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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.

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).

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.

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.

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.

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.

BACKGROUND AND PURPOSE The initial diagnosis of medullary infarction can be challenging since CT and even MRI results in the very acute phase are often negative. METHODS A retrospective, observer-blinded study of horizontal conjugate eye deviation was performed in 1) 50 consecutive patients [age 58±15 years (mean±SD), 74% male, National Institutes of Health Stroke Scale 2±1] with acute unilateral lateral medullary infarction as seen in MRI (infarction group), 2) 54 patients with transient brainstem symptoms [transient ischemic attack of brainstem (TIA) group; age 69±16 years, 59% male], and 3) 53 patients (age 59±20 years, 49% male) with diagnoses other than stroke (control group). RESULTS Conjugate eye deviation was found in all patients in the infarction group [n=47 (94%) with ipsilesional deviation and n=3 (6%) with contralesional deviation] compared to 41% (n=22) in the brainstem TIA group and 15% (n=8) in the control group (p20°.

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.

Objective: To evaluate the effect of time between the movements/steps, angle of body movements as well as the angular velocity of the maneuvers in an in-vitro model of a semicircular canal (SCC) to improve the efficacy of the Semont maneuver in benign paroxysmal positional vertigo (BPPV). Methods: Semont maneuvers were performed on an in-vitro SCC model. Otoconia trajectories were captured by a video camera. The effects of time between the movements, angles of motion (0°, 10°, 20°, 30° below the horizontal line), different angular velocities (90, 135, 180°/s) and otoconia size (36 and 50µm) on the final position of the otoconia in the SCC were tested. Results: Without extension of the movements beyond the horizontal, the in-vitro experiments (with particles corresponding to 50 m diameter) did not yield successful canalith repositioning. If the movements were extended by 20° beyond the horizontal position, Semont maneuvers were successful with resting times of at least 16 s. For larger extension angles the required time decreased. However, for smaller particles (36 m) the required time doubled. The angular maneuver velocity (tested between 90 and 180°/s) did not have a major impact on the final position of the otoconia. Interpretation: The two primary determinants for success of the Semont maneuver are the time between the movements and the extension of the movements beyond the horizontal. The time between the movements should be at least 45 s. Angles of 20° or more below horizontal line (so-called Semont ++) should increase the success rate of SM.

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.

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.

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.

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.

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.

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

Background: In a recent study, the authors found that blinks in healthy volunteers always triggered ocular torsion quick phases during dynamic roll movements of the head. On the basis of this observation, they hypothesized that blinks in patients with a vestibular tone imbalance would also trigger torsional quick phases. Methods: Using video-oculography with a fixation target, the authors recorded the ocular torsion position of the left eye of 37 participants while they made voluntary blinks once every 6 to 10 seconds. The participants were recruited from four groups: two age groups of healthy volunteers with a mean ± SD age of 32 ± 4 (n = 9) and 65 ± 11 y (n = 9); patients with a unilateral vestibular disorder in an acute state (n = 12, 53 ± 17 y); and those in a persisting state in which spontaneous nystagmus had already faded (n = 9, 65 ± 13 y). Results: In the control groups of healthy volunteers, blinks triggered no or only small quick phases on the order of 0.1 deg. In both patient groups blinks always triggered quick phases with significantly higher amplitudes of 1.85 ± 1.02 deg and were followed by exponentially decaying slow-phases with time constants on the order of 1 to 2 seconds. Patients in the persisting state clearly differed from patients in the acute state in that their torsional spontaneous nystagmus had already vanished due to vestibular compensation. But surprisingly, these two groups did not show a large difference in terms of the effect of blinks on ocular torsion. The authors always observed torsional quick phases with the upper pole of the eye beating away from the side of the lesion. Conclusions: Blinks are able to trigger torsional quick phases in patients with both acute and persisting vestibular disorders. The side of the impairment can be determined from the direction in which the eye is rotated after a blink. Thus, ocular torsion recordings during blinks can be used as a simple clinical test for a vestibular tone imbalance, particularly during a persisting failure in which spontaneous nystagmus has resolved and can therefore no longer be used for diagnosis.

