- Email: [email protected]
Deep brain stimulation for dystonia due to cerebral palsy: A review
Accepted Manuscript The European Journal of Paediatric Neurology – Review Deep brain stimulation for dystonia due to cerebral palsy: a review Antonio E. Elia, MD, PhD, Caterina F. Bagella, MD, PhD, Francesca Ferré, MPsych, Giovanna Zorzi, MD, Daniela Calandrella, MD, Luigi M. Romito, MD, PhD PII:
S1090-3798(17)31936-0
DOI:
10.1016/j.ejpn.2017.12.002
Reference:
YEJPN 2333
To appear in:
European Journal of Paediatric Neurology
Received Date: 17 October 2017 Revised Date:
7 December 2017
Accepted Date: 7 December 2017
Please cite this article as: Elia AE, Bagella CF, Ferré F, Zorzi G, Calandrella D, Romito LM, The European Journal of Paediatric Neurology – Review Deep brain stimulation for dystonia due to cerebral palsy: a review, European Journal of Paediatric Neurology (2018), doi: 10.1016/j.ejpn.2017.12.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT The European Journal of Paediatric Neurology – Review
Deep brain stimulation for dystonia due to cerebral palsy: a review
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Running title: DBS for DCP Antonio E. Elia, MD, PhD1, Caterina F. Bagella, MD, PhD1,2, Francesca Ferré, MPsych1, Giovanna Zorzi, MD3, Daniela Calandrella, MD1, *Luigi M. Romito, MD, PhD1 3
Department of Neurology – Movement Disorders, Department of Paediatric Neurology, IRCCS Fondazione C. Besta,
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1
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Milan, Italy, Department of Neuro-Rehabilitation, Multimedica, Limbiate, Italy
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*Corresponding author
Luigi M. Romito, MD, PhD, Istituto Neurologico Carlo Besta, Via G. Celoria, 11,
Address correspondence to:
Milan, Italy, Tel: +39 02 2394 2448; Fax: +39 02 2394 2539; Email:
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[email protected]
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ACCEPTED MANUSCRIPT Highlights •
Cerebral palsy is a complex condition frequently dominated by dystonic features
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Bilateral deep brain stimulation of the GPi has been associated with a variable improvement of dystonia in cerebral palsy patients, in the range of 1-50%
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The appropriate selection of patients with prominent dystonic symptoms in of key importance for
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the therapeutic success of DBS
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•
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ACCEPTED MANUSCRIPT Keywords: Dystonia; Cerebral Palsy; Deep Brain Stimulation; Globus Pallidus; Cerebellum; Acquired Dystonia
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Abbreviations BFMDRS, Burke-Fahn-Marsden Dystonia Rating Scale; BFMDRS-M, BFMDRS-Motor scale; BFMDRS-D, BFMDRS-Disability scale; SF-36, 36-Item Short Form Survey; DBS, Deep Brain Stimulation; CP, Cerebral
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palsy; GPi, Globus Pallidus Internus.
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ACCEPTED MANUSCRIPT Abstract Cerebral palsy (CP) is a heterogeneous group of syndromes that cause a non-progressive disorder of early onset, with abnormal control of movement and posture. Various aetiologies can cause the CP clinical spectrum, but all have a disruption of motor control in common. CP can be divided into four major types
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based on the motor disability: predominant spastic, dyskinetic, ataxic and mixed form. Dyskinetic CP (DCP) is the most common cause of acquired dystonia in children. The treatment of DCP is challenging because most individuals have mixed degrees of chorea, athetosis and dystonia. Pharmacological treatment is often
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unsatisfactory. Functional neurosurgery, in particular deep brain stimulation targeting the basal ganglia or the cerebellum, is emerging as a promising therapeutic approach in selected patients with DCP. We
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evaluated herein the effects of DBS on patients with DCP in a review of published patient data in the largest
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available studies.
