Journal of Neural Transmission

Eye movement study in essential tremor patients and its clinical correlates
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Manuscript Number: JONT-D-23-00005

Full Title: Eye movement study in essential tremor patients and its clinical correlates

Article Type: Original Article

Keywords: Essential tremor; Eye movement; Cognition; Cerebellum

Abstract: Background: Essential tremor(ET) encompasses a wide spectrum of motor and non-
motor features. Eye movement abnormalities were first reported two decades ago as
an atypical finding in ET. Today, a growing number of publications about eye
movement abnormalities in neurodegenerative diseases helped understand their
pathophysiology and the basis of their phenotypic variability. Thus, addressing such
aspect in ET may disentangle, based on the oculomotor network abnormalities, the
dysfunctional brain pathways in ET. In this study, we aimed to describe
neurophysiological eye movement abnormalities in ET and their clinical correlates in
terms of cognition and other associated clinical signs.
Methods: We conducted a cross-sectional study in a tertiary Neurology referral center
including consecutive ET patients and cognitively-normal healthy controls(HC)
matched for age and sex. The study protocol included the assessment of voluntary
horizontal saccades, smooth pursuit, anti-saccades and saccadic intrusions. We
assessed the associated motor signs, cognitive functions and the presence of rapid
eye movement disorder(RBD).
Results: Sixty-two ET patients and 66 HC were enrolled in the study. Eye movement
examination showed significant abnormalities in comparison with
HC(46.7%vs.20%,p=0.002). Prolonged saccadic latency(38.7%, p=0.033) and altered
smooth pursuit(38.7%, p=0.033) were the most common abnormalities in ET patients.
Anti-saccadic errors(16% vs 0% in HC,p=0.034) correlated with the presence of
rigidity(p=0.046), bradykinesia(p=0.001), cognitive dysfunction(p=0.006), executive
dysfunction(p=0.0002), apraxia(p=0.0001), altered verbal fluency(p=0.013) and altered
backward digit span(p=0.045) along with the presence of RBD(p=0.035). Square wave
jerks(11.5% vs 0% in HC,p=0.0024) correlated with rest tremor.
Conclusion: A distinctive phenotype of ET could emerge out of this study characterized
by anti-saccadic errors and a sub-cortical cognitive profile, consecutive to the
disruption of the cerebello-thalamo-cortical loop. Patients with anti-saccadic errors
could be cognitively vulnerable and in need of a close monitoring of their cognitive
efficiency during disease progression. They may as well convert to Parkinson disease
if they present with parkinsonism, RBD and square wave jerks and require,
consequently, a close observation on their motor progression.

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Eye movement study in essential tremor patients and its clinical correlates

Arwa Rekik1, Saloua Mrabet123, Amina Nasri123, Youssef Abida1, Alya Gharbi123, Amina Gargouri123, Imen Kacem123,
Riadh Gouider123

Authors affiliations:

1: Neurology Department, LR18SP03, Razi University Hospital, 1 rue des orangers Manouba, 2010, Tunis, Tunisia

2: Clinical Investigation Center (CIC) “Neurosciences and Mental Health”, Razi University Hospital, 1 rue des orangers
Manouba, 2010, Tunis, Tunisia

3: Faculty of Medicine of Tunis, University of Tunis El Manar, 15, Rue Djebel Akhdhar, La Rabta, 1007, Tunis, Tunisia

*Corresponding author: Department of Neurology, Razi University Hospital, 1 rue des orangers Manouba, PC: 2010;
Tunis-Tunisia

Tel: +216 70 162 243

Fax: +216 71 601 300

E-mail: riadh.gouider@gnet.tn

ORCID : https://orcid.org/. 0000-0001-9615-3797.

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Abstract :

Background: Essential tremor(ET) encompasses a wide spectrum of motor and non-motor features. Eye movement
abnormalities were first reported two decades ago as an atypical finding in ET. Today, a growing number of publications
about eye movement abnormalities in neurodegenerative diseases helped understand their pathophysiology and the basis
of their phenotypic variability. Thus, addressing such aspect in ET may disentangle, based on the oculomotor network
abnormalities, the dysfunctional brain pathways in ET. In this study, we aimed to describe neurophysiological eye
movement abnormalities in ET and their clinical correlates in terms of cognition and other associated clinical signs.