The effect of the potassium channel blocker 4-aminopyridine (4-AP) on spontaneous upbeat nystagmus (UBN) was investigated with the search coil technique during fixation in different gaze positions and smooth pursuit in a patient before and after ingestion of 10 mg 4-AP. UBN was reduced from 8.6 deg/s to 2.0 deg/s by 4-AP causing subjective relief from distressing oscillopsia, and impaired upward smooth pursuit was restored (gains: before medication 0.38; after medication 0.86). In the dark, UBN was slightly stronger and not affected by 4-AP. We propose that 4-AP improved the function of cerebellar pathways that mediate gaze holding and smooth pursuit by intensifying the excitability of cerebellar Purkinje cells.

OBJECTIVE: Animal experiments have demonstrated that aminopyridines increase Purkinje cell excitability, and in clinical studies, 4-aminopyridine (4-AP) and 3,4-diaminopyridine (3,4-DAP) improved downbeat nystagmus. In this double-blind, prospective, crossover study, the effects of equivalent doses of 4-AP and 3,4-DAP on the slow-phase velocity (SPV) of downbeat nystagmus were compared. METHODS: Eight patients with downbeat nystagmus due to different etiologies (cerebellar degeneration [n = 1], bilateral vestibulopathy [n = 1], bilateral vestibulopathy and cerebellar degeneration [n = 1], Arnold-Chiari I malformation and cerebellar ataxia [n = 1], cryptogenic cerebellar ataxia [n = 4]) were included. They were randomly assigned to receiving a single capsule of 10 mg of 3,4-DAP or 4-AP followed by 6 days with no medication. One week later, the treatment was switched, that is, 1 single capsule (10 mg) of the other agent. Recordings with 3-dimensional video-oculography were performed before and 45 and 90 minutes after drug administration. RESULTS: Both medications had a significant effect throughout time (pre vs post 45 vs post 90) (F() = 8.876; P < 0.01). Following the administration of 3,4-DAP, mean slow velocity decreased from -5.68°/s (pre) to -3.29°/s (post 45) to -2.96°/s (post 90) (pre vs post 45/post 90 P < 0.01). In 4-AP, the mean SPV decreased from -6.04°/s (pre) to -1.58°/s (post 45) to -1.21°/s (post 90) (pre vs post 45/post 90 P < 0.00001). Both after 45 and after 90, the mean SPVs were significantly lower for 4-AP than for 3,4-DAP (P < 0.05). None of the patients reported serious side effects. CONCLUSION: Based on these results, 10-mg doses of 4-AP lead to a more pronounced decrease of the SPV of downbeat nystagmus than do equivalent doses of 3,4-DAP.

Patients with bilateral vestibular failure (BVF) suffer from oscillopsia during head movements. This is secondary to the loss of the vestibulo-ocular reflex which is responsible for stabilising retinal images during head movements of high frequency or velocity. Previous studies documented decreased visual motion sensitivity in such patients at low velocities. The authors now examine motion coherence tasks, which have two advantages: (1) the task is associated with the functions of the middle temporal area; and (2) it affords testing at low and high motion velocities, as relevant for patients with oscillopsia due to BVF.Nine BVF patients and nine healthy control subjects were examined with a random dot pattern with variable percentages of dots moving in the target direction. Participants were asked to indicate in which of two possible directions they perceived the coherent motion. Horizontal and vertical planes were tested at speeds from 0.156 to 40°/s.Motion coherence thresholds were lower at higher speeds in both groups (p0.0001). BVF patients had raised motion coherence thresholds (p=0.002) across all velocities as compared with the control subject group.In a motion coherence paradigm, BVF patients show raised thresholds. This is the first demonstration of diminished visual motion processing at high velocities, supporting the view that the changes allow BVF patients to partly compensate for the oscillopsia. The findings are interpreted as an adaptive process likely to involve the middle temporal visual motion processing areas.