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ACCEPTED MANUSCRIPT 1. Introduction Cerebral palsy (CP) is a heterogeneous group of syndromes that cause a non-progressive disorder of early onset, with abnormal control of movement and posture.1,2 The incidence of CP is between 1.5 and 2.5 per
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1000 live births and the risk is higher in low birth weight infants and in twins’ pregnancies.3 Various aetiologies can cause the CP clinical spectrum1 but all have a disruption of motor control in common. In addition to prematurity, other known aetiologies include developmental defects of the brain,
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perinatal stroke, hypoxia, shock, and foetal or neonatal inflammation or infection.4 Among others, genetic factors,5 maternal disease, preterm birth, low birthweight and birth asphyxia are associated with an
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increased risk of CP.6 However, CP may also occur in low-risk children for whom there is no obvious aetiology or risk factor.4
The physical impairment is often accompanied by disturbances in cognition and perception. CP is often accompanied by comorbidities such as seizures, communication deficits, hearing and vision deficits, and
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intellectual disability. There is a wide spectrum of motor dysfunction and of functional outcomes from normal educational, career, and social activities to complete disability and dependence.4 Most often, the pathology of CP in preterm infants can be ascribed to periventricular leukomalacia or peri-
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or intraventricular haemorrhage. Some cases of CP in infants born at term are caused by birth asphyxia or
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neonatal arterial infarction, but often a clear underlying pathology is not found.7 CP can be divided into four major types based on the motor disability: predominant spastic, dyskinetic, ataxic and mixed form.2 Dyskinetic CP is the most common cause of acquired dystonia in children.8 The dyskinetic CP is characterized by the presence of the involuntary movements as chorea, athetosis and dystonia. Abnormal movements usually involve all four extremities, with prominent involvement of the upper body. The phenomenology of cerebral palsy is heterogeneous, and frequently both dystonic and non-dystonic features might co-exist in the same patient, leading to variable causes of functional impairment. 9
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ACCEPTED MANUSCRIPT The treatment of dyskinetic CP is challenging because most individuals have mixed degrees of chorea, athetosis and dystonia.9-11 Pharmacological treatment is often unsatisfactory.12-16 The general approach to therapy is to target the dyskinetic movement that is causing the greatest difficulty. Therapeutic trials are largely empiric and responses often individualized. During the last decade, several case reports and case
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series have been published about the therapeutic outcome of surgical approaches 17-21 or more recently on deep brain stimulation (DBS) in patients with dyskinetic CP, reporting that basal ganglia or cerebellar targeting can be an effective treatment option for dyskinetic CP.22,23 The precise mechanism of action of
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DBS is far from clear: stimulation should create a signal modification in the target nuclei or replace a physiological signal into an aberrant output from the target nuclei.24
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We evaluated herein the effects of DBS on patients with dyskinetic CP in a review of published patient data in the largest available studies.
2. Search strategy and selection criteria
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The MEDLINE database (1966 to November 2017) was searched for articles describing the effect of DBS in patients affected by CP. Searches used a combination of text words and MeSH terms that combine "Cerebral Palsy" and "Deep Brain Stimulation" [or “DBS”]. The bibliographies of all eligible articles were also
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examined for relevant studies. We selected studies according to the following inclusion criteria: 1) clinical trials or observational studies with at least 5 patients treated; 2) articles written in English; 3) publications
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which reported individual clinical outcome data of the patients affected by CP. Studies which reported clinical outcome data on series of patients affected by different aetiologies, such as other causes of secondary dystonia as metabolic or neurodegenerative diseases, were excluded. All articles were reviewed for pertinent patient data. Information on aetiology of dystonia, age at operation, target of operation, duration of follow-up, stimulation parameters, adverse events, and outcome measures was obtained.
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ACCEPTED MANUSCRIPT 3. Results The original database search revealed 72 articles. After selecting only those reports according to inclusion/exclusion criteria, 13 eligible articles corresponding to twelve studies were identified [Table 1], assessing a total of 124 patients with dyskinetic CP who underwent bilateral GPi DBS in all or in almost all
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patients.25-35 In one study,36,37 bilateral GPi DBS was compared with the effect of DBS in bilateral GPi plus unilateral Vo thalamotomy. Available studies were eight case series observational studies,25-27,29,32,33,36,37 two cohort studies,28,31 one cross sectional study,34 one uncontrolled trial 35 and one registry.30 The age at
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DBS implant was variable, including both paediatric and adult patients (overall range 3.5-47 years). These studies are quite different for the considered follow up after surgery, that was very variable ranging from 2
3.1. Efficacy of DBS on dystonia
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months to 11 years. All studies used BFMDRS as primary outcome measure.
Bilateral GPi DBS was reported to be effective in reduction of motor symptoms of dystonia in all studies,
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however the magnitude of such effect was reported to be very variable between the different studies, ranging from a mean percentage reduction of 1.2% to 49.5% of motor score of BFMDRS [Figure 1]. The effect of GPi DBS on disability was very variable [Figure 2], in five studies an improvement of disability score
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of BFMDRS was reported ranging from -0.5% to 32%,31,32,34-37 and in two of them a significant improvement of SF-36 was also observed.34,35 In two other studies a slight worsening of disability score was reported.25,29
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A clear benefit of pallidal DBS in speech and swallowing was found in only two studies,27,34 whereas no significant improvement was reported in the study of Vidailhet 35 and in one study stimulation ‘on’ and ‘off’ did not lead to any significant clinical changes.29 The responsiveness of dystonia to DBS treatment is reported to be less beneficial than in patients with dystonia due to DYT1 gene mutation in two comparative studies,28,31 because DYT1 patients demonstrated continued improvement with ongoing pallidal stimulation during the follow up which was not observed in cerebral palsy patients, who showed sustained benefit after first months of treatment. A possible time-
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ACCEPTED MANUSCRIPT effect of DBS after implant for DCP, was however proposed in a larger follow up study that reported progressive improvements in motor and disability scores later than one/two years after implant .34 In a study the effect of bilateral GPi DBS was compared with bilateral GPi DBS plus unilateral thalamotomy; 36,37
the authors did not find significant difference in overall BFMDRS scores between the two treatments,
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however they suggest that unilateral thalamotomy could be useful in reducing movements of the contralateral upper extremities and associated with a better health-related quality of life.
