Judith Wagner

Downbeat nystagmus: aetiology and comorbidity in 117 patients

Objectives: Downbeat nystagmus (DBN) is the most common form of acquired involuntary ocular oscillation overriding fixation. According to previous studies, the cause of DBN is unsolved in up to 44% of cases. We reviewed 117 patients to establish whether analysis of a large collective and improved diagnostic means would reduce the number of cases with “idiopathic DBN” and thus change the aetiological spectrum. Methods: The medical records of all patients diagnosed with DBN in our Neurological Dizziness Unit between 1992 and 2006 were reviewed. In the final analysis, only those with documented cranial MRI were included. Their workup comprised a detailed history, standardised neurological, neuro-otological and neuro-ophthalmological examination, and further laboratory tests. Results: In 62% (n = 72) of patients the aetiology was identified (“secondary DBN”), the most frequent causes being cerebellar degeneration (n = 23) and cerebellar ischaemia (n = 10). In 38% (n = 45), no cause was found (“idiopathic DBN”). A major finding was the high comorbidity of both idiopathic and secondary DBN with bilateral vestibulopathy (36%) and the association with polyneuropathy and cerebellar ataxia even without cerebellar pathology on MRI. Conclusions: Idiopathic DBN remains common despite improved diagnostic techniques. Our findings allow the classification of “idiopathic DBN” into three subgroups: “pure” DBN (n = 17); “cerebellar” DBN (ie, DBN plus further cerebellar signs in the absence of cerebellar pathology on MRI; n = 6); and a “syndromatic” form of DBN associated with at least two of the following: bilateral vestibulopathy, cerebellar signs and peripheral neuropathy (n = 16). The latter may be caused by multisystem neurodegeneration.

Long-term prophylactic treatment of attacks of vertigo in Meniere's disease--comparison of a high with a low dosage of betahistine in an open trial

Conclusion. Despite the considerable limitations of an open, non-masked trial, particularly in Menières disease (MD), a higher dosage of betahistine-dihydrochloride and a long-term treatment seems to be more effective than a low dosage and short-term treatment. Objective. To evaluate the prophylactic effects of a low versus high dosage long-term treatment with betahistine-dihydrochloride on the number of attacks in MD. Patients and methods. We performed an open, non-masked trial, in which patients with MD received either a low dosage of betahistine-dihydrochloride (16 or 24 mg tid) or a higher dosage of 48 mg tid for at least 12 months. The outcome measure was the number of attacks per month during a 3-month period. Non-parametric tests and a random effects model were used for statistical analysis. Results. A total of 112 patients were included in the analysis: 50 received betahistine-dihydrochloride in a low dosage (16 mg tid, n=21, 24 mg, n=29) and 62 received 48 mg tid. Follow-up examination every 3 months showed that the number of attacks per month decreased in both groups over time. For instance, after 12 months the mean (median) number of attacks dropped from 7.6 (4.5) to 4.4 (2.0) (p<0.0001) in the low-dosage group, and from 8.8 (5.5) to 1.0 (0.0) (p<0.0001) in the high dosage group. The number of attacks after 12 months was significantly lower in the high dosage group than in the low dosage group (p12M=0.0002). The treatment was well tolerated in both groups.

Supraspinal locomotor control in quadrupeds and humans

Locomotion in humans and other vertebrates is based on spinal pattern generators, which are regulated by supraspinal control. Most of our knowledge about the hierarchical network of supraspinal locomotion centres derives from animal experiments, mainly in the cat. Here we summarize evidence that the supraspinal network of quadrupeds is conserved in humans despite their transition to bipedalism. By use of mental imagery of locomotion in fMRI we found (1), locomotion modulates sensory systems and is itself modulated by sensory signals. During automated locomotion in healthy subjects cortical sensory inhibition occurs in vestibular and somatosensory areas; this inhibition is cancelled in the congenitally blind; (2), we delineated separate and distinct areas in the brainstem and cerebellum which are remarkably similar to the feline locomotor network. The activations found here include homologues to 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 cerebellar cortex. This conservation of the basic organization of supraspinal locomotor control during vertebrate phylogeny opens new perspectives for both, the diagnosis and treatment of common gait disorders. It is conceivable that electrical stimulation of locomotor brain stem centres may initiate and improve gait in selected patients suffering from Parkinsons disease or progressive supranuclear palsy.

Mind the bend: cerebral activations associated with mental imagery of walking along a curved path

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.

Aminopyridines for the treatment of cerebellar and ocular motor disorders.

