[Video-based head impulse test. Importance for routine diagnostics of patients with vertigo]. / Videobasierter Kopfimpulstest. Bedeutung für die Routinediagnostik von Schwindelerkrankungen.

Dizziness is one of the most common complaints in Germany which leads to medical consultation. Diagnosis is based on patient history, clinical examination and laboratory tests. In order to find or exclude a vestibular lesion, methods such as caloric irrigation, rotational chair tests or vestibular-evoked myogenic potentials were previously applied. Recently, a new diagnostic tool has been made available for application in daily practice: the video head impulse test (vHIT). Due to the easy and fast application for the examiner, good tolerance by the patient and high sensitivity for vestibular lesions, the vHIT has the potential to improve the diagnosis and therapy of patients suffering from vertigo in widespread medical care in Germany. This article reports on experiences with this new method after examination of over 1,500 patients in the academic vertigo centre in Lübeck. The principles and application of the vHIT in daily clinical routine are described and the many advantages but also some pitfalls are highlighted. As a consequence of a wider clinical use it is expected that the vHIT will lead to an increased detection of vestibular dysfunctions not only in clinically suspected vestibular diseases but also in other common neurological diseases (e.g. polyneuropathy or cerebellar ataxia). This may change the prevalence of different vestibular diseases, broaden knowledge about other common diseases with gait imbalance as the leading symptom and provide a quantitative measure that can be used to longitudinally assess the effects of therapeutic interventions.

Reliability of modeling evoked flow responses.

PURPOSE: Visually evoked flow characterises the relative changes of blood flow velocity in the posterior cerebral artery in response to visual stimulation. The present study is the first to address the reliability of model fitting to evoked flow responses, rigorously defined by Cronbach's alpha. MATERIALS AND METHODS: We fitted two models to the evoked flow responses recorded from 19 subjects on two different days. Model 1 characterises a harmonic oscillator with frequency omega and damping coefficient xi which (after a delay DeltaT) is driven from zero towards a new equilibrium K by an impulse with magnitude T. Model 2 is the sum of a first order system subjected to a step and a transient smoothed pulse, both again delayed by DeltaT. RESULTS: Model 1 exhibited slightly smaller fit errors and convergence was less dependent on starting values for the parameters. As judged from the residual noise in the evoked flow response, there was no clear indication of sustained oscillations characterising model 1 exclusively. Both models showed considerable retest errors. Nonetheless, Cronbach's alpha was significant for K and omega, and highest for K. CONCLUSION: Retest errors were considerable, particularly so for the damping coefficient xi and impulse magnitude T. A physiological interpretation of these parameters is limited by our findings.

Association between clinical disease activity and Epstein-Barr virus reactivation in MS.

OBJECTIVE: To assess the potential significance of Epstein-Barr virus (EBV) reactivation in disease activity in MS patients. METHODS: The prevalence of antibodies against herpes simplex virus type 1 (HSV-1), HSV-2, EBV, and cytomegalovirus was determined in a group of 108 MS patients and in 163 healthy control subjects. Sera were analyzed using combinations of novel assay systems employing highly purified viral and recombinant antigens. In addition, PCR for the detection of EBV DNA was performed in serial samples. RESULTS: In contrast to the control populations, antibodies against EBV were present in 100% of MS patients. Among the tested human herpesviruses, this high extent of seropositivity was only found for EBV. Primary infection was found exclusively in the control group (3.7%), whereas serologic evidence of EBV reactivation was seen in MS patients (13. 9%) as well as control subjects (17.2%). There was no temporal coincidence between EBV reactivation and disease activity in MS patients. However, in 19 patients followed monthly for 1 year, active viral replication as measured by increased immunoglobulin (Ig) M and IgA responses to EBV early antigens (p54 + p138) and positive serum DNA was seen in 72.7% of patients with exacerbations during the study period and in none of the patients with clinically stable disease. CONCLUSIONS: The results demonstrate an association between EBV reactivation and disease activity in MS patients over time, and suggest that EBV might play an indirect role in MS as an activator of the underlying disease process.

