in relaying premotor signals for vertical gaze holding to the cerebellum. Our model shows that the disruption in cerebellar input from PMT can lead to the velocity-increasing waveform of the nystagmus, whereas the velocity-decreasing waveform could be related to a mismatch between the innervational commands to the ocular muscles (the pulse and step) needed to hold gaze steady.

Background and ObjectivesLesions of the cerebellar flocculus cause enduring downbeat nystagmus (DBN) with unrelenting oscillopsia. Unlike most patients with DBN, the flocculus is structurally spared in nonalcoholic Wernicke encephalopathy (nWE) with chronic DBN. The objective was to study the effects of alcohol in nWE.MethodsWe recorded eye movements of a unique patient with nWE under controlled alcohol consumption who said his oscillopsia disappeared with a few drinks of alcohol.ResultsHis DBN was markedly diminished by alcohol (by 77.4%), although he remained alert with normal saccades.DiscussionThis striking observation may be caused by the differential effect of alcohol on the perihypoglossal complex and the paramedian tract neurons, which control the level of activity in the flocculus, with opposite (inhibition and excitation, respectively) effects. The finding suggests new ideas about the treatment and pathophysiology of DBN with a structurally intact cerebellum.

Objective Gaze‐evoked nystagmus (GEN) is a central sign in patients with the acute vestibular syndrome (AVS); however, discriminating between a pathological and a physiologic GEN is a challenge. Here we evaluate GEN in patients with AVS. Methods In this prospective cross‐sectional study, we used video‐oculography (VOG) to compare GEN in the light (target at 15° eccentric) in 64 healthy subjects with 47 patients seen in the emergency department (ED) who had AVS; 35 with vestibular neuritis and 12 with stroke. All patients with an initial non‐diagnostic MRI received a confirmatory, delayed MRI as a reference standard in detecting stroke. Results Healthy subjects with GEN had a time constant of centripetal drift >18 s. VOG identified pathologic GEN (time constant ≤ 18 s) in 33% of patients with vestibular strokes, specificity was 100%, accuracy was 83%. Results were equivalent to examination by a clinical expert. As expected, since all patients with GEN had a SN in straight‐ahead position, they showed the pattern of a Bruns’ nystagmus. Conclusions One third of patients with AVS due to central vestibular strokes had a spontaneous SN in straight‐ahead gaze and a pathological GEN, producing the pattern of a Bruns’ nystagmus with a shift of the null position. The localization of the side of the lesion based on the null was not consistent, presumably because the circuits underlying gaze‐holding are widespread in the brainstem and cerebellum. Nevertheless, automated quantification of GEN with VOG was specific, and accurately identified patients in the ED with AVS due to strokes., One third of patients with an acute vestibular syndrome due to central vestibular strokes had a spontaneous nystagmus in straight‐ahead gaze and a pathological gaze‐evoked nystagmus, producing the pattern of a Bruns’ nystagmus with a shift of the null position.

BackgroundNystagmus identification and interpretation is challenging for non-experts who lack specific training in neuro-ophthalmology or neuro-otology. This challenge is magnified when the task is performed via telemedicine. Deep learning models have not been heavily studied in video-based eye movement detection.MethodsWe developed, trained, and validated a deep-learning system (aEYE) to classify video recordings as normal or bearing at least two consecutive beats of nystagmus. The videos were retrospectively collected from a subset of the monocular (right eye) video-oculography (VOG) recording used in the Acute Video-oculography for Vertigo in Emergency Rooms for Rapid Triage (AVERT) clinical trial (#NCT02483429). Our model was derived from a preliminary dataset representing about 10% of the total AVERT videos (n = 435). The videos were trimmed into 10-sec clips sampled at 60 Hz with a resolution of 240 × 320 pixels. We then created 8 variations of the videos by altering the sampling rates (i.e., 30 Hz and 15 Hz) and image resolution (i.e., 60 × 80 pixels and 15 × 20 pixels). The dataset was labeled as “nystagmus” or “no nystagmus” by one expert provider. We then used a filtered image-based motion classification approach to develop aEYE. The model's performance at detecting nystagmus was calculated by using the area under the receiver-operating characteristic curve (AUROC), sensitivity, specificity, and accuracy.ResultsAn ensemble between the ResNet-soft voting and the VGG-hard voting models had the best performing metrics. The AUROC, sensitivity, specificity, and accuracy were 0.86, 88.4, 74.2, and 82.7%, respectively. Our validated folds had an average AUROC, sensitivity, specificity, and accuracy of 0.86, 80.3, 80.9, and 80.4%, respectively. Models created from the compressed videos decreased in accuracy as image sampling rate decreased from 60 Hz to 15 Hz. There was only minimal change in the accuracy of nystagmus detection when decreasing image resolution and keeping sampling rate constant.ConclusionDeep learning is useful in detecting nystagmus in 60 Hz video recordings as well as videos with lower image resolutions and sampling rates, making it a potentially useful tool to aid future automated eye-movement enabled neurologic diagnosis.

