PRIMER

Essential tremor
Thomas Welton 1,2, Francisco Cardoso 3, Jonathan A. Carr4, Ling-Ling Chan5,6,
Günther Deuschl7, Joseph Jankovic8 and Eng-King Tan1,2,9 ✉
Abstract | Essential tremor (ET) is one of the most common movement disorders, with a reported
>60 million affected individuals worldwide. The definition and underlying pathophysiology of
ET are contentious. Patients present primarily with motor features such as postural and action
tremors, but may also have other non-motor features, including cognitive impairment and
neuropsychiatric symptoms. Genetics account for most of the ET risk but environmental factors
may also be involved. However, the variable penetrance and challenges in validating data make
gene–environment analysis difficult. Structural changes in cerebellar Purkinje cells and
neighbouring neuronal populations have been observed in post-mortem studies, and other studies
have found GABAergic dysfunction and dysregulation of the cerebellar–thalamic–cortical circuitry.
Commonly prescribed medications include propranolol and primidone. Deep brain stimulation
and ultrasound thalamotomy are surgical options in patients with medically intractable ET.
Further research in post-mortem studies, and animal and cell-based models may help identify
new pathophysiological clues and therapeutic targets and, together with advances in omics and
machine learning, may facilitate the development of precision medicine for patients with ET.

Action tremor
Tremor that occurs with
the voluntary movement
of a muscle.
Postural tremor
Tremor that occurs when a
person maintains a position
against gravity.
Kinetic tremor
Tremor that occurs with
movement.
ET plus
Essential tremor (ET) with other
neurological signs.
✉e-mail: gnrtek@sgh.com.sg
https://doi.org/10.1038/
s41572-021-00314-w
Essential tremor (ET) is the most common movement
disorder encountered in the clinic. In its purest form, ET
is characterized by an isolated upper limb action tremor
of at least 3 years’ duration without other neurologi-
cal signs1, although some patients may exhibit a range
of other symptoms and signs. ET is defined accord-
ing to clinical characteristics rather than aetiology, as
described by axis 1 of the 2018 Consensus Statement by
the task force on tremor of the International Parkinson
and Movement Disorder Society (MDS) and, as such,
is considered a tremor ‘syndrome’1. Although ET most
often affects the hands, it can also affect the head, legs,
arms, vocal cords, torso or other regions. Action trem-
ors can be further subdivided into postural tremor or
kinetic tremor.
Although both genetic and environmental factors are
thought to be involved in its aetiology, no single marker
or test alone can identify ET. The pathophysiological
mechanisms are not well understood but likely involve a
cerebellar–thalamic–cortical loop and in many patients,
neuropathological changes in the cerebellum. Moreover,
genetic studies have identified several loci, genes, risk
factors and protective factors for ET. Neuroimaging
studies have found dysfunctional structural, functional
and metabolic changes in the cerebellum, thalamus and
cerebral cortex in patients with ET, and pathological
studies have found neuronal changes in the cerebellum.
The annual economic burden of ET in the USA is
estimated as US$143 billion2. Costs include therapies,
but the larger burden is from loss of work opportunities
and income, as up to 88% of people with ET are unem-
ployed, partly owing to impairment from the disease.
Moreover, the estimated annual amount of lost income
for a family affected by ET is US$50,000 (REF.2). However,
despite its high prevalence, evidence for the economic
burden of ET is limited. This is primarily because few
studies have attempted to measure the impact of the
disease and it is not included as a category in the Global
Burden of Disease database. The latter issue may be due
to the contentions and variability in the definition of ET
mentioned herein, and the ensuing scarcity of reliable
epidemiological data. Additionally, the burden of com-
mon co-occurring symptoms, such as disorders of mood,
gait and hearing, is unknown and difficult to estimate.
The diagnosis, investigation and management of ET
are challenging and debated. First, ET is aetiologically
and clinically heterogeneous and there are different
expert opinions regarding its classification and defi-
nition. Diagnostic guidelines have been proposed 1,3,
but certain categorizations such as ET plus have been
debated. Since the ET plus entity was proposed in the
2018 Consensus Statement1, several studies have found
that ET plus is more common than isolated ET 4,5.
Furthermore, diagnostic criteria have historically been
applied inconsistently. Second, the differential diagnosis
for ET in general is challenging as no specific tests that
distinguish ET from other forms of tremor are availa-
ble. Third, the pathophysiology of ET — for example,
regarding whether ET is primarily a neurodegenerative
disease — is debated.

