Sarah Marti

Interruption of the Guillain-Mollaret triangle interconnecting the red nucleus, the inferior olivary nucleus and the contralateral dentate nucleus is predicted to interfere with the dentate nucleus’ role in estimating direction of gravity. In a patient with pendular nystagmus due to hypertrophic inferior olivary nucleus degeneration secondary to ponto-mesencephalic hemorrhage, perceived vertical shifted from clockwise to counter-clockwise deviations within 4 months. We hypothesize that synchronized oscillations of inferior olivary nucleus neurons induce a loss of inhibitory control, leading to hyperactivity of the contralateral dentate nucleus and, as a result, to perceived vertical roll-tilt to the side of the overactive dentate nucleus.

Recently, aminopyridines (AP) have been shown to be an effective therapy for downbeat nystagmus (DBN). Since AP improve both (i) resting discharge and (ii) excitability of floccular Purkinje cells (PC), we investigated the effect of AP on the vertical eye position sensitivity (EPS) and the gravity dependence (GD) in a large group of patients with idiopathic DBN. We recorded vertical ocular drift velocity in gaze straight ahead and different vertical (±10°) and horizontal gaze positions in five pitch positions of the head between prone and supine (including upright) prior and 45 minutes after the ingestion of 3,4-diaminopyridine (DAP) or 4-AP. Gravity dependent modulation of vertical ocular drift was calculated from the difference between the lowest and highest slow phase velocity (SPV) of the different head positions (GD=“gravity-dependence“). AP reduced SPV of DBN in lateral gaze with the head upright by 24% and with the head half-prone by 28%. GD ranged from 2°/s to 42°/s. Vertical gaze evoked drift (eye position sensitivity, EPS) did not significantly change in different head pitch positions, neither before nor after AP treatment. AP significantly reduced GD modulation of vertical drift by more than 25%. Cluster analysis revealed that AP changed GD in about 60% and EPS in 40% of patients. In conclusion, AP exert a distinct influence on the GD of DBN. In the majority of patients (>50%), the improvement of the GD component in DBN is not related to an improvement of gaze holding function (EPS).

The pathomechanism of downbeat nystagmus (DBN), an ocular motor sign typical for vestibulo-cerebellar lesions, remains unclear. Previous hypotheses conjectured various deficits such as an imbalance of central vertical vestibular or smooth pursuit pathways to be causative for the generation of spontaneous upward drift. However, none of the previous theories explains the full range of ocular motor deficits associated with DBN, i.e., impaired vertical smooth pursuit (SP), gaze evoked nystagmus, and gravity dependence of the upward drift. We propose a new hypothesis, which explains the ocular motor signs of DBN by damage of the inhibitory vertical gaze-velocity sensitive Purkinje cells (PCs) in the cerebellar flocculus (FL). These PCs show spontaneous activity and a physiological asymmetry in that most of them exhibit downward on-directions. Accordingly, a loss of vertical floccular PCs will lead to disinhibition of their brainstem target neurons and, consequently, to spontaneous upward drift, i.e., DBN. Since the FL is involved in generation and control of SP and gaze holding, a single lesion, e.g., damage to vertical floccular PCs, may also explain the associated ocular motor deficits. To test our hypothesis, we developed a computational model of vertical eye movements based on known ocular motor anatomy and physiology, which illustrates how cortical, cerebellar, and brainstem regions interact to generate the range of vertical eye movements seen in healthy subjects. Model simulation of the effect of extensive loss of floccular PCs resulted in ocular motor features typically associated with cerebellar DBN: (1) spontaneous upward drift due to decreased spontaneous PC activity, (2) gaze evoked nystagmus corresponding to failure of the cerebellar loop supporting neural integrator function, (3) asymmetric vertical SP deficit due to low gain and asymmetric attenuation of PC firing, and (4) gravity-dependence of DBN caused by an interaction of otolith-ocular pathways with impaired neural integrator function.

We describe a family with an R1668W mutation in the CACNA1A gene who presented with a broader clinical spectrum and more variable features than previously reported. The mother had a pure progressive cerebellar ataxia of late onset with downbeat nystagmus, whereas her daughter suffered from episodic ataxia, hemiplegic migraine, and progressive cerebellar ataxia with horizontal gaze-evoked and rebound nystagmus. In both patients, treatment with acetazolamide was ineffective and worsened baseline ataxia, whereas flunarizine ameliorated episodic symptoms. Our report highlights profound phenotypic variability that can be associated with CACNA1A mutations and adds important therapeutic considerations.