Fatal familial insomnia (FFI) is a rare inherited prion disease characterized by sleep, autonomic, and motor disturbances. Neuro-ophthalmological abnormalities have been reported at the onset of disease, although not further characterized. We analyzed video recordings of eye movements of 6 patients with FFI from 3 unrelated kindreds, seen within 6 months from the onset of illness. Excessive saccadic intrusions were the most prominent findings. In patients with severe insomnia, striking saccadic intrusions are an early diagnostic clue for FFI. The fact that the thalamus is the first structure affected in FFI also suggests its role in the control of steady fixation. ANN NEUROL 2021;89:823–827.

Ocular lateral deviation (OLD) is a conjugate, ipsilesional, horizontal ocular deviation associated with brief (3-5 s) closing of the eyes, commonly linked to the lateral medullary syndrome (LMS). There is limited information regarding OLD in patients with the acute vestibular syndrome (AVS). In one case series 40 years ago OLD was suggested to be a central sign. Recently, horizontal ocular deviation on imaging (RadOLD) was frequently associated with anterior circulation stroke and horizontal gaze palsy. Similarly, RadOLD has been associated with posterior circulation stroke, e.g., LMS and cerebellar stroke, but without clinical correlation with OLD.This is a prospective, cross-sectional diagnostic study of 151 acute AVS patients. Patients had spontaneous nystagmus. Horizontal gaze paralysis was an exclusion criterion. We noted the effect of brief 3-5 s eyelid closure on eye position, and then used the HINTS algorithm (the head-impulse test, nystagmus characteristics and skew deviation) and RadOLD, to establish a correlation between clinical and radiologic findings RESULTS: Of the 151 AVS patients, 100 had a central lesion and 51 a peripheral lesion; 29 of the central lesions were LMS, and 11 had OLD. Additionally, one lateral pontine syndrome had OLD. On opening the eyes 11 patients with OLD and LMS made multiple, hypometric corrective saccades to bring gaze back to straight ahead. 10/11 patients with LMS showed RadOLD.OLD with multiple hypometric corrective saccades on opening the eyes was infrequent but highly localizing and lateralizing. We emphasize how simple it is to test for OLD, with the caveat that to be specific, it must be present after just brief (3-5 s) eyelid closure.

Fixation nystagmus refers to the nystagmus that appears or markedly increases with fixation. While relatively common in infantile (congenital) nystagmus, acquired fixation nystagmus is unusual and has been ascribed to lesions involving the cerebellar nuclei or the fibers projecting from the cerebellum to the brainstem. We aimed to report the clinical features of patients with acquired fixation nystagmus and discuss possible mechanisms using a model simulation and diagnostic significance. We describe four patients with acquired fixation nystagmus that appears or markedly increases with visual fixation. All patients had lesions involving the cerebellum or dorsal medulla. All patients showed direction-changing gaze-evoked nystagmus, impaired smooth pursuit, and decreased vestibular responses on head-impulse tests. The clinical implication of fixation nystagmus is that it may occur in central lesions that impair both smooth pursuit and the vestibulo-ocular reflex (VOR) but without creating a spontaneous nystagmus in the dark. We develop a mathematical model that hypothesizes that fixation nystagmus reflects a central tone imbalance due to abnormal function in cerebellar circuits that normally optimize the interaction between visual following (pursuit) and VOR during attempted fixation. Patients with fixation nystagmus have central lesions involving the cerebellar circuits that are involved in visual-vestibular interactions and normally eliminate biases that cause a spontaneous nystagmus.

BACKGROUND Acquired pendular nystagmus (APN) is a back and forth, oscillatory eye movement in which the 2 oppositely directed slow phases have similar waveforms. APN occurs commonly in multiple sclerosis and causes a disabling oscillopsia that impairs vision. Previous studies have proven that symptomatic therapy with gabapentin or memantine can reduce the nystagmus amplitude or frequency. However, the effect of these medications on visual acuity (VA) is less known and to our knowledge the impact of non-pharmacological strategies such as blinking on VA has not been reported. This is a single observational study without controls (Class IV) and is meant to suggest a future strategy for study of vision in patients with disabling nystagmus and impaired vision. CASE REPORT A 49-year-old woman with primary progressive multiple sclerosis with spastic paraparesis and a history of optic atrophy presented with asymmetrical binocular APN and bothersome oscillopsia. We found that in the eye with greater APN her visual acuity improved by 1 line (from 0.063 to 0.08 decimals) immediately after blinking. During treatment with memantine, her VA without blinking increased by 2 lines, from 0.063 to 0.12, but improved even more (from 0.12 to 0.16) after blinking. In the contralateral eye with a barely visible nystagmus, VA was reduced by 1 line briefly (~500 ms) after blinking. CONCLUSIONS In a patient with APN, blinking transiently improved vision. The combination of pharmacological treatment with memantine and the blinking strategy may induce better VA and less oscillopsia than either alone.

Introduction Benign paroxysmal positional vertigo (BPPV) of the horizontal semicircular canal (hSCC) can present with otoconia blocking its lumen (canalith jam), with signs and symptoms that make it difficult to distinguish from central nervous system pathology. Objective Here we report two cases of canalith jam affecting the hSCC and offer a theoretical mechanism based on known vestibular neurophysiology. Methods We use video‐oculography to document the canalith jam and show the moment the otoconia loosen. Results Canalith jam is a rare form of BPPV remedied with repositioning maneuvers. Conclusion Clinicians should consider canalith jam as a mechanism for BPPV when the nystagmus is (a) Direction fixed with fixation removed and during positional testing; (b) Velocity dependent on supine head position; (c) Converts to geotropic directional changing nystagmus.

