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Schizophrenia is a severe mental disorder, in which 50% of the patients present with motor abnormalities such as psychomotor slowing. Slow spontaneous gait has been reported in schizophrenia. However, comprehensive objective instrumental assessments of multiple gait conditions are missing. Finally, the specific gait patterns of subjects with psychomotor slowing are still unknown. Therefore, this study aimed to objectively assess multiple gait parameters at different walking conditions in patients with schizophrenia with and without psychomotor slowing. Also, we hypothesised gait impairments to correlate with expert ratings of hypokinetic movement disorders and negative symptoms. We collected gait data (GAITRite®) in 70 patients with psychomotor slowing (SRRS (Salpetriere retardation rating scale) ≥15), 22 non-psychomotor slowed patients (SRRS 16.18, all p

Background Vestibular symptoms are a frequent reason for presenting at the emergency department (ED). Underlying conditions range in severity from life-threatening to benign, but often remain undiagnosed despite extensive investigations. We aimed to identify clinical characteristics that are associated with ED consultations by patients with vestibular symptoms of unknown origin (VUO) and to quantify the ED resources consumed during the investigations. Methods This retrospective one-year, single-centre, cross-sectional study assessed ED consultations with patients whose chief complaint was ‘vestibular symptoms’. Data on risk factors, clinical characteristics, management and ED resources were extracted from the administrative database and medical records. Consultations were grouped according to the discharge diagnosis as either VUO or non-VUO. We determined clinical factors associated with VUO and compared ED resource consumption by the two patient groups using multivariable analysis. Results A total of 1599 ED consultations were eligible. Of these, 14.3% (n = 229) were consultations with patients with VUO. Clinical characteristics included in the final multivariable model to determine associations with VUO were sensory disorders, aural fullness, improvement at rest, absence of situational provocation, pre-existing neurological conditions, and age Conclusion One in seven emergency patients with vestibular symptoms is dismissed without a diagnosis. Clinical characteristics of VUO patients are distinct from patients in whom a diagnosis was made in the ED. VUO triggers higher ED resource consumption, which can be justified if appropriately indicated.

Objective Cold and warm water ear irrigation, also known as bithermal caloric testing, has been considered for over 100 years the ‘Gold Standard’ for the detection of peripheral vestibular hypofunction. Its discovery was awarded a Nobel Prize. We aimed to investigate the diagnostic accuracy of Caloric Testing when compared to the video head impulse test (vHIT) in differentiating between vestibular neuritis and vestibular strokes in acute dizziness. Design Prospective cross-sectional study (convenience sample). Setting All patients presenting with signs of an acute vestibular syndrome at the emergency department of a tertiary referral center. Participants One thousand, six hundred seventy-seven patients were screened between February 2015 and May 2020 for Acute Vestibular Syndrome (AVS), of which 152 met the inclusion criteria and were enrolled. Inclusion criteria consisted of a state of continuous dizziness, associated with nausea or vomiting, head-motion intolerance, new gait or balance disturbance and nystagmus. Patients were excluded if they were younger than 18 years, if symptoms lasted 72 h after symptom onset. Of the 152 included patients 85 completed testing. We assessed 58 vestibular neuritis and 27 stroke patients. Main outcome measures All patients underwent calorics and vHIT followed by a delayed MRI which served as a gold standard for vestibular stroke confirmation. Results The overall sensitivity and specificity for detecting stroke with a caloric asymmetry cut-off of 30.9% was 75% and 86.8%, respectively [negative likelihood ratio (NLR) 0.29] compared to 91.7% and 88.7% for vHIT (NLR 0.094). Best VOR gain cut-off was 0.685. Twenty-five percent of vestibular strokes were misclassified by calorics, 8% by vHIT. Conclusions Caloric testing proved to be less accurate than vHIT in discriminating stroke from vestibular neuritis in acute dizziness. Contrary to classic teaching, asymmetric caloric responses can also occur with vestibular strokes and might put the patient at risk for misdiagnosis. We, therefore, recommend to abandon caloric testing in current practice and to replace it with vHIT in the acute setting. Caloric testing has still its place as a diagnostic tool in an outpatient setting.

Objectives Psychomotor slowing (PS) occurs in up to half of schizophrenia patients and is linked to poorer outcomes. As standard treatment fails to improve PS, novel approaches are needed. Here, we applied the RDoC framework using 3 units of analysis, ie, behavior, self-report, and physiology to test, whether patients with PS are different from patients without PS and controls. Methods Motor behavior was compared between 71 schizophrenia patients with PS, 25 without PS, and 42 healthy controls (HC) using 5 different measures: (1) for behavior, an expert rating scale: Motor score of the Salpêtrière Retardation Rating Scale, (2) for self-report, the International Physical Activity Questionnaire; and for physiology, (3) Actigraphy, which accounts for gross motor behavior, (4) Gait velocity, and (5) coin rotation task to assess manual dexterity. Results The ANCOVAs comparing the 3 groups revealed differences between patients with PS and HC in expert ratings, self-report, and instrumental measures (all P ≤ .001). Patients with PS also scored higher in expert ratings and had lower instrumental activity levels compared to patients without PS (all P ≤ .045). Instrumental activity levels correlated with an expert rating of PS (rho = −0.51, P-fdr corrected Conclusions PS is characterized by slower gait, lower activity levels, and slower finger movements compared to HC. However, only actigraphy and observer ratings enable to clearly disentangle PS from non-PS patients. Actigraphy may become the standard assessment of PS in neuroimaging studies and clinical trials.

