Parkinsonism and Related Disorders 36 (2017) 41e46

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Parkinsonism and Related Disorders

journal homepage: www.elsevier.com/locate/parkreldis

Editor's Comment: Tremor, arguably the cardinal sign of Parkinson's disease, remains fairly enigmatic in terms of its pathophysiology. From
the group of Berardelli, a group of 210 patients with PD were consecutively assessed for the presence of re-emergent tremor (RET). This was
present in about 20 % of the sample, and was unilateral in half of those. No patient had a history of familial tremor.
The principal nding of this study is that disease severity was milder in patients with RET. It is well known that disease severity is less in
patients with tremor predominant PD, but the authors further demonstrated that patients with RET had milder disease as compared to those
with action tremor. This report appears to conrm Jankovic's original postulate that RET is a form of rest tremor. All in all, this interesting
article underscores how careful clinical observations may lead to interesting hypotheses and potentially illuminate basic disease processes.

Jonathan Carr, Associate Editor, University of Stellenbosch, Ward A-8-L, Tygerberg Hospital, Tygerberg, Western Cape, 7075, South Africa.

Re-emergent tremor in Parkinson's disease

Daniele Belvisi a, Antonella Conte a, b, Matteo Bologna a, b, Maria Carmela Bloise b,
Antonio Suppa a, b, Alessandra Formica a, Matteo Costanzo b, Pierluigi Cardone b,
Giovanni Fabbrini a, b, Alfredo Berardelli a, b, *
a
Neuromed Institute IRCCS, Via Atinense 18, 86077, Pozzilli (IS), Italy
b
30, 00185 Rome, Italy
Department of Neurology and Psychiatry, Sapienza University of Rome, Viale dellUniversita

a r t i c l e i n f o a b s t r a c t

Article history: Introduction: Re-emergent tremor (RET) is a postural tremor that appears after a variable delay in pa-
Received 13 September 2016 tients with Parkinson's disease (PD). The aim of the present study was to evaluate the occurrence and the
Received in revised form clinical characteristics of RET in a population of patients with PD.
4 November 2016
Methods: We consecutively assessed 210 patients with PD. We collected the patients' demographic and
Accepted 15 December 2016
clinical data. RET was clinically characterized in terms of latency, severity and body side affected. We also
investigated a possible relationship with motor and non-motor symptoms and differences in the clinical
Keywords:
features in patients with and without RET.
Re-emergent tremor
Rest tremor
Results: RET was present in 42/210 patients. The mean latency of RET was 9.20 6.8 seconds. Mean
Action tremor severity was 2.4 1.9. RET was unilateral in 21 patients. Patients with RET had less severe speech,
Parkinson's disease posture and gait disorders and upper limb and global bradykinesia than patients without RET. Similar
Subtype ndings were observed when we compared patients with RET with patients with tremor at rest asso-
ciated with action tremor, patients with isolated action tremor and patients with no tremor. By contrast,
patients with RET tremor did not clinically differ from those with isolated tremor at rest.
Conclusion: Our results suggest that patients with RET and patients with isolated tremor at rest represent
the same clinical subtype, whereas patients with action tremor (whether isolated or associated with
tremor at rest) might belong to a distinct subtype that is clinically worse. Patients with RET represents a
benign subtype of PD, even within the tremor-dominant phenotype.
2016 Elsevier Ltd. All rights reserved.