This paper presents a classification and definitions for types of nystagmus and other oscillatory eye movements relevant to evaluation of patients with vestibular and neurological disorders, formulated by the Classification Committee of the Barany Society, to facilitate identification and communication for research and clinical care. Terminology surrounding the numerous attributes and influencing factors necessary to characterize nystagmus are outlined and defined. The classification first organizes the complex nomenclature of nystagmus around phenomenology, while also considering knowledge of anatomy, pathophysiology, and etiology. Nystagmus is distinguished from various other nystagmus-like movements including saccadic intrusions and oscillations.View accompanying videos at http://www.jvr-web.org/ICVD.html.

The number of trinucleotide CAG repeats is inversely correlated with the age at onset (AAO) of motor symptoms in individuals with Spinocerebellar Ataxia type 3 (SCA 3) and may be responsible for 50%-60% of the variability in AAO. Drawing from a social determinants of health model, we sought to determine if educational attainment further contributes to the AAO and motor symptom progression of SCA 3.We performed a retrospective chart review in which twenty individuals met criteria for inclusion and had been seen by an ataxia specialist at our hospital between January 2005 and July 2019. AAO of motor symptoms and Scale for Assessment and Rating of Ataxia (SARA) scores were used as primary outcome measures.Using a linear regression, we found that having greater CAG repeat length and greater than 16 years of education results in an earlier AAO. The importance of the CAG repeat length on AAO, however, is greater amongst individuals with lower education. Using a linear mixed model evaluating SARA score over time with AAO, we found that less than 16 years of education is associated with faster progression of the disease.In our group of SCA 3 patients, level of education correlated with both the AAO and SARA scores. Though our findings need to be confirmed with a larger cohort, our study suggests that level of education can have a strong influence on health outcomes in SCA 3 and possibly other groups of patients with ataxia.

Patients with acute vestibular disorders are often a diagnostic challenge for neurologists, especially when the evaluation must be conducted remotely. The clinical dilemma remains: Does the patient have a benign peripheral inner ear problem or a worrisome central vestibular disorder, such as a stroke? The use of a focused history and the virtual HINTS (head impulse test, nystagmus evaluation, and test of skew) examination are key steps towards correctly diagnosing and triaging the acute vertiginous patient. When looking for signs of vestibulo-ocular dysfunction, there are important technological and practical considerations for an effective clinical interpretation.

Background and purpose A peripheral spontaneous nystagmus (SN) is typically enhanced or revealed by removing fixation. Conversely, failure of fixation suppression of SN is usually a sign of a central disorder. Based on Luebke and Robinson (Vision Res 1988, vol. 28 (8), pp. 941–946), who suggested that the normal fixation mechanism is disengaged during pursuit, it is hypothesized that vertical tracking in the light would bring out or enhance a horizontal SN. Methods Eighteen patients with acute vestibular neuritis were studied. Eye movements were recorded using video‐oculography at straight‐ahead gaze with and without visual fixation, and during smooth pursuit. The slow‐phase velocity and the fixation suppression indices of nystagmus (relative to SN in darkness) were compared in each condition. Results During vertical tracking, the slow‐phase velocity of horizontal SN with eyes near straight‐ahead gaze was significantly higher (median 2.7°/s) than under static visual fixation (median 1.2°/s). Likewise, the fixation index was significantly higher (worse suppression) during pursuit (median 48%) than during fixation (median 26%). A release of SN was also suggested during horizontal pursuit, if one assumes superposition of SN on a normal and symmetrical pursuit capability., In patients who have a spontaneous horizontal nystagmus from a peripheral labyrinthine disorder, such as acute vestibular neuritis, suppression of the nystagmus by vision can be less effective when following a pursuit stimulus, than when fixating a stationary target.

Inborn errors of metabolism in adults are still largely unexplored. Despite the fact that adult-onset phenotypes have been known for many years, little attention is given to these disorders in neurological practice. The adult-onset presentation differs from childhood-onset phenotypes, often leading to considerable diagnostic delay. The identification of these patients at the earliest stage of disease is important, given that early treatment may prevent or lessen further brain damage. Neurological and psychiatric symptoms occur more frequently in adult forms. Abnormalities of eye movements are also common and can be the presenting sign. Eye movement disorders can be classified as central or peripheral. Central forms are frequently observed in lysosomal storage disorders, whereas peripheral forms are a key feature of mitochondrial disease. Furthermore, oculogyric crisis is an important feature in disorders affecting dopamine syntheses or transport. Ocular motor disorders are often not reported by the patient, and abnormalities can be easily overlooked in a general examination. In adults with unexplained psychiatric and neurological symptoms, a special focus on examination of eye movements can serve as a relatively simple clinical tool to detect a metabolic disorder. Eye movements can be easily quantified and analyzed with video-oculography, making them a valuable biomarker for following the natural course of disease or the response to therapies. Here, we review, for the first time, eye movement disorders that can occur in inborn errors of metabolism, with a focus on late-onset forms. We provide a step-by-step overview that will help clinicians to examine and interpret eye movement disorders. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