BACKGROUND Slipped capital femoral epiphyses (SCFE) is associated with out-toeing of the foot and external rotation gait. But it is unknown if SCFE patients treated with the modified Dunn procedure have out-toeing at follow up.Therefore, we used instrumented gait analysis and questioned (1) do severe SCFE patients treated with a modified Dunn procedure have symmetrical foot progression angle (FPA) compared with contralateral side and compared with asymptomatic volunteers (2) what is the prevalence of out-toeing gait and what are the outcome socres at follow up. METHODS Gait analysis of 22 patients (22 hips) treated with an unilateral modified Dunn procedure for severe SCFE (slip angle >60 degrees, 2002 to 2011) was retrospectively evaluated. Of 38 patients with minimal 5-year follow up, 2 hips (4%) had avascular necrosis of the femoral head and were excluded for gait analysis. Twenty-two patients were available for gait analysis at follow up (mean follow up of 9��2���y). Mean age at follow up was 22��3 years. Mean preoperative slip angle was 64��8 degrees (33% unstable slips) and decreased postoperatively (slip angle of 8��4 degrees). Gait analysis was performed with computer-based instrumented walkway system (GAITRite) to measure FPA with embedded pressure sensors. Patients were compared with control group of 18 healthy asymptomatic volunteers (36 feet, mean age 29��6���y). RESULTS (1) Mean FPA of SCFE patients (3.6��6.4 degrees) at follow up was not significantly different compared with their contralateral side (5.6��5.5 degrees) and compared with FPA of controls (4.0��4.5 degrees). (2) Of the 22 SCFE patients, most of them (19 hips, 86%) had normal FPA (-5 to 15 degrees), 2 patients had in-toeing (FPA15 degrees) and was not significantly different compared with control group. (3) Mean modified Harris hip score (mHHS) was 93��11 points, mean Hip Disability and Osteoarthritis Outcome Score (HOOS) score was 91��10 points. Three patients (14%) had mHHS 95 points. CONCLUSIONS Patients with severe SCFE treated with modified Dunn procedure had mostly symmetrical FPA and good hip scores at long term follow up. This is in contrast to previous studies. Although 1 patient had out-toeing and 2 patients had in-toeing at follow up, they had good hip scores. LEVEL OF EVIDENCE Level III-retrospective comparative study.

Background: There is no authorized treatment for ataxia telangiectasia (AT). As cerebellar symptoms of storage diseases were improved by acetyl-DL-leucine (ADLL), the authors hypothesized a symptomatic and disease-modifying effect in AT upon supplementation with ADLL. Methods: Six patients were treated with ADLL 3 g/day for 1 week followed by 5g/day for 3 weeks to 1 year. Cerebellar ataxia was evaluated by validated scales. Gaze-holding, saccades and smooth pursuit were examined by video-oculography. Measurements took place at baseline, at 1 month of therapy in 5 patients, and after 6 and 12 months in 1 patient. Results: The Scale for Assessment and Rating of Ataxia changed from the baseline, mean, (SD, min-max) of 22.1 (5.88, 11-28.5) to 18 points (5.39, 8.5-23.5) after 1 month on medication ( P = .0028). All patients demonstrated gaze-holding deficits; 3 patients had central-position downbeat-nystagmus. Mean slow-phase velocity of this nystagmus with the gaze straight-ahead changed from 5.57°/s (1.8, 3.53-6.99) to 4.7°/s (0.79, 3.97-5.56) after 1 month on treatment (1.35, -2.56-4.17) ( P = .046). Interpretation: ADLL may improve ataxia and ocular stability in AT patients, while the molecular basis still remains to be elucidated. A multicentric, rater-blinded, phase II trial currently investigates the effects of acetyl-L-leucine in AT (NCT03759678).

In-toeing of the foot was associated with high femoral version (FV), while Out-toeing was associated with femoral-retroversion. Therefore, we report on (i) foot-progression-angle (FPA), (ii) prevalence of In-toeing and Out-toeing, and (iii) clinical outcome of patients treated with femoral-derotation-osteotomy (FDO). We performed a retrospective analysis involving 20 patients (20 hips) treated with unilateral FDO (2017-18). Of them, 14 patients had increased FV, 6 patients had femoral-retroversion. Follow-up time was mean 1 ± 1 years. All patients had minimal 1-year follow-up and the mean age was 29 ± 8 years. Patients with increased FV (FV 35°) presented with positive posterior-impingement-test and mean FV was 49 ± 11° (Murphy method). Six patients with femoral-retroversion (FV 10°) had positive anterior impingement test and mean FV of 5 ± 4°. Instrumented gait analysis was performed preoperatively and at follow-up using the Gaitrite system to measure FPA and was compared to a control group of 18 healthy asymptomatic volunteers (36 feet, mean age 29 ± 6 years). (i) Mean FPA increased significantly (

We aimed to determine the incidence of all vestibular symptoms in a large interdisciplinary tertiary emergency department (ED) and to assess stroke prevalence, and frequency of other life-threatening aetiologies. In this 1-year retrospective study, we manually screened all medical records of 23,608 ED visits for descriptions of vestibular symptoms. Symptoms were classified according to the International Classification of Vestibular Disorders of the Barany Society. We evaluated all patients older than 16 years in whom vestibular symptoms were the main or accompanying complaint. We extracted clinical, radiological, and laboratory findings as well as aetiologies from medical records. We identified a total of 2596 visits by 2464 patients (11% of ED visits) who reported at least one vestibular symptom. In 1677/2596 visits (64.6%), vestibular symptoms were the main reason for the ED consultation. Vestibular symptoms were classified as dizziness (43.8%), vertigo (33.9%), postural symptoms (6.5%), or more than one symptom (15.8%). In 324/2596 visits (12.5%), cerebrovascular events were the aetiology of vestibular symptoms, and in 355/2596 visits (13.7%), no diagnosis could be established. In 23.8% of visits with vestibular symptoms as the main complaint, the underlying condition was life-threatening. Frequency and impact of vestibular symptoms in patients visiting the ED were higher than previously reported, and life-threatening aetiologies such as strokes are common. Therefore, awareness among physicians regarding the importance of vestibular symptoms has to be improved.