Downbeat nystagmus (DBN) is the most frequent form of acquired persisting fixation nystagmus. It is hypothesized to occur when physiological inhibitory cerebellar input, namely of the flocculus, to the vestibular nuclei is inhibited. The second most frequent form of acquired nystagmus is upbeat nystagmus (UBN). UBN is probably caused by an imbalance of vertical vestibulo-ocular reflex tone. GABA-ergic substances like baclofen have been used to treat DBN and UBN, but they have had only moderate success. Animal experiments have shown that aminopyridines [3,4-diaminopyridine (3,4-DAP) and 4-aminopyridine (4-AP)], nonselective blockers of the Kv family of voltage-gated potassium channels, increase Purkinje-cell (PC) excitability. It was assumed that such enhancement of PC activity could restore to normal levels the inhibitory influence of the cerebellar cortex on vertical eye movements. On the basis of these assumptions, we evaluated the efficacy and underlying mechanisms of aminopyridines in DBN and UBN as well as in another cerebellar disorder with an impaired PC function: episodic ataxia type 2 (EA2), which is caused by mutations of the PQ-calcium channel. In a placebo-controlled trial on 17 patients we demonstrated that 3,4-DAP significantly reduces the intensity of DBN. This was confirmed in a recent study with 4-AP, which also showed that 4-AP restores gaze-holding ability independently of fixation in DBN. The efficacy of 4-AP in UBN was demonstrated in single patients. Finally, in an open trial on three patients with EA2 we showed that 4-AP prevents attacks of ataxia. This was also found in an animal model (the tottering mouse) of EA2. The clinical efficacy of 4-AP in EA2 is being further evaluated in an ongoing randomized controlled crossover trial. In conclusion, the use of aminopyridines in DBN, UBN, and EA2 is a new treatment principle for vestibular, cerebellar, and ocular motor disorders.

Human Hippocampal Activation during Stance and Locomotion: fMRI Study on Healthy, Blind, and Vestibular-Loss Subjects

The hippocampal formation, including the parahippocampal gyrus, is known to be involved in different aspects of navigation and spatial orientation. Recently, bilateral parahippocampal activation during mental imagery of walking and running was demonstrated in fMRI. For the current study the question was whether distinct functional regions within the hippocampal formation could be defined from the analysis of brain activity during imagery of stance and locomotion in healthy, blind, and vestibular‐loss subjects. Using the same experimental paradigm in all groups (fMRI during mental imagery of stance and locomotion after training of actual performance, regions of interest [ROI] analysis), activations were found in the hippocampal formation, predominantly on the right side, in all subjects. In healthy subjects, standing was associated with anterior hippocampal activation; during locomotion widespread activity was found in the right parahippocampal gyrus. Compared to healthy controls, blind subjects showed less activity in the right dorsal parahippocampal region, whereas vestibular‐loss subjects had less activity in the anterior hippocampal formation. The findings show that the hippocampal formation in humans processes visual and vestibular signals in different regions. The data support the assumption that the anterior hippocampus and the entorhinal cortex in the parahippocampal region are input areas for vestibular and somatosensory signals. Posterior parahippocampal and fusiform gyri, which are connected to visual cortical areas, are more important for visually guided locomotion and landmark recognition during navigation. The right‐sided dominance reflects the importance of the right hemisphere for spatial orientation.

Efficacy and safety of betahistine treatment in patients with Meniere’s disease: primary results of a long term, multicentre, double blind, randomised, placebo controlled, dose defining trial (BEMED trial)

Study question What is the long term efficacy of betahistine dihydrochloride on the incidence of vertigo attacks in patients with Meniere’s disease, compared with placebo? Methods The BEMED trial is a multicentre, double blind, randomised, placebo controlled, three arm, parallel group, phase III, dose defining superiority trial conducted in 14 German tertiary referral centres (for neurology or ear, nose, and throat). Adults aged 21-80 years (mean age 56 years) with definite unilateral or bilateral Meniere’s disease were recruited from March 2008 to November 2012. Participants received placebo (n=74), low dose betahistine (2×24 mg daily, (n=73)), or high dose betahistine (3×48 mg daily, (n=74)) over nine months. The primary outcome was the number of attacks per 30 days, based on patients’ diaries during a three month assessment period at months seven to nine. An internet based randomisation schedule performed a concealed 1:1:1 allocation, stratified by study site. Secondary outcomes included the duration and severity of attacks, change in quality of life scores, and several observer-reported parameters to assess changes in audiological and vestibular function. Study answer and limitations Incidence of attacks related to Meniere’s disease did not differ between the three treatment groups (P=0.759). Compared with placebo, attack rate ratios were 1.036 (95% confidence interval 0.942 to 1.140) and 1.012 (0.919 to 1.114) for low dose and high dose betahistine, respectively. The overall monthly attack rate fell significantly by the factor 0.758 (0.705 to 0.816; P<0.001). The population based, mean monthly incidence averaged over the assessment period was 2.722 (1.304 to 6.309), 3.204 (1.345 to 7.929), and 3.258 (1.685 to 7.266) for the placebo, low dose betahistine, and high dose betahistine groups, respectively. Results were consistent for all secondary outcomes. Treatment was well tolerated with no unexpected safety findings. Without a control group of patients who did not receive any intervention to follow the natural course of the disease, the placebo effect could not be accurately assessed and differentiated from spontaneous remission and fluctuation of symptoms. What this study adds Current evidence is limited as to whether betahistine prevents vertigo attacks caused by Meniere’s disease, compared with placebo. The trial provides information on symptom relief on placebo intervention which is relevant for the design of future studies on potential disease modifying treatments in patients with Meniere’s disease. Funding, competing interests, data sharing Support from the German Federal Ministry of Education and Research (BMBF support code 01KG0708). Potential competing interests have been reported in full at the end of the paper on thebmj.com. Data are available from the corresponding author (Michael.Strupp@med.uni-muenchen.de) or biostatistician (mansmann@ibe.med.uni-muenchen.de). Study registration EudraCT no 2005-000752-32; ISRCTN no ISRCTN44359668.