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Author addresses
1
Department of Research, National Neuroscience Institute, Singapore, Singapore.
2
Neuroscience Academic Clinical Programme, Duke-NUS Medical School,
Singapore, Singapore.
3
Movement Disorders Unit, Neurology Service, Internal Medicine Department,
University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
4
Division of Neurology, Faculty of Medicine and Health Sciences, Stellenbosch University,
Cape Town, South Africa.
5
Department of Diagnostic Radiology, Singapore General Hospital, Singapore,
Singapore.
6
Radiological Sciences Academic Clinical Programme and Neuroscience & Behavioral
Disorders Signature Research Programme, Duke-NUS Medical School, Singapore,
Singapore.
7
Department of Neurology, Christian Albrechts University, Kiel, Germany.
8
Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology,
Baylor College of Medicine, Houston, TX, USA.
9
Department of Neurology, National Neuroscience Institute, Singapore, Singapore.
This Primer reviews the current epidemiology,
pathophysiology, diagnosis and management of ET. This
Primer provides a balanced review, highlighting the con-
trasting hypotheses on whether the pathophysiology of
ET includes neurodegeneration.
Epidemiology
Prevalence and incidence
The estimated prevalence of ET is 3.2 cases per 1,000
individuals globally, rising to 28.7 cases per 1,000 indi-
viduals in those aged >80 years6. The incidence of ET
increases with age, with an estimated annual incidence
of 0.2 per 1,000 individuals in those aged ≥65 years in
a study in the USA7, and a Spanish study reported an
annual incidence of 6.2 per 1,000 individuals8.
Studies evaluating the prevalence of ET have been
carried out in several countries (FIG. 1), including assess-
ment of whole populations and two-phase ‘door-to-door’
studies, which comprise population-based screening
using a questionnaire, followed by specialist confirma-
tion of potential cases. A key criticism of epidemiological
studies of ET is the inconsistent application of diagnos-
tic criteria, which could result in the misclassification
of ET. The inclusion of individuals with mild tremor as
ET cases likely accounts for the reporting of very high
prevalence figures in some studies, for example, a prev-
alence of 55% in individuals aged >40 years in Finland
(with a prevalence of 66% in men >40 years old)9. The
introduction of new MDS guidelines for tremor in 2018
(REF.1) may lead to the harmonization of ET diagnosis,
but it is likely that older studies may reflect a range of
underlying diagnostic entities, affecting their accuracy.
To our knowledge, no published epidemiological studies
have explicitly used the 2018 MDS criteria for tremor.
Familial ET Comparing the prevalence of ET in populations with
Essential tremor (ET) in a large socioeconomic differences may be difficult10 and,
patient with a family history
although commonly used, screening questionnaires for
of ET, usually consistent
with autosomal dominant ET have low sensitivity (15% for mild ET and 73%
transmission. for moderate or severe ET)11. Perhaps owing to the use
of variable approaches and diagnostic criteria, the preva-
Sporadic ET lence and incidence of ET vary substantially across epide-
Essential tremor (ET) in a
patient without an underlying
miological studies12. This apparent difference (FIG. 1) may
cause or family history (also reflect methodological differences rather than true dif-
known as idiopathic ET). ferences in disease burden. Carrying out meta-analyses
2 | Article citation ID: (2021) 7:83
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of ET prevalence is difficult owing to variation in study
design, even between studies in the same country.
However, prevalence estimates of ET do vary accord-
ing to geographical region between studies of similar
design; for example, a prevalence of 0.8% was found in
Arab individuals in Israel13, 6.3% in Turkish individuals14
and 6.4% in Basque people 15, all aged ≥60  years,
with the same definition of ET and examination12.
However, what precise phenotypic or environmental
factors are reflected by these differences is unclear.
Demographics
Epidemiological studies originally suggested a bimodal
age at onset of ET, with peaks occurring in the twenties
and sixties16,17. Approximately 5% of new cases occur
before age 20 years with most cases occurring in those
>40 years of age7,18,19. Age at onset has important clin-
ical consequences: familial ET tends to have a younger
onset whereas older-onset sporadic ET tends to have a
rapid disease progression20 owing to reduced reserve and
ageing-associated neuronal loss20. The age at onset of ET
correlates with the age at onset of relatives21. However,
studies of ET onset are limited, as onset is insidious and,
therefore, often difficult for patients to precisely recall.
In general, the prevalence of ET is similar in men
and women, but women have a higher prevalence of
head tremor and also tend to have more severe head
tremor, whereas men tend to have more severe postural
tremor22,23. These findings are speculated by some to
be caused by differences in health-seeking behaviour
or hormones. Although one study has indicated that
patients with ET live longer than individuals without
ET24, other studies found increased mortality in patients
with ET compared with the general population (risk
ratio 1.59)25,26.
Some studies have directly investigated ethnic or
racial differences in ET prevalence and clinical char-
acteristics, and could help highlight susceptible geno-
types or environmental exposures associated with ET27.
For example, studies have found significant variation
in prevalence between populations defined by lan-
guage in Papua New Guinea18, marginally higher prev-
alence in Indians than in Chinese or Malay individuals
in Singapore28 and nonsignificant trends towards higher
prevalence in white than Black individuals in Mississippi,
USA29. However, another study found lower severity of
ET in white individuals than in non-white individuals
in Manhattan, USA30.
Genetic risk factors
Approximately 50–70% of patients with ET have a pos-
itive family history of this disorder31, and first-degree
relatives of patients with ET are ~4.7 times more likely
to have ET than controls32. Although the inheritance
pattern varies, in some families inheritance seems to
follow an autosomal dominant pattern with incom-
plete penetrance33. Some family members of patients
with ET may have other movement disorders, such as
parkinsonism34 or dystonia35. Several putative genetic
loci and/or possible pathogenetic gene variants for ET
have been identified (TABLE 1; FIG. 2), including both risk
factors and protective factors.
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Italy
1.2
Austria
Faroe Islands
3.4
2.9
Spain
USA
4.8 4.8 8.6
5.5
Brazil Nigeria
Crude
prevalence (%)
9 3.4 1.2
Fig. 1 | Prevalence of essential tremor based on studies from 2001–2021. Crude prevalence estimates based on studies
in populations with varying age structure and methodology. Data for each country are from the following studies, listed in
alphabetical order: Austria259, Bangladesh260, Brazil261, China262,263, Faroe Islands264, India265, Israel13,266, Italy267, South Korea268,
Nigeria269, Singapore28, Spain15,270,271, Tanzania272, Turkey14,273–275 and the USA30.
The first genetic locus for ET (ETM1) was identified in
16 families (75 affected members) in Iceland, on chromo-
some 3q13, with an apparent autosomal dominant pat-
tern of inheritance36. However, the link between ET and
this locus could not be consistently replicated in other
populations. A functional variant (Ser9Gly) of DRD3
(encoding dopamine D(3) receptor, which is located in
the ETM1 locus) subsequently attracted considerable
interest; however, genetic association studies produced
conflicting findings, with mostly negative results.
Exome sequencing studies identified a p.Gln290(∗)
mutation in FUS (encoding RNA-binding protein FUS)
in a family with ET and two rare missense FUS vari-
ants in a cohort of white patients with ET37. Moreover,
other studies identified a novel variant, Met392Ile, in
exon 12 of FUS that increases risk of ET among Chinese
individuals in Taiwan and Singapore38. Of note, one
whole-exome study of multigenerational families with
ET and autosomal dominant inheritance found no sig-
nificant enrichment of rare variants in patients with ET
compared with controls, although some variants that
have potential significance need further evaluation39.
More recent identification of putative causative var-
iants in ET probands or families have either not been
replicated or are awaiting further replication (TABLE 1).
Evaluating genetic risk and protective factors for ET,
particularly in patients with no apparent family history,
is also important in addition to identifying monogenic
causes of ET. Both genome- wide association studies
(GWAS) and candidate gene association studies have been
used to identify these genetic risk and protective factors.
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Turkey China
1.6 3.1 4 5.8 3.3 6.5
South
Korea
Israel
3.6
Bangladesh
1.4 1.8
2.5
India
Singapore
Tanzania 1.4
0.2
0.04
A variant of LINGO1 (which encodes a central
nervous system transmembrane glycoprotein that is
expressed in the cerebellum and deep grey matter nuclei)
was the first genetic risk factor with genome-wide sig-
nificant association in a GWAS of ET40–42. Variants of
LINGO2 (a paralogue of LINGO1 that is thought to have
similar functions) are also associated with ET43,44. Thus
far, meta-analysis has suggested overall robust associa-
tion of LINGO1 with ET. A variant of SLC1A2 (encoding
a glial high-affinity glutamate reuptake transporter) was
identified as a risk variant for ET in a European cohort
in one GWAS45, but the same variant was later shown to
be protective in a Chinese cohort46. A variant in STK32B
(encoding a serine/threonine kinase) was protective
against ET in two studies47,48. Moreover, a risk variant
in PPARGC1A (encoding a transcriptional co-activator
for mitochondrial function and energy metabolism)
was identified in one study47 but that was not replicated
in two other studies48,49. Several variants in CTNNA3
(encoding a cell–cell adhesion molecule) were associated
with ET in another study47, which has been replicated48.
The clinical association between ET and Parkinson
disease (PD) is relevant, as patients with ET have a
higher risk of PD than the general population50. A report
of a PD- linked variant of LRRK2 conferring similar
risk in patients with ET is intriguing and needs further
replication51. Similarly, patients with ET harbour patho-
genetic genes (such as NOTCH2 and NLC)52 that are
responsible for other neurodegenerative diseases, sug-
gesting potential overlap of pathophysiological path-
ways. This finding also suggests that ET-like phenotypes
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Table 1 | Gene loci and disease-causing genes for essential tremor in ET63 and by the contradicting effects of other die-
tary factors; for example, in wine, which has a high
Locus or OMIM Chromosomal Function Refs antioxidant content62.
gene location
Other dietary factors include β-carboline alkaloids,
ETM1 190300 3q13 NA 36
antioxidants and caffeine. β-Carboline alkaloids are natu-
ETM2 602134 2p24.1 NA 249
rally present in many foods and, in large quantities, cause
ETM3 611456 6p23 NA 250 acute tremor owing to neurotoxicity in both humans and
animals64. In support of a role for β-carboline in ET, the
ETM4 614782 16p11.2 NA 37
concentration of these alkaloids is higher in blood and
ETM5 616736 11q14.1 NA 251
brain tissue from patients with ET than in controls65
ETM6 618025 1q21.2 NA 52,252 despite no evidence for increased dietary consumption
SCN11A 604385 3p22.2 Voltage-gated sodium channel 253 of β-carboline alkaloids in patients with ET. Dietary anti-
oxidants may have a protective effect on neurodegener-
HAPLN4 – 19p13.11 Binds to hyaluronic acid; involved 254
ative disease and have also been studied in ET66,67. One
in extracellular matrix formation
study found that adherence to a Mediterranean diet was
SORT1 602458 1p13.3 Sorting of receptors involved in 255
associated with lower odds of ET68. Moreover, studies
intracellular protein transport
evaluated the involvement of caffeine in ET because of its
HTRA2 606441 2p13.1 Caspase-dependent apoptosis; 256
action as a nonselective adenosine antagonist; however,
inactivates mutations associated
with neurodegenerative disorders
two studies59,69 did not find any significant association
between caffeine intake and ET duration or severity.
CACNA1G 604065 17q21.33 Voltage-gated calcium channel 257
Occupational and lifetime exposures to pesticides,
SCN4A 603967 17q23.3 Voltage-gated sodium channel 258
farming and heavy metals have also been studied in
NOS3 163729 7q36.1 Regulation of vascular tone 254 relation to ET risk. One study identified agricultural
work and exposure to frosted glass as significant pre-
USP46 612849 4q12 Deubiquitinating enzyme, regulates 254

