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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.

In this appreciation of the scientific contributions of David A. Robinson by his former students, examples are provided of his seminal work in the fields of ocular motor and vestibular research. Drawing on a mathematical and engineering background, Robinson first invented a reliable method for measuring eye movements and then employed a bottom-up approach, defining the mechanical forces acting on the eyeballs, quantifying the neural code by which ocular motoneurons program eye movements. He then moved on to elucidate the premotor neural processing required to generate eye movements that respond to visual and vestibular needs. Each of his many contributions has had a sustained impact within and beyond his field – so that the neural control of eye movements has become a microcosm for motor control in general. Examples include understanding the mechanical properties of the orbital tissues, which has influenced treatment of strabismus; identification of mathematical integration of sensory signals by networks of neurons to hold gaze steady; central interaction of vestibular and visual signals to generate appropriate eye movements during self-rotation; adaptive properties of eye movements to optimize their contributions to clear vision; and internal interactions of motor and feedback signals to guide rapid eye movements (saccades). Robinson promoted translational research by proposing models based on normal biology that made specific, testable predictions about how abnormal eye movements, such as nystagmus, could arise. His pioneering contributions continue to have relevance in neurophysiology, computation neuroscience, neurology, ophthalmology, and otolaryngology.

When evaluating patients with dizziness, knowledge of basic vestibular physiology and bedside examination techniques is critical to reach the correct diagnosis. During the vestibular examination, the clinician should look for signs of static and dynamic vestibular imbalance in the semicircular canal and otolith function. Here we outline the key components of the clinical vestibular examination considering recent technical advances in video-oculography and mobile devices such as tablet computers. Using these portable technologies, the vestibular examination can be quantified at the bedside to improve diagnostic accuracy and clinical management. In this process, a careful and thorough clinical evaluation of all subtypes of eye movements, stance, and gait is critical because of the close anatomic and physiologic connections among vestibular, postural, and ocular motor functions.

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.

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.

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.

ObjectiveTo explain (1) why an initial upbeat nystagmus (UBN) converts to a permanent downbeat nystagmus (DBN) in Wernicke encephalopathy (WE) and (2) why convergence and certain vestibular provocative maneuvers may transiently switch UBN to DBN.MethodsFollowing a literature review and study of our 2 patients, we develop hypotheses for the unusual patterns of vertical nystagmus in WE.ResultsOur overarching hypothesis is that there is a selective vulnerability and a selective recovery from thiamine deficiency of neurons within brainstem gaze-holding networks. Furthermore, since the circuits affected in WE are commonly paraventricular, especially medially, just under the floor of the fourth ventricle where lie structures important for control of vertical gaze, we suggest the patterns of involvement in WE also reflect a breakdown in vulnerable areas of the blood–brain barrier. Many of the initial deficits of our patients improved over time, but their DBN did not. Irreversible changes in paramedian tract neurons, which project to the cerebellar flocculus, may be the cause. Here we suggest that conversion of UBN to permanent DBN points to thiamine deficiency and may argue for a chronic, nonprogressive DBN/truncal ataxia syndrome. Finally, we posit that the transient switch of UBN to DBN reflects abnormal processing of otolith information about linear acceleration, and often points to a diagnosis of WE.ConclusionRecognizing the unusual patterns of transient switching and then permanent conversion of UBN to DBN in WE is vital since long-term disability from WE may be prevented by timely, parenteral high-dose thiamine.

The purpose of this consensus paper is to review electrophysiological abnormalities and to provide a guideline of neurophysiological assessments in cerebellar ataxias. All authors agree that standard electrophysiological methods should be systematically applied in all cases of ataxia to reveal accompanying peripheral neuropathy, the involvement of the dorsal columns, pyramidal tracts and the brainstem. Electroencephalography should also be considered, although findings are frequently non-specific. Electrophysiology helps define the neuronal systems affected by the disease in an individual patient and to understand the phenotypes of the different types of ataxia on a more general level. As yet, there is no established electrophysiological measure which is sensitive and specific of cerebellar dysfunction in ataxias. The authors agree that cerebellar brain inhibition (CBI), which is based on a paired-pulse transcranial magnetic stimulation (TMS) paradigm assessing cerebellar-cortical connectivity, is likely a useful measure of cerebellar function. Although its role in the investigation and diagnoses of different types of ataxias is unclear, it will be of interest to study its utility in this type of conditions. The authors agree that detailed clinical examination reveals core features of ataxia (i.e., dysarthria, truncal, gait and limb ataxia, oculomotor dysfunction) and is sufficient for formulating a differential diagnosis. Clinical assessment of oculomotor function, especially saccades and the vestibulo-ocular reflex (VOR) which are most easily examined both at the bedside and with quantitative testing techniques, is of particular help for differential diagnosis in many cases. Pure clinical measures, however, are not sensitive enough to reveal minute fluctuations or early treatment response as most relevant for pre-clinical stages of disease which might be amenable to study in future intervention trials. The authors agree that quantitative measures of ataxia are desirable as biomarkers. Methods are discussed that allow quantification of ataxia in laboratory as well as in clinical and real-life settings, for instance at the patients' home. Future studies are needed to demonstrate their usefulness as biomarkers in pharmaceutical or rehabilitation trials.