Objective: It has been shown in normal subjects that opening the eyes in darkness without external visual stimulation increases activity in the ocular motor and attentional systems. By contrast, closing the eyes causes a relative signal increase in multiple sensory areas such as the visual, somatosensory, vestibular, auditory, and gustatory cortical areas. These two states of „resting“ activity of the human brain in complete darkness, which can be imaged using fMRI, were termed the „exteroceptive“ state (contrast OPEN>CLOSED) and the „interoceptive“ state (contrast CLOSED>OPEN). In the present study we investigated whether similar brain activity states can be found in blind subjects when opening and closing their eyes. Methods: Seven congenitally, totally blind individuals participated in the study. Subjects were trained outside the scanner to perform the following tasks: eyes open (OPEN) or eyes closed (CLOSED) at rest while looking straight ahead in complete darkness. Functional images were acquired on a 1.5 T standard clinical scanner using echo-planar imaging. The data were compared to data published earlier of a matched group of healthy volunteers (Marx et al. 2003). Analysis was performed using SPM2. Results: Overall, the differences between the OPEN and CLOSED conditions were less pronounced in the blind subjects than in the controls. In congenitally, totally blind subjects the contrast OPEN>CLOSED revealed a relative increase in activity in the middle occipital gyrus bilaterally as well as in the anterior cingulate cortex. The intergroup comparison (congenitally, totally blind subjects vs. controls) for this contrast showed an activity increase in regions similar to those found in the blind subjects alone. Discussion: There are also differences in brain activity patterns between eyes-open or eyes-closed at rest in congenitally, totally blind subjects, but they are not those of the above-described „intero-“/“exteroceptive“ states. They are rather diametrically opposed to those observed in sighted controls: the activity increases in the occipital cortex for the contrast OPEN>CLOSED suggest a functional reorganization of the visual cortex. While the visual cortex has been previously shown to mediate attentional tasks in congenitally blind subjects, its activation during the eyes-open condition in conjunction with the anterior cingulate might be indicative of an increased attentional load.

Background: Neurologic disorders in which the etiology and pathogenesis are not yet understood are termed idiopathic. Downbeat nystagmus (DBN) is a frequent eye movement disorder that clinically manifests with oscillopsia and postural instability. Forty percent of patients with DBN are classified as having idiopathic DBN, because no underlying pathology can be demonstrated by conventional MRI or laboratory tests. Methods: We evaluated gray matter brain volumes of 11 patients with idiopathic DBN and compared them to those of healthy controls using voxel-based morphometry. In a second, functional MRI experiment, patients and controls performed downward smooth pursuit eye movements (DOWN), which were then compared with straight-ahead fixation of a stationary target (MID). Results: Small areas of localized gray matter atrophy were detected in the lateral cerebellar hemispheres (lobule VI) and ocular motor vermis of patients with idiopathic DBN, but not in the flocculus and paraflocculus. The functional imaging data, however, revealed reduced activation in the parafloccular lobule and in the ponto-medullary brainstem of the patients when they performed smooth pursuit eye movements downwards. Conclusions: The applied specialized imaging and data analysis techniques disclosed pathologies in an idiopathic eye movement disorder. The focal atrophy found in the vermal and lateral cerebellar regions in downbeat nystagmus (DBN) may lead to deficits in smooth pursuit eye movement initiation, which in turn causes hypofunction of the parafloccular lobe, associated with DBN. Our data are in line with experiments in primates showing that ablation of the floccular and parafloccular lobes disrupts smooth pursuit and causes DBN.

Untersuchungen aus jungerer Zeit legen nahe, dass die transcranielle magnetische Stimulation (TMS) der frontalen Augenfelder und des parietalen Kortex zu einer reduzierten Verarbeitung eines visuellen Zielreizes fuhrt, wenn dieser durch eine Merkmalskombination ('Konjunktion', Farbe und Form) definiert wird, jedoch nicht bei einer einfachen Merkmalssuche ('Pop-out', Farbe) (Ashbridge et al, 1997, Muggleton et al, 2003). In bildgebenden Studien bilden diese Areale Teile eines Netzwerks, das wahrend der visuellen Konjunktionssuche aktiv ist (e.g. Donner et al, 2002). Weiterhin ist die Aktivierung von Teilen des dorsolateralen prefrontalen Kortex (DLPFC) in der visuellen Konjunktionssuche berichtet worden (Makino et al., 2004). Wir applizierten TMS uber dem DLPFC unter Verwendung eines Offline Stimulationsparadigmas (Theta-Burst-Stimulation: 3 Pulse zu 50Hz wiederholt mit 5Hz fur 20s. 40% Geratleistung; siehe Huang et al., 2005). Die Versuchspersonen (n=12) fuhrten unter kontinuierlichem Augenmonitorring (Eye-Link System) sowohl eine Konjunktionssuche als auch eine einfache Pop-out Suchaufgabe durch, wobei beide Tests hinsichtlich ihrer Schwierigkeit gleich gematched waren (in Bezug auf die Genauigkeit der Testleistung). Es wurden kleine Suchdisplays (Grose: 2 Grad x 2 Grad) verwendet, so dass keine zusatzlichen Augenbewegungen fur eine erfolgreiche visuelle Erkennung des Zielobjekts erforderlich waren (Durchgange mit zusatzlichen Augenbewegungen wahrend der visuellen Suche wurden verworfen). Die Testleistung wurde mit dem Kriteriums-unabhangigen Mas fur Sensitivitat (d-prime) bewertet. Hierbei zeigte sich eine signifikante Reduktion der d-prime Werte wahrend der Konjunktionssuche fur die TMS-Stimulation uber dem DLPFC, relativ verglichen zu der TMS-Baseline und der TMS-Kontrollbedingung (Sham-Stimulation). Keine TMS-Effekte zeigten sich bei der einfachen Merkmalssuche. Diese Ergebnisse lassen darauf schliesen, dass der DLPFC fur die erfolgreiche visuelle Konjunktionssuche notwendige ist, wobei zu untersuchen bleibt, ob sich dieser Beitrag von dem der frontalen Augenfelder oder des parietalen Kortexes unterscheidet.