Methods: We conducted a cross-sectional study in a tertiary Neurology referral center including consecutive ET patients
and cognitively-normal healthy controls(HC) matched for age and sex. The study protocol included the assessment of
voluntary horizontal saccades, smooth pursuit, anti-saccades and saccadic intrusions. We assessed the associated motor
signs, cognitive functions and the presence of rapid eye movement disorder(RBD).

Results: Sixty-two ET patients and 66 HC were enrolled in the study. Eye movement examination showed significant
abnormalities in comparison with HC(46.7%vs.20%,p=0.002). Prolonged saccadic latency(38.7%, p=0.033) and altered
smooth pursuit(38.7%, p=0.033) were the most common abnormalities in ET patients. Anti-saccadic errors(16% vs 0%
in HC,p=0.034) correlated with the presence of rigidity(p=0.046), bradykinesia(p=0.001), cognitive
dysfunction(p=0.006), executive dysfunction(p=0.0002), apraxia(p=0.0001), altered verbal fluency(p=0.013) and altered
backward digit span(p=0.045) along with the presence of RBD(p=0.035). Square wave jerks(11.5% vs 0% in
HC,p=0.0024) correlated with rest tremor.

Conclusion: A distinctive phenotype of ET could emerge out of this study characterized by anti-saccadic errors and a
sub-cortical cognitive profile, consecutive to the disruption of the cerebello-thalamo-cortical loop. Patients with anti-
saccadic errors could be cognitively vulnerable and in need of a close monitoring of their cognitive efficiency during
disease progression. They may as well convert to Parkinson disease if they present with parkinsonism, RBD and square
wave jerks and require, consequently, a close observation on their motor progression.

Keywords: Essential tremor, Eye movement, Cognition, Cerebellum

Statements and Declarations

No funds, grants, or other support was received.

The authors have no relevant financial or non-financial interests to disclose.

No conflicts of interest to declare.

Acknowledgments: None.

Data availability statement

Data will be made available on a reasonable request.

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Introduction
Essential tremor (ET), this reputed monosymptomatic disease (Dana CL 1887), has been put under the microscope during
the last decade only to recognize its complexity and phenotypic variability that goes beyond the isolated upper limb
bilateral action tremor misconception (Bhatia et al. 2018). Today, progress regarding its pathophysiological process has
been accomplished and ET is considered as a cerebellum pathology (Benito-León et al. 2016; Louis 2016; Marin-Lahoz
and Gironell 2016). Pinpointing its origin helped to digest the variety of additional motor signs associated to this disease
such as gait ataxia, dysmetria, eye movement abnormalities and non-motor symptoms such as cognitive impairment
(Bermejo-Pareja et al. 2012; Helmchen et al. 2003; Louis et al. 2010). Studies investigating the characteristics of eye
movements in ET, looking to understand the physiopathological basis for such clinical diversity and linking different
signs to each other are mostly lacking. However, such links have been established in other neurodegenerative diseases
such as Alzheimer’s disease (AD) where eye movement abnormalities were identified as a valuable tool to reflect the
cognitive burden of the disease (Heuer et al. 2013). Eye movement abnormalities in Parkinson’s disease (PD) and
idiopathic rapid eye movement disorder (iRBD) had also turned out to be a marker of cognitive impairment and disease
severity (Hanuška et al. 2019).

Eye movement network includes a range of cortical and sub-cortical regions where the cerebellum plays a crucial role
(Beh et al. 2017). Thus, by investigating the link between altered eye movements and clinical features, we can point out
the defective regions of this pathway and further fathom the pathophysiology of ET. Characterizing the pattern of eye
movement abnormalities and its associated clinical signs could also represent a potential fingerprint of a specific
phenotype of the disease. In this context, we aimed to describe the peculiarities of eye movement abnormalities in ET as
compared to healthy controls (HC) and to investigate their correlates in terms of cognition and other associated motor
signs.

Materials and methods

 Study population

We included patients presenting with ET-syndrome and ET-plus syndrome as defined in the latest classification of tremor
published in 2018 by the Task force on Tremors of the International Parkinson and Movement Disorder Society (Bhatia
et al. 2018). Patients who developed Parkinson’s disease (PD), as defined by the Movement disorder society (MDS)
criteria published in 2015 (Postuma et al. 2015), during their disease course were excluded from the study. Taking into
account the current classification of tremors (Bhatia et al. 2018), we also excluded patients with: isolated focal tremors
(voice, head), orthostatic tremor, task- and position-specific tremors and sudden onset and step-wise deterioration. We,
as well, excluded patients treated with benzodiazepines or anti-psychotics that may potentially impact eye movement
recording (Glue 1991; Reilly et al. 2008).