Random walks, random sequences, and nonlinear dynamics in human optokinetic nystagmus.

Optokinetic nystagmus (OKN) is a reflexive eye movement with target-following slow phases (SP) alternating with oppositely directed fast phases (FP). We measured the following from OKN in three humans: FP beginning and ending positions, amplitudes, and intervals and SP amplitudes and velocities. We sought to predict future values of each parameter on the basis of past values, using state-space representation of the sequence (time-delay embedding) and local second-order approximation of trajectories. Predictability is an indication of determinism: this approach allows us to investigate the relative contributions of random and deterministic dynamics in OKN. FP beginning and ending positions showed good predictability, but SP velocity was less predictable. FP and SP amplitudes and FP intervals had little or no predictability. FP beginnings and endings were as predictable as randomized versions that retain linear autocorrelation; this is typical of random walks. Predictability of FP intervals did not change under random rearrangement, which is characteristic of a random process. Only linear determinism was demonstrated; nonlinear interactions may exist that would not be detected by our present approach.

CNV and temporal uncertainty with 'ageing' and 'non-ageing' S1-S2 intervals.

OBJECTIVES: Uncertainty about the timing of a known external event is an everyday phenomenon but has been rarely investigated with electrophysiological methods. We studied how the amplitude of the contingent negative variation (CNV) is affected by temporal variation of S2 presentation. Competing hypotheses about the development of CNV during the foreperiod until S2 presentation were that CNV either would follow a monotonic trend, be it increasing or decreasing, or alternatively that the time-course of CNV would be affected by the probability with which S2 was presented at each time-point in a given task. METHODS: The interval between cueing stimulus and imperative stimulus was randomly chosen from 3 different values between 1.3 and 2.6 s, using 3 different probability distributions in separate blocks: an 'ageing', a 'non-ageing' and a 'Gaussian' distribution. RESULTS: As previously shown, reaction times were determined by the probability of the imperative stimulus at the given length of the foreperiod. The same was found for CNV amplitude: the effects of temporal uncertainty on CNV mainly depended on the particular distribution of temporal probabilities used in a block. The relevant parameter was the a posteriori probability of event occurrence, very similar to the effects of this parameter on response times. In fact, the major part of the effect of a posteriori probability on CNV was common variation of CNV and response times. CONCLUSIONS: Thus, under temporal uncertainty the amplitude of CNV reflects the subjective expectancies for the occurrence of a given event, with this variation being related to variations in response times.

Adaptive control of pursuit, vergence and eye torsion in humans: basic and clinical implications.

Recent research from our laboratory has been directed at understanding the range of capabilities for adaptive control of eye movements in normal human subjects. For smooth pursuit, different motor responses to the same sensory stimulus (horizontal target motion) can be learned, stored and gated in or out, according to context (vertical eye position). The dynamic properties of the 'open-loop' portion of horizontal, disparity-driven vergence eye movements are under adaptive control. Eye torsion is also subject to adaptive control, including torsional 'phoria adaptation' and cross-coupling of torsion into the horizontal vestibulo-ocular reflex (VOR). Finally, lesions of the oculomotor vermis in monkeys produce disordered binocular ocular motor function: 'esodeviations' in the absence of disparity cues, and decreased adaptation of the horizontal phoria to a sustained disparity induced by wearing a horizontal prism in front of one eye.

Brain mapping with transcranial magnetic stimulation using a refined correlation ratio and Kendall's tau.

Transcranial magnetic stimulation provides a mean to stimulate the brain non-invasively and painlessly. The effect of the stimulation hereby depends on the stimulation coil used and on its placement. This paper presents a mapping algorithm based on the assumption of a monotonous functional relationship between the applied electric field strength at the representation point of a muscle and the evoked motor potential. We combine data from coil characteristics, coil placement, and stimulation outcome to calculate a likelihood map for the representation of stimulated muscles in the brain. Hereby, correlation ratio (CR) and Kendall's rank coefficient tau are used to find areas in the brain where there is most likely a functional or monotonous relationship between electric field strength applied to this area and the muscle response. First results show a good accordance of our method with mapping from functional magnetic resonance imaging. In our case, classical evaluation of CR with binning is impossible, because sample data sets are too small and data are continuous. We therefore introduce a refined CR formula based on a Parzen windowing of the X-data to solve the problem. In contrast to usual windowing approaches, which require numeric integration, it can be evaluated directly in O(n2) time. Hence, its advantage lies in fast evaluation while maintaining robust applicability to small sample sets. We suggest that the presented formula can generally be used in CR-related problems where sample size is small and data range is continuous.

