RESEARCH ARTICLE
Early- and Late-Onset Essential Tremor Patients
Represent Clinically Distinct Subgroups
Franziska Hopfner, MD,1 Anjuli Ahlf, MD,1 Delia Lorenz, MD,1 Stephan Klebe, MD,2 Kirsten E. Zeuner, MD,1
Gregor Kuhlenba umer, MD, PhD,1 and Gu nther Deuschl, MD1*
1
Department of Neurology, University Hospital Schleswig Holstein, Kiel, Germany
2
Department of Neurology, University Hospital of Freiburg, Freiburg, Germany
A B S T R A C T : O b j e c t i v e : Essential tremor is a very
common disease defined by sparse clinical criteria. It is
unlikely that essential tremor is an etiologically homoge-
neous disease. Stratifying broadly defined diseases
using clinical characteristics has often aided the etiopa-
thological understanding. Most studies of essential
tremor show 2 distinct age at onset peaks: early and
late. This study investigates phenotypical differences
between early- and late-onset essential tremor patients.
M e t h o d s : We studied a sample of 1137 tremor
patients. Of these patients, 978 suffered from definite or
probable essential tremor. All of the patients underwent
the same standardized examination encompassing,
among other items, drawing of the Archimedes spiral
and assessment of the Fahn-Tolosa-Marin scale.
R e s u l t s : Two subgroups of early-onset ( 24 years of
age, n 5 317) and late-onset ( 46 years of age, n 5 356)
patients were selected based on the visual and mathe-
Essential tremor (ET) is the second most common
movement disorder with prevalence estimates between
0.4% and 3.9%.1,2 The predominant symptom is a
symmetric postural or kinetic tremor of the upper
extremities with or without subtle cerebellar signs.3-5
------------------------------------------------------------
*Correspondence to: Prof. Dr. Gu nther Deuschl, Department of
Neurology, University-Hospital-Schleswig-Holstein, Campus Kiel,
Christian-Albrechts-University Kiel, Germany, Schittenhelmstr. 10,
24105 Kiel, Germany; g.deuschl@neurologie.uni-kiel.de
Funding agency: ET research was supported by the Deutsche
Forschungsgemeinschaft (KL 1433/2-1, KU1194/9-1 KU1194/8-1,
De 438/16, SFB 855 1261).
Relevant conflicts of interests/financial disclosures: Nothing to report.
Full financial disclosures and author roles may be found in the online ver-
sion of this article.
Received: 23 June 2015; Revised: 14 May 2016; Accepted: 30 May
2016
Published online 7 July 2016 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.26708
1560 Movement Disorders, Vol. 31, No. 10, 2016
matical analysis of the age-at-onset distribution. Tremor
severity in both groups was comparable. Tremor progres-
sion measured as Archimedes spiral score and the Fahn-
Tolosa-Marin subscales divided by the disease duration
in 10-year bins was significantly faster in late-onset
patients when compared with early-onset patients. Early-
onset patients more frequently reported a positive family
history and alcohol sensitivity of the tremor.
C o n c l u s i o n s : The age-at-onset distribution suggests
a distinction between early- and late-onset tremor.
Early-onset and late-onset essential tremor differ in the
progression rates and the frequencies of a positive fam-
ily history and history of a positive effect of alcohol on
tremor. V C 2016 International Parkinson and Movement
Disorder Society
K e y W o r d s : Essential tremor; classification; sub-
groups; family history; alcohol-response; progression
The diagnosis of ET is solely based on the clinical exam-
ination. The most commonly used research diagnostic
criteria for ET are the consensus criteria proposed by
the Tremor Investigation Group.3 A number of findings
raised the question of whether ET is one disease entity
or a group of clinically and etiologically divergent dis-
eases.6,7 In particular, studies of elderly ET patients
reported a number of additional clinical features, for
example, dementia and increased mortality, usually
found in neurodegenerative disorders.8-10 Most young
onset patientsalthough systematic studies are lack-
ingperform apparently normal during education and
working life for decades. Although neurophysiologic
studies point toward a neurofunctional basis of ET
caused by abnormal oscillatory activity in distinct brain
regions, some postmortem studies suggest a neurodege-
nerative disorder mainly affecting the cerebellum,
whereas others find no cerebellar pathology.11-15