1. Introduction postural and kinetic tremors may also be present [3e5]. Jankovic
et al. described 12 PD patients with RT that showed a postural
Patients with Parkinson's disease (PD) may display different tremor that appeared after a variable delay when the upper limbs
types of tremor. Tremor at rest (RT) is common in PD [1,2], though had been held outstretched [6]. The authors dened this tremor as
re-emergent tremor (RET) and suggested that RET might be a
* Corresponding author. Department of Neurology and Psychiatry, and Neuromed
possible clinical variant of RT [6]. This hypothesis was based on the
Institute, Sapienza, University of Rome Viale dellUniversita
30, 00185 Rome, Italy.
E-mail addresses: daniele.belvisi@uniroma1.it (D. Belvisi), antonella.conte@ observation that the two tremors share similar frequency charac-
uniroma1.it (A. Conte), matteo.bologna@uniroma1.it (M. Bologna), bloise.mc@ teristics [6,7] and a similar asynchronous muscle activation pattern
gmail.com (M.C. Bloise), antonio.suppa@uniroma1.it (A. Suppa), [8].
alessandraformica@yahoo.it (A. Formica), matteo_cos90@hotmail.it (M. Costanzo), Investigating a population of 197 PD, Louis et al. found 67 pa-
pierluigicardone91@gmail.com (P. Cardone), giovanni.fabbrini@uniroma1.it
(G. Fabbrini), alfredo.berardelli@uniroma1.it (A. Berardelli).
tients with RET (32%) but did not investigate the clinical features of