We included cognitively-normal HC who were matched in age and gender and had no significant medical history.

 Study protocol

We noted the socio-demographic features along with the findings of the initial neurological examination including tremor
characteristics including its severity assessed using the Fahn-Tolosa-Marin rating scale (FTM-RS), and the associated
motor signs: bradykinesia, rest tremor, rigidity, postural instability, parkinsonism, myoclonus, dystonia, ataxia and

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dysmetria. We used the unified Parkinson’s disease rating scale Part III (UPDRS-III) to assess parkinsonism when present.

Each patient underwent a neuropsychological examination at first consultation. This examination comprised the 30-item
standardized validated Tunisian version of the mini-mental state examination (MMSE) adjusted according to age and
educational level to assess overall cognitive efficiency (Ben Jemaa et al. 2017). According to the Diagnostic and Statistical
Manual of Mental Disorders (DSM V), we defined cognitive dysfunction by the presence of cognitive complaint
expressed by the patient or one of the caregivers along with the presence of one altered cognitive domain during the
cognitive assessment conducted by the examiner, leading to a noticeable decrement in cognitive functioning that goes
beyond normal changes seen in aging. Based on the DSM V criteria, they were classified into patients either with minor
cognitive impairment (MCI) or with major neurocognitive impairment or dementia.

The evaluation of executive functions was based on the frontal assessment battery (FAB) where a score less than 16 was
considered abnormal. Episodic memory was assessed with the Free and Cued Selective Reminding Test (FCSRT) of
Grober & Buschke. Visuo-spatial functions were evaluated using the Clock-Drawing Test. Apraxia assessment protocol
was extracted from the corresponding section of the Modular evaluation of occupational therapy (Kalfat et al. 2003).Time
and space orientation were assessed based of the first part of the MMSE score. For judgement capacities, we used the
situational judgement test, while reasoning capacities were assessed with proverb interpretation and similarities section
of the FAB for abstract reasoning.

We also used the RBD-screening questionnaire to look for Rapid eye movement sleep behavior disorder (RBD).

 Eye Movement Recording technique and normative values for eye movement study interpretation

Eye movements were recorded monocularly, using infrared video-oculography and Ulmer’s program for video-
nystagmography performed in a quiet, dark room. All participants underwent a standardized evaluation by a single skilled
neuro-ophtalmologist who was kept uninformed of the diagnosis. The patient was seated with the head fixed, at a distance
of 75 cm from a television screen. The eye movements were recorded in the horizontal plane to assess smooth pursuits,
voluntary saccadic latencies and anti-saccadic tasks. All records were visually inspected for quality assurance. Eye
movement during smooth pursuit was evoked by a white spot moving sinusoidally across the screen horizontally (less
than 10° per second). To study saccades, we used the zero-gap method. The subjects were instructed to fixate the central
point and the eccentric target, as accurately and as fast as possible (Rekik, et al. 2022).

Concerning normative values for oculomotor findings interpretation, we used our previously validated normative values,
laboratory and device-specific, distinctive of our Tunisian population in order to avoid any potential biases (Rekik et al.
2022). Regarding anti-saccades, we calculated the rate of errors in comparison with the total recorded trials and were
considered altered when the error rate exceeded 10%. Latencies of the voluntary horizontal saccades were noted for all
subjects and evaluated using a normal cut-off value of 300 ms. We also measured the peak eye velocity of saccade of 20°
and the gain defined as the amplitude of the primary saccade divided by the amplitude of the target step saccade for each
eye. A gain value equal to 1 means that the eye in movement met the target perfectly. Saccades were considered
hypometric if gain was less than 0.7 and hypermetric if it exceeded 1.1 (Bucci et al. 2009; Kang and Kim 2015; Sinno et
al. 2019). However, in order to discriminate hypometria/hypermetria as pathological features, these morphological
abnormalities need to be repetitive and consistent since they may occur in normal individuals. Consequently, prolonged

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latency of saccadic eye movement remains the key criterion to define abnormal voluntary saccades in our study.