GABA action dictors of ET58, and other studies have suggested that
lead exposure leads to progressive disorders with action
KCNS2 602906 8q22.2 Voltage-gated potassium channel 254

subunit tremor and cerebellar pathology70, with patients with ET

GABA, γ-aminobutyric acid; NA, not applicable; OMIM, Online Mendelian Inheritance in Man.
in other genetic syndromes may pose considerable
challenge in early diagnosis unless appropriate genetic
testing is carried out for those syndromes.
Although genetic studies have provided insights into
the possible mechanisms of ET, these studies have sev-
eral limitations, such as clinical heterogeneity, the lack
of gold standard diagnostic criteria with post-mortem
validation, genetic heterogeneity and incomplete clinical
penetrance, small sample sizes, the presence of ET-like
phenotype in other genetic syndromes and a lack of
good animal models that fully recapitulate the disease.
Another limitation is the question of whether ET is a
single condition or a syndrome.
Environmental risk factors
Although concordance between monozygotic twins
is high for ET (60–93% compared with 25–59% for
dizygotic twins)53,54, it is not complete, implying that
non-genetic factors have an aetiological role in some
patients55 (FIG. 2). Despite studies providing some evi-
dence about putative environmental causes of ET,
further research is required.
Diet has been highlighted as a potential factor in
ET. First, ethanol has acute tremor-relieving effects via
suppression of the inferior olivary nucleus (ION)56 and
GABA transmission57; however, other studies suggest
that alcohol could, conversely, be a risk factor for ET58,59,
owing to a degenerative effect on the cerebellum, includ-
ing atrophy and loss of Purkinje cells (PCs)60. In gen-
eral, studies on the effects of ethanol on ET have yielded
positive61, negative62 and inconclusive58,59 results. These
studies are complicated by links with chronic alcoholism
having higher blood lead concentrations than controls71.
On pesticides, the evidence is contradictory, with studies
finding no differences in serum pesticide concentration72
or self-reported exposure58,69 in patients with ET ver-
sus controls, and others finding positive associations
between self-reported exposure and ET73,74.
Smoking has a protective effect for ET, which is
believed to be due to an effect of nicotine at nicotinic
acetylcholine receptors 75. Three studies found that
individuals who never smoked had double the risk of
ET compared with those who had smoked at any time,
and that there was a dose- dependent response58,76,77.
One study suggested that shorter sleep duration was
associated with incident ET risk78.
Mechanisms/pathophysiology
The pathophysiology of ET is still being elucidated,
with multiple overlapping hypotheses and supporting
evidence and many unanswered questions. In essence,
both genetic and non-genetic risk factors contribute to
changes in molecular, biochemical and cellular compo-
nents and oscillatory neuronal activity, resulting in clin-
ical tremor. Mechanistic studies of ET have been limited
by clinical and aetiological heterogeneity, adding to the
debate on whether ET is a syndrome, a single disease or
a family of diseases. Here, we summarize the key find-
ings in order of biological scale, from macroscopic and
morphological changes to molecular perturbations.
Neuroimaging
Studies with structural MRI have been lacking in sample
size and show only weak or unreplicated associations
with clinical severity. Reductions in volume of brain
parenchyma — most frequently in the cerebellum —
have been observed in patients with ET; however,

