Essential Tremor

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 Essential tremor (ET) is the most common movement and income, as up to 88% of people with ET are unem-
Tremor that occurs with disorder encountered in the clinic. In its purest form, ET ployed, partly owing to impairment from the disease.
the voluntary movement is characterized by an isolated upper limb action tremor Moreover, the estimated annual amount of lost income
of a muscle. of at least 3 years’ duration without other neurologi- for a family affected by ET is US$50,000 (REF.2). However,
Postural tremor
cal signs1, although some patients may exhibit a range despite its high prevalence, evidence for the economic
Tremor that occurs when a of other symptoms and signs. ET is defined accord- burden of ET is limited. This is primarily because few
person maintains a position ing to clinical characteristics rather than aetiology, as studies have attempted to measure the impact of the
against gravity. described by axis 1 of the 2018 Consensus Statement by disease and it is not included as a category in the Global
the task force on tremor of the International Parkinson Burden of Disease database. The latter issue may be due
Kinetic tremor
Tremor that occurs with
and Movement Disorder Society (MDS) and, as such, to the contentions and variability in the definition of ET
movement. is considered a tremor ‘syndrome’1. Although ET most mentioned herein, and the ensuing scarcity of reliable
often affects the hands, it can also affect the head, legs, epidemiological data. Additionally, the burden of com-
ET plus arms, vocal cords, torso or other regions. Action trem- mon co-occurring symptoms, such as disorders of mood,
Essential tremor (ET) with other
neurological signs.
ors can be further subdivided into postural tremor or gait and hearing, is unknown and difficult to estimate.
kinetic tremor. The diagnosis, investigation and management of ET
Although both genetic and environmental factors are are challenging and debated. First, ET is aetiologically
thought to be involved in its aetiology, no single marker and clinically heterogeneous and there are different
or test alone can identify ET. The pathophysiological expert opinions regarding its classification and defi-
mechanisms are not well understood but likely involve a nition. Diagnostic guidelines have been proposed 1,3,
cerebellar–thalamic–cortical loop and in many patients, but certain categorizations such as ET plus have been
neuropathological changes in the cerebellum. Moreover, debated. Since the ET plus entity was proposed in the
genetic studies have identified several loci, genes, risk 2018 Consensus Statement1, several studies have found
factors and protective factors for ET. Neuroimaging that ET plus is more common than isolated ET 4,5.
studies have found dysfunctional structural, functional Furthermore, diagnostic criteria have historically been
and metabolic changes in the cerebellum, thalamus and applied inconsistently. Second, the differential diagnosis
cerebral cortex in patients with ET, and pathological for ET in general is challenging as no specific tests that
studies have found neuronal changes in the cerebellum. distinguish ET from other forms of tremor are availa-
✉e-mail: gnrtek@sgh.com.sg The annual economic burden of ET in the USA is ble. Third, the pathophysiology of ET — for example,
https://doi.org/10.1038/ estimated as US$143 billion2. Costs include therapies, regarding whether ET is primarily a neurodegenerative
s41572-021-00314-w but the larger burden is from loss of work opportunities disease — is debated.
NATURE REVIEWS | DISEASE PRIMERS | Article citation ID: (2021) 7:83 1
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Author addresses of ET prevalence is difficult owing to variation in study

design, even between studies in the same country.
1
Department of Research, National Neuroscience Institute, Singapore, Singapore. However, prevalence estimates of ET do vary accord-
2
Neuroscience Academic Clinical Programme, Duke-NUS Medical School, ing to geographical region between studies of similar
Singapore, Singapore.
design; for example, a prevalence of 0.8% was found in
3
Movement Disorders Unit, Neurology Service, Internal Medicine Department,
Arab individuals in Israel13, 6.3% in Turkish individuals14
University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
4
Division of Neurology, Faculty of Medicine and Health Sciences, Stellenbosch University, and 6.4% in Basque people 15, all aged ≥60 years,
Cape Town, South Africa. with the same definition of ET and examination12.
5
Department of Diagnostic Radiology, Singapore General Hospital, Singapore, However, what precise phenotypic or environmental
Singapore. factors are reflected by these differences is unclear.
6
Radiological Sciences Academic Clinical Programme and Neuroscience & Behavioral
Disorders Signature Research Programme, Duke-NUS Medical School, Singapore, Demographics
Singapore. Epidemiological studies originally suggested a bimodal
7
Department of Neurology, Christian Albrechts University, Kiel, Germany. age at onset of ET, with peaks occurring in the twenties
8
Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology,
and sixties16,17. Approximately 5% of new cases occur
Baylor College of Medicine, Houston, TX, USA.
before age 20 years with most cases occurring in those
9
Department of Neurology, National Neuroscience Institute, Singapore, Singapore.
>40 years of age7,18,19. Age at onset has important clin-
ical consequences: familial ET tends to have a younger
This Primer reviews the current epidemiology, onset whereas older-onset sporadic ET tends to have a
pathophysiology, diagnosis and management of ET. This rapid disease progression20 owing to reduced reserve and
Primer provides a balanced review, highlighting the con- ageing-associated neuronal loss20. The age at onset of ET
trasting hypotheses on whether the pathophysiology of correlates with the age at onset of relatives21. However,
ET includes neurodegeneration. studies of ET onset are limited, as onset is insidious and,
therefore, often difficult for patients to precisely recall.
Epidemiology In general, the prevalence of ET is similar in men
Prevalence and incidence and women, but women have a higher prevalence of
The estimated prevalence of ET is 3.2 cases per 1,000 head tremor and also tend to have more severe head
individuals globally, rising to 28.7 cases per 1,000 indi- tremor, whereas men tend to have more severe postural
viduals in those aged >80 years6. The incidence of ET tremor22,23. These findings are speculated by some to
increases with age, with an estimated annual incidence be caused by differences in health-seeking behaviour
of 0.2 per 1,000 individuals in those aged ≥65 years in or hormones. Although one study has indicated that
a study in the USA7, and a Spanish study reported an patients with ET live longer than individuals without
annual incidence of 6.2 per 1,000 individuals8. ET24, other studies found increased mortality in patients
Studies evaluating the prevalence of ET have been with ET compared with the general population (risk
carried out in several countries (FIG. 1), including assess- ratio 1.59)25,26.
ment of whole populations and two-phase ‘door-to-door’ Some studies have directly investigated ethnic or
studies, which comprise population-based screening racial differences in ET prevalence and clinical char-
using a questionnaire, followed by specialist confirma- acteristics, and could help highlight susceptible geno-
tion of potential cases. A key criticism of epidemiological types or environmental exposures associated with ET27.
studies of ET is the inconsistent application of diagnos- For example, studies have found significant variation
tic criteria, which could result in the misclassification in prevalence between populations defined by lan-
of ET. The inclusion of individuals with mild tremor as guage in Papua New Guinea18, marginally higher prev-
ET cases likely accounts for the reporting of very high alence in Indians than in Chinese or Malay individuals
prevalence figures in some studies, for example, a prev- in Singapore28 and nonsignificant trends towards higher
alence of 55% in individuals aged >40 years in Finland prevalence in white than Black individuals in Mississippi,
(with a prevalence of 66% in men >40 years old)9. The USA29. However, another study found lower severity of
introduction of new MDS guidelines for tremor in 2018 ET in white individuals than in non-white individuals
(REF.1) may lead to the harmonization of ET diagnosis, in Manhattan, USA30.
but it is likely that older studies may reflect a range of
underlying diagnostic entities, affecting their accuracy. Genetic risk factors
To our knowledge, no published epidemiological studies Approximately 50–70% of patients with ET have a pos-
have explicitly used the 2018 MDS criteria for tremor. itive family history of this disorder31, and first-degree
Familial ET Comparing the prevalence of ET in populations with relatives of patients with ET are ~4.7 times more likely
Essential tremor (ET) in a large socioeconomic differences may be difficult10 and, to have ET than controls32. Although the inheritance
patient with a family history
although commonly used, screening questionnaires for pattern varies, in some families inheritance seems to
of ET, usually consistent
with autosomal dominant ET have low sensitivity (15% for mild ET and 73% follow an autosomal dominant pattern with incom-
transmission. for moderate or severe ET)11. Perhaps owing to the use plete penetrance33. Some family members of patients
of variable approaches and diagnostic criteria, the preva- with ET may have other movement disorders, such as
Sporadic ET lence and incidence of ET vary substantially across epide- parkinsonism34 or dystonia35. Several putative genetic
Essential tremor (ET) in a
patient without an underlying
miological studies12. This apparent difference (FIG. 1) may loci and/or possible pathogenetic gene variants for ET
cause or family history (also reflect methodological differences rather than true dif- have been identified (TABLE 1; FIG. 2), including both risk
known as idiopathic ET). ferences in disease burden. Carrying out meta-analyses factors and protective factors.
2 | Article citation ID: (2021) 7:83 www.nature.com/nrdp
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Italy
1.2
Austria
Turkey China
Faroe Islands
3.4
1.6 3.1 4 5.8 3.3 6.5
2.9
Spain South
USA Korea
4.8 4.8 8.6 Israel