Regarding smooth pursuit, it was evaluated visually based on the accordance of its morphology with the reference line.
Morphology of smooth pursuits is one among the validated criteria for their assessment, in addition to gain and left–right
asymmetry. We also noted the presence of saccadic intrusions, particularly the presence of square waves jerks (SWJ). We
defined a SWJ as the combination of one small saccade that moves the eye away from the fixation target, followed after
a short period by a second corrective saccade ‘a catch-up saccade’ directed back towards the target (Leigh and Zee 2015).

 Statistical analysis

For categorical variables; we calculated frequencies. As for quantitative variables, we determined mean score (median if
variable was not normally distributed), standard deviation (inter-quartile deviation if variable was not normally
distributed) and minimum and maximum of each variable. Statistical analyses were performed using SPSS (version 22;
Chicago, IL, USA). When categorical variables were normally distributed, we used chi-square test to compare
percentages. When the size of the population of study was less than 5, we used Fisher’s Test. For comparison between
categorical and quantitative variables, we used one-way analysis of variance (ANOVA). Pearson’s correlation coefficient
was used to compare the mean values of two quantitative variables (Spearman test if variable were not normally
distributed). For parameters that were not normally distributed, non-parametric approaches were used (Kruskal–Wallis
test). The Pearson correlation coefficient, r, was indicative of the degree of correlation: 0 indicated a positive association;
that is, as the value of one variable increases, so does the value of the other variable. A p-value less than 0.05 was
considered statistically significant in all of the different adopted statistical tests.

 Ethics

All subject investigations conformed to the principles outlined in the Declaration of Helsinki and have been performed
with permission of the Razi hospital ethic committee.

Results

 Clinical characteristics of the study population

Sixty-two ET patients were included in the study with a sex-ratio equal to 1.4. Mean age of onset of tremor was 54.8±16
years [20-75]. Mean age of patients by the time they were enrolled in the study for eye movement examination was 65±13
years [22-85] with mean disease duration of 11.8±13 years.

On initial examination, mean total FTM-RS was equal to 30.6±45 points. We noted the presence of associated motor
signs other than tremor: dystonia (6 cases), rest tremor (18 cases), bradykinesia (10 cases), rigidity (6 cases) and 2 cases
of postural instability. Mean UPDRS-III among the six patients presenting with parkinsonism was equal to 19.7±14 points
[9; 36]. However, we did not note gait ataxia, dysmetria or myoclonus among our population of study.

Regarding cognitive functions, cognitive impairment was present in 58% of cases. Fourteen patients (22.6%) presented
with dementia (mild to moderate stages) and twenty-two (35.5%) had MCI. Mean MMSE score was 27±3 points [18-
30]. Hallmark features of the cognitive profile were: impaired attention (53.6%), episodic memory impairment (42.5%)
and executive dysfunction (42%) with mean FAB score equal to14.4±4 points [3-16]. Altered verbal fluency was noted

5
in 26% of cases. Working memory was altered among 21% of our patients. Apraxia was present in 16 patients (25.8%).
Time and space disorientation were noted in 10 and 6 patients consecutively. RBD were present in 19% of cases.

 Findings of neurophysiological study of eye movements in ET patients versus healthy controls

In addition to our ET patients, 66 HC matched for age and sex were included for the neurophysiological study of eye
movements. Overall, abnormalities in eye movement recordings were found in 46.7% of cases in ET patients and 20% of
HC (p=0.002). The comparison between the different eye movement parameters (gain, voluntary horizontal saccades
latencies, smooth pursuit, anti-saccadic error rates) in both groups is outlined in Table 1.

Table 1: Eye movement examination findings among ET patients and healthy controls

Parameters ET patients Healthy p value

(N=62) controls
(N=66)
Age (years) 65±13 58±15 0.097
Gender (Male: Female) (n) (36:26) (28:38) 0.11
Altered eye movement examination (%, (n)) 46.7, (29) 20 (14) 0.002
Horizontal voluntary saccades
Mean voluntary horizontal saccades Right 319±64 280+42 0.0003
latencies (msec) Left 317±99 250+50 0.0006
Prolonged latency (%, (n)) 38.7, (24) 19(13) 0.033
Gain of voluntary horizontal saccades Right 0.65±0.25 0.96±0.32 0.046
Left 0.57±0.2 0.98±0.73 0.035
Hypometria (%, (n)) 74.2, (46) 6, (4) 0.001
Hypermetria (%, (n)) 6, (4) 3, (2) 0.098
Smooth pursuit
Altered smooth pursuit (%, (n)) 38.7, (24) 19, (13) 0.033
Anti-saccades
Anti-saccadic error rate 12.6±3 5±3 0.023
Alerted anti-saccades (%, (n)) 16, (10) 0, (0) 0.034
Saccadic intrusions
Square-wave jerks (%, (n)) 11.5 (7) 0 0.024