This review summarizes topical papers from the fields of neuro-ophthalmology and neuro-otology published from August 2013 to February 2015. The main findings are: (1) diagnostic criteria for pseudotumor cerebri have been updated, and the Idiopathic Intracranial Hypertension Treatment Trial evaluated the efficacy of acetazolamide in patients with mild vision loss, (2) categorization of vestibular disorders through history and ocular motor examination is particularly important in the acute vestibular syndrome, where timely distinction between a central or peripheral localization is essential, (3) the newly described "sagging eye syndrome" provides a mechanical explanation for an isolated esodeviation that increases at distance in the aging population and (4) eye movement recordings better define how cerebellar dysfunction and/or sixth nerve palsy may play a role in other patients with esodeviations that increase at distance.

Cervical dystonia is characterized by abnormal posturing of the head, often combined with tremor-like oscillatory head movements. The nature and source of these oscillatory head movements is controversial, so they were quantified to delineate their characteristics and develop a hypothetical model for their genesis. A magnetic search coil system was used to measure head movements in 14 subjects with cervical dystonia. Two distinct types of oscillatory head movements were detected for most subjects, even when they were not clinically evident. One type had a relatively large amplitude and jerky irregular pattern, and the other had smaller amplitude with a more regular and sinusoidal pattern. The kinematic properties of these two types of oscillatory head movements were distinct, although both were often combined in the same subject. Both had features suggestive of a defect in a central neural integrator. The combination of different types of oscillatory head movements in cervical dystonia helps to clarify some of the current debates regarding whether they should be considered as manifestations of dystonia or tremor and provides novel insights into their potential pathogenesis.

Individuals working next to strong static magnetic fields occasionally report disorientation and vertigo. With the increasing strength of magnetic fields used for magnetic resonance imaging studies, these reports have become more common. It was recently learned that humans, mice, and zebrafish all demonstrate behaviors consistent with constant peripheral vestibular stimulation while inside a strong, static magnetic field. The proposed mechanism for this effect involves a Lorentz force resulting from the interaction of a strong static magnetic field with naturally occurring ionic currents flowing through the inner ear endolymph into vestibular hair cells. The resulting force within the endolymph is strong enough to displace the lateral semicircular canal cupula, inducing vertigo and the horizontal nystagmus seen in normal mice and in humans. This review explores the evidence for interactions of magnetic fields with the vestibular system.

OBJECTIVE Vestibular neuritis is often mimicked by stroke (pseudoneuritis). Vestibular eye movements help discriminate the two conditions. We report vestibulo-ocular reflex (VOR) gain measures in neuritis and stroke presenting acute vestibular syndrome (AVS). METHODS Prospective cross-sectional study of AVS (acute continuous vertigo/dizziness lasting >24 h) at two academic centers. We measured horizontal head impulse test (HIT) VOR gains in 26 AVS patients using a video HIT device (ICS Impulse). All patients were assessed within 1 week of symptom onset. Diagnoses were confirmed by clinical examinations, brain magnetic resonance imaging with diffusion-weighted images, and follow-up. Brainstem and cerebellar strokes were classified by vascular territory-posterior inferior cerebellar artery (PICA) or anterior inferior cerebellar artery (AICA). RESULTS Diagnoses were vestibular neuritis (n = 16) and posterior fossa stroke (PICA, n = 7; AICA, n = 3). Mean HIT VOR gains (ipsilesional [standard error of the mean], contralesional [standard error of the mean]) were as follows: vestibular neuritis (0.52 [0.04], 0.87 [0.04]); PICA stroke (0.94 [0.04], 0.93 [0.04]); AICA stroke (0.84 [0.10], 0.74 [0.10]). VOR gains were asymmetric in neuritis (unilateral vestibulopathy) and symmetric in PICA stroke (bilaterally normal VOR), whereas gains in AICA stroke were heterogeneous (asymmetric, bilaterally low, or normal). In vestibular neuritis, borderline gains ranged from 0.62 to 0.73. Twenty patients (12 neuritis, six PICA strokes, two AICA strokes) had at least five interpretable HIT trials (for both ears), allowing an appropriate classification based on mean VOR gains per ear. Classifying AVS patients with bilateral VOR mean gains of 0.70 or more as suspected strokes yielded a total diagnostic accuracy of 90%, with stroke sensitivity of 88% and specificity of 92%. CONCLUSION Video HIT VOR gains differ between peripheral and central causes of AVS. PICA strokes were readily separated from neuritis using gain measures, but AICA strokes were at risk of being misclassified based on VOR gain alone.

