Ulrich Büttner

Treatment of downbeat nystagmus with 3,4-diaminopyridine: A placebo-controlled study

Background: Several drugs that primarily act on γ-aminobutyrate or muscarinic receptors have been used to treat downbeat nystagmus (DBN) syndrome despite their having only moderate success and causing several side effects that limit their effectiveness. These drugs were tested under the assumption that DBN was caused by a disinhibition of a physiologic inhibitory cerebellar input on vestibular nuclei. Objective: To evaluate the effects of a single dose of the potassium channel blocker 3,4-diaminopyridine (3,4-DAP), which is known to increase the excitability of Purkinje cells, on DBN in a prospective, placebo-controlled, double-blind study with a crossover design. Methods: Seventeen patients with DBN due to cerebellar atrophy (5), infarction (3), Arnold–Chiari malformation (1), or unknown etiology (8) were included in the study (1 of 18 patients had to be excluded). Mean peak slow-phase velocity (PSPV) was measured before and 30 minutes after randomized ingestion of 20 mg of 3,4-DAP or placebo orally; at least 1 week later, the treatments were switched. Results: 3,4-DAP reduced mean PSPV of DBN from 7.2 ± 4.2°/s (mean ± SD) before treatment to 3.1 ± 2.5°/s 30 minutes after ingestion of the 3,4-DAP (p < 0.001, two-way analysis of variance). Placebo had no measurable effect. In 10 of 17 subjects, the mean PSPV decreased by >50% and in 12 of 17 by >40%. In parallel, the subjects had less oscillopsia and felt more stable while standing and walking. Nine of the subjects continued to take the drug with success. Except for transient minor perioral or digital paresthesia reported by three subjects and nausea and headache reported by one, no other side effects were observed. Conclusions: In this study, the authors demonstrated that a single dose of 3,4-DAP significantly improved DBN. In view of animal studies reporting that micromolar concentrations of 4-aminopyridine increased the excitability of Purkinje cells, it is suggested that the efficacy of 3,4-DAP may be due to an increase of the physiologic inhibitory influence of the vestibulocerebellum on the vestibular nuclei.

Diagnostic Criteria for Central versus Peripheral Positioning Nystagmus and Vertigo: a Review

Head positioning can lead to pathological nystagmus and vertigo. In most instances the cause is a peripheral vestibular disorder, as in benign paroxysmal positioning vertigo (BPPV). Central lesions can lead to positional nystagmus (central PN) or to paroxysmal positioning nystagmus and vertigo (central PPV). Lesions in central PPV are often found dorsolateral to the fourth ventricle or in the dorsal vermis. This localization, together with other clinical features (associated cerebellar and oculomotor signs), generally allows one to easily distinguish central PPV from BPPV. However, in individual cases this may prove difficult, since the two syndromes share many features. Even if only BPPV as a peripheral lesion is considered, differentiation based on such features as latency, course, and duration of nystagmus during an attack, fatigability, vertigo, vomiting, and time period during which nystagmus bouts occur, may be impossible. Only the direction of nystagmus during an attack can allow differentiation.

The effects of baclofen and cholinergic drugs on upbeat and downbeat nystagmus.

The GABAergic drug baclofen and the cholinergic drug physostigmine were administered to patients with upbeat and downbeat nystagmus. Baclofen (orally, 5 mg three times daily) reduced nystagmus slow phase velocity and distressing oscillopsia by 25-75% in four out of five patients (two upbeat nystagmus; two downbeat nystagmus). Physostigmine (1 mg single intravenous injection) increased nystagmus in five additional patients with downbeat (1) or positional downbeat nystagmus (4) for a duration of 15-20 minutes. The different interactions of baclofen and physostigmine on neurotransmission subserving vertical vestibulo-ocular reflex could account for these effects. The response to baclofen appears to be a GABA-B-ergic effect with augmentation of the physiological inhibitory influence of the vestibulo-cerebellum on the vestibular nuclei. Similarly baclofen has an inhibitory effect on the velocity storage mechanism. Cholinergic action may cause the increment of nystagmus by physostigmine.

Deficits in vertical and torsional eye movements after uni- and bilateral muscimol inactivation of the interstitial nucleus of Cajal of the alert monkey

