Impact of Clinician Training Background and Stroke Location on Bedside Diagnostic Test Accuracy in the Acute Vestibular Syndrome - A Meta-Analysis.

OBJECTIVE: Acute dizziness/vertigo is usually due to benign inner-ear causes but is occasionally due to dangerous neurologic ones, particularly stroke. Because symptoms and signs overlap, misdiagnosis is frequent and overuse of neuroimaging is common. We assessed the accuracy of bedside findings to differentiate peripheral vestibular from central neurologic causes. METHODS: We performed a systematic search (MEDLINE and Embase) to identify studies reporting on diagnostic accuracy of physical examination in adults with acute, prolonged dizziness/vertigo ("acute vestibular syndrome" [AVS]). Diagnostic test properties were calculated for findings. Results were stratified by examiner type and stroke location. RESULTS: We identified 6,089 citations and included 14 articles representing 10 study cohorts (n = 800). The Head Impulse, Nystagmus, Test of Skew (HINTS) eye movement battery had high sensitivity 95.3% (95% confidence interval [CI] = 92.5-98.1) and specificity 92.6% (95% CI = 88.6-96.5). Sensitivity was similar by examiner type (subspecialists 94.3% [95% CI = 88.2-100.0] vs non-subspecialists 95.0% [95% CI = 91.2-98.9], p = 0.55), but specificity was higher among subspecialists (97.6% [95% CI = 94.9-100.0] vs 89.1% [95% CI = 83.0-95.2], p = 0.007). HINTS sensitivity was lower in anterior cerebellar artery (AICA) than posterior inferior cerebellar artery (PICA) strokes (84.0% [95% CI = 65.3-93.6] vs 97.7% [95% CI = 93.3-99.2], p = 0.014) but was "rescued" by the addition of bedside hearing tests (HINTS+). Severe (grade 3) gait/truncal instability had high specificity 99.2% (95% CI = 97.8-100.0) but low sensitivity 35.8% (95% CI = 5.2-66.5). Early magnetic resonance imaging (MRI)-diffusion-weighted imaging (DWI; within 24-48 hours) was falsely negative in 15% of strokes (sensitivity 85.1% [95% CI = 79.2-91.0]). INTERPRETATION: In AVS, HINTS examination by appropriately trained clinicians can differentiate peripheral from central causes and has higher diagnostic accuracy for stroke than MRI-DWI in the first 24-48 hours. These techniques should be disseminated to all clinicians evaluating dizziness/vertigo. ANN NEUROL 2023;94:295-308.

Corrective saccades in acute vestibular neuritis: studying the role of prediction with automated passively induced head impulses.

When the demands for visual stabilization during head rotations overwhelm the ability of the vestibuloocular reflex (VOR) to produce compensatory eye movements, the brain produces corrective saccades that bring gaze toward the fixation target, even without visual cues (covert saccades). What triggers covert saccades and what might be the role of prediction in their generation are unknown. We studied 14 subjects with acute vestibular neuritis. To minimize variability of the stimulus, head impulses were imposed with a motorized torque generator with the subject on a bite bar. Predictable and unpredictable (timing, amplitude, direction) stimuli were compared. Distributions of covert corrective saccade latencies were analyzed with a "LATER" (linear approach to threshold with ergodic rate) approach. On the affected side, VOR gain was higher (0.47 ± 0.28 vs. 0.39 ± 0.22, P ≪ 0.001) with predictable than unpredictable head impulses, and gaze error at the end of the head movement was less (5.4 ± 3.3° vs. 6.9 ± 3.3°, P ≪ 0.001). Analyzing trials with covert saccades, gaze error at saccade end was significantly less with predictable than unpredictable head impulses (4.2 ± 2.8° vs. 5.5 ± 3.2°, P ≪ 0.001). Furthermore, covert corrective saccades occurred earlier with predictable than unpredictable head impulses (140 ± 37 vs. 153 ± 37 ms, P ≪ 0.001). Using a LATER analysis with reciprobit plots, we were able to divide covert corrective saccades into two classes, early and late, with a break point in the range of 88-98 ms. We hypothesized two rise-to-threshold decision mechanisms for triggering early and late covert corrective saccades, with the first being most engaged when stimuli are predictable.NEW & NOTEWORTHY 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) and late (>90 ms) covert saccades. Predictability led to an increase in VOR gain and a decrease in saccade latency.