Hintergrund: In einer kurzlich erschienenen Studie konnten wir zeigen, dass es bei Patienten mit erworbener, beidseitiger vestibularer Deafferentierung zu Defiziten im raumlichen Gedachtnis und bei der Navigation kommt. Daruber hinaus wiesen diese Patienten eine selektive und beidseitige Atrophie des Hippocampus auf. Dies deutet darauf hin, dass raumliches Gedachtnis und Navigation von vestibularem Input beeinflusst werden. Methoden: In der aktuellen Studie wurden 16 Patienten mit einseitiger vestibularer Deafferentierung aufgrund eines Akustikusneurinoms 5–13 Jahre nach der Operation untersucht und mit gesunden Kontrollpersonen gleichen Alters und Geschlechtes verglichen. Alle Patienten und Kontrollpersonen waren Rechtshander. Raumliches Gedachtnis und Navigation wurden mit der virtuellen Version des „Morris Water Task“ gepruft. Eine Volumetrie des Hippocampus wurde durch manuelles Vermessen der Struktur auf koronaren MRI Sequenzen, sowie mittels voxel-basierter Volumetrie (VBM) durchgefuhrt. Ergebnisse: Bei den Patienten mit linksseitiger vestibularer Deafferentierung fanden sich keine signifikanten Defizite bezuglich des raumlichen Gedachtnisses oder der Navigation. Die Patienten, bei denen es jedoch zu einem Verlust des rechtsseitigen vestibularen Inputs gekommen war, zeigten dagegen ein tendenziell schlechteres Abschneiden bei den Navigationstests. Statistisch war dieses Defizit nur fur einen Wert (den „Heading Error“) signifikant. Weder mittels der manuellen noch der automatisierten Hippocampus Volumetrie lies sich eine Atrophie des Hippocampus im Vergleich zum Kontrollkollektiv nachweisen. Diskussion: Geringgradige Defizite bei der Testung von raumlichem Gedachtnis und Navigation fanden sich nur bei der Patientengruppe mit rechtsseitiger vestibularer Deafferentierung; sie stehen im Einklang mit der kurzlich beschriebenen Dominanz des vestibularen Kortex in der rechten Hemisphare. Eine Atrophie des Hippocampus lies sich nach einseitiger vestibularer Deafferentierung nicht nachweisen, dies deutet darauf hin, dass die vestibularen Projektionen zum Hippocampus zumindest teilweise bilateral erfolgen.