Cerebellar ataxia is a frequent and often disabling syndrome severely impairing motor functioning and quality of life. Patients suffer from reduced mobility, and restricted autonomy, experiencing an even lower quality of life than, e.g., stroke survivors. Aminopyridines have been demonstrated viable for the symptomatic treatment of certain forms of cerebellar ataxia. This article will give an outline of the present pharmacotherapy of different cerebellar disorders. As a current key-therapy for the treatment of downbeat nystagmus 4-aminopyridine (4-AP) is suggested for the treatment of downbeat nystagmus (5–10 mg Twice a day [TID]), a frequent type of persisting nystagmus, due to a compromise of the vestibulo-cerebellum. Studies with animals have demonstrated, that a nonselective blockage of voltage-gated potassium channels (mainly Kv1.5) increases Purkinje- cell (PC) excitability. In episodic ataxia type 2 (EA2), which is frequently caused by mutations of the PQ-calcium channel, the efficacy of 4-AP (5–10 mg TID) has been shown in a randomized controlled trial (RCT). 4-AP was well tolerated in the recommended dosages. 4-AP was also effective in elevating symptoms in cerebellar gait ataxia of different etiologies (2 case series). A new treatment option for cerebellar disease is the amino-acid acetyl-DL-leucine, which has significantly improved cerebellar symptoms in three case series. There are on-going randomized controlled trials for cerebellar ataxia (acetyl-DL-leucine vs placebo; ALCAT), cerebellar gait disorders (SR-form of 4-AP vs placebo; FACEG) and EA2 (sustained-release/SR-form of 4-AP vs acetazolamide vs placebo; EAT2TREAT), which will provide new insights into the pharmacological treatment of cerebellar disorders.

ObjectiveFailure of fixation suppression of spontaneous nystagmus is sometimes seen in patients with vestibular strokes involving the cerebellum or brainstem; however, the accuracy of this test for the discrimination between peripheral and central causes in patients with an acute vestibular syndrome (AVS) is unknown.MethodsPatients with AVS were screened and recruited (convenience sample) as part of a prospective cross-sectional study in the emergency department between 2015 and 2020. All patients received neuroimaging, which served as a reference standard. We recorded fixation suppression with video-oculography (VOG) for forward, right, and left gaze. The ocular fixation index (OFI) and the spontaneous nystagmus slow velocity reduction was calculated.ResultsWe screened 1,646 patients reporting dizziness in the emergency department and tested for spontaneous nystagmus in 148 patients with AVS. We analyzed 56 patients with a diagnosed acute unilateral vestibulopathy (vestibular neuritis) and 28 patients with a confirmed stroke. There was a complete nystagmus fixation suppression in 49.5% of patients with AVS, in 40% of patients with vestibular neuritis, and in 62.5% of patients with vestibular strokes. OFI scores had no predictive value for detecting strokes; however, a nystagmus reduction of less than 2 °/s showed a high accuracy of 76.9% (confidence interval 0.59–0.89) with a sensitivity of 62.2% and specificity of 84.8% in detecting strokes.ConclusionsThe presence of fixation suppression does not rule out a central lesion. The magnitude of suppression was lower compared to patients with vestibular neuritis. The nystagmus suppression test predicts vestibular strokes accurately provided that eye movements are recorded with VOG.Classification of EvidenceThis study provides Class II evidence that in patients with an AVS, decreased fixation suppression recorded with VOG occurred more often in stroke (76.9%) than in vestibular neuritis (37.8%).

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

Background Tinnitus and dizziness are frequent in old age and often seen as concomitant symptoms in patients with dementia. In earlier clinical trials, Ginkgo biloba extract EGb 761® was found to alleviate tinnitus and dizziness in elderly patients. Consequently, a meta-analysis was conducted to evaluate the effects of EGb 761® at a daily dose of 240 mg on tinnitus and dizziness associated with dementia.

Resting in an upright position during daytime decreases downbeat nystagmus (DBN). When measured in brightness only, that is, without intermitting exposure to darkness, it does not make a significant difference whether patients have previously rested in brightness or in darkness. In real-world scenarios, people are often exposed to brightness and darkness intermittently. The aim of this study was to analyze whether resting in brightness or resting in darkness was associated with a lower post-resting DBN after intermitting exposures to brightness and darkness. Eight patients were recorded with three-dimensional video-oculography in brightness and darkness conditions, each following two 2-h resting intervals under either brightness or darkness resting conditions. The dependent variable was DBN intensity, measured in mean slow phase velocity. A repeated measures ANOVA with the factors measurement condition (brightness vs. darkness), resting condition (brightness vs. darkness), and time (after first vs. second resting interval) showed a significant effect for the factor resting condition, where previous resting in darkness was associated with a significantly lower DBN relative to previous resting in brightness (P < 0.01). The clinical relevance is to advise patients with DBN to rest in darkness.

An overview of the current pharmacotherapy of central vestibular syndromes and the most common forms of central nystagmus as well as cerebellar disorders is given. 4-aminopyridine (4-AP) is recommended for the treatment of downbeat nystagmus, a frequent form of acquired persisting fixation nystagmus, and upbeat nystagmus. Animal studies showed that this non-selective blocker of voltage-gated potassium channels increases Purkinje cell excitability and normalizes the irregular firing rate, so that the inhibitory influence of the cerebellar cortex on vestibular and deep cerebellar nuclei is restored. The efficacy of 4-AP in episodic ataxia type 2, which is most often caused by mutations of the PQ-calcium channel, was demonstrated in a randomized controlled trial. It was also shown in an animal model (the tottering mouse) of episodic ataxia type 2. In a case series, chlorzoxazone, a non-selective activator of small-conductance calcium-activated potassium channels, was shown to reduce the DBN. The efficacy of acetyl-DL-leucine as a potential new symptomatic treatment for cerebellar diseases has been demonstrated in three case series. The ongoing randomized controlled trials on episodic ataxia type 2 (sustained-release form of 4-aminopyridine vs. acetazolamide vs. placebo; EAT2TREAT), vestibular migraine with metoprolol (PROVEMIG-trial), cerebellar gait disorders (sustained-release form of 4-aminopyridine vs. placebo; FACEG) and cerebellar ataxia (acetyl-DL-leucine vs. placebo; ALCAT) will provide new insights into the pharmacotherapy of cerebellar and central vestibular disorders.

