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The treatment of dystonic tremor: a

systematic review
Alfonso Fasano, Francesco Bove and Anthony E Lang

J Neurol Neurosurg Psychiatry published online October 28, 2013

doi: 10.1136/jnnp-2013-305532

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JNNP Online First, published on October 28, 2013 as 10.1136/jnnp-2013-305532
1
Division of Neurology, Toronto
Western Hospital, University of
Toronto, Toronto, Ontario,
Canada
2
Department of Neurology,
Istituto di Neurologia,
Università Cattolica del Sacro
Cuore, Roma, Italy
3 available up to July 2013 on the treatment of these
Department of Neurology, The
Edmond J. Safra Program in
Parkinson’s Disease, Toronto,
Ontario, Canada
Correspondence to
Dr Alfonso Fasano, Movement
Disorders Center, Toronto
Western Hospital, 399 Bathurst
Street, Toronto, Ontario,
Canada M5T 2S8;
alfonso.fasano@gmail.com
Received 1 April 2013
Revised 16 September 2013
Accepted 26 September 2013
To cite: Fasano A, Bove F,
Lang AE. J Neurol Neurosurg
Psychiatry Published Online
First: [ please include Day
Month Year] doi:10.1136/
jnnp-2013-305532
Copyright
Fasano Article
A, et al. J Neurol author
Neurosurg
Downloaded from jnnp.bmj.com on November 1, 2013 - Published by group.bmj.com
Movement disorders
REVIEW
The treatment of dystonic tremor: a systematic review
Alfonso Fasano,1 Francesco Bove,2 Anthony E Lang1,3
ABSTRACT
Tremor is one of the clinical manifestations of dystonia;
however, there are no specific therapeutic trials
evaluating the efficacy of treatments for dystonic tremor
(DT), tremor associated with dystonia or primary writing
tremor (PWT). We systematically reviewed the literature
tremors and retrieved the data of 487 patients published
in 43 papers detailing the effects of given interventions
on tremor severity. Treatment outcome was highly
variable, depending on the specific type of intervention
and tremor distribution. No specifically designed studies
were available for the treatment of tremor associated
with dystonia. As for the other tremors, drug efficacy
was generally disappointing and a moderate effect was
only found with anticholinergics, tetrabenazine,
clonazepam, β-blockers and primidone; levodopa was
only efficacious on tremor due to dopa-responsive
dystonia. The largest amount of data was available for
botulinum toxin injections, which provided a marked
improvement, particularly for the management of axial
tremors (head or vocal cords). In refractory DTs, deep
brain stimulation of several targets was attempted. Deep
brain stimulation of globus pallidus internus, thalamus or
subthalamic area led to a marked improvement of
dystonic axial or appendicular tremors in most cases
refractory to other treatments. Few other non-invasive
treatments, for example, orthotic device in PWT, have
been used with anecdotal success. In conclusion,
considering the lack of good-quality studies, future
randomised controlled trials are needed. In absence of
evidence-based guidelines, we propose an algorithm for
the treatment of DT based on currently available data.
INTRODUCTION
Different forms of tremor can be associated with
dystonia. Dystonic tremor (DT) is defined as a pos-
tural/kinetic tremor occurring in the body region
affected by dystonia.1 Generally these are focal
tremors with irregular amplitudes and variable fre-
quencies (mostly below 7 Hz). In many patients
with DT antagonistic gestures lead to a reduction in
the tremor amplitude. Moreover, DT usually
worsens when the patient voluntarily moves the
affected body part against the major direction of
pulling caused by dystonia (eg, a patient with right
torticollis might present more DT when he turns
the head towards left). Conversely, DT may dimin-
ish and even disappear when the body part is posi-
tioned where the dystonia wants to place it. Some
patients exhibit focal tremors even without overt
signs of dystonia. They have been included among
DTs because some of them later develop dystonia.2
Tremor associated with dystonia (TAD) is another
type of tremor, which is present in a body region
(or2013;0:1–11.
Psychiatry their employer) 2013. Produced
doi:10.1136/jnnp-2013-305532 by BMJ Publishing Group Ltd under licence.
not affected by dystonia, but dystonia is present
elsewhere (eg, bilateral hand tremor in a patient
with cervical dystonia). This is a relatively symmet-
ric, postural and kinetic tremor usually showing
higher frequencies than typical DT.3 Dystonia
gene-associated tremor is analogous to TAD, but it is
an isolated finding in a patient with a dystonic pedi-
gree but not personally suffering from dystonia.4
The prevalence of DT or TAD is not known.
Head tremor in the context of cervical dystonia is
the most common form of DT, found in up to 68%
of these patients in one survey.5 In one Brazilian
cross-sectional study, it was estimated that approxi-
mately 20% of patients with dystonia have postural
tremor of the upper limbs (ie, TAD).6 This propor-
tion does not differ between idiopathic and acquired
dystonia but seems to be more common in cervical
dystonia than in other forms.7 DT is still a debated
entity and different definitions have been proposed
by clinicians.8–10 Virtually, every dystonic syndrome
may present with DT.
Primary writing tremor (PWT) is a condition in
which tremor predominantly or only occurs during
writing.11 Although there is some resemblance to
essential tremor (ET) (where tremor is present on
action, on maintenance of a posture, and may affect
hand writing), its focal task-specific nature, the lack
of response to propranolol and a well-documented
effect of central cholinergic drugs12 have suggested
that PWT may be more closely related to focal dys-
tonia than ET.13 14 Other task-specific DTs have
been reported. A 5 Hz jaw tremor induced only
when speaking or attempting to drink from a glass
has been reported15 16 as well as tremors of the lips
induced by smiling17 or by speaking18 or orolingual
tremor in patients with embouchure dystonia.19
The pathophysiology of these tremor conditions
is largely unknown but is likely related to the basal
ganglia abnormality postulated for dystonia itself.1
Consequently, in spite of their profound impact on
patients’ functioning and quality of life, there is a
paucity of information about the treatment of the
DT syndromes.20 The present systematic review is
aimed at collecting the available evidence guiding
clinicians in the treatment of DT, TAD and PWT.
METHODS
We searched PubMed until July 2013 with the
search terms “Dystonic Tremor”, “Tremor
Associated with Dystonia” or “Primary Writing
Tremor” (yielding 321, 0 and 50 papers, respect-
ively) and with the search terms “dystonia” AND
“tremor” AND “therapy” OR “treatment” (yielding
693 papers). Additional 476 papers, retrieved from
the references quoted in the papers found in our
literature search, were also evaluated. Given the
1
 Movement disorders
lack of meta-analyses or randomised controlled trials, we
included all the available studies. We only considered papers on