Hintergrund: Imaginiertes Gehen fuhrt zu einer funktions-kernspintomographisch darstellbaren Aktivierung eines frontoparietalen Netzwerks. Diese Studie erfolgte unter der Fragestellung, ob imaginiertes Kurvengehen und damit assoziierte Blickdeviationen zu einer asymmetrischen Aktivierung dieses Netzwerkes fuhren, wie dies fur die Fixation exzentrischer Blickziele gezeigt wurde (Deutschlander et al., Neuroimage, 2005). Methoden: Zunachst erfolgte eine Trainingsphase, wahrend der die Probanden jeweils funfmal eine durch auf dem Boden ausgelegte Sportmatten markierte Links-/Rechtskurve bzw. gerade Strecke abliefen. Wahrend des Trainings wurden die Augenbewegungen der Probanden videookulographisch aufgezeichnet. Der Kopf wurde zur Vermeidung unwillkurlicher Kopfwendungen durch eine Halskrause fixiert. Anschliesend erfolgte die Funktions-MRI-Messung, wahrend der die Probanden auf akustische Signale hin die vier Bedingungen „Stehen“, „Geradeausgehen“, „Linkskurve“ und „Rechtskurve“ aus der Eigenperspektive imaginieren sollten. Auch hier erfolgte eine videookulographische Aufzeichnung der Augenbewegungen. 12 Probanden wurden in die endgultige Auswertung eingeschlossen. Ergebnisse: Lokomotion fuhrte ahnlich wie vorbeschrieben (Jahn et al., Neuroimage, 2004) zu einer Aktivierung von Gyrus frontalis medius rechts, Gyrus frontalis inferior links, Lobulus parietalis inferior links, Insula links, Gyrus fusiformis rechts, Putamens beidseits und Cerebellum. Der Kontrast Kurvengehen vs. Geradegehen erbrachte Aktivierungen des Gyrus frontalis superior beidseits und des Vermis. Der Vergleich Linkskurve – Rechtskurve zeigte nur wenige Aktivierungen ohne klare richtungsassoziierte Hemispharendominanz. In der Videookulographie fanden sich bei allen Probanden ipsilateral zur vorgestellten Kurvenrichtung weisende Augenbewegungen. Schlussfolgerung

The authors evaluated floccular activity with fMRI during the performance of vertical smooth pursuit eye movements in four patients with downbeat nystagmus (DBN) due to cerebellar degeneration and in 16 healthy controls. Region of interest analysis revealed a significantly diminished activation of both floccular lobes during downward but not upward pursuit in DBN. These imaging data support the view that a functional deficiency of the flocculi in downward pursuit causes DBN.

The potassium channel blocker 4-aminopyridine (4-AP) restored vertical smooth pursuit and gaze holding in light in one patient with upbeat (UBN) and in one with downbeat nystagmus (DBN). Without a visible target, however, 4-AP had no effect on UBN, but DBN vanished. We hypothesize that this difference in the effects of 4-AP, which is known to increase the excitability of cerebellar Purkinje cells, can be attributed to the different lesion sites involved in UBN and DBN.

Patients with episodic ataxia type 2 (EA2) can often be successfully treated with acetazolamide. The authors report three patients with EA2 (two with proven mutations in the CACNA1A gene) whose attacks were prevented with the potassium channel blocker 4-aminopyridine (4-AP; 5 mg tid). Attacks recurred after treatment was stopped; subsequent treatment alleviated the symptoms (mean follow-up time 6 months). These effects might be due to an improvement of the impaired functioning of Purkinje cells.

Downbeat nystagmus (DBN), the most frequent form of acquired persisting fixation nystagmus, is hypothesized to occur when physiologic, inhibitory cerebellar input to the vestibular nuclei is inhibited. Bilateral cerebellar lesions affecting the vestibulocerebellum or bilateral paramedian brainstem lesions could induce such inhibition.1 GABAergic, glutaminergic, or cholinergic drugs have been used to manage DBN with moderate success.2 3,4-Diaminopyridine (3,4-DAP) was shown recently to effectively suppress DBN.3 In animal experiments, the related 4-aminopyridine (4-AP) increased the excitability of Purkinje cells (PCs).4 Both agents seem to influence DBN by increasing the physiologic, inhibitory influence of the vestibulocerebellum on the vestibular nuclei.3 4-AP penetrates the blood–brain barrier better than 3,4-DAP but has not yet been tested for management of ocular motor disorders. To evaluate how aminopyridines affect DBN and to test whether 4-AP is also effective, we measured DBN, smooth pursuit, gaze holding, and the gain of the vestibular ocular reflex (VOR) with the search coil technique in one patient. A 65-year-old pharmacist had blurred vision for 7 years that increased during lateral gaze. Neurologic examination was normal, except for DBN during fixation, impaired smooth pursuit, and postural imbalance. DBN increased during lateral and downward gaze and convergence. Brain MRI and blood chemistry (including vitamin B12 and Mg2+ …

{#article-title-2} “A randomized trial of 4-aminopyridine in EA2 and related familial episodic ataxias”1 follows this group's preliminary report on how 4-aminopyridine (4-AP) is one of few compounds that effectively blocks attacks in EA2 patients.1,2 The authors convincingly demonstrate that 4-AP reduces the frequency of attacks, but it would be interesting to know if it modified the severity or duration of the attacks. A …