Brain Advance Access originally published online on April 8, 2003
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Brain, Vol. 126, No. 6, 1319-1332,
June 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg132
Eye movement abnormalities in essential tremor may indicate cerebellar dysfunction
Department of Neurology, University of Luebeck, 1 Department of Neurology, University of Kiel, Germany
Correspondence to: Professor Dr Christoph Helmchen, Department of Neurology, University of Luebeck, Ratzeburger Allee 16023538, Luebeck, Germany E-mail: helmchen_ch{at}neuro.mu-leubeck.de
Received November 7, 2002. Revised January 21, 2003. Accepted January 23, 2003.
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Summary |
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Experimental and clinical data indicate that the cerebellum is involved in the pathophysiology of advanced stages of essential tremor (ET). The aim of this study was to determine whether a dysfunction also affects cerebellar structures involved in eye movement control. Eye movements of 14 patients with ET and 11 age-matched control subjects were recorded using the scleral search-coil technique. Vestibular function was assessed by electro-oculography. Eight ET patients had clinical evidence of intention tremor (ETIT); six had a predominantly postural tremor (ETPT) without intention tremor. ET patients showed two major deficits that may indicate cerebellar dysfunction: (i) an impaired smooth pursuit initiation; and (ii) pathological suppression of the vestibulo-ocular reflex (VOR) time constant by head tilts (‘otolith dumping’). In the step ramp smooth pursuit paradigm, the initial eye acceleration in the first 60 ms of pursuit generation was significantly reduced in ET patients, particularly in ETIT patients, by
44% (mean 23.4°/s2) compared with that of control subjects (mean 41.3°/s2). Subsequent steady-state pursuit velocity and sinusoidal pursuit gain (e.g. 0.4 Hz: 0.90 versus 0.78) were also significantly decreased in ET patients, whereas pursuit latency was unaffected. The intention tremor score correlated with the pursuit deficit, e.g. ETIT patients were significantly more affected than ETPT patients. Gain and time constant (
) of horizontal VOR were normal, but suppression of the VOR time constant by head tilt (‘otolith dumping’) was pathological in 41% of ET patients, particularly in ETIT patients. Saccades and gaze-holding function were not impaired. The deficit of pursuit initiation, its correlation with the intensity of intention tremor, and the pathological VOR dumping provide additional evidence of a cerebellar dysfunction in the advanced stage of ET, when intention tremor becomes part of the clinical symptoms, and point to a common pathomechanism. The oculomotor deficits may indicate an impairment of the caudal vermis in ET. Keywords: cerebellum; essential tremor; eye movements; intention tremor
Abbreviations: ET = essential tremor; ETIT = essential tremor with intention tremor; ETPT = essential tremor with postural tremor; ITS = intention tremor score; PT = postural tremor; VOR = vestibulo-ocular reflex; = time constant of VOR
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Introduction |
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TopSummaryIntroductionSubjects and methodsResultsDiscussionReferences |
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The pathophysiology of essential tremor (ET) is still unclear. Since the inferior olive is one of the main sites for suspected lesions in ET, one experimental approach is to investigate the function of its efferent projections, i.e. the olivo-cerebellar pathways. If the lesion-induced oscillating activity of the inferior olive is transmitted to the cerebellum, as suggested by the harmaline animal model of ET (Wilms et al., 1999
), it might affect the normal functioning of cerebellar feed-forward functions involved in executing rapid and smooth eye movements. Clinically, some patients with essential tremor show an intention tremor in addition to postural tremor (Deuschl et al., 1998). Recent clinical and electrophysiological studies revealed signs of cerebellar dysfunction in arm movements (Deuschl et al., 2000; Köster et al., 2002) and gait (Singer et al., 1994; Stolze et al., 2001) of ET patients. This intention tremor cannot be clinically distinguished from the classic intention tremor in cerebellar disorders. Kinematic studies of arm movements in a reach and grasp task in ET patients showed cerebellar dysmetria, possibly indicating that the cerebellum plays a role in ET (Deuschl et al., 2000).
Methodologically, kinematic analyses of arm and hand movements may be contaminated by various types of tremor (postural, simple kinetic, intention tremor). Although cerebellar dysmetria in ET patients is probably not secondary to tremor components (Deuschl et al., 2000), we sought highly reliable clinical parameters that (i) can be recorded with great accuracy; (ii) cannot be disturbed by hand tremor artefacts; and (iii) potentially indicate cerebellar region-specific dysfunction. We therefore recorded eye movements in ET patients, which are known to indicate cerebellar dysfunction, and tried to correlate them with the clinical intention tremor components. The absence of eye movement disorders had been used to distinguish the cerebellar dysfunction in ET patients from that of patients with cerebellar degeneration (Deuschl and Bain, 1998). However, we will show that distinct eye movement disorders in ET patients probably indicate cerebellar dysfunction although they are not obvious during clinical bedside testing.
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Subjects and methods |
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TopSummaryIntroductionSubjects and methodsResultsDiscussionReferences |
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Subjects
Seventeen outpatients with ET (seven women, 10 men; age range 24–81 years, mean 54.8 ± 16.7 years) were examined. The age at onset of the disease varied, ranging from 7 to 64 years (mean 27.6 ± 17.3 years), and disease duration was 6–74 years (mean 26.7 ± 18.6 years). Fourteen patients reported a family history (Table 1). Six of the patients were on anti-tremor agents (e.g. ß-blocker, primidone). Eleven of 17 ET patients responded to alcohol consumption. Seven of the patients showed head tremor. None of them had a history of any other neurological disease apart from ET. All patients had a neurological examination and were also examined clinically to determine tremor scales (see below). Except for two cases (patients 1 and 3, who were on primidone), ET patients did not take any medication known to affect eye movements. All patients fulfilled the diagnostic criteria of classic ET as defined by the consensus statement of the Movement Disorder Society (Deuschl et al., 1998
). Besides a neurological examination, the patients also underwent a standardized assessment of clinical features of the tremor and eye movements. The patients were compared [clinically, electro-oculography (EOG), scleral search-coil recordings] with a group of 11 (six women, five men) age-matched healthy subjects (mean age 56.6 years, range 31–74 years).
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Clinical scores
For intention and postural tremor rating we used a modification of the clinical tremor rating scale (rates 0–3) of Fahn and colleagues (Fahn et al., 1993
). The upper limb on each side was rated. Intention tremor, as defined in the consensus statement of the Movement Disorder Society (Deuschl et al., 1998), is present if the tremor amplitude increases during visually guided movements toward a target, provided that a position-specific tremor and a postural tremor at the end of the movement is excluded, and if the amplitude fluctuates significantly when approaching the target. To rate the intention tremor, the terminal period of the finger-to-nose test was evaluated: 0 = no intention tremor; 1 = probable intention component; 2 = definite intention component; 3 = functionally incapacitated due to intention tremor. Taking the uni- versus bilateral tremor involvement into account, we computed a score for the intention tremor of each hand, subsequently termed the intention tremor score (ITS) [e.g. a probable (score = 1) intention component in both hands yielded 2 points on the ITS].
In addition, subjects were evaluated for resting tremor and postural tremor (Deuschl et al., 2000). None had resting tremor. Postural tremor (PT) was examined with respect to disability, i.e. we examined patient ability to hold a glass of water: 0 = no tremor visible; 1 = slight tremor, but no water is spilled; 2 = spills some water, but <30%; 3 = spills >30% of the water.
Tremor rating and ET subgroups
Patients who showed a definite intention tremor on at least one hand (rating score of 2 unilaterally) were classified as ‘essential tremor with intention tremor’ (ETIT) (n = 10). Patients with a postural tremor of the hands without definite intention tremor (rating 0 or 1 uni- or bilaterally, with 1 indicating only a probable intention tremor) were classified as ‘essential tremor with predominantly postural tremor’ (ETPT) (n = 7). None of the control subjects showed any form of tremor.