human subjects and written in English; among them, we only
considered those detailing the effect of a given intervention on
tremor severity (a total of 43 papers). No study on TAD fulfilled
the aforementioned research criteria. Dystonia was retrospect-
ively classified using the information from the articles according
to recently published criteria.21
The outcomes of papers not reporting rating scales but only
descriptive results were arbitrary transformed to the percentage of
improvement (ie, no improvement=0%, slight improvement=1–
25%, moderate improvement=26–50%, marked improve-
ment=51–75%, tremor disappearance=76–100%). When asses-
sing the effects on a specific body site, we only considered cases
with tremor exclusively involving one region (eg, only head).
When assessing the effects of a specific intervention, we did not
consider cases undergoing combined treatments (eg, drugs and
surgery).
Due to the small and inhomogeneous sample, statistical ana-
lysis was performed by means of nonparametric tests (Mann–
Whitney U Test and χ2 with Yates and Fisher corrections, as
needed).
RESULTS
No study on the treatment of TAD was found, whereas a total
of 43 studies enrolling 487 patients with DT or PWT were
included in the analysis (table 1): 12 were prospective, all but
two were not blinded or controlled and only one was rando-
mised; assessment tool was detailed in only 19 studies. The vast
majority of studies enrolled a small sample size (median of 2
cases, range: 1–44), genders were almost equally distributed
(male to female ratio of 1.2 : 1), the majority of patients were
adults (range: 1–76 years) and disease duration ranged from 1
to 60 years. Idiopathic dystonia was the most common under-
lying aetiology (in 35 studies), other causes were acquired
(largely perinatal anoxia and head injury) and ‘dystonia-plus’
(dopa-responsive dystonia—DRD—and myoclonus-dystonia) (in
6 and 4 studies, respectively). The majority of patients had
tremor only involving head/trunk (63.0%), followed by hands
(25.3%), vocal cords (9.0%) and lower face (0.8%); remaining
cases had a variable combination of body sites involved.
Drugs
Different dugs in variable combinations were used in 71 cases
(13 studies, table 2); no controlled or randomised studies are
available and detailed information is generally missing (eg, in
many of these studies drug doses were not specified). Overall,
many drugs have been used unsuccessfully in patients with DT.
Data on carbamazepine, acetazolamide, baclofen, amitriptyline,
imipramine, fluvoxamine and sulpiride are too scanty to draw
any useful conclusions as these drugs were anecdotally employed
in single cases.22 23
Given their consolidated use in the treatment of dystonia,24–26
many DT/PWT patients have been treated with anticholinergics.
Trihexyphenidyl 4 to 10 mg has been the most commonly
used.27–29 Anticholinergics were found to have slight to moderate
effectiveness in reducing tremor amplitude in a total of 16
patients with hand or head DT.27 30–33 However, in three studies,
a total of five patients did not achieve any benefit from anti-
cholinergic treatment.22 23 30 Anticholinergics may also provide
benefit in patients with PWT.12
Many patients were also treated with drugs commonly used
in the treatment of ET.34 A positive effect of propranolol at
unknown doses has been described in two studies, in which a
2 Fasano A, et al. J Neurol Neurosurg Psychiatry 2013;0:1–11. doi:10.1136/jnnp-2013-305532
moderate to marked improvement of arm tremor was reported
in nine patients with idiopathic focal dystonia.30 31 By contrast,
three other studies did not show efficacy of propranolol in a
total of 10 patients with head and jaw tremor.22 23 35 Another
β-blocker, timolol, was found to improve head DT in one
patient at the dose of 15 mg.35 Primidone failed in one patient
with head tremor35 and improved PWT in three of four cases.31
Benzodiazepines (in particular clonazepam at the dose of 0.5
to 3 mg) have been used in patients with DTs involving the
arms, jaw and head. Tremor outcome was quite variable,
ranging from no effect (two patients)22 to slight–moderate
improvement (six patients).22 23 27 35 The total abolishment of
tremor was reported in three patients, so that the authors
defined this tremor as “clonazepam-sensitive dystonic
tremor”.36 Interestingly, clonazepam dramatically suppressed the
tremor presented in 14 patients believed to be affected by a
‘kinetic predominant’ variant of ET.37 The diagnosis of ET in
these cases was supported by the absence of cerebellar signs, a
positive family history of tremor and alcohol responsiveness;
however, the frequency of tremor (3.5–6 Hz) and its poor
responsiveness to propranolol in contrast to the striking
response to clonazepam might also suggest a diagnosis of
“clonazepam-sensitive dystonic tremor” in these cases.
Although tetrabenazine has been successfully used in dys-
tonia,25 38 its role in the management of DT/PWT has been
poorly investigated to date. Tetrabenazine was found to improve
a case of PWT31 and one of three cases with dystonic jaw
tremor.23 Levodopa is the treatment of choice in patients with
DRD and accordingly it was found to improve dystonic postures
and the associated tremor.39 The limited published data on levo-
dopa treatment in patients with DT not related to DRD did not
demonstrate a reduction in tremor amplitude, but instead occa-
sionally showed worsening.40 41
Riluzole 100 mg/day was associated with a slight to moderate
improvement of dystonic head tremor in one study42; unfortu-
nately, no other report confirms these findings.
Finally, when addressing the outcome of the drugs lumped
according to the main mechanism of action (anticholinergic,
antiepileptic or β-blocker), no significant differences emerged
(figure 1A).
Botulinum neurotoxin
Botulinum neurotoxin (BoNT) injections have been employed
in a total of 330 patients (8 studies) with PWT,33 head
tremor43–46 or tremulous spasmodic dysphonia.47 As a conse-
quence, its effectiveness in the management of these tremor dis-
orders is well documented.48 Task-specific jaw tremor has been
found to improve after BoNT injections into the digastric and
masseter muscles.16 Fewer studies on PWT are available and
BoNT has been reported to be successful in some of them.33
No conclusion can be drawn about the efficacy of BoNT in
patients with arm tremor not caused by PWT, as no case has
been reported.
Surgery
A surgical approach (either deep brain stimulation—DBS—or
ablation of different brain nuclei) was employed in 37 patients
(20 studies). Severe cases of DT in the setting of a generalised
dystonia have been successfully treated with DBS of the globus
pallidus internus (Gpi),49 although none of the larger DBS trials
for dystonia have specifically taken into account the effect on
tremor. Seven cases were treated with only GPi stimulation or
ablation: two had dramatic improvements,50 51 four had moder-
ate improvement,52 whereas one with cervical DT did not
Fasano A, et al. J Neurol Neurosurg Psychiatry 2013;0:1–11. doi:10.1136/jnnp-2013-305532