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a newly recognized disorder characterized by cerebellar ataxia, nonlength‐dependent sensory impairment, and bilateral vestibular loss. Sudomotor dysfunction has been described in CANVAS; however, the underlying pathology is not well characterized. To describe novel histopathological features of this syndrome, 2 siblings are presented who had CANVAS with unique findings of sweat gland denervation. Skin biopsy testing was performed to assess sudomotor structure and revealed markedly reduced sweat gland nerve fiber density below the 2.5th percentile in both patients. These histopathological findings suggest that postganglionic sudomotor dysfunction is an additional feature of CANVAS.

Public Health Concern Dizziness and vertigo are responsible for an estimated 4.4 million emergency department (ED) visits in the United States each year and account for 4% of chief symptoms in the ED.1 Strokes are the underlying cause of ≈3% to 5% of such visits (130 000–220 000).2 These visits are associated with a high cost, estimated now to exceed $10 billion per year in the United States.3 This results from neuroimaging obtained in roughly half the patients1 and admissions for nearly 20%.4 ED physicians worldwide rank vertigo a top priority for developing better diagnostic tools.5 An evidence-based, cost-effective approach to diagnosing acute dizziness and vertigo is needed. ### Diagnostic Errors Improving diagnosis is recognized by the National Academy of Medicine as a public health priority.6 Nearly 10% of strokes are misdiagnosed at first medical contact.7 Of the ≈130 000 to 220 000 patients with stroke presenting with vertigo or dizziness to the ED, it is estimated that perhaps 45 000 to 75 000 are initially missed,3 with misdiagnosis disproportionately affecting the young (age

Previous experiments have shown that the vestibulo-ocular reflex (VOR) is partially suppressed during large head-free gaze (gaze = eye-in-head + head-in-space) shifts when both the eyes and head are moving actively, on a fixed body, or when the eyes are moving actively and the head passively on a fixed body. We tested, in human subjects, the hypothesis that the VOR is also suppressed during gaze saccades made withen bloc, head and body together, rotations. Subjects made saccades by following a target light. During some trials, the chair rotated so as to move the entire body passively before, during, or after a saccade. The modulation of the VOR was a function of both saccade amplitude and the time of the head perturbation relative to saccade onset. Despite the perturbation, gaze remained accurate. Thus, VOR modulation is similar when gaze changes are programmed for the eyes alone or for the eyes and head moving together. We propose that the brain always programs a change in gaze using feedback based on gaze and head signals, rather than on separate eye and head trajectories.

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 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.

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.

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.

Introduction Pseudoabducens palsy refers to abduction paresis in the absence of a pontine or peripheral nerve process. This finding has been described with mesodiencephalic lesions, and likely has a common mechanism with thalamic esotropia. Case report We describe the case of a 55-year-old man who presented with near-complete ophthalmoparesis, sparing only adduction of the left eye. Magnetic resonance imaging of the brain demonstrated midbrain infarction. Conclusions Pseudoabducens palsy is likely underrecognized, but can be highly localizing when identified. Possible pathophysiologic mechanisms for this finding are discussed.