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3.2. DBS parameters
DBS programming basically relies on the adjustments of four parameters: contacts configuration,
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amplitude, pulse width, and frequency of stimulation. Extensive programming sessions are reported in many studies to define the most optimal stimulation parameters, with variable amplitude (range, 1-6.5 V), pulse width (range, 60-240 µs) and frequency (range, 30–185 Hz), so the analyses revealed a wide spectrum of stimulation parameters used probably mainly rely only on neurologist’s experience [Table 1].
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3.3. Post-operative neuropsychological issues
Neuropsychological features were analysed in only two studies, which reported that cognition and mood were not affected after surgery.34,35 In a study, cognitive measures were reported to be stable without
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clinically relevant neuropsychological complications after a long term follow up. 34 Moreover, improvement
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of some aspects of psychological distress, particularly regarding interpersonal sensitivity, depression, paranoid ideation, and psychotic symptoms, was also reported.35
3.4. DBS Safety
Data regarding safety are scanty. Only few studies clearly reported adverse events, which were almost all described as serious adverse events. The most frequent post-operative complications were hardware infection that was reported in 7 patients and dysarthria that was reported in 7 patients. In one study,35 four patients developed a worsening of dystonia after surgery. Death unrelated to DBS procedure, due to acute
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ACCEPTED MANUSCRIPT cardiac failure, was reported in only one patient.34 Table 2 lists post-operative adverse events that can be assigned to individual CP patients.
4. Discussion
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The studies considered in this review have established that pallidal DBS is mostly effective in the treatment of dystonia in patients affected by CP. The results of these studies were very variable, with an overall better response when considering the measures of motor symptoms of dystonia than the measures of disability.
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In a recent systematic review, a meta-analysis of individual patient data showed a significant improvement in the BFMDRS-M of 23.6% and an overall improvement of BFMDRS-D of 9.2%.22
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The difference between the motor improvement and functional improvement after DBS could be related to the presence of disability due to symptoms other than dystonia in CP patients, because cerebral palsy can cause functional impairment in many ways, affecting patients’ posture, balance and ability to move, communicate, eat, sleep and learn.26,29,38,39 It is also likely that studies reporting no significant improvement
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of disability after DBS could have included patients with ataxic features, that usually determine a severe functional impairment and cannot improve after GPi-DBS. 9 It is remarkable that improvement in disability is higher in the studies that had inclusion criteria suitable to select patients with disabling dystonia.31,34,35
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Another possibility is that clinical scales, commonly used to evaluate disability in CP patients, as the BFMDRS-D, are unable to detect meaningful qualitative change in relevant functional areas for these
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patients.26 It was proposed that a documented multidimensional assessment pre- and post- DBS in CP is needed to elucidate what DBS offers to patients in terms of function, participation, care, comfort and quality of life, particularly in the paediatric population.25 The responsiveness of dystonia to DBS treatment in CP is usually considered less beneficial than in patients with idiopathic or genetic dystonias, who have substantial improvement of motor symptoms and disability with pallidal stimulation.40,41 However, in the only two available comparative studies between genetic dystonia and CP, severity of dystonia was generally worse at baseline among patients with cerebral palsy
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ACCEPTED MANUSCRIPT than those with genetic dystonias, and patients with cerebral palsy presented with a baseline disability that was significantly more severe than patients with genetic dystonia.28,31 Differences between genetic dystonias and cerebral palsy in the response to GPi-DBS could be due to differences in pathophysiological mechanisms. 11 In inherited and idiopathic dystonias pathophysiological
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deficits include reduced inhibition at many levels of the motor system, including spinal cord, brainstem and motor cortex, enhanced synaptic plasticity and cerebellar deficits. 11,42 These deficits were not
demonstrated in dystonia caused by structural brain lesions. 43 Thus therapeutic interventions that could
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modify motor cortex plasticity might be less useful in patients with acquired dystonia due to cerebral palsy.
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43,44
The findings about treatment of speech and swallowing in CP are controversial and a clear benefit on these outcomes was reported in only two studies.27,34 Further studies, which consider the treatment of speech and swallowing impairment as primary outcome, are needed to define the effect of DBS on these relevant
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clinical problems.