Upbeat Nystagmus with an Unusual Velocity-Decreasing and Increasing Waveform: a Sign of Gaze-Holding Dysfunction in the Paramedian Tracts in the Medulla?

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.

Bioinformatics-Based Identification of Expanded Repeats: A Non-reference Intronic Pentamer Expansion in RFC1 Causes CANVAS.

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)11 short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 CANVAS-affected families and identified a core ancestral haplotype, estimated to have arisen in Europe more than twenty-five thousand years ago. WGS of the four RFC1-negative CANVAS-affected 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.

Neuro-Ophthalmological Findings in Early Fatal Familial Insomnia.

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.

Modeling the interaction among three cerebellar disorders of eye movements: periodic alternating, gaze-evoked and rebound nystagmus.

A woman, age 44, with a positive anti-YO paraneoplastic cerebellar syndrome and normal imaging developed an ocular motor disorder including periodic alternating nystagmus (PAN), gaze-evoked nystagmus (GEN) and rebound nystagmus (RN). During fixation there was typical PAN but changes in gaze position evoked complex, time-varying oscillations of GEN and RN. To unravel the pathophysiology of this unusual pattern of nystagmus, we developed a mathematical model of normal function of the circuits mediating the vestibular-ocular reflex and gaze-holding including their adaptive mechanisms. Simulations showed that all the findings of our patient could be explained by two, small, isolated changes in cerebellar circuits: reducing the time constant of the gaze-holding integrator, producing GEN and RN, and increasing the gain of the vestibular velocity-storage positive feedback loop, producing PAN. We conclude that the gaze- and time-varying pattern of nystagmus in our patient can be accounted for by superposition of one model that produces typical PAN and another model that produces typical GEN and RN, without requiring a new oscillator in the gaze-holding system or a more complex, nonlinear interaction between the two models. This analysis suggest a strategy for uncovering gaze-evoked and rebound nystagmus in the setting of a time-varying nystagmus such as PAN. Our results are also consistent with current ideas of compartmentalization of cerebellar functions for the control of the vestibular velocity-storage mechanism (nodulus and ventral uvula) and for holding horizontal gaze steady (the flocculus and tonsil).

Pendular Oscillation and Ocular Bobbing After Pontine Hemorrhage.

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.

Bruns' nystagmus revisited: A sign of stroke in patients with the acute vestibular syndrome.

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.

Impaired fixation suppression of horizontal vestibular nystagmus during smooth pursuit: pathophysiology and clinical implications.

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.

Eye movements in demyelinating, autoimmune and metabolic disorders.

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.

Benign Paroxysmal Positional Vertigo: What We Do and Do Not Know.

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.

A decade of magnetic vestibular stimulation: from serendipity to physics to the clinic.

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.

Expansion of the clinical spectrum associated with AARS2-related disorders.

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.

Characteristics and mechanism of apogeotropic central positional nystagmus.