The horizontal head impulse test (HIT) is a valuable clinical tool that can help identify peripheral vestibular hypofunction by the refixation (compensatory) saccade that returns the eyes to the target of interest after the head has stopped. We asked if there were differences in the compensatory saccade responses during the HIT when the head was rotated away or toward straight ahead (outward versus inward). We also investigated the influence of a fixation target. Using scleral search-coils, we tested five patients with chronic unilateral vestibular hypofunction (UVH) and three healthy control subjects. In UVH patients, the latencies of both overt and covert saccades were longer when the head was rotated inward from an initially eccentric position, regardless of a visual target. The proportion of HIT with covert saccades was independent of a visual target. In control subjects no compensatory saccades were observed and there were no differences in either angular vestibulo-ocular reflex gain or latency between inward and outward HIT. Our data suggest that inward applied HIT in chronic UVH is more likely to include an overt compensatory saccade based on its lengthened latency. Neither latency nor the occurrence of covert compensatory saccades during HIT depended on a visual target, suggesting they have become a learned behavior in response to chronic UVH.

Describe characteristics of small strokes causing acute vestibular syndrome (AVS).Ambispective cross-sectional study of patients with AVS (acute vertigo or dizziness, nystagmus, nausea/vomiting, head-motion intolerance, unsteady gait) with at least one stroke risk factor from 1999 to 2011 at a single stroke referral center. Patients underwent nonquantitative HINTS "plus" examination (head impulse, nystagmus, test-of-skew plus hearing), neuroimaging to confirm diagnoses (97% by MRI), and repeat MRI in those with initially normal imaging but clinical signs of a central lesion. We identified patients with diffusion-weighted imaging (DWI) strokes ≤10 mm in axial diameter.Of 190 high-risk AVS presentations (105 strokes), we found small strokes in 15 patients (median age 64 years, range 41-85). The most common vestibular structure infarcted was the inferior cerebellar peduncle (73%); the most common stroke location was the lateral medulla (60%). Focal neurologic signs were present in only 27%. The HINTS "plus" battery identified small strokes with greater sensitivity than early MRI-DWI (100% vs 47%, p0.001). False-negative initial MRIs (6-48 hours) were more common with small strokes than large strokes (53% [n = 8/15] vs 7.8% [n = 7/90], p0.001). Nonlacunar stroke mechanisms were responsible in 47%, including 6 vertebral artery occlusions or dissections.Small strokes affecting central vestibular projections can present with isolated AVS. The HINTS "plus" hearing battery identifies these patients with greater accuracy than early MRI-DWI, which is falsely negative in half, up to 48 hours after onset. We found nonlacunar mechanisms in half, suggesting greater risk than might otherwise be assumed for patients with such small infarctions.

ObjectiveTo propose an etiology for a syndrome of bilateral vestibular hypofunction and sound and/or pressure-evoked eye movements with normal hearing thresholds.DesignRetrospective case series.SettingTertiary care referral center.PatientsFour patients with bilateral vestibular hypofunction, sound a

The oculomotor abnormalities with isolated infarction of the cerebellar tonsil are unknown. In a patient with acute infarction of the right tonsil, we found (1) nearly completely abolished ipsilateral smooth pursuit and impaired contralateral pursuit, (2) a low-amplitude ipsilesional right-beating nystagmus without fixation, (3) gaze-holding deficits, and (4) normal vestibulo-ocular reflex. These findings contrast with striking vestibular abnormalities reported with unilateral flocculus and anterior tonsil infarction. Taken together, these findings allow more diagnostic certainty in cerebellar patients, help resolve controversies about interpretation of experimental findings in monkeys, and clarify homologies between the monkey and human cerebellum.

Although the pull of gravity, primarily detected by the labyrinth, is the fundamental input for our sense of upright, vision and proprioception must also be integrated with vestibular information into a coherent perception of spatial orientation. Here, we used transcranial magnetic stimulation (TMS) to probe the role of the cortex at the temporal parietal junction (TPJ) of the right cerebral hemisphere in the perception of upright. We measured the perceived vertical orientation of a visual line; that is, the subjective visual vertical (SVV), after a short period of continuous theta burst stimulation (cTBS) with the head upright. cTBS over the posterior aspect of the supramarginal gyrus (SMGp) in 8 right-handed subjects consistently tilted the perception of upright when tested with the head tilted 20° to either shoulder (right: 3.6°, left: 2.7°). The tilt of SVV was always in the direction opposite to the head tilt. On the other hand, there was no significant tilt after sham stimulation or after cTBS of nearby areas. These findings suggest that a small area of cerebral cortex--SMGp--has a role in processing information from different sensory modalities into an accurate perception of upright.