Overall, we found cognitive measures stable or mildly improved in two studies. 34-36 Cognitive and psychiatric safety after bilateral pallidal stimulation is in keeping with earlier reports on idiopathic and
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symptomatic dystonia patients treated with DBS. 45-47 However, cognitive changes with transient deteriorations were previously reported in individual patients, 46 thus more studies are needed to identify
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predictors for postsurgical cognitive outcome. The data on DBS in dyskinetic CP patients have some limitations and important questions remain unanswered. Because of heterogeneity in outcome and lack of established eligibility criteria, selection of suitable patients is often difficult.39 On one side there is the question of the best timing for DBS implantation: CP patients have absent or reduced chance for a normal motor development and an early DBS may facilitate overcoming maladaptive neuroplasticity and learning processes. There was a significant negative correlation between severity of dystonia and clinical outcome;22 fixed skeletal deformities or cervical myelopathy are associated with a 10
ACCEPTED MANUSCRIPT poorer outcome. Moreover, the precise description of motor phenotype, radiological imagines and neurophysiological measurements contribute to identify prognostic factors for therapy response.38 A better outcome and further improvement probably can depend on the homogeneity of patients and procedures, as reported in a recent study.34
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On the other side, DBS in CP can be complicated by adverse events, transient, persistent, occurring during surgical procedures, device-related and stimulation-induced. The risk of adverse events due to DBS seems to be higher in paediatric patients than in adult, especially in patients aged less than 10 years,39 even
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though recently was reported a multistage surgical plan for paediatric CP patients undergoing DBS that helps to reduce the risk of infection.48 The safety issue could indicate the way for a post-implant
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management strategy in these patients. At last, data regarding disability, quality of life and pain are poor. Functional impairment in cerebral palsy is due to variable causes, regarding both dystonic and non-dystonic features, thus selection of candidates for DBS should be made focusing on specific goals, related to
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dystonia and potentially achievable, to increase the probability of success.
In summary, because of the large variability of the reported effect of the GPi DBS in patients effected by CP, it is of utmost importance the proper selection of candidates for this treatment, identifying those patients
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who are affected by prominent and disabling dystonia, without or with only minimal occurrence of other neurological manifestations, such as spasticity or ataxia.
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In conclusion, severity of dystonia influence surgery outcome, but the role of age at onset, duration of symptoms or age at time of surgery should be elucidated. For this reason, there is a need for more reliable markers that will help to accurately select CP patients who will benefit from DBS. There is a need for welldesign trials with a longer-term (5–10 years) follow up and an accurate data collection to increase knowledge on results in CP patients treated with DBS and to establish the clinical predictive factors of favourable outcome.
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Acknowledgment
numbers GR-2009-1594645 and GR-2009-1607326].
Conflict of Interest
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The authors declare that they have no conflict of interest.
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Authors were partly sustained (A.E.E., C.B., F.M.F, L.M.R.) by the Italian National Institutes of Health [grant
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Vidailhet et al. 35 2009
Uncontrolled trial
Number of patients
Bilateral GPi
Mean age at surgery (years)
32.6 ±8.6 (range 20-44)
13
Follow up (months)
(High quality)
Outcome measures
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V: variable
BFMDRS-D
(range, 2-3.8 V)
SF-36 SCL-90
Case series #
(Moderate quality)
Bilateral GPi in 13 patients; unilateral GPi in 1 patient.
15 (14 evaluated, 1 patient required removal of hardware because of
BFMDRS-M: -24.3 ±21.1
BFMDRS-D: -13.3 ±31.1 PW: variable SF-36: 15 SCL-90: -34.9 F: 130 Hz
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Main results with dystonia score variation (%) at last FU
(range, 60-150 µs)
14.4 ±5.9 (range 7–26)
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Marks et al. 2011
Stimulation parameters**
BFMDRS-M
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#
Target
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Design
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Study (reference)
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Table 1 - Observational studies and trials evaluating bilateral GPi (±other brain targets) deep brain stimulation for patients affected by dystonic/dyskinetic cerebral palsy.