Saccular function less affected than canal function in bilateral vestibulopathy

Bilateral vestibulopathy (BV) is characterized by impaired or lost function of both labyrinths or eighth nerves. The diagnosis is routinely established by the head-thrust test, caloric irrigation and rotational testing with electronystagmography to determine the high- and low-frequency deficit of the vestibulo-ocular reflex. All three methods evaluate semicircular canal function only. Vestibular-evoked myogenic potentials (VEMPs) provide a measure of saccular otolith function. The aim of this study was to evaluate the frequency and extent of saccular dysfunction in patients with BV and to correlate saccular with horizontal semicircular canal dysfunction. A total of 84 BV-patients (23 females, mean age 62 ± 15 (SD) years at the time of diagnosis assessment) were examined with VEMPs, electronystagmography with caloric irrigation and a standardized neuro-ophthalmological and -otological examination; 47 healthy subjects (18 females, mean 56 ± 19 years) served as controls. Amplitudes P1-N1 were significantly lower in patients with BV compared to controls (mean P1-N1 of all ears 82.1 ± 50.7 μV in the patients vs. 130.8 ± 85.9 μV in healthy volunteers). VEMPs were absent unilaterally in four patients with BV and in none bilaterally. In contrast, caloric responses were absent bilaterally in 40 patients. There was no correlation between amplitude P1-N1 and caloric-induced nystagmus. The latencies P1 and N1 were not significantly different between patients and controls. Thus, in our study population saccular function appeared to be less affected than horizontal semicircular canal function.

Imagined locomotion in the blind: An fMRI study

Functional magnetic resonance imaging (fMRI) in sighted individuals previously showed parahippocampal and fusiform activations during locomotor imagery, which were interpreted to reflect visuospatial navigation. Concurrent deactivations of multisensory vestibular and somatosensory cortical areas may reflect suppression of vestibular and somatosensory input, in order to prevent adverse interactions of sensory signals with the optimized automated locomotion pattern. In this fMRI study we compared blood oxygen level dependent (BOLD) activations and deactivations during the kinesthetic imagery of standing, walking, and running in seven congenitally totally blind subjects, seven sighted age-matched controls, and five subjects with age at onset of complete blindness > or =9 y or minimal residual vision. Imagined lying served as the rest condition. As opposed to their sighted controls, congenitally totally blind individuals activated multisensory vestibular areas in the posterior insula and superior temporal gyrus during imagined locomotion. Further, congenitally blind individuals did not show activations in parahippocampal and fusiform regions during locomotor tasks. In the intergroup comparisons, congenitally blind subjects exhibited higher BOLD activity levels than sighted subjects in multisensory vestibular (posterior insula and adjacent temporal sites), somatosensory (postcentral gyrus), and primary motor cortical areas, while sighted subjects showed higher activity levels in the parahippocampal and fusiform gyri. These findings indicate that blind subjects rely more on vestibular and somatosensory feedback for locomotion control than sighted subjects. This is accompanied by enhanced voluntary motor control and enhanced motor-kinesthetic processing. Thus, we provide neuroimaging evidence of distinct sensorimotor strategies in the blind for locomotor control.

Vestibular Function and Quality of Life in Vestibular Schwannoma: Does Size Matter?

Objectives: Patients with vestibular schwannoma (VS) frequently suffer from disabling vestibular symptoms. This prospective follow-up study evaluates vestibular and auditory function and impairment of quality of life due to vertigo, dizziness, and imbalance in patients with unilateral VS of different sizes before/after microsurgical or radiosurgical treatment. Methods: Thirty-eight patients with unilateral VS were included. Twenty-two received microsurgery, 16 CyberKnife radiosurgery. Two follow-ups took place after a median of 50 and 186.5 days. Patients received a standardized neuro-ophthalmological examination, electronystagmography with bithermal caloric testing, and pure-tone audiometry. Quality of life was evaluated with the Dizziness Handicap Inventory (DHI). Patient data was grouped and analyzed according to the size of the VS (group 1: <20 mm vs group 2: ≥20 mm). Results: In group 1, the median loss of vestibular function was +10.5% as calculated by Jongkees Formula (range −43 to +52; group 2: median +36%, range −56 to +90). The median change of DHI scores was −9 in group 1 (range −68 to 30) and +2 in group 2 (−54;+20). Median loss of hearing was 4 dB (−42; 93) in group 1 and 12 dB in group 2 (5; 42). Conclusion: Loss of vestibular function in VS clearly correlates with tumor size. However, loss of vestibular function was not strictly associated with a long-term deterioration of quality of life. This may be due to central compensation of vestibular deficits in long-standing large tumors. Loss of hearing before treatment was significantly influenced by the age of the patient but not by tumor size. At follow-up 1 and 2, hearing was significantly influenced by the size of the VS and the manner of treatment.