Among the ET group, the study of horizontal voluntary saccades showed prolonged latency in 38.7% of our patients
versus 19% in HC (p=0.033). Hypometric saccades were noted among 74.2% of ET patients versus 6% of HC (p=0,001).
Hypermetria was less frequent, noted among 4 patients only and showed no statistically significant difference in
comparison with HC (p=0.098) (Fig.1). The horizontal smooth pursuit was abnormal in 38.7% of ET cases versus 19%
of HC (p=0.033) (Fig. 2). We noted the presence of square waves in 11.5% of ET cases assessed during the voluntary
horizontal saccades task with a multiple step pattern, yet none of the HC showed square waves on eye movement
recordings (p=0.024) (Fig.3). Altered anti-saccades were observed in 16% of our ET patients (mean error rate equal to
12.6±3 errors/minute) and none of HC (p=0.034) (Fig.4) (Table 1).

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 Fig.1 Voluntary horizontal saccades study: The green blackline is the target reference curve and the red line
represents actual eye movement. (a) Normal saccades in a 57-year-old healthy control. (b) Horizontal saccades study in
a 60-year-old ET patient illustrating prolonged latency as the interval colored in light yellow separating the initiation of
target movement and the eye movement of the patient. (c) Solid black arrows point out hypometric saccades followed
by corrective saccade which colored in light blue in a 63-year-old ET patient. (d) Dotted black arrows shows
hypermetric saccades in a 68-year-old ET patient.

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Fig.2 Smoot pursuit study: The green blackline is the target reference curve; the red line is right actual eye movement
and the blue line corresponding to the left eye. (a) Normal smooth pursuit in a 58-year-old healthy control. (b) Altered
smooth pursuit in a 64-year-old ET patient more marked within the left eye. We also note the presence of saccade
intrusions while tracking the target as illustrated by the solid black arrows.

Fig.3 The green blackline is the target reference curve, and the red line is right actual eye movement. Solid black arrows
pinpoint the multiple step pattern characterizing square wave jerks during the horizontal eye movement tracking in a 69-
year-old ET patient.

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 Fig.4 Anti-saccades study. The green blackline is the target reference curve, and the red line is the actual eye
movement. Solid arrows in green and red show opposed correct eye movement in comparison with the moving target.
Dark red dotted arrows illustrate anti-saccadic errors. (a) A 65-year-old healthy control with normal error-free anti-
saccades. (b) A 62-year-old ET patient with two anti-saccadic errors as pinpointed by the dotted dark red arrows. The
blue circles represent saccadic intrusions corresponding to macro-square wave jerks.

 Clinical correlates of neurophysiological study of eye movements in ET patients

Eye movement abnormalities did not correlate with gender, age or disease’s duration. As illustrated in Fig.5, the presence
of anti-saccadic errors correlated with extrapyramidal signs such as bradykinesia (p=0.001) and rigidity (p=0.046). It was
also correlated with MMSE (p=0.006) and FAB (p=0.0002) scores along with the presence of apraxia (p=0.0001), altered
verbal fluency (p=0.013) and altered backward digit span (p=0.045). We noted that RBD were also associated with anti-
saccadic errors (p=0.035), as well as hypometric (p=0.022) and hypermetric (p=0.035) saccades. Square waves were
associated with the presence of rest tremor (p=0.011). No significant correlations were noted regarding prolonged
saccades latency or altered smooth pursuit.

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 Fig.5 Heatmap showing correlations (p value) of eye movement abnormalities in ET with clinical features, altered
cognitive domains and presence of RBD.

Discussion
To our knowledge, only a few studies had investigated eye movements in ET and they have shown dissimilar findings
(Table 2). Our study is the first to investigate the correlates of eye movement abnormalities in terms of associated motor
signs, cognitive dysfunction, and the presence of RBD. It is the second in literature to study anti-saccadic errors in ET as
well.