Eye movement recordings
Eye movements were recorded with the magnetic scleral search-coil system and direct current (DC) EOG. EOG was used in particular to investigate optokinetic nystagmus and vestibularly elicited eye movements [vestibulo-ocular reflex (VOR) gain, time constant].
Scleral search-coil
Eye movements were recorded by a search-coil system (2 m3; CNC Engineering, Seattle, WA, USA) with standard annulus search coils (Skalar, Delft, The Netherlands). Search coil recordings were approved by the ethical committee of the medical faculty of the University of Luebeck. All subjects signed an informed consent statement, which was obtained in accordance with the Declaration of Helsinki. Data were stored in binary format at 500 Hz sampling rate on the recording PC (personal computer) by an ADC (analogue digital converting) device (PCI 6170; National Instruments, Munich, Germany). The stimulus was a red laser dot (diameter of 0.1°) presented on a translucent screen (Marata screen) in a completely darkened room. The laser dot was moved by two galvanometer scanners (GSI Lumonics, Munich, Germany), driven by an analogue output card in the stimulus PC (AT-AO6/10; National Instruments, Munich, Germany). The subject was seated in a comfortable wooden chair with the head fixed in a head-holding device and the chin resting on a chin rest bar. In addition, head movements were recorded with a search coil mounted to the forehead to account for possible head movement components. The eye-to-screen distance was 140 cm. After the cornea was desensitized by a local anaesthetic (oxybuprocaine, Conjucain®, Mann, Berlin, Germany), the scleral search-coil was placed in the right eye. Eye movements were calibrated by an in vivo calibration as described previously (Rambold et al., 2001, 2002a).
Electro-oculography
Vestibular and optokinetic nystagmus were examined using conventional EOG (Heide et al., 1999). Subjects were seated in a darkened room on a vestibular chair with their head in the centre of a hemispheric white screen (distance 0.9 m). Horizontal eye movements were recorded using DC EOG by means of four electrodes: one each placed on the outer canthi of the eyes, the other two vertically above and another below one eye. The signals were amplified and low-pass filtered with a cut-off frequency of 70 Hz.
Experimental paradigms and data analysis
Smooth pursuit eye movements, saccades, optokinetic nystagmus, gaze-holding function and horizontal VOR were investigated.
Paradigms in scleral search-coil recordings
Step ramp paradigm. To investigate initial smooth pursuit eye movements, subjects performed two sequences of 28 horizontal step ramp stimuli in accordance with the Rashbass paradigm. Each sequence consisted of 10 foveopetal pursuit ramps (3° step, opposite to ramp direction, 15°/s ramp velocity, duration 800 ms) to either side and four foveofugal ramps in the same direction as the step (3° step, 15°/s ramp velocity, duration 800 ms) in both directions. The stimuli were presented in a random order. To prevent anticipatory effects, the duration of fixation before each trial was varied from 1500 to 2000 ms.
Pursuit eye movements were analysed offline using an interactive program. Pursuit eye position was filtered by a 3rd order polynomial smoothing filter (Savatzky-Golay filter; Orfanidis, 1995) and differentiated. Saccades were excluded from the pursuit velocity data and the data were interpolated linearly (Moschner et al., 1999). Latency, initial acceleration, steady-state velocity and the position error of the first saccade in the step ramp smooth pursuit response were analysed.
For the analysis of initial smooth pursuit and its latency, all trials with saccades in the initial phase were excluded. The initial acceleration of smooth pursuit was calculated as reported elsewhere (Carl and Gellman, 1987; Moschner et al., 1999). We used eye acceleration in the first 60 ms to characterize the initial phase of the smooth pursuit response (Carl and Gellman, 1987; Moschner et al., 1999), since averaging eye acceleration in the entire open-loop period may not reveal subtle deficits in pursuit acceleration (Takagi et al., 2000). Initial eye acceleration was quantified by a linear regression of the velocity trace. The linear regression started when eye velocity exceeded its SD during fixation by 3.2-fold. The initial eye acceleration was computed by regression of the following 60 ms (Fig. 1). The onset of the smooth pursuit response was defined by the intersection of the regression line with the mean of pursuit eye velocity during fixation. The latency of pursuit initiation was defined as pursuit onset minus stimulus onset. To determine smooth pursuit latency, each individual trial was analysed separately.
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To analyse the potential effects of deficient motion perception on initial pursuit acceleration, we calculated the position error of the first saccade elicited by the step ramp stimulus as the difference between eye position at the end of the first saccade and the target (Moschner et al., 1999
). Pathological motion perception was assumed when position errors deviated significantly from those of the control subjects. Mean eye velocity during pursuit maintenance (steady-state velocity) was measured in each individual trial, in intervals of 200 ms at 400, 600 and 800 ms after the onset of the ramp. Maximum steady-state velocity was defined by the maximum of all three intervals.
Sinusoidal smooth pursuit paradigm. The frequency dependence of smooth pursuit was tested in a sinusoidal smooth pursuit paradigm of 0.2 and 0.4 Hz (15° amplitude). After desaccadation, the eye velocity signal was fitted by a Marquard-Levenberg method (Borse, 1997), using nine cycles of smooth pursuit. The gain was calculated by the ratio of eye velocity to target velocity and the phase difference, by target phase minus eye velocity phase.
Saccade paradigm. Subjects performed horizontal saccades of 10 and 20° to either side, starting from gaze straight ahead, i.e. 10 centrifugally and 10 centripetally. Centrifugal and centripetal saccades were investigated since saccade dysmetria is more likely to appear in centripetal saccades (Helmchen et al., 1994b). The paradigm was randomized for the order of saccade appearance (direction and amplitude) and for the intersaccadic interval, i.e. the fixation duration of the target varied from 1000 to 1600 ms in order to exclude anticipatory latency effects. The 10 and 20° saccades were analysed separately. Saccades were filtered by a 100 Hz Gaussian filter (–3dB) and detected automatically using peak velocity (20°/s) and acceleration criteria (Rambold et al., 2002a). Anticipatory and spontaneous saccades were excluded by filtering only saccades with a latency between 80 and 530 ms. All computerized saccade detections were controlled and adjusted manually if required. Saccade amplitude gain was calculated as the ratio between the amplitudes of the primary saccade and target displacement. We used the comparison of: (i) saccadic amplitude gain; (ii) frequency of dysmetric saccades; and (iii) the position errors and the number of corrective saccades between patients and control subjects to determine saccadic dysmetria (Bötzel et al., 1993; Moschner et al., 1994; Wessel et al., 1998). Dysmetria was considered pathological if the primary saccade had an amplitude gain of <0.85 (hypometria) or of >1.0 (hypermetria) (Bötzel et al., 1993; Moschner et al., 1994; Wessel et al., 1998). This analysis was performed for each subject and the mean results are given for each group (control, ET patients; see Results). In the next step, the frequency of dysmetric saccades was calculated for each subject in per cent of the total number of visually guided saccades. Pathological dysmetria was assumed when the frequency of hypometric or hypermetric saccades exceeded 23% (Wessel et al., 1998). The pattern of corrective (primary, secondary, tertiary) saccades was considered as pathological if the number, amplitude and/or direction of corrective saccades was significantly different from that of the control subjects.
Spontaneous nystagmus and gaze-holding function. Spontaneous nystagmus was examined with the eyes closed and in darkness (30 s). Fixation nystagmus was tested with eyes opened during fixation in the ‘gaze straight ahead’ position. Gaze-holding nystagmus was tested during at least 30 s of sustained fixation of vertical and horizontal eccentric laser targets. Rebound nystagmus was assessed in the gaze straight ahead position after prolonged periods of eccentric fixation.