http://dx.doi.org/10.1016/j.parkreldis.2016.12.012
1353-8020/ 2016 Elsevier Ltd. All rights reserved.
42 D. Belvisi et al. / Parkinsonism and Related Disorders 36 (2017) 41e46
this type of tremor [4]. As the clinical features of RET have never
been exhaustively investigated, it is still unclear whether PD pa-
tients with RET differ from PD patients with other types of tremor
and thus represent a distinct clinical subtype of PD.
The aim of the present study was to assess the occurrence of
RET and to describe the characteristics of RET in a sample of 210
consecutive PD patients evaluated on their usual treatment
regimen. We also sought a possible relationship between RET and
other motor and non-motor symptoms of PD. Lastly, to investigate
whether the presence of RET is indicative of a particular subtype of
PD, we compared the clinical features of PD patients with RET
with those of patients with other types of tremor and of patients
without tremor.
2. Methods
2.1. Subjects
We consecutively assessed 210 patients with PD who were
attending our Movement Disorder outpatient clinic, between
January and June 2015. The diagnosis of PD was based on clinical
criteria [9,10]. We collected the PD patients' demographic and
clinical data, including age, age at onset, disease duration, duration
of treatment with dopaminergic drugs, dosages of dopaminergic
therapy, and presence of dyskinesia and motor uctuations. The
severity of the disease was assessed by means of the Hoehn and
Yahr scale (H&Y) [11] and Movement Disorder Society-sponsored
revision of the Unied Parkinson's Disease Rating Scale (MDS -
UPDRS) part III [12]. Non-motor symptoms were evaluated by
means of the Non-Motor Symptoms assessment scale for PD
(NMSS) [13]. The levodopa-equivalent daily dose (LEDD) was
calculated.
In order to assess the presence of RT we asked patients to sit
comfortably on a chair, with the upper limbs at rest for 60 seconds.
To evaluate the presence of RET and postural tremor, we asked
patients to extend both arms and to hold them outstretched for 90
seconds. Lastly, to assess the presence of kinetic tremor, we asked
patients to perform the nger-to-nose and nger-to-nger tests (15
times for each side for each test).
RET was dened as a tremor that appeared in the outstretched
upper limbs after at least 1 second while maintaining the posture
[6]. In patients with RET, we carefully evaluated the latency (time
interval between the arm extension and the onset of tremor,
expressed in seconds), severity (0e4 according to the MDS-UPDRS)
[12] and body side affected (unilateral or bilateral).
The clinical evaluation, including the H&Y and MDS-UPDRS
scales and the assessment of the different types of tremor, was
performed while patients were on their usual treatment regimen.
After 3 months from the rst clinical assessment, all the patients
with PD underwent a re-evaluation performed by the same rater
without checking previous data.
All the patients enrolled participated in the study. Each patient
signed an informed consent form and the study was approved by
the local ethics committee.
2.2. Statistical analysis
We performed a multivariate analysis to investigate which
variable (gender, age, age at onset, disease duration or
tremor type) best discriminated the clinical subtypes, stratied
according to the characteristics of tremor. The demographic and
clinical features were compared in patients with unilateral or
bilateral RET by using a Mann-Whitney U Test. In patients with
bilateral RET, we used a Mann-Whitney U test to compare the mean
latency between patients with the right and the left affected body
side. In patients with RET, we also evaluated possible correlations
between RET severity and other demographic and clinical features
by means of a Spearman rank correlation coefcient.
To ascertain whether patients with RET represent a distinct PD
subtype, we compared the demographic and clinical features of
patients with RET with those of patients without RET by using a
Mann -Whitney U Test. In a subsequent analysis, we compared the
demographic and clinical features of patients with different types
of tremor and with no tremor by using a Kruskall Wallis test with
the between group factor GROUP as main factor of analysis. The
Mann-Whitney U test was performed for the post-hoc analysis.
A multiple logistic regression analysis with RET (1, present; 0,
absent) as the outcome variable was performed to investigate the
association with motor and non-motor symptoms and the possible
confounding effect of relevant demographic and clinical variables.
Odds ratios, two-sided 95% condence intervals and P values
(likelihood ratio statistic) were calculated. A subsequent stepwise
analysis was performed.
In order to verify whether the classication of clinical subtypes
was correct, we performed a Wilcoxon test to evaluate whether the
patients' classication according to their tremor subtypes changed
at a second assessment performed the 3-months later.
Holmes' correction was applied for multiple comparisons and
correlations. P values < 0.05 were considered to indicate statistical
signicance.
We used SPSS software for the statistical analysis.
3. Results
3.1. Demographic and clinical features of PD patients
Eighty-two women and 128 men participated in the study. Their
mean age was 70.4 8.8 years, mean age at onset of parkinsonian
symptoms was 62.3 10.4 years and mean disease duration was
7.6 5.2 years. The mean H&Y score was 1.9 0.8 and mean MDS-
UPDRS part III score was 24.3 12.5. Six patients were drug-free.
The remaining patients received antiparkinsonian medication,
including levodopa alone (48), dopamine agonists alone (29),
monoamine oxidase inhibitor alone (11) and a combination of
drugs (116). Dyskinesias were present in 42 patients. Motor uc-
tuations were present in 101 patients.
3.2. Clinical subtypes according to the characteristics of tremor
The clinical evaluation disclosed that RET was present in 42
patients (20%), isolated RT in 18 patients (8%), RT associated with
action tremor (AT) (postural and/or kinetic) in 82 patients (40%),
isolated AT in 6 patients (2%), while the remaining 62 patients had
no tremor (30%). The demographic and clinical data of the ve
subtypes of patients are reported in Table 1.
3.3. Multivariate analysis
The multivariate analysis showed that, among the several clin-
ical and demographic features, type of tremor best discriminated
the PD sample in the ve subgroups (p < 0.001).
3.4. Characteristics of RET
The mean latency of RET was 9.2 6.8 seconds (range: 1e35
seconds), and the mean severity 2.4 1.9 (range1e4). All patients
with RET were right-handed. RET was unilateral in 21 (right side: 13
patients; left side: 8 patients) and bilateral in 21 of the 42 patients.
Fifteen patients with unilateral RET also had unilateral RT and 6 had
bilateral RT. Both types of tremor (RT and RET) were present on the
 D. Belvisi et al. / Parkinsonism and Related Disorders 36 (2017) 41e46 43

Table 1
The demographic and clinical data of patients with re-emergent tremor, isolated tremor at rest, tremor at rest associated with action tremor, isolated action tremor and no
tremor.

Re-emergent tremor Isolated tremor at rest Tremor at rest and action tremor Isolated action tremor No tremor P values

Age (yrs) 72.1 8 70.6 8.5 71.3 9 68.8 9.5 69.4 9.1 n.s.
Age at onset (yrs) 65 8.3 63 10.7 64.7 9 58.3 12 60.8 12 n.s.
Disease duration (yrs) 7.2 5.9 7.71 6 6.4 4.7 8.3 2.1 8.5 7.6 n.s.
MDS-UPDRS part III 19.06 11 19.66 9.5 30.9 16 26.2 16 25.85 10.06 <0.001*
Hoehn and Yahr 1.9 0.6 1.8 0.6 2.0 0.8 1.7 1.3 2.3 0.8 n.s.
LEDD (mg) 475 325 484 329 464 316 525 363 495 349 n.s.