El vértigo y el desequilibrio son síntomas habituales con los que los pacientes acuden a la consulta del especialista. La falta de un método sistemático para examinar y realizar pruebas de laboratorio para valorar el sistema vestibular conduce con frecuencia a diagnósticos incorrectos y a una atención mediocre. Si se posee un conocimiento básico de la fisiología vestibular y las técnicas adecuadas de exploración, generalmente se puede hacer un diagnóstico correcto. Aquí revisamos los principios del examen otoneurológico, incluyendo la valoración del desequilibrio vestibular estático, la función vestibular dinámica, las maniobras de provocación, el examen oculomotor y las pruebas vestibuloespinales.

Human subjects placed in strong magnetic fields such as in an MRI scanner often feel dizzy or vertiginous. Recent studies in humans and animals have shown that these effects arise from stimulation of the labyrinth and are accompanied by nystagmus. Here, we measured the three-dimensional pattern of nystagmus using video eye tracking in five normal human subjects placed in a 7T MRI to infer which semicircular canals are activated by magnetic vestibular stimulation. We found that the nystagmus usually had a torsional as well as a horizontal component. Analysis of the relative velocities of the three eye movement components revealed that the lateral and anterior (superior) canals are the only canals activated, and by a similar amount.

Benign paroxysmal positional vertigo (BPPV) is common, sometimes terrifying, but rarely portends serious disease. It is usually easily diagnosed and treated, and both the patient and the physician are immediately gratified. While much has been learned about the pathogenesis of BPPV in the past decades, many of its features remain mysterious, and one must still be wary of the rare times it mimics a dangerous brain disorder. Here we review common, relatively well understood clinical features of BPPV but also emphasize what we do not know and when the physician must look deeper for a more ominous cause.

The human brain uses information from various sensory systems to gauge orientation of the body with respect to the external environment. Our perception of space is based on the image of the external world as registered by various senses and continuously updated and stabilized through sensory feedback from motor activities. In this process, multisensory integration can resolve ambiguities associated with the inherent “noise” from discrete sensory modalities. Accordingly, convergence of visual and vestibular inputs plays a significant role in our perceptions of spatial orientation and motion, which are essential for motor planning and interaction with the external environment. Once movements are generated, the visual–vestibular integration is imperative for optimizing vision and stabilizing the line of sight during movements of the head (i.e., gaze stabilization). Such visual–vestibular interactions are vital for maintaining a coherent perception of spatial orientation during static or dynamic changes in positions of the head and body. In this chapter, we will discuss the basic principles of visual–vestibular interaction within the frameworks of heading (e.g., walking or running) and head tilt with relation to gravity (e.g., a lateral tilt of the head on body). We first describe the fundamental aspects of multisensory integration in these processes along with the underlying physiological and anatomical correlates. We then discuss experimental hypotheses and research findings related to visual–vestibular interaction and outline their clinical applications in human diseases.

Objective: Alexander's law (AL) states the intensity of nystagmus increases when gaze is toward the direction of the quick phase. What might be its cause? A gaze-holding neural integrator (NI) that becomes imperfect as the result of an adaptive process, or saturation in the discharge of neurons in the vestibular nuclei?Methods: We induced nystagmus in normal subjects using a rapid chair acceleration around the yaw (vertical) axis to a constant velocity of 200°/second [s] and then, 90 s later, a sudden stop to induce post-rotatory nystagmus (PRN). Subjects alternated gaze every 2 s between flashing LEDs (right/left or up/down). We calculated the change in slow-phase velocity (ΔSPV) between right and left gaze when the lateral semicircular canals (SCC) were primarily stimulated (head upright) or, with the head tilted to the side, stimulating the vertical and lateral SCC together.Results: During PRN AL occurred for horizontal eye movements with the head upright and for both horizontal and vertical components of eye movements with the head tilted. AL was apparent within just a few seconds of the chair stopping when peak SPV of PRN was reached. When slow-phase velocity of PRN faded into the range of 6–18°/s AL could no longer be demonstrated.Conclusions: Our results support the idea that AL is produced by asymmetrical responses within the vestibular nuclei impairing the NI, and not by an adaptive response that develops over time. AL was related to the predicted plane of eye rotations in the orbit based on the pattern of SCC activation.