Functional dissociation of saccade and hand reaching control with bilateral lesions of the medial wall of the intraparietal sulcus: implications for optic ataxia.

The posterior parietal cortex (PPC) is essential for the integration of visuomotor information during visually guided reaching. Studies in macaque monkeys have demonstrated a functional specialisation around the intraparietal sulcus (IPS) with a more medial representation of hand movements ("parietal reach region") and a more lateral representation of saccadic eye movements (lateral intraparietal area, LIP). Here we present evidence for the validity of this concept with respect to the human parietal cortex. We recorded isolated and combined goal-directed eye-hand movements in normal control subjects and in a patient with bilateral parieto-occipital lesions and incomplete Balint's syndrome including severe optic ataxia (misreaching to visual targets). Brain lesions in the patient were caused by acute posterior leucoencephalopathy in association with aortic surgery because of Takayasu's arteritis. MRI scans showed bilateral line-shaped hemorrhagic lesions, restricted to the cortex at the medial banks of the intraparietal sulcus, but leaving its lateral banks largely intact. In the patient visually guided reaching was significantly dysmetric, whereas the metrics of visually guided saccades were within normal limits. Dysmetria was more pronounced for the right visual field, with a gross hypermetria. Variability of the movement improved when a delay of 5 or 10 s was introduced between target presentation and movement execution. Lesion data support the concept of a functional specialisation around the human IPS: The cortex medial to the IPS predominantly controls rapid goal-directed reaching movements, comparable to the parietal reach region in monkeys, whereas saccadic eye movements appear to be controlled rather by the cortex lateral to the IPS.

Functional MRI reveals activation of a subcortical network in a 5-year-old girl with genetically confirmed myoclonus-dystonia.

We investigated a five-year-old girl suffering from genetically confirmed, action-induced myoclonus-dystonia (M-D) with functional magnetic resonance imaging (MRI). We compared the activation pattern by movements of her right hand as if drawing a picture, which elicited M-D, with simple snapping movements (without overt M-D). The drawing and snapping conditions resulted in activation of a motor network including the motor cortex, the putamen, and the cerebellar hemispheres. The direct comparison of the drawing condition with snapping as control revealed specific activations within the thalamus and the dentate nucleus. An age matched healthy control did not show significant activation within the thalamus or dentate nucleus.

[Pharmacological strategies for clozapine-induced hypersalivation: treatment with botulinum toxin B in one patient and review of the literature]. / Therapie der Clozapin-induzierten Hypersalivation mit Botulinum-Toxin B.

Hypersalivation is frequently observed in patients treated with clozapine. Current strategies to counteract sialorrhea include the introduction of antimuscarinergic (anticholinergic) and alpha(2)-agonistic treatment. However, the use of these substances is limited in part by lack of efficacy and by adverse side effects. In cases of intractable sialorrhea, the application of botulinum toxin may be a new and safe therapeutic option. We here present an overview on current treatment strategies for sialorrhea and describe a patient who received botulinum toxin B for clozapine-induced hypersalivation.

On the distribution of fast-phase intervals in optokinetic and vestibular nystagmus.

Histograms of fast-phase intervals in human optokinetic and vestibular nystagmus were generated, and fitted to statistical distributions used in previous studies. The distributions did not depend on stimulation type (optokinetic or vestibular). An inverse Gaussian or a gamma distribution fitted the data better than did a reciprocal Gaussian distribution, but none fitted the data especially well. In some cases, however, the interpretation of these distributions is more physiologically satisfactory than in others. Recommendations are made on which class of models is preferred, and the experiments needed to support the particular models. Our results call into question the validity of previous studies that fit statistical distributions to data sets of a size comparable to ours.