Whether the rotational vertebral artery syndrome (RVAS), consisting of attacks of vertigo, nystagmus and tinnitus elicited by head-rotation induced compression of the dominant vertebral artery (VA), reflects ischemic dysfunction of uni- or bilateral peripheral or central vestibular structures, is still debated. We report on a patient with bilateral high-grade carotid stenoses, in whom rightward headrotation led to RVAS symptoms including a prominent nystagmus. Three-dimensional kinematic analysis of the nystagmus pattern, recorded with search coils, revealed major downbeat nystagmus with minor horizontal and torsional components. Magnetic resonance angiography demonstrated a hypoplastic right VA terminating in the posterior inferior cerebellar artery, a dominant left VA, and a hypoplastic P1-segment of the left posterior cerebral artery (PCA) that was supplied by the left posterior communicating artery (PCoA). The right PCA and both anterior inferior cerebellar arteries were supplied by the basilar artery. The right PCoA originated from the right internal carotid artery. Color duplex sonography showed severe reduction of diastolic blood flow velocities in the left VA during RVAS attacks. The nystagmus pattern can be best explained by vectorial addition of 3D sensitivity vectors of stimulated right and left anterior and horizontal semicircular canals with slightly stronger stimulation on the left side. We hypothesize that in RVAS, compression of dominant VA leads to acute vertebrobasilar insufficiency with bilateral, but asymmetric ischemia of the superior labyrinth. With regard to RVAS etiology, our case illustrates a type of pure vascular RVAS. Severity of attacks markedly decreased after successful bilateral carotid endarterectomy.

Objective: Spontaneous ocular drift in cerebellar downbeat nystagmus typically contains both a gravity-dependent and a gravity-independent component. We specifically examined the effect of the potassium channel blocker 3,4-diaminopyridine, which has been shown to suppress overall vertical ocular drift in patients with downbeat nystagmus, on the gravity-dependent vertical drift component in eleven patients with idiopathic cerebellar ataxia. Methods: Eye movements were recorded at gaze straight ahead and at horizontal and vertical gaze eccentricities in five different head pitch positions, ranging from nose down to nose up. Slow phase velocity (SPV) of downbeat nystagmus was measured prior to and 45 minutes after 20mg DAP ingestion. Results: With the head tilted downward by 45 degrees, DAP reduced SPV on lateral gaze by 28% (seven out of eleven patients improved by 36%). DAP could change the gravity-dependent or the gravity-independent components or both. The gravity-dependent modulation of SPV was correlated with the efficacy of DAP, i.e. the larger the modulation the stronger SPV was reduced. Conclusions: DAP exerts two distinct effects on vertical ocular drift in patients with cerebellar downbeat nystagmus: It both minimizes the gravity-independent velocity bias and improves deficient inhibitory cerebellar control on overacting otolith-ocular reflexes. We provide first evidence for a pharmacological, clinically beneficial effect on the cerebellar control of the otolithic-ocular reflex in patients.

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 degrees ), 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.

Anatomical and electrophysiological studies have demonstrated up–down asymmetries in vertical ocular motor pathways. We investigated whether these asymmetries extend to the capacity for short-term adaptation of the vertical vestibulo-ocular reflex (VVOR) in humans. Specifically, we asked whether smooth pursuit signals are sufficient to asymmetrically adapt the VVOR. Healthy human subjects (N=8), positioned 90° left-ear-down and fixating with their eyes upon a small laser dot (diameter: 0.1°) projected on a sphere (distance: 1.4 m) were trained toward low VVOR gain for 30 min with symmetric and asymmetric visual VVOR cancellation paradigms, while being oscillated (0.2 Hz, ±20°) on a motorized turntable about the interaural earth-vertical axis. During asymmetric VVOR cancellation, the target was head-fixed in either the pitch-up or pitch-down half-cycles of oscillation (=trained direction) and space-fixed during the other half-cycles (=untrained direction). During symmetric VVOR cancellation, the target was head-fixed throughout the oscillations. Before and after adaptation, the pitch-up and pitch-down VOR gains were assessed during turntable oscillation in complete darkness. Before adaptation, average gains of pitch-up (0.75±0.15 SD) and pitch-down (0.79±0.19 SD) VOR were not significantly different (paired t test: P>0.05). On an average, relative gain reductions induced by selective pitch-up (pitch-up VOR: 32%; pitch-down VOR: 21%) and pitch-down (pitch-up VOR: 18%; pitch-down VOR: 30%) VOR cancellation were significantly (PP<0.01) larger relative gain reduction of the pitch-down (41%) than the pitch-up (33%) VOR. None of the paradigms led to significant changes of phase or offset. We conclude that, in human subjects, the smooth pursuit system is capable to asymmetrically decrease the gain of the VVOR equally well in both the upward and downward direction. The unexpected asymmetric decrease of the VVOR gain after symmetric visual cancellation may be related to the directional preferences of vertical gaze–velocity sensitive Purkinje cells in the flocculus for the downward direction.