5.5 3.6
Bangladesh
1.4 1.8
2.5
Brazil Nigeria India
Crude
prevalence (%) Singapore
9 3.4 1.2 Tanzania 1.4
0.2
0.04
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 A variant of LINGO1 (which encodes a central
16 families (75 affected members) in Iceland, on chromo- nervous system transmembrane glycoprotein that is
some 3q13, with an apparent autosomal dominant pat- expressed in the cerebellum and deep grey matter nuclei)
tern of inheritance36. However, the link between ET and was the first genetic risk factor with genome-wide sig-
this locus could not be consistently replicated in other nificant association in a GWAS of ET40–42. Variants of
populations. A functional variant (Ser9Gly) of DRD3 LINGO2 (a paralogue of LINGO1 that is thought to have
(encoding dopamine D(3) receptor, which is located in similar functions) are also associated with ET43,44. Thus
the ETM1 locus) subsequently attracted considerable far, meta-analysis has suggested overall robust associa-
interest; however, genetic association studies produced tion of LINGO1 with ET. A variant of SLC1A2 (encoding
conflicting findings, with mostly negative results. a glial high-affinity glutamate reuptake transporter) was
Exome sequencing studies identified a p.Gln290(∗) identified as a risk variant for ET in a European cohort
mutation in FUS (encoding RNA-binding protein FUS) in one GWAS45, but the same variant was later shown to
in a family with ET and two rare missense FUS vari- be protective in a Chinese cohort46. A variant in STK32B
ants in a cohort of white patients with ET37. Moreover, (encoding a serine/threonine kinase) was protective
other studies identified a novel variant, Met392Ile, in against ET in two studies47,48. Moreover, a risk variant
exon 12 of FUS that increases risk of ET among Chinese in PPARGC1A (encoding a transcriptional co-activator
individuals in Taiwan and Singapore38. Of note, one for mitochondrial function and energy metabolism)
whole-exome study of multigenerational families with was identified in one study47 but that was not replicated
ET and autosomal dominant inheritance found no sig- in two other studies48,49. Several variants in CTNNA3
nificant enrichment of rare variants in patients with ET (encoding a cell–cell adhesion molecule) were associated
compared with controls, although some variants that with ET in another study47, which has been replicated48.
have potential significance need further evaluation39. The clinical association between ET and Parkinson
More recent identification of putative causative var- disease (PD) is relevant, as patients with ET have a
iants in ET probands or families have either not been higher risk of PD than the general population50. A report
replicated or are awaiting further replication (TABLE 1). of a PD- linked variant of LRRK2 conferring similar
Evaluating genetic risk and protective factors for ET, risk in patients with ET is intriguing and needs further
particularly in patients with no apparent family history, replication51. Similarly, patients with ET harbour patho-
is also important in addition to identifying monogenic genetic genes (such as NOTCH2 and NLC)52 that are
causes of ET. Both genome- wide association studies responsible for other neurodegenerative diseases, sug-
(GWAS) and candidate gene association studies have been gesting potential overlap of pathophysiological path-
used to identify these genetic risk and protective factors. 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