Paradigms in EOG
To investigate the VOR, the vestibular chair was rotated, in the dark, (i) sinusoidally and (ii) with a constant chair velocity around an earth vertical axis as described previously (Wessel et al., 1998). VOR gain was calculated by the ratio of the fastest slow phase velocity of vestibular nystagmus to chair velocity. For sinusoidal stimulation, a frequency of 0.2 and 0.33 Hz with a ±90°/s chair peak velocity after an initial acceleration of 90°/s2 was used. After vestibular stimulation with constant chair velocity (90°/s) for at least 2 min, post-rotatory nystagmus was analysed after sudden deceleration (from 90°/s2 to 0°/s2) of the chair within 1 s to characterize the velocity storage mechanism. It was determined with the head in an upright position by the time constant () of the decay of the post-rotatory vestibular nystagmus (Heide et al., 1999), defined as a decay of 37% of maximum slow phase velocity of post-rotatory vestibular nystagmus.
The VOR suppression (attenuation of the post-rotatory nystagmus) by fixation of a head-stationary target was calculated by the reduction in VOR gain. Pathological VOR suppression was assumed when the sinusoidal VOR gain could not be suppressed below 0.12 (Heide et al., 1999). In addition, VOR tilt suppression (i.e. ‘dumping’ of its time constant) was induced by a head tilt of 90° forward off the vertical axis of rotation (‘otolith dumping’) 4 s after the chair stopped rotating. It was measured as a reduction of the time constant of post-rotatory nystagmus compared with trials without head tilts (Heide et al., 1988; Wessel et al., 1998). Dumping was considered normal, if the time constant ( = decay of post-rotatory slow phase velocity by 37%) after head tilt was reduced to <70% of the time constant of post-rotatory VOR without head tilt (Wessel et al., 1998). Under normal circumstances the discharge (dumping) of the velocity storage mechanism of the VOR by otolith input (head tilt) is thought to be a cerebellar sign of the nodulus and caudal vermis (Waespe et al., 1985; Heide et al., 1988). For a better comparison, we compared the otolith dumping effect in ET patients with five patients (aged 33–69 years) with cerebellar lesions in the midline vestibulo-cerebellum (Heide et al., 1988).
Horizontal optokinetic nystagmus (OKN) was elicited by 60°/s and 90°/s full-field stimulation (constant velocity) generated by random light dots moving horizontally as described previously (Wessel et al., 1998). The gain was calculated as the ratio of peak slow phase velocity to stimulus velocity.
Statistical analysis
The univariate analysis of variance (ANOVA) was used to compare the groups. In case of a significant influence of the group factor on the dependent variables, post hoc comparisons were computed using Bonferroni’s test. The level of significance was set at P < 0.05 unless stated otherwise. For correlation analysis we used Pearson’s test. Normal distribution was shown in all experimental data by using the Shapiro–Wilk test.
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Results |
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Clinical tremor scores
Clinical examination of the patients showed no rest tremor. Postural tremor was found in all 17 patients. Sixteen had probable or definite intention tremor in at least one hand; six had a probable intention tremor, while 10 had a definite intention tremor (Table 1).
The two ET subgroups, ETPT (‘essential tremor with predominantly postural tremor’; n = 7) and ETIT (‘essential tremor with definite intention tremor’, i.e. rating score of at least 2 unilaterally; n = 10), showed significant differences in the following aspects: ETIT patients were older (62.0 ± 14.9 versus 44.4 ± 14.2 years in ETPT) and had a longer history of ET (34.3 ± 20.4 versus 16.0 ± 9.0 years in ETPT); however, there was no difference in age at disease onset. Age did not significantly differ between ETIT patients and control subjects. Furthermore, ETIT patients not only had a higher ITS [3.63 ± 0.52 (ETIT) versus 1.17 ± 0.75 (ETPT), P < 0.01], but also a higher postural tremor score [1.6 ± 0.52 (ETIT) versus 1.0 ± 0.58 (ETPT)]. The ITS of each patient did not differ by more than one point in the right compared with the left hand.
Head tremor was found in four ETPT patients and in three ETIT patients. There was a positive family history in all seven ETPT patients and in eight out of 10 ETIT patients (Table 1). Five ET patients (one ETPT and four ETIT patients) had been examined by quantitative accelerometry previously (Deuschl et al., 2000). One clinical investigator (C.H.) was blinded for the previous accelerometry results, but all of those five patients were clinically assigned to the appropriate ETIT and ETPT patient groups.
On clinical neuro-ophthalmological examination, seven out of 17 patients had cogwheel horizontal smooth pursuit eye movements. Otherwise the patients did not show oculomotor abnormalities.
Eye movement recordings
The scleral search-coil technique was used to investigate horizontal pursuit eye movements, randomized visually guided saccades, and impairment of gaze-holding function in 14 ET patients (six ETPT, eight ETIT) and 10 healthy subjects. In one patient (number 13), initial smooth pursuit acceleration was too poor (too many saccades and blinks during pursuit onset) for an appropriate analysis criterion. In three (one ETPT, two ETIT) of all 17 patients, search-coil recordings could not be obtained (e.g. the patients refused to allow them); eye movements were thus recorded by EOG only. These data were included only in the analysis of the VOR. Since there were generally no significant directional effects in all experimental paradigms, the amplitude-matched data were pooled, unless stated otherwise.
Smooth pursuit eye movements
Mean latency of smooth pursuit onset in the step ramp paradigm in ET patients (169.4 ± 20.5 ms) did not differ from that in the controls (168.60 ± 15.5 ms), nor in the ET subgroups (ETPT: 155.3 ± 11.6 ms; ETIT: 181.5 ± 18.9 ms). The initial eye acceleration in the first 60 ms of smooth pursuit eye movements in the step ramp paradigm was significantly decreased in patients (mean eye acceleration ± SD: 33.6 ± 15.0°/s2) compared with that of our (mean 41.3 ± 20.2°/s2) and other control subjects (Kao and Morrow, 1994; Moschner et al., 1999). Examples of individual ETPT and ETIT patients are shown as eye position traces with respect to the target displacement (Fig. 2) and as eye velocity traces (Fig. 3). Both show smooth pursuit deficits not only in the maintenance (steady-state velocity) phase, but also in the initial phase of smooth pursuit acceleration. In the comparison of ET subgroups, ETIT patients (mean 23.4 ± 9.0°/s2) showed a significantly ( 50%) lower initial pursuit acceleration than ETPT patients (mean 45.5 ± 11.5°/s2) and control subjects (Figs 3 and 4). The peak of steady-state eye velocity was significantly decreased in ET patients (9.18 ± 2.6°/s) compared with the control subjects (11.7 ± 2.2°/s) and was significantly lower in ETIT (7.98 ± 1.6°/s) than in ETPT patients (10.6 ± 2.9°/s) (Fig. 5A). The initial eye acceleration correlated positively with the peak steady-state eye velocity (P < 0.01) in healthy subjects (r = 0.92) and in ET patients (ETPT: r = 0.84; ETIT: r = 0.66). Horizontal sinusoidal smooth pursuit showed a significantly lower velocity gain of ETIT patients compared with the control group, i.e. 0.90 versus 0.98 for 0.2 Hz and 0.75 versus 0.90 for 0.4 Hz (P < 0.01; Fig. 5B). The gain of the ET subgroups did not differ significantly among themselves. Visual fixation suppression of the sinusoidal VOR was impaired in five patients (one ETPT and four ETIT patients). Those four ETIT patients with an impaired VOR suppression during visual fixation (mean gain 0.14) also showed a low sinusoidal pursuit gain (0.73).
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When impaired smooth pursuit was compared with clinical data there was a negative correlation of the ITS with initial pursuit acceleration (Spearman Rho correlation coefficient: r = –0.58, P < 0.05) and peak eye velocity (r = –0.56, P < 0.05), i.e. the more intention tremor the patients showed, the more impaired was initial eye acceleration (Fig. 6A) and peak pursuit velocity (Fig. 6B).
