Consensus Paper: Neurophysiological Assessments of Ataxias in Daily Practice.

The purpose of this consensus paper is to review electrophysiological abnormalities and to provide a guideline of neurophysiological assessments in cerebellar ataxias. All authors agree that standard electrophysiological methods should be systematically applied in all cases of ataxia to reveal accompanying peripheral neuropathy, the involvement of the dorsal columns, pyramidal tracts and the brainstem. Electroencephalography should also be considered, although findings are frequently non-specific. Electrophysiology helps define the neuronal systems affected by the disease in an individual patient and to understand the phenotypes of the different types of ataxia on a more general level. As yet, there is no established electrophysiological measure which is sensitive and specific of cerebellar dysfunction in ataxias. The authors agree that cerebellar brain inhibition (CBI), which is based on a paired-pulse transcranial magnetic stimulation (TMS) paradigm assessing cerebellar-cortical connectivity, is likely a useful measure of cerebellar function. Although its role in the investigation and diagnoses of different types of ataxias is unclear, it will be of interest to study its utility in this type of conditions. The authors agree that detailed clinical examination reveals core features of ataxia (i.e., dysarthria, truncal, gait and limb ataxia, oculomotor dysfunction) and is sufficient for formulating a differential diagnosis. Clinical assessment of oculomotor function, especially saccades and the vestibulo-ocular reflex (VOR) which are most easily examined both at the bedside and with quantitative testing techniques, is of particular help for differential diagnosis in many cases. Pure clinical measures, however, are not sensitive enough to reveal minute fluctuations or early treatment response as most relevant for pre-clinical stages of disease which might be amenable to study in future intervention trials. The authors agree that quantitative measures of ataxia are desirable as biomarkers. Methods are discussed that allow quantification of ataxia in laboratory as well as in clinical and real-life settings, for instance at the patients' home. Future studies are needed to demonstrate their usefulness as biomarkers in pharmaceutical or rehabilitation trials.

Continuous theta-burst stimulation of the right superior temporal gyrus impairs self-motion perception.

Sensory input from the semicircular canals (SCC) and otolith organs is centrally combined with signals from other sensory modalities to continuously update the internal estimate of self-motion. Constant velocity vertical on-axis rotation leads to decay of the nystagmus response from the horizontal SCC and of perceived angular velocity (PAV), and when the rotation stops, a similar oppositely directed post-rotatory response occurs. Case reports and electrical stimulation studies suggest an involvement of the temporo-peri-Sylvian vestibular cortex in generating the PAV. Here, we transiently inhibited the right superior temporal gyrus (STG) by use of continuous theta-burst stimulation (cTBS) and predicted an accelerated decay of PAV compared to controls (n = 5 control session first, n = 1 cTBS session first). Constant velocity (100°/s) vertical on-axis rotations were applied over 75 s before (1 block) and after (3 blocks) cTBS over the right STG in six subjects. Breaks between the rotations (75 s) were initiated by abrupt stops. By use of a rotating potentiometer, subjects indicated the PAV during and after the chair rotations. Simultaneously eye positions were recorded using a scleral search coil. One subject was excluded for per-rotary analysis. Early after cTBS, the post-rotary PAV decay time constant (DTC) was significantly (9.4 ± 5.7 vs. 13.6 ± 5.9 s; p = 0.049) reduced (no directionality to this effect observed). Overall, post-rotary PAV showed a trend toward shortened DTC compared to the control trials (p = 0.086) in the first 25 min after cTBS, while per-rotary PAV was not significantly changed. Per-rotary and post-rotary aVOR DTC were not significantly changed after cTBS (p > 0.05). These findings support the hypothesis that the right STG is involved in mediating self-motion perception and can be modulated by cTBS.

How stable is perceived direction of gravity over extended periods in darkness?

Previous studies reported linear drift of perceived vertical for brief (≤10 min) observation periods. Here, we repeated estimates of direction of gravity up to 60 min to evaluate whether the drift is sustained, shows saturation or even reverses over time. Fifteen healthy human subjects repetitively adjusted a luminous line along subjective visual vertical (SVV) and horizontal (SVH) over periods of 5 min (constituting one block). We obtained seven blocks within 60 min in each subject for SVV and SVH. In between the first six blocks, subjects remained in darkness for 5 min each, whereas the lights were briefly turned on before block 7. We noted significantly (p < 0.05) increased errors in perceived direction of gravity by block 2 (SVV) and 3 (SVH). These increases disappeared after turning on the lights before block 7. Focusing on blocks 2-6, significant drift started from similar offset positions and pointed to the same direction in a majority of runs in 9/15 (SVV) and 11/15 (SVH) subjects. When pooling data from all blocks, orthogonality of errors was lost in all subjects. Trial-to-trial variability remained stable over the seven runs for SVV and SVH. Only when pooling all runs, precision was significantly (p < 0.05) higher for the SVH. Our findings suggest that perceived direction of gravity continues to fluctuate over extended recording periods with individuals showing unique patterns of direction-specific drift while variability remains stable. As subjects were upright during the entire experiment and as drift persisted over several blocks, sensory adaptation seems unlikely. We therefore favor a central origin of this kind of drift.