Ataxia-telangiectasia (A-T) is a progressive neurodegenerative disorder with prominent eye movement deficits localizing to the cerebellum. We sought to determine if 4-aminopyridine (4-AP), which putatively enhances the precision of Purkinje neurons, could improve the disorders of eye movements and vestibular function in A-T. The influence of 4-AP on disorders of eye movements and vestibular function was studied in four A-T patients. The effects on the cerebellar control of vestibulo-ocular reflex (VOR) was quantitatively assessed by the decay time constant of per- and post-rotational nystagmus during constant velocity en bloc rotations. The length of the VOR time constant determines the fidelity of the vestibular velocity storage, a neural mechanism that increases the bandwidth of VOR under cerebellar control. The VOR time constant was not increased in A-T patients. The latter is explained by the extent of cerebellar lesion as previously described in A-T and other cerebellar disorders. Nevertheless, 4-AP shortened the VOR time constant during horizontal rotations. Severe disinhibition of velocity storage in subjects with putatively profound cerebellar degeneration manifest periodic alternating nystagmus (PAN). Among two A-T subjects who manifested PAN, 4-AP reduced the peak slow phase velocity of the more severely affected individual and abrogated the PAN in the other. Two A-T subjects manifested horizontal and vertical spontaneous nystagmus (SN) in primary gaze, 4-AP reduced its slow phase velocity. We conclude that in subjects with A-T 4-AP has a prominent effect on the ocular motor and vestibular deficits that are ascribed to the loss of cerebellar Purkinje neurons.

BACKGROUND AND PURPOSE:: The recording of fall events is usually subjective and imprecise, which limits clinical practice and falls-related research. We sought to develop and validate a scale to grade near-fall and fall events on the basis of their severity represented by the use of health care resources, with the goal of standardizing fall reporting in the clinical and research settings. METHODS:: Qualitative instrument development was based on a literature review and semistructured interviews to assess face and content validity. We queried older individuals and health care professionals with expertise in the care of patients at risk of falling about clinically important differences to detect and how to optimize the scale's ease of use. To assess the scale's interrater reliability, we created 30 video-vignettes of falls and compared how health care professionals and volunteers rated each of the falls according to our grading scale. RESULTS:: We developed the illustrated 4-point Hopkins Falls Grading Scale (HFGS). The grades distinguish a near-fall (grade 1) from a fall for which an individual did not receive medical attention (grade 2), a fall associated with medical attention but not hospital admission (grade 3), and a fall associated with hospital admission (grade 4). Overall, the HFGS exhibited good face and content validity and had an intraclass correlation coefficient of 0.998. CONCLUSION:: The 4-point HFGS demonstrates good face and content validity and high interrater reliability. We predict that this tool will facilitate the standardization of falls reporting in both the clinical and research settings. Language: en

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.

Isolated floccular infarction is extremely rare, and impairments of the vestibulo-ocular reflex (VOR) have not been explored in humans with isolated floccular lesions. The purpose of this study was to examine and report selective impairment of VOR in response to high acceleration using head impulse in a patient with isolated floccular infarction. The patient underwent bedside and laboratory evaluation of vestibular function, which included video-oculography, ocular torsion and the subjective visual vertical, cervical and ocular vestibular-evoked myogenic potentials, bithermal caloric irrigation, rotatory chair test, and the head impulse test (HIT) using search coils. A 70-year-old woman with a unilateral floccular infarction presented with an acute vestibular syndrome with spontaneous nystagmus beating to the lesion side, impaired ipsilesional pursuit, contraversive ocular torsion and tilt of the subjective visual vertical. With rotatory chair testing at low frequencies, horizontal VOR gains were increased. However, VOR gains were decreased with the higher-frequency, higher-speed HIT. While HIT is often normal in patients with central vestibular disorders, decreased HIT responses do not exclude an isolated cerebellar lesion as a cause of the acute vestibular syndrome.