The pathophysiology of acute, vertical spontaneous eye movements following pontine hemorrhage is not well understood. Here, we present and discuss the video-oculography findings of a patient with acute pontine hemorrhage who developed vertical pendular oscillation and ocular bobbing while comatose. The amplitudes, peak velocities, frequency distribution, and phase planes (velocity versus position) of the eye movements were analyzed. The vertical pendular oscillation was rhythmic with a peak frequency of 1.7 Hz, but amplitudes (mean 1.9°, range 0.2-8.2°) and peak velocities (mean 20.6°/s; range 5.9-60.6°/sec) fluctuated. Overall, their peak velocities were asymmetric, faster with downward than upward. Higher peak velocities were seen with larger amplitudes (downward phase r = 0.95, p < 0.001; upward phase r = 0.91, p < 0.001) and with movements beginning at eye positions lower in the orbit (downward phase r = - 0.64, p < 0.001; upward phase r = - 0.86, p < 0.001). Interspersed were typical ocular bobbing waveforms with a fast (peak velocity 128.8°/s), large-amplitude (17.5°) downward movement, sometimes followed by a flat interphase interval (0.5 s) when the eye was nearly stationary, and then a slow return to mid-position with a decaying velocity waveform. To account for the presence and co-existence of pendular oscillations and bobbing, we present and discuss three hypothetical models, not necessarily mutually exclusive: (1) oscillations originating in the inferior olives due to disruption of the central tegmental tract(s); (2) unstable neural integrator function due to pontine cell group damage involving neurons involved in gaze-holding; (3) low-frequency saccadic intrusions following omnipause neuron damage.

Purpose of review In the last three decades, the use of eye movements and vestibular testing in many neurological disorders has accelerated, primarily because of practical technologic developments. Although the acute vestibular syndrome is a prime example of this progress, more chronic neurologic and systemic disorders have received less attention. We focus here on recent contributions relating vestibular and ocular motor abnormalities in inflammatory, demyelinating, metabolic, and peripheral nervous system disorders RECENT FINDINGS: Vestibular abnormalities have been identified in acute demyelinating neuropathies (AIDP), in novel genetic mutations responsible for CANVAS (cerebellar ataxia, neuropathy vestibular areflexia syndrome), and in other inherited neuropathies (variants of Charcot-Marie-Tooth disease). In addition, there are differentiating characteristics between the most common CNS demyelinating disorders: multiple sclerosis and neuromyelitis optica (NMO). We summarize new information on Vitamin D metabolism in benign paroxysmal positional vertigo (BPPV), followed by a brief review of the vestibular and ocular motor findings in Wernicke's encephalopathy. We conclude with findings in several paraneoplastic/autoimmune disorders. Summary This literature review highlights the impact of a careful vestibular and ocular motor evaluation in common neurologic disorder, not only for the initial diagnosis but also for monitoring disease and rehabilitation. A careful examination of eye movements and vestibular function, supplemented with new video techniques to quantify the findings, should be part of the standard neurologic examination.

The cerebellum works as a network hub for optimizing eye movements through its mutual connections with the brainstem and beyond. Here, we review three key areas in the cerebellum that are related to the control of eye movements: (1) the flocculus/paraflocculus (tonsil) complex, primarily for high-frequency, transient vestibular responses, and also for smooth pursuit maintenance and steady gaze holding; (2) the nodulus/ventral uvula, primarily for low-frequency, sustained vestibular responses; and (3) the dorsal vermis/posterior fastigial nucleus, primarily for the accuracy of saccades. Although there is no absolute compartmentalization of function within the three major ocular motor areas in the cerebellum, the structural-functional approach provides a framework for assessing ocular motor performance in patients with disease that involves the cerebellum or the brainstem.

Rebound nystagmus, a common cerebellar sign, is a transient nystagmus that appears on returning to straight-ahead gaze after prolonged eccentric gaze. The slow phases of rebound nystagmus are in the direction of prior eccentric gaze. After eccentric gaze, healthy subjects also show rebound nystagmus when fixation is removed. Rebound nystagmus is thought to be related to the function of the oculomotor neural integrator-the circuit that ensures accurate gaze holding after any eye movement-but the exact mechanism of rebound nystagmus is unknown. Here, we combine experimental data with mathematical modeling to test several hypotheses for the generation of rebound nystagmus. We show that two mechanisms contribute, one relies on vision and the other does not. Future experiments must determine if (1) the non-visual mechanism is related to eye position or to eye velocity signals and (2) whether these signals are based on afferent (proprioception) or efferent (corollary) information.

Opsoclonus consists of bursts of involuntary, multidirectional, back-to-back saccades without an intersaccadic interval. We report a 60-year-old man with post-concussive headaches and disequilibrium who had small amplitude opsoclonus in left gaze, along with larger amplitude flutter during convergence. Examination was otherwise normal and brain MRI was unremarkable. Video-oculography demonstrated opsoclonus predominantly in left gaze and during pursuit in the left hemifield, which improved as post-concussive symptoms improved. Existing theories of opsoclonus mechanisms do not account for this eye position-dependence. We discuss theoretical mechanisms of this behavior, including possible dysfunction of frontal eye field and/or cerebellar vermis neurons; review ocular oscillations in traumatic brain injury; and consider the potential relationship between the larger amplitude flutter upon convergence and post-traumatic ocular oscillations.

This paper presents a classification and definitions for types of nystagmus and other oscillatory eye movements relevant to evaluation of patients with vestibular and neurological disorders, formulated by the Classification Committee of the Bárány Society, to facilitate identification and communication for research and clinical care. Terminology surrounding the numerous attributes and influencing factors necessary to characterize nystagmus are outlined and defined. The classification first organizes the complex nomenclature of nystagmus around phenomenology, while also considering knowledge of anatomy, pathophysiology, and etiology. Nystagmus is distinguished from various other nystagmus-like movements including saccadic intrusions and oscillations.View accompanying videos at http://www.jvr-web.org/ICVD.html.