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a meta-analysis of these studies found no reliable mor-
phological differences between patients with ET and
controls79 and, although atrophy of the cerebellum
was found in several studies, it did not survive overall
robustness analysis. Atrophy of the cerebellar peduncles
(comprising spinocerebellar and vestibular afferents,
and the olivo-cerebellar pathway) may also be present80.
Moreover, diffusion MRI studies of ET have found
increased mean diffusivity and decreased fractional
anisotropy of various white matter tracts, predomi-
nantly in the cerebellum and cerebellar peduncles81,82,
among other regions83,84, including a cortico-pontine
tract (FIG. 3). By contrast, some diffusion MRI studies did
not find differences in the cerebellum85 or non-motor
regions in patients with ET81. Magnetic resonance spec-
troscopy (MRS) studies have found a reduction in the
ratio of N-acetyl-l-aspartate and total creatine in the cer-
ebellar cortex of people with ET86,87 that correlated with
tremor severity87 and blood harmane concentration88,
suggesting metabolic damage. Overall, some structural
MRI studies support differences in morphology and
microstructure of the brain in patients with ET but many
findings are unreplicated or not robust.
Functional MRI techniques including positron emis-
sion tomography (PET), single-photon emission com-
puted tomography (SPECT) and blood oxygenation
level- dependent (BOLD) imaging have been used in
small-scale studies of ET. Regional cerebral blood flow was
first quantified using PET in patients with ET, and bilat-
eral increased activity was found in the cerebellum during
resting and active states, in addition to in the striatum,
Environmental Genetic Epigenetic
factors factorsa factorsa
• Exposure to • ETM1–5 Possible
pesticides or • FUS involvement
heavy metals • TENM of epigenetic
• Dietary factors • LINGO1 factors
• Smoking • SLC1A2
• CTNNA3
Biological interactions
• Gene–gene interactions
• Genetic modifications
• Gene–lifestyle interactions
• Protective genetic factors
• Protective lifestyle factors
At-risk individuals
Time and ageing
Clinical ET
Fig. 2 | Risk and aetiology of essential tremor. Essential
tremor (ET) is caused by the biological interaction of environ-
mental, genetic and epigenetic risk and protective factors.
In turn, the interaction of these factors raises the overall risk
of ET in some individuals and, in combination with ageing,
results in the clinical manifestation of ET. More research on
environmental factors is required to confirm their association
with ET. aLimited supporting evidence.
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thalamus, motor cortex and red nucleus89. However, two
subsequent SPECT studies of regional cerebral blood flow
in the cerebellum showed divergent findings90,91. SPECT
has also been used to study dopamine transporter bind-
ing in the striatum in patients with ET, but studies did not
find decreased striatal dopamine uptake92. Studies using
BOLD functional MRI have observed increased activa-
tion predominantly in the cerebellum and red nucleus
in patients with ET compared with mimicked tremor in
controls93. Moreover, studies during rest found abnor-
mal functional connectivity of a cerebellar–thalamic–
cortical network94,95 and decreased functional connectivity
locally within the cerebellum in patients with ET96. Taken
together, data from functional MRI studies support
changes in metabolism, activity and connectivity in the
cerebellum and a possible wider tremor-related network
in ET, but these studies are limited by low temporal reso-
lution precluding direct correlation to tremor signals and
wide variation in approach and methodology.
Electrophysiology
Electrophysiological studies using electroencepha-
lography (EEG), magnetoencephalography and brain
stimulation have provided insights on the links between
oscillations in peripheral muscle activity and oscillations
in brain circuits. Historically, a single central oscilla-
tory (the ION) was suggested on the basis of lesioning
studies97 and because of the capability of cells in the
ION for rhythmic excitation98; however, this model
was later refuted99 and is no longer widely supported.
In an updated model based on electrophysiological and
neuroimaging data, various brain regions have been
identified as nodes of a tremor-related network includ-
ing cerebellum, thalamus and motor cortex, intercon-
nected by pre-lemniscal and cortico-pontine tracts, and
the Guillain–Mollaret triangle100 (FIG. 3). This network
has been implicated in peripheral tremor101 and tremor
syndromes such as physiological tremor102, parkinso-
nian tremor and ET101. Several studies have evaluated
the initiation and maintenance of the tremor network
during action tremor using electromyography and EEG,
and have demonstrated that, while the network becomes
simultaneously active103, the participation of the cortex is
intermittent104. Lesioning of any single component of the
tremor network greatly diminishes tremor105. Studies of
non-invasive brain stimulation show preliminary signs
of reduced tremor when the stimulation is applied to the
motor cortex or cerebellum106.
Neuropathology
Post-mortem studies of patients with ET have identi-
fied morphological changes in various neuronal sub-
types in the cerebellum. One group found a loss of
PCs107, although this finding was not replicated by two
other groups108,109. Other observations in PCs include
swelling of neuronal processes110, reduced dendritic
complexity111, terminal axonal sprouting112, arciform
PC axons (which gradually curve back towards the PC
layer)113, increased spacing between PCs and abnor-
mal positioning of the PC soma (known as heteroto-
pia)114. Morphological changes have also been observed
in basket cells (GABAergic interneurons that form
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Motor cortex
VIM
Red
nucleus
Pons
Dentate
nucleus
ION
Cerebellar cortex
Cortico-pontine tract
Pre-lemniscal radiation
Guillain–Mollaret triangle
Spino-cerebellar tract Spinal cord
Other interconnecting
white matter tracts
Fig. 3 | Key pathways involved in the pathophysiology of essential tremor. The brain
circuits involved in essential tremor pathophysiology can be conceptualized as four
intersecting pathways within the cerebellar cortex. The inferior olivary nucleus (ION),
dentate nucleus, pons, red nucleus, thalamus and motor cortex are key loci interconnected
by these pathways. VIM, ventral intermediate nucleus.
pericellular ‘baskets’ around PC somas) and climbing
fibres (excitatory projections from the ION to the cere-
bellum)113. In basket cells, the Pinceau process (which
encapsulates the initial segment of the PC axon) is
elongated and the basket-shaped elaborations around
the PC soma are sometimes empty115 or are dense and
tangled116. Moreover, climbing fibres have abnormal
distributions of connections onto PC dendrites117,118,
extending in greater numbers to the outer molecular
layer and synapsing more frequently with the distal PC
spiny branchlets than age-matched controls117,118. Overt
morphological changes have not been observed in other
brain regions in ET, including the thalamus, red nucleus,
dentate nucleus and ION119,120. However, overall there is
no widespread consensus or support for the presence of
neuropathological changes in ET.
GABA dysfunction
The presence of GABA dysfunction in ET has been stud-
ied for several years. The concentration of GABA in the
cerebrospinal fluid of patients with ET is reduced, with
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an increase in glutamate concentration121. Moreover,
expression of GABAA and GABAB receptors is reduced
in the dentate nucleus in post- mortem brain tissue
and correlates with tremor severity122, although other
studies found a reduction in a GABA marker, parval-
bumin, in the pons and locus coeruleus, rather than
the cerebellum123. Despite these findings, other stud-
ies have demonstrated a pacemaker-like behaviour of
deep cerebellar nuclei (dentate nucleus) that may be
moderated by GABAergic input from PCs124 and can
be transmitted to thalamic target neurons125. Congruent
findings from [18F]flumazenil-PET MRI studies have
shown a reduced GABAergic content of the cerebel-
lum in patients with ET126,127. In support of a role for
GABA in ET pathophysiology, most medications used
to treat ET enhance GABAergic tone128. By contrast,
a genetic basis for GABAergic dysfunction in ET has not
been identified129. Nevertheless, most investigators now
believe that GABAergic dysfunction may be associated
with ET.
Animal models
Animal models have provided important insights into
the mechanisms of tremor113 and include genetic, phar-
macological and lesioning models, in species includ-
ing Drosophila melanogaster, mice, rats, monkeys and
pigs130. Although a comprehensive review of ET animal
studies is beyond the scope of this Primer, we discuss
some notable examples. First, in mammals, harmaline
elicits a burst-firing of neurons in the ION that mani-
fests as action tremor131. Importantly, drugs that sup-
press tremor in patients with ET are also effective in the
harmaline model, demonstrating its usefulness for drug
screening130. Second, genetic mutations identified in
human studies can be overexpressed in animals such as
in D. melanogaster, which has been used for large-scale
screening and genetic manipulation132. Third, mice defi-
cient in GluRδ2 (which regulates pruning of climbing
fibres and PC and parallel-fibre and PC synapses133 and
which is abnormal in patients with ET117,118) have a 20 Hz
action tremor. Rescue of GluRδ2 improves tremor and
causes rewiring of climbing fibre synapses133. Subsequent
lesioning and optogenetic experiments supported links
between the ION (as the origin of climbing fibres), PCs
and interposed nucleus in this model134. Of note, similar
to the situation in humans, ET in animal models is hetero-
geneous; thus, although animal models cannot reca-
pitulate the spectrum of human ET, they can represent
individual features or contributing mechanisms.
Interpretations
GABA dysfunction. Although GABAergic dysfunction
is widely linked with ET pathophysiology, how it inter-
acts with other pathophysiological alterations in ET
remains to be elucidated. Some proponents have drawn
putative links in a specific order: from PC loss (as a sug-
gested primary driver) to the reduction in activity of the
GABAergic system in deep cerebellar neurons, subse-
quent disinhibition of pacemaker activity and, finally,
propagation of rhythmic activity to wider tremor net-
work circuitry135. Although PC depletion is known to
reduce GABAergic cerebellar corticofugal output136, the
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loss of PCs in ET is debated (see Neurodegeneration,
below). Furthermore, dentate neurons rarely exhibit
pacemaker- like behaviour in the tremor frequency
band125. Other groups have proposed that tremor may
instead originate from dysfunction and compensa-
tory upregulation of GABAergic activity in the dentate
nucleus, followed by oscillation of the olivo-cerebellar
loop and subsequent oscillation of the thalamus and
motor cortex137 (FIG. 3). Consistent with this hypothesis,
one study in mutant mice (the ‘pcd’ mutant) showed that
PC degeneration alone was not enough to cause sus-
tained thalamic–cortical oscillation138. Thus, although
GABA may have a key role in ET pathophysiology, its
position in the overall causal chain still needs to be
clarified.
Network dysfunction. The presence of a tremor-related
brain network comprising the cerebellum, thalamus,
motor cortex and brainstem nuclei (FIG. 3) is widely
accepted. The presence of this network is supported by
data from an array of neuroimaging and physiological
studies, which place the olivo-cerebellar system at the
core of the network, with the intermittent involvement
of cortical regions via the thalamus100. This network
is likely not static: dynamic changes in its configura-
tion and regional involvement are related to initiation
of tremor and voluntary movements. Moreover, the
tremor network is aberrant in several tremor syndromes,
including ET, and is present in normal subjects, suggest-
ing that it is a disinhibited physiological network. The
mutual entrainment of this network is supported by
the reduced tremor severity with lesioning of any network
component105 and by the theoretical ability of any com-
ponent to initiate tremor activity139. The wide distribu-
tion of the tremor network and its abnormal functional
connectivity during rest95 has led some to question
whether subtle cognitive and emotional functions140 in
ET could be secondary to its disorganized functioning100.
Neurodegeneration. A proposed neurodegenerative
ET model141 centres on ET as a degenerative disease of
the cerebellum and attaches a preliminary sequence
of events to the observed cellular morphological
changes113. The reduction in the number of PCs, basket
cell remodelling110, formation and hypertrophy of PC
arciform and recurrent collateral processes113, rewiring
of climbing fibres142 and pruning of the PC dendritic
arbour may suggest reorganization of the cerebellar
cortex113. Physiologically, these changes may result in the
formation of aberrant PC synapses and development of
abnormal circuits in ET110,113.
However, despite these findings, the neurodegener-
ation hypothesis of ET has yet to gain widespread trac-
tion. First, the potential secondary effects of neuronal
circuit dysregulation on the morphological changes to
cerebellar neurons still need investigation. Moreover,
the clinical–pathological correlation in ET is not yet
clear, and PC loss was not found by two independent
groups108,109,143. Although the failed replications of PC
loss can be explained by differences in study method-
ology (case selection and definition, post-mortem sam-
pling, confounding and statistical power), further studies
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are needed to address this uncertainty. Another expla-
nation for the pathological findings in ET could be plas-
ticity of the cerebellum, rather than neurodegeneration,
as some changes seem to be reversible in patients with
reduced tremor after deep brain stimulation (DBS)144.
Pruning. Preliminary studies suggest a pruning-related
paradigm based on data obtained from the GluRδ2-
deficient mouse model134. Studies have found an over-
all reduction in GluRδ2 in ET, which, combined with
the function of this protein in cerebellar fibre pruning,
suggests that the deficiency could lead to the abnormal
distribution of PC synapse formation. Indeed, rescue of