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BFMDRS-M
V: variable
BFMDRS-D
(range 2–6.5 V)
BFMDRS-M: -5.46 ±23.97
BADS PW: 210 µs
BFMDRS-D: -8.95 ±13.42
F: variable
BADS: -1.73 ±19.29
infection)
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(range, 30–185 Hz) 36
Bilateral GPi (group 1, 4 patients)
BFMDRS-M:
Case series
26.8 ±5.1 (range 18–37)
10
Case series #
(Low quality)
Bilateral GPi plus unilateral Vo thalamotomy (group 2, 6 patients)
Bilateral GPi
31.8 ±24.9 (range 12– 86)
6
9.8 ±3.4 (range 513)
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V: 2.15 V BFMDRS-D:
BFMDRS-M
-14.3 for group 1 PW: 139.9 µs
BFMDRS-D
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(Low quality)
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#
BFMDRS-M: -31.5 for group 2 F: 95.9 Hz
BFMDRS-D: -0.18 for group 2 BFMDRS-M
Not reported
BFMDRS-M: -5.9 ±2.9
BFMDRS-D CPCHILD
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Gimeno et al. 25 2012
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BFMDRS-D: 0.5 ±4.5
PPP/NRS
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Kim et al. 2011 37 and 2012 , B
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-32.0 for group 1
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Kim et al. 2011 37 and 2012 , A
COPM
CPCHILD: -22.6 ±28.5
GAS PPP/NRS: Significant reduction in perceived pain
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31
Cohort
Bilateral GPi
#
11.02 ±3.09 (range 7.9-15.9)
37.12 ±12.05 (range 2156)
BFMDRS-M
GAS: In all cases at least 60% of GAS goals achieved V: Not reported
BFMDRS-M: -21.8 ±19.3
PW: Not reported
BFMDRS-D: -15.8 ±29.1
F: 76.7 ±34.1 Hz (range 30-135)
BADS:
BFMDRS-D BADS GMCS for ambulation
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(Moderate quality)
12 (3 excluded because hardware removal due to infection or unilateral disease) compared with 8 patients with DYT1 dystonia
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Marks et al. 2013
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COPM: Clinically significant improvement
-15.8 ±15.4
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Olaya et al. 2013
Case series #
(Low quality)
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GMCS for ambulation:
Bilateral GPi (8 patients)
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unchanged for the CP group
16.3 ±5.1 (range 6-20)
3.8 ±3.3 (range 0.5-9)
BFMDRS BADS
Bilateral GPi plus bilateral STN (1
Not reported
BFMDRS: -10.5 ±15.8
BADS:
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patient) Case series
Bilateral GPi
8.9 ±4.1 (range 3.5-18)
14
#
Case series
Kim et al. 2014
28
11.4 ±4.2 (range 8–17)
5
(Low quality)
Cohort
26.6 ±15.6 (range 2–42)
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#
Bilateral GPi
Bilateral GPi
#
Not reported
7 (compared with 5 patients affected by DYT1 or idiopathic dystonia)
COPM COPM: Significant improvement in individualised goal attainment
BFMDRS-M
V: variable
BADS
(range 1–4.7 V)
Case series #
Bilateral GPi
8
BADS: -16,3 ±12.5
BFMDRS: -27.9 ±13.2 PW: 120 µs
29.0 ±4.4 (range 21-34)
24
BFMDRS-M BFMDRS-D
Not reported
BFMDRS-M: -39.2 ±11.2
SSS BFMDRS-D: -0.5 ±6.6
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Koy et al. 2014
BFMDRS-M: -3.5 ±7.9
F: 180 Hz
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(Moderate quality)
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27
Keen et al. 2014
BFMDRS-M
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(Moderate quality)
8.9 ±3.9 (range 3.518.25)
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Gimeno et al. 26 2014
-7.9 ±12.1
SSS: decreased satisfaction 26.1 ±6.5 (range 16.1-33.8)
(Low quality)
16
44.5 ±27.2 (range 8-83)
AIMS
V: variable
BFMDRS-M
(range 1.2–3.8 V)
BFMDRS-M: -1.2 ±17.9
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BFMDRS-D
Cross sectional
Romito et al. 34 2015
Bilateral GPi
29.8 ±9.5 (range 15-47)
15
(Moderate quality)
Registry #
10
13.3 ±3.8 (range not available)
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(Moderate quality)
Bilateral GPi in 9 and VIM in 1 patient
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30
Koy et al. 2017
52.8 ±21.6 (range 2484)
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#
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PW: variable (range, 90-240 µs)
* Percentage improvement in primary outcome (motor score), mean (SD); ** Best stimulation parameters at last FU
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2.3
BFMDRS-M
BFMDRS-D (difference between switched “on” and “off”): 4.2 ±11.8
F: 130 Hz
AIMS (difference between switched “on” and “off”): 3.7 ±20.1
V: 3.1 ±0.7 V
BFMDRS-M: -49.5 ±19.0
PW: 111.4 ±38.1 µs
BFMDRS-D: -32.6 ±18.4
F: 132.6 ±19.5 Hz
SF-36: 82.3 ±31.4
Wide spectrum of stimulation
BFMDRS-M: -14 (Mean postoperative
parameters (mean values: V: 2.7 V [range 1-6.5 V]; current: 3.0 mA [2.0-3.8], F: 133 Hz [60-210]; PW: 136 µs [60 -450]). The two ventralmost contacts were used in most GPi DBS patients
Improvement of 9.8 ±10.3)
BFMDRS-D SF-36
BFMDRS-M
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Abbreviations: GPi, Globus Pallidus Internus; BFMDRS, Burke-Fahn-Marsden Dystonia Rating Scale; BFMDRS-M, BFMDRS-Motor scale; BFMDRS-D, BFMDRS-Disability scale; SF-36, 36-Item Short Form Survey; SCL-90, Symptom Checklist-90; BADS, Behavioural Assessment of the Dysexecutive Syndrome; CPCHILD, Caregiver Priorities and Child Health Index of Life with Disabilities questionnaire; PPP/NRS, Paediatric Pain Profile/ Numerical Rating Scale; COPM, Canadian Occupational Performance Measure; GAS, Goal Attainment Scaling; GMCS for ambulation, Gross Motor Functional Classification System for ambulation; SSS, Subjective satisfaction scale; AIMS, Abnormal involuntary movement scale; UDRS, Unified Dystonia Rating Scale. V, Voltage; PW, Pulse width; F, Frequency.