 E A R L Y
FIG. 1. Overview of the study population. ET, essential tremor; yrs, years.
Despite the high heritability of ET, genetic studies were
not able to identify reliably any of the molecular genetic
determinants of the disease.16,17
These apparently contradictory findings could be
reconciled if ET is not a single biological disease. In
patients older than 70 years, the occurrence of tremor
has shown to be a strong predictor for earlier mortal-
ity and worse aging parameters.18 Because of this pre-
dicting value, this tremor has tentatively been labeled
as aging-related tremor.18 These patients are clinically
fulfilling some features of ET, but its relation to ET is
not yet fully clear. Most clinical studies of ET
reported a bimodal distribution of the age at onset,
and a number of studies noted that a positive family
history of ET as well as alcohol sensitivity of the
tremor are more frequent in young onset patients.19-22
A number of studies noted that ET not uncommonly
manifests in childhood.23,24 In this study, we demon-
strate that the age-at-onset distribution in our large
sample of ET patients is clearly not unimodal. We
determine mathematically the most likely modality
and parameters (mean and standard deviation) of the
underlying distributions and show that the patient
subgroups represented by these distributions differ in
their clinical characteristics.
Patients and Methods
The patient sample comprised 1137 individuals
recruited through the Department of Neurology of
Kiel University hospital (Fig. 1). The patient recruit-
ment took place between 2001 and 2013 and was
conducted by 5 movement disorder specialists. Patients
were recruited within the framework of the cross-
sectional study Population Based Assessment of
Genetic Risk Factors for ET (PopGen ET) in north-
ern Germany or by newspaper calls (articles as well as
advertisements) for patients suffering from tremor dis-
orders in different towns in northern Germany. All ET
cases were diagnosed with a personal history taking
and assessment according to the consensus criteria of
A N D L A T E O N S E T E S S E N T I A L T R E M O R
the Movement Disorder Society.3 The study was
approved by the local ethical committee, and written
informed consent was obtained from all participants.
The age at onset, the family history, handedness, and
alcohol responsiveness were determined based on the
patients statements. All patients underwent a detailed
neurological assessment by 1 of 5 movement disorder
experts. In case of a history or signs of other neuro-
logical diseases, patients were excluded. In all patients,
we took special care to exclude patients with Parkin-
sons disease and dystonia by examining gait, rest
tremor, hypokinesia, rigidity of the arms, and signs of
abnormal posturing or action dystonia of the head as
well as the arms in the pronator drift test. If rest
tremor was present we examined rest tremor suppres-
sion during movement. In the tremor examination, the
same standardized questionnaire and investigation
form was applied to all patients. The investigation
included assessment of the Fahn-Tolosa-Marin (FTM)
scale and drawing the Archimedes spiral. Ascertain-
ment of some items was incomplete because of time
constraints. The number and frequency of missing
items is reported together with the results in Table 1.
Measurements of tremor severity included the Archi-
medes spiral. The Archimedes spirals had to be drawn
with the dominant and nondominant hands from
inside to outside. The spirals were rated quantitatively
according to the Bain criteria on a 10-point scale
(Archimedes spiral rating [ASR]: 0 5 no detectable
tremor to 9 5 severe tremor).25 This instrument is a
valid measure of tremor.26-28 A rater training was per-
formed for all raters. Interrater reliability was deter-
mined in a subset of 3260 spirals rated by 2
independent examiners. The second measurement of
tremor severity was the FTM scale. The FTM scale is
the standard instrument for assessing motor symptoms
and activities of daily living in tremor patients.29,30
The scale contains the following 3 parts: FTM A
(maximum 80 points) comprises the motor examina-
tion, FTM B (maximum 36 points) assesses perform-
ance tests (writing, drawing, and pouring), and FTM
Movement Disorders, Vol. 31, No. 10, 2016 1561
H O P F N E R E T A L