Cross-axis adaptation of torsional components in the yaw-axis vestibulo-ocular reflex.

The three pairs of semicircular canals within the labyrinth are not perfectly aligned with the pulling directions of the six extraocular muscles. Therefore, for a given head movement, the vestibulo-ocular reflex (VOR) depends upon central neural mechanisms that couple the canals to the muscles with the appropriate functional gains in order to generate a response that rotates the eye the correct amount and around the correct axis. A consequence of these neural connections is a cross-axis adaptive capability, which can be stimulated experimentally when head rotation is around one axis and visual motion about another. From this visual-vestibular conflict the brain infers that the slow-phase eye movement is rotating around the wrong axis. We explored the capability of human cross-axis adaptation, using a short-term training paradigm, to determine if torsional eye movements could be elicited by yaw (horizontal) head rotation (where torsion is normally inappropriate). We applied yaw sinusoidal head rotation (+/-10 degrees, 0.33 Hz) and measured eye movement responses in the dark, and before and after adaptation. The adaptation paradigm lasted 45-60 min, and consisted of the identical head motion, coupled with a moving visual scene that required one of several types of eye movements: (1) torsion alone (-Roll); (2) horizontal/torsional, head right/CW torsion (Yaw-Roll); (3) horizontal/torsional, head right/CCW torsion (Yaw+Roll); (4) horizontal, vertical, torsional combined (Yaw+Pitch-Roll); and (5) horizontal and vertical together (Yaw+Pitch). The largest and most significant changes in torsional amplitude occurred in the Yaw-Roll and Yaw+Roll conditions. We conclude that short-term, cross-axis adaptation of torsion is possible but constrained by the complexity of the adaptation task: smaller torsional components are produced if more than one cross-coupling component is required. In contrast, vertical cross-axis components can be easily trained to occur with yaw head movements.

Target anticipation and impairment of smooth pursuit eye movements in schizophrenia.

A reduced gain of smooth pursuit eye velocity has frequently been reported in schizophrenic patients. With respect to predictable stimuli, this could be due to a deficit in predicting the target path. To determine this contribution to smooth pursuit eye movement performance, we analyzed the ocular smooth pursuit response to a sinusoidally moving target that was suddenly stopped after some cycles of regular movement. Horizontal eye movements were recorded with infrared reflection oculography in a group of 17 schizophrenic in-patients and 16 age-matched healthy subjects for controls. The patients exhibited a reduced gain of smooth pursuit velocity, but phase lag was not different from the control group. After the unpredictable stop of target movement, predictive sinusoidal smooth pursuit was maintained for 150 to 200 ms in both groups. The resulting maximal position and velocity error was larger in the patient group. In conclusion, schizophrenic patients were able to generate a normal anticipatory component of smooth pursuit and to switch it off in response to external demands. They showed, however, an increased velocity of anticipatory pursuit, which might be used to compensate for the primary deficit of smooth pursuit velocity frequently found in schizophrenics.

Effect of high-dose methylprednisolone administration on immune functions in multiple sclerosis patients.

OBJECTIVES: To investigate the in vivo effect of corticosteroid pulse therapy on immunocompetent cells in 18 patients given methylprednisolone to treat an acute episode of MS. MATERIAL AND METHODS: Blood was sampled before and after 3 days of methylprednisolone administration at doses of 1 g/day. Lymphocyte subtyping was performed and whole blood cell cultures were used to measure the cytokine producing capacity for interleukin-1 (IL-1), interleukin-2 (IL-2), interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) and interferon-alpha (IFN-alpha). In addition, serum levels of the immunoglobulin classes IgG, IgA and IgM were determined. RESULTS: Before treatment, production of IL-1 was significantly increased in MS patients as compared to healthy controls. After therapy, production of all cytokines was significantly decreased, whereas there were significant increases in the numbers of monocytes, neutrophils and T and B lymphocytes. Treatment had no effect on serum immunoglobulin levels. CONCLUSION: An important mechanism for the antiinflammatory effect of corticosteroids in MS results from a suppression of the activation of the peripheral immune compartment through inhibition of cytokine production and lymphocyte endothelial adhesiveness.