Recently, ocular vestibular evoked myogenic potentials (oVEMP) have emerged as a tool for assessment of utricular function. They are short-latency myogenic potentials which can be elicited in response to vestibular stimulation, e.g. by air-conducted sound (ACS) or bone-conducted vibration (BCV) (reviewed in (Kantner and Gurkov, 2012)). Otolithic afferent neurons trigger reflexive electromyographic activity of the extraocular muscles which can be recorded beneath the eye contralateral to the stimulated ear by use of surface electrodes.

A large body of research demonstrated that participants preferably look back to the encoding location when retrieving visual information from memory. However, the role of this 'looking back to nothing' is still debated. The goal of the present study was to extend this line of research by examining whether an important area in the cortical representation of the oculomotor system, the frontal eye field (FEF), is involved in memory retrieval. To interfere with the activity of the FEF, we used inhibitory continuous theta burst stimulation (cTBS). Before stimulation was applied, participants encoded a complex scene and performed a short-term (immediately after encoding) or long-term (after 24 h) recall task, just after cTBS over the right FEF or sham stimulation. cTBS did not affect overall performance, but stimulation and statement type (object vs. location) interacted. cTBS over the right FEF tended to impair object recall sensitivity, whereas there was no effect on location recall sensitivity. These findings suggest that the FEF is involved in retrieving object information from scene memory, supporting the hypothesis that the oculomotor system contributes to memory recall.

Recent research provides evidence that galvanic vestibular stimulation (GVS) has a modulating effect on somatosensory perception and spatial cognition. However, other vestibular stimulation techniques have induced changes in affective control and decision making. The aim of this study was to investigate the effect of GVS on framing susceptibility in a risky-choice game. The participants were to decide between a safe and a risky option. The safe option was framed either positively or negatively. During the task, the participants were exposed to either left anodal/right cathodal GVS, right anodal/left cathodal GVS, or sham stimulation (control condition). While left anodal/right cathodal GVS activated more right-hemispheric vestibular brain areas, right anodal/left cathodal GVS resulted in more bilateral activation. We observed increased framing susceptibility during left anodal/right cathodal GVS, but no change in framing susceptibility during right anodal/left cathodal GVS. We propose that GVS results in increased reliance on the affect heuristic by means of activation of cortical and subcortical vestibular-emotional brain structures and that this effect is modulated by the lateralization of the vestibular cortex.

Treatment of motor symptoms of degenerative cerebellar ataxia remains difficult. Yet there are recent developments that are likely to lead to significant improvements in the future. Most desirable would be a causative treatment of the underlying cerebellar disease. This is currently available only for a very small subset of cerebellar ataxias with known metabolic dysfunction. However, increasing knowledge of the pathophysiology of hereditary ataxia should lead to an increasing number of medically sensible drug trials. In this paper, data from recent drug trials in patients with recessive and dominant cerebellar ataxias will be summarized. There is consensus that up to date, no medication has been proven effective. Aminopyridines and acetazolamide are the only exception, which are beneficial in patients with episodic ataxia type 2. Aminopyridines are also effective in a subset of patients presenting with downbeat nystagmus. As such, all authors agreed that the mainstays of treatment of degenerative cerebellar ataxia are currently physiotherapy, occupational therapy, and speech therapy. For many years, well-controlled rehabilitation studies in patients with cerebellar ataxia were lacking. Data of recently published studies show that coordinative training improves motor function in both adult and juvenile patients with cerebellar degeneration. Given the well-known contribution of the cerebellum to motor learning, possible mechanisms underlying improvement will be outlined. There is consensus that evidence-based guidelines for the physiotherapy of degenerative cerebellar ataxia need to be developed. Future developments in physiotherapeutical interventions will be discussed including application of non-invasive brain stimulation.

Objective: Downbeat nystagmus (DBN) is the most frequent form of acquired persisting fixation nystagmus with different symptoms such as unsteadiness of gait, postural instability, and blurred vision with reduced visual acuity (VA) and oscillopsia. However, different symptomatic therapeutic principles are required, such as 3,4-diaminopyridine and 4-aminopyridine, that effectively suppress DBN. Chlorzoxazone (CHZ) is a nonselective activator of small conductance calcium-activated potassium (SK) channels that modifies the activity of cerebellar Purkinje cells. We evaluated the effects of this agent on DBN in an observational proof-of-concept pilot study. Methods: Ten patients received CHZ 500 mg 3 times a day for 1 or 2 weeks. Slow-phase velocity of DBN, VA, postural sway, and the drug's side effects were evaluated. Recordings were conducted at baseline, 90 minutes after first administration, and after 1 or 2 weeks. Results: Mean slow-phase velocity significantly decreased from a baseline of 2.74°/s ± 2.00 to 2.29°/s ± 2.12 (mean ± SD) 90 minutes after first administration and to 2.04°/s ± 2.24 (p < 0.001; post hoc both p = 0.024) after long-term treatment. VA significantly increased and postural sway in posturography showed a tendency to decrease on medication. Fifty percent of patients did not report any side effects. The most common reported side effect was abdominal discomfort and dizziness. Conclusions: The treatment with the SK-channel activator CHZ is a potentially new therapeutic agent for the symptomatic treatment of DBN. Classification of evidence: This study provides Class IV evidence that CHZ 500 mg 3 times a day may improve eye movements and visual fixation in patients with DBN.

