Thurid Sander

Vergence deficits in patients with cerebellar lesions.

The cerebellum is part of the cortico-ponto-cerebellar circuit for conjugate eye movements. Recent animal data suggest an additional role of the cerebellum for the control of binocular alignment and disconjugate, i.e. vergence eye movements. The latter is separated into two different components: fast vergence (to step targets) and slow vergence (to ramp and sinusoidal targets). The aim of this study was to investigate whether circumscribed cerebellar lesions affect these dynamic vergence eye movements. Disconjugate fast and slow vergence, conjugate smooth pursuit and saccades were binocularly recorded by a scleral search coil system in 20 patients with acute cerebellar lesions (all ischemic strokes except for one) and 20 age-matched healthy controls. Patients showed impairment of slow vergence while fast vergence was unaffected. Slow vergence gain to sinusoidal targets was significantly reduced, both in convergence and divergence direction. Divergence but not convergence velocity to ramp targets was reduced. Conjugate smooth pursuit eye movements to sinusoidal and to step-ramp targets were impaired. Patients had saccadic hypometria. All defects were particularly expressed in patients with vermis lesions. In contrast to recent animal data fast vergence was not impaired in any of our patient subgroups. We conclude that (i) the human cerebellum, in particular the vermis, is involved in the processing of dynamic vergence eye movements and (ii) cerebellar lesions elicit dissociable effects on fast and slow vergence.

Age-related changes of vergence under natural viewing conditions

Vergence eye movements were recorded with the scleral search-coil system in 32 healthy subjects (ages 19-73 years) to characterize the age-related effects on the dynamic parameters of vergence responses to step (transient components) and ramp or sinusoidal targets (sustained components) under natural viewing conditions. Transient vergence showed an age-related increase in latency and decreases in peak velocity and acceleration in the binocular stimulus condition but not in accommodative vergence. Sustained vergence showed no age-related effect in the binocular condition, but there was an age-related decrease in accommodative vergence steady-state velocity and an increase in latency. Age-related changes of the transient and sustained components were very similar to those reported for saccades and smooth pursuit; they thus might support a distinction between a sustained and transient vergence system. Furthermore, such age-related effects have to be taken into account when assessing eye movement disorders in neurodegenerative and cerebrovascular diseases.

Structural Changes in the Human Brain following Vestibular Neuritis Indicate Central Vestibular Compensation

Vestibular neuritis (VN) is a sudden unilateral vestibular failure (UVF) with a variable course. Caloric hyporesponsiveness often persists, and it is largely unknown why patients with the same degree of hyporesponsiveness show different functional recovery. As the peripheral vestibular deficit alone does not seem to determine functional recovery, it was the aim of this study to elucidate whether structural (morphological) brain changes (1) contribute to central vestibular compensation, and (2) account for the variability of clinical recovery in VN. Structural global gray‐matter volume (GMV) changes in 15 VN patients were compared with age‐matched controls. Morphometric changes in multisensory vestibular cortices, which may be related to functional disability scores, were hypothesized. Patients were examined with neuro‐otological tests and clinical scores to assess vestibular disability. Using voxel‐based morphometry (VBM, SPM2), categorical comparison revealed GMV increase in patients’ multisensory vestibular cortices [insula, inferior parietal lobe (IPL), superior temporal gyrus (STG)], cerebellum, and motion‐sensitive areas in the middle temporal area (MT). GMV decrease was found in the midline pontomedullary junction. Simple regression analysis revealed (1) GMV increase in insula and retroinsular vestibular cortex and STG with improving clinically assessed vestibular deficits, and (2) GMV increase in insula vestibular cortex and STG with improving self‐assessed vestibular impairment. For the first time, these data suggest structural cortical plasticity in multisensory vestibular‐cortex areas in VN that are related to clinical vestibular function and vertigo. As increase of GMV was related to an improvement of vestibular function, structural alterations may be related to central vestibular compensation.

Central representation of cold-evoked pain relief in capsaicin induced pain: an event-related fMRI study.

Abstract The termination of an unpleasant or painful somatic condition can produce a rewarding sense of relief, even if the stimulus that causes the termination is itself unpleasant or painful under normal circumstances. We aimed to identify central neural mechanisms of pain relief from capsaicin‐elicited heat‐hyperalgesia by administering cold stimuli. We hypothesized that cooling might facilitate endogenous descending inhibitory mechanisms. We compared intraindividual neural responses of 15 healthy male volunteers to cold (20, 0 °C), intermediate (30 °C) and heat stimuli (43 °C) on untreated vs. capsaicin‐treated skin using event‐related fMRI in a 2 × 4 factorial design. Thermal stimuli were applied at the right hand in two separate imaging sessions using a Peltier‐element. Psychophysical ratings of the perceived valence and intensity (VAS: 1–100) were obtained after each stimulus. The 43 °C‐stimulus was perceived as excessively painful on capsaicin‐treated skin as opposed to an unpleasant sensation on normal skin. In contrast, the 0 °C‐stimulus was perceived unpleasant when applied on untreated skin while subjects rated the same stimulus pleasant in the capsaicin‐treated condition. When neural responses to the 0 °C‐stimulus were compared between the untreated and capsaicin‐treated skin condition there were stronger BOLD‐responses in prefrontal cortex (PFC) and periaqueductal grey (PAG) which correlated with increasing perceived pleasantness (VAS). Based on a connectivity analysis which identified cold‐dependent contributions of PFC activity with PAG in heat‐hyperalgesia we propose that cold‐induced pain relief partly results from activation of endogenous descending inhibition of nociception. The data illustrate that perception of nociceptive input may largely be determined by competing aversive‐appetitive motivational states.