Deficits of smooth pursuit initiation in patients with degenerative cerebellar lesions.

It is well known that cerebellar dysfunction can lead to an impairment of eye velocity during sustained pursuit tracking of continuously moving visual target. We have now studied the initiation of smooth pursuit eye movements towards predictable and randomized visual step-ramp stimuli in six patients with degenerative cerebellar lesions and six age-matched healthy controls using the magnetic scleral search-coil technique. In comparison with the control subjects, the cerebellar patients showed a significant delay of pursuit onset, and their initial eye acceleration was significantly decreased. These cerebellar deficits of pursuit initiation were similarly found in response to both randomized and predictable step-ramps, suggesting that predictive input does not compensate for cerebellar deficits in the initiation period of smooth pursuit. When we compared initial saccades during smooth tracking of foveofugal and foveopetal step-ramps, the absolute position error of these saccades did not significantly differ between patients and controls. In fact, none of the patients showed any bias of the saccadic position error that was related to the direction or velocity of the ongoing target motion. This work presents further evidence that the effect of cerebellar degeneration is not limited to the impaired velocity gain of steady-state smooth pursuit. Instead, it prolongs the processing time required to initiate smooth pursuit and impairs the initial eye acceleration. These two deficits were not associated with an abnormal assessment of target velocity and they were not modified by predictive control mechanisms, suggesting that cerebellar deficits of smooth initiation are not primarily caused by abnormal information on target motion being relayed to the cerebellum.

Consequences of altered cerebellar input for the cortical regulation of motor coordination, as reflected in EEG potentials.

The cerebellum is certainly involved in fine coordination of movements, but has no efferences of its own to the muscles. Thus, it can exert its influence only via other cerebral areas that have those efferences. This study investigated in patients with cerebellar atrophy how cortical motor areas are affected by dysfunction of the cerebellum. The main question was whether the patients' slow cortical electroencephalogram (EEG) potentials during key-press preparation and execution would be generally altered or would be specifically altered when fine coordination was needed. In the coordination task, right- and left-hand keys had to be pressed simultaneously with different forces, under visual feedback. Control tasks were to press with both hands equally or with one hand only. The patients indeed had a performance deficit in the coordination task. Their cortical EEG potentials were already drastically reduced in the simple tasks, but were enhanced by the same amount as in healthy subjects when more coordination was needed. These results suggest that the cerebellum is not exclusively active in fine coordination, but is generally involved in any kind of preparatory and executive activity, whereas the motor cortex becomes more active with fine coordination. The role of the cerebellum might be to provide the motor cortex with information needed for coordinating movements. In cerebellar atrophy, this altered input may be sufficient for the motor cortex in controlling simple tasks, but not for complex ones.

Reduced intracortical facilitation in patients with cerebellar degeneration.

OBJECTIVES: Transcranial magnetic stimulation (TMS) was used to study intracortical inhibitory and excitatory phenomena in patients with cerebellar ataxia. METHODS: Motor evoked potentials (MEP) following single and paired TMS were recorded from the first dorsal interosseus muscle (FDI) in 15 patients with autosomal-dominant or idiopathic cerebellar ataxia and 15 age matched normal controls. RESULTS: MEP amplitudes after paired TMS with short interstimulus intervals (1-4 ms) showing intracortical inhibition in the control group were not significantly different in the patient group. In contrast, with longer interstimulus intervals (8-20 ms) mean MEP amplitudes were significantly reduced in the patient group, indicating a decrease of intracortical facilitation. The mean postexcitatory inhibition after TMS was also significantly prolonged in the patient group. CONCLUSION: Our findings support the idea that the cerebellum physiologically exerts a facilitatory influence on the motor cortex which is decreased in patients with a cerebellar degeneration.