The effects of 4-aminopyridine (4-AP) on downbeat nystagmus (DBN) were analysed in terms of slow-phase velocity (SPV), stance, locomotion, visual acuity (VA), patient satisfaction and side effects using standardised questionnaires.Twenty-seven patients with DBN received 5 mg 4-AP four times a day or placebo for 3 days and 10 mg 4-AP four times a day or placebo for 4 days. Recordings were done before the first, 60 min after the first and 60 min after the last drug administration.SPV decreased from 2.42 deg/s at baseline to 1.38 deg/s with 5 mg 4-AP and to 2.03 deg/s with 10 mg 4-AP (p0.05; post hoc: 5 mg 4-AP: p=0.04). The rate of responders was 57%. Increasing age correlated with a 4-AP-related decrease in SPV (p0.05). Patients improved in the 'get-up-and-go test' with 4-AP (p0.001; post hoc: 5 mg: p=0.025; 10 mg: p0.001). Tandem-walk time (both p0.01) and tandem-walk error (4-AP: p=0.054; placebo: p=0.059) improved under 4-AP and placebo. Posturography showed that some patients improved with the 5 mg 4-AP dose, particularly older patients. Near VA increased from 0.59 at baseline to 0.66 with 5 mg 4-AP (p0.05). Patients with idiopathic DBN had the greatest benefit from 4-AP. There were no differences between 4-AP and placebo regarding patient satisfaction and side effects.4-AP reduced SPV of DBN, improved near VA and some locomotor parameters. 4-AP is a useful medication for DBN syndrome, older patients in particular benefit from the effects of 5 mg 4-AP on nystagmus and postural stability.

We investigated the effects of dalfampridine, the sustained-release form of 4-aminopyridine, on slow phase velocity (SPV) and visual acuity (VA) in patients with downbeat nystagmus (DBN) and the side effects of the drug. In this proof-of-principle observational study, ten patients received dalfampridine 10 mg bid for 2 weeks. Recordings were conducted at baseline, 180 min after first administration, after 2 weeks of treatment and after 4 weeks of wash-out. Mean SPV decreased from a baseline of 2.12 deg/s ± 1.72 (mean ± SD) to 0.51 deg/s ± 1.00 180 min after first administration of dalfampridine 10 mg and to 0.89 deg/s ± 0.75 after 2 weeks of treatment with dalfampridine (p < 0.05; post hoc both: p < 0.05). After a wash-out period of 1 week, mean SPV increased to 2.30 deg/s ± 1.6 (p < 0.05; post hoc both: p < 0.05). The VA significantly improved during treatment with dalfampridine. Also, 50 % of patients did not report any side effects. The most common reported side effects were abdominal discomfort and dizziness. Dalfampridine is an effective treatment for DBN in terms of SPV. It was well-tolerated in all patients.

The frontal eye fields (FEFs) and posterior parietal cortex (PPC) are important for target detection in conjunction visual search but the relative timings of their contribution have not been compared directly. We addressed this using temporally specific double pulse transcranial magnetic stimulation delivered at different times over FEFs and PPC during performance of a visual search task. Disruption of performance was earlier (0/40 ms) with FEF stimulation than with PPC stimulation (120/160 ms), revealing a clear and substantial temporal dissociation of the involvement of these two areas in conjunction visual search. We discuss these timings with reference to the respective roles of FEF and PPC in the modulation of extrastriate visual areas and selection of responses.

Resting in an upright position during daytime decreases downbeat nystagmus (DBN). When measured in brightness only, that is, without intermitting exposure to darkness, it does not make a significant difference whether patients have previously rested in brightness or in darkness. In real-world scenarios, people are often exposed to brightness and darkness intermittently. The aim of this study was to analyze whether resting in brightness or resting in darkness was associated with a lower post-resting DBN after intermitting exposures to brightness and darkness. Eight patients were recorded with three-dimensional video-oculography in brightness and darkness conditions, each following two 2-h resting intervals under either brightness or darkness resting conditions. The dependent variable was DBN intensity, measured in mean slow phase velocity. A repeated measures ANOVA with the factors measurement condition (brightness vs. darkness), resting condition (brightness vs. darkness), and time (after first vs. second resting interval) showed a significant effect for the factor resting condition, where previous resting in darkness was associated with a significantly lower DBN relative to previous resting in brightness (P0.01). The clinical relevance is to advise patients with DBN to rest in darkness.

Motion coherence thresholds are consistently higher at lower velocities. In this study we analysed the influence of the position and direction of moving objects on their perception and thereby the influence of gravity. This paradigm allows a differentiation to be made between coherent and randomly moving objects in an upright and a reclining position with a horizontal or vertical axis of motion. 18 young healthy participants were examined in this coherent threshold paradigm. Motion coherence thresholds were significantly lower when position and motion were congruent with gravity independent of motion velocity (p=0.024). In the other conditions higher motion coherence thresholds (MCT) were found at lower velocities and vice versa (p

During priming of pop-out, performance at discriminating a pop-out feature target in visual search is affected by whether the target on the previous trial was defined by the same feature as on the upcoming trial. Recent studies suggest that priming of pop-out relies on attentional processes. With the use of simultaneous, combined transcranial magnetic stimulation and event-related potential recording (TMS-ERP), we tested for any critical role of the right angular gyrus (rANG) and left and right frontal eye fields (FEFs)—key attentional sites—in modulating both performance and the ERPs evoked by such visual events. Intertrial TMS trains were applied while participants discriminated the orientation of a color pop-out element in a visual search array. rANG TMS disrupted priming of pop-out, reducing reaction time costs on switch trials and speeding responses when the color of the pop-out target switched. rANG TMS caused a negativity in the ERP elicited in response to the visual stimulus array, starting 210 ms after stimulus onset. Both behavioral and ERP effects were apparent only after rANG TMS, on switch trials, and when the target in the visual search array was presented in the left visual field, with no effects after left or right FEF TMS. These results provide evidence for an attentional reorienting mechanism, which originates in the rANG and is modulated by the implicit memory of the previous trial. The rANG plays a causal role on switch trials during priming of pop-out by interacting with visual processing, particularly in the ipsilateral hemisphere representing the contralateral hemifield.