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Levels of evidence are adapted from EFNS guidance and GRADE system. 49
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#
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Table 2. Adverse events reported in bilateral GPi (±other brain targets) DBS studies on dystonic CP.
Vidailhet et al. 2009
Adverse events
35
Number of dropped out
Worsening of dystonia (n = 4), deterioration after 1 year/cervical myelopathy (n = 1), sub-clavicular pain (n = 1), stimulation
32
Infection (n = 1)
36
37
Kim et al. 2011 and 2012 25
31
Infection (3)
33
Olaya et al. 2013
Gimeno et al. 2014
Not reported
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Marks et al. 2013
Dysarthria, hemiparesis (n = 3)
Not reported 26
27
Infections (n = 2)
0 3
0 2
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Keen et al. 2014
Not reported
0
0
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Gimeno et al. 2012
1
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Marks et al. 2011
0
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arrest/magnetic field (n = 1)
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Study (reference)
28
Not reported
29
Revision of the electrodes because of hardware breakage (n = 1)
0
Fever (2), seizure (1), spasms of pharynx (1), dysphagia and
0
Kim et al. 2014 Koy et al. 2014
34
Romito et al. 2015
0
hypophonia (1), hypophonia (1), dysarthria (4), local pain (2),
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paraesthesia (2), muscular strain (1), visual disturbance (1), extracranial lead damage (1), sub-clavear seroma (1), unexplained
hardware infection (1), death for acute cardiac failure (1) Not reported (authors reported 42 adverse events reported in a
Not reported (authors reported 13 dropped out among a whole series of 44 patients, 10 of them affected by CP)
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whole series of 44 patients, 10 of them affected by CP)
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30
Koy et al. 2017
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implantable pulse generator switching-off (1), lead migration (1),
20
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Figure 1. BFMRS-Motor scales variations in the individual studies on bilateral GPi (±other brain targets) deep brain stimulation in cerebral palsy. Negative values represent improvement. Standard error bars are showed.
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Figure 2. BFMRS-Disability scale variations in the individual studies on bilateral GPi (±other brain targets) deep brain stimulation in cerebral palsy. Negative values represent improvement. Standard error bars are showed.
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ACCEPTED MANUSCRIPT REFERENCES
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2. Tochen, L and Singer, HS. Movement Disorders in Children. In: Jankovic J, Tolosa E, eds. Parkinson's Disease & Movement Disorders, Sixth Edition.6th Edition ed. Philadelphia, United States: Wolter Kluver, 2015:408-419.
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3. Kuban, KC and Leviton, A. Cerebral palsy. N Engl J Med. 1994; 330:188-195.
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4. Lungu, C, Hirtz, D, Damiano, D, et al. Report of a workshop on research gaps in the treatment of cerebral palsy. Neurology. 2016; 87:1293-1298.
5. Fahey, MC, Maclennan, AH, Kretzschmar, D, et al. The genetic basis of cerebral palsy. Dev Med Child Neurol. 2017; 59:462-469.
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6. McIntyre, S, Taitz, D, Keogh, J, et al. A systematic review of risk factors for cerebral palsy in children born at term in developed countries. Dev Med Child Neurol. 2013; 55:499-508.
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7. Herskind, A, Greisen, G, and Nielsen, JB. Early identification and intervention in cerebral palsy. Dev Med Child Neurol. 2015; 57:29-36.
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8. Lin, JP, Lumsden, DE, Gimeno, H, et al. The impact and prognosis for dystonia in childhood including dystonic cerebral palsy: a clinical and demographic tertiary cohort study. J Neurol Neurosurg Psychiatry. 2014; 85:1239-1244.
9. Eggink, H, Kremer, D, Brouwer, OF, et al. Spasticity, dyskinesia and ataxia in cerebral palsy: Are we sure we can differentiate them? Eur J Paediatr Neurol. 2017; 21:703-706.
10. Supiot, F. Identification and measurement of dystonia in cerebral palsy. Dev Med Child Neurol. 2017. 23
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11. Monbaliu, E, Himmelmann, K, Lin, JP, et al. Clinical presentation and management of dyskinetic cerebral palsy. Lancet Neurol. 2017; 16:741-749.
12. Panteliadis, CP, Hagel, C, Karch, D, et al. Cerebral Palsy: A Lifelong Challenge Asks for Early Intervention. Open Neurol J. 2015; 9:45-52.
dystonic cerebral palsy. J Child Neurol. 2014; 29:534-537.