having higher blood lead concentrations than controls71.
GABA, γ-aminobutyric acid; NA, not applicable; OMIM, Online Mendelian Inheritance in Man.
On pesticides, the evidence is contradictory, with studies
finding no differences in serum pesticide concentration72
in other genetic syndromes may pose considerable or self-reported exposure58,69 in patients with ET ver-
challenge in early diagnosis unless appropriate genetic sus controls, and others finding positive associations
testing is carried out for those syndromes. between self-reported exposure and ET73,74.
Although genetic studies have provided insights into Smoking has a protective effect for ET, which is
the possible mechanisms of ET, these studies have sev- believed to be due to an effect of nicotine at nicotinic
eral limitations, such as clinical heterogeneity, the lack acetylcholine receptors 75. Three studies found that
of gold standard diagnostic criteria with post-mortem individuals who never smoked had double the risk of
validation, genetic heterogeneity and incomplete clinical ET compared with those who had smoked at any time,
penetrance, small sample sizes, the presence of ET-like and that there was a dose- dependent response58,76,77.
phenotype in other genetic syndromes and a lack of One study suggested that shorter sleep duration was
good animal models that fully recapitulate the disease. associated with incident ET risk78.
Another limitation is the question of whether ET is a
single condition or a syndrome. Mechanisms/pathophysiology
The pathophysiology of ET is still being elucidated,
Environmental risk factors with multiple overlapping hypotheses and supporting
Although concordance between monozygotic twins evidence and many unanswered questions. In essence,
is high for ET (60–93% compared with 25–59% for both genetic and non-genetic risk factors contribute to
dizygotic twins)53,54, it is not complete, implying that changes in molecular, biochemical and cellular compo-
non-genetic factors have an aetiological role in some nents and oscillatory neuronal activity, resulting in clin-
patients55 (FIG. 2). Despite studies providing some evi- ical tremor. Mechanistic studies of ET have been limited
dence about putative environmental causes of ET, by clinical and aetiological heterogeneity, adding to the
further research is required. debate on whether ET is a syndrome, a single disease or
Diet has been highlighted as a potential factor in a family of diseases. Here, we summarize the key find-
ET. First, ethanol has acute tremor-relieving effects via ings in order of biological scale, from macroscopic and
suppression of the inferior olivary nucleus (ION)56 and morphological changes to molecular perturbations.
GABA transmission57; however, other studies suggest
that alcohol could, conversely, be a risk factor for ET58,59, Neuroimaging
owing to a degenerative effect on the cerebellum, includ- Studies with structural MRI have been lacking in sample
ing atrophy and loss of Purkinje cells (PCs)60. In gen- size and show only weak or unreplicated associations
eral, studies on the effects of ethanol on ET have yielded with clinical severity. Reductions in volume of brain
positive61, negative62 and inconclusive58,59 results. These parenchyma — most frequently in the cerebellum —
studies are complicated by links with chronic alcoholism have been observed in patients with ET; however,
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a meta-analysis of these studies found no reliable mor- thalamus, motor cortex and red nucleus89. However, two
phological differences between patients with ET and subsequent SPECT studies of regional cerebral blood flow
controls79 and, although atrophy of the cerebellum in the cerebellum showed divergent findings90,91. SPECT
was found in several studies, it did not survive overall has also been used to study dopamine transporter bind-
robustness analysis. Atrophy of the cerebellar peduncles ing in the striatum in patients with ET, but studies did not
(comprising spinocerebellar and vestibular afferents, find decreased striatal dopamine uptake92. Studies using
and the olivo-cerebellar pathway) may also be present80. BOLD functional MRI have observed increased activa-
Moreover, diffusion MRI studies of ET have found tion predominantly in the cerebellum and red nucleus
increased mean diffusivity and decreased fractional in patients with ET compared with mimicked tremor in
anisotropy of various white matter tracts, predomi- controls93. Moreover, studies during rest found abnor-
nantly in the cerebellum and cerebellar peduncles81,82, mal functional connectivity of a cerebellar–thalamic–
among other regions83,84, including a cortico-pontine cortical network94,95 and decreased functional connectivity
tract (FIG. 3). By contrast, some diffusion MRI studies did locally within the cerebellum in patients with ET96. Taken
not find differences in the cerebellum85 or non-motor together, data from functional MRI studies support
regions in patients with ET81. Magnetic resonance spec- changes in metabolism, activity and connectivity in the
troscopy (MRS) studies have found a reduction in the cerebellum and a possible wider tremor-related network
ratio of N-acetyl-l-aspartate and total creatine in the cer- in ET, but these studies are limited by low temporal reso-
ebellar cortex of people with ET86,87 that correlated with lution precluding direct correlation to tremor signals and
tremor severity87 and blood harmane concentration88, wide variation in approach and methodology.
suggesting metabolic damage. Overall, some structural
MRI studies support differences in morphology and Electrophysiology
microstructure of the brain in patients with ET but many Electrophysiological studies using electroencepha-
findings are unreplicated or not robust. lography (EEG), magnetoencephalography and brain
Functional MRI techniques including positron emis- stimulation have provided insights on the links between
sion tomography (PET), single-photon emission com- oscillations in peripheral muscle activity and oscillations
puted tomography (SPECT) and blood oxygenation in brain circuits. Historically, a single central oscilla-
level- dependent (BOLD) imaging have been used in tory (the ION) was suggested on the basis of lesioning
small-scale studies of ET. Regional cerebral blood flow was studies97 and because of the capability of cells in the
first quantified using PET in patients with ET, and bilat- ION for rhythmic excitation98; however, this model
eral increased activity was found in the cerebellum during was later refuted99 and is no longer widely supported.
resting and active states, in addition to in the striatum, In an updated model based on electrophysiological and
neuroimaging data, various brain regions have been
identified as nodes of a tremor-related network includ-
Environmental Genetic Epigenetic ing cerebellum, thalamus and motor cortex, intercon-
factors factorsa factorsa
• Exposure to • ETM1–5 Possible nected by pre-lemniscal and cortico-pontine tracts, and
pesticides or • FUS involvement the Guillain–Mollaret triangle100 (FIG. 3). This network
heavy metals • TENM of epigenetic has been implicated in peripheral tremor101 and tremor
• Dietary factors • LINGO1 factors
• Smoking • SLC1A2 syndromes such as physiological tremor102, parkinso-
• CTNNA3 nian tremor and ET101. Several studies have evaluated
the initiation and maintenance of the tremor network
during action tremor using electromyography and EEG,
Biological interactions and have demonstrated that, while the network becomes
• Gene–gene interactions simultaneously active103, the participation of the cortex is
• Genetic modiﬁcations
• Gene–lifestyle interactions intermittent104. Lesioning of any single component of the
• Protective genetic factors tremor network greatly diminishes tremor105. Studies of
• Protective lifestyle factors non-invasive brain stimulation show preliminary signs
of reduced tremor when the stimulation is applied to the
motor cortex or cerebellum106.
At-risk individuals
Neuropathology
Post-mortem studies of patients with ET have identi-
Time and ageing
fied morphological changes in various neuronal sub-
types in the cerebellum. One group found a loss of
Clinical ET PCs107, although this finding was not replicated by two
other groups108,109. Other observations in PCs include
Fig. 2 | Risk and aetiology of essential tremor. Essential swelling of neuronal processes110, reduced dendritic
tremor (ET) is caused by the biological interaction of environ-
complexity111, terminal axonal sprouting112, arciform
mental, genetic and epigenetic risk and protective factors.
In turn, the interaction of these factors raises the overall risk PC axons (which gradually curve back towards the PC
of ET in some individuals and, in combination with ageing, layer)113, increased spacing between PCs and abnor-
results in the clinical manifestation of ET. More research on mal positioning of the PC soma (known as heteroto-
environmental factors is required to confirm their association pia)114. Morphological changes have also been observed
with ET. aLimited supporting evidence. in basket cells (GABAergic interneurons that form
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an increase in glutamate concentration121. Moreover,