The first models that were proposed to account for the neural control of eye movements applied a classic control systems approach, including feedback, and measured system responses to sinusoidal and transient stimuli. Although such models provided many insights, their limitations were quickly recognized, such as their inability to account for anticipatory responses. Another question was whether models with lumped transfer functions could usefully represent a population of neurons, in which individual units were shown to encode a spectrum of different signals, including resting discharge rates and noise. Recent trends have been towards neural network models and Bayesian operators, which account for observed properties such as the variability of responses and predictive behavior, but often puzzle clinicians by their complexity and non-intuitive operations. We propose that, since all models are incomplete, it makes sense to select the simplest model that can address the topic of interest. We examine two aspects of abnormal ocular motor control, affecting the common integrator for eye movements, and the vestibular velocity storage mechanism. In both cases, we show how classic control systems provided substantial insights into clinical disorders-such as gaze-evoked nystagmus and periodic alternating nystagmus-as well as suggesting new questions, experiments, and potential treatments.

Traditionally, clinicians have used their experience and intuition to diagnose and treat disease states, including neurological disorders. However, the rapid increase in basic knowledge, coupled with a realization that human judgments are often flawed, has made it helpful to approach many clinical disorders by casting them in the form of models (quantitative hypotheses) that can be tested experimentally; in this way the power of the scientific method can be applied. This is especially the case in systems neuroscience, in which the experimental testing of mathematical models has proven an effective approach to understanding a range of clinical problems. Here, we focus on disorders of the neural control of eye movements, which offer many advantages to clinician scientists, providing examples of how thorny clinical mysteries became much clearer once they were formulated as models, and tested experimentally. Such an approach inevitably raises new questions and experimental tests and may suggest novel therapies.

For many years, people working near strong static magnetic fields of magnetic resonance imaging (MRI) machines have reported dizziness and sensations of vertigo. The discovery a decade ago that a sustained nystagmus can be observed in all humans with an intact labyrinth inside MRI machines led to a possible mechanism: a Lorentz force occurring in the labyrinth from the interactions of normal inner ear ionic currents and the strong static magnetic fields of the MRI machine. Inside an MRI, the Lorentz force acts to induce a constant deflection of the semicircular canal cupula of the superior and lateral semicircular canals. This inner ear stimulation creates a sensation of rotation, and a constant horizontal/torsional nystagmus that can only be observed when visual fixation is removed. Over time, the brain adapts to both the perception of rotation and the nystagmus, with the perception usually diminishing over a few minutes, and the nystagmus persisting at a reduced level for hours. This observation has led to discoveries about how the central vestibular mechanisms adapt to a constant vestibular asymmetry and is a useful model of set-point adaptation or how homeostasis is maintained in response to changes in the internal milieu or the external environment. We review what is known about the effects of stimulation of the vestibular system with high-strength magnetic fields and how the understanding of the mechanism has been refined since it was first proposed. We suggest future ways that magnetic vestibular stimulation might be used to understand vestibular disease and how it might be treated.

Genomic technologies such as Next Generation Sequencing (NGS) are revolutionizing molecular diagnostics and clinical medicine. However, these approaches have proven inefficient at identifying pathogenic repeat expansions. Here, we apply a collection of bioinformatics tools that can be utilized to identify either known or novel expanded repeat sequences in NGS data. We performed genetic studies of a cohort of 35 individuals from 22 families with a clinical diagnosis of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Analysis of whole genome sequence (WGS) data with five independent algorithms identified a recessively inherited intronic repeat expansion [(AAGGG)exp] in the gene encoding Replication Factor C1 (RFC1). This motif, not reported in the reference sequence, localized to an Alu element and replaced the reference (AAAAG)11short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 CANVAS families and identified a core ancestral haplotype, estimated to have arisen in Europe over twenty-five thousand years ago. WGS of the fourRFC1negative CANVAS families identified plausible variants in three, with genomic re-diagnosis of SCA3, spastic ataxia of the Charlevoix-Saguenay type and SCA45. This study identified the genetic basis of CANVAS and demonstrated that these improved bioinformatics tools increase the diagnostic utility of WGS to determine the genetic basis of a heterogeneous group of clinically overlapping neurogenetic disorders.

Patients with Wernicke's encephalopathy (WE) often have unusual patterns of vertical nystagmus. Initially there is often a spontaneous upbeating nystagmus that may change to downbeat nystagmus with a change in the direction of gaze, convergence or with vestibular stimuli. Patients also often show a profound loss of the horizontal but not the vertical vestibulo-ocular reflex (VOR). Furthermore, the acute upbeat nystagmus may change to a chronic downbeat nystagmus. We present hypotheses for these features based on (1) the location of vertical gaze-holding networks near the area postrema of the dorsomedial medulla where the blood-brain barrier is located, which we suggest becomes compromised in WE, (2) the location of the vestibular nuclei in the brainstem, medially for the horizontal VOR, and laterally for the vertical VOR, (3) neuronal circuits differ in susceptibility to and in the ability to recover from thiamine deficiency, and (4) impaired processing of otolith information in WE, normally used to modulate translational vestibulo-ocular reflexes, leads to some of the characteristics of the spontaneous vertical nystagmus including the peculiar reversal in its direction with a change in gaze or convergence.