Objective: The therapeutic effects of 4-aminopyridine (4AP) were investigated in a randomized, double-blind, crossover trial in 10 subjects with familial episodic ataxia with nystagmus. Methods: After randomization, placebo or 4AP (5 mg 3 times daily) was administered for 2 3-month-long treatment periods separated by a 1-month-long washout period. The primary outcome measure was the number of ataxia attacks per month; the secondary outcome measures were the attack duration and patient-reported quality of life (Vestibular Disorders Activities of Daily Living Scale [VDADL]). Nonparametric tests and a random-effects model were used for statistical analysis. Results: The diagnosis of episodic ataxia type 2 (EA2) was genetically confirmed in 7 subjects. Patients receiving placebo had a median monthly attack frequency of 6.50, whereas patients taking 4AP had a frequency of 1.65 ( p = 0.03). Median monthly attack duration decreased from 13.65 hours with placebo to 4.45 hours with 4AP ( p = 0.08). The VDADL score decreased from 6.00 to 1.50 ( p = 0.02). 4AP was well-tolerated. Conclusions: This controlled trial on EA2 and familial episodic ataxia with nystagmus demonstrated that 4AP decreases attack frequency and improves quality of life. Level of evidence: This crossover study provides Class II evidence that 4AP decreases attack frequency and improves the patient-reported quality of life in patients with episodic ataxia and related familial ataxias.

It is estimated that by 2020 road accidents will rise from ninth to third place in the worldwide ranking of the burden of disease. Traffic calming can reduce road accidents; however, many motorists do not adhere to speed limits. We report on an intervention that can influence many motorists at dangerous sites, where accidents are likely to occur (e.g., near playgrounds, schools). The intervention is a speed-displaying device mounted next to the road (visible to both motorists and the public). Our findings indicate that the device is associated with a significant speed reduction relative to the control condition.

A 45-year-old man presented to the neurotology clinic, suffering from recurrent attacks of vertigo associated with falls, of unknown origin. Pure tone audiometry revealed a profound right-sided and...

Human neuroimaging studies have implicated a number of brain regions in long-term memory formation. Foremost among these is ventrolateral prefrontal cortex. Here, we used double-pulse transcranial magnetic stimulation (TMS) to assess whether the contribution of this part of cortex is crucial for laying down new memories and, if so, to examine the time course of this process. Healthy adult volunteers performed an incidental encoding task (living/nonliving judgments) on sequences of words. In separate series, the task was performed either on its own or while TMS was applied to one of two sites of experimental interest (left/right anterior inferior frontal gyrus) or a control site (vertex). TMS pulses were delivered at 350, 750, or 1,150 ms following word onset. After a delay of 15 min, memory for the items was probed with a recognition memory test including confidence judgments. TMS to all three sites nonspecifically affected the speed and accuracy with which judgments were made during the encoding task. However, only TMS to prefrontal cortex affected later memory performance. Stimulation of left or right inferior frontal gyrus at all three time points reduced the likelihood that a word would later be recognized by a small, but significant, amount (∼4%). These findings indicate that bilateral ventrolateral prefrontal cortex plays an essential role in memory formation, exerting its influence between ≥350 and 1,150 ms after an event is encountered.

Animal experiments have demonstrated that the vast majority of vertical gaze-velocity Purkinje cells in the cerebellar floccular lobe, whose firing rate is modulated during vertical smooth pursuit eye movements, show a preference for downward pursuit. Here we validate the functional vertical asymmetry of the cerebellar flocculus in humans using functional magnetic resonance imaging by demonstrating a significantly higher activation of the floccular lobe for downward than for upward pursuit. The findings corroborate our recent hypothesis on the pathogenesis of cerebellar downbeat nystagmus.

ZusammenfassungVertikaler Nystagmus ist ein klinisches Zeichen einer zentralen Läsion. Downbeat und Upbeat Nystagmus unterscheiden sich jedoch bezüglich Lokalisation, Ätiologie, Pathophysiologie und Prognose. Diese sowie die aktuellen Therapieansätze sollen im folgenden Übersichtsartikel dargestellt werden.

Smooth pursuit eye movements are used to continuously track slowly moving visual objects. A peculiar property of the smooth pursuit system is the nonlinear increase in sensitivity to changes in target motion with increasing pursuit velocities. We investigated the role of the frontal eye fields (FEFs) in this dynamic gain control mechanism by application of transcranial magnetic stimulation. Subjects were required to pursue a slowly moving visual target whose motion consisted of 2 components: a constant velocity component at 4 different velocities (0, 8, 16, and 24 deg/s) and a superimposed high-frequency sinusoidal oscillation (4 Hz, +/-8 deg/s). Magnetic stimulation of the FEFs reduced not only the overall gain of the system, but also the efficacy of the dynamic gain control. We thus provide the first direct evidence that the FEF population is significantly involved in the nonlinear computation necessary for continuously adjusting the feedforward gain of the pursuit system. We discuss this with relation to current models of smooth pursuit.

The use of functional magnetic resonance imaging (fMRI) to examine mental imagery of locomotion has become an attractive way to investigate supraspinal gait control in humans. Whereas cerebral activation patterns associated with walking along a straight line have already been investigated, data on activations associated with the initiation of turns and the maintenance of a curved path are sparse. Electrophysiological findings in animals show that electrical stimulation of the striatum induces a contraversive turn of eyes, head, and body. In the present study, fMRI was used to investigate brain activity in 12 healthy volunteers during mental imagery of walking along a curved path, walking straight ahead, and upright stance. The major findings were as follows: (1) A shift of activation to the hemisphere contralateral to the turn was found in the putamen, and-for initiation of the turn-in the caudate nucleus. These findings confirm the important role of the striatum in the initiation of movement and the execution of contraversive body turns. (2) Parahippocampal and fusiform gyri, known to be involved in visually guided navigation, showed more activity when walking along a curved path than when walking straight ahead. (3) Deactivations were found in the superior and medial temporal gyri, areas belonging to the multisensory and vestibular cortical network. This reduced activity may reflect the suppression of vestibular signal processing in favour of-potentially conflicting-visual input. (4) Mental imagery of walking along a curved path induced ipsiversive eye movements in most subjects, as did actually walking along a curve. These data complement earlier findings on the role of anticipatory eye movements during initiation of turns and suggest that there is a very close neurophysiologic relation between locomotion and its mental imagery.