Here we characterize persistent apogeotropic type of central positional nystagmus, and compare it with the apogeotropic nystagmus of benign paroxysmal positional vertigo involving the lateral canal. Nystagmus was recorded in 27 patients with apogeotropic type of central positional nystagmus (22 with unilateral and five with diffuse cerebellar lesions) and 20 patients with apogeotropic nystagmus of benign paroxysmal positional vertigo. They were tested while sitting, while supine with the head straight back, and in the right and left ear-down positions. The intensity of spontaneous nystagmus was similar while sitting and supine in apogeotropic type of central positional nystagmus, but greater when supine in apogeotropic nystagmus of benign paroxysmal positional vertigo. In central positional nystagmus, when due to a focal pathology, the lesions mostly overlapped in the vestibulocerebellum (nodulus, uvula, and tonsil). We suggest a mechanism for apogeotropic type of central positional nystagmus based on the location of lesions and a model that uses the velocity-storage mechanism. During both tilt and translation, the otolith organs can relay the same gravito-inertial acceleration signal. This inherent ambiguity can be resolved by a 'tilt-estimator circuit' in which information from the semicircular canals about head rotation is combined with otolith information about linear acceleration through the velocity-storage mechanism. An example of how this mechanism works in normal subjects is the sustained horizontal nystagmus that is produced when a normal subject is rotated at a constant speed around an axis that is tilted away from the true vertical (off-vertical axis rotation). We propose that when the tilt-estimator circuit malfunctions, for example, with lesions in the vestibulocerebellum, the estimate of the direction of gravity is erroneously biased away from true vertical. If the bias is toward the nose, when the head is turned to the side while supine, there will be sustained, unwanted, horizontal positional nystagmus (apogeotropic type of central positional nystagmus) because of an inappropriate feedback signal indicating that the head is rotating when it is not.

Eye movement disorders and neurological symptoms in late-onset inborn errors of metabolism.

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.

Eye Movement Research in the Twenty-First Century-a Window to the Brain, Mind, and More.

The study of eye movements not only addresses debilitating neuro-ophthalmological problems but has become an essential tool of basic neuroscience research. Eye movements are a classic way to evaluate brain function-traditionally in disorders affecting the brainstem and cerebellum. Abnormalities of eye movements have localizing value and help narrow the differential diagnosis of complex neurological problems. More recently, using sophisticated behavioral paradigms, measurement of eye movements has also been applied to disorders of the thalamus, basal ganglia, and cerebral cortex. Moreover, in contemporary neuroscience, eye movements play a key role in understanding cognition, behavior, and disorders of the mind. Examples include applications to higher-level decision-making processes as in neuroeconomics and psychiatric and cognitive disorders such as schizophrenia and autism. Eye movements have become valued as objective biomarkers to monitor the natural progression of disease and the effects of therapies. As specific genetic defects are identified for many neurological disorders, ocular motor function often becomes the cornerstone of phenotypic classification and differential diagnosis. Here, we introduce other important applications of eye movement research, including understanding movement disorders affecting the head and limbs. We also emphasize the need to develop standardized test batteries for eye movements of all types including the vestibulo-ocular responses. The evaluation and treatment of patients with cerebellar ataxia are particularly amenable to such an approach.

The Floccular Syndrome: Dynamic Changes in Eye Movements and Vestibulo-ocular Reflex in Isolated Infarction of the Cerebellar Flocculus.

The cerebellar flocculus is a critical structure involved in the control of eye movements. Both static and dynamic abnormalities of the vestibulo-ocular reflex (VOR) have been described in animals with experimental lesions of the flocculus/paraflocculus complex. In humans, lesions restricted to the flocculus are rare so they can become an exceptional model to contrast with the clinical features in experimental animals or in patients with more generalized cerebellar diseases. Here, we examined a 67-year-old patient with an acute vestibular syndrome due to an isolated infarct of the right flocculus. We evaluated him multiple times over 6 months-to follow the changes in eye movements and vestibular function-with caloric testing, video-oculography and head-impulse testing, and the anatomical changes on imaging. Acutely, he had an ipsilateral-beating spontaneous nystagmus, bilateral gaze-evoked nystagmus, borderline impaired smooth pursuit, and a complete contraversive ocular tilt reaction. The VOR gain was reduced for head impulses directed contralateral to the lesion, and there was also an ipsilesional caloric weakness. All abnormalities progressively improved at follow-up visits but with a considerable reduction in volume of the affected flocculus on imaging. The vestibular and ocular motor findings, qualitatively similar to a previously reported patient, further clarify the "acute floccular syndrome" in humans. We also add new information about the pattern of recovery from such a lesion with corresponding changes in the size of the affected flocculus on imaging.

New insights into vestibular-saccade interaction based on covert corrective saccades in patients with unilateral vestibular deficits.