Our study showed the highest rate so far (46.7%) of abnormal findings on neurophysiological eye movement recordings
in ET. This could be explained by the protocol we used combining different eye movement parameters. It is noteworthy
to pinpoint that all of the oculomotor measures were independent of disease duration, tremor severity, gender and
comorbidities which is in line with all previously conducted studies (Helmchen et al. 2003; Trillenberg et al. 2006; Yerram
et al. 2013).

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 Table 2: A summary of studies protocols and eye movement examination findings in previously conducted research including ET patients and in our study

Main author Population of study Methodology of eye Smooth pursuit Anti- Saccadic eye movement Square
[year of movement evaluation saccades waves
publication]
Helmchen el al. 17 ET patients: ET- Smooth pursuit (latency, eye Altered in ET NA -Normal saccadic gain. NA
(2003) postural tremor (ET-PT) acceleration velocity) patients/ HC.
and ET-Intentional Voluntary saccades (latency, Altered in ET-IT /
tremor (ET-IT) gain) ET-PT.
Trillenberg et 12 ET patients vs. HC Voluntary saccades (latency, NA NA Normal saccadic gain and NA
al (2006) velocity and gain) latency.

George T. 60 ET patients vs. HC Reflexive saccades (latency, NA NA Slow peak velocities and Increased
Gitchel et al gain, velocity) prolonged latency of reflexive frequency
(2013) Square waves saccades. among ET
Normal saccadic gain patients
(25%)
F. Visser et al. 50 ET patients: Anti-saccades (latency and Reduced gain in ET Error rate Prolonged latency of voluntary NA
(2019) ET-cerebellar; rate of errors) patients ( = 48% saccades among ET patients with
ET-parkinsonism; Smooth pursuit (gain) ET-parkinsonism) cerebellar signs.
ET-mixed Voluntary, reflexive and Normal saccadic gain compared
vs. HC cued saccades (latency) to HC.

Dysmetria in 40% (76%

hypometric saccades, 24%
hypermetric)
Our study 62 ET patients Voluntary Saccades (latency, Altered (38.7%) Altered Prolonged latency (37.8%) Present in
vs. 66 HC gain) (16%) 11.5%
Smooth pursuit Hypometria: 74.2%
Anti-saccades Hypermetria 6%
Saccadic Intrusions
NA: not available; HC: healthy controls

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In contrast with our findings, Helmchen el al. (Helmchen et al. 2003) and Trillenberg et al. (Trillenberg et al. 2006)
demonstrated that voluntary saccades were normal in ET. However, the relatively small size of these previous studies
samples (17 and 12 patients respectively) and the focus on one unique feature of eye movement study, which is the
gain, could explain these discrepancies. Gitchel et al. study described prolonged latencies of reflexive saccades.
However, it was the recent work conducted by F. Visser et al. that demonstrated prolonged latency of voluntary
saccades in ET patients presenting with cerebellar signs (Visser et al. 2019). Prolonged latency of voluntary saccades
was one of the most common eye movement abnormalities among our ET patients. Yet, none presented with cerebellar
features which implies that such eye movement abnormality does characterize ET patients in general and not just those
with clinically patent cerebellar signs. In our analysis of clinical correlates, prolonged saccades latency was not
associated with any clinical feature assessed in our study. Yet, interestingly, the rate of hypometric saccades exceeded
that reported in literature and was correlated with the presence of RBD (p=0.022). This correlation with RBD was also
noted for hypermetric saccades (p=0.035) (Table 2). (Fig.5). RBD is an established marker of synucleinopathy with
Lewy-body-pathology invading the brainstem and mainly the locus cœruleus (LC) (Dauvilliers 2021). It is in the light
of recent research that we do acknowledge that patients presenting with iRBD do not only present with structural
changes of the brainstem including the LC but also with a remarkable atrophy of the cerebellum (Boucetta et al. 2016).
This link gathering both RBD and cerebellar diseases has been intrigued by the findings of the neuropathology in ET
dichotomizing ET patients into two categories: those with prominent cerebellar degeneration and those with Lewy
body pathology affecting the brainstem in a selective pattern (Louis and Vonsattel 2008). However, this dichotomy
isn’t that sharp since on a functional level, the main efferent connections of the LC are directed towards Purkinje cells
helping to maintain their inhibitory output (Moises et al. 1981; Moises and Woodward 1980; Y Wang et al. 1999)
.Thus, we may speculate that the alteration of the brainstem among ET patients presenting with RBD does affect the
function of Purkinje cells manifesting clinically with dysmetria of the eyes combining both under and overshooting
(hypo/hypermetria).