GluRδ2 in GluRδ2-deficient mice reduces tremor and
climbing fibre synapses, suggesting a possible causal
relationship between trembling, synaptic rewiring and
GluRδ2 expression133. In the same model, cerebellar EEG
correlated with mouse peripheral tremor, and local field
potentials (due to activity of the ION) were related to
tremor. Collectively, these data suggest that the loop
between the inferior olive, PCs and interposed nucleus
may be the circuit producing tremor in this mouse
model.
Ageing. Two key findings in ET are not yet clearly
understood. First, life expectancy seems to be lower in
people with ET26 and may145 or may not24 be specific to
those with older-onset disease. Second, cognitive dis-
turbances are present in some patients with ET146 that
may be restricted to, or have faster progression in, the
subgroup of those with older-onset ET145. These find-
ings are supported by data from the large Danish Twin
Registry53,147. Moreover, in the Danish Twin Registry,
survival depended on tremor severity, with shorter life
expectancy and poorer cognitive function in those with
more severe tremor. These patients with older- onset
ET have earlier signs of ageing (such as difficulties in
activities of daily living, grip strength reduction) that are
also related to tremor severity145, and differ from patients
with early-onset ET in heredity148, disease progression148,
central tremor network function149 and age-related pro-
longation of the blink reflex150. These findings have
been interpreted to reflect a special form of ageing.
Patients with older- onset ET could, therefore, repre-
sent an ‘ageing-related tremor’ subgroup140. Although
this hypothesis has not yet been thoroughly explored, it
could explain some contradictory findings in ET, such
as the shorter life expectancy, earlier onset of dementia
and lack of critical unifying cause for death.
Diagnosis, screening and prevention
Classification and definition
ET was defined by Critchley in 1949 as a single entity
characterized by hand and/or head tremor without
additional features but with familial predisposition151.
Despite the ongoing application of this definition, some
movement disorder experts disagreed with it152 and
identified a lack of consensus on the diagnostic criteria
being applied, specifically regarding the types of tremor
and associated symptoms.
In the 2018 Consensus Statement 1 two axes are
defined: axis 1, relating to clinical characteristics, and
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axis 2, relating to aetiology. Tremor syndromes are
classified only according to axis 1 (by clinical features)
and, importantly, not by aetiology. In this classification,
ET is defined as an isolated tremor syndrome of bilat-
eral upper limb action tremor that occurs with at least
3 years’ duration, with or without tremor in other loca-
tions and the absence of other neurological signs, such as
dystonia, ataxia or parkinsonism1. The 2018 Consensus
Statement establishes as exclusion criteria for ET syn-
dromes the following features: isolated focal tremors
(voice, head); orthostatic tremor with a frequency
>12 Hz; task- and position-specific tremors; and sud-
den onset and step-wise deterioration. Interestingly, the
MDS task force consider as another category of axis 1
these syndromes of isolated tremors. Over the past few
years, some groups have proposed that ET is either a
syndrome or a group of diseases, with possible distinct
clinical features and differing underlying mechanisms
and aetiologies153. This change of concept is reflected in
the evolution of its definition.
Other terms can be used to refer to different types of
ET. Sporadic ET and familial ET are widely used terms in
clinical practice but lack formal definition. The propor-
tion of familial ET in different series ranges from 50%
to 70%31.
The concept of ‘ET plus’ is debated. The 2018
Consensus Statement defines ET plus as “tremor with
the characteristics of ET and additional neurological
signs of uncertain significance such as impaired tandem
gait, questionable dystonic posturing, memory impair-
ment, or other mild neurological signs of unknown
significance that do not suffice to make an additional
syndrome classification or diagnosis.” The authors of this
consensus statement also add that patients who meet cri-
teria for ET and present with tremor at rest should be
classified as ET plus1. Critics of this definition state that
the additional features might reflect a progression of the
ET pathology instead of a different disease5, but evidence
shows no differences of cerebellar pathology between
ET and ET plus154. Another possibility is that patients
classified as ET plus may have myriad conditions that
initially present with a phenomenology that mimics ET.
Moreover, ET likely comprises different subtypes that
may represent separate entities with unique aetiopatho-
genesis. In light of these criticisms, the concept of ET
plus will likely not be widely adopted in clinical practice
and the scientific world.
Additional signs and symptoms
ET can be accompanied by a wide array of additional
signs and symptoms that are often functionally rele-
vant but usually mild, although sometimes they can be
disabling155.
One study found that the most common comorbidi-
ties in patients with ET were hypertension (52%), other
nervous system disorders (45%), lipid metabolism dis-
orders (44%) and mood and anxiety disorders (37%)156.
Hearing impairment is also common in patients with
ET, with studies finding significantly higher rates of
self-reported impairment157,158, hearing handicap ques-
tionnaire scores159 and use of hearing aids than the gen-
eral population160. There is a well- established link of
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ET to gait impairment161. Sleep disorders are also fre-
quent in ET, most commonly poor sleep quality and
daytime somnolence162.
Moreover, psychiatric disturbances such as depres-
sion, anxiety, personality disorders and other mood dis-
turbances have been reported in up to 30% of patients
with ET 163. Of note, depressive symptoms are not
necessarily due to severe disability, as they have been
reported to occur before the onset of motor symptoms164.
Psychiatric disturbances may, however, be related
to head tremor more than other types of tremor165.
Cognitive deficits are also common in patients with ET,
particularly executive functioning166 and are not fully
accounted for by depression167. Mild cognitive impair-
ment is significantly more likely in patients with ET than
in controls168, and Alzheimer disease dementia is also
more prevalent in patients with ET169, although it has
not been confirmed post mortem and may be limited to
an older-onset subgroup170. Although the basis for these
cognitive deficits is unclear, some studies have suggested
that they are mediated by dysregulation of the same cere-
bellar–thalamic–cortical circuits as ET171. Others may be
related to co-occurring degenerative pathologies172. This
is further supported by evidence of improved cognition
1 year after DBS implantation specifically in patients
with earlier- onset ET173. However, studies of cogni-
tive disturbances in ET have been criticized for being
underpowered174.
The topic of comorbidities raises an important issue
related to ET nosology and classification. Although
the conditions described above may accompany ET,
they may also represent unique subtypes of ET with
overlapping clinical features and possibly aetiopatho-
genesis. Indeed, it has been suggested that ET may be
categorized based on the presence of specific comorbid
disease as isolated ET, ET–parkinsonism, ET–dystonia,
ET–ataxia, ET–neuropathy, ET–deafness, ET–task-specific
tremor, ET–orthostatic tremor or, based on the age of
onset, as early-onset ET or older-onset ET175.
Diagnostic and screening tests
Diagnosis of ET is based on the presence of suggestive
clinical signs and symptoms. Diagnostic tests are carried
out to rule out alternative causes of tremor, as there are
no laboratory, neurophysiological or imaging markers
that are specific for ET1. Neurological examination can
include assessments of muscle strength and tone, sensory
function, posture and coordination, gait and reflexes. For
tremor symptoms, pen and paper tasks are often used,
including handwriting, line drawing and Archimedes
spiral tests176. Medication side effects and caffeine use
should be considered during diagnostic work-up. Brain
MRI is justified if the tremor had sudden onset and/or
the neurological examination disclosed other signs in
addition to tremor. Particularly in those individuals with
onset before 50 years of age, a practical approach for a
patient who presents with action tremor of the upper
limbs and lack of additional features and without history
of use of tremor-inducing drugs involves study of thy-
roid function and work-up for Wilson disease (that is,
serum ceruloplasmin levels, 24 h urine copper levels and
ophthalmological evaluation for Kayser–Fleischer ring).
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Sensory trick
Differential diagnosis ET178. Of note, the frequency of ET is not changed by
A motor or sensory manoeuvre The range of conditions to consider in differential diag- loading the limb, unlike enhanced physiological tremor1.
that temporarily alleviates nosis of ET is broad (BOX 1); however, in practice, the Distinguishing ET from dystonic tremor depends
dystonia. most important conditions to be ruled out are enhanced on careful observation of manifestations, as the dys-
physiological tremor (particularly drug-induced tremor), tonic signs are invariably subtle. Other signs of dystonic
dystonic tremor, PD, spinocerebellar ataxia type 12 and tremor are discreet dystonic posturing of the hand, pres-
fragile X-associated tremor/ataxia syndrome. ence of sensory trick and identification of a null point of
The manifestations of drug- enhanced tremor are tremor (a specific position that alleviates tremor)179. ‘Soft
often indistinguishable from those of ET; thus, clinical signs’ can also be used to identify dystonia, including
history and identification of exposure to agents capable hyperextended fingers, tight grip or asymmetrical swing
of inducing tremor are key to differential diagnosis177. of the arms.
Kinematic assessment may be helpful in differentiating PD and ET often exhibit clinical overlap and may
ET from drug-induced tremor, as shown in one study coexist within the same individual180. The presence of
of valproate-induced tremor in which the patients with tremor at rest, the lack of action tremor and bradykinesia
valproate tremor had greater rest tremor and occurrence are usually, but not always, indicative of PD. For exam-
of head, voice and lower limb tremor than patients with ple, bradykinesia has been observed in ET specifically
in the fingers and without a sequence effect (progres-
sive slowing of sequential movements)181, as has action
Box 1 | Differential diagnosis of essential tremor
tremor in PD182. Dopamine transporter (DAT)-SPECT
Chromosomal aneuploidy • Tuberculosis imaging can be used to identify PD, as striatal radio-
• XXY (Klinefelter syndrome) • West Nile virus disease tracer uptake is reduced in those with PD relative to
• XXYY • Zika those with ET183. Moreover, tremor suppression tests
• XYY (that is, to quantify the difference between resting and
Neurodegenerative diseases
action tremor) may be used to help separate ET from
Drugs • Pre-mutation of fragile-X gene
parkinsonian tremor184.
• Amiodarone • Parkinson disease The hallmarks of functional tremors are variability
• Anticonvulsants: carbamazepine, • Spinocerebellar ataxias of frequency and pattern of contraction as well as the
lamotrigine, phenytoin, valproate • Wilson disease occurrence of entrainment185. Other tests can be ordered
• Anticancer agents: cisplatin, cytosine Peripheral neuropathies on demand in those with features suggestive of any of the
arabinoside, doxorubicin, 5-fluorouracil, potential alternative causes of ET (BOX 1).
ifosfamide, methotrexate, paclitaxel, • Charcot–Marie–Tooth disease
tacrolimus, vincristine • Chronic inflammatory demyelinating
polyradiculopathy Management
• Antidepressants Several treatments are available for ET, with varying lev-
• Cocaine • Gammopathy-induced neuropathies
els of supporting evidence and of varying efficacy. The
• Guillain–Barré syndrome
• Corticosteroids MDS evidence-based review of treatments for limb ET
• Dopamine depletors: reserpine, Toxins concluded that propranolol, primidone and topiramate
tetrabenazine, deutetrabenazine, • Arsenic at certain doses should be classified as ‘clinically useful’,
valbenazine • Carbon monoxide with alprazolam and botulinum toxin type A classified
• Lithium • Cyanide as possibly useful186, while the American Academy of
• Neuroleptics • Dichlorodiphenyltrichloroethane (DDT) Neurology rated propranolol and primidone more highly
• Prokinetic agents: bromopride, • Lead
(level A) than topiramate (level B) for efficacy187. Of the
metoclopramide surgical options, unilateral ventralis intermedius thalamic
• Lindane
• Sympathomimetics DBS, radiofrequency thalamotomy and MRI- guided
• Manganese
• Thyroid hormone replacement focused ultrasound (FUS) thalamotomy were classified as
• Mercury possibly useful186. Propranolol is the only drug approved
Endocrine and metabolic disorders • Naphthalene by the FDA for treatment of ET, but second-line options
• Hypocalcaemia • Toluene (benzodiazepines and anticonvulsants) are commonly
• Hypoglycaemia Others used off label. Both DBS and FUS thalomotomy are
• Hyperglycaemia • Anxiety FDA-approved for ET. In the European Union, medicines
• Hyperthyroidism for ET are approved by the European Medicines Agency
• Brain injury
• Liver failure (EMA) or individual member states according to their
• Brain neoplasm
• Renal failure own regulatory frameworks. The diagnosis and treatment
• Brain vascular disease of ET are summarized in FIG. 4 and measures to quantify
Infections • Cooling response to treatment for ET are discussed in BOX 2.
• HIV • Drug and alcohol withdrawal
• Japanese encephalitis • Dystonia Propranolol
• Malaria • Functional or psychogenic tremor Propranolol, a nonselective β- adrenergic receptor
• Measles • Multiple sclerosis antagonist, is the first-line treatment in most patients
• Neuroborreliosis • Neuromyelitis optica with ET, with most patients reporting a favourable
• Neurocysticercosis • Physiological tremor
response188,189. Although early studies provided evi-
dence that β-blockers attenuate tremor predominantly
• Syphilis Partially based on REFS1,3.
via peripheral action on the muscle spindle, other studies

