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Rainer Spiegel,1 Roger Kalla,2 Georgios Mantokoudis,3 Raphael Maire,4 Heiko Mueller,5 Robert Hoerr,5 Ralf Ihl6 1Division of Internal Medicine, Basel University Hospital, University of Basel, Basel, Switzerland; 2Department of Neurology, Inselspital, Bern University Hospital, Bern, Switzerland; 3Department of Otorhinolaryngology, Head and Neck Surgery, Inselspital, Bern University Hospital, Bern, Switzerland; 4Lausanne University Hospital, Lausanne, Switzerland; 5Clinical Research Department, Dr Willmar Schwabe GmbH & Co. KG, Karlsruhe, Germany; 6Department of Psychiatry, University of Duesseldorf, Alexian Research Center Krefeld, Krefeld, Germany 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 240mg on tinnitus and dizziness associated with dementia. Methods: Randomized, placebo-controlled clinical trials of G. biloba extract EGb 761® identified by a systematic database search were included in a meta-analysis if they met all of the following selection criteria: 1) diagnosis of dementia according to generally accepted criteria, 2) treatment period of at least 20 weeks, 3) outcome measures covering at least two of the three conventional domains of assessment, 4) presence and severity of dizziness and tinnitus were assessed, and 5) assessment was done before and after randomized treatment. Results: Five trials that met the inclusion criteria were included in the meta-analysis. The risk of bias was judged as low, with Jadad scores of 3 and 5. In all trials, 11-point box scales were used to assess the severity of tinnitus and dizziness. Overall, EGb 761® was superior to placebo, with weighted mean differences for change from baseline, calculated in meta-analyses using random effects models, of -1.06 (95% CI: -1.77, -0.36) for tinnitus (p = 0.003) and -0.77 (95% CI: -1.44, -0.09) for dizziness (p = 0.03). Conclusion: Our findings support the notion that EGb 761® is also effective in alleviating concomitant neurosensory symptoms in patients with dementia. Keywords: neurodegenerative disorders, gait, unsteadiness, inner ear, hearing, review

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.

BACKGROUND Patients with downbeat nystagmus syndrome suffer from oscillopsia, which leads to an unstable visual perception and therefore impaired visual acuity. The aim of this study was to use real-time computer-based visual feedback to compensate for the destabilizing slow phase eye movements. METHODS The patients were sitting in front of a computer screen with the head fixed on a chin rest. The eye movements were recorded by an eye tracking system (EyeSeeCam®). We tested the visual acuity with a fixed Landolt C (static) and during real-time feedback driven condition (dynamic) in gaze straight ahead and (20°) sideward gaze. In the dynamic condition, the Landolt C moved according to the slow phase eye velocity of the downbeat nystagmus. The Shapiro-Wilk test was used to test for normal distribution and one-way ANOVA for comparison. RESULTS Ten patients with downbeat nystagmus were included in the study. Median age was 76 years and the median duration of symptoms was 6.3 years (SD +/- 3.1y). The mean slow phase velocity was moderate during gaze straight ahead (1.44°/s, SD +/- 1.18°/s) and increased significantly in sideward gaze (mean left 3.36°/s; right 3.58°/s). In gaze straight ahead, we found no difference between the static and feedback driven condition. In sideward gaze, visual acuity improved in five out of ten subjects during the feedback-driven condition (p = 0.043). CONCLUSIONS This study provides proof of concept that non-invasive real-time computer-based visual feedback compensates for the SPV in DBN. Therefore, real-time visual feedback may be a promising aid for patients suffering from oscillopsia and impaired text reading on screen. Recent technological advances in the area of virtual reality displays might soon render this approach feasible in fully mobile settings.

In this thesis, three aspects of downbeat nystagmus (DBN) were examined. First, changes of its intensity during daytime; second, an analysis of the underlying mechanisms, in particular, the modulation of otolith input; and third, the effects of a pharmacotherapy with potassium channel blockers 4-aminopyridine in comparison with 3,4-diaminopyridine. Downbeat nystagmus consists of ocular drifts upwards. These upward drifts cannot be deliberately controlled. As a correcting mechanism, the upward drifts are followed by downward saccades. Downbeat nystagmus is either due to lesions in the cerebellum, due to lesions to the brainstem or due to cryptogenic/idiopathic causes. In order to reduce symptoms effectively, it is of particular importance to increase our knowledge about DBN. In chapter 1 of this thesis it is shown that the intensity of DBN decreases during daytime. In chapter 2, it is demonstrated that resting positions have an influence on the extent of DBN. During daytime, where people are generally in upright body position, DBN decreases effectively when people remain upright during their resting periods, i.e. when people sit instead of lying down to rest. There is a possible reason why DBN in upright position significantly decreases when people rest upright. This could have been due to otoliths exerting a stabilizing influence on the central vestibular neurons of the patients while remaining upright for a continuous period. Moreover, it does not make a difference whether patients with DBN rest with the light switched on or with the light switched off. Chapters 1 and 2 also have implications for symptomatic treatment. It can be suggested to patients to rest in an upright position during the day, and to engage in activities such as reading or screen-related work in the afternoon rather than in the morning. In chapter 3, another way of symptom reduction is presented, where the aminopyridines 4-AP and 3,4-DAP are compared against each other. The efficacy of reducing DBN had previously been demonstrated individually for both aminopyridines. In this thesis, the efficacy of both aminopyridines was examined in a double-blind study with cross-over design. The major finding was that 4-AP is more effective than 3,4-DAP in terms of reducing the intensity of DBN. Moreover, 4-AP revealed a tentative trend towards a particular efficacy for cerebellar patients, which is in line with experimental evidence, where it had been reported to better cross the blood-brain barrier and to have at least the same (probably even a longer) half-life than 3,4-DAP. In conclusion, no causative treatment is in sight for DBN, but clinical studies can lead to a better understanding of DBN and may contribute to symptom alleviation.

In this paper we present a tentative neuropsychological explanation on sign-language comprehension. A spatial probability interface is applied to study levels of comprehension with regard to British Sign Language (BSL) sequences. The results of this study not only support the validity of the spatial probability interface as a means of expressing learning and comprehension, but also refer to gender differences. These differences are discussed in the light of present neuropsychological theory.