Unmet needs in the management of cervical dystonia Maria Fiorella Contarino1, 2, Marenka Smit3, Joost Van Den Dool3, 5, 4, Jens Volkmann6, Marina Tijssen3* 1
Neurology, Leiden University Medical Center, Netherlands, 2Neurology, Haga Teaching
Hospital, Netherlands, 3Neurology, University Medical Center Groningen, Netherlands, 4
Neurology, Academic Medical Center, Netherlands, 5Faculty of Health, Amsterdam
University of Applied Sciences, Netherlands, 6Neurology, University Clinic of Würzburg, Germany Submitted to Journal: Frontiers in Neurology Specialty Section: Movement Disorders
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ISSN: 1664-2295 Article type: Perspective Article
i v o r P Received on: 13 Mar 2016 Accepted on: 16 Sep 2016
Provisional PDF published on: 16 Sep 2016 Frontiers website link: www.frontiersin.org
Citation: Contarino M, Smit M, Van_den_dool J, Volkmann J and Tijssen M(2016) Unmet needs in the management of cervical dystonia. Front. Neurol. 7:165. doi:10.3389/fneur.2016.00165 Copyright statement: © 2016 Contarino, Smit, Van_den_dool, Volkmann and Tijssen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution and reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
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Conflict of interest statement The authors declare a potential conflict of interest and state it below. - M.F.Contarino: Advisory board: Medtronic, Boston Scientific. Is co-inventor on a patent application relevant to Deep Brain Stimulation (2014). Speaking fees: Abbvie, Medtronic, Boston Scientific, ECMT. Grant: Stichting Parkinson Fonds. - M Smit: Grants: University Medical Centre Groningen, Stichting Wetenschapsfonds Dystonie Vereniging - Joost van den Dool: Grants: Dutch organizations in scientific research, the Fonds Nutsohra, Jacques & Gloria Gossweiler foundation and Stichting Wetenschapsfonds Dystonie Vereniging - J. Volkmann: advisory boards: Boston Scientific, Medtronic; grant support: Boston Scientific, Medtronic; Speaking fees: Boston Scientific, Medtronic, St. Jude, UCB, TEVA, and Allergan. - Marina A.J. Tijssen: Grants: Netherlands organization for scientific research- NWO, Medium, Fonds Nuts-Ohra , Prinses Beatrix Fonds , Gossweiler foundation, Stichting wetenschapsfonds dystonie vereniging, Phelps Stichting, educational grants and national DystonieNet grants from Ipsen & Allergan Famaceutics, Merz, Medtronic and Actelion.
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Unmet needs in the management of cervical dystonia
2
Maria Fiorella Contarino1,2, Marenka Smit3, Joost van den Dool 3,4,5, Jens Volkmann6*,
3
Marina A.J. Tijssen3*#
4 5
1
6
2
7
3
8
Groningen, the Netherlands
9
4
Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands. Department of Neurology, Haga Teaching Hospital, Den Haag, The Netherlands. Department of Neurology, University Medical Center Groningen, University of Groningen,
ACHIEVE Centre of Applied Research, Faculty of Health, Amsterdam University of Applied
10
Sciences, Amsterdam, the Netherlands
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5
12
6
Department of Neurology, Academic Medical Center, Amsterdam, The Netherlands
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Department of Neurology, University Clinic of Würzburg, Würzburg, Germany
13 14
*These two authors contributed equally to the manuscript
15
#Corresponding author
16
Marina A.J. Tijssen
17
Department of Neurology AB 51, University Medical Center Groningen (UMCG), University of
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Groningen, PO Box 30.001, Groningen, the Netherlands.
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Email:
[email protected]
20
Conflict of interest/funding
21
-
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M.F. Contarino: Advisory board: Medtronic, Boston Scientific. Is co-inventor on a patent
22
application relevant to Deep Brain Stimulation (2014). Speaking fees: Abbvie, Medtronic,
23
Boston Scientific, ECMT. Grant: Stichting Parkinson Fonds.