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Tremor Establish diagnosis of ET Education and support Is there a need for prescription therapy? No

Rule out other conditions Yes

• Parkinson disease Administer ‘as needed’ therapy Administer continuous therapy

• Cerebellar disease • Judicious use of alcohol 10–15 min before or • Propranolol
• Dystonia anticipated eventa • Primidone
• Neuropathy • Propranolol 1 h before anticipated event • Topiramate

If tremor is not controlled use combination therapy

(primidone and propranolol)

Is therapy successful?

No

• Benzodiazepinesa
• Gabapentin
• Zonisamide
• BoNT injection

Is therapy successful?

No

DBS or FUS

Fig. 4 | Management of essential tremor. After diagnosis of essential tremor (ET) is established and other conditions have
been ruled out, support and education should be provided to all patients. The first-line pharmacological therapy for ET is
propranolol or primidone. Surgical intervention is indicated in those with uncontrolled tremor with combination therapy
or other drugs. BoNT, botulinum toxin; DBS, deep brain stimulation; FUS, focused ultrasound. aRisk of dependency.

have provided substantial evidence that their effects are
dependent on central nervous system penetration190. In
addition to improving hand tremor, propranolol may
also ameliorate head and voice tremor191,192.
Although several β- blockers are useful for treat-
ment of ET, propranolol seems to be the most effective.
Some, with partial sympathomimetic properties, such as
pindolol and practolol, do not improve tremor or may
even worsen it193. Propranolol is generally well toler-
ated, but some patients report fatigue, weight gain and
light-headedness; the latter may be related to bradycardia
and hypotension. Relative contraindications to propran-
olol include asthma, heart block and poorly controlled
congestive heart failure, bradycardia, hypotension,
sick sinus syndrome and pheochromocytoma.
Primidone
Numerous open and controlled trials have found that
primidone (an anticonvulsant that presumably enhances
GABAergic inhibition) improves ET, and its overall effi-
cacy may be comparable to that of propranolol187. The
mechanism of action of primidone in ET is poorly under-
stood, but is proposed to involve an alteration of trans-
membrane calcium and sodium ion fluxes190. Moreover,
primidone is partly metabolized to phenobarbital and
increases the duration of GABA receptor opening190.
The most important limitation for the use of prim-
idone for ET is a relatively high frequency of adverse
effects, particularly sedation, ataxia and nausea. The tol-
erability of primidone can be improved by starting with a
low dose at night and gradually increasing the dose over
a period of several weeks. There seems to be a synergistic
effect when propranolol and primidone are combined194.
Topiramate
Topiramate is a sulfamate-substituted monosaccharide
with several mechanisms of action including inhibition
of voltage-gated sodium channels and augmentation of
the inhibitory chloride ion influx mediated by GABA195.
Several studies have confirmed the efficacy of topiramate
in patients with ET196,197. Although the effectiveness of
topiramate is less established than that of propranolol or
primidone187, it provides a useful alternative or addition
for patients who do not benefit from either of these two
drugs. The major barriers to the use of topiramate for the
treatment of ET are frequent adverse effects including
memory disturbance, poor concentration, word-finding
difficulties, paraesthesia, weight loss and increased
risk of kidney stones and thus higher discontinuation
rate198. Owing to these potential adverse effects, starting
topiramate at a low dose and gradually increasing the
dosage as tolerated is recommended.

