Tremor—Some Controversial Aspects
Niall P. Quinn, MD,1* Susanne A. Schneider, MD, PhD,1Petra Schwingenschuh, MD,1,2and
Kailash P. Bhatia, MD, DM1
1Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square,
London, United Kingdom
2Department of Neurology, Division of Special Neurology, Medical University Graz, Austria
Abstract: The commonest cause of pathological tremor is
essential tremor (ET). However, it has proved difficult to identify
genetic mutations causing ET, particularly because other causes
of tremor continue to be misdiagnosed as ET. Whether subjects
with dystonia or Parkinson’s disease (PD) carry an increased
genetic risk of developing ET, or vice versa, is controversial. In
addition, the notion of a separate disorder of benign tremulous
parkinsonism (BTP) has been debated. This article gives a selec-
tive viewpoint on some areas of uncertainty and controversy in
tremor. ? 2010 Movement Disorder Society
Key words: essential tremor; dystonia; dystonic tremor;
WHAT IS ET?
The 1998 Movement Disorder Society (MDS) Con-
sensus Statement on Tremor1defines essential tremor
(ET) as ‘‘a bilateral, largely symmetrical, postural or
kinetic tremor affecting hands and forearms that is
visible and persistent. ... Additional or isolated tremor
of the head may occur, but without abnormal postur-
ing. ... Exclusion criteria include other neurological
signs, especially dystonia, and the presence of isolated
position-specific or task-specific tremor.’’
HOW COMMON IS ET?
Studies have generated at least 28 different popu-
lation-based prevalence rates for ET that vary 2,050-
fold from 10 to 20,500 per 100,000. The best
designed studies averaged 400 per 100,000.2In these
community studies, the vast majority of cases identi-
fied had mild disease. Thus, ‘‘99.5% of community
dwellers with ET have mild tremor and do not
attend clinics,’’3and ‘‘ET patients—seeking medical
attention—represent a small proportion of all ET
cases.’’2Patients who do present to a neurologist are
likely to be more severely affected or atypical, and
many of those identified in movement disorder clin-
ics are picked up only because of some new event,
e.g., developing Parkinson’s disease (PD).
IS ET CLINICALLY ONE DISEASE?
Some studies have shown a bimodal age at onset,
which may represent more than one disease. Some
authors4,5who initially regarded ET as a single entity
now consider that it is heterogeneous6or encompasses
several different conditions.7
Potential conflict of interest: Nothing to report.
Received 23 November 2009; Revised 26 February 2010;
Accepted 10 May 2010
Published online in Wiley Online Library (wileyonlinelibrary.
com). DOI: 10.1002/mds.23289
Additional Supporting Information may be found in the online
version of this article.
*Correspondence to: Niall P. Quinn, Sobell Department of Motor
Neuroscience and Movement Disorders, UCL Institute of Neurology,
Queen Square, London WC1N 3BG, United Kingdom
Vol. 00, No. 00, 2010, pp. 000–000
? 2010 Movement Disorder Society
IS ET ASSOCIATED WITH DYSTONIA OR
DYSTONIA ASSOCIATED WITH ET?
In 1991, Lou and Jankovic8reported 350 patients
diagnosed as ET, based on the presence of tremor of
the head, hand, or voice ‘‘in the absence of other dis-
eases that may cause tremor.’’ However, 47% of these
subjects also had dystonia (spasmodic torticollis in
27%, dystonic writer’s cramp in 14%, blepharospasm
in 7%, laryngeal dystonia in 4%, and cranial–cervical
dystonia in 2.5%). These authors nevertheless con-
cluded: ‘‘This analysis finds no support for differentia-
tion of ET subtypes and it suggests that ET, although
heterogenous in its clinical presentation, is a single dis-
ease entity.’’ However, if one accepts MDS criteria
and also that postural tremor is one phenotypic mani-
festation of dystonia, then approaching 47% of these
‘‘ET’’ patients did not have ET.
HOW COMMONLY ARE ET AND PD
Undoubtedly, ET is very frequently misdiagnosed—
two studies estimated rates of 37% and 50%, respec-
tively,9,10and the final clinical misdiagnosis rate of PD
in pathologically verified cases was reported as 24% in
1992,11falling to 10% in 2001.12
IS ET ASSOCIATED WITH PD OR PD
ASSOCIATED WITH ET?