Regarding the network controlling voluntary saccades, it is initiated by the frontal eye fields (FEF) and the parietal eye
fields (PEF), implicating the cerebellum under the control of the substantia nigra (SN), then projections to the caudate
nucleus and the cortical eye fields constituting the cerebello-thalamo-cortical loop (Fig.6). Having altered saccades in
ET with a prolonged latency reflects a dysfunction in the initiation process generated mainly by the frontal cortex and
a dysfunction in the adaptive process implied by the cerebellum. Since both cerebellum and frontal eye field are linked
via the cerebello-thalamo-cortical loop, they work in synergy and could be both inculpated once the eye saccades are
dysfunctional.

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Fig.6 A representation of the network controlling saccadic eye movement including the cerebellum. The network
controlling voluntary saccades is initiated by the frontal eye fields (FEF) and the parietal eye fields (PEF). Following
the visual target identification, an excitatory signal from both FEF and PEF is directly transmitted to the superior
colliculus then to the brainstem generating orientated well-measured saccadic eye movements. Thus, defective saccade
initiation is due to a dysfunction of frontal eye fields. The cerebellum also represents a major web in the saccadic eye
movement network and do receive input from the cortical eye fields and premotor burst-neurons in the brainstem. This
pathway is subject to control by the substantia nigra (SN) which inhibits the superior colliculus (SC) with a tonic
discharge of GABA inhibiting as a consequence the brainstem saccade-generator and the cerebellum (the oculomotor
vermis (OMV) and CFN specifically). The saccadic control is also managed by the dorsolateral prefrontal cortex
through projections to the caudate nucleus and the cortical eye fields. The cerebellum in return projects efferent back
to the cortical eye fields (via the thalamus) and SC via the cerebello-thalamo-cortical loop.

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Similar to our study, Helmchen el al.(Helmchen et al. 2003) and Visser et al. (Visser et al. 2019) demonstrated that
smooth pursuit was altered among ET patients. Smooth movements are based on a cerebro-ponto-cerebellar pathway.
Cortical regions are considered as the generators of the pursuit movement realizing the starting point of a network. The
final destination of this pathway is the cerebellum targeting specific regions including the flocculus-paraflocculus
complex, the OMV and the CFN. Its role remains crucial in the smooth eye tracking of a moving target. Such statement
is further supported by the fact that complete cerebellectomy abolishes smooth pursuit in humans and monkeys (Leigh
and Zee 2015). Furthermore, the frontal lobe is as well implicated via the FEF which encode the pursuit trajectories
and predict it (Leigh and Zee 2015).Thus, having altered smooth pursuit as a main finding of abnormal eye movements
in ET (38.7%) is not surprising since it encompasses the cerebellum dysfunction. Yet, here again, there were no
significant clinical correlates of altered smooth pursuit in our ET patients.

The most interesting clinical correlations were found with anti-saccades in ET patients. Indeed, Visser et al. reported
an error rate of 48% without defining a cut-off value for abnormal anti-saccades. In our study, anti-saccades were
considered abnormal if error rate exceeded 10%. The disparity of results interpretation makes both studies
incomparable. Yet, we demonstrated that anti-saccades abnormality was associated with poorer performance during
both FAB and MMSE assessment, presence of apraxia and with multi-domain MCI. In fact, anti-saccades are
increasingly becoming a valuable tool to assess cognitive dysfunction and mainly executive dysfunction in various
neurological and psychiatric disorders (Yerram et al. 2013). Heuer et al. demonstrated that anti-saccades task is a useful
measure of executive function across the AD spectrum (Heuer et al. 2013). Additionally, they stated that anti-saccade
performance during MCI may reflect disease burden within cortical brain regions involved in oculomotor control,
mainly the frontal lobe which lines with our results and do confirm again the frontal dysfunction in ET. Although much
less is known of the neurophysiology of anti-saccades, according to Evdokimidis I. el al (Evdokimidis et al. 1996), it
is mainly due to the failure of the dorsolateral prefrontal cortex which is responsible for the inhibition of the unwanted
reflexive saccades. Impaired performance in anti-saccades has also been associated with the posterior parietal cortex
(Ouerfelli-Ethier et al. 2021) which explains the correlation of anti-saccadic abnormality with apraxia in our study.
Regarding the correlation of altered anti-saccades with RBD in our study, Hanuška et al. compared the rate of error of
anti-saccades between three groups of patients: patients with idiopathic RBD (iRBD), treatment-naïve patients with
early PD and healthy controls (Hanuška et al. 2019). They found an increased error rate in the anti-saccade task in both
PD and iRBD patients, compared with controls. Additionally, altered anti-saccades within these groups were correlated
with Montreal cognitive assessment score (MoCA) (p = 0.03) which is in accordance with our findings showing
significant correlations of anti-saccadic errors with MMSE score (Fig. 5). The high anti-saccadic error rate in iRBD
was considered as a reflection of prefrontal cortex dysfunction.