Patients with unilateral vestibular failure (UVF) experience oscillopsia (apparent motion of the visual scene) during rapid head movements due to increased retinal slip caused by vestibulo-ocular reflex impairment. Oscillopsia is always smaller than the net retinal slip and decreases over time in patients with acquired vestibular loss; this correlates with increased thresholds for visual motion detection and increased tolerance to retinal slip. We investigated the underlying cortical adaptive processes using visual motion stimulation during blood oxygen level-dependent (BOLD) fMRI. Optokinetic nystagmus was elicited in seven patients with right-sided and seven patients with left-sided unilateral vestibular neurectomy and in seven age- and gender-matched healthy controls. Patients showed diminished activation of bilateral visual cortex areas (including the motion-sensitive area MT/V5, cuneus, middle occipital, fusiform and lingual areas) and ocular motor regions compared to their controls during visual motion stimulation. Concurrent BOLD signal decreases of temporo-parietal and insular multisensory cortical areas occurred in controls and patients. The diminished activation of visual motion processing areas plausibly reflects an adaptive mechanism that suppresses distressing oscillopsia in patients with UVF and thereby stabilizes the perceived visual surroundings. This study provides for the first time neuroimaging evidence of suppressed cortical visual motion processing in patients with vestibulopathy.

An erect posture with bipedal locomotion is a characteristic feature of humans compared to other mammals. Most of our knowledge about the hierarchical network of supraspinal locomotor centers derives from animal experiments, mainly in the cat. We posed the question of whether evolutionary transition from quadrupedal to bipedal locomotion – with associated change of foreleg function – caused reorganization of these supraspinal locomotor centers. Using functional magnetic resonance imaging, we identified separate and distinct cerebellar and brainstem BOLD signal increases related to posture and gait during mental imagery of standing, walking, and running in healthy volunteers ( n = 26). Comparison with the locomotion centers in the cat showed that these activations include the pacemakers for gait initiation and speed regulation in the interfastigial cerebellum and bilateral midbrain tegmentum (cerebellar and mesencephalic locomotor regions), their descending target regions in the pontine reticular formation, and the rhythm generators in the cerebellar vermis and paravermal cortex. Moreover, during mental imagery of stance, a BOLD signal increase was observed in the dorsal pons, reflecting an activation of the dorsal tegmental field, a locomotion-suppressing site in the cat. These results support the view that the organization of supraspinal locomotor centers was preserved during the transition to bipedal locomotion. The clinical relevance of these centers has so far been largely neglected. However, Parkinson's disease, for example, is associated with reduced cell counts in the pedunculopontine nucleus, a part of the mesencephalic locomotor region. This association suggests that deep brain stimulation of locomotion centers may provide new therapeutic approaches for common gait disorders.

Downbeat nystagmus (DBN), the most common form of acquired fixation nystagmus, is often caused by cerebellar degeneration, especially if the vestibulo-cerebellum is involved. The upward ocular drift in DBN has a spontaneous and a vertical gaze-evoked component. Since cerebellar involvement is suspected to be the underlying pathomechanism of DBN, we tested in 15 patients with DBN whether the application of the potassium-channel blocker 4-aminopyridine (4-AP), which increases the excitability of cerebellar Purkinje cells as shown in animal experiments, reduces the vertical ocular drift leading to nystagmus. Fifteen age-matched healthy subjects served as the control group. 4-AP may affect spontaneous drift or gaze-evoked drift by either enhancing visual fixation ability or restoring vision-independent gaze holding. We therefore recorded 3D slow-phase eye movements using search coils during attempted fixation in nine different eye positions and with or without a continuously visible target before and 45 min after ingestion of 10mg 4-AP. Since the effect of 4-AP may depend on the associated etiology, we divided our patients into three groups (cerebellar atrophy, n = 4; idiopathic DBN, n = 5; other etiology, n = 6). 4-AP decreased DBN during gaze straight ahead in 12 of 15 patients. Statistical analysis showed that improvement occurred predominantly in patients with cerebellar atrophy, in whom the drift was reduced from -4.99 +/- 1.07 deg/s (mean +/- SE) before treatment to -0.60 +/- 0.82 deg/s afterwards. Regression analysis of slow-phase velocity (SPV) in different eye positions revealed that vertical and horizontal gaze-evoked drift was significantly reduced independently of the patient group and caused perfect gaze holding on the average. Since the observed improvements were independent of target visibility, 4-AP improved fixation by restoring gaze-holding ability. All in all, the present study demonstrates that 4-AP has a differential effect on DBN: drift with gaze straight ahead was predominantly reduced in patients with cerebellar atrophy, but less so in the remaining patients; 4-AP on the average improved neural integrator function, i.e. gaze-evoked drift, regardless of etiology. Our results thus show that 4-AP was a successful treatment option in the majority of DBN patients, possibly by increasing Purkinje cell excitability in the cerebellar flocculi. It may work best when DBN is associated with cerebellar atrophy. Furthermore, 4-AP may be a promising treatment option for patients with a dominant gaze-evoked component of nystagmus, regardless of its etiology.

OBJECTIVE Ocular vestibular-evoked myogenic potentials (oVEMPs) represent extraocular muscle activity in response to vestibular stimulation. The authors sought to investigate whether posture-induced increase of the intracranial pressure (ICP) modulated oVEMP frequency tuning, that is, the amplitude ratio between 500-Hz and 1000-Hz stimuli. DESIGN Ten healthy subjects were enrolled in this study. The subjects were positioned in the horizontal plane (0 degree) and in a 30-degree head-downwards position to elevate the ICP. In both positions, oVEMPs were recorded using 500-Hz and 1000-Hz air-conducted tone bursts. RESULTS When tilting the subject from the horizontal plane to the 30-degree head-down position, oVEMP amplitudes in response to 500-Hz tone bursts distinctly decreased (3.40 μV versus 2.06 μV; p < 0.001), whereas amplitudes to 1000 Hz were only slightly diminished (2.74 μV versus 2.48 μV; p = 0.251). Correspondingly, the 500/1000-Hz amplitude ratio significantly decreased when tilting the subjects from 0- to 30-degree inclination (1.59 versus 1.05; p = 0.029). Latencies were not modulated by head-down position. CONCLUSIONS Increasing ICP systematically alters oVEMPs in terms of absolute amplitudes and frequency tuning characteristics. oVEMPs are therefore in principle suited for noninvasive ICP monitoring.