Table 1 The features of the 43 studies (enrolling 487 patients with DT or PWT) retrieved by the systematic review of the literature
No of Age Dystonia duration
Reference points Sex (years) Dystonia type Dystonia distribution Tremor site (years) Assessing tool Study design* Blinded Randomisation Controlled
27
3 ? ? Isolated/sporadic Focal Neck ? EMG Prospective (IV) No No No
54
2 1M/1F 22.0±1.4 Acquired (perinatal Generalised Arm 22.0±1.4 ? Retrospective (IV) No No No
anoxia)
30
8 6M/2F 40.8 Idiopathic Focal Arm 5.4±3.9 0–4 scale Retrospective (IV) No No No
±14.6
71
1 M 34 Idiopathic Segmental Four limbs ? ? Retrospective (IV) No No No
43
17 ? ? Idiopathic Focal Neck ? ? Prospective (IV) No No No
22
2 1M/1F 28.0±2.8 Idiopathic Focal Neck 9.0±1.4 ? Retrospective (IV) No No No
48
14 ? 55.8† Idiopathic Focal Neck, hand 13.9† 0–4 scale Retrospective (IV) No No No
44
34 15M, 19F 50.3 Idiopathic Focal Neck 9.5 1–4 scale Retrospective (IV) No No No
31
21 20M, 1F 57.6 Idiopathic Focal Hand 7.5 ? Retrospective (IV) No No No
36
3 3M 18.7±3.1 Idiopathic Focal (2), Head, arms, 4.7±6.4 ? Retrospective (IV) No No No
segmental (1) trunk
45
29 6M/23F 53.8 Idiopathic Focal Head 8.7 Tsui rating scale Prospective (IV) No No No
32
1 M 34 Idiopathic Multifocal Arms 18 ? Retrospective (IV) No No No
69
1 M 40 Idiopathic Focal Right hand 24 TRS Retrospective (IV) No No No
35
4 3M/1F 1–11 Idiopathic Multifocal Neck 2–10 ? Retrospective (IV) No No No
66
1 F 52 Idiopathic Multifocal Arms 37 ? Retrospective (IV) No No No
72
27 ? ? Idiopathic and Focal Neck ? Head tremor Retrospective (IV) No No No
acquired rating scale
62
4 2M/2F 46.5 Idiopathic Multifocal (1), Arms 12.5±6.2 ? Retrospective (IV) No No No
±10.4 generalised (3)
55
1 M 58 Idiopathic Focal Right hand 33 TRS Retrospective (IV) No No No
42
5 3M/2F 52.4±7.8 Idiopathic Focal (4), Head 18.6±4.8 Tsui rating scale‡ Prospective (IV) No No No
segmental (1)
53
1 F 46.5 Idiopathic Focal Neck 13.5 ? Prospective (IV) No No No
47
44 ? ? Idiopathic Focal Vocal cords ? Prospective (IV) No No No
63
1 M 54 Idiopathic Segmental Head, arms 15 ? Retrospective (IV) No No No
75
9 8M/1F 59.1 Idiopathic Focal Hand 9.3±12.2 Tremor VAS Prospective (III) Yes No Yes (no
±11.9 (single) device)
33
5 3M/2F 53.4 Idiopathic Focal (3), Hands 6.2±3.1 0–3 scale Retrospective (IV) No No No
±14.9 multifocal (1)
82
1 M 30 DRD Multifocal Hands 15 ? Retrospective (IV) No No No
59
1 ? ? Idiopathic Generalised ? ? ? Retrospective (IV) No No No
23