Background and Purpose— Strokes can be distinguished from benign peripheral causes of acute vestibular syndrome using bedside oculomotor tests (head impulse test, nystagmus, test-of-skew). Using head impulse test, nystagmus, test-of-skew is more sensitive and less costly than early magnetic resonance imaging for stroke diagnosis in acute vestibular syndrome but requires expertise not routinely available in emergency departments. We sought to begin standardizing the head impulse test, nystagmus, test-of-skew diagnostic approach for eventual emergency department use through the novel application of a portable video-oculography device measuring vestibular physiology in real time. This approach is conceptually similar to ECG to diagnose acute cardiac ischemia. Methods— Proof-of-concept study (August 2011 to June 2012). We recruited adult emergency department patients with acute vestibular syndrome defined as new, persistent vertigo/dizziness, nystagmus, and (1) nausea/vomiting, (2) head motion intolerance, or (3) new gait unsteadiness. We recorded eye movements, including quantitative horizontal head impulse testing of vestibulo-ocular-reflex function. Two masked vestibular experts rated vestibular findings, which were compared with final radiographic gold-standard diagnoses. Masked neuroimaging raters determined stroke or no stroke using magnetic resonance imaging of the brain with diffusion-weighted imaging obtained 48 hours to 7 days after symptom onset. Results— We enrolled 12 consecutive patients who underwent confirmatory magnetic resonance imaging. Mean age was 61 years (range 30–73), and 10 were men. Expert-rated video-oculography–based head impulse test, nystagmus, test-of-skew examination was 100% accurate (6 strokes, 6 peripheral vestibular). Conclusions— Device-based physiological diagnosis of vertebrobasilar stroke in acute vestibular syndrome should soon be possible. If confirmed in a larger sample, this bedside eye ECG approach could eventually help fulfill a critical need for timely, accurate, efficient diagnosis in emergency department patients with vertigo or dizziness who are at high risk for stroke.

Objectives Dizziness and vertigo account for about 4 million emergency department (ED) visits annually in the United States, and some 160,000 to 240,000 (4% to 6%) have cerebrovascular causes. Stroke diagnosis in ED patients with vertigo/dizziness is challenging because the majority have no obvious focal neurologic signs at initial presentation. The authors sought to compare the accuracy of two previously published approaches purported to be useful in bedside screening for possible stroke in dizziness: a clinical decision rule (head impulse, nystagmus type, test of skew [HINTS]) and a risk stratification rule (age, blood pressure, clinical features, duration of symptoms, diabetes [ABCD2]). Methods This was a cross-sectional study of high-risk patients (more than one stroke risk factor) with acute vestibular syndrome (AVS; acute, persistent vertigo or dizziness with nystagmus, plus nausea or vomiting, head motion intolerance, and new gait unsteadiness) at a single academic center. All underwent neurootologic examination, neuroimaging (97.4% by magnetic resonance imaging [MRI]), and follow-up. ABCD2 risk scores (0–7 points), using the recommended cutoff of ≥4 for stroke, were compared to a three-component eye movement battery (HINTS). Sensitivity, specificity, and positive and negative likelihood ratios (LR+, LR–) were assessed for stroke and other central causes, and the results were stratified by age. False-negative initial neuroimaging was also assessed. Results A total of 190 adult AVS patients were assessed (1999–2012). Median age was 60.5 years (range = 18 to 92 years; interquartile range [IQR] = 52.0 to 70.0 years); 60.5% were men. Final diagnoses were vestibular neuritis (34.7%), posterior fossa stroke (59.5% [105 infarctions, eight hemorrhages]), and other central causes (5.8%). Median ABCD2 was 4.0 (range = 2 to 7; IQR = 3.0 to 4.0). ABCD2 ≥ 4 for stroke had sensitivity of 61.1%, specificity of 62.3%, LR+ of 1.62, and LR– of 0.62; sensitivity was lower for those younger than 60 years old (28.9%). HINTS stroke sensitivity was 96.5%, specificity was 84.4%, LR+ was 6.19, and LR– was 0.04 and did not vary by age. For any central lesion, sensitivity was 96.8%, specificity was 98.5%, LR+ was 63.9, and LR– was 0.03 for HINTS, and sensitivity was 99.2%, specificity was 97.0%, LR+ was 32.7, and LR– was 0.01 for HINTS “plus” (any new hearing loss added to HINTS). Initial MRIs were falsely negative in 15 of 105 (14.3%) infarctions; all but one was obtained before 48 hours after onset, and all were confirmed by delayed MRI. Conclusions HINTS substantially outperforms ABCD2 for stroke diagnosis in ED patients with AVS. It also outperforms MRI obtained within the first 2 days after symptom onset. While HINTS testing has traditionally been performed by specialists, methods for empowering emergency physicians (EPs) to leverage this approach for stroke screening in dizziness should be investigated.