The human hippocampal formation plays a crucial role in various aspects of memory processing. Most literature on the human hippocampus stresses its non-spatial memory functions, but older work in rodents and some other species emphasized the role of the hippocampus in spatial learning and memory as well. A few human studies also point to a direct relation between hippocampal size, navigation and spatial memory. Conversely, the importance of the vestibular system for navigation and spatial memory was until now convincingly demonstrated only in animals. Using magnetic resonance imaging volumetry, we found that patients (n = 10) with acquired chronic bilateral vestibular loss (BVL) develop a significant selective atrophy of the hippocampus (16.9% decrease relative to controls). When tested with a virtual variant (on a PC) of the Morris water task these patients exhibited significant spatial memory and navigation deficits that closely matched the pattern of hippocampal atrophy. These spatial memory deficits were not associated with general memory deficits. The current data on BVL patients and bilateral hippocampal atrophy revive the idea that a major--and probably phylogenetically ancient--function of the archicortical hippocampal tissue is still evident in spatial aspects of memory processing for navigation. Furthermore, these data demonstrate for the first time in humans that spatial navigation critically depends on preserved vestibular function, even when the subjects are stationary, e.g. without any actual vestibular or somatosensory stimulation.

During fixation of a stationary, dim light-emitting diode (LED) in complete darkness, a subtle, apparent motion is perceived which is called autokinesis. This autokinetic illusion increases with increasing fixation time. Eleven healthy subjects were examined by fMRI while fixating an LED in darkness for 35 s. BOLD signal changes of the first and the second half of the fixation period were compared. While the stimulus was the same for both periods, perception differed in that autokinesis was more pronounced in the second half. This second half of the period was associated with bilateral activations in the motion-sensitive middle occipito-temporal area known as MT/V5. Our finding suggests that area MT/V5 is involved in the mediation of autokinesis.

Since 2003, aminopyridines have been used to treat downbeat nystagmus (DBN) [1] and more recently to treat episodic ataxia type 2 (EA2) [2] and cerebellar gait disorders [3]. Therefore, aminopyridines have become a treatment option as symptomatic therapy for different cerebellar disorders (for ref. see [4]). Here we report on a case of idiopathic DBN that exhibited a transition from persistent DBN to transient upbeat nystagmus (UBN) during medication with sustained-release 4-aminopyridine (fampridine, Fampyra). A 68-year-old woman presented in with permanent dizziness, unsteadiness of gait, spontaneous vertical oscillopsia and blurred vision. The symptoms started about 1 year prior to examination at our center. Neurological examination revealed a DBN during fixation, which increased on lateral gaze. In addition, a gaze-evoked nystagmus, saccadic smooth pursuit particularly in downward direction, reduced optokinetic nystagmus and impaired visual fixation suppression of the vestibulo ocular reflex (VOR) were found. Thus, a DBN syndrome was diagnosed. The patient had no family history of neurodegenerative disease. Brain MRI showed supratentorial microangiopathic lesions and no cerebellar atrophy or infratentorial lesions. Blood chemistry was normal. As in most cases [5], the etiology remained unclear. Eye movements were measured in an upright position by a 30-second eye movement recording carried out with 3-D video-oculography (EyeSeeCam ) according to prior work (Resolution = 0.02 , Accuracy = 0.6 , Sampling rate = 120 Hz, Range ±20 in horizontal and vertical direction) [6]. Data were analyzed off-line using Matlab version R2011b (The Mathworks, Natick, MA, USA) to analyse the slow-phase velocity (SPV) of DBN. Slow-phase velocity of DBN was evaluated in primary position with fixed straight position of head in a frame at three different times (before medication, 180 min after the first administration and after 2 weeks of treatment). Tests were performed in darkness. Due to the dependence of DBN of daytime [7], all tests were performed until noon. Patients were seated upright while recording in the following order: (1) calibration primary position and 8.5 right, left, up and down, (2) gaze straight ahead with fixation. Targets were video-projected at eye level onto a wall with white projector screen paint located 180 cm in front of the patient [6]. After giving her written consent, the patient was treated with a test dose of fampridine, the sustained-release of 4-aminopyridine (Fampyra) 10 mg orally. Then she was treated for a period of 2 weeks with 10 mg twice daily. Before treatment, she exhibited a linear vertical nystagmus with a slow upward phase velocity (SPV ± SD) during fixation straight ahead of 1.04 /s ± 0.60. One hundred and eighty minutes after ingestion of the first dose of 10 mg of Fampyra she had a transition from a DBN to an UBN with a mean SPV of -1.40 /s ± 0.70 (Fig 1). After the first administration the patient already did not notice any symptoms. After a treatment period of 2 weeks with Fampyra 10 mg twice daily, the patient had no nystagmus at all in the video-oculography and no subjective symptoms, i.e., she responded very well to this treatment. Downbeat nystagmus is the most frequent form of acquired persisting fixation nystagmus [8, 9]. It is most often caused by bilaterally impaired function of the K. Feil (&) J. Claasen S. Bardins J. Teufel M. Habs R. Kalla M. Strupp Department of Neurology and German Center for Vertigo and Balance Disorders, University Hospital Munich, Campus Grosshadern, Marchioninistrasse 15, 81377 Munich, Germany e-mail: katharina.feil@med.uni-muenchen.de