24
-
25 26
M Smit: Grants: University Medical Centre Groningen, Stichting Wetenschapsfonds Dystonie Vereniging
-
Joost van den Dool: Grants: Dutch organizations in scientific research, the Fonds Nutsohra,
27
Jacques & Gloria Gossweiler foundation and Stichting Wetenschapsfonds Dystonie
28
Vereniging
29
-
J. Volkmann: advisory boards: Boston Scientific, Medtronic; grant support: Boston Scientific,
30
Medtronic; Speaking fees: Boston Scientific, Medtronic, St. Jude, UCB, TEVA, and
31
Allergan.
1
-
Marina A.J. Tijssen: Grants: Netherlands organization for scientific research- NWO,
2
Medium, Fonds Nuts-Ohra , Prinses Beatrix Fonds , Gossweiler foundation, Stichting
3
wetenschapsfonds dystonie vereniging, Phelps Stichting, educational grants and national
4
DystonieNet grants from Ipsen & Allergan Famaceutics, Merz, Medtronic and Actelion.
5 6
Abstract
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Cervical dystonia is a movement disorder which affects daily living of many patients. In
8
clinical practice several unmet treatment needs remain open. This article focusses on the
9
four main aspects of treatment. We describe existing and emerging treatment approaches
10
for cervical dystonia, including botulinum toxin injections, surgical therapy, management
11
of non-motor symptoms and rehabilitation strategies. The unsolved issues regarding each
12
of these treatments are identified and discussed, and possible future approaches and
13
research lines are proposed.
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Introduction
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Cervical dystonia (CD) is the most prevalent form of adult-onset focal dystonia, and is
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characterized by abnormal postures of head and neck, that can considerably impair daily
18
living.
19
There are several unmet needs in the management of CD. In this article we focused on
20
four main aspects of the treatment of this disorder, including botulinum toxin injections,
21
surgical therapy, management of non-motor symptoms and rehabilitation strategies.
22
For each of these issues the state-of-the art is presented and some of the current
23
knowledge gaps are highlighted. In addition we propose potential research lines that
24
could be developed to manage these issues.
25
Botulinum toxin
26
What is known?
27
Botulinum neurotoxin (BoNT) injections are the treatment of choice for CD.
1
There is class I evidence to support efficacy and safety of the three commercially
2
available formulations of BoNT-A (onabotulinumtoxinA, abobotulinumtoxinA and
3
incobotulinumtoxinA) [1; 2; 3], and of BoNT B (rimabotulinumtoxin B)[4].
4
As much as 70-85% of the patients report a significant benefit from the treatment[5].
5
Efficacy on motor symptoms varies from 20 to 70%, based on the assessing method used.
6
Significant improvement is also documented on pain and quality of life (QoL).[6]
7
Although BoNT treatment is routinely performed worldwide and is satisfying for many
8
patients, the obtained effect is still far from optimal. In addition, BoNT treatment is in
9
some cases associated with the occurrence of side effects, such as dysphagia or excessive
10
muscle weakness. These side effects are due to an excessive dose of BoNT or to the
11
spread of BoNT to adjacent structures, and may limit the efficacy of the treatment.
12
What is uncertain?
13
In order to further improve the efficacy and safety of the treatment, the accurate
14
placement of the minimum effective dose of toxin in the dystonic muscles should be
15
ensured. At present, there is still no agreement on a recommended starting dose or on the
16
minimum effective dose per muscle.
17
Moreover, there is still great variability concerning treatment strategies. Multi-point
18
BoNT injections have been proposed as more effective than single point injections,[7] but
19
convincing evidence on these topics is still lacking.
20
The use of polymyography to identify dystonic muscles before treatment, and the use of
21
electromyography (EMG) to guide injections, has been proposed to improve the accuracy
22
of BoNT delivery. While some studies show that this approach may provide a significant
23
advantage in BoNT-naïve patients,[8; 9] as well as in patients unsatisfactorily treated
24
with standard injections[10; 11], this still need to be further confirmed in larger series.
25
Moreover, the modalities and indications of the neurophysiological approach need to be
26
further specified.