A 33-year-old man participating in a research study underwent MRI in a 7-tesla MRI scanner. On entering the scanner, he had a spinning sensation for 2 minutes. Nystagmus, recorded with infrared goggles and shown in a video, continued for the entire 90-minute scanning period.

OBJECTIVE The video head impulse test (HIT) measures vestibular function (vestibulo-ocular reflex [VOR] gain - ratio of eye to head movement), and, in principle, could be used to make a distinction between central and peripheral causes of vertigo. However, VOG recordings contain artifacts, so using unfiltered device data might bias the final diagnosis, limiting application in frontline healthcare settings such as the emergency department (ED). We sought to assess whether unfiltered data (containing artifacts) from a video-oculography (VOG) device have an impact on VOR gain measures in acute vestibular syndrome (AVS). METHODS This cross-sectional study compared VOG HIT results 'unfiltered' (standard device output) versus 'filtered' (artifacts manually removed) and relative to a gold standard final diagnosis (neuroimaging plus clinical follow-up) in 23 ED patients with acute dizziness, nystagmus, gait disturbance and head motion intolerance. RESULTS Mean VOR gain assessment alone (unfiltered device data) discriminated posterior inferior cerebellar artery (PICA) strokes from vestibular neuritis with 91% accuracy in AVS. Optimal stroke discrimination cut points were bilateral VOR gain >0.7099 (unfiltered data) versus >0.7041 (filtered data). For PICA stroke sensitivity and specificity, there was no clinically-relevant difference between unfiltered and filtered data-sensitivity for PICA stroke was 100% for both data sets and specificity was almost identical (87.5% unfiltered versus 91.7% filtered). More impulses increased gain precision. CONCLUSIONS The bedside HIT remains the single best method for discriminating between vestibular neuritis and PICA stroke in patients presenting AVS. Quantitative VOG HIT testing in the ED is associated with frequent artifacts that reduce precision but not accuracy. At least 10-20 properly-performed HIT trials per tested ear are recommended for a precise VOR gain estimate.

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.

Windmill nystagmus is characterized by a clock-like rotation of the beating direction of a jerk nystagmus suggesting separate horizontal and vertical oscillators, usually 90° out of phase. We report oculographic characteristics in three patients with variants of windmill nystagmus in whom the common denominator was profound visual loss due to retinal diseases. Two patients showed a clock-like pattern, while in the third, the nystagmus was largely diagonal (in phase or 180° out of phase) but also periodically changed direction by 180°. We hypothesize that windmill nystagmus is a unique manifestation of “eye movements of the blind.” It emerges when the central structures, including the cerebellum, that normally keep eye movements calibrated and gaze steady can no longer perform their task, because they are deprived of the retinal image motion that signals a need for adaptive recalibration.

Vertigo, dizziness and balance disorders have major impact on independence, employability, activities and participation. There are many measures for the assessment of the impact of vertigo, but no consensus exists on which aspects should be measured. The objective of this study was to develop international standards (ICF Core Sets) for patients with vertigo and dizziness to describe functioning. The development of the ICF Core Sets involved a formal decision-making and consensus process, integrating evidence from preparatory studies including qualitative interviews with patients, a systematic review of the literature, a survey with health professionals, and empirical data collection from patients. Twenty-seven experts selected 100 second level categories for the comprehensive Core Set and 29 second level categories for the Brief Core Set. The largest number of categories was selected from the ICF component Activities and Participation (40). Twenty-five categories were selected from the component Body Functions, six from Body Structures, and 29 from Environmental Factors. The ICF Core Set for vertigo is designed for physicians, nurses, therapists and other health professionals working in inpatient or ambulatory settings. ICF Core Sets create patient-relevant outcomes that can be used as evidence for the success of treatments.

Previous studies reported linear drift of perceived vertical for brief (≤10 min) observation periods. Here, we repeated estimates of direction of gravity up to 60 min to evaluate whether the drift is sustained, shows saturation or even reverses over time. Fifteen healthy human subjects repetitively adjusted a luminous line along subjective visual vertical (SVV) and horizontal (SVH) over periods of 5 min (constituting one block). We obtained seven blocks within 60 min in each subject for SVV and SVH. In between the first six blocks, subjects remained in darkness for 5 min each, whereas the lights were briefly turned on before block 7. We noted significantly (p