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To determine whether the initial pursuit acceleration deficit is secondary to an impaired motion perception in ET patients, the position error of the first saccade elicited by the step ramp stimulus was investigated. There were no significant differences between patients and controls with respect to: (i) amplitude (ET patients: 2.13 ± 0.5°; controls: 2.31 ± 0.8°); (ii) latency (ET patients: 227 ± 33.9 ms; controls: 239 ± 37 ms); or (iii) position errors (ET patients: 1.27 ± 0.7°; controls: 0.87 ± 0.4°) of the initial saccade while tracking the step ramp stimulus, in particular in foveofugal saccades. This indicates that ET patients show no deficit in taking into account the target velocity when programming the saccade, i.e. they probably do not have a perceptual deficit of target motion.
Saccades
Since centripetal and centrifugal saccades did not show significant differences with respect to saccadic latency, gain and peak velocity, they were pooled for further analysis. There were no significant differences between ET patients and control subjects with respect to the latency of saccade onset, gain and peak velocity (Table 2), either in 10 or 20° saccades. The subgroups (ETPT versus ETIT) did not reveal any significant differences either.
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The saccadic position error (difference of target position to eye position after the first saccade) was not significantly different in patients and controls for 10° (ET patients versus control: 0.04 ± 0.02° versus 0.04 ± 0.02°) and 20° saccades (ET patients versus control: 0.02 ± 0.01° versus 0.02 ± 0.02°). There were no subgroup differences (ETPT versus ETIT) for 10 and 20° saccades. Frequency and amplitude of corrective saccades (secondary and tertiary on- and off-saccades; Bötzel et al., 1993
) did not differ between patients and control subjects. The frequency of tertiary off-saccades was normal (<10%; Bötzel et al., 1993), and there was no significant difference between ET patients (6.1%) and controls (4.0%). The frequency of dysmetric saccades did not differ between ET patients and controls for neither hypermetric nor hypometric saccades: according to the frequency criteria of dysmetria (>23%; see Subjects and methods), 16% of ET patients had hypometric saccades, while 20% of control subjects had hypometric saccades.
Spontaneous nystagmus and gaze-holding function
No patient showed a spontaneous nystagmus (>5°/s slow phase velocity). Gaze-holding function was not impaired, i.e. there was no gaze-evoked nystagmus. Neither was there rebound or periodic alternating nystagmus.
Vestibulo-ocular reflex (VOR)
VOR was investigated in 17 patients with essential tremor (seven ETPT and 10 ETIT patients) and 11 healthy control subjects. The mean VOR gain showed no significant differences between ET patients (0.77 ± 0.16) and control subjects (0.85 ± 0.12) during either sinusoidal or vestibular ramp stimulation. Neither was VOR gain in the ET subgroups significantly different (ETPT: 0.72 ± 0.16; ETIT: 0.80 ± 0.15). Dumping of the VOR time constant by head tilts (‘otolith-dumping’; see Methods) was pathological in ET patients; the VOR time constant () without head tilt (13.9 s) was diminished on average to only 70.1 ± 14.8% of VOR time constant with head tilt (9.75 s), which was significantly less diminished than in the control subjects (14.9 to 8.46 s; reduction to 56.8 ± 3.9%). This deficit was particularly evident in the ETIT patients who were on the average unable to reduce the VOR time constant (14.1 s to 11.2 s; 79.4 ± 13.0%) (Fig. 7), whereas the ETPT patient group (13.69 s to 8.52; 62.9 ± 13.2%) did not show significant differences to healthy control subjects (57.8 ± 3.9%). Accordingly, the mean reduction of the time constant after head tilt was shorter in ETIT patients (3.45 ± 1.7 s) compared with ETPT patients (5.17 ±1.9 s) and control subjects (6.14 ± 1.14 s). Evaluation of single subjects showed a normal dumping to <70% of the time constant without head tilt in four of seven ETPT patients and in three of 10 ETIT patients, while none of the healthy control subjects failed to dump the VOR time constant. For better comparison, the deficient otolith dumping effect was added in five patients (aged 33–69 years) with cerebellar lesions in the midline vestibulo-cerebellum (Heide et al., 1988) (Fig. 7A and B, right side), who were virtually unable to reduce the post-rotatory time constant, i.e. they could not discharge the velocity storage mechanism.
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Optokinetic nystagmus
The gain of horizontal optokinetic nystagmus examined with a 60°/s stimulus (control: 0.95 ± 0.07; ET: 0.88 ± 0.15) and 90°/s (control: 0.81 ± 0.18; ET: 0.70 ± 0.19) stimulus was not significantly impaired in ET patients. Subgroup comparison did not show any significant difference either (60°/s: ETPT 0.92 ± 0.11, ETIT 0.85 ± 0.17; 90°/s: ETPT 0.75 ± 0.18, ETIT 0.67 ± 0.20).
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Discussion |
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TopSummaryIntroductionSubjects and methodsResultsDiscussionReferences |
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This is the first study to show oculomotor deficits in patients with essential tremor. Several lines of evidence from animal (Wilms et al., 1999
), physiological (Deuschl et al., 2000; Stolze et al., 2001; Köster et al., 2002) and imaging (Colebatch et al., 1990; Jenkins et al., 1993; Wills et al., 1994; Pagan et al., 2002) studies pointed to a cerebellar role in ET. Thus, the aim of this study was to look for cerebellar eye movement disorders in patients with essential tremor that might help to characterize their cerebellar dysfunction. Our main findings were two distinct oculomotor deficits, which are assumed to be of cerebellar origin: (i) decreased initial pursuit acceleration (Straube et al., 1997; Moschner et al., 1999); and (ii) deficient capacity to discharge the velocity storage mechanism, i.e. the impaired vestibulo cerebellar function to reduce the time constant of post-rotatory vestibular nystagmus by head tilts (Hain et al., 1988; Heide et al., 1988; Wessel et al., 1998). The pursuit deficit is of clinical significance since it is related to the amount of intention tremor, suggesting that progressive ET involves the cerebellum in the natural course of the disease (Deuschl et al., 2000). Thus, cerebellar dysfunction in ET does not only involve the cerebellar control of arm (Deuschl et al., 2000; Köster et al., 2002) and leg movements (Stolze et al., 2001), but also of oculomotor and vestibular function (this study), of which the latter can at least in part be localized to midline (vermal) cerebellar structures. Although these oculomotor deficits can usually not be detected by clinical neurologists, they might shed light on the pathophysiology of ET. Therefore the oculomotor deficits will be discussed in the light of their localizing value and potential implications for the pathomechanism of essential tremor.
Smooth pursuit deficits
Smooth pursuit eye movements consist of an initial acceleration phase and a maintenance phase with steady-state velocity. The initial phase represents the first 60 ms of eye acceleration (open-loop period), which is largely driven by retinal slip. In the maintenance phase, gaze velocity reaches target velocity via a closed-loop visual pathway. ET patients in our study showed impairment of both smooth pursuit initiation and maintenance, whereas the latency of pursuit onset was not affected. Smooth pursuit initiation impairment that has a normal latency is unlikely to be of cortical (e.g. parieto-occipital) origin (Heide et al., 1996) and can also not be explained by attentional deficits.
An impaired perception of visual target motion is also unlikely to account for the impairment of pursuit acceleration in our ET patients. There were no significant differences in amplitude, latency or position errors of the initial saccade between patients and controls while tracking the step ramp stimulus, nor in foveopetal or in foveofugal saccades. Increased saccadic position errors of initial pursuit without evidence of large amplitude saccadic dysmetria is thought to reflect impaired estimation of visual target velocity (Heide et al., 1996). This has also been shown in some cerebellar patients (Nawrot and Rizzo, 1995; Moschner et al., 1999). However, even normal motion perception and normal latency eventually do not completely exclude cortical dysfunction. Impaired smooth pursuit eye movements can also be caused by pontine lesions, but neither the clinical examination nor the oculomotor findings pointed to a pontine dysfunction.