The bedside examination of the vestibulo-ocular reflex (VOR): an update.

Diagnosing dizzy patients remains a daunting challenge to the clinician in spite of modern imaging and increasingly sophisticated electrophysiological testing. Here we review the major bedside tests of the vestibulo-ocular reflex and how, when combined with a proper examination of the other eye movement systems, one can arrive at an accurate vestibular diagnosis.

Penlight-cover test: a new bedside method to unmask nystagmus.

BACKGROUND: Most patients with acute vestibular syndrome have vestibular neuritis or labyrinthitis. Some harbour strokes that can only be differentiated on the basis of subtle eye movement findings, including nystagmus. Peripheral nystagmus should be enhanced by removal of visual fixation. Current bedside methods for removing fixation require expensive equipment or technical skill not routinely available. We sought to test a new method for blocking fixation. METHODS: Proof-of-concept study for a new bedside oculomotor diagnostic test using an established physiological measurement of eye movements (electro-oculography (EOG)) as the reference standard. We sampled unselected patients undergoing caloric testing (surrogate model for neuritis) in an academic vestibular clinic. During the brief (30-60 s) decay phase of caloric-induced peripheral vestibular nystagmus, we shone a penlight in the left eye while intermittently occluding the right. We assessed nystagmus intensity (slow-phase velocity) clinically in all subjects and quantified change in two exemplar cases. RESULTS: Caloric responses frequently decayed before the test was complete, and artefacts rendered many EOGs uninterpretable during the short decay period. A clinically evident increase in nystagmus was seen 18 times in 10 patients and corroborated by EOG in 15. In quantified cases, slow-phase velocity increased as expected (mean change +42%) with fixation blocked. CONCLUSION: The penlight-cover test could offer a low-cost, simple means of disrupting visual fixation in clinical settings where differentiating peripheral from central vestibular disorders is crucial, such as the emergency department. Prospective studies are needed to determine the test's utility for excluding dangerous central causes among patients with suspected peripheral lesions.

Gaze fixation deficits and their implication in ataxia-telangiectasia.

BACKGROUND AND AIMS: Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterised by progressive neurological deficits, including prominent ocular motor dysfunction. Unstable fixation often leads to difficulty reading and blurred vision. Here we characterise the disturbance of visual fixation in A-T. METHODS: Eye movements were recorded from 13 A-T patients (with dual search coils in five patients and video oculography in seven) during attempted fixation. RESULTS: Two abnormalities--nystagmus and saccadic intrusions--were common. Horizontal, vertical and torsional nystagmus was present in straight ahead (spontaneous nystagmus) and eccentric gaze (gaze evoked nystagmus). In eight patients the horizontal nystagmus changed directions--periodic alternating nystagmus (PAN). Two types of saccadic intrusions were seen--micro-saccadic oscillations (SO) and square wave saccadic intrusions (SWSI). SO were small amplitude (0.1-0.9 degrees) and high frequency (14-33 Hz) back to back horizontal saccades. SWSI ranged between 1 degree and 18 degrees (median 3 degrees) with an intersaccadic interval ranging between 50 and 800 ms (median 300 ms). The potential impact of abnormal gaze stabilisation on vision was quantified. DISCUSSION: Degeneration of cerebellar Purkinje neurons disinhibit the caudal fastigial oculomotor region (FOR) and vestibular nuclei (VN). Disinhibition of VN can cause nystagmus, including PAN, while disinhibition of FOR can affect saccade generating mechanisms, leading to SWSI and SO.

Irregularity distinguishes limb tremor in cervical dystonia from essential tremor.

INTRODUCTION: Patients with cervical dystonia (CD) often have limb tremor that is clinically indistinguishable from essential tremor (ET). Whether a common central mechanism underlies the tremor in these conditions is unknown. We addressed this issue by quantifying limb tremor in 19 patients with CD and 35 patients with ET. METHOD: Postural, resting and kinetic tremors were quantified (amplitude, mean frequency and regularity) using a three-axis accelerometer. RESULTS: The amplitude of limb tremor in ET was significantly higher than in CD, but the mean frequency was not significantly different between the groups. The cycle-to-cycle variability of the frequency (ie the tremor irregularity), however, was significantly greater (approximately 50%) in CD. Analysis of covariance excluded the possibility that the increased irregularity was related to the smaller amplitude of tremor in CD (ANCOVA: p = 0.007, F = 5.31). DISCUSSION: We propose that tremor in CD arises from oscillators with different dynamic characteristics, producing a more irregular output, whereas the tremor in ET arises from oscillators with similar dynamic characteristics, producing a more regular output. We suggest that variability of tremor is an important parameter for distinguishing tremor mechanisms. It is possible that changes in membrane kinetics based on the pattern of ion channel expression underlie the differences in tremor in some diseases.