Importance Video-oculography (VOG) goggles have been integrated into the assessment of semicircular canal function in patients with vestibular disorders. However, a similar bedside VOG method for testing otolith function is lacking. Objective To evaluate the use of VOG-based measurement of ocular counter-roll (vOCR) as a clinical test of otolith function. Design, setting, and participants A case-control study was conducted to compare vOCR measurement among patients at various stages of unilateral loss of vestibular function with healthy controls. The receiver operating characteristic curve method was used to determine the diagnostic accuracy of the vOCR test in detecting loss of otolith function. Participants were recruited at a tertiary center including the Johns Hopkins outpatient clinic and Johns Hopkins Hospital, Baltimore, Maryland. Participants included 56 individuals with acute (≤4 weeks after surgery), subacute (4 weeks-6 months after surgery), and chronic (>6 months after surgery) unilateral vestibular loss as well as healthy controls. A simple bedside maneuver with en bloc, 30° lateral tilt of the head and trunk was used for vOCR measurement. The study was conducted from February 2, 2017, to March 10, 2019. Intervention In each participant vOCR was measured during static tilts of the head and trunk en bloc. Main outcomes and measures The vOCR measurements and diagnostic accuracy of vOCR in detecting patients with loss of vestibular function from healthy controls. Results Of the 56 participants, 28 (50.0%) were men; mean (SD) age was 53.5 (11.4) years. The mean (SD) time of acute unilateral vestibular loss was 9 (7) days (range, 2-17 days) in the acute group, 61 (39) days (range, 28-172 days) in the subacute group, and 985 (1066) days (range 185-4200 days) in the chronic group. The vOCR test showed reduction on the side of vestibular loss, and the deficit was greater in patients with acute and subacute vestibular loss than in patients with chronic loss and healthy controls (acute vs chronic: -1.81°; 95% CI, -3.45° to -0.17°; acute vs control: -3.18°; 95% CI, -4.83° to -1.54°; subacute vs chronic: -0.63°; 95% CI, -2.28° to 1.01°; subacute vs control: -2.01°; 95% CI, -3.65° to -0.36°; acute vs subacute: -1.17°; 95% CI, -2.88° to 0.52°; and chronic vs control: -1.37°; 95% CI, -2.96° to 0.21°). The asymmetry in vOCR between the side of vestibular loss and healthy side was significantly higher in patients with acute vs chronic loss (0.28; 95% CI, 0.06-0.51). Overall, the performance of the vOCR test in discriminating between patients with vestibular loss and healthy controls was 0.83 (area under the receiver operating characteristic curve). The best vOCR threshold to detect vestibular loss at the 30° tilt was 4.5°, with a sensitivity of 80% (95% CI, 0.62%-0.88%) and specificity of 82% (95% CI, 0.57%-1.00%). Conclusions and relevance The findings of this case-control study suggest that the vOCR test can be performed with a simple bedside maneuver and may be used to detect or track loss of otolith function.

vOCR can detect loss of otolith-ocular function without specifying the side of vestibular loss. Since vOCR is measured with a simple head tilt maneuver, it can be potentially used as a bedside clinical test in combination with video head impulse test.Video-oculography (VOG) goggles are being integrated into the bedside assessment of patients with vestibular disorders. Lacking, however, is a method to evaluate otolith function. This study validated a VOG test for loss of otolith function.VOG was used to measure ocular counter-roll (vOCR) in 12 healthy controls, 14 patients with unilateral vestibular loss (UVL), and six patients with bilateral vestibular loss (BVL) with a static lateral head tilt of 30°. The results were compared with vestibular evoked myogenic potentials (VEMP), a widely-used laboratory test of otolith function.The average vOCR for healthy controls (4.6°) was significantly different from UVL (2.7°) and BVL (1.6°) patients (p 0.0001). The vOCR and VEMP measurements were correlated across subjects, especially the click and tap oVEMPs (click oVEMP R = 0.45, tap oVEMP R = 0.51; p 0.0003). The receiver operator characteristic (ROC) analysis showed that vOCR and VEMPs detected loss of otolith function equally well. The best threshold for vOCR to detect vestibular loss was at 3°. The vOCR values from the side of vestibular loss and the healthy side were not different in UVL patients (2.53° vs 2.8°; p = 0.59).

Objective: To describe the ocular motor abnormalities in 9 patients with a lesion involving the nucleus prepositus hypoglossi (NPH), a key constituent of a vestibular-cerebellar-brainstem neural network that ensures that the eyes are held steady in all positions of gaze. Methods: We recorded eye movements, including the vestibulo-ocular reflex during head impulses, in patients with vertigo and a lesion involving the NPH. Results: Our patients showed an ipsilesional-beating spontaneous nystagmus, horizontal gaze-evoked nystagmus more intense on looking toward the ipsilesional side, impaired pursuit more to the ipsilesional side, central patterns of head-shaking nystagmus, contralateral eye deviation, and decreased vestibulo-ocular reflex gain during contralesionally directed head impulses. Conclusions: We attribute these findings to an imbalance in the NPH–inferior olive–flocculus–vestibular nucleus loop, and the ocular motor abnormalities provide a new brainstem localization for patients with acute vertigo.