There is a known age-dependency of smooth pursuit eye movements, which also holds for the open-loop phase (Morrow and Sharpe, 1993). This is compatible with our results demonstrating that ETPT patients showed a better initial pursuit acceleration compared with the two other groups of older subjects, i.e. ETIT patients and controls. Thus, we cannot rule out that the difference between ETPT patients and controls is age dependent. However, there was no statistically significant difference in age between ETIT patients and controls, yet they showed a significant difference in initial pursuit acceleration. Thus, we believe that this effect is specifically related to essential tremor and probably reflects cerebellar dysfunction.
The cerebellum is crucial for smooth pursuit eye movements. Indeed, cerebellectomy abolishes them (Westheimer and Blair, 1974; Burde et al., 1975). At least two main cerebellar structures participate in the generation of smooth pursuit eye movements forming two parallel pathways: (i) the flocculus/paraflocculus (Zee et al., 1981; Stone and Lisberger, 1990; Rambold et al., 2002b); and (ii) the vermal lobules VI,VII and the uvula (Heinen and Keller, 1996) with the underlying deep cerebellar nuclei (Suzuki and Keller, 1988). However, lesions of neither structure alone can fully account for the loss of smooth pursuit eye movements after cerebellectomy.
The maintenance of a constant pursuit velocity is primarily subserved by the flocculus (Stone and Lisberger, 1990). The fastigial nuclei (Robinson et al., 1997) and the posterior vermis (Ohtsuka and Enoki, 1998; Takagi et al., 2000) participate in direction-specific smooth pursuit initiation and maintenance (Krauzlis and Miles, 1998). Magnetic stimulation of the posterior vermis in human subjects increases (ipsilaterally) or decreases (contralaterally) both initial acceleration and steady-state pursuit velocity (Ohtsuka and Enoki, 1998). Therefore initial pursuit deficits have been proposed to indicate cerebellar dysfunction (Straube et al., 1997; Takagi et al., 2000), and the posterior vermis/fastigial nucleus complex probably plays a major role.
A few previous clinical studies have implicated diffuse (Lekwuwa et al., 1995; Moschner et al., 1999) or circumscribed (Straube et al., 1997) cerebellar lesions in the impairment of initial pursuit acceleration. However, only some of the focal cerebellar lesions (Straube et al., 1997), causing impaired initial pursuit acceleration, are involved the midline vermal cortex. Moreover, lesions of the oculomotor vermis (lobules VI,VII) should also have led to saccade dysmetria (Ritchie, 1976; Sato and Noda, 1992; Ohtsuka and Enoki, 1998; Takagi et al., 1998, 2000; Barash et al., 1999), but we did not find this (see below).
Saccades
A hallmark of cerebellar saccadic dysfunction is saccadic dysmetria (Bötzel et al., 1993). It is largely controlled by saccade-related neurons in the posterior vermis (Sato and Noda, 1992; Helmchen and Büttner, 1995) and fastigial nuclei (Fuchs et al., 1993; Helmchen et al., 1994a). Accordingly, lesions of the oculomotor vermis (Sato and Noda, 1992; Vahedi et al., 1995; Takagi et al., 1998) and fastigial nuclei (Robinson et al., 1993) cause direction-specific saccade dysmetria.
Since abnormal olivocerebellar neural rhythmicity, which is thought to be transmitted to the cerebellar Purkinje cells and the deep cerebellar nuclei (Lamarre, 1995), is a probable pathomechanism in ET, saccade dysmetria may also be caused by lesions affecting the afferent cerebellar projections in the brainstem. Impaired climbing fibres in the medullary brainstem at the level of the inferior olive, e.g. in Wallenberg’s syndrome, may cause deficient climbing fibre input to the cerebellar Purkinje cells, leading to direction-specific saccadic dysmetria (Helmchen et al., 1994b) by increased inhibition (inactivation) of the fastigial nuclei.
Although we considered all criteria of saccadic dysmetria together (see Subjects and methods; Bötzel et al., 1993), we did not find significant dysmetria in ET patients, nor in ETPT or ETIT patients. This was independent of the direction and amplitude of the saccade. Since the saccade system is constantly recalibrated by the cerebellar cortex (Barash et al., 1999), saccade dysmetria can be a transient sign and may be absent in patients with chronic cerebellar disease (Fetter et al., 1994; Moschner et al., 1994).
Vestibulo-ocular reflex, velocity storage mechanism and gaze-holding function
The vestibulo-cerebellum controls and adjusts the gain of the VOR. It may be increased in patients with cerebellar lesions (Baloh et al., 1975; Baloh and Demer, 1993), but we did not find this. Accordingly, we did not find dynamic signs of a vestibular imbalance, i.e. vestibular spontaneous nystagmus. Another vestibulo-cerebellar function, in particular of the caudal vermal lobules, uvula and nodulus, is the capacity to discharge the velocity storage mechanism by otolith input (Schrader et al., 1985; Waespe et al., 1985). This is detected by the reduction of the time constant of the post-rotatory VOR following head tilts (Han et al., 2001). Patients with lesions of the vestibulo-cerebellum show impaired tilt suppression of the VOR (Hain et al., 1988; Heide et al., 1988). In contrast to the normal tilt suppression in all our control subjects, only two ET patients with intention tremor were able to produce a sufficient tilt suppression. Since ETPT patients were much less affected than ETIT patients, the impaired VOR tilt suppression by head tilts is a sensitive sign of cerebellar (uvula/nodulus) dysfunction in the advanced stage of ET. However, this deficit was incomplete when compared with patients with cerebellar lesions affecting the vestibulo-cerebellum (uvula/nodulus) (Heide et al., 1988) (Fig. 7). Uvula and nodulus lesions may also elicit periodic alternating nystagmus (Waespe et al., 1985), which we did not find. Finally, the cerebellum, particularly the flocculus, contributes to the gaze-holding function, i.e. cerebellar lesions may reduce the time constant of the slow phase of gaze-evoked nystagmus to 2 s (Optican and Robinson, 1980). The absence of gaze-evoked nystagmus in our ET patients argues against any considerable dysfunction of the flocculus.
Pathophysiology of essential tremor
The pathophysiological research of ET is presently concentrating on the cerebellum, and many lines of evidence are now supporting a cerebellar dysfunction. The two oculomotor deficits described in this study are among the most recent arguments for such an abnormality. The impairment of smooth pursuit eye movements is even strengthening such a relation as we found a correlation between the initial pursuit acceleration deficit and the clinical ITS. The latter is considered the clinical hallmark for a cerebellar-like tremor. This correlation may indicate a similar pathophysiological background. This supports the hypothesis that intention tremor in ET patients is one of several cerebellar signs to probably indicate advanced stages of ET. Thus, we propose that not only arm and leg movements (dysmetria, intention tremor), but also smooth pursuit eye movements, constitute signs of cerebellar dysfunction in the advanced stages of ET. This correlation not only suggests a pathophysiological link between both systems (arm and eye movements), but it may also be helpful since the kinematic analysis of dysmetric arm movements may be contaminated by the tremor components that can be excluded by eye movement recordings. Our data strongly support the assumption that ETPT and ETIT patients constitute a continuum of the same disease (Deuschl et al., 2000), which may exert cerebellar (vermal) signs in the late stage that cannot be distinguished from patients with nodulus lesions (Fig. 7).
The common hypothesis about the pathomechanism of ET involves an abnormal olivocerebellar rhythmicity (Deuschl and Elble, 2000) and this may cause signs of cerebellar dysfunction. The climbing fibres originate from the inferior olive, travel through the inferior cerebellar peduncle, and terminate in the ipsilateral cerebellar cortex and cerebellar nuclei. In the animal model of ET, harmaline-induced tremor (Lamarre and Mercier, 1971; Elble, 1998), the cerebellar cortex and the deep cerebellar nuclei synchronously show a similar oscillation (Wilms et al., 1999). To ensure the accuracy of movements, the cerebellum is crucially involved in acceleration and deceleration. Thus, a pathological olivocerebellar oscillation may in particular lead to a pathological acceleration or deceleration of movements, affecting not only arm movements (Deuschl et al., 2000), but also eye movements as seen in the initial pursuit acceleration of our ET patients.