LEDD: levodopa-equivalent daily dose. n.s. non signicant.

same side in the majority of cases (14 of 15 cases). In the 21 patients
with bilateral RET, RT was bilateral in 17 patients and unilateral in 4
patients. In patients with bilateral RET, we found a similar mean
latency between the right and the left sides (mean latency: right
side: 9.0 6.6 seconds; left side: 9.4 7.1, p > 0.05).
When we compared the demographic and clinical features of
patients with unilateral RET with those of patients with bilateral
RET, we found no differences of the demographic or clinical vari-
ables considered (all ps > 0.05).
In patients with RET, we found a signicant positive correlation
between RET severity and ipsilateral RT severity (right side:
r 0.65; p < 0.0001; left side: r 0.46; p < 0.002). We did not
detect any other signicant correlations between RET severity and
the other demographic and clinical variables (p > 0.05).
3.5. Clinical differences between patients with and without RET
We found that patients with RET achieved lower total
(p < 0.001) and single item (Table 2) MDS-UPDRS part III scores
than patients without RET. The other clinical and demographic
variables were instead similar in the two groups (p > 0.05). When
we compared the demographic and clinical features in patients
with different types of tremor and no tremor in a subsequent
analysis, we found that the total MDS-UPDRS part III score
(p < 0.001) and presence of dyskinesia (p < 0.005) differed signif-
icantly in the ve groups. There was also a signicant difference in
the MDS-UPDRS part III sub-scores for the items speech, nger
tapping, hand movements, prono-supination movements of
hands, gait, bradykinesia, postural tremor, kinetic tremor,
RT amplitude and constancy of RT (all ps < 0.001). No differ-
ences were detected between the ve groups of patients for the
other demographic and clinical variables examined (Table 1). The
post-hoc analysis did not detect any differences in the variables
considered between patients with RET and those with isolated RT
(Table 3). By contrast, patients with RET had a signicantly lower
H&Y score (p < 0.003), MDS-UPDRS part III sub-scores and a
decreased frequency of dyskinesia (p < 0.001) than patients with no
tremor (Table 3). Similarly, the MDS-UPDRS part III total score and
sub-scores were lower in patients with RET than in those with RT
associated with AT or in those with isolated AT (Table 3).
The multiple logistic regression analysis yielded a signicant
positive association of RET with RT scores (odds ratio: 4.8473; 95%
condence interval: 1.5570 to 15.0904 852; p 0.006) and a
negative association with prono-supination (odds ratio: 0.2107;
95% condence interval: 0.0758 to 0.5852; p < 0.005) and speech
(odds ratio: 0.1819; 95% condence interval: 0.0478 to 0.6924;
p 0.01) scores. Neither a signicant association nor any trend was
detected between RET and the other motor and non-motor vari-
ables (Table 4). The stepwise logistic regression analysis yielded a
positive association between RET and RT severity (coefcient:
0.139; p < 0.0001) and a negative association between RET and
speech (coefcient: 0.09; p < 0.01) and prono-supination
(coefcient: 0.137; p < 000.1) scores.
Wilcoxon's test showed that the patients' classication accord-
ing to the presence and type of tremor at the 3-month assessment
was unchanged (p > 0.05).
4. Discussion
Our ndings show that RET was present in 42/210 patients with
PD. Patients with RET had milder speech, posture and gait disorders
and upper limb and global bradykinesia than patients without RET.

Table 2
Patients with and without re-emergent tremor MDS-UPDRS part III subscores.