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Other pharmacological therapies
Many other drugs are used for treatment of ET, but the
selection of the most appropriate treatment must be
individualized. Other drugs used include benzodiaze-
pines (especially clonazepam and alprazolam), gabapen-
tin, zonisamide and levetiracetam. Other oral therapies
are being investigated in clinical trials188 (TABLE 2). In
this regard, a trial of CX-8998, a Cav3 T-type calcium
channel blocker, demonstrated improvement in some
assessments of ET, although the primary end point was
not met (a reduction in tremor based on the video-rated
Tremor Research Group’s The Essential Tremor Rating
Assessment Scale (TETRAS) performance subscale)199.
Botulinum toxin injections
Botulinum toxin (BoNT) is used to treat various invol-
untary movements, including ET involving the hands,
arms, legs, head or neck and voice, in addition to
PD-related rest tremor, dystonic tremor and cerebellar
outflow tremor200.
BoNT treatment must be individualized to select the
most appropriate muscles and dose to achieve optimal
outcomes201. For example, to minimize finger and wrist
extensor weakness the extensor forearm muscles are
often not injected, or a very low dose is used, and the
dose in forearm flexors is adjusted to prevent hand grip
weakness, the most frequent, albeit transient and rarely
disabling, adverse effect202. Large multicentre, controlled
trials of onabotulinumtoxinA and incobotulinumtoxinA
for ET are currently in development.
DBS and FUS
Patients with troublesome or disabling tremor who
obtain insufficient benefit from pharmacological ther-
apies are usually considered candidates for surgical
intervention such as DBS or FUS thalamotomy. Before
the advent of DBS, ablative thalamotomy using stereo-
taxic radiofrequency was the most frequently performed
surgery for such patients203,204. Other surgical treat-
ments include unilateral laser thalamotomy205, gamma
Box 2 | Quantification of treatment response
Several methods designed to assess the severity of
tremor can be used to quantify response to the various
therapeutic interventions for essential tremor (ET).
Although accelerometers and other computer-based
technologies and devices have been used to measure
tremor, most trials use various clinical rating scales for this
purpose. One such scale, The Essential Tremor Rating
Clinimotia Abre Assessment Scale (TETRAS)276, was developed by the
Tremor Research Group to overcome limitations of other
scales, such as the Fahn–Tolosa–Marin Clinical Rating
Scale277, the Bain and Findley Clinical Tremor Rating Scale,
the Glass Scale and the Quality of Life Essential Tremor
Questionnaire278. Although accelerometers and other
kinematic assessments can measure the amplitude of
tremor at a particular time point, as the amplitude varies
(up to 23% over a 6 h period in one study279) the clinical
rating scales capture the overall severity of the tremor
and its effect on quality of life280. TETRAS rates amplitude
of tremor in different body parts (head, face, voice, limbs
and trunk), handwriting, spiral and dot approximation on
a 0–4 scale (0–64) and activities of daily living (0–48).
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knife thalomotomy206 and virtual cone (a non-invasive
radiosurgical technique)207, albeit with limited evidence.
DBS for patients with ET usually targets the ventral
intermediate (VIM) thalamus208, and has been found
to robustly (68–100%) reduce the amplitude of con-
tralateral tremor in patients with disabling ET209. More
recently, the posterior subthalamic area encroaching on
the inferior borders of the VIM and sensory thalamus
has been considered the ‘sweet spot’ as a target for DBS
treatment of ET210. Three different systems are used for
DBS in patients with ET. Stimulation can be performed
in one direction (omnidirectional) or two directions,
allowing for control of stimulation across the horizon-
tal plane. This directional stimulation may facilitate a
more targeted approach and help maximize the benefits
of DBS while minimizing adverse effects. DBS for ET
is usually well tolerated but dysarthria (difficulty with
speech) and disequilibrium are relatively common,
particularly with bilateral stimulation; surgery-related
complications, such as haemorrhage and infection, and
long-term complications are rare211.
Over the past decade, FUS lesioning has been increas-
ingly used to create highly targeted brain lesions in the
treatment of ET. One large, sham-controlled, blinded,
trial of FUS lesioning demonstrated marked tremor
reduction in the contralateral arm in patients with ET212.
Adverse events included transient sensory disturbance
and dysarthria. Of note, although one 4-year open label
report showed continued benefit of FUS lesioning, there
is a concern about potential loss of effect over time that
could require repeat procedures 213. No prospective
head-to-head comparisons of FUS lesioning and DBS
have been carried out, but retrospective studies suggest
comparable efficacy and safety214. FUS lesioning seems
to be cost-effective compared with DBS, and the device
is approved by the FDA for unilateral treatment of ET215.
FUS lesioning requires patients to shave their head, and
~8% of the population is not eligible owing to skull
thickness216.
Adverse effects of DBS and FUS lesioning are well
documented217. These effects are often related to the sur-
gical procedure; for example, haemorrhage (in 0.5–1.5%
of patients), infection (in 1.7–5.4% of patients) or frac-
ture or migration of the inserted hardware (in 1.4–3.8%
of patients)218. Moreover, the long-term effects of stim-
ulation or ablation can cause a range of complications,
for example, neurological adverse effects such as ataxia,
dysarthria, paraesthesia, worsening verbal fluency,
sensory disturbances, hemiparesis, confusion or cog-
nitive impairment217. Stimulation-related effects may
be resolved by adjustment of the stimulation parame-
ters. Different adverse effects can occur depending on
whether interventions are unilateral or bilateral219. DBS
also has a gradual loss of efficacy related to habituation
to disease progression204.
Alcohol (ethanol)
About two-thirds of patients with ET report transient
improvement of their tremor after one or two alcoholic
drinks17. Despite this observation, alcohol responsiveness
was considered “not consistent enough to be included in
the definition of ET” in the 2018 Consensus Statement1.
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Table 2 | Investigational treatments for essential tremor
Drug Mechanism of action NCT number
SAGE-324, SAGE-547 Allopregnanolone, NCT04305275, NCT02277106
positive allosteric
modulator of GABAA
receptors
CX-8998 Cav3 T-type calcium NCT03101241
channel blocker
PRAX-944 T-type calcium channel NCT05021991
blocker
CAD-1883 Positive allosteric NCT03688685
modulator of the
small conductance
calcium-activated
potassium ion channels
Cannabidiol Multiple targets NCT03805750
OnabotulinumtoxinA Chemodenervation NCT03136341, NCT02551848,
and incobotulinumtoxinA NCT02427646, NCT02207946,
NCT02555982
GABA, γ-aminobutyric acid.
Although alcohol may transiently (3–4 h) suppress
tremor in social situations with judicious use, it should
not be recommended as a routine treatment for ET
owing to rebound tremor exacerbation the following
morning and risk of alcohol abuse with frequent use63.
The exact physiological mechanism by which alco-
hol improves ET is not well understood. Several studies
have shown that alcohol can inhibit the function of both
NMDA and non-NMDA glutamatergic receptors, but it
probably acts primarily as a GABAA receptor agonist,
although alcohol also modulates serotoninergic, dopa-
minergic, glycinergic and adenosinergic pathways220.
Furthermore, PET studies have shown that alcohol is
associated with a reduction in cerebral blood flow in the
cerebellum and an increase in blood flow in the ION56.
Octanol, an 8-carbon alcohol used as a food flavour-
ing agent, is metabolized to octanoic acid, which has
been shown to provide a short (90–120 minutes) benefit
in patients with ET in some open label and controlled
studies221. Although well tolerated, octanoic acid has
not yet been approved for the treatment of ET, partly
because it requires large volumes to be effective with oral
administration222. One small open label study showed
that sodium oxybate, an alcohol analogue, may reduce
tremor amplitude in ET223; however, it has limited use in
the treatment of tremor owing to sedation and potential
for abuse.
Other treatments
Non-invasive brain stimulation techniques including
repetitive transcranial magnetic stimulation, theta burst
stimulation, transcranial alternating current stimula-
tion (tACS) and transcranial direct current stimulation
have all shown preliminary signs of reducing tremor106.
Studies have varied in stimulation method, target and
assessment, but support consecutive daily sessions
and the cerebellum as a key target; for example, tACS
of the cerebellum can have a therapeutic effect when
phase-locked with the tremor224. Non-medical thera-
pies such as relaxation and biofeedback may be effective
in some patients. Transcutaneous afferent patterned
stimulation of the median and radial nerves in the wrist
could reduce tremor severity for more than an hour in
some patients225.
Quality of life
For most patients with ET with mild tremor, quality of
life (QOL) is not greatly affected. Nonetheless, ET can
affect many aspects of life including social, emotional,
physical and mental domains. ET may also affect basic
daily tasks such as writing, eating and using electronic
devices, and activities such as work or employment and
hobbies.
Studies show that QOL is reduced in patients with
ET163 and that QOL issues are often not sufficiently
addressed in treatment discussions226. Accordingly, con-
sideration of QOL issues of the individual in a holistic
approach to care, and not only tremor characteristics,
is important for treatment considerations. Clinical tri-
als for ET commonly use QOL as an outcome measure,
for example, in studies of surgical interventions227, new
drugs228 or other interventions229, therefore, QOL is a
convenient, functionally relevant and individual-focused
concept in the study of ET.
Generalized QOL measures
Some studies of QOL in ET have used generalized QOL
scales, such as the Short-Form 36-item health survey
(SF-36) or Rand SF-36. One study in Germany found
lower QOL scores in all domains (evaluated using the
SF-36) in patients with ET compared with controls163.
The domain with the largest difference from controls
was the mental health domain, particularly in the
>40-year-old subgroup. Moreover, one Australian study
found significantly poorer QOL (assessed using Rand
SF-36) in patients with ET compared with controls230.
An Egyptian study was concordant with these studies,
also demonstrating worse QOL in all eight domains of
the SF-36 in patients with ET compared with controls231.
ET-specific QOL measures
A drawback of generalized QOL measures is that they
are not specific to the problems faced by patients with
ET. To address this issue, the Quality of Life in Essential
Tremor Questionnaire (QUEST) was developed in
2005. The QUEST contains 36 items and comprises five
domains: physical, psychosocial, communication, hob-
bies and work/finance232. Another ET-specific scale is
TETRAS, which includes sections for performance and
activities of daily living233.
Studies using the QUEST found significantly reduced
QOL across all domains in patients with ET. One study
in India noted that tremor is a cause of poor QOL in
patients with ET and that it particularly affects the
psychosocial domain234. Forty-six per cent of participants
responded that their tremor always interferes with their
job or profession, 34% of participants responded that
their tremor always makes them feel negative about
themselves and 32% responded that their tremor causes
embarrassment234. These data agree with the literature
associating ET with symptoms of depression, anxiety
and social isolation235,236. Regarding the effect of ET on
work, early retirement and hesitance to apply for jobs or