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13. Pozin, I, Bdolah-Abram, T, and Ben-Pazi, H. Levodopa does not improve function in individuals with
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14. Chaleat-Valayer, E, Parratte, B, Colin, C, et al. A French observational study of botulinum toxin use in the management of children with cerebral palsy: BOTULOSCOPE. Eur J Paediatr Neurol. 2011;
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15:439-448.
15. Pin, TW, McCartney, L, Lewis, J, et al. Use of intrathecal baclofen therapy in ambulant children and adolescents with spasticity and dystonia of cerebral origin: a systematic review. Dev Med Child Neurol. 2011; 53:885-895.
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16. Motta, F, Antonello, CE, and Stignani, C. Intrathecal baclofen and motor function in cerebral palsy. Dev Med Child Neurol. 2011; 53:443-448.
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17. Hornyak, M, Rovit, RL, Simon, AS, et al. Irving S. Cooper and the early surgical management of
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movement disorders. Video history. Neurosurg Focus. 2001; 11:E6.
18. Speelman, D and van, MJ. Cerebral palsy and stereotactic neurosurgery: long term results. J Neurol Neurosurg Psychiatry. 1989; 52:23-30.
19. Broggi, G, Angelini, L, Bono, R, et al. Long term results of stereotactic thalamotomy for cerebral palsy. Neurosurgery. 1983; 12:195-202.
20. Zervas, NT. Long-term review of dentatectomy in dystonia musculorum deformans and cerebral palsy. Acta Neurochir (Wien ). 1977;49-51.
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21. PERLMUTTER, I and FAIRMAN, D. SURGICAL TREATMENT OF HYPERKINETIC DISORDERS: PARKINSONISM, CEREBRAL PALSY, DYSTONIA, CEREBELLAR TREMOR. J Fla Med Assoc. 1963; 50:275-276.
22. Koy, A, Hellmich, M, Pauls, KA, et al. Effects of deep brain stimulation in dyskinetic cerebral palsy: a
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meta-analysis. Mov Disord. 2013; 28:647-654.
23. Trejos, H and Araya, R. Stereotactic surgery for cerebral palsy. Stereotact Funct Neurosurg. 1990;
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54-55:130-135.
24. Herrington, TM, Cheng, JJ, and Eskandar, EN. Mechanisms of deep brain stimulation. J
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Neurophysiol. 2016; 115:19-38.
25. Gimeno, H, Tustin, K, Selway, R, et al. Beyond the Burke-Fahn-Marsden Dystonia Rating Scale: deep brain stimulation in childhood secondary dystonia. Eur J Paediatr Neurol. 2012; 16:501-508.
26. Gimeno, H, Tustin, K, Lumsden, D, et al. Evaluation of functional goal outcomes using the Canadian
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Occupational Performance Measure (COPM) following Deep Brain Stimulation (DBS) in childhood dystonia. Eur J Paediatr Neurol. 2014; 18:308-316.
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27. Keen, JR, Przekop, A, Olaya, JE, et al. Deep brain stimulation for the treatment of childhood
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dystonic cerebral palsy. J Neurosurg Pediatr. 2014; 14:585-593.
28. Kim, AR, Chang, JW, Chang, WS, et al. Two-year outcomes of deep brain stimulation in adults with cerebral palsy. Ann Rehabil Med. 2014; 38:209-217.
29. Koy, A, Pauls, KA, Flossdorf, P, et al. Young adults with dyskinetic cerebral palsy improve subjectively on pallidal stimulation, but not in formal dystonia, gait, speech and swallowing testing. Eur Neurol. 2014; 72:340-348.
30. Koy, A, Weinsheimer, M, Pauls, KA, et al. German registry of paediatric deep brain stimulation in patients with childhood-onset dystonia (GEPESTIM). Eur J Paediatr Neurol. 2017; 21:136-146. 25
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31. Marks, W, Bailey, L, Reed, M, et al. Pallidal stimulation in children: comparison between cerebral palsy and DYT1 dystonia. J Child Neurol. 2013; 28:840-848.
32. Marks, WA, Honeycutt, J, Acosta, F, Jr., et al. Dystonia due to cerebral palsy responds to deep brain stimulation of the globus pallidus internus. Mov Disord. 2011; 26:1748-1751.
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33. Olaya, JE, Christian, E, Ferman, D, et al. Deep brain stimulation in children and young adults with secondary dystonia: the Children's Hospital Los Angeles experience. Neurosurg Focus. 2013; 35:E7.
palsy: beyond 5 years. Eur J Neurol. 2015; 22:426-e32.
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34. Romito, LM, Zorzi, G, Marras, CE, et al. Pallidal stimulation for acquired dystonia due to cerebral
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35. Vidailhet, M, Yelnik, J, Lagrange, C, et al. Bilateral pallidal deep brain stimulation for the treatment of patients with dystonia-choreoathetosis cerebral palsy: a prospective pilot study. Lancet Neurol. 2009; 8:709-717.