27
The use of imaging techniques has also been proposed to identify the dystonic muscles
28
before treatment and to improve the accuracy of the placement of BoNT. Preliminary
29
reports suggest that the use of ultrasound-guided injections might help localizing the
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target muscles and reducing the episodes of dysphagia in patients who had experienced it
2
with standard treatment.[12]
3
A number of patients do not respond to BoNT treatment, or develop a secondary
4
resistance. A currently accepted definition of secondary non-responsiveness implies
5
“insufficiently improved posture after three or more unsuccessful injection cycles in CD
6
patient’s previously achieving satisfactory results”.[13]
7
Change in CD pattern across time, with the appearance of more complex multiaxial
8
dystonic movements or tremor, account for some of the non-responders. Another well-
9
known cause of non-responsiveness is the development of antibodies against BoNT
10
formulations[14]. This issue has been described with different BoNT formulations,
11
including onabotulinumtoxinA, abobotulinumtoxinA, and rimabotulinumtoxinB[15],
12
while it doesn’t seem to be a concern when incobotulinumtoxinA is used[16]. At present,
13
there is no agreement on the strategies to avoid the formation of antibodies. Although this
14
problem likely occurs only sporadically, a minimum safe interval of 12 weeks or longer
15
is still used in most centers[17]. This strategy, however, limits treatment of a larger
16
number of patients, who report reemergence of symptoms before this time. The safety of
17
shorter intervals between injections and of the so-called booster injections still needs to
18
be explored.
19
Another unsolved and largely debated practical issue concerns the optimal conversion
20
ratio between different formulation of BoNT-A, or between BoNT-A and BoNT-B.
21
Based on studies using different methodology, a conversion of onabotulinumtoxinA to
22
abobotulinumtoxinA 1:3 IU,[18; 19] as well as ratios of 1:2.5[20] have been proposed
23
over time, while a conversion ratio of 1:1 is proposed for onabotulinumtoxinA to
24
incobotulinumtoxinA.
25
Future perspectives
26
Future research lines should focus on improving the benefit/side effects ratio of BoNT
27
treatment and on reducing the rate of primary and secondary non-responsive patients.
28
A standardized working definition of non-responsiveness should be developed, which
29
should take into account an objective measure of the lack of improvement as well as an
30
evaluation of the appropriateness of BoNT treatment. An objective and universally
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accepted working definition would be of crucial importance to assess new treatment
2
strategies and to identify patients for whom more invasive (surgical) treatment are
3
indicated.
4
Dose-finding studies and comparative studies across different toxins should be
5
performed. The additional value of neurophysiology and imaging in improving the
6
intramuscular placing of BoNT should be explored. In order to minimize patients’
7
discomfort, the minimum safe interval between treatments should be determined.
8
Surgical treatment
9
What is known?
10
Deep Brain Stimulation (DBS) of the internal globus pallidus (GPi) is an established
11
surgical treatment for patients with generalized dystonia [21; 22]. Because the initial
12
studies suggested an equally beneficial effect for all body regions, the method was soon
13
applied to patients with focal or segmental dystonias, who no longer responded to BoNT.