Motor cortex
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-
VIM
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
Red believe that GABAergic dysfunction may be associated
nucleus with ET.
Pons Animal models

Dentate
nucleus 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
ION pigs130. Although a comprehensive review of ET animal
studies is beyond the scope of this Primer, we discuss
Cerebellar cortex
some notable examples. First, in mammals, harmaline
elicits a burst-firing of neurons in the ION that mani-
Cortico-pontine tract
Pre-lemniscal radiation fests as action tremor131. Importantly, drugs that sup-
Guillain–Mollaret triangle press tremor in patients with ET are also effective in the
Spino-cerebellar tract Spinal cord
Other interconnecting
harmaline model, demonstrating its usefulness for drug
white matter tracts screening130. Second, genetic mutations identified in
human studies can be overexpressed in animals such as
Fig. 3 | Key pathways involved in the pathophysiology of essential tremor. The brain in D. melanogaster, which has been used for large-scale
circuits involved in essential tremor pathophysiology can be conceptualized as four screening and genetic manipulation132. Third, mice defi-
intersecting pathways within the cerebellar cortex. The inferior olivary nucleus (ION), cient in GluRδ2 (which regulates pruning of climbing
dentate nucleus, pons, red nucleus, thalamus and motor cortex are key loci interconnected fibres and PC and parallel-fibre and PC synapses133 and
by these pathways. VIM, ventral intermediate nucleus.
which is abnormal in patients with ET117,118) have a 20 Hz
action tremor. Rescue of GluRδ2 improves tremor and
pericellular ‘baskets’ around PC somas) and climbing causes rewiring of climbing fibre synapses133. Subsequent
fibres (excitatory projections from the ION to the cere- lesioning and optogenetic experiments supported links
bellum)113. In basket cells, the Pinceau process (which between the ION (as the origin of climbing fibres), PCs
encapsulates the initial segment of the PC axon) is and interposed nucleus in this model134. Of note, similar
elongated and the basket-shaped elaborations around to the situation in humans, ET in animal models is hetero-
the PC soma are sometimes empty115 or are dense and geneous; thus, although animal models cannot reca-
tangled116. Moreover, climbing fibres have abnormal pitulate the spectrum of human ET, they can represent
distributions of connections onto PC dendrites117,118, individual features or contributing mechanisms.
extending in greater numbers to the outer molecular
layer and synapsing more frequently with the distal PC Interpretations
spiny branchlets than age-matched controls117,118. Overt GABA dysfunction. Although GABAergic dysfunction
morphological changes have not been observed in other is widely linked with ET pathophysiology, how it inter-
brain regions in ET, including the thalamus, red nucleus, acts with other pathophysiological alterations in ET
dentate nucleus and ION119,120. However, overall there is remains to be elucidated. Some proponents have drawn
no widespread consensus or support for the presence of putative links in a specific order: from PC loss (as a sug-
neuropathological changes in ET. gested primary driver) to the reduction in activity of the
GABAergic system in deep cerebellar neurons, subse-
GABA dysfunction quent disinhibition of pacemaker activity and, finally,
The presence of GABA dysfunction in ET has been stud- propagation of rhythmic activity to wider tremor net-
ied for several years. The concentration of GABA in the work circuitry135. Although PC depletion is known to
cerebrospinal fluid of patients with ET is reduced, with reduce GABAergic cerebellar corticofugal output136, the
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loss of PCs in ET is debated (see Neurodegeneration, are needed to address this uncertainty. Another expla-
below). Furthermore, dentate neurons rarely exhibit nation for the pathological findings in ET could be plas-
pacemaker- like behaviour in the tremor frequency ticity of the cerebellum, rather than neurodegeneration,
band125. Other groups have proposed that tremor may as some changes seem to be reversible in patients with
instead originate from dysfunction and compensa- reduced tremor after deep brain stimulation (DBS)144.
tory upregulation of GABAergic activity in the dentate
nucleus, followed by oscillation of the olivo-cerebellar Pruning. Preliminary studies suggest a pruning-related
loop and subsequent oscillation of the thalamus and paradigm based on data obtained from the GluRδ2-
motor cortex137 (FIG. 3). Consistent with this hypothesis, deficient mouse model134. Studies have found an over-
one study in mutant mice (the ‘pcd’ mutant) showed that all reduction in GluRδ2 in ET, which, combined with
PC degeneration alone was not enough to cause sus- the function of this protein in cerebellar fibre pruning,
tained thalamic–cortical oscillation138. Thus, although suggests that the deficiency could lead to the abnormal
GABA may have a key role in ET pathophysiology, its distribution of PC synapse formation. Indeed, rescue of
position in the overall causal chain still needs to be GluRδ2 in GluRδ2-deficient mice reduces tremor and
clarified. climbing fibre synapses, suggesting a possible causal
relationship between trembling, synaptic rewiring and
Network dysfunction. The presence of a tremor-related GluRδ2 expression133. In the same model, cerebellar EEG
brain network comprising the cerebellum, thalamus, correlated with mouse peripheral tremor, and local field
motor cortex and brainstem nuclei (FIG. 3) is widely potentials (due to activity of the ION) were related to
accepted. The presence of this network is supported by tremor. Collectively, these data suggest that the loop
data from an array of neuroimaging and physiological between the inferior olive, PCs and interposed nucleus
studies, which place the olivo-cerebellar system at the may be the circuit producing tremor in this mouse
core of the network, with the intermittent involvement model.
of cortical regions via the thalamus100. This network
is likely not static: dynamic changes in its configura- Ageing. Two key findings in ET are not yet clearly
tion and regional involvement are related to initiation understood. First, life expectancy seems to be lower in
of tremor and voluntary movements. Moreover, the people with ET26 and may145 or may not24 be specific to
tremor network is aberrant in several tremor syndromes, those with older-onset disease. Second, cognitive dis-
including ET, and is present in normal subjects, suggest- turbances are present in some patients with ET146 that
ing that it is a disinhibited physiological network. The may be restricted to, or have faster progression in, the
mutual entrainment of this network is supported by subgroup of those with older-onset ET145. These find-
the reduced tremor severity with lesioning of any network ings are supported by data from the large Danish Twin
component105 and by the theoretical ability of any com- Registry53,147. Moreover, in the Danish Twin Registry,
ponent to initiate tremor activity139. The wide distribu- survival depended on tremor severity, with shorter life
tion of the tremor network and its abnormal functional expectancy and poorer cognitive function in those with
connectivity during rest95 has led some to question more severe tremor. These patients with older- onset
whether subtle cognitive and emotional functions140 in ET have earlier signs of ageing (such as difficulties in
ET could be secondary to its disorganized functioning100. activities of daily living, grip strength reduction) that are
also related to tremor severity145, and differ from patients
Neurodegeneration. A proposed neurodegenerative with early-onset ET in heredity148, disease progression148,
ET model141 centres on ET as a degenerative disease of central tremor network function149 and age-related pro-
the cerebellum and attaches a preliminary sequence longation of the blink reflex150. These findings have
of events to the observed cellular morphological been interpreted to reflect a special form of ageing.
changes113. The reduction in the number of PCs, basket Patients with older- onset ET could, therefore, repre-
cell remodelling110, formation and hypertrophy of PC sent an ‘ageing-related tremor’ subgroup140. Although
arciform and recurrent collateral processes113, rewiring this hypothesis has not yet been thoroughly explored, it
of climbing fibres142 and pruning of the PC dendritic could explain some contradictory findings in ET, such
arbour may suggest reorganization of the cerebellar as the shorter life expectancy, earlier onset of dementia
cortex113. Physiologically, these changes may result in the and lack of critical unifying cause for death.
formation of aberrant PC synapses and development of
abnormal circuits in ET110,113. Diagnosis, screening and prevention
However, despite these findings, the neurodegener- Classification and definition
ation hypothesis of ET has yet to gain widespread trac- ET was defined by Critchley in 1949 as a single entity
tion. First, the potential secondary effects of neuronal characterized by hand and/or head tremor without
circuit dysregulation on the morphological changes to additional features but with familial predisposition151.
cerebellar neurons still need investigation. Moreover, Despite the ongoing application of this definition, some
the clinical–pathological correlation in ET is not yet movement disorder experts disagreed with it152 and
clear, and PC loss was not found by two independent identified a lack of consensus on the diagnostic criteria