In response to passive high-acceleration head impulses, patients with low vestibulo-ocular reflex (VOR) gains often produce covert (executed while the head is still moving) corrective saccades in the direction of deficient slow phases. Here we examined 23 patients using passive, and 9 also active, head impulses with acute (< 10 days from onset) unilateral vestibular neuritis and low VOR gains. We found that when corrective saccades are larger than 10°, the slow-phase component of the VOR is inhibited, even though inhibition increases further the time to reacquire the fixation target. We also found that 1) saccades are faster and more accurate if the residual VOR gain is higher, 2) saccades also compensate for the head displacement that occurs during the saccade, and 3) the amplitude-peak velocity relationship of the larger corrective saccades deviates from that of head-fixed saccades of the same size. We propose a mathematical model to account for these findings hypothesizing that covert saccades are driven by a desired gaze position signal based on a prediction of head displacement using vestibular and extravestibular signals, covert saccades are controlled by a gaze feedback loop, and the VOR command is modulated according to predicted saccade amplitude. A central and novel feature of the model is that the brain develops two separate estimates of head rotation, one for generating saccades while the head is moving and the other for generating slow phases. Furthermore, while the model was developed for gaze-stabilizing behavior during passively induced head impulses, it also simulates both active gaze-stabilizing and active gaze-shifting eye movements.NEW & NOTEWORTHY During active or passive head impulses while fixating stationary targets, low vestibulo-ocular gain subjects produce corrective saccades when the head is still moving. The mechanisms driving these covert saccades are poorly understood. We propose a mathematical model showing that the brain develops two separate estimates of head rotation: a lower level one, presumably in the vestibular nuclei, used to generate the slow-phase component of the response, and a higher level one, within a gaze feedback loop, used to drive corrective saccades.

Novel PNKP mutation in siblings with ataxia-oculomotor apraxia type 4.

The phenotypic and genetic spectrum of ataxia with oculomotor apraxia (AOA) disorders is rapidly evolving and new technologies such as genetic mapping using whole exome sequencing reveal subtle distinctions among the various subtypes. We report a novel PNKP mutation in two siblings with progressive ataxia, abnormal saccades, sensorimotor neuropathy and dystonia consistent with the AOA type 4 phenotype. Laboratory evaluation revealed hypoalbuminemia, hypercholesterolemia with elevated LDL, elevated IgE levels and normal α fetoprotein levels. Eye movement examination demonstrated a marked saccade initiation defect with profound hypometric horizontal saccades. Vertical saccades were also affected but less so. Also present were conspicuous thrusting head movements when attempting to change gaze, but rather than an apraxia these were an adaptive strategy to take advantage of an intact vestibulo-ocular reflex to carry the eyes to a new target of interest. This is demonstrated in accompanying videos.

Impaired Motor Learning in a Disorder of the Inferior Olive: Is the Cerebellum Confused?

An attractive hypothesis about how the brain learns to keep its motor commands accurate is centered on the idea that the cerebellar cortex associates error signals carried by climbing fibers with simultaneous activity in parallel fibers. Motor learning can be impaired if the error signals are not transmitted, are incorrect, or are misinterpreted by the cerebellar cortex. Learning might also be impaired if the brain is overwhelmed with a sustained barrage of meaningless information unrelated to simultaneously appearing error signals about incorrect performance. We test this concept in subjects with syndrome of oculopalatal tremor (OPT), a rare disease with spontaneous, irregular, roughly pendular oscillations of the eyes thought to reflect an abnormal, synchronous, spontaneous discharge to the cerebellum from the degenerating neurons in the inferior olive. We examined motor learning during a short-term, saccade adaptation paradigm in patients with OPT and found a unique pattern of disturbed adaptation, quite different from the abnormal adaption when the cerebellum is involved directly. Both fast (seconds) and slow (minutes) timescales of learning were impaired. We suggest that the spontaneous, continuous, synchronous output from the inferior olive prevents the cerebellum from receiving the error signals it needs for appropriate motor learning. The important message from this study is that impaired motor adaptation and resultant dysmetria is not the exclusive feature of cerebellar disorders, but it also highlights disorders of the inferior olive and its connections to the cerebellum.