Movement disorders
4§ 4F 71.0±7.7 Idiopathic Segmental Jaw, head, arms 10.0±12.7 ? Retrospective (IV) No No No
65
1 M 53 Idiopathic Generalised Limbs 8 TRS Prospective (IV) No No No
67
2 1M/1F 41.5±4.9 Idiopathic and Focal Hand 6.5±2.1 TRS Prospective (IV) No No No
acquired (head
injury)
64
1 M 28 Acquired Multifocal Head, neck, right 14 TRS Retrospective (IV) No No No
(perinatal anoxia) upper limb
56
1 F 74 Myoclonus dystonia Multifocal Arms ? ? Retrospective (IV) No No No
57
1 M 14 Hemidystonia Right hemibody 10 ? Retrospective (IV) No No No
Continued
3
4

Movement disorders
Table 1 Continued
No of Age Dystonia duration
Reference points Sex (years) Dystonia type Dystonia distribution Tremor site (years) Assessing tool Study design* Blinded Randomisation Controlled

Acquired (head
injury)
39
22 ? ? DRD ? Arms ? ? Retrospective (IV) No No No
60
2 2F 52.0 Idiopathic and Segmental Head, trunk 13.0±2.8 ? Prospective (IV) No No No
±31.1 acquired (head
injury)
58
3 1M/2F 51.3 Idiopathic Segmental (1), Head, voice, hands 6.7±3.8 ? Retrospective (IV) No No No
±17.9 multifocal (1),
generalised (1)
61
1 M 23 Myoclonus dystonia Segmental Head, right arm 10 TRS Retrospective (IV) No No No
50
1 F 76 Idiopathic Focal Head 60 ? Retrospective (IV) No No No
Fasano A, et al. J Neurol Neurosurg Psychiatry 2013;0:1–11. doi:10.1136/jnnp-2013-305532

46
186 31.5%M/ 51.9 ? ? Head ? Tsui rating scale‡ Prospective (III) No No No
68.5%F¶ ±12.7¶
74
9 M 61.6 Idiopathic Focal Right hand ? TRS** Prospective (III) Yes Yes Yes
(placebo)
73
1 F 28 Idiopathic Focal Lower jaw 1 ? Retrospective (IV) No No No
51
1 F 64 Idiopathic Segmental Neck 3 ? Retrospective (IV) No No No
52
10 5M/5F 38.9 Idiopathic Generalised (6), Arms ? WHIGET Retrospective (IV) No No No
±14.5 hemidystonia (3),
segmental (1)
70
1 F 66 Idiopathic Focal Right hand 6 ? Retrospective (IV) No No No
83
*Classification of evidence according to EFNS into brackets.
†Value refers to the total sample of 51 patients enrolled in this study (14 of them had dystonic tremor).
‡Subscore head tremor/jerk.
§Out of seven patients.
¶The value refers to the total sample of 515 patients enrolled in this study (186 of them had dystonic tremor).
**Part B for dominant hand.
?, not available; DRD, dopa-responsive dystonia; DT, dystonic tremor; EMG, electromyography; F, female; M, male; PWT, Primary writing tremor; TRS, tremor rating scale; VAS, visual analogue scale; WHIGET, Washington Heights-Inwood Genetic Study of
Essential Tremor.
Fasano A, et al. J Neurol Neurosurg Psychiatry 2013;0:1–11. doi:10.1136/jnnp-2013-305532

Table 2 Tremor distribution and outcome according to the treatment

Dystonia Total
duration Dystonia Tremor number of Case Outcome (or % of
Reference Dystonia type (years) distribution Body site site cases No Sex Age Treatment (daily dose in mg) improvement when available)

Drugs
27
Idiopathic ? Focal Neck Head 3 ? ? ? Trihexyphenidyl (6–8), levodopa (1500), Lower tremor frequency in two
diazepam (2) cases, no more tremor in one
case
30
Idiopathic 7 Focal Arm Arm 8 1 M 46 Anticholinergics* 25
Idiopathic 7 Focal Arm Arm 1 M 46 β-blockers* 25
Idiopathic 1.5 Focal Arm Arm 2 M 52 Anticholinergics* 75
Idiopathic 9 Focal Arm Arm 3 M 43 Anticholinergics* 100
Idiopathic 9 Focal Arm Arm 3 M 43 β-blockers* 50
Idiopathic 12 Focal Arm Arm 4 F 55 Anticholinergics* 25
Idiopathic 12 Focal Arm Arm 4 F 55 β-blockers* 50
Idiopathic 0.5 Focal Arm Arm 5 M 36 Anticholinergics* 0
Idiopathic 5 Focal Arm Arm 6 M 18 β-blockers* 100
Idiopathic 5.5 Focal Arm Arm 7 M 55 Anticholinergics* 0
Idiopathic 3 Focal Arm Arm 8 M 21 Anticholinergics* 25
Idiopathic 3 Focal Arm Arm 8 M 21 β-blockers* 100
22
Idiopathic 8 Focal Neck Head 2 1 M 26 Carbamazepine, diazepam, propranolol 0
Idiopathic 8 Focal Neck Head 1 M 26 Clonazepam (1) Marked decrease in frequency
and duration of attacks
Idiopathic 10 Focal Neck Head 2 M 30 Acetazolamide, trihexyphenidyl, 0
carbamazepine, clonazepam, diazepam
31
Idiopathic ? Focal Hand PWT 4 ? ? ? Propranolol Improvement
Idiopathic ? Focal Hand PWT 8 ? ? ? Propranolol No change
Idiopathic ? Focal Hand PWT 3 ? ? ? Primidone Improvement
Idiopathic ? Focal Hand PWT 1 ? ? ? Primidone No change
Idiopathic ? Focal Hand PWT 3 ? ? ? Trihexyphenidyl Improvement
Idiopathic ? Focal Hand PWT 1 ? ? ? Tetrabenazine Improvement
Idiopathic ? Focal Hand PWT 1 ? ? ? Orphenadrine Improvement
36
Idiopathic 12 Segmental Neck, arms, Head, 3 1 M 22 Clonazepam (0.5) Significant reduction in tremor
trunks arms, trunk
Idiopathic 0.1 Focal Neck Head 2 M 18 Clonazepam (3) 100
Idiopathic 2 Focal Arm Arm 3 M 16 Clonazepam (0.5) 100
32
Idiopathic 18 Multifocal Arms Arms 1 1 M 34 Trihexyphenidyl (10) Clear improvement in symptoms
35
Idiopathic 10.7 Multifocal Neck, legs Head 1 1 M 11 Trihexyphenidyl (4) Slight improvement
Idiopathic 10.7 Multifocal Neck, legs Head 1 M 11 Clonazepam (3) Slight improvement
Idiopathic 10.7 Multifocal Neck, legs Head 1 M 11 Timolol (15) Sustained improvement
Idiopathic 10.7 Multifocal Neck, legs Head 1 M 11 Propranolol (40) 0
Idiopathic 10.7 Multifocal Neck, legs Head 1 M 11 Primidone (150) 0