12 | Article citation ID: (2021) 7:83 www.nature.com/nrdp

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promotion are more common in patients with ET com-
pared with controls237,238. Together, studies of ET-specific
QOL have highlighted the strong influence of psycho-
social aspects on perceived QOL, whereas tremor char-
acteristics such as age of onset, duration or distribution
have a relatively minor influence234.
Outlook
Achieving the following high- level goals will require
broad cooperation of research teams: a more open
approach to ET research, collaboration, reproducibil-
ity, replication of findings and sharing of research data.
Useful and simple steps include pre- registration of
ET studies in online databases, publication of analysis
protocols and publication of anonymized data sets.
Genetics
Despite the high prevalence of ET, most studies have
been based on small sample sizes, and this is particu-
larly evident in GWAS and genetic association stud-
ies. To overcome this issue, a large-scale global clinical
and genetic consortium to gather data from patients of
different ethnicities who have ET is required.
Future studies should include additional efforts to
identify monogenic forms of ET. Moreover, composite
scores for genetic risk should be evaluated for sporadic
ET, which is most likely caused by additive effects of
multiple genes and other factors. To formulate aggregate
measures of risk and for subtyping or stratification of ET,
in-depth phenotyping of individual patients should be
carried out, and should span all relevant biological layers
from genetics through to behaviour. This so-called deep
phenotyping approach has been previously raised by
the MDS Tremor Study Group as an important research
goal239. Use of machine learning tools will be key to ana-
lysing these large data sets240. This approach will require
coordination across several fields of expertise.
Experimental models
With the advances in stem cell technology, ET-linked
genetic variants can be studied in induced pleuripotent
stem cells from patient fibroblasts or blood. Isogenic
human cell lines can be created to investigate the conse-
quences of the genetic perturbations. However, genera-
tion of PCs from stem cells is challenging and, despite
insightful observations from studies using animal mod-
els of ET, these models do not fully recapitulate all the
features of human disease nor do we know whether
the cellular phenotypes from cultured PCs reflect ataxia or
tremor. In addition, developing a validated standardized
evaluation tool that captures the components of tremor
in humans is difficult. Although there have been some
improvements in this area, for example, using machine
learning methods to track leg positions using high-speed
video recording in Drosophila that express mutant
neurodegenerative genes241, further work is needed.
Pathophysiology
Collaborative post-mortem studies using brains from
patients with ET are needed to further address and
characterize the morphological changes in the circuits
and neuronal subtypes in the cerebellum and other
NATURE REVIEWS | DISEASE PRIMERS | Article citation ID: (2021) 7:83
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PRIMER
brain regions involved in tremor networks. Correlation
of these changes with the severity of ET will enable
more robust classification and staging of the disease.
Pathophysiological studies in different ET subtypes
will also provide useful insights in this regard. More
integrative work that aims to investigate links between
pathophysiological data and other data in ET, such as
neuroimaging or genetic data, is needed to bridge the
gap between systems-level and neurobiological obser-
vations and, ultimately, inform a more unified model of
ET pathogenesis.
Neuroimaging
The role of neuroimaging in clinical practice for ET has
been limited, but several technological developments in
MRI acquisition and analysis have improved sensitiv-
ity of neuroimaging to evaluate ET pathology. Indeed,
multi-band imaging has increased the temporal resolu-
tion of functional MRI acquisitions by twofold to five-
fold, with minimal loss of signal to noise ratio, and it can
extend the capability of diffusion imaging242,243. A sec-
ond advance is the maturation of ultra-high-field MRI
(≥7 Tesla); 7-Tesla MRI platforms were FDA-approved
in 2017 and 2020, and offer improved performance and
increasing availability. The increased signal to noise ratio
of 7-Tesla MRI confers greater resolution and contrast,
and therefore, improved capability to depict and charac-
terize brain structures244. Owing to these improvements,
further studies using these neuroimaging technologies in
ET should be carried out, including studies before and
after treatment and of at-risk asymptomatic individuals.
Neuroimaging may have a key role in selecting patients
for specific therapies, in uncovering underlying tremor
mechanisms and in identifying reproducible new multi-
modal biomarkers245, for example, those based on brain
connectomics243,246,247. Neuroimaging may also be useful
to identify the neural correlates of comorbid cognitive
changes in ET, for example, in executive functioning248.
Therapeutics
Identification of new causative genes and environmen-
tal or lifestyle risk factors for ET will lead to develop-
ment of more experimental therapeutics and, ultimately,
clinical trials of novel compounds. Both invasive and
non-invasive neuromodulation approaches should be
further investigated for ET treatment, and available
methodologies should be improved. The use of better
wearable orthoses, assistive feeding devices and refine-
ment of electrical stimulation systems (both trans-
cutaneous and functional stimulators) will address the
challenges patients face in their daily life. In light of this,
clinical trials of devices in combination with pharma-
cological treatments should be considered. Moreover,
a multidisciplinary approach with the involvement of
patient advocacy groups to address the real-world fac-
tors that affect patients’ QOL will help to reduce the
disease burden for patients with ET and their caregivers.
Clinical outlook
The ultimate goal of ET research is to enable a person-
alized medicine approach. To achieve this, a central
research theme in the next decade should be identifying
13
PRIMER
subtypes of ET based on validated and reproducible
quantitative measurements. The clinical and aetiolog-
ical heterogeneity of ET coupled with the variability
of research findings in many areas undermines other
areas of ET research and suggests that there is much
progress to be made in better defining the disease. With
improved theories and evidence for ET definition and
subtyping, all other areas of research will benefit from
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Acknowledgements
The authors gratefully acknowledge E. Louis (University of
Texas Southwestern Medical Center, USA) for his input on the
pathophysiology section. They acknowledge support of
the National Medical Research Council under its Open Fund
Large Collaborative Grant (MOH- OFLCG18May-0002 and
STAR award to E.K.-T.). T.W. acknowledges the support of the
National Medical Research Council (OFYIRG20nov-0032).
Author contributions
Introduction (E.-K.T., T.W., J.A.C., L.-L.C., G.D. and J.J.);
Epidemiology (E.-K.T., T.W. and J.A.C.); Mechanisms/
pathophysiology (E.-K.T., T.W. and G.D.); Diagnosis, screening
and prevention (E.-K.T., T.W., F.C. and J.J.); Management
(T.W.); Quality of life (E.-K.T. and T.W.); Outlook (E.-K.T., T.W.,
F.C., J.A.C., L.-L.C., G.D. and J.J.); Overview of Primer (E.-K.T.).
Competing interests
The authors declare no competing interests.
Peer review information
Nature Reviews Disease Primers thanks Alfonso Fasano, Félix
Jiménez-Jiménez, Sheng-Han Kuo and the other, anonymous,
reviewer(s) for their contribution to the peer review of this
work.
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