14
Krauss was the first to describe the beneficial outcome in three patients with CD in
15
1999[23]. Meanwhile three controlled clinical studies were conducted evaluating GPi-
16
DBS in CD patients who failed on medical treatment: a Canadian prospective,
17
multicenter and observer-blinded study assessed 10 CD patients who were further
18
followed for 12 months [24]. Motor improvement was 28% at 6 months and 43% at 12
19
months (TWSTRS motor score). Pain and disability scores were also improved by 66%
20
and 64%, as well as mood (Beck´s Depression Inventory (BDI)) and QoL (SF-36) by
21
58% and 24% respectively. Another prospective single-center study followed eight CD
22
patients for up to 48 months after GPi-DBS,[25] reporting a median reduction in the
23
TWSTRS motor score of 50% at 6 months and of 73% at last follow-up. The only
24
randomized sham-controlled multicenter study of bilateral GPi-DBS in CD followed
25
patients for a total of six to nine months after surgery.[26] Sixty-two patients were
26
implanted with a neurostimulation system and randomly assigned to either active or sham
27
stimulation (stimulator output 0V). After three months, TWSTRS severity score was
28
reduced by 26% in the treatment group compared to 6% in the sham group. There was a
29
3.8 point difference between both groups, which was significant. TWSTRS disability
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score and Bain tremor score were also significantly improved in the neurostimulation
2
group, whereas TWSTRS pain score and QoL (Craniocervical Dystonia Questionnaire
3
24- score) were not different. Evaluations were repeated in all patients after receiving six
4
months of effective neurostimulation. At the follow-up, significant improvements
5
compared to the pre-surgical baseline were found for TWSTRS severity score (28%),
6
disability score (46%) and pain (51%), Tsui score (57%), Bain tremor score (66%), and
7
global dystonia ratings by patients (49%) or physicians (53%). BDI was reduced by 20%,
8
the cranio-cervical dystonia questionnaire-24 showed a 28% improvement. No permanent
9
adverse effects were found. Transient adverse effects included device infection (n=3),
10
misplacement/dislocation of electrodes (n=3) or neurostimulator (n=1),
11
stroke/hemorrhage (n=1) and seizure (n=1). Four patients claimed pain at the extension
12
cable. The most frequent stimulation-induced side-effect was dysarthria (7 patients).
13
Stimulation-induced bradykinesia was observed in one patient, but has previously been
14
described as a relevant adverse effect of pallidal neurostimulation in several series.[27;
15
28]
16
It has been suggested that the subthalamic nucleus could be a better target for DBS in CD
17
with equal motor benefit but less risk of stimulation-induced parkinsonism.[29]
18
What is uncertain?
19
Larger series are needed to ascertain which types of CD respond best to pallidal DBS,
20
and to assess predisposing factors and the true prevalence and risk factors of stimulation-
21
induced parkinsonism. Subthalamic stimulation, which was forwarded as an alternative,
22
induces (transient) dyskinesia in a large proportion of patients and the cognitive and
23
behavioral safety has not been evaluated yet. So far, DBS has been advocated only in
24
patients no longer responding to BoNT treatment, as a last line therapy. A comparative
25
trial of BoNT treatment in comparison to DBS has not been performed yet.
26
Future perspectives
27
Registry data of DBS surgery in CD would help to evaluate outcomes in daily practice,
28
define responder profiles, and assess the frequency of less common adverse effects. The
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effect of DBS on non-motor features should be systematically assessed. Randomized
2
controlled trials (RCTs) are needed to compare pallidal and subthalamic neurostimulation
3
and DBS in general vs. best conservative management of CD.
4
Management of non-motor symptoms
5
What is known?
6
Growing evidence suggests that the phenotype of dystonia includes also non-motor
7
symptoms (NMS), which could in part account for the reduced QoL in CD.[30; 31]
8
Sensory abnormalities are the most frequently NMS associated with CD. The onset of
9
motor symptoms can be preceded by a feeling of discomfort in the neck and dystonic
10
movements are sometimes interpreted as an attempt to decrease this feeling.[32]
11
Involvement of the sensory system is also indicated by the geste antagoniste, which
12
modifies cortical EEG activity and GPi local field potentials, even before touching the
13
head.[33] Furthermore, several studies found abnormalities in temporal and spatial
14
discrimination thresholds in CD patients, both in affected and unaffected body parts, and
15
in unaffected first degree relatives.[34; 35]
16
Pain is present in up to 90% of CD patients, which is rated as moderate to severe by
17
70%.[36] Two/third of the patients use analgesics. Pain might be a consequence of motor
18
symptom severity[37], but could also be influenced by depressive and anxiety
19
symptoms.[31] It is proven that BoNT treatment as well as surgical treatments like
20
DBS[26] or selective peripheral denervation[38], significantly improve pain associated
21
with CD.[36; 37]
22
The prevalence of psychiatric disorders in CD can reach up to 91.4%, compared to 35%
23
in the general population.[39] This could logically be the consequence of living with a
24
chronic, visible and invalidating disorder. However, compared to the prevalence of
25
psychiatric symptoms in other chronic and visible diseases like alopecia areata, CD
26
patients still have a significantly increased odds ratio to develop psychiatric co-
27
morbidity.[40] The most prevalent psychiatric disorders include depressive
28
symptoms[40; 41; 42; 43; 44; 45], anxiety symptoms/panic disorders[39; 40; 44; 45],
29
obsessive-compulsive symptoms[41; 45] and substance abuse.[45] Importantly, a few
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studies showed that psychiatric co-morbidity is the most important predictor of poorer
2
health-related QoL, especially for the domains general health, role functioning, bodily
3
pain and emotional and mental health. [46; 47; 48]
4
At this moment, no treatment trials have been described with the aim to directly improve
5
psychiatric symptoms in CD patients.