Regarding ET, Wang XX. et al. demonstrated in his recently published article that the presence of RBD could be
considered as a prodromal marker of synucleinopathy and potential risk factor of conversion to PD (Wang et al. 2020).
Thus, we can speculate that observed altered anti-saccades in ET in association with RBD could represent a potential
marker of underlying synucleinopathy. This hypothesis is further supported by the established correlations between

14
bradykinesia and rigidity and anti-saccadic errors in our study. However, we did not note significant correlations of
altered anti-saccades with the UPDRS-III score (p=0.142).

In summary, we hypothesize that anti-saccadic errors might correspond to early prefrontal and parietal cortex
involvement in ET patients. This observation may be corroborated by correlations with the results of
neuropsychological testing. It is also suggested as a potential indicator of underlying alpha-synucleinopathy.

Regarding SWJ, Gitchel et al. were the first to state increased frequency of such abnormality (25%) among ET patients,
which is higher than the rate reported in our study (11.5%). Both rates were higher than the frequency of SWJ in
healthy controls ranging from 2 to 5.6% (Gitchel et al. 2013). Such feature represents a prominent sign in certain
cerebellar disorders such as Friedreich ataxia and spinocerebellar ataxia 8. It represents also a hallmark feature of
dementia-parkinsonian syndromes such as progressive supranuclear palsy and Parkinson’s disease dimentia, which
might explain, consequently, the correlation of SWJ with the presence of rest tremor in our study (Otero-Millan et al.
2013). While the precise physiopathological basis is unclear, some have suggested that a dysfunctional inhibitory
system, including the cerebellum, might be responsible of such finding supporting the presumed cerebellar pathology
in ET (Gitchel et al. 2013).

The findings of our study have to be seen in light of some limitations. Our study is cross-sectional reflecting little about
the chronology of developing eye movement abnormalities and cognitive dysfunction. Even though we established
that the common dominator of eye movement abnormalities in ET is the cerebellum pathology, none of our patients
presented with clinical cerebellar signs. Regarding eye movements parameters, the pathological character of
hypometria was not clearly established since its frequency was not precisely established.

Conclusions

Essential tremor remains an umbrella term encompassing a multitude of clinically heterogeneous features. A distinctive
phenotype of ET could emerge out of this study characterized by the presence of eye movement abnormalities and sub-
cortical cognitive profile advancing further our understanding of frontal dysfunction in ET consecutive to the disruption
of the cerebello-thalamo-cortical loop. Patients with anti-saccadic errors could be cognitively vulnerable and in need
of a close monitoring of their cognitive efficiency during the disease’s progression. They may as well convert to PD if
they present with parkinsonism, RBD and square wave jerks and require, consequently, a close observation on their
motor progression. The presence of eye movement abnormalities remains fully embedded in the neuropathological
process of ET centered on cerebellar dysfunction. The alteration of the cerebellar connections with the cortical fields
including the prefrontal, frontal and posterior parietal fields do meet the characteristics of eye movement abnormalities
and its corresponding altered cognitive fields in ET. The overlap of eye movement abnormalities with features such as
extrapyramidal signs and RBD suggests the potential presence of an underlying synucleinopathy. The confirmation of
such speculations needs further prospective studies in order to depict the trajectories of ET patients according to their
eye movement abnormalities.

15
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