groups108,109,143. Although the failed replications of PC being applied, specifically regarding the types of tremor
loss can be explained by differences in study method- and associated symptoms.
ology (case selection and definition, post-mortem sam- In the 2018 Consensus Statement 1 two axes are
pling, confounding and statistical power), further studies defined: axis 1, relating to clinical characteristics, and
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PRIMER
axis 2, relating to aetiology. Tremor syndromes are ET to gait impairment161. Sleep disorders are also fre-
classified only according to axis 1 (by clinical features) quent in ET, most commonly poor sleep quality and
and, importantly, not by aetiology. In this classification, daytime somnolence162.
ET is defined as an isolated tremor syndrome of bilat- Moreover, psychiatric disturbances such as depres-
eral upper limb action tremor that occurs with at least sion, anxiety, personality disorders and other mood dis-
3 years’ duration, with or without tremor in other loca- turbances have been reported in up to 30% of patients
tions and the absence of other neurological signs, such as with ET 163. Of note, depressive symptoms are not
dystonia, ataxia or parkinsonism1. The 2018 Consensus necessarily due to severe disability, as they have been
Statement establishes as exclusion criteria for ET syn- reported to occur before the onset of motor symptoms164.
dromes the following features: isolated focal tremors Psychiatric disturbances may, however, be related
(voice, head); orthostatic tremor with a frequency to head tremor more than other types of tremor165.
>12 Hz; task- and position-specific tremors; and sud- Cognitive deficits are also common in patients with ET,
den onset and step-wise deterioration. Interestingly, the particularly executive functioning166 and are not fully
MDS task force consider as another category of axis 1 accounted for by depression167. Mild cognitive impair-
these syndromes of isolated tremors. Over the past few ment is significantly more likely in patients with ET than
years, some groups have proposed that ET is either a in controls168, and Alzheimer disease dementia is also
syndrome or a group of diseases, with possible distinct more prevalent in patients with ET169, although it has
clinical features and differing underlying mechanisms not been confirmed post mortem and may be limited to
and aetiologies153. This change of concept is reflected in an older-onset subgroup170. Although the basis for these
the evolution of its definition. cognitive deficits is unclear, some studies have suggested
Other terms can be used to refer to different types of that they are mediated by dysregulation of the same cere-
ET. Sporadic ET and familial ET are widely used terms in bellar–thalamic–cortical circuits as ET171. Others may be
clinical practice but lack formal definition. The propor- related to co-occurring degenerative pathologies172. This
tion of familial ET in different series ranges from 50% is further supported by evidence of improved cognition
to 70%31. 1 year after DBS implantation specifically in patients
The concept of ‘ET plus’ is debated. The 2018 with earlier- onset ET173. However, studies of cogni-
Consensus Statement defines ET plus as “tremor with tive disturbances in ET have been criticized for being
the characteristics of ET and additional neurological underpowered174.
signs of uncertain significance such as impaired tandem The topic of comorbidities raises an important issue
gait, questionable dystonic posturing, memory impair- related to ET nosology and classification. Although
ment, or other mild neurological signs of unknown the conditions described above may accompany ET,
significance that do not suffice to make an additional they may also represent unique subtypes of ET with
syndrome classification or diagnosis.” The authors of this overlapping clinical features and possibly aetiopatho-
consensus statement also add that patients who meet cri- genesis. Indeed, it has been suggested that ET may be
teria for ET and present with tremor at rest should be categorized based on the presence of specific comorbid
classified as ET plus1. Critics of this definition state that disease as isolated ET, ET–parkinsonism, ET–dystonia,
the additional features might reflect a progression of the ET–ataxia, ET–neuropathy, ET–deafness, ET–task-specific
ET pathology instead of a different disease5, but evidence tremor, ET–orthostatic tremor or, based on the age of
shows no differences of cerebellar pathology between onset, as early-onset ET or older-onset ET175.
ET and ET plus154. Another possibility is that patients
classified as ET plus may have myriad conditions that Diagnostic and screening tests
initially present with a phenomenology that mimics ET. Diagnosis of ET is based on the presence of suggestive
Moreover, ET likely comprises different subtypes that clinical signs and symptoms. Diagnostic tests are carried
may represent separate entities with unique aetiopatho- out to rule out alternative causes of tremor, as there are
genesis. In light of these criticisms, the concept of ET no laboratory, neurophysiological or imaging markers
plus will likely not be widely adopted in clinical practice that are specific for ET1. Neurological examination can
and the scientific world. include assessments of muscle strength and tone, sensory
function, posture and coordination, gait and reflexes. For
Additional signs and symptoms tremor symptoms, pen and paper tasks are often used,
ET can be accompanied by a wide array of additional including handwriting, line drawing and Archimedes
signs and symptoms that are often functionally rele- spiral tests176. Medication side effects and caffeine use
vant but usually mild, although sometimes they can be should be considered during diagnostic work-up. Brain
disabling155. MRI is justified if the tremor had sudden onset and/or
One study found that the most common comorbidi- the neurological examination disclosed other signs in
ties in patients with ET were hypertension (52%), other addition to tremor. Particularly in those individuals with
nervous system disorders (45%), lipid metabolism dis- onset before 50 years of age, a practical approach for a
orders (44%) and mood and anxiety disorders (37%)156. patient who presents with action tremor of the upper
Hearing impairment is also common in patients with limbs and lack of additional features and without history
ET, with studies finding significantly higher rates of of use of tremor-inducing drugs involves study of thy-
self-reported impairment157,158, hearing handicap ques- roid function and work-up for Wilson disease (that is,
tionnaire scores159 and use of hearing aids than the gen- serum ceruloplasmin levels, 24 h urine copper levels and
eral population160. There is a well- established link of 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 The most important limitation for the use of prim-
dependent on central nervous system penetration190. In idone for ET is a relatively high frequency of adverse
addition to improving hand tremor, propranolol may effects, particularly sedation, ataxia and nausea. The tol-
also ameliorate head and voice tremor191,192. erability of primidone can be improved by starting with a
Although several β- blockers are useful for treat- low dose at night and gradually increasing the dose over
ment of ET, propranolol seems to be the most effective. a period of several weeks. There seems to be a synergistic
Some, with partial sympathomimetic properties, such as effect when propranolol and primidone are combined194.
pindolol and practolol, do not improve tremor or may
even worsen it193. Propranolol is generally well toler- Topiramate
ated, but some patients report fatigue, weight gain and Topiramate is a sulfamate-substituted monosaccharide
light-headedness; the latter may be related to bradycardia with several mechanisms of action including inhibition
and hypotension. Relative contraindications to propran- of voltage-gated sodium channels and augmentation of
olol include asthma, heart block and poorly controlled the inhibitory chloride ion influx mediated by GABA195.
congestive heart failure, bradycardia, hypotension, Several studies have confirmed the efficacy of topiramate
sick sinus syndrome and pheochromocytoma. in patients with ET196,197. Although the effectiveness of
topiramate is less established than that of propranolol or
Primidone primidone187, it provides a useful alternative or addition
Numerous open and controlled trials have found that for patients who do not benefit from either of these two
primidone (an anticonvulsant that presumably enhances drugs. The major barriers to the use of topiramate for the
GABAergic inhibition) improves ET, and its overall effi- treatment of ET are frequent adverse effects including
cacy may be comparable to that of propranolol187. The memory disturbance, poor concentration, word-finding
mechanism of action of primidone in ET is poorly under- difficulties, paraesthesia, weight loss and increased
stood, but is proposed to involve an alteration of trans- risk of kidney stones and thus higher discontinuation
membrane calcium and sodium ion fluxes190. Moreover, rate198. Owing to these potential adverse effects, starting
primidone is partly metabolized to phenobarbital and topiramate at a low dose and gradually increasing the
increases the duration of GABA receptor opening190. dosage as tolerated is recommended.
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Other pharmacological therapies knife thalomotomy206 and virtual cone (a non-invasive