6
What is uncertain?
7
The prevalence and characteristics of the different NMS in CD, including sleep
8
disturbances and cognition, have not been systematically studied and existing studies
9
show contrasting results. A recurring debate is whether NMS are a direct consequence of
10
the motor symptoms of dystonia or intrinsic to the neurobiology and thereby part of the
11
phenotype.
12
CD patients showed an impaired sleep quality compared to healthy controls: in two
13
studies this was correlated with depressive symptom scores,[49; 50] while in one study it
14
appeared to be independent from psychiatric disorders and medication use.[51]
15
Successful BoNT treatment did not improve sleep quality, arguing against a secondary
16
discomfort due to the dystonia motor symptoms.[51] Excessive daytime sleepiness was
17
detected in one study, but at least in part explained by the use of anticholinergic
18
drugs.[52] Other studies did not find significant differences in daytime sleepiness.[49;
19
50]
20
Studies concerning cognitive impairment in CD are still very limited. One study showed
21
impairments in the domains working memory, processing speed, visual motor ability and
22
short term memory.[53] Other small studies found impairment of visuospatial
23
function[54] and a sustained attention deficit, the latter disappearing after BoNT
24
treatment. [55]
25
Convincing data support a disruption of sensory-motor system also in healthy first degree
26
relatives of dystonic patients, suggesting a possible endophenotype.[56] For example
27
temporal discrimination threshold (TDT) was found abnormal in about 80% of dystonia
28
patients, but also in about 50% of first-degree female relatives older than 48. In male
29
relatives, the penetrance was reduced.[34; 57]
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The onset of psychiatric disorders before the onset of the movement disorder in
2
approximately 70% of the cases[44; 45; 58] is one of the strongest arguments towards a
3
shared pathophysiology. This is also supported by a men-to-women ratio of psychiatric
4
disorders of 1:1 in CD patients compared to 1:2 in the general population, higher
5
incidence of psychiatric disorders in CD patients compared to other visible and chronic
6
disorders, and different personality profiles found in CD patients, which develop long
7
before adolescence and onset of motor symptoms.[35]
8
Drawing firm conclusions on the etiology of NMS in CD remains difficult, also
9
considering the tight correlation between pain, psychiatric symptoms, sleep disturbances
10
and motor symptoms.
11
Future perspectives
12
In order to solve the issue of the etiology of NMS in CD, prospective studies are
13
necessary. Selecting an appropriate group for prospective studies has proven challenging.
14
This might change with the identification of genetic forms of CD, like the GNAL and
15
ANO3 gene,[59; 60; 61; 62] which would allow studying homogenous clinical subgroups,
16
even in the pre-symptomatic phase.
17
Another strategy could be the identification of endophenotypes in larger groups, based on
18
biomarker such as the TDT.
19
Clinical trials are required towards the effect of treatment of NMS on health-related QoL.
20
Rehabilitation strategies
21
What is known?
22
Evidence towards the effectiveness of rehabilitation strategies is scarce. Two systematic
23
reviews described the effects of different rehabilitation strategies in various forms of
24
primary dystonia[63] and CD alone [64], suggesting that multimodal physical therapy
25
(PT) programs, added to BoNT treatment, further improve disability and pain compared
26
to BoNT treatment alone.[63; 64] Only three clinical trials[65; 66; 67] and one case-
27
control study[68] investigated the effects of a multimodal PT program in combination
28
with BoNT treatment.