TABLE 1. Characteristics of early- and late-onset essential tremor patients (chisq: Chi-square; MWU: Mann Whitney U test)

Early age-at-onset ET (age at Late age-at-onset ET

onset  24 year) (age at onset  46 years)

n/total n with data (%) n/total n with data (%)

(standard deviation if (standard deviation if Significance,
General statistics applicable) Missing, n applicable) Missing, n P value (test)

Total number 317 na 356 na -

Male 199/317 (63%) 0 205 / 356 (58%) 0 .1958 (chisq)
Female 118/317 (37%) 0 151 / 356 (42%) 0
Mean age at onset 13.0 years (5.4 years) 0 61.6 years (7.8 years) 0 <.0001 (t test)
Mean age at examination 51.2 years (17.2 years) 2 71.2 years (6.4 years) 0 <.0001 (t test)
Disease duration 37.9 years (17.0 years) 2 11.1 years (6.7 years) 0 <.0001 (t test)
Alcohol responsiveness pos. 203/266 (76%) 51 113/251 (45%) 105 <.0001 (chisq)
Family history pos. 232/310 (75%) 7 207/349 (59%) 7 <.0001 (chisq)
Tremor severity median (mad) n median (mad) n
Bain mean 5 (1.48) 1 5 (1.48) 3 .0010 (MWU)
FTM A 6 (2.97) 61 6 (2.97) 107 .5059 (MWU)
FTM B 11 (5.93) 62 13 (7.41) 110 .2068 (MWU)
FTM C 4 (2.97) 49 4 (2.97) 86 .9258 (MWU)
Tremor localization n/% n n/% n
Hands 315/317 (99%) 0 350/354 (99%) 2 .6889 (Fisher)
Head 82/317 (26%) 0 94/354 (27%) 2 .7679 (chisq)
Voice 33/317 (10%) 0 45/354 (13%) 2 .3530 (chisq)
Legs 32/317 (10%) 0 22/354 (6%) 2 .0651 (chisq)

N: number, %: number or ratio expressed as a fraction of 100, p-val: p-value, function of the observed sample results, ChiSq: chi-squared test, t-test: Stu-
dents t-test, MWU: MannWhitney U test, Fisher: Fishers exact test

C (maximum 28 points) assesses the activities of daily Statistical Analysis

living. Tremor progression was calculated by dividing
the tremor severity measures (ASR and FTM A, B,
and C) by the disease duration calculated as age at
examination minus age at onset in years. The disease
duration was binned in 10-year intervals and the pro-
gression markers calculated for each bin.
All statistical analyses were performed using R (version
3.1.2 for Windows).31 The following packages were used
to estimate the most likely distributions underlying the
age-at-onset distributions of our sample: (1) diptest (v.
0.75-6), mclust (v. 4.4), and mixtools (v. 1.0.2).32-34

FIG. 2. Correlation between Bain spiral rating (ASR) and Fahn-Tolosa-Marin (FTM) A scale and age-at-onset distribution. A: Correlation between the
mean ASR (spiral ratings) on the x-axis and the log2 of the FTM A scale values on the y-axis. Error bars: standard deviation (SD) of the FTM A scale
values. Regression line (blue) with 95% confidence interval of the regression line (gray). B: Histogram of the age-at-onset distribution with overlay of
the 3 subdistributions for early-onset (red), indeterminate-onset (black), and late-onset (blue) patients. Red-dotted vertical line: upper age border of
the early-onset group (mean 1 2 SD). Blue-dotted vertical line: lower age border of the late-onset group (mean 2 SD). [Color figure can be viewed
in the online issue, which is available at wileyonlinelibrary.com.]

1562 Movement Disorders, Vol. 31, No. 10, 2016

 E A R L Y A N D L A T E O N S E T E S S E N T I A L T R E M O R

FIG. 3. Disease progression in the early-onset and late-onset groups. A-D: Age at onset on the x-axis versus log2 of the progression as (A) ASR, (B)
FTM A, (C) FTM B, and (D) FTM C per 10-year duration bin stratified by early-onset (red) late-onset (blue) groups. P values: significance of the com-
parison between progression in the early-onset group versus progression in the late-onset group (MannWhitney U test) for each bin and for all
3 bins together (below parentheses). ASR, Bain spiral rating; FTM, Fahn-Tolosa-Marin. [Color figure can be viewed in the online issue, which is avail-
able at wileyonlinelibrary.com.]