Effect of 3,4‐Diaminopyridine on the Postural Control in Patients with Downbeat Nystagmus

Abstract: Downbeat nystagmus (DBN) is a common, usually persistent ocular motor sign in vestibulocerebellar midline lesions. Postural imbalance in DBN may increase on lateral gaze when downbeat nystagmus increases. 3,4‐Diaminopyridine (3,4‐DAP) has been shown to suppress the slow‐phase velocity component of downbeat nystagmus and its gravity‐dependent component with concomitant improvement of oscillopsia. Because the pharmacological effect is thought to be caused by improvement of the vestibulocerebellar Purkinje cell activity, the effect of 3,4‐DAP on the postural control of patients with downbeat nystagmus syndrome was examined. Eye movements were recorded with the video‐based Eyelink II system. Postural sway and pathway were assessed by posturography in lateral gaze in the light and on eye closure. Two out of four patients showed an improvement of the area of postural sway by 57% of control (baseline) on eye closure. In contrast, downbeat nystagmus in gaze straight ahead and on lateral gaze did not benefit in these two patients, implying a specific influence of 3,4‐DAP on the vestibulocerebellar control of posture. It was concluded that 3,4‐DAP may particularly influence the postural performance in patients with downbeat nystagmus.

Structural brain changes following peripheral vestibulo-cochlear lesion may indicate multisensory compensation

Background Do central mechanisms account for the variability of clinical recovery following peripheral vestibulo-cochlear lesions? Objective To investigate structural (morphological) plasticity in the human brain following unilateral vestibulo-cochlear lesions which might contribute to central vestibular compensation. Methods The authors compared regional grey matter volume (GMV) changes in patients after surgical removal of unilateral acoustic neuroma with age-matched control subjects, and hypothesised morphometric changes in the vestibular and auditory cortices which may be related to functional disability scores. Patients were examined with a battery of neuro-otological tests and clinical scores to assess vestibular and auditory disability. Results Voxel-based morphometry was used for categorical comparison between patients and age- and gender-matched controls. GMV increase was found bilaterally in primary somatosensory cortices and motion-sensitive areas in the medial temporal gyrus (MT). Simple regression analysis revealed a GMV increase (1) in the contralesional superior temporal gyrus/posterior insula to be correlated with decreasing clinically assessed vestibular deficits; (2) in the contralesional inferior parietal lobe with decreasing functional impairment of daily living activities; and (3) in the contralesional auditory cortex (Heschl gyrus) with decreasing hearing impairment. Conclusions These data may suggest structural cortical plasticity in multisensory vestibular cortex areas of patients with unilateral peripheral vestibulo-cochlear lesion after surgical removal of acoustic neuroma. As changes of GMV were related to vestibular function, structural brain changes may reflect central mechanisms of vestibular compensation.

Treatment of the gravity dependence of downbeat nystagmus with 3,4-diaminopyridine

The authors examined the effect of 3,4-diaminopyridine (DAP) on the gravity-dependent (GD) vertical ocular drift component of downbeat nystagmus in 11 patients with idiopathic cerebellar ataxia. With the head tilted downward (45°), DAP reduced slow phase velocity (SPV) in 7 of 11 patients by 36%. Its efficacy correlated with the GD modulation. DAP minimizes the gravity-independent velocity bias and may improve deficient inhibitory cerebellar control on overacting otolith–ocular reflexes.

Palsy of “fast” and “slow” vergence by pontine lesions

The role of pontine nuclei in vergence eye movements to “step” targets (“fast” vergence) is unknown. Eye movements were recorded in two patients with unilateral pontine infarctions and in 11 healthy controls. In addition to the deficit of “slow” vergence, “fast” vergence was particularly impaired. However, conjugate saccades did not differ from controls, but smooth pursuit eye movements did. The authors conclude that “fast” vergence palsy is not only caused by midbrain but also upper pontine lesions.