The termination of the climbing fibres responsible for this pursuit deficit remains to be determined. Cooling of the inferior olive results in suppression of the activity in the deep cerebellar nuclei (Benedetti et al., 1983). Thus, lesions or the inactivation of climbing fibres in the inferior olive might elicit oculomotor deficits resembling deep cerebellar nuclei inactivation, e.g. saccadic dysmetria (Helmchen et al., 1994b), which we did not find. Some mossy fibres that enter the cerebellar peduncle at the level of the inferior olive travel to the flocculus and paraflocculus through the inferior peduncle (Langer et al., 1985), but there were no signs of floccular dysfunction (gaze-evoked nystagmus) in our ET patients. Most recently, experimental ventral paraflocculus lesions have been shown to affect not only smooth pursuit maintenance, but also initial pursuit acceleration during open-loop pursuit tracking (Rambold et al., 2002b). Thus, parafloccular dysfunction in our ET patients may be a possible explanation.
Straube and coworkers found initial smooth pursuit deficits in patients with lesions in the cerebellar hemispheres and the interpositus nuclei, whereas the flocculus and paraflocculus were not involved (Straube et al., 1997). This agrees with some experimental animal stimulation studies (Ron and Robinson, 1973; Robinson and Brettler, 1998). The lateral cerebellar hemispheres are thought to be involved in the control of the accuracy of limb movements (Bastian and Thach, 1995), but it remains to be shown whether the initial pursuit deficit and the intention tremor and arm dysmetria in ET patients reflect a common cerebellar hemispheric lesion site. Additional evidence in favour of a hemispheric lesion site comes from recent spectroscopy findings in ET patients showing neurochemical abnormalities in the cerebellar hemispheres (Louis et al., 2002; Pagan et al., 2002). This is of localizing significance since previous imaging data pointing to hyperactive states of the cerebellum by PET (Colebatch et al., 1990; Jenkins et al., 1993; Wills et al., 1994) could not identify specific regional abnormalities within the cerebellum.
In summary, neither the oculomotor vermis (lobulus VI/VII) and underlying fastigial nucleus, nor the flocculus and paraflocculus, nor the cerebellar hemispheres alone can explain both the smooth pursuit deficit with intact saccades and the deficient tilt suppression of the VOR (pathological ‘VOR dumping’) together. In contrast, the cerebellar structure that could elicit both deficits in ET patients is the caudal vermis (uvula, nodulus): first, the uvula receives climbing and mossy fibre afferents supplying signals for visual motion processing that are important for the generation of smooth pursuit. These projections come from the dorsolateral pontine nuclei, and travel through the inferior olive to the paraflocculus and uvula (Glickstein et al., 1994) and may carry the pathological oscillatory signal supected in ET. Secondly, uvula lesions elicit profound smooth pursuit deficits, including impairment of initial eye velocity (Heinen and Keller, 1996), and a pathological ‘VOR dumping’ (Waespe et al., 1985; Heide et al., 1988). Thirdly, caudal vermis lesions do not impair saccades. Taking all these lines of converging aspects together the caudal vermis seems to play a critical role in the oculomotor disorders found in ET patients.
The cerebellar hypothesis of ET is now based on a number of observations. Arm movements (Deuschl et al., 2000; Köster et al., 2002), leg movements (Stolze et al., 2001) and eye movements (this paper) show a cerebellar-like abnormality in advanced ET. The timing of arm muscle activity shows a delay of the second agonist muscle (Britton et al., 1994) and this feature is more pronounced in patients with ETIT, which probably reflects a disturbed cerebellar timing function in ET (Köster et al., 2002). Cerebellar hypermetabolism is reversed with reduction of ET during alcohol consumption (Boecker et al., 1996) and this effect is probably mediated by an effect on the central oscillator (Zeuner et al., 2002). The improvement of ipsilateral ET after a cerebellar stroke (Dupuis et al., 1989; Nagaratnam and Kalasabail, 1997) and the improvement of ET by cerebellar stimulation, either by direct magnetic stimulation (Gironell et al., 2002) or indirectly by deep brain (ventrolateral thalamic) stimulation of cerebello-thalamic afferent fibres (Zackowski et al., 2002), are further arguments favouring a critical role for the cerebellum in producing or suppressing ET. Further studies can now be based on a more solid hypothesis and will include more detailed imaging techniques.
In conclusion, our data support the assumption that cerebellar (uvular) dysfunction occurs in advanced stages of ET, particularly in ETIT patients. The oculomotor signs (pursuit deficit and impaired discharge of the velocity storage mechanism) have previously not attracted much attention (Stolze et al., 2001), since they are clinically difficult to examine and usually require advanced eye movement recording techniques. The correlation of cerebellar intention tremor with the oculomotor deficits in ET implies an inherent relationship between both parameters that might be used as a marker for progress of the disease in ET patients. However, our study cannot answer the question of whether cerebellar signs of eye and arm movement impairment reflect the oscillatory olivocerebellar activity in advanced stages of the disease or whether the cerebellum itself participates in the pathogenesis of ET.
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The authors wish to thank D. S. Zee for helpful comments and J. Benson for copy-editing the manuscript. The study was supported by the German Research Council (Deutsche Forschungsgemeinschaft He 2689/2-1) and German Ministry of Research (BMBF Kompetenznet Parkinson’s disease).
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TopSummaryIntroductionSubjects and methodsResultsDiscussionReferences |
|---|
Baloh RW, Demer JL. Optokinetic-vestibular interaction in patients with increased gain of the vestibulo-ocular reflex. Exp Brain Res 1993; 97: 334–42.[Web of Science][Medline]
Baloh RW, Konrad HR, Honrubia V. Vestibulo-ocular function in patients with cerebellar atrophy. Neurology 1975; 25: 160–8.
Barash S, Melikyan A, Sivakov A, Zhang M, Glickstein M, Thier P. Saccadic dysmetria and adaptation after lesions of the cerebellar cortex. J Neurosci 1999; 19: 10931–9.
Bastian AJ, Thach WT. Cerebellar outflow lesions: a comparison of movement deficits resulting from lesions at the levels of the cerebellum and thalamus. Ann Neurol 1995; 38: 881–92.[CrossRef][Web of Science][Medline]
Benedetti F, Montarolo PG, Strata P, Tempia F. Inferior olive inactivation decreases the excitability of the intracerebellar and lateral vestibular nuclei in the rat. J Physiol 1983; 340: 195–208.
Boecker H, Wills AJ, Ceballos-Baumann A, Samuel M, Thompson PD, Findley LJ, et al. The effect of ethanol on alcohol-responsive essential tremor: a positron emission tomography study. Ann Neurol 1996; 39: 650–8.[CrossRef][Web of Science][Medline]
Borse GJ. Numerical methods with MATLAB. Boston (MA): PWS Publishing; 1997. p. 344.
Bötzel K, Rottach K, Büttner U. Normal and pathological saccadic dysmetria. Brain 1993; 116: 337–53.
Britton TC, Thompson PD, Day BL, Rothwell JC, Findley LJ, Marsden CD. Rapid wrist movements in patients with essential tremor. The critical role of the second agonist burst. Brain 1994; 117: 39–47.
Burde RM, Stroud MH, Roper-Hall G, Wirth FP, O’Leary JL. Ocular motor dysfunction in total and hemicerebellectomized monkeys. Br J Ophthalmol 1975; 59: 560–5.
Carl JR, Gellman RS. Human smooth pursuit: stimulus-dependent responses. J Neurophysiol 1987; 57: 1446–63.