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One single-blind RCT in 40 patients showed significant improvements on pain and daily
2
life activities, and a prolonged duration of the BoNT effect, after a six-week PT program
3
of active exercises, muscle stretching and massage compared to BoNT treatment
4
alone.[65] A second single-blind RCT in 40 patients showed decreased disability and a
5
significant decrease of head deviation and improved hand functions after a six-week PT
6
program of active exercise, muscle stretching and TENS in addition to BoNT
7
treatment.[66] The third single-blind RCT of 20 patients found only a trend towards
8
greater improvement on head posture, pain and disability in the group that received 12
9
weeks of active exercise, relaxation and BoNT treatment compared to the group that
10
received relaxation and BoNT treatment only.[67]
11
One case-control study followed 40 patients in a four-week PT program of active
12
exercise, muscle stretching, active and passive neck mobilizations and electrostimulation
13
of the dystonic muscles in adjunction to BoNT treatment, or BoNT treatment alone. The
14
PT group showed significantly more improvement on pain, and on some subscales of the
15
SF-36.[68]
16
What is uncertain?
17
The available results should be interpreted with caution. The content of PT programs
18
varied across studies, including motor learning exercises (Bleton method[69]), passive or
19
active mobilization techniques of the cervical spine, stretching of the dystonic muscles,
20
relaxation, and electrotherapy such as EMG biofeedback or TENS. It is therefore difficult
21
to identify the most effective intervention or combination of interventions.
22
Frequency and duration of PT sessions also varied from 40 minutes every other day for
23
six weeks[66], 75 minutes five days a week for five weeks[68], 90 minutes a day for 2
24
weeks[65] up to a 12-week program with a weekly 30-minute session during the first four
25
weeks and a session every fortnight for the remaining eight weeks[67]. Besides, current
26
studies mainly show short-term effects associated with brief and intensive PT
27
programs,[65; 66; 68] which could be difficult to implement in current regular care of a
28
chronic disease such CD. The long-term effects of less intense and longer PT programs
29
have not been explored yet.
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Future perspectives
2
Future research should focus on standardized PT programs which are effective but also
3
adequate to treat patients with a chronic conditions and an active life. PT programs with
4
longer treatment periods and the emphasis on self-management of symptoms and the
5
ability of patients to improve their performance of daily life tasks should be the focus.
6
Currently, such a PT program is being investigated in a large Dutch RCT.[70]
7
The effect of PT interventions on the pathophysiological mechanisms of CD should also
8
be studied. Although the pathophysiology of CD remains largely unclear, maladaptive
9
neuroplastic changes may play an important role.[71] By integrating PT programs with
10
modern training principles that have proven relevant for neural rehabilitation and motor
11
learning, these deficit may be altered.[72; 73; 74; 75; 76]
12
Additionally, high quality research combining electrophysiological parameters or
13
imaging techniques with clinical outcomes, can help to further unravel the effects of PT
14
programs on CD.
15
Final considerations
16
There are still many unmet needs in the management of CD. A better understanding of
17
the pathophysiology of CD is necessary to plan new treatment strategies and to improve
18
existing treatments. In addition, the available rating scales for CD have some clinimetric
19
issues and do not equally address all the domains of the disease. This points to a need for
20
updated scoring instruments in order to support studies on the pathogenesis and
21
progression of the disease and to more accurately evaluate the outcomes of clinical trials.
22
Specific standardized rating scale for NMS in (cervical) dystonia should also be
23
developed.
24
Finally, it is widely accepted that motor improvement is not the only determinant of
25
treatment success in CD: pain, social distress and psychological factors play sometimes a
26
greater role toward patient satisfaction. This calls for a multi-disciplinary approach
27
posing more attention to the subjective determinants of QoL in CD.
28
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Author Contributions
3
conception or design of the work; drafted part of the manuscript and revised the rest of
4
the manuscript critically for important intellectual content; approved the final version to
5
be published; agreed to be accountable for all aspects of the work.
All the authors (MFC, MS, JvdD, JV, MAJT) provided substantial contributions to the
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