Dizziness and vertigo are among the most common symptoms to bring a patient to a neurologist. Because symptoms are often vague and imprecise, a systematic approach is essential. By categorizing vestibular disorders based on timing, triggers, and duration, as well as through focused oculomotor and vestibular examinations, the vast majority of neuro-otologic diagnoses can be made at the bedside. Here the authors discuss historical and examination pearls for the most common neuro-otologic disorders.

Ocular motor neural integrators ensure that eyes are held steady in straight-ahead and eccentric positions of gaze. Abnormal function of the ocular motor neural integrator leads to centripetal drifts of the eyes with consequent gaze-evoked nystagmus. In 2002 a neural integrator, analogous to that in the ocular motor system, was proposed for the control of head movements. Recently, a counterpart of gaze-evoked eye nystagmus was identified for head movements; in which the head could not be held steady in eccentric positions on the trunk. These findings lead to a novel pathophysiological explanation in cervical dystonia, which proposed that the abnormalities of head movements stem from a malfunctioning head neural integrator, either intrinsically or as a result of impaired cerebellar, basal ganglia, or peripheral feedback. Here we briefly recapitulate the history of the neural integrator for eye movements, then further develop the idea of a neural integrator for head movements, and finally discuss its putative role in cervical dystonia. We hypothesize that changing the activity in an impaired head neural integrator, by modulating feedback, could treat dystonia. * Abbreviation : INC : interstitial nucleus of Cajal

Summary A major focus in neurobiology is how the brain adapts its motor behavior to changes in its internal and external environments [1, 2]. Much is known about adaptively optimizing the amplitude and direction of eye and limb movements, for example, but little is known about another essential form of learning, "set-point" adaptation. Set-point adaptation balances tonic activity so that reciprocally acting, agonist and antagonist muscles have a stable platform from which to launch accurate movements. Here, we use the vestibulo-ocular reflex—a simple behavior that stabilizes the position of the eye while the head is moving—to investigate how tonic activity is adapted toward a new set point to prevent eye drift when the head is still [3, 4]. Set-point adaptation was elicited with magneto-hydrodynamic vestibular stimulation (MVS) by placing normal humans in a 7T MRI for 90 min. MVS is ideal for prolonged labyrinthine activation because it mimics constant head acceleration and induces a sustained nystagmus similar to natural vestibular lesions [5, 6]. The MVS-induced nystagmus diminished slowly but incompletely over multiple timescales. We propose a new adaptation hypothesis, using a cascade of imperfect mathematical integrators, that reproduces the response to MVS (and more natural chair rotations), including the gradual decrease in nystagmus as the set point changes over progressively longer time courses. MVS set-point adaptation is a biological model with applications to basic neurophysiological research into all types of movements [7], functional brain imaging [8], and treatment of vestibular and higher-level attentional disorders by introducing new biases to counteract pathological ones [9].

We sought to determine the cerebellar structures responsible for tilt suppression of post-rotatory nystagmus. We investigated ocular motor findings and MRI lesions in 73 patients with isolated cerebellar lesions who underwent recording of the vestibulo-ocular reflex (VOR) using rotatory chair tests. Tilt suppression of post-rotatory nystagmus was diminished in 27 patients (27/73, 37.0 %). The gains of the VOR and the TCs of per- and post-rotatory nystagmus did not differ between the patients with diminished and with normal tilt suppression. The patients with impaired tilt suppression showed perverted ("cross-coupled") head-shaking nystagmus (pHSN) and central positional nystagmus (CPN) more frequently than those with normal responses. Tilt suppression was impaired in five (71.4 %) of the seven patients with isolated nodulus and uvular infarction. Probabilistic lesion-mapping analysis showed that the nodulus and uvula are responsible for tilt suppression. Impaired tilt suppression may be ascribed to disruption of cerebellar contribution to the vestibular velocity-storage mechanism, which integrates information from the semicircular canals and otolith organs to help derive the brain's estimate of the head orientation relative to the pull of gravity.

Biallelic pathogenic variants in AARS2, a gene encoding the mitochondrial alanyl-tRNA synthetase, result in a spectrum of findings ranging from infantile cardiomyopathy to adult-onset progressive leukoencephalopathy. In this article, we present three unrelated individuals with novel compound heterozygous pathogenic AARS2 variants underlying diverse clinical presentations. Patient 1 is a 51-year-old man with adult-onset progressive cognitive, psychiatric, and motor decline and leukodystrophy. Patient 2 is a 34-year-old man with childhood-onset progressive tremor followed by the development of polyneuropathy, ataxia, and mild cognitive and psychiatric decline without leukodystrophy on imaging. Patient 3 is a 57-year-old woman with childhood-onset tremor and nystagmus which preceded dystonia, chorea, ataxia, depression, and cognitive decline marked by cerebellar atrophy and white matter disease. These cases expand the clinical heterogeneity of AARS2-related disorders, given that the first and third case represent some of the oldest known survivors of this disease, the second is adult-onset AARS2-related neurological decline without leukodystrophy, and the third is biallelic AARS2-related disorder involving a partial gene deletion.