Colebatch JG, Findley LJ, Frackowiak RS, Marsden CD, Brooks DJ. Preliminary report: activation of the cerebellum in essential tremor. Lancet 1990; 336: 1028–30.[CrossRef][Web of Science][Medline]
Deuschl G, Elble RJ. The pathophysiology of essential tremor [Review]. Neurology 2000; 54 (11 Suppl 4): S14–20. [CrossRef][Web of Science][Medline]
Deuschl G, Bain P, Brin M. Consensus statement of the Movement Disorder Society on Tremor. Ad Hoc Scientific Committee. Mov Disord 1998; 13 Suppl 3: 2–23.[CrossRef][Web of Science][Medline]
Deuschl G, Wenzelburger R, Loffler K, Raethjen J, Stolze H. Essential tremor and cerebellar dysfunction: clinical and kinematic analysis of intention tremor. Brain 2000; 123: 1568–80.
Dupuis MJ, Delwaide PJ, Boucquey D, Gonsette RE. Homolateral disappearance of essential tremor after cerebellar stroke. Mov Disord 1989; 4: 183–7.[CrossRef][Web of Science][Medline]
Elble RJ. Animal models of action tremor. Mov Disord 1998; 13 Suppl 3: 35–9.
Fahn S, Tolosa E, Marin C. Clinical rating scale for tremor. In: Jankovic J, Tolosa E, editors. Parkinson’s disease and movement disorders. 2nd ed. Baltimore: Williams and Wilkins; 1993. p. 271–80.
Fetter M, Klockgether T, Schulz JB, Faiss J, Koenig E, Dichgans J. Oculomotor abnormalities and MRI findings in idiopathic cerebellar ataxia. J Neurol 1994; 241: 234–41.[CrossRef][Web of Science][Medline]
Fuchs AF, Robinson FR, Straube A. Role of the caudal fastigial nucleus in saccade generation. 1. Neuronal discharge pattern. J Neurophysiol 1993; 70: 1723–40.
Gironell A, Kulisevsky J, Lorenzo J, Barbanoj M, Pascual-Sedano B, Otermin P. Transcranial magnetic stimulation of the cerebellum in essential tremor: a controlled study. Arch Neurol 2002; 59: 413–7.
Glickstein M, Gerrits N, Kralj-Hans I, Mercier B, Stein J, Voogd J. Visual pontocerebellar projections in the macaque. J Comp Neurol 1994; 349: 51–72.[CrossRef][Web of Science][Medline]
Hain TC, Zee DS, Maria BL. Tilt suppression of vestibulo-ocular reflex in patients with cerebellar lesions. Acta Otolaryngol 1988; 105: 13–20.[Medline]
Han GC, Cha HE, Hwang SH. Head tilt suppression test as a differential diagnostic tool in vertiginous patients. Acta Otolaryngol Suppl 2001; 545: 94–6.[CrossRef][Medline]
Heide W, Schrader V, Koenig E, Dichgans J. Impaired discharge of the eye velocity storage mechanism in patients with lesions of the vestibulo-cerebellum. Adv Otorhinolaryngol 1988; 41: 44–8.[Medline]
Heide W, Kurzidim K, Kömpf D. Deficits of smooth pursuit eye movements after frontal and parietal lesions. Brain 1996; 119: 1951–69.
Heide W, Koenig E, Trillenberg P, Kömpf D, Zee DS. Electrooculography: technical standards and applications. The International Federation of Clinical Neurophysiology. Electroencephalogr Clin Neurophysiol Suppl 1999; 52: 223–40.[Medline]
Heinen SJ, Keller EL. The function of the cerebellar uvula in monkey during optokinetic and pursuit eye movements: single-unit responses and lesion effects. Exp Brain Res 1996; 110: 1–14.[Web of Science][Medline]
Helmchen C, Büttner U. Saccade-related Purkinje cell activity in the oculomotor vermis during spontaneous eye movements in light and darkness. Exp Brain Res 1995; 103: 198–208.[Web of Science][Medline]
Helmchen C, Straube A, Büttner U. Saccade-related activity in the fastigial oculomotor region of the macaque monkey during spontaneous eye movements in light and darkness. Exp Brain Res 1994a; 98: 474–82.[Web of Science][Medline]
Helmchen C, Straube A, Büttner U. Saccadic lateropulsion in Wallenberg’s syndrome may be caused by a functional lesion of the fastigial nucleus. J Neurol 1994b; 241: 421–6.[CrossRef][Web of Science][Medline]
Jenkins IH, Bain PG, Colebatch JG, Thompson PD, Findley LJ, Frackowiak RS, et al. A positron emission tomography study of essential tremor: evidence for overactivity of cerebellar connections. Ann Neurol 1993; 34: 82–90.[CrossRef][Web of Science][Medline]
Kao GW, Morrow M.J. The relationship of anticipatory smooth eye movement to smooth pursuit initiation. Vision Res 1994; 34: 3027–36.[CrossRef][Web of Science][Medline]
Köster B, Deuschl G, Lauk M, Timmer J, Guschlbauer B, Lücking CH. Essential tremor and cerebellar dysfunction: abnormal ballistic movements. J Neurol Neurosurg Psychiatry 2002; 73: 400–5.
Krauzlis RJ, Miles FA. Role of the oculomotor vermis in generating pursuit and saccades: effects of microstimulation. J Neurophysiol 1998; 80: 2046–62.
Lamarre Y. Central mechanisms of experimental tremor and their clinical relevance. In: Findley LJ, Koller WC, editors. Handbook of tremor disorders. New York: Marcel Dekker; 1995. p. 103–18.
Lamarre Y, Mercier LA. Neurophysiological studies of harmaline-induced tremor in the cat. Can J Physiol Pharmacol 1971; 49: 1049–58.[Web of Science][Medline]
Langer T, Fuchs AF, Scudder CA, Chubb MC. Afferents to the flocculus of the cerebellum in the rhesus macaque as revealed by retrograde transport of horseradish peroxidase. J Comp Neurol 1985; 235: 1–25.[CrossRef][Web of Science][Medline]
Lekwuwa GU, Barnes GR, Grealy MA. Effects of prediction on smooth pursuit velocity gain in cerebellar patients and controls. In: Findlay JM, Walker R, Kentridge RW, editors. Eye movement research. Mechanisms, processes and applications. Amsterdam: Elsevier; 1995. p. 119–29.
Louis ED, Shungu DC, Chan S, Mao X, Jurewicz EC, Watner D. Metabolic abnormality in the cerebellum in patients with essential tremor: a proton magnetic resonance spectroscopic imaging study. Neurosci Lett 2002; 333: 17–20.[CrossRef][Web of Science][Medline]
Morrow MJ, Sharpe JA. Smooth pursuit initiation in young and elderly subjects. Vision Res 1993; 33: 203–10.[CrossRef][Web of Science][Medline]
Moschner C, Perlman S, Baloh RW. Comparison of oculomotor findings in the progressive ataxia syndromes. Brain 1994; 117: 15–25.
Moschner C, Crawford TJ, Heide W, Trillenberg P, Kömpf D, Kennard C. Deficits of smooth pursuit initiation in patients with degenerative cerebellar lesions. Brain 1999; 122: 2147–58.
Nagaratnam N, Kalasabail G. Contralateral abolition of essential tremor following a pontine stroke. J Neurol Sci 1997; 149: 195–6.[CrossRef][Web of Science][Medline]
Nawrot M, Rizzo M. Motion perception deficits from midline cerebellar lesions in human.Vision Res 1995; 35: 723–31.[CrossRef][Web of Science][Medline]
Ohtsuka K, Enoki T. Transcranial magnetic stimulation over the posterior cerebellum during smooth pursuit eye movements in man. Brain 1998; 121: 429–35.