Mclust uses an expectation maximization algorithm for
mixtures of multivariate Gaussian distributions penaliz-
ing the addition of components via the Bayesian infor-
mation criterion to avoid overfitting. Mixtools was
used to visualize the results of mclust. Means and
standard deviations (SD) were used for interval-scaled
data. Median and median absolute difference were
used for ordinal-scaled data (ASR and FTM A, B, and
C). Statistical significance was calculated via chi-
squared tests for contingency tables or Fishers exact
test if 1 cell contained less than 5 entries. Students t
test was used for the comparison of normally distrib-
uted ratio-scaled data between groups. The nonpara-
metric MannWhitney U test was used for ordinal-
scaled data, such as disease severity and progression
markers. The FTM A scale was log2 transformed for
the correlation analysis with the ASR to normalize the
distribution of the values and achieve a linear correla-
tion (Fig. 2A). The progression measures ASR divided
by disease duration and the FTM A, -B, and C values
were log2 transformed for the generation of Figure 3.
Results
Sample Description
Of the 1137 tremor patients, 978 were diagnosed as
definite or probable ET, and for 839 of these patients,
the age at onset was available (Fig. 1). Each patient had
drawn at least 1 spiral for each hand, and in summary
4548 Archimedes spirals were available. Two raters
evaluated 3260 Archimedes spirals. The mean interrater
reliability was 0.81 6 0.014 (kappa correlation coeffi-
cient), indicating a strong agreement of spiral rating.
The correlation between the mean ASR (mean of both
hands) and the FTM A values was high (Spearman rho