Re-emergent tremor Non-re-emergent tremor patients P value

(42 patients) (168 patients)

Speech 0.51 0.59 1.1 0.74 <0.0001*

Facial expression 1 0.59 1.29 0.7 n.s
Rigidity 2.64 2.77 3.67 2.39 n.s
Finger tapping 1.84 1.18 2.62 1.41 <0.0001*
Hand movements 1.71 1.08 2.44 1.36 <0.0001*
Prono-supination movements of hands 0.38 0.81 1.6 1.43 <0.0001*
Leg agility Toe tapping 2.61 1.36 3.56 2.48 n.s
Arising from chair 0.48 1.06 0.73 0.91 n.s.
Gait 0.64 0.61 1.14 0.88 <0.0001*
Freezing of gait 0.25 0.58 0.37 0.9 n.s.
Postural stability 0.43 0.81 0.9 0.99 n.s.
Posture 0.66 0.79 1.11 1 <0.002*
Body bradykinesia 1.05 0.55 1.48 0.83 <0.0001*
Postural tremor 0 0.78 0.52 <0.0001*
Kinetic tremor 0 0.66 0.56 <0.0001*
Tremor at rest amplitude 3.15 2.5 1.35 0.96 <0.0001*
Constancy of tremor at rest 1.71 1.03 0.79 0.57 <0.0001*

n.s. non signicant.

44 D. Belvisi et al. / Parkinsonism and Related Disorders 36 (2017) 41e46

Table 3
MDS-UPDRS part III subscores of the ve clinical subtypes.

Re-emergent tremor Isolated tremor at rest Tremor at rest and action tremor Isolated action tremor No tremor
(42 patients) (18 patients) (82patients) (6 patients) (62 patients)

Speech 0.51 0.59 0.62 0.51 1.07 0.83** 1.4 1.02* 1.32 0.62***
Facial expression 1 0.59 0.92 0.62 1.31 0.81 1.44 0.75 1.52 0.62
Rigidity 2.64 2.77 2.38 1.78 4.02 2.85 3.8 2.23 4.51 2.73
Finger tapping 1.84 1.18 2.15 1.29 2.82 1.54*** 2.60 1.36 2.94 1.44***
Hand movements 1.71 1.08 1.77 1.25 2.67 1.46*** 2.42 1.47 2.92 1.27***
Prono-supination 0.38 0.81 1.08 1.89 1.79 1.41*** 1.8 1.4** 1.73 1.03***
Leg agility toe tapping 2.61 1.36 2.46 1.55 3.63 2.85 3.8 2.99 4.37 2.53**
Arising from chair 0.48 1.06 0.38 0.49 0.88 1.18 0.8 0.88 0.89 1.08
Gait 0.64 0.61 0.69 0.62 1.28 1.02** 1.15 0.98 1.45 0.91***
Freezing of gait 0.25 0.58 0.17 0.37 0.34 0.86 0.6 1.2 0.39 0.77
Postural stability 0.43 0.81 0.85 0.71 0.88 1.14 1 1.11 0.87 1.01
Posture 0.66 0.79 0.85 0.82 1.07 0.91* 1.4 1.12 1.15 1.16**
Body bradykinesia 1.05 0.55 0.92 0.83 1.61 0.75** 1.6 1.02 1.79 0.7***
Postural tremor 0 0 1.74 1.26*** 1.4 0.85*** 0
Kinetic tremor 0 0 1.64 1.34*** 1 0.9*** 0
Tremor at rest amplitude 3.15 2.5 2.8 1.71 2.6 2.12 0*** 0***
Constancy of tremor at rest 1.71 1.03 1.62 1.12 1.55 1.14 0*** 0***

* p < 0.05; ** p < 0.01; *** p < 0.001.

Table 4
Non-motor symptoms scores of patients with and without re-emergent tremor. Each item evaluates the frequency and severity separately, and a score ranging from 0 to 12 is
obtained by multiplying both concepts.

Domain Patients with re-emergent tremor Patients without re-emergent tremor p

1.cardiovascular including falls 1.05 2.31 1.7 3.06 n.s

2.sleep/fatigue 6.46 6.88 8.15 9.09 n.s
3.mood/cognition 6 9.65 10.85 10.22 n.s
4. perceptual problems/hallucination 0.8 2.78 1.46 3.99 n.s
5. attention/memory 3.38 4.85 4.32 6.42 n.s
6. gastrointestinal tract 4 4.09 4.48 5.49 n.s
7. urinary 6.71 8.31 7.23 8.64 n.s
8. sexual function 6.72 9.08 7.26 9.31 n.s
9.pain 0.66 1.81 1.08 2.35 n.s
10.smell/taste 2 3.34 2.66 7.46 n.s
NMSS total score 37.82 30.46 49.23 44.04 n.s

n.s. non signicant.