36. Kim, JP, Chang, WS, and Chang, JW. Treatment of secondary dystonia with a combined stereotactic
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procedure: long-term surgical outcomes. Acta Neurochir (Wien ). 2011; 153:2319-2327.
37. Kim, JP, Chang, WS, Cho, SR, et al. The effect of bilateral globus pallidus internus deep brain
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stimulation plus ventralis oralis thalamotomy on patients with cerebral palsy. Stereotact Funct
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Neurosurg. 2012; 90:292-299.
38. Cif, L. Deep brain stimulation in dystonic cerebral palsy: for whom and for what? Eur J Neurol. 2015; 22:423-425.
39. Koy, A and Timmermann, L. Deep brain stimulation in cerebral palsy: Challenges and opportunities. Eur J Paediatr Neurol. 2017; 21:118-121.
40. Coubes, P, Roubertie, A, Vayssiere, N, et al. Treatment of DYT1-generalised dystonia by stimulation of the internal globus pallidus. Lancet. 2000; 355:2220-2221.
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41. Krauss, JK, Pohle, T, Weber, S, et al. Bilateral stimulation of globus pallidus internus for treatment of cervical dystonia. Lancet. 1999; 354:837-838.
42. Quartarone, A and Hallett, M. Emerging concepts in the physiological basis of dystonia. Mov Disord. 2013; 28:958-967.
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43. Kojovic, M, Parees, I, Kassavetis, P, et al. Secondary and primary dystonia: pathophysiological differences. Brain. 2013; 136:2038-2049.
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44. Andrews, C, viles-Olmos, I, Hariz, M, et al. Which patients with dystonia benefit from deep brain stimulation? A metaregression of individual patient outcomes. J Neurol Neurosurg Psychiatry. 2010;
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81:1383-1389.
45. Gruber, D, Trottenberg, T, Kivi, A, et al. Long-term effects of pallidal deep brain stimulation in tardive dystonia. Neurology. 2009; 73:53-58.
46. Halbig, TD, Gruber, D, Kopp, UA, et al. Pallidal stimulation in dystonia: effects on cognition, mood,
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and quality of life. J Neurol Neurosurg Psychiatry. 2005; 76:1713-1716.
47. Pillon, B, Ardouin, C, Dujardin, K, et al. Preservation of cognitive function in dystonia treated by
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pallidal stimulation. Neurology. 2006; 66:1556-1558.
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48. Johans, SJ, Swong, KN, Hofler, RC, et al. A Stepwise Approach: Decreasing Infection in Deep Brain Stimulation for Childhood Dystonic Cerebral Palsy. J Child Neurol. 2017; 32:871-875.
49. Leone, MA, Brainin, M, Boon, P, et al. Guidance for the preparation of neurological management guidelines by EFNS scientific task forces - revised recommendations 2012. Eur J Neurol. 2013; 20:410-419.
27
S1090-3798(17)31936-0
DOI:
10.1016/j.ejpn.2017.12.002
Reference:
YEJPN 2333
To appear in:
European Journal of Paediatric Neurology
Received Date: 17 October 2017 Revised Date:
7 December 2017
Accepted Date: 7 December 2017
Please cite this article as: Elia AE, Bagella CF, Ferré F, Zorzi G, Calandrella D, Romito LM, The European Journal of Paediatric Neurology – Review Deep brain stimulation for dystonia due to cerebral palsy: a review, European Journal of Paediatric Neurology (2018), doi: 10.1016/j.ejpn.2017.12.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT The European Journal of Paediatric Neurology – Review
Deep brain stimulation for dystonia due to cerebral palsy: a review
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Running title: DBS for DCP Antonio E. Elia, MD, PhD1, Caterina F. Bagella, MD, PhD1,2, Francesca Ferré, MPsych1, Giovanna Zorzi, MD3, Daniela Calandrella, MD1, *Luigi M. Romito, MD, PhD1 3
Department of Neurology – Movement Disorders, Department of Paediatric Neurology, IRCCS Fondazione C. Besta,
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1
2
Milan, Italy, Department of Neuro-Rehabilitation, Multimedica, Limbiate, Italy
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*Corresponding author
Luigi M. Romito, MD, PhD, Istituto Neurologico Carlo Besta, Via G. Celoria, 11,
Address correspondence to:
Milan, Italy, Tel: +39 02 2394 2448; Fax: +39 02 2394 2539; Email:
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[email protected]
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ACCEPTED MANUSCRIPT Highlights •
Cerebral palsy is a complex condition frequently dominated by dystonic features
•
Bilateral deep brain stimulation of the GPi has been associated with a variable improvement of dystonia in cerebral palsy patients, in the range of 1-50%
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The appropriate selection of patients with prominent dystonic symptoms in of key importance for
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the therapeutic success of DBS
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•
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ACCEPTED MANUSCRIPT Keywords: Dystonia; Cerebral Palsy; Deep Brain Stimulation; Globus Pallidus