Abstract The mesencephalic interstitial nucleus of Cajal (iC) is considered the neural integrator for vertical and torsional eye movements and has also been proposed to be involved in saccade generation. The aim of this study was to elucidate the function of iC in neural integration of different types of eye movements and to distinguish eye movement deficits due to iC impairment from that of the immediately adjacent rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF). We addressed the following questions: (1) According to the neural integrator hypothesis, all eye movements including the saccadic system and the vestibulo-ocular reflex (VOR) share a common neural integrator. Do iC lesions impair gaze-holding function for vertical and torsional eye positions and the torsional and vertical VOR gain to a similar degree? (2) What are the dynamic properties of vertical and torsional eye movements deficits after iC lesions, e.g., the specificity of torsional and vertical nystagmus? (3) Is iC involved in saccade generation? We performed 13 uni- and three bilateral iC inactivations by muscimol microinjections in four alert monkeys. Three-dimensional eye movements were studied under head-stationary conditions during vertical and torsional VOR. Under static conditions, unilateral iC injections evoked a shift of Listing’s plane to the contralesional side (up to 20°), which increased (ipsilesional ear down) or decreased (ipsilesional ear up) by additional static vestibular stimulation in the roll plane, i.e., ocular counterroll was preserved. The monkeys showed a spontaneous torsional nystagmus with a profound downbeat component. The fast phases of torsional nystagmus always beat toward the lesion side (ipsilesional). Pronounced gaze-holding deficit for torsional and vertical eye positions (neural integrator failure) was reflected by the reduction of time constants of the exponential decay of the slow phase to 330–370 ms. Whereas the vertical oculomotor range was profoundly decreased (up to 50%) and vertical saccades were reduced in amplitude, saccade velocity remained normal and horizontal eye movements were not affected. Bilateral iC injections reduced the shift of Listing’s plane caused by unilateral injections, i.e., back toward the plane of zero torsion. Torsional nystagmus reversed its direction and ceased, whereas vertical nystagmus persisted. In contrast to unilateral injection, there was additional upbeating nystagmus. Time constants of the position integrator of the gaze-holding system did not differ between unilateral and bilateral injections. The range of stable vertical eye positions and saccade amplitude was smaller when compared with unilateral injections, but the main sequence remained normal. Dynamic vestibular stimulation after unilateral iC injections had virtually no effect on torsional and vertical VOR gain and phase at the same time when time constants already indicated severe integrator failure. Torsional VOR elicited a constant slow-phase velocity offset up to 30° toward the contralesional side, i.e., in the opposite direction to spontaneous torsional nystagmus. Likewise, vertical VOR showed a velocity offset in an upward direction, i.e., opposite to the spontaneous downbeat nystagmus. Contralesional torsional and upward vertical quick phases were missing or severely reduced in amplitude but showed normal velocity. In contrast, bilateral iC injections reduced the gain of the torsional and vertical VOR by 50% and caused a phase lead of 10–20° (eye compared with head velocity). We propose that the slow-phase velocity offset during torsional and vertical VOR reflects a vestibular imbalance. It therefore appears likely that the vertical and torsional nystagmus after iC lesions is not only caused by a neural integrator failure but also by a vestibular imbalance. Unilateral iC injections have clearly differential effects on the VOR and the gaze-holding function. These results are not compatible with a single common neural integrator model, which would predict a much stronger VOR gain reduction and phase advance, as found in our data. Our data support the existence of multiple integrators in iC with parallel processing.

Differential effects of bicuculline and muscimol microinjections into the vestibular nuclei on simian eye movements

Summary1.) Eye movements were recorded in four Java monkeys (M. fascicularis) after unilateral microinjections (1 μl, concentration 1 μg/μl) of the GABA antagonist, bicuculline, and the GABA agonist, muscimol, into oculomotor related regions of the vestibular nuclei. Eye movements were investigated in the dark and light during spontaneous eye movements, vestibular stimulation (sinusoidal: 0.2 Hz, ±40 deg/s, and velocity trapezoid: 40 deg/s2 acceleration, 120 deg/s constant velocity), and visual-vestibular conflict stimulation. 2.) Bicuculline and muscimol injections consistently led to specific eye movement changes, which were maximal 5–10 min after bicuculline injection (muscimol 10–30 min), and lasted 90–120 min (muscimol 2–4 h). Control injections with NaCl (0.9%) into the responsive area and with bicuculline 2–3 mm more lateral showed no effect. 3.) Bicuculline induced a spontaneous nystagmus of 40.9 deg/s (average, range 10.5–93 deg/s), beating in 60% of the cases to the contralateral and in 40% to the ipsilateral side. The analysis of the slope of the slow phase gave no evidence for an additional gaze holding deficit. The VOR gain in the dark showed a slight decrease (pre: 0.96; post: 0.86) on average. The time constant of decay for slow phase nystagmus velocity after vestibular ramp stimulation was reduced, reflecting a ‘velocity storage’ deficit. After bicuculline injections nystagmus suppression in the light and during visual-vestibular conflict stimulation was generally well preserved. 4.) After muscimol injections horizontal gaze holding was severely affected. Each saccade was followed by an exponentially decreasing postsaccadic drift with a time constant as short as 250 ms (average 414 ms). The eyes always drifted towards a null-position, which generally did not coincide with the midposition of the eye. The null-position could move up to 35 deg to the contra-lateral or ipsilateral side. The highly distorted eye movements after muscimol injections prevented VOR-measurements based on eye velocity. Instead vestibular stimulation led to a shift of the null-position with an amplitude corresponding to a gain (eye position/stimulus position) of 0.17 (average) at 0.2 Hz (±40 deg/s). Vertical eye movements did not show a major gaze holding deficit. 5.) From the experiments it can be concluded that the inhibitory transmitter GABA plays an important role for eye movement generation within the vestibular nuclei. Bicuculline induces mainly a vestibular imbalance with little evidence for a neural integrator deficit. In contrast unilateral muscimol injections lead to a complete, reversible loss of function for the common horizontal neural integrator, which converts eye velocity into eye position signals. The accompanying shift of the null-position reflects an additional vestibular imbalance.