Movement disorders
42
Idiopathic 19 Segmental Eyes, jaw, neck Head 5 1 M 62 Riluzole (100) 58
Idiopathic 15 Focal Neck Head 2 M 58 Riluzole (100) 50
Idiopathic 25 Focal Neck Head 3 M 50 Riluzole (100) 67
Idiopathic 21 Focal Neck Head 4 F 42 Riluzole (100) 17
Idiopathic 13 Focal Neck Head 5 F 50 Riluzole (100) 33
33
Idiopathic 3 Focal Hand PWT 3 M 73 Trihexyphenidyl (6) 66
82
DRD 15 Multifocal Neck, vocal Hands 1 1 M 30 Levodopa (300) 0
cords, hands
23
Idiopathic 2 Segmental Head, jaw Jaw 3 1 F 61 0
Continued
5
6

Table 2 Continued

Movement disorders
Dystonia Total
duration Dystonia Tremor number of Case Outcome (or % of
Reference Dystonia type (years) distribution Body site site cases No Sex Age Treatment (daily dose in mg) improvement when available)

Trihexyphenidyl, propranolol, imipramine,

tetrabenazine, fluvoxamine, sulpiride,
benzodiazepines
Idiopathic 29 Segmental Neck, jaw Jaw 2 F 76 Trihexyphenidyl, tetrabenazine, clonazepam, 0
baclofen, amitriptyline
Idiopathic 5 Segmental Head, face Jaw 4 F 69 Diazepam, tetrabenazine Improvement
64
Acquired 14 Multifocal Neck, arms, Head, arm 1 1 M 28 Bilateral STN DBS 64,9
(perinatal foot
anoxia)
39
DRD ? Generalised Arms 22 ? ? ? Levodopa Excellent response
Botulinum neurotoxin injections
43
Idiopathic ? Focal Neck Head 17 ? ? ? BoNT-A (50–100 U onabotulinumtoxinA) 65†
48
Idiopathic 13.9‡ Focal Neck Head 13 ? ? 55.8‡ BoNT-A (107§) 107
Idiopathic 13.9‡ Focal Hand Hand 1 ? ? 55.8‡ BoNT-A (95¶) 95
44
Idiopathic 9.5 Focal Neck Head 34 ? 15 M/19 F 50.3 BoNT 39.3
45
Idiopathic 8.7 Focal Neck Head 29 ? 6M/23F 53.8 BoNT-A (500 U abobotulinumtoxinA) 49
47
Idiopathic ? Focal Vocal cords Voice 23 ? ? ? BoNT-A (0.25–2.5 U onabotulinumtoxinA) 12**
Idiopathic ? Focal Vocal cords Voice 21 ? ? ? BoNT-A (0.25–2.5 U onabotulinumtoxinA) 13.1**
33
Idiopathic 7 Focal Hand PWT 5 1 M 65 BoNT-A (12.5 U onabotulinumtoxinA) 100
Fasano A, et al. J Neurol Neurosurg Psychiatry 2013;0:1–11. doi:10.1136/jnnp-2013-305532