Similar ndings were observed when we compared patients with
RET with patients with RT associated with AT, patients with isolated
AT and patients with no tremor. By contrast, patients with RET did
not clinically differ from those with isolated RT. We found a positive
correlation in patients with RET between the severity of RET and RT.
In the whole sample, we observed a positive association between
RET and RT severity and a negative association between RET and
speech disorder and upper limb bradykinesia.
In the present study, RET was observed in 20% of PD patients
enrolled. In 2001, Louis et al. found RET in 32% of the patients
recruited [4], while Jankovic et al. found a greater percentage of
patients with RET (67%) [6]. The present study and Louis study were
conducted on similar number of patients (210 and 197 patients,
respectively), whereas Jankovic study was based on 12 patients.
Differences in the sample size likely explain the discrepancies in the
occurrence of RET across studies.
We found that only a minority of patients had isolated RT or
isolated AT. In PD, the occurrence of RT and AT is highly variable
among clinical studies. Hughes et al. reported that 75% of patients
had tremor during the course of their disease [14] while a pro-
spective study in patients with autopsy-proven PD found that 100%
of patients had RT at some point [15]. Both studies, however,
included patients with different types of tremor and did not specify
the number of patients with isolated RT or AT. Studies assessing
tremor by laboratory methods yielded a large variability in AT
occurrence (55%e100%) [16e19]. A similar variability was observed
in clinical studies: Louis et al. (2001) found that 93% of patients
showed AT while Gigante et al. (2015) recently observed AT in a
signicantly lower number of patients (46%). However, when Louis
excluded patients with RET, the percentage of patients with AT
decreased to 60%. The variability of the previous ndings on the
occurrence of the various types of tremor might be, at least in part,
due to a lack of differentiation between RET and AT. Moreover,
patients with RT and RET may have been considered to be affected
by RT and AT, thus inducing a bias in the classication of patients
with RT.
A novel nding is that patients with RET had lower axial
symptoms (speech, gait and posture), upper limb and global bra-
dykinesia sub-scores than patients without RET. This difference
cannot be attributed to differences in the patients' clinical features
because we found that age, gender and disease duration were
similar in the two groups. Supporting this assumption, we found
that the variable tremor subtype best differentiates patients' sub-
groups. Another possible explanation for the lower MDS-UPDRS
part III sub-scores in patients with RET than in those without RET,
might be that the group of patients without RET included patients
without tremor, who usually yield higher segmental and global
bradykinesia scores. However, even this hypothesis was excluded
by the post-hoc analysis.
We observed that patients with RET did not differ clinically from
patients with isolated RT. Differently, we found that the severity of
bradykinesia and axial symptoms was lower in patients with RET
than in those with AT (whether isolated or associated with RT).
Overall these observations suggest that patients with RET and
 D. Belvisi et al. / Parkinsonism and Related Disorders 36 (2017) 41e46
patients with isolated RT represent the same clinical subtype,
whereas patients with AT (whether isolated or associated with RT)
belong to a distinct subtype that is clinically worse. This implies
that different pathophysiological mechanisms might underlie RET
and AT, whereas RET may share similar pathophysiological path-
ways with RT. This hypothesis is supported by the positive corre-
lation we observed between RT and RET severity and the high rate
of concordance in upper limb distribution between RET and RT
(unilateral or bilateral). These ndings agree with previous studies
suggesting RET as a variant of RT [4,6e8]. RET and RT might
therefore reect the pathological activity of the same central cir-
cuits [6]. The ventrolateral thalamus and the globus pallidus
internus are involved in the generation of RT [20]. Neuronal dis-
charges in these structures are markedly affected by sensory inputs.
The latency between rest and RET may reect a transitory inhibi-
tion of the tremor generator induced by the proprioceptive feed-
back generated by the repositioning of the limbs from rest to
outstretched [6]. This hypothesis is supported by the similarity in