Optican LM, Robinson DA. Cerebellar-dependent adaptive control of primate saccadic system. J Neurophysiol 1980; 44: 1058–76.
Orfanidis SJ. Introduction to signal processing. Englewood Cliffs (NJ): Prentice-Hall; 1995.
Pagan FL, Butman JA, Hallett M. Multivoxel magnetic resonance spectroscopy in essential tremor [abstract]. Neurology 2002; 58 Suppl 3: A140.
Rambold H, Heide W, Sprenger A, Händler G, Helmchen C. Perilymph fistula associated with pulse-synchronous eye oscillations. Neurology 2001; 56: 1769–71.
Rambold H, Sprenger A, Helmchen C. Effects of voluntary blinks on saccades, vergence eye movements, and saccade-vergence interactions in humans. J Neurophysiol 2002a; 88: 1220–33.
Rambold H, Churchland A, Selig Y, Jasmin L, Lisberger SG. Partial ablations of the flocculus and ventral paraflocculus in monkeys cause linked deficits in smooth pursuit eye movements and adaptive modification of the VOR. J Neurophysiol 2002b; 87: 912–24.
Ritchie L. Effects of cerebellar lesions on saccadic eye movements. J Neurophysiol 1976; 39: 1246–56.
Robinson FR, Brettler SC. Smooth pursuit properties of neurons in the ventrolateral posterior interpositus nucleus of the monkey cerebellum [abstract]. Soc Neurosci Abstr 1998; 24: 1405.
Robinson FR, Straube A, Fuchs AF. Role of the caudal fastigial nucleus in saccade generation. II. Effects of muscimol inactivation. J Neurophysiol 1993; 70: 1741–58.
Robinson FR, Straube A, Fuchs AF. Participation of caudal fastigial nucleus in smooth pursuit eye movements. II. Effects of muscimol inactivation. J Neurophysiol 1997; 78: 848–59.
Ron S, Robinson DA. Eye movements evoked by cerebellar stimulation in the alert monkey. J Neurophysiol 1973; 36: 1004–22.
Sato H, Noda H. Saccadic dysmetria induced by transient functional decortication of the cerebellar vermis. Exp Brain Res 1992; 88: 455–8.[CrossRef][Web of Science][Medline]
Schrader V, Koenig E, Dichgans J. Direction and angle of active head tilts influencing the Purkinje effect and the inhibition of postrotatory nystagmus I and II. Acta Otolaryngol 1985; 100: 337–43.[Medline]
Singer C, Sanchez-Ramos J, Weiner WJ. Gait abnormality in essential tremor. Mov Disord 1994; 9: 193–6.[CrossRef][Web of Science][Medline]
Stone LS, Lisberger SG. Visual responses of Purkinje cells in the cerebellar flocculus during smooth-pursuit eye movements in monkeys. II. Complex spikes. J Neurophysiol 1990; 63: 1262–75.
Stolze H, Petersen G, Raethjen J, Wenzelburger R, Deuschl G. The gait disorder of advanced essential tremor. Brain 2001; 124: 2278–86.
Straube A, Scheuerer W, Eggert T. Unilateral cerebellar lesions affect initiation of ipsilateral smooth pursuit eye movements in humans. Ann Neurol 1997a; 42: 891–8.[CrossRef][Web of Science][Medline]
Straube A, Scheuerer W, Eggert T. Target velocity and age influence the initial smooth pursuit response in humans. Neuro-ophthalmology 1997b; 18: 191–8.
Suzuki DA, Keller EL. The role of the posterior vermis of monkey cerebellum in smooth-pursuit eye movement control. II. Target velocity-related Purkinje cell activity. J Neurophysiol 1988; 59: 19–40.
Takagi M, Zee DS, Tamargo RJ. Effects of lesions of the oculomotor vermis on eye movements in primate: saccades. J Neurophysiol 1998; 80: 1911–31.
Takagi M, Zee DS, Tamargo RJ. Effects of lesions of the oculomotor cerebellar vermis on eye movements in primate: smooth pursuit. J Neurophysiol 2000; 83: 2047–62.
Vahedi K, Rivaud S, Amarenco P, Pierrot-Deseilligny C. Horizontal eye movement disorders after posterior vermis infarctions. J Neurol Neurosurg Psychiatry 1995; 58: 91–4.
Waespe W, Cohen B, Raphan T. Dynamic modification of the vestibulo-ocular reflex by the nodulus and uvula. Science 1985; 228: 199–202.
Wessel K, Moschner C, Wandinger KP, Kompf D, Heide W. Oculomotor testing in the differential diagnosis of degenerative ataxic disorders. Arch Neurol 1998; 55: 949–56.
Westheimer G, Blair SM. Functional organization of primate oculomotor system revealed by cerebellectomy. Exp Brain Res 1974; 21: 463–72.[Web of Science][Medline]
Wills AJ, Jenkins IH, Thompson PD, Findley LJ, Brooks DJ. Red nuclear and cerebellar but no olivary activation associated with essential tremor: a positron emission tomographic study. Ann Neurol 1994; 36: 636–42.[CrossRef][Web of Science][Medline]
Wilms H, Sievers J, Deuschl G. Animal models of tremor. Mov Disord 1999; 14: 557–71.[CrossRef][Web of Science][Medline]
Zackowski KM, Bastian AJ, Hakimian S, Mink JW, Perlmutter JS, Koller WC, et al. Thalamic stimulation reduces essential tremor but not the delayed antagonist muscle timing. Neurology 2002; 58: 402–10.
Zee DS, Yee RD, Cogan DG, Robinson DA, Engel WK. Ocular motor abnormalities in hereditary cerebellar ataxia. Brain 1976; 99: 207–34.
Zee DS, Yamazaki A, Butler PH, Gucer G. Effects of ablation of flocculus and paraflocculus of eye movements in primate. J Neurophysiol 1981; 46: 878–99.
Zeuner KE, Molloy FM, Shoge RO, Goldstein SR, Wesley R, Hallett M. Effect of alcohol on the central oscillator in essential tremor [abstract]. Neurology 2002; 58 Suppl 3: A219.
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 F. B Nahab, E. Peckham, and M. Hallett Essential tremor, deceptively simple ... Practical Neurology, August 1, 2007; 7(4): 222 - 233. [Abstract] [Full Text] [PDF]
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M. Kronenbuerger, M. Gerwig, B. Brol, F. Block, and D. Timmann Eyeblink conditioning is impaired in subjects with essential tremor Brain, June 1, 2007; 130(6): 1538 - 1551. [Abstract] [Full Text] [PDF]
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C. Daniels, M. Peller, S. Wolff, K. Alfke, K. Witt, C. Gaser, O. Jansen, H. R. Siebner, and G. Deuschl Voxel-based morphometry shows no decreases in cerebellar gray matter volume in essential tremor Neurology, October 24, 2006; 67(8): 1452 - 1456. [Abstract] [Full Text] [PDF]
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A. Shatunov, N. Sambuughin, J. Jankovic, R. Elble, H. S. Lee, A. B. Singleton, A. Dagvadorj, J. Ji, Y. Zhang, V. E. Kimonis, et al. Genomewide scans in North American families reveal genetic linkage of essential tremor to a region on chromosome 6p23 Brain, September 1, 2006; 129(9): 2318 - 2331. [Abstract] [Full Text] [PDF]
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S. Klebe, H. Stolze, K. Grensing, J. Volkmann, R. Wenzelburger, and G. Deuschl Influence of alcohol on gait in patients with essential tremor Neurology, July 12, 2005; 65(1): 96 - 101. [Abstract] [Full Text] [PDF]
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G. F. Molnar, A. Sailer, C. A. Gunraj, D. I. Cunic, A. E. Lang, A. M. Lozano, E. Moro, and R. Chen Changes in cortical excitability with thalamic deep brain stimulation Neurology, June 14, 2005; 64(11): 1913 - 1919. [Abstract] [Full Text] [PDF]
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