Movement Disorders, Vol. 31, No. 10, 2016 1563

H O P F N E R E T A L
FIG. 4. Histograms of family history for essential tremor and alcohol responsiveness in relation to the age of onset. A: Histogram of a positive (white
bars) or negative (black bars) family history for essential tremor in percent of patients on the y-axis in relation to the age at onset (x-axis). B: Histo-
gram of a positive (white bars) or negative (black bars) history of alcohol sensitivity of the tremor in percent of patients on the y-axis in relation to
the age at onset (x-axis).
5 0.66, P < 2.2 3 10-16, Fig. 2A). In the following anal-
yses, we used the ASR as main tremor severity indicator
because the ASR ratings were approximately normally
distributed whereas the FTM A, B, and C values were
strongly asymmetric (right skewed) and not available
for all patients. Visually, the age at onset had a bimodal
distribution (Fig. 2B). Hartigans dip test for unimodality
confirmed that the distribution was not unimodal (P <
2.2 3 10-16). Finite-mixture modeling assuming underly-
ing normal distributions with unequal variance favored
a 3-component over a 2-component model (Fig. 2B,
Supporting Information Figures e-1 and e-2). The first
component contained the early-onset patients (mean
13.0 years, SD 6 5.4 years), the second component con-
tained patients with an intermediate age at onset (mean
39.1 years, SD 6 12.7 years), and the third component
contained late-onset patients (mean 61.6 years, SD 6
7.8 years). We chose the 3-component model because it
provided a clear separation between the early-onset
group and the late-onset group and a better fit especially
for the late-onset group (Supporting Information Fig. e-
2). We defined the early- and late-onset groups based on
2 standard deviations: early-onset group rounded age at
onset  24 years, and late-onset group age at onset  46
years. The total number of patients per group was com-
parable, and the sex ratio does not differ significantly
between groups (Table 1). The early-onset patients were
younger at examination (mean 51.2 years, SD 6 17.2
years) than late-onset patients (mean 71.2 years, SD 6
6.4 years, P < .0001, Table 1).
Despite much longer mean disease duration in early-
onset patients (37.9 years, SD 6 17.0 years)
versus late-onset patients (11.1 years, SD 6 6.7 years,
1564 Movement Disorders, Vol. 31, No. 10, 2016
P < .0001, Table 1), the median scores of the tremor
severity markers ASR and FTM A, B, and C at the
time of examination differed very little between early-
and late-onset patients (Table 1). Figure 3A shows the
tremor progression measured as ASR and FTM A, B,
and C divided by disease duration in bins of 10 years
in relation to the age-at-onset group. It is apparent
that the tremor progression is faster in patients with a
late onset for all progression markers (Fig. 2B). The
difference in tremor progression is significant for all
but 1 of the comparisons (FTM A in the 10-year bin)
and highly significant for all comparisons if all
patients with a disease duration of 0 to 30 years are
binned. Only 1 early-onset patient fell in the duration
bin of 70 to 80 years, and 3 late-onset patients fell in
the duration bin of 30 to 40 years, which were not
assessed because of the small number of patients per
bin. A positive family history of tremor is more com-
mon in early-onset patients (75%) than in late-onset
patients (59%; Fig. 4A, P < .0001, Table 1). The
same applies to alcohol sensitivity of the tremor,
which was reported by 76% of early-onset patients
versus 45% of late-onset patients (P < .0001, Table
1). No statistically significant differences between the
groups were observed concerning the tremor localiza-
tions (Table 1).
Discussion
We describe the phenotypical characteristics of 673
patients with definite or probable ET and either early
or late onset. The background for this manuscript is
 E A R L Y
the search for clinical subtypes of ET, and there is pre-
liminary evidence that the age at onset may provide a
marker for these subtypes. Earlier studies have sug-
gested that ET patients have a higher mortality and
that patients with a tremor onset beyond 65 years
have a higher incidence of dementia.9,10 Based on a
cohort of epidemiologically characterized patients, we
recently demonstrated that action tremor beyond the
age of 70 years is an independent predictor of mortal-
ity associated with signs of earlier aging as measured
with motor and cognitive parameters.18 Furthermore,
we have demonstrated by EMG-EEG coherence that
different central tremor networks underlie early- and
late-onset tremor.35 The present study showed a
bimodal age at onset, confirming earlier smaller stud-
ies.19-22 It has been suggested that the visually bimodal
distribution might be an artifact seen only in tertiary
referral centers.21 However, our patients were
recruited via a regional cross-sectional study and via
newspapers. Nearly half of all patients (46%, data not
shown) had not been diagnosed with ET before,
emphasizing that we did not study a sample with char-
acteristics found in a tertiary referral center. Mathe-
matical modeling showed that a trimodal distribution
provides a better fit for the observed data.
We did not examine the intermediate-onset group
for the following reasons: (I) it does not currently cor-
respond to a group recognized on clinical grounds; (II)
if it is a separate group, the distribution shows strong
overlap with the early- as well as the late-onset group;
and (III) looking at only 2 groups allows a clear sepa-
ration between groups. Further studies are needed to
define nonmotor and additional motor characteristics
of this group. Indeed, the patients with early- and
late-onset differ in several respects, thereby confirming
earlier studies: A faster disease progression in late-
onset tremor has been shown by at least 1 previous
study.36 Patients with early onset showed significantly
more often a positive family history and alcohol
responsiveness, whereas patients with late-tremor
onset turned out to be more frequently of sporadic
origin with lower alcohol responsiveness in previous
studies.37 Our study has a number of methodological
limitations. The most important is the necessity to
judge progression from a cross-sectional study by
dividing the disease severity scale values ASR and
FTM A, B, and C by the disease duration. We reduced
this problem by binning the patients in 10-year disease
duration categories for the progression markers. The
finding that disease progression is fast at the beginning
of the disease irrespective of the age at onset and
slows down later, rather than showing an erroneous
progression pattern (eg, deceleration and acceleration
at different time points), suggests that this method is
feasible. The age at onset was based on the patient
reports, and a longitudinal study with incidence data
A N D L A T E O N S E T E S S E N T I A L T R E M O R
would have been better. However, a longitudinal
study of this scope with an observation period of
around 70 years is unrealistic. Regarding drug treat-
ment of ET, we would like to mention that both
groups did not differ significantly in the percentage of
patients receiving treatment nor in the fraction of
patients reporting either a good, a fair, or no-
treatment effect and that a separate analysis of all pro-
gression parameters in the group of patients without
treatment yielded the same results as the analysis in all
patients, albeit with lower significances because of the
severely reduced number of patients (data not shown).
Our conclusions were based on a large number of
patients per group, the differences were large, and all
progression measures, based on different nonoverlap-
ping parts of the examination, showed a congruent
behavior. Disease progression of ET was measured
using the same approach of dividing the tremor sever-
ity by the disease duration judged from the history in
a number of prior studies.36,38,39 The strong logarith-
mic relation between the validated FTM scale and the
ASR (Fig. 2A) suggests that the ASR is indeed a valid
measure for tremor severity.28,40 Early- and late-onset
ET patients differ in important clinical characteristics
that might be markers of etiopathological differences
as is the case for many other diseases. Prominent
examples are Parkinsons disease and Alzheimers dis-
ease. Both disorders are commonly monogenic in
early-onset patients and genetically complex in late-
onset patients. We suggest ascertaining the age at
onset and including as well as stratifying analysis for
the age at onset of ET patients in future studies. This
will enable a better phenotypic definition and differen-
tiation possibly resolving some of the seemingly con-
tradictory findings concerning ET.
Acknowledgments: We are indebted to the ET patients for partici-
pating in our research. Our ET research is supported by the Deutsche
Forschungsgemeinschaft (KL 1433/2-1, KU1194/9-1 KU1194/8-1, De
438/16, SFB 855).
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