It is also claimed that ET patients have an increased
genetic risk of developing PD.6In Jankovic’s study8
‘‘about 20% of patients with a history of ET later devel-
oped parkinsonism.’’ However, as far as we know, this
was not a community population of ET patients who,
whilst being followed up for their ET, later developed
PD. Instead, these were probably mostly patients who
had presented to the authors with PD and been found on
examination to have a postural or action arm tremor, of-
ten of longer duration, and a positive family history.
Most probably, they did have ET, but only came to med-
ical attention because they had subsequently developed
PD. If they had not developed PD, they would never
have found their way to a movement disorder clinic.
Some other authors13–16have also claimed an associa-
tion between ET and PD, but others17,18have not. In
our view, the former have not sufficiently addressed the
substantial clinical misdiagnosis rates indicated earlier.
It is not as if one is examining the relationship between,
for example, smoking and PD, since smoking cannot be
confused with PD. In a situation where each of the two
conditions is frequently misdiagnosed as the other, the
bar has to be set very high to prove a true association.
A recent article19reporting an association between the
LINGO1 gene and both ET and PD cautioned about this
issue of potential misdiagnosis. We remain unconvinced
of a genetic relationship between ET and PD.
IS ET PATHOLOGICALLY ONE DISEASE?
In the two autopsy series of ET,20,21totaling 57
cases, 11 (19 %) had brainstem Lewy bodies (LBs),
mainly in locus ceruleus (LC) and dorsal nucleus of
vagus (Braak et al.22stages 1 and 2). In one series, 25
of 33 showed lower Purkinje cell and higher torpedo
counts than the other eight with LB pathology; in the
other series, 7 of 24 showed some cerebellar pathol-
ogy. None in the first, but 9 of 24 in the second series,
showed neither LBs nor cerebellar pathology.
It seems to us likely that in most cases these LBs
are coincidental, being found in restricted sites in very
elderly subjects who have often had ET for decades,
making it unlikely that they were either present or
playing a causative role when their tremor began (e.g.,
the case reported by Louis et al.,23who died aged 91,
after 46 years of ET and on alpha-synuclein staining
showed many LBs in LC, rare in substantia innominata
and dorsal vagal nucleus, and none in substantia nigra
The (usually mild) histological features suggesting
cerebellar changes in 30% (7 of 24) to 76% (25 of 33)
of autopsied cases of ET have been proposed to be part
of its underlying pathological basis. However, some of
these changes could be secondary to ‘‘therapeutic’’ alco-
hol abuse. Whilst it would be no surprise if cerebellar
pathology were involved, we consider that there is still
no consistent neuropathology underpinning ET.
WHAT PROPORTION OF ET PATIENTS HAVE
A POSITIVE FAMILY HISTORY?
In 17 to 100% of patients with ‘‘ET,’’ a family his-
tory of tremor in at least one affected relative is
found,24usually compatible with autosomal-dominant
inheritance, and therefore a genetic basis is expected.
DESPITE ET BEING VERY COMMON AND
STRONGLY FAMILIAL, WHY HAS IT PROVED
SO DIFFICULT TO ISOLATE CAUSATIVE
It has proved surprisingly difficult to identify genetic
mutations causing ET. Again, one particular problem
2N.P. QUINN ET AL.
Movement Disorders, Vol. 00, No. 00, 2010
has been misdiagnosis. Jankovic25described ‘‘familial
essential tremor’’ in four kindreds, three of which had
varying combinations of tremor and dystonia. Subse-
quently, three possible loci, ETM 1, 2 & 3, have been
identified.26–28However, 23% of the ETM3 ‘‘definite
ET’’ subjects28also had dystonia. More recently, using
genome-wide association, a significant association with
ET of a sequence variant in the LINGO1 gene has
WHAT CONDITIONS ACCOUNT FOR
PATIENTS SUSPECTED OF PD WHO HAVE
SCANS WITHOUT EVIDENCE OF
In three drug trials in subjects with a clinical diagnosis
of early ‘‘de novo’’ PD that used dopamine transporter
(DaT) single photon emission computed tomography
(SPECT) or F-DOPA positron emission tomography
(PET) scans as putative biomarkers for underlying disease
progression, 11 to 15% of patients studied30–32had scans
without evidence of dopaminergic deficit (SWEDDs). Fol-
low-up scans remained normal in patients rescanned after
4 years.33Some have claimed that these subjects may
have a benign form of PD. We disagree, and suggest that
some have ET, others adult onset dystonic tremor
(AODT),34and yet others some other disorder.
WHAT IS BTP? IS IT A SINGLE DISORDER?