Visual Search Disorders in Acute and Chronic Homonymous Hemianopia: Lesion Effects and Adaptive Strategies

Patients with homonymous hemianopia due to occipital brain lesions show disorders of visual search. In everyday life this leads to difficulties in reading and spatial orientation. It is a matter of debate whether these disorders are due to the brain lesion or rather reflect compensatory eye movement strategies developing over time. For the first time, eye movements of acute hemianopic patients (n= 9) were recorded during the first days following stroke while they performed an exploratory visual‐search task. Compared to age‐matched control subjects their search duration was prolonged due to increased fixations and refixations, that is, repeated scanning of previously searched locations. Saccadic amplitudes were smaller in patients. Right hemianopic patients were more impaired than left hemianopic patients. The number of fixations and refixations did not differ significantly between both hemifields in the patients. Follow‐up of one patient revealed changes of visual search over 18 months. By using more structured scanpaths with fewer saccades his search duration decreased. Furthermore, he developed a more efficient eye‐movement strategy by making larger but less frequent saccades toward his blind side. In summary, visual‐search behavior of acute hemianopic patients differs from healthy control subjects and from chronic hemianopic patients. We conclude that abnormal visual search in acute hemianopic patients is related to the brain lesion. We provide some evidence for adaptive eye‐movement strategies developed over time. These adaptive strategies make the visual search more efficient and may help to compensate for the persisting visual‐field loss.

Beneficial effects of 3,4-diaminopyridine on positioning downbeat nystagmus in a circumscribed uvulo-nodular lesion

Sirs: Central positioning downbeat nystagmus (pDBN) presents with transient nystagmus in supine or the head hanging position in the absence of DBN in the head erect position. In contrast to central positional downbeat nystagmus, pDBN requires rapid head positioning manoeuvres to be elicited. The pathomechanism and therapy of central pDBN is not yet known and circumscribed lesions are missing so far [1, 2]. We examined the effect of 3,4-diaminopyridine (DAP) [3, 4] on the oculomotor behavior of a patient with pDBN. The 43-year old man had a 4 years history of gait unsteadiness. Cranial MRI and histology revealed a multi-nodular dysembroplastic neuroepithelial tumor. Immediately after partial neurosurgical removal he suffered from head positioning vertigo and vertical oscillopsia on bending the head rapidly into the supine or head hanging position. Neurological examination revealed mild gait ataxia and impaired downward smooth pursuit eye movements. Rapid but not slow head positioning manoeuvres into the head hanging position elicited a typical DBN which increased within a few seconds and lasted for about 30 s. Eye movements were recorded with the Eyelink II system [3], electro-oculography and the scleral search coil system. Vertical vestibulo-ocular reflex (VOR) was tested by rapid head pulses. Visually guided saccades were examined with targets presented on lateral gaze; smooth pursuit eye movements at 0.2 and 0.3 (±16 ). Vestibular turntable stimulation and the VOR tilt suppression were analyzed [5]. Eye movements were recorded prior and up to 90 minutes after DAP ingestion (20 mg). The patient gave informed written consent. The protocol was approved by the local ethics committee. Statistical differences were significant for p < 0.05. There was no nystagmus on lateral gaze with the head erect. When the head was rapidly turned back into the head hanging position there was profound downbeat nystagmus, which increased on lateral and downward gaze (Fig. 1A). Slow phase velocity (SPV) of pDBN was linear and revealed a crescendo/decrescendo time course (Fig. 1B) with a maximal peak SPV of 72 /s. Downward but not upward smooth pursuit was impaired (Fig. 1C, D; grey). Horizontal pursuit, saccades, subjective visual vertical and responses to caloric irrigation were normal. Vertical (up: 0.93 ± 0.4; down: 0.93 ± 0.6) and horizontal VOR gain was normal. Prolonged head shaking elicited a perverted nystagmus [6]. Time constants of postrotatory nystagmus were severely prolonged and dumping of the postrotatory vestibular time constant by head tilts was virtually abolished (without: 20.5 s, with head tilt: 22.3 s). Following DAP ingestion downward smooth pursuit (gain: 0.63 ± 0.13 to 0.77 ± 0.1; p < 0.001; Fig. 1C, D; dark) and peak SPV of pDBN (72 /s–56 /s; p < 0.001; Fig. 1B) significantly improved by on average 22% and 21%, respectively. Before surgery, T2-weighted cranial MR images showed multilocular lesions in the nodulus, ventral uvula, and immediately adjacent to the fourth ventricle (Fig. 1E–H). The lesions did not affect the flocculus, paraflocculus, posterior vermis (Fig. 1G) and the vestibular nuclei. Several lines of evidence indicate that pDBN was caused by the uvulo-nodular lesion: (1) the prolongation of postrotatory nystagmus [7], (2) the abolished tilt suppression of the postrotatory vestibular nystagmus by pitching the head forward [7], (3) perverted headshaking nystagmus [6] and (4) the fact that pDBN appeared immediately after the uvulo-nodular tumor resection. Importantly, there was exclusively pDBN suggesting inappropriate velocity storage mechanisms of vertical angular VOR signals. For the first time we describe small but beneficial effects of DAP on pDBN. DAP reduced pDBN and downward pursuit to a similar extent suggesting a common pathomechanism. Deficient downward smooth pursuit has recently been Prof. Dr. C. Helmchen, MD (&) T. Sander Æ P. Trillenberg, MD H. Rambold, MD Æ A. Sprenger Dept. of Neurology University of Lübeck Ratzeburger Allee 160 D-23538 Lübeck, Germany Tel.: +49-451/500-2927 Fax: +49-451/500-2489 E-Mail: Christoph.Helmchen@neuro.uniluebeck.de