Idiopathic 10 Multifocal Hands PWT 2 F 43 BoNT-A (25 U onabotulinumtoxinA) 66

Idiopathic 3 Focal Hand PWT 4 F 48 BoNT-A (30 U onabotulinumtoxinA) 66
Idiopathic 8 Focal Hand PWT 5 M 38 BoNT-A (10 U onabotulinumtoxinA) 66
23
Idiopathic 4 Segmental Jaw, neck, Jaw, head, 1 3 F 78 BoNT Improvement
arms arms
46
? ? ? Head Head 186 ? 31.5%M/ 51.9 BoNT (500 U abobotulinumtoxinA) 45
68.5%F†† ±12.7††
CNS surgery
54
Acquired 23 Generalised Arm 2 1 M 23 Thalamotomy+Unilateral Vim DBS Improvement
(perinatal
anoxia)
Acquired 21 Generalised Arm 2 F 21 Thalamotomy+Unilateral Vim DBS Improvement
(perinatal
anoxia)
69
Idiopathic 24 Focal Hand PWT 1 1 M 40 Unilateral Vim DBS 85.2
66
Idiopathic 37 Multifocal Arms Arms 1 1 F 52 Bilateral PSA DBS Remarkably reduced
55
Idiopathic 33 Focal Hand PWT 1 1 M 58 Unilateral Vim DBS 94.4
62
Idiopathic 13 Generalised Arm 4 1 M 55 Unilateral VLp DBS Improvement
Idiopathic 19 Generalised Right limbs 2 M 32 Unilateral VLp DBS Improvement
Idiopathic 4 Multifocal Arms 3 F 53 Bilateral VLp DBS Improvement
Idiopathic 14 Generalised Arm 4 F 46 Unilateral VLp DBS 100
53
Idiopathic 13.5 Focal Neck Head 1 1 F 46.5 Bilateral Gpi DBS 0
63
Idiopathic 15 Segmental Neck, head Head, arms 1 1 M 54 Bilateral STN DBS Moderate head tremor
suppression, complete arm
tremor suppression
59
Idiopathic ? Generalised 1 1 ? ? Thalamotomy+Unilateral Vim+Gpi DBS Dramatic improvement
65
Idiopathic 8 Generalised Limbs 1 1 M 53 Bilateral cZi DBS 70.5
Fasano A, et al. J Neurol Neurosurg Psychiatry 2013;0:1–11. doi:10.1136/jnnp-2013-305532

67
Idiopathic 8 Focal Hand Hand 2 1 F 38 Bilateral PSA DBS 100
Acquired (head 5 Focal Hand Hand 2 M 45 Bilateral PSA DBS 100
injury)
56
Myoclonus ? Multifocal Arms Arms 1 1 F 74 Bilateral Vim DBS 100
dystonia
57
Acquired (head 10 Hemidystonia Right limbs 1 1 M 14 Thalamotomy Slight improvement
injury)
60
Idiopathic 15 Segmental Neck, arms, Trunk 2 1 F 30 Bilateral Gpi+Vim DBS Marked improvement
trunk
Acquired (head 11 Segmental Eyes, jaw, vocal Head 2 F 74 Bilateral Gpi+Vim DBS Marked improvement
injury) cords neck,
trunk
58
Idiopathic 5 Generalised Head, 3 1 F 47 Bilateral Gpi+Vim DBS 45
voice,
hands
Idiopathic 11 Multifocal Hands, vocal Hands, 2 M 36 Unilateral Vim DBS 51.2
cords voice
Idiopathic 4 Segmental Neck, hands Head, 3 F 71 Bilateral Vim DBS 29.2
hands
61
Myoclonus 10 Segmental Neck, arm Head, arm 1 1 M 23 Bilateral Gpi DBS+Unilateral Vim DBS 62
dystonia
50
Idiopathic 60 Focal Neck Head 1 1 F 76 Unilateral Gpi DBS 75
51
Idiopathic 3 Segmental Eyes, face, neck Head 1 1 F 64 Unilateral Gpi DBS 100
52
Idiopathic ? Hemidystonia ? Right arm 10 1 M 61 Unilateral Vim DBS 88.9
Idiopathic ? Hemidystonia ? Right arm 2 F 52 Unilateral Vim DBS 93.8
Idiopathic ? Hemidystonia ? Right arm 3 F 50 Unilateral Vim DBS 100
Idiopathic ? Generalised ? Arms 4 M 63 Bilateral Vim DBS 88.3
Idiopathic ? Segmental ? Right arm 5 M 28 Bilateral GPi DBS 44.4
Idiopathic ? Generalised ? Arms 6 F 53 Bilateral GPi DBS 60
Idiopathic ? Generalised ? Arms 7 M 13 Bilateral GPi DBS 50
Idiopathic ? Generalised ? Arms 8 F 74 Bilateral GPi DBS 53.3
Idiopathic ? Generalised ? Arms 9 F 54 Bilateral GPi DBS+unilateral Vim DBS 78.9
Idiopathic ? Generalised ? Arms 10 M 23 Thalamotomy+bilateral GPi DBS+unilateral 70.6
Vim DBS
70
Idiopathic 6 Focal Right hand PWT 1 1 F 66 Unilateral Vim DBS 100
Other treatments
71
Idiopathic ? Segmental Arms, neck Limbs 1 1 M 34 TENS Relief of tremor
72
Idiopathic and ? Focal Neck Head 27 ? ? ? SPD 8
acquired
75
Idiopathic 9.3 Focal Hand PWT 9 ? 8M/1F ? Writing device 136
74
Idiopathic ? Focal Hand PWT 9 ? M 61.6 TENS (5 Hz) flexor carpi 7.7
Idiopathic ? Focal Hand PWT 9 ? ? ? TENS (25 Hz) flexor carpi 20.4