Josephs et al.35reported 16 patients with benign trem-
ulous parkinsonism [BTP: ‘‘tremor-predominant parkin-
sonism, with mild nontremor components’’] followed
for at least 8 years. Although resting tremor worsened
insix, their other symptoms
unchanged. All had a resting component, seven had
chin tremor, most also displayed prominent action hand
tremor that impaired eating and writing, and they were
refractory to levodopa treatment. Furthermore, six had a
family history of tremor. Although none of these sub-
jects had functional imaging, we suspect that in most of
them DaT SPECT scanning would have been normal.
Conversely, Chaudhuri et al.36reported 13 subjects who
had originally presented with asymmetric postural
tremor, thought to represent ET, but who subsequently
developed rest tremor. In all five who had a DaT
SPECT scan, it was abnormal. Ghaemi et al.37also
reported eight subjects with monosymptomatic resting
tremor, all of whom had abnormal 18F-DOPA PET
scans. Thus, as well as ET being potentially misdiag-
nosed as PD, the opposite error is also frequent.
Clarimon et al.38recently reported on 26 patients with
tremor dominant parkinsonism (TDP). All had resting
tremor, but ‘‘rigidity and/or bradykinesia were clinically
irrelevant in most of them’’. A family history of tremor
was found in 61.5% of the patients. DaT scan was normal
in 35%, but showed ‘‘mild and bilateral decrease of stria-
tal tracer uptake’’ in the remaining 65%. They stated that
this series may represent a subgroup of ET patients ulti-
mately ‘‘converting’’ to PD and concluded that TDP
‘‘seems to be a subtype of PD with mild clinical signs and
a more benign prognosis, rather than a distinct clinical en-
tity.’’ Their total group of TDP subjects is probably heter-
ogeneous—some, with abnormal DaT scans, having a be-
nign form of PD, whilst the others with normal scans
The notion of ET converting to PD is confusing and
misleading to us and best avoided. Instead, there are
PD patients initially misdiagnosed as ET, and ET
patients who subsequently developed additional coinci-
DOES AODT MASQUERADE AS ET
AS WELL AS ‘‘BTP’’?
In 2007, we reported ten patients with unilateral or
asymmetric rest tremor, with a postural component,
resembling the tremor of PD who had normal DaT
scans.34Careful examination revealed dystonia in eight of
them. We concluded that dystonic tremor can mimic par-
kinsonian tremor and that some patients labeled as ET,
PD, or BTP may actually have AODT instead. We have
since reported a further 25 such patients,39whose mean
age of symptom onset was 59 years, 52% of whom had a
positive family history of tremor or parkinsonism.
ARE ISOLATED HEAD OR NECK TREMOR,
ISOLATED VOCAL TREMOR, JAW TREMOR,
REST TREMOR AND UNILATERAL TREMOR,
OR PROMINENT LEG TREMOR
MANIFESTATIONS OF ET? WHAT
ABOUT PATIENTS WITH SEVERAL OF
Many patients who present with head tremor subse-
quently develop features of spasmodic torticollis. We
think it unwise to diagnose ET in subjects with isolated
head tremor, a presentation of head tremor before the
appearance of hand tremor, or in whom head tremor is
more severe than their arm tremor (indeed, we suggest
that in ET arm tremor should always be more severe
than tremor elsewhere).
Movement Disorders, Vol. 00, No. 00, 2010
Leegwater-Kim et al.40described 10 (9%) of 111
ET patients with ‘‘intention tremor of the head’’—
seven with neck tremor and three with a chin (jaw)
tremor. These patients were more likely to have mod-
erate-to-severe postural arm tremor, to be women, and
to have had surgery for their tremor. The published
video of Patient 1 shows unilateral arm dystonia, dys-
tonic tremor and shoulder elevation, and a tremulous
torticollis. We suspect that most such patients have
tremulous torticollis, but in many, the dystonia has ei-
ther not been recognized or not yet appeared. The
same authors41also recently studied the prevalence of
isolated ‘‘head (i.e., neck) tremor’’ among 583 ET
cases, finding no case of head tremor in the complete
absence of arm tremor, and head tremor with mild
arm tremor in only 2.7% of cases, nearly all women.
Bain et al.4found no individuals with isolated head
tremor in their 20 families with three-generational
We would also consider isolated voice tremor, voice
tremor before hand tremor, and voice tremor more
severe than hand tremor to be much more suggestive
of dystonic tremor. In fact, many of these subjects
have laryngeal dystonia.
Jaw tremor is well recognized in PD and also seen
in dystonia.42It is uncommon (7.5–18%) in patients
with a label of ET.43Many of these patients may have
PD or dystonic tremor instead.