Ocular stability and set-point adaptation.

A fundamental challenge to the brain is how to prevent intrusive movements when quiet is needed. Unwanted limb movements such as tremor impair fine motor control and unwanted eye drifts such as nystagmus impair vision. A stable platform is also necessary to launch accurate movements. Accordingly, nature has designed control systems with agonist (excitation) and antagonist (inhibition) muscle pairs functioning in push-pull, around a steady level of balanced tonic activity, the set-point Sensory information can be organized similarly, as in the vestibulo-ocular reflex, which generates eye movements that compensate for head movements. The semicircular canals, working in coplanar pairs, one in each labyrinth, are reciprocally excited and inhibited as they transduce head rotations. The relative change in activity is relayed to the vestibular nuclei, which operate around a set-point of stable balanced activity. When a pathological imbalance occurs, producing unwanted nystagmus without head movement, an adaptive mechanism restores the proper set-point and eliminates the nystagmus. Here we used 90 min of continuous 7 T magnetic field labyrinthine stimulation (MVS) in normal humans to produce sustained nystagmus simulating vestibular imbalance. We identified multiple time-scale processes towards a new zero set-point showing that MVS is an excellent paradigm to investigate the neurobiology of set-point adaptation.This article is part of the themed issue 'Movement suppression: brain mechanisms for stopping and stillness'.

Eye movements in vestibular disorders.

The differential diagnosis of patients with vestibular symptoms usually begins with the question: is the lesion central or is it peripheral? The answer commonly emerges from a careful examination of eye movements, especially when the lesion is located in otherwise clinically silent areas of the brain such as the vestibular portions of the cerebellum (flocculus, paraflocculus which is called the tonsils in humans, nodulus, and uvula) and the vestibular nuclei as well as immediately adjacent areas (the perihypoglossal nuclei and the paramedian nuclei and tracts). The neural circuitry that controls vestibular eye movements is intertwined with a larger network within the brainstem and cerebellum that also controls other types of conjugate eye movements. These include saccades and pursuit as well as the mechanisms that enable steady fixation, both straight ahead and in eccentric gaze positions. Navigating through this complex network requires a thorough knowledge about all classes of eye movements to help localize lesions causing a vestibular disorder. Here we review the different classes of eye movements and how to examine them, and then describe common ocular motor findings associated with central vestibular lesions from both a topographic and functional perspective.

Acute vestibular neuritis: prognosis based upon bedside clinical tests (thrusts and heaves).

We compared bedside tests of vestibulo-ocular function (head thrust and head heave signs) with caloric testing results in 68 patients with acute vestibular neuritis seen at onset and in follow-up for one year. The head thrust and head heave signs each were strong predictors of a decreased probability of recovery, and if both were present, there was a trend for a slower recovery and a further decrease in the probability of recovery. If the head thrust sign was absent, recovery was assured. Our results suggest that careful bedside testing of semicircular canal (head thrust maneuver) and otolith (head heave maneuver) function provides useful information for predicting prognosis in patients with acute vestibular neuritis.

Predictive saccades to a regularly alternating target in cerebellar patients.

Predictive saccade tracking (targets stepping back and forth at frequencies of 1.25 = 1.0 Hz) and self-paced saccades between two stationary targets were measured in patients with cerebellar degeneration and in normal subjects. Cerebellar patients produced similar predictive latencies and generated the same percentage of predictive saccades as did normal subjects. Only the variability in the self-paced saccade paradigm was different between the groups.

Relative atrophy of the flocculus and ocular motor dysfunction in SCA2 and SCA6.

Two hereditary ataxia syndromes show distinct profiles of region-specific atrophy and ocular motor deficits. Selective pontine atrophy is associated with slowed saccades in ataxin-2 mutations, and selective floccular atrophy is associated with impaired pursuit and gaze-holding abnormalities in Ca(V)2.1 mutations. Although the flocculus seems to be spared relative to the pons in ataxin-2 mutations, and pursuit and gaze-holding appear to be relatively normal, these can be difficult to assess at the bedside, as corrective saccades are also slow and hard to discern. Here, we show the presence of significant floccular atrophy compared with controls in both ataxin-2 and Ca(V)2.1 mutations, which raises the possibility that abnormalities of smooth pursuit or gaze-holding are present in both conditions.

The cerebellum in eye movement control: nystagmus, coordinate frames and disconjugacy.