Movement disorders
Idiopathic ? Focal Hand PWT 9 ? ? ? TENS (50 Hz) flexor carpi Worsened by 24.3% (p<0.05)
73
Idiopathic 1 Focal Lower jaw Jaw 1 1 F 28 Dental splint 100
*Dose and drug not specified.
†The outcome is the percentage of treatment responders.
‡The outcome is the benefit duration (weeks).
§The value refers to the total sample of 51 patients enrolled in this study (14 of them had dystonic tremor).
¶Average dose injected in the total sample of patients with head tremor (not only dystonic tremors).
**Average dose injected in the total sample of patients with hand tremor (not only dystonic tremors).
††Value refers to the total sample of 515 patients enrolled in this study (186 of them had dystonic tremor).
BoNT, botulinum neurotoxin; cZi, caudal zona incerta; DBS, deep brain stimulation, DRD, dopa-responsive dystonia; F, female; Gpi, globus pallidus internus; M, male; PSA, posterior subthalamic area; PWT, primary writing tremor; SPD, selective peripheral
denervation; STN, subthalamus; TENS, transcutaneous electrical nerve stimulation; Vim, ventralis intermedius nucleus of thalamus; VLp, posterior part of the ventrolateral thalamus.
CNS, central nervous system.
7
 Movement disorders
Figure 1 Improvement of dystonic tremor or primary writing tremor according to the involved body site and the specific pharmacological or
surgical approach (either stimulation or ablation). Numbers under the bars represent the respective number of studies and enrolled patients (note
that the sum of studies does not match the total because patients with more than one tremor site have been excluded). Gpi, globus pallidus
internus.
improve.53 Stimulation of the thalamic ventralis intermedius
nucleus (Vim) or ablations within the same region improved
tremor in all cases in which they were employed: in 11 cases as
unique target54–58 and in seven cases combined with GPi
DBS.58–61 In addition, stimulation of the posterior part of the
ventrolateral thalamic nucleus (VLp) also led to the improve-
ment of tremor (notably, without improving dystonia) in four
patients with dystonic arm tremor.62
Bilateral stimulation of subthalamus has been reported to
improve cervical dystonia, dystonic head and hands tremor in
two patients.63 64 Others reported that DBS of the subthalamic
white matter, including the zona incerta, remarkably improved
proximal DT that had been refractory to Vim thalamotomy.65
Moreover, stimulation of posterior subthalamic area provided
encouraging results in three patients with dystonic arm
tremor.66 67
Thalamotomy68 as well as Vim DBS55 69 70 have been success-
fully performed in patients with PWT.
Finally, when considering the outcome of specific surgical
targets (thalamus, globus pallidus, subthalamic area), no signifi-
cant differences emerged (figure 1B).
Other treatments
Other treatments were employed in 65 cases (five studies, table 2).
Transcutaneous electrical nerve stimulation (TENS) in patients
with dystonic arm tremor,71 selective peripheral denervation in
patients with dystonic head tremor72 or other approaches did not
show great efficacy in most of the reported cases with few excep-
tions. For example, dystonic jaw tremor completely disappeared in
a single case treated with dental splint, which probably acted as a
sensory trick.73 Recently, TENS has been also used in patients
with PWT, again with inconsistent results.74 In contrast, a signifi-
cant improvement with a simple hand orthotic device has been
demonstrated, leading the authors to suggest that this non-invasive
risk-free therapy could be useful during the initial assessment,
before any other invasive option is considered.75
Comparison of outcomes according to tremor distribution
Figure 2 and table 2 detail the tremor distribution and the
outcome of the given treatment. Treatment outcomes were
highly variable. Overall, BoNT and surgery were the most suc-
cessful strategies, significantly more effective than drugs (−69.9
±21.3% and 69.9±25.1% vs −42.2±33.2%, p=0.02 for both
comparisons). With respect to tremor distribution, BoNT was
8 Fasano A, et al. J Neurol Neurosurg Psychiatry 2013;0:1–11. doi:10.1136/jnnp-2013-305532
the most useful strategy in the management of axial (head/trunk
or vocal cord) tremor, although no statistically significant differ-
ence emerged. As to hand tremor, BoNT and surgery were
equally effective (−74.5±17.0% and −74.7±23.7%), signifi-
cantly more than other strategies, though the outcome of BoNT
was only based on PWT data (figure 2A). When specifically ana-
lysing the outcome of the PWT group, BoNT and surgery were
found to be more effective than drugs (−74.5±17.0% and 93.2
±7.5% vs −30.3±26.0%, p=0.0005 and p=0.01, respectively).
By contrast, no data were available on the efficacy of BoNT
treatment for DT involving upper limbs (figure 2B).
DISCUSSION AND RECOMMENDATIONS
There are very few studies specifically addressing the treatment
of the DTs and, more importantly, almost all of them are retro-
spective and not randomised. Moreover, in many studies the
tremor outcome was poorly documented as were the assessment
tools, which were very rarely based on objective measurements
(electromyography (EMG) or kinematics). These limitations
account for the lack of evidence-based guidelines in the treat-
ment of these tremor disorders.34 76
In addition, it is impossible to know whether the reviewed
studies reliably distinguished TAD and DT. In order to clarify this
issue, we also reviewed the literature on TAD but unfortunately
we did not find any study specifically addressing its treatment.
TAD is usually treated with the medications used for ET77 and
believed to respond in a comparable fashion, although there is
little available data to support this supposition. Consequently, the
data on the effectiveness of β-blockers or primidone in DT are
limited by these diagnostic difficulties. Indeed, sometimes it is
very difficult to distinguish between different tremor conditions,
particularly with writing tremor, and isolated head or voice
tremor.77 Therefore, it is possible that some of the DT patients
reported in the literature were actually affected by TAD or even
ET. In order to limit this bias, we focused our recommendations
on DT and PWT.
In this systematic review, we found that the outcome of all
the possible interventions (drugs, BoNT, surgery and alternative
approaches) is highly variable, depending on the specific type of
intervention and tremor distribution. Figure 3 provides a pos-
sible algorithm for the treatment of DT/PWT, admittedly based
on very limited evidence available to date. On the basis of
tremor distribution, BoNT is the most useful strategy in the
management of axial (head or vocal cord) tremors and has the
 Movement disorders