the mean latency between our patients and in those reported by
Jankovic (9.20 6.8 seconds in our patients vs. 9.37 10.66 seconds
in those of Jankovic et al.) as well as by the comparable latency
between the right and left sides observed in our study in patients
with bilateral RET.
The different clinical features of patients with RET and of those
with AT may reect different pathophysiological mechanisms.
Previous studies have suggested the involvement of the cerebellum
in AT though not in RT [21,22], and have shown that striatum
serotoninergic dysfunction correlates with AT severity [23]. Given
that patients with RET and patients with RT seem to belong to the
same subtype, it is likely that similar differences exist between
patients with RET and patients with AT. Future neuroimaging,
neurophysiological and neuropathological studies are needed to
conrm whether the milder disease severity of patients with RET in
comparison with patients with AT reects the activity of different
pathophysiological mechanisms. In 2015, Gigante et al. observed
that AT is associated with rigidity [5]. Since rigidity is believed not
to depend exclusively on dopaminergic cell loss in the substantia
nigra [24,25], the authors concluded that non-dopaminergic
mechanisms contribute to the generation of AT. In keeping with
the hypothesis that pathophysiological mechanisms underlying
RET and AT differ, we found no association between the presence of
RET and rigidity scores.
By comparing patients with RET and patients without RET, we
observed similar non-motor symptoms scores. We did not nd any
signicant correlation between RET and non-motor severity.
Although patients with no tremor showed the highest non-motor
symptoms scores, the post hoc analysis did not show signicant
differences among the ve clinical subtypes. These results partly
differ from previous studies reporting a lower non-motor symptom
burden in patients with tremor dominant phenotype when
compared with patients with akinetic-rigid [20,26e30]. A possible
explanation for the difference between our results and those of
previous studies may depend on the relatively small sample of pure
akinetic-rigid patients in our population.
A strength of our study is that we studied RET in a sample of PD
patients at different stages of the disease. The diagnosis was based
on standard clinical criteria [9,10], limiting the possibility of
including patients with tremor due to other causes. Patients with
isolated AT had no family history of tremor, a long disease duration
and high bradykinesia and rigidity scores, making unlikely the
possibility that these patients had essential tremor. A further
strength is that patient samples have been classied according to
the type of tremor. This allowed us to clearly dene the occurrence
of RET and other types of tremor.
Although our study adds new ndings regarding RET, some
45
methodological limitations should be acknowledged. Since the aim
of the study was to verify the occurrence of RET in a population of
PD patients, we consecutively enrolled PD patients while they were
on their usual treatment regimen. This experimental approach
implies the limitation that the antiparkinsonian treatment might
have underestimated the occurrence of tremor and of other clinical
symptoms thus affecting the clinical classication of the patients.
To reduce the possible bias due to uctuations of motor symptoms
related to dopaminergic therapy, we evaluated with the same
methods 210 patients twice in a 3-months period and we found a
strong concordance between the rst and the second evaluation.
The presence of treatment might also explain the low percentage of
patients with isolated RT that we found. A study specically
designed to evaluate RET while patients are off therapy is in
progress.
In conclusion, our ndings suggest that PD patients with RET
have a lower disease severity in terms of bradykinesia and axial
symptoms than either patients with AT (whether isolated or
associated with RT) or akinetic-rigid patients. The study suggests
that patients with RET represent a particularly benign subtype of
PD, even within the tremor-dominant phenotype. Future clinical
studies are needed to clarify whether patients with RET have also a
better disease progression than patients without RET and whether
patients show the same type of tremor during the disease.
Authors disclosures
All authors reported no disclosures.
Competing interests
Nothing to declare.
Study sponsorship or funding
Nothing to declare.
Acknowledgements
we thank Mr. Lewis Baker for English language editing.
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