Louis et al.43also found an association between jaw
tremor and older age, more severe action tremor of the
arms, and the presence of head and voice tremor, sug-
gesting to them that jaw tremor in ET is a marker for
subsequent ‘‘conversion to PD,’’ but to us the possibil-
ity of dystonic tremor.
Rest tremor is uncommon in ET, being found by
Cohen et al.44in 19% of 64 tertiary referral center ET
patients, who were also more likely to have head
ET is classically largely symmetrical. Louis et al.45found
small-to-moderate side differences in 54 community-based
subjects. Phibbs et al.46reported unilateral arm tremor in
only 4.4% of 412 patients in dominantly inherited ET kin-
dreds. In our experience, unilateral tremor is much more
suggestive of dystonia or of early PD than of ET.
Among 487 individuals diagnosed with ET, Whaley
et al.47found unilateral arm tremor in 10%, chin
tremor in 9 to 11%, and leg tremor in 9 to 11%; 14%
had resting tremor ‘‘suggestive of possible comorbid
PD or misclassification.’’ Putzke et al.48found that,
among 128 patients diagnosed with ET, voice tremor
and unilateral tremor onset were associated with
increasing tremor severity.
Poston et al.,49in a series of 63 ET cases, found ki-
netic leg tremor rated as at least grade 1.5 severity in
In a 1997 survey of movement disorder specialists,50
81% would diagnose ET based on isolated head
tremor, 70% on isolated voice tremor, 46% based on
position- and task-specific tremor of the arms, 37% on
isolated postural tremor of the legs, 26% on isolated
tongue tremor on tongue protrusion, 26% on isolated
chin tremor, and 21% on primary orthostatic tremor.
Moreover, 60% did not consider that bilateral arm
involvement was necessary in ET! We hope that a
repeat survey conducted today would paint a different
picture of ET.
WHAT DO WE KNOW ABOUT THE RESPONSE
OF ET TO ALCOHOL, DRUGS AND SURGERY?
Many patients labeled as ET respond to alcohol,
beta-blockers, or other drugs. However, some dystonic
tremor patients also respond to alcohol. In all ET drug
trials, other tremulous patients have probably been
included. Which patients with which disease responded
to which drug is uncertain.
Surgery is restricted to subjects with disabling drug-
resistant tremor. Commonly, these patients are disabled
because of the extreme task-specific exacerbation of
their tremor, e.g., on attempting to write. We believe
that many subjects operated for ET have had dystonic
HOW OFTEN ARE PATIENTS WITH DYSTONIA
MISDIAGNOSED AS ET?
In the MDS teaching tape on tremor,1Segment 2,
‘‘Essential Tremor with Intention Tremor,’’ shows a
68-year-old woman with an 8-year history of ‘‘head
and voice tremor’’ preceding the development of arm
tremor. In our opinion, the video shows tremulous
torticollis, voice tremor probably due to laryngeal dys-
tonia, and asymmetric (L > R) terminal or position-
specific arm tremor, with no postural tremor, but with
dystonic posturing of the left forearm when held flexed
in front of the body. Segment 4, ‘‘Voice Tremor,’’
shows another woman with gross laryngeal dystonia
and dystonic posturing of her outstretched left fingers.
The teaching video for the assessment of essential
tremor51gives examples of four different severity
grades, each for six different tasks. Three of us (NQ,
KB, and PS) simultaneously but independently rated
these clips as showing no dystonia, possible dystonia,
or clinically obvious dystonia. There was complete
4 N.P. QUINN ET AL.
Movement Disorders, Vol. 00, No. 00, 2010
unanimity on 15 clips, and a 2:1 split on the other
four, for which we have taken the majority verdict. We
considered that 37% of examples show possible dysto-
nia, and an additional 26% obvious dystonia, the per-
centage increasing with higher severity grades. These
segments can be viewed in the linked archival video-
tapes in the supplementary material.
DOES THE DEFINITION OF DYSTONIC
TREMOR (AND ALSO THAT OF ET) NEED TO
The MDS Consensus Statement1defines ‘‘dystonic
tremor’’ as tremor in a body part also affected by dysto-
nia, while ‘‘tremor associated with dystonia’’ refers to
tremor in a body part not affected by dystonia, although
dystonia is present elsewhere. We propose that, in the
absence of any alternative cause for their tremor, both of
these groups should be called dystonic tremor.
