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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.

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.

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.

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.

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.