Figure 2 Improvement of dystonic tremor (DT) or primary writing tremor (PWT) according to the involved body site and the given treatment: the
outcomes were highly variable, depending on the specific type of intervention and tremor distribution. Numbers under the bars represent the
respective number of studies and enrolled patients (note that the total of studies exceeds 43 because some of them adopted more than a single
therapeutic approach). Botulinum neurotoxin (BoNT) and surgery are the most successful strategies, significantly more effective than drugs. With
respect to tremor distribution, BoNT was the most useful strategy in the management of axial (head/trunk or vocal cord) tremor, although no
statistically significant difference emerged. As for hand tremor as a whole group (PWT or tremor in the context of upper limb dystonia), BoNT and
surgery were equally effective, significantly more than other strategies (A). When splitting the hand tremor group into PWT and DT involving upper
limbs, drugs are less effective in PWT than other strategies, whereas no data are available for BoNT in DT (B).

largest amount of data in the literature confirming its efficacy. upper limbs. Drugs are generally less efficacious but could be
With respect to appendicular tremor, BoNT and surgery might tried especially when tremor involves different body regions,
be effective in PWT, whereas no data are available for DT of the thus allowing the use of BoNT in a stepwise approach (in order

Figure 3 A possible algorithm for the treatment of dystonic tremor (DT) or primary writing tremor (PWT) on the basis of the limited evidence
available to date. Botulinum neurotoxin (BoNT) is the most useful strategy in the management of axial (head or vocal cord) tremors, whereas
appendicular tremor—with the exception of PWT—should be firstly treated with drugs, thus allowing the use of BoNT in a stepwise approach (in
order to further improve the regions not adequately improved). By contrast, BoNT might be first-choice therapy in PWT, followed by drugs or
surgery. Surgery (DBS) should be considered only when the disability derived by tremor overcomes the risks of its invasiveness. Unilateral procedures
can be tried in case of appendicular tremor, whereas bilateral surgery is indicated for head tremor. As for the target of DBS, Vim and Gpi are the
most used ones, based on the predominance of tremor (Vim) or dystonic postures (Gpi). The combined approach Vim+Gpi might be considered in
case of failure of the single target procedure. Other targets (VLp, STN and surrounding areas, ie, PSA or cZi) might be considered in very selected
cases. cZi, caudal zona incerta; DBS, deep brain stimulation; Gpi, globus pallidus internus; PSA, posterior subthalamic area; STN, subthalamus; Vim,
ventralis intermedius nucleus of thalamus; VLp, posterior part of the ventrolateral thalamus.

Fasano A, et al. J Neurol Neurosurg Psychiatry 2013;0:1–11. doi:10.1136/jnnp-2013-305532 9

 Movement disorders
to further improve the regions not adequately controlled by
drugs). Apart from tremor in DRD, which typically responds to
levodopa, the first-line drugs should be anticholinergics, as their
use has been described in large samples of patients.27 30–33
Second-line drugs have been less extensively investigated; trials
might include tetrabenazine, due to the reported efficacy in dys-
tonia25 and DT/PWT,23 31 and clonazepam, especially in the
light of the description of “clonazepam-sensitive dystonic
tremor”.36 37 Third-line drugs could be β-blockers, primidone
and many others occasionally found to improve DT. Drug toler-
ability is an important issue for clinical decision-making as most
of adult patients experience unwanted effects at lower doses
than those needed for yielding a benefit. Even though the avail-
able literature did not specifically address the side effects pro-
duced by medications, the choice to rely on medications
(eg, increasing the dose or adding another compound) or to
adopt other approaches (ie, BoNT and/or surgery) should be
based on these aspects as well.
Finally, DBS could be considered only when the disability
derived from tremor overcomes the risks of its invasiveness. For
example, the disability caused by PWT can vary from mild to
considerable, depending on the profession of the patient. The
handicap that it produces in Western cultures has generally not
been considered sufficient to merit the risks involved in stereo-
tactic surgery. However, in Japan where calligraphy is an
important occupation, neurosurgery has been successfully per-
formed for this condition, as it can threaten the professional
career of the patient.68 Taking into account the potential ameli-
orative effect on the other dystonic features, GPi should be
viewed as the preferred target for either stimulation50 or abla-
tion51; thalamic stimulation may be added in cases in which the
benefit is insufficient,59–61 because it can also alleviate the
tremor but can occasionally lead to worsening of dystonia
itself.54 56–58 Stimulation of thalamic VLp is considered as less
efficacious in dystonia and tremor treatment than GPi DBS.62
Noteworthy, a recent study challenged this assumption, conclud-
ing that DT patients with a mild dystonia should be considered
for Vim DBS while the coexistence of severe DT and dystonia
may be successfully controlled by combined GPi and Vim
DBS.52 Subthalamic area might be an interesting target for
stimulation, given the early experiences with lesions and the
hypothesis that many fibres can be modulated in this ‘bottle-
neck’ anatomical region78; however, the available data are too
scanty to support its use beyond an experimental approach.
In conclusion, paradoxically the most important result of our
systematic review is the demonstration of the lack of good-
quality studies addressing the treatment of DT. For instance,
although surgery seems to be a useful treatment for tremor
refractory to drugs or BoNT, the outcomes of either DBS or
ablations of different brain nuclei have been reported in only 37
patients (20 studies); even the recent GPi DBS trials79–81 did
not focus on the outcome of tremor, although they were con-
ducted according to the criteria of evidence-based medicine.
Future randomised controlled trials are needed, particularly
those with active comparators, thus allowing the comparison of
different treatment approaches (eg, BoNT vs drugs or GPi vs
thalamic DBS).
Contributors AF: conception and design, analysis and interpretation of data,
drafting the article and revising it critically for important intellectual content; final
approval of the version to be published. FB: analysis and interpretation of data,
drafting the article, final approval of the version to be published. AEL: conception
and design, revising the article critically for important intellectual content, final
approval of the version to be published.
Competing interests None.
10
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement We have the excel sheets where we collected the
information retrieved from the literature.
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