Many other drugs are used for treatment of ET, but the radiosurgical technique)207, albeit with limited evidence.
selection of the most appropriate treatment must be DBS for patients with ET usually targets the ventral
individualized. Other drugs used include benzodiaze- intermediate (VIM) thalamus208, and has been found
pines (especially clonazepam and alprazolam), gabapen- to robustly (68–100%) reduce the amplitude of con-
tin, zonisamide and levetiracetam. Other oral therapies tralateral tremor in patients with disabling ET209. More
are being investigated in clinical trials188 (TABLE 2). In recently, the posterior subthalamic area encroaching on
this regard, a trial of CX-8998, a Cav3 T-type calcium the inferior borders of the VIM and sensory thalamus
channel blocker, demonstrated improvement in some has been considered the ‘sweet spot’ as a target for DBS
assessments of ET, although the primary end point was treatment of ET210. Three different systems are used for
not met (a reduction in tremor based on the video-rated DBS in patients with ET. Stimulation can be performed
Tremor Research Group’s The Essential Tremor Rating in one direction (omnidirectional) or two directions,
Assessment Scale (TETRAS) performance subscale)199. allowing for control of stimulation across the horizon-
tal plane. This directional stimulation may facilitate a
Botulinum toxin injections more targeted approach and help maximize the benefits
Botulinum toxin (BoNT) is used to treat various invol- of DBS while minimizing adverse effects. DBS for ET
untary movements, including ET involving the hands, is usually well tolerated but dysarthria (difficulty with
arms, legs, head or neck and voice, in addition to speech) and disequilibrium are relatively common,
PD-related rest tremor, dystonic tremor and cerebellar particularly with bilateral stimulation; surgery-related
outflow tremor200. complications, such as haemorrhage and infection, and
BoNT treatment must be individualized to select the long-term complications are rare211.
most appropriate muscles and dose to achieve optimal Over the past decade, FUS lesioning has been increas-
outcomes201. For example, to minimize finger and wrist ingly used to create highly targeted brain lesions in the
extensor weakness the extensor forearm muscles are treatment of ET. One large, sham-controlled, blinded,
often not injected, or a very low dose is used, and the trial of FUS lesioning demonstrated marked tremor
dose in forearm flexors is adjusted to prevent hand grip reduction in the contralateral arm in patients with ET212.
weakness, the most frequent, albeit transient and rarely Adverse events included transient sensory disturbance
disabling, adverse effect202. Large multicentre, controlled and dysarthria. Of note, although one 4-year open label
trials of onabotulinumtoxinA and incobotulinumtoxinA report showed continued benefit of FUS lesioning, there
for ET are currently in development. is a concern about potential loss of effect over time that
could require repeat procedures 213. No prospective
DBS and FUS head-to-head comparisons of FUS lesioning and DBS
Patients with troublesome or disabling tremor who have been carried out, but retrospective studies suggest
obtain insufficient benefit from pharmacological ther- comparable efficacy and safety214. FUS lesioning seems
apies are usually considered candidates for surgical to be cost-effective compared with DBS, and the device
intervention such as DBS or FUS thalamotomy. Before is approved by the FDA for unilateral treatment of ET215.
the advent of DBS, ablative thalamotomy using stereo- FUS lesioning requires patients to shave their head, and
taxic radiofrequency was the most frequently performed ~8% of the population is not eligible owing to skull
surgery for such patients203,204. Other surgical treat- thickness216.
ments include unilateral laser thalamotomy205, gamma Adverse effects of DBS and FUS lesioning are well
documented217. These effects are often related to the sur-
Box 2 | Quantification of treatment response gical procedure; for example, haemorrhage (in 0.5–1.5%
Several methods designed to assess the severity of
of patients), infection (in 1.7–5.4% of patients) or frac-
tremor can be used to quantify response to the various ture or migration of the inserted hardware (in 1.4–3.8%
therapeutic interventions for essential tremor (ET). of patients)218. Moreover, the long-term effects of stim-
Although accelerometers and other computer-based ulation or ablation can cause a range of complications,
technologies and devices have been used to measure for example, neurological adverse effects such as ataxia,
tremor, most trials use various clinical rating scales for this dysarthria, paraesthesia, worsening verbal fluency,
purpose. One such scale, The Essential Tremor Rating sensory disturbances, hemiparesis, confusion or cog-
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
nitive impairment217. Stimulation-related effects may
be resolved by adjustment of the stimulation parame-
ters. Different adverse effects can occur depending on
Scale277, the Bain and Findley Clinical Tremor Rating Scale,
the Glass Scale and the Quality of Life Essential Tremor
whether interventions are unilateral or bilateral219. DBS
Questionnaire278. Although accelerometers and other also has a gradual loss of efficacy related to habituation
kinematic assessments can measure the amplitude of to disease progression204.
tremor at a particular time point, as the amplitude varies
(up to 23% over a 6 h period in one study279) the clinical Alcohol (ethanol)
rating scales capture the overall severity of the tremor About two-thirds of patients with ET report transient
and its effect on quality of life280. TETRAS rates amplitude improvement of their tremor after one or two alcoholic
of tremor in different body parts (head, face, voice, limbs drinks17. Despite this observation, alcohol responsiveness
and trunk), handwriting, spiral and dot approximation on was considered “not consistent enough to be included in
a 0–4 scale (0–64) and activities of daily living (0–48).
the definition of ET” in the 2018 Consensus Statement1.
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Table 2 | Investigational treatments for essential tremor stimulation of the median and radial nerves in the wrist
could reduce tremor severity for more than an hour in
Drug Mechanism of action NCT number some patients225.
SAGE-324, SAGE-547 Allopregnanolone, NCT04305275, NCT02277106
positive allosteric Quality of life
modulator of GABAA
receptors For most patients with ET with mild tremor, quality of
life (QOL) is not greatly affected. Nonetheless, ET can
CX-8998 Cav3 T-type calcium NCT03101241 affect many aspects of life including social, emotional,
channel blocker
physical and mental domains. ET may also affect basic
PRAX-944 T-type calcium channel NCT05021991 daily tasks such as writing, eating and using electronic
blocker
devices, and activities such as work or employment and
CAD-1883 Positive allosteric NCT03688685 hobbies.
modulator of the Studies show that QOL is reduced in patients with
small conductance
calcium-activated ET163 and that QOL issues are often not sufficiently
potassium ion channels addressed in treatment discussions226. Accordingly, con-
Cannabidiol Multiple targets NCT03805750 sideration of QOL issues of the individual in a holistic
approach to care, and not only tremor characteristics,
OnabotulinumtoxinA Chemodenervation NCT03136341, NCT02551848,
is important for treatment considerations. Clinical tri-
and incobotulinumtoxinA NCT02427646, NCT02207946,
NCT02555982 als for ET commonly use QOL as an outcome measure,
GABA, γ-aminobutyric acid.
for example, in studies of surgical interventions227, new
drugs228 or other interventions229, therefore, QOL is a
Although alcohol may transiently (3–4 h) suppress convenient, functionally relevant and individual-focused
tremor in social situations with judicious use, it should concept in the study of ET.
not be recommended as a routine treatment for ET
owing to rebound tremor exacerbation the following Generalized QOL measures
morning and risk of alcohol abuse with frequent use63. Some studies of QOL in ET have used generalized QOL
The exact physiological mechanism by which alco- scales, such as the Short-Form 36-item health survey
hol improves ET is not well understood. Several studies (SF-36) or Rand SF-36. One study in Germany found
have shown that alcohol can inhibit the function of both lower QOL scores in all domains (evaluated using the
NMDA and non-NMDA glutamatergic receptors, but it SF-36) in patients with ET compared with controls163.
probably acts primarily as a GABAA receptor agonist, The domain with the largest difference from controls
although alcohol also modulates serotoninergic, dopa- was the mental health domain, particularly in the
minergic, glycinergic and adenosinergic pathways220. >40-year-old subgroup. Moreover, one Australian study
Furthermore, PET studies have shown that alcohol is found significantly poorer QOL (assessed using Rand
associated with a reduction in cerebral blood flow in the SF-36) in patients with ET compared with controls230.
cerebellum and an increase in blood flow in the ION56. An Egyptian study was concordant with these studies,
Octanol, an 8-carbon alcohol used as a food flavour- also demonstrating worse QOL in all eight domains of
ing agent, is metabolized to octanoic acid, which has the SF-36 in patients with ET compared with controls231.
been shown to provide a short (90–120 minutes) benefit
in patients with ET in some open label and controlled ET-specific QOL measures
studies221. Although well tolerated, octanoic acid has A drawback of generalized QOL measures is that they
not yet been approved for the treatment of ET, partly are not specific to the problems faced by patients with
because it requires large volumes to be effective with oral ET. To address this issue, the Quality of Life in Essential
administration222. One small open label study showed Tremor Questionnaire (QUEST) was developed in
that sodium oxybate, an alcohol analogue, may reduce 2005. The QUEST contains 36 items and comprises five
tremor amplitude in ET223; however, it has limited use in domains: physical, psychosocial, communication, hob-
the treatment of tremor owing to sedation and potential bies and work/finance232. Another ET-specific scale is
for abuse. TETRAS, which includes sections for performance and
activities of daily living233.
Other treatments Studies using the QUEST found significantly reduced
Non-invasive brain stimulation techniques including QOL across all domains in patients with ET. One study
repetitive transcranial magnetic stimulation, theta burst in India noted that tremor is a cause of poor QOL in
stimulation, transcranial alternating current stimula- patients with ET and that it particularly affects the
tion (tACS) and transcranial direct current stimulation psychosocial domain234. Forty-six per cent of participants
have all shown preliminary signs of reducing tremor106. responded that their tremor always interferes with their
Studies have varied in stimulation method, target and job or profession, 34% of participants responded that
assessment, but support consecutive daily sessions their tremor always makes them feel negative about
and the cerebellum as a key target; for example, tACS themselves and 32% responded that their tremor causes
of the cerebellum can have a therapeutic effect when embarrassment234. These data agree with the literature
phase-locked with the tremor224. Non-medical thera- associating ET with symptoms of depression, anxiety
pies such as relaxation and biofeedback may be effective and social isolation235,236. Regarding the effect of ET on
in some patients. Transcutaneous afferent patterned work, early retirement and hesitance to apply for jobs or
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PRIMER
promotion are more common in patients with ET com- brain regions involved in tremor networks. Correlation
pared with controls237,238. Together, studies of ET-specific of these changes with the severity of ET will enable
QOL have highlighted the strong influence of psycho- more robust classification and staging of the disease.
social aspects on perceived QOL, whereas tremor char- Pathophysiological studies in different ET subtypes
acteristics such as age of onset, duration or distribution will also provide useful insights in this regard. More
have a relatively minor influence234. integrative work that aims to investigate links between
pathophysiological data and other data in ET, such as
Outlook neuroimaging or genetic data, is needed to bridge the
Achieving the following high- level goals will require gap between systems-level and neurobiological obser-
broad cooperation of research teams: a more open vations and, ultimately, inform a more unified model of
approach to ET research, collaboration, reproducibil- ET pathogenesis.
ity, replication of findings and sharing of research data.
Useful and simple steps include pre- registration of Neuroimaging
ET studies in online databases, publication of analysis The role of neuroimaging in clinical practice for ET has
protocols and publication of anonymized data sets. been limited, but several technological developments in
MRI acquisition and analysis have improved sensitiv-
Genetics ity of neuroimaging to evaluate ET pathology. Indeed,
Despite the high prevalence of ET, most studies have multi-band imaging has increased the temporal resolu-
been based on small sample sizes, and this is particu- tion of functional MRI acquisitions by twofold to five-
larly evident in GWAS and genetic association stud- fold, with minimal loss of signal to noise ratio, and it can
ies. To overcome this issue, a large-scale global clinical extend the capability of diffusion imaging242,243. A sec-
and genetic consortium to gather data from patients of ond advance is the maturation of ultra-high-field MRI
different ethnicities who have ET is required. (≥7 Tesla); 7-Tesla MRI platforms were FDA-approved
Future studies should include additional efforts to in 2017 and 2020, and offer improved performance and
identify monogenic forms of ET. Moreover, composite increasing availability. The increased signal to noise ratio
scores for genetic risk should be evaluated for sporadic of 7-Tesla MRI confers greater resolution and contrast,
ET, which is most likely caused by additive effects of and therefore, improved capability to depict and charac-
multiple genes and other factors. To formulate aggregate terize brain structures244. Owing to these improvements,
measures of risk and for subtyping or stratification of ET, further studies using these neuroimaging technologies in
in-depth phenotyping of individual patients should be ET should be carried out, including studies before and
carried out, and should span all relevant biological layers after treatment and of at-risk asymptomatic individuals.
from genetics through to behaviour. This so-called deep Neuroimaging may have a key role in selecting patients
phenotyping approach has been previously raised by for specific therapies, in uncovering underlying tremor
the MDS Tremor Study Group as an important research mechanisms and in identifying reproducible new multi-
goal239. Use of machine learning tools will be key to ana- modal biomarkers245, for example, those based on brain
lysing these large data sets240. This approach will require connectomics243,246,247. Neuroimaging may also be useful
coordination across several fields of expertise. to identify the neural correlates of comorbid cognitive
changes in ET, for example, in executive functioning248.
Experimental models
With the advances in stem cell technology, ET-linked Therapeutics
genetic variants can be studied in induced pleuripotent Identification of new causative genes and environmen-
stem cells from patient fibroblasts or blood. Isogenic tal or lifestyle risk factors for ET will lead to develop-
human cell lines can be created to investigate the conse- ment of more experimental therapeutics and, ultimately,
quences of the genetic perturbations. However, genera- clinical trials of novel compounds. Both invasive and
tion of PCs from stem cells is challenging and, despite non-invasive neuromodulation approaches should be
insightful observations from studies using animal mod- further investigated for ET treatment, and available
els of ET, these models do not fully recapitulate all the methodologies should be improved. The use of better
features of human disease nor do we know whether wearable orthoses, assistive feeding devices and refine-
the cellular phenotypes from cultured PCs reflect ataxia or ment of electrical stimulation systems (both trans-
tremor. In addition, developing a validated standardized cutaneous and functional stimulators) will address the
evaluation tool that captures the components of tremor challenges patients face in their daily life. In light of this,
in humans is difficult. Although there have been some clinical trials of devices in combination with pharma-
improvements in this area, for example, using machine cological treatments should be considered. Moreover,
learning methods to track leg positions using high-speed a multidisciplinary approach with the involvement of
video recording in Drosophila that express mutant patient advocacy groups to address the real-world fac-
neurodegenerative genes241, further work is needed. tors that affect patients’ QOL will help to reduce the
disease burden for patients with ET and their caregivers.
Pathophysiology
Collaborative post-mortem studies using brains from Clinical outlook
patients with ET are needed to further address and The ultimate goal of ET research is to enable a person-
characterize the morphological changes in the circuits alized medicine approach. To achieve this, a central
and neuronal subtypes in the cerebellum and other research theme in the next decade should be identifying
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PRIMER
subtypes of ET based on validated and reproducible more homogeneous, rationalized samples. Establishing
quantitative measurements. The clinical and aetiolog- methods to better quantify tremor features, including in
ical heterogeneity of ET coupled with the variability animal models, will help to effectively subtype ET, and
of research findings in many areas undermines other to measure pharmacological response and generaliza-
areas of ET research and suggests that there is much bility. This includes new clinical tremor rating scales in
progress to be made in better defining the disease. With patients.
improved theories and evidence for ET definition and
subtyping, all other areas of research will benefit from Published online xx xx xxxx
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e3000346 (2019). 264. Eliasen, E. H., Ferrer, M., Gaini, S., Louis, E. D. The authors declare no competing interests.
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for deep brain stimulation based on 7 Tesla MRI. Gershoni-Baruch, R. & Hassoun, G. Essential Springer Nature remains neutral with regard to jurisdictional
PLoS ONE 13, e0201469 (2018). tremor prevalence is low in the Druze population claims in published maps and institutional affiliations.
245. Welton, T. et al. Diffusion kurtosis and quantitative in northern Israel. Tremor other Hyperkinet. Mov. 2,
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NATURE REVIEWS | DISEASE PRIMERS | Article citation ID: (2021) 7:83 1

Author addresses of ET prevalence is difficult owing to variation in study

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

4.8 4.8 8.6 Israel

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subunit tremor and cerebellar pathology70, with patients with ET

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an increase in glutamate concentration121. Moreover,

Pons Animal models

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Rule out other conditions Yes

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

If tremor is not controlled use combination therapy

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Other pharmacological therapies knife thalomotomy206 and virtual cone (a non-invasive

Clinimotia Abre Assessment Scale (TETRAS)276, was developed by the

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