In this review we discuss several aspects of eye movement control in which the cerebellum is thought to have a key role, but have been relatively ignored. We will focus on the mechanisms underlying certain forms of cerebellar nystagmus, as well as the contributions of the cerebellum to binocular alignment in healthy and diseased states. A contemporary review of our understanding provides a basis for directions of further inquiry to address some of the uncertainties regarding the contributions of the cerebellum to ocular motor control.

Vestibular testing in comatose patients.

The analysis of vestibular responses in a comatose patient often provides the critical information for making a correct preliminary diagnosis and directing the subsequent laboratory evaluation. Because of some uncertainties about what is being tested with the various bedside maneuvers that are used to elicit vestibular responses, we review the physiologic basis for the oculomotor responses that occur with head rotation or with caloric stimuli. We further urge precise and unambiguous terminology to describe both stimulus and response. We suggest using physiologically well-defined terms such as vestibulo-ocular reflex and cervico-ocular reflex and avoiding potentially misleading terms such as the doll's head and the oculocephalic maneuvers.

Slow saccades in spinocerebellar degeneration.

Two patients with spinocerebellar degeneration made abnormally slow horizontal refixations. One patient produced quick phases of nystagmus with identical maximum velocities, suggesting her refixations were abnormal saccades and not voluntary pursuit movements. In response to double target jumps, neither patient showed an obligatory refractory period after each saccade; they responded to every target movement after one reaction time. Their slow refixations were not preprogrammed since they could be modified in flight. To reconcile these observations with normal saccadic behavior, we hypothesized a neural network that made saccades by driving the eyes to an orbital position rather than preprogramming a distance for movement. Computer simulation of this model produced both realistically appearing normal saccades and, when appropriately "lesioned" to simulate a loss of saccadic "burst" neurons in the pontine reticular formation, slow saccades that could be modified in flight.

The effect of hyperventilation on downbeat nystagmus in cerebellar disorders.

Hyperventilation can affect nystagmus in patients with vestibular disorders. However, the effects on nystagmus in patients with cerebellar disease have not been systematically studied. Using the magnetic field search coil technique, we studied the effects of hyperventilation on nystagmus in a series of cerebellar patients. In four of eight patients, hyperventilation produced an increase in the slow-phase velocity of downbeat nystagmus. We speculate that this effect may be mediated through metabolic effects on cerebellar calcium channels.

Postural stability in patients with Huntington's disease.

We characterized postural stability in patients with Huntington's disease (HD) by examining their ability to use different sensory cues to maintain balance and by recording their automatic postural responses to externally applied perturbations. Our HD patients, like normal subjects, depended more on proprioceptive than on visual cues to maintain balance. HD patients, however, developed more sway than normal subjects when proprioceptive cues, or when proprioceptive cues and vision, were altered. Thus, HD patients showed a defect in using vestibular information alone to maintain normal postural stability. The onset of compensatory motor responses in the lower extremities following sudden translations of the support surface was delayed by 30 to 60 msec in HD patients as compared with normal subjects. HD patients also had more sway and falls during unexpected rotations of the support surface, although they could appropriately reduce their motor responses on the next trial.

Hyperventilation-induced nystagmus in patients with vestibular schwannoma.

OBJECTIVE: To analyze the nystagmus evoked by hyperventilation in patients with unilateral vestibular schwannoma and to use this information to predict the effects of hyperventilation on individual ampullary nerves. METHODS: Three-dimensional scleral search coil eye movement recording techniques were used to record the magnitude and time course of eye movements in six patients with unilateral vestibular schwannoma and hyperventilation-induced nystagmus. The presenting complaints in five of these patients were vertigo or dysequilibrium. RESULTS: The eye movement response to hyperventilation was a "recovery" nystagmus with slow-phase components corresponding to excitation of the affected vestibular nerve. Projection of the eye velocity vector into the plane of the semicircular canals revealed that fibers arising from the ampulla of the horizontal canal were most affected by hyperventilation with lesser activation of fibers to the superior canal and smaller, more variable responses from posterior canal fibers. CONCLUSIONS: The three-dimensional characteristics of the nystagmus evoked by hyperventilation in patients with vestibular schwannoma provide insight into the vestibular end organs affected by the tumor and the mechanism responsible for the nystagmus. This finding indicates that hyperventilation resulted in a transient increase in activity from these partially demyelinated axons.

Unilateral pursuit-induced congenital nystagmus.

We describe two patients with a lifelong history of oscillopsia only when following objects moving toward their left side. Neurologic examination was normal except for eye movements. The patients showed nystagmus during any tasks that required visual following toward the left (ie, smooth pursuit, optokinetic nystagmus, and vestibulo-ocular-reflex-suppression), but had no nystagmus during fixation of stationary targets or visual following tasks to the right. Eye-movement recordings showed waveforms during pursuit to the left that were typical of congenital nystagmus.