4-aminopyridine restores visual ocular motor function in upbeat nystagmus

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.

4-Aminopyridine improves downbeat nystagmus, smooth pursuit, and VOR gain

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+ …

Differential Effect of a Bilateral Deep Cerebellar Nuclei Lesion on Externally and Internally Triggered Saccades in Humans

Visually guided saccades were recorded which occurred either at the onset of a peripheral target (externally triggered) or when scanning a static display (internally triggered) in a patient with a bilateral lesion of the nucleus fastigii and nucleus interpositus caused by a hemangioblastoma. The externally triggered saccades were hypermetric before and after surgery. In contrast, the internally triggered saccades (scanning saccades) were normometric. This finding supports the view that the midline cerebellum is involved in the control of saccades in a way that depends on the mode of saccade elicitation.

Saccade-related activity in the fastigial oculomotor region of the macaque monkey during spontaneous eye movements in light and darkness

Saccade-related burst neurons were recorded in the caudal part of the fastigial nucleus (fastigial oculomotor region) during spontaneous eye movements and fast phases of optokinetic and vestibular nystagmus in light and darkness from three macaque monkeys. All neurons (n=47) were spontaneously active and exhibited a burst of activity with each saccade and fast phase of nystagmus. Most neurons (n=31) only exhibited a burst of activity, whereas those remaining also exhibited a pause in firing rate before or after the burst. Burst parameters varied considerably for similar saccades. For horizontal saccades all neurons, except for three, had a preferred direction with an earlier onset of burst activity to the contralateral side. For contralateral saccades the burst started on average 17.5 ms before saccade onset, whereas the average lead-time for ipsilateral saccades was only 6.5 ms. Three neurons were classified as isotropic with similar latencies and peak burst activity in all directions. None of the neurons had a preferred direction with an earlier onset of burst activity to the ipsilateral side. Burst duration increased with saccade amplitude, whereas peak burst activity was not correlated with amplitude. There was no relationship between peak burst activity and peak eye velocity. In the dark, neurons generally continued to burst with each saccade and fast phase of nystagmus. Burst for saccades in the dark was compared with burst for saccades of similar amplitude and direction in the light. Saccades in the dark had a longer duration and peak burst activity was reduced on average to 62% (range 36–105%). In three neurons a burst in the dark was no longer clearly distinguishable above the ongoing spontaneous activity. These data suggest that the saccade-related burst neurons in the FOR modify saccadic profiles by directly influencing acceleration and deceleration, respectively, of individual eye movements. This could be achieved by an input to the inhibitory and excitatory burst neurons of the saccadic burst generator in the brainstem. From neuroanatomical studies it is known that FOR neurons project directly to the brainstem regions containing the immediate premotor structures for saccade generation.

Fastigial oculomotor region and the control of foveation during fixation.

When primates maintain their gaze directed toward a visual target (visual fixation), their eyes display a combination of miniature fast and slow movements. An involvement of the cerebellum in visual fixation is indicated by the severe gaze instabilities observed in patients suffering from cerebellar lesions. Recent studies in non-human primates have identified a cerebellar structure, the fastigial oculomotor region (FOR), as a major cerebellar output nucleus with projections toward oculomotor regions in the brain stem. Unilateral inactivation of the FOR leads to dysmetric visually guided saccades and to an offset in gaze direction when the animal fixates a visual target. However, the nature of this fixation offset is not fully understood. In the present work, we analyze the inactivation-induced effects on fixation. A novel technique is adopted to describe the generation of saccades when a target is being fixated (fixational saccades). We show that the offset is the result of a combination of impaired saccade accuracy and an altered encoding of the foveal target position. Because they are independent, we propose that these two impairments are mediated by the different projections of the FOR to the brain stem, in particular to the deep superior colliculus and the pontomedullary reticular formation. Our study demonstrates that the oculomotor cerebellum, through the activity in the FOR, regulates both the amplitude of fixational saccades and the position toward which the eyes must be directed, suggesting an involvement in the acquisition of visual information from the fovea.