In contrast, we consider that ET should start, and
remain most severe, in the hands, where it should be
bilateral and relatively symmetrical, with no other cause
identified. A very small number of patients, difficult to
identify, will coincidentally have both ET and dystonic
tremor. There are some electrophysiological features that
might help distinguish between ET, BTP, and AODT,39
but they are beyond the scope of this article. At present,
one of the principal clinical clues is ‘‘the company they
keep’’—i.e., associated clinical features.
There is a third group of patients with tremor that is
unilateral or very asymmetric, irregular or jerky, posi-
tion- or task-specific (and therefore more likely to be
disabling), relieved by a geste antagoniste, pronation-
supination rather than vertical, or occurring in flurries,
but without (at least yet) frank dystonia. In the future,
they may be identified as having underlying dystonia
but until then, or until clinical evidence of overt dysto-
nia supervenes, we suggest labeling these individuals
as having indeterminate tremor, thereby avoiding mis-
classification as ET or premature classification as dys-
What has been diagnosed in the past as ET has
included several different entities. Most probably do
have true ET. A second group have what we would
consider dystonic tremor. A third group may also well
turn out to have dystonic tremor, but until the dystonia
emerges or can be otherwise recognized, they should
currently be called indeterminate tremor. Hopefully,
such a classification will place genetic research on
firmer ground, provide more accurate prognosis, and
enable more rigorous treatment studies.
We also consider that patients described in the liter-
ature as having BTP are heterogenous, some having
tremor-dominant PD, some having ET, and some hav-
ing AODT. We remain to be convinced of any genetic
relationship between ET and dystonia or between ET
and PD. Finally, we feel that the definitions of dystonic
and ET need to be revisited.
LEGENDS TO THE VIDEO
Video clip 1: This published video of patient 1 of
Leegwater-Kim et al.40in our opinion shows a unilateral right-
sided dystonic arm tremor, together with a tremulous torticollis.
Video clip 2: This is Segment 2 of the MDS teaching tape
on tremor,1titled ‘‘Essential Tremor with Intention Tremor.’’
In our opinion, the patient displays tremulous torticollis,
probable laryngeal dystonia, and dystonic arm tremor with
abnormal angling of the left forearm when held flexed in
front of the body.
Video clip 3: This is Segment 4 of the MDS teaching tape
on tremor, titled ‘‘Vocal Tremor.’’ In our opinion, it shows
marked laryngeal dystonia, together with dystonic posturing
of the ulnar fingers of the outstretched left hand.
Video clip 4: This is available as supplementary material.
It is the whole of the teaching video for the assessment of
essential tremor by Louis et al.51An accompanying table gives
our opinion on the presence on the segment of no, possible, or
clinically obvious dystonia.
Financial Disclosures: N.P. Quinn: Advisory Boards:
Oxford BioMedica, Honoraria: UCB and Orion Pharma. S.A.
Schneider: Funded by Lady Astor Studentship from The Brain
Research Trust, UK. P. Schwingenschuh: Funded by the
Austrian Science Fund (Erwin-Schroedinger Grant J2764);
Financial support to attend meetings from UCB, GSK, and
Ipsen pharma, and research grant from the Austrian Science
Fund (FWF) [Erwin Schro ¨dinger Grant J 2764]. K.P. Bhatia:
Advisory boards/honoraria/financial support to speak/attend
meetings from GSK, Boehringer-Ingelheim, Ipsen, Merz, and
Orion Pharma; Grant from the Dystonia Society, UK.
Author Roles: N.P. Quinn: Writing of the first draft. N.P.
Quinn, S.A. Schneider, P. Schwingenschuh, and P.P. Bhatia:
Review and critique.
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6N.P. QUINN ET AL.
Movement Disorders, Vol. 00, No. 00, 2010
Since this article was accepted an important paper
was published by Hedera et al, who hypothesized that
tremor with dystonia represents a distinct subtype of
ET. They studied patients with ET as their predomi-
nant phenotype from 97 kindreds with autosomal dom-
inant inheritance, and found ‘‘pure’’ ET in 79% of
cases, and focal or segmental dystonia in 21%. Inter-
estingly, all patients with dystonia were clustered in
28% of all included pedigrees. Whether to consider
this a distinct subtype of ET, or a separate disease
under the rubric of dystonia, needs to be debated.
Hedera P, Phibbs FT, Fang JY, Cooper MK, Charles
PD, Davis TL. Clustering of dystonia in some pedi-
grees with autosomal dominant tremor suggests the ex-
istence of a distinct subtype of essential tremor. BMC
Neurology 2010, 10:66.
Movement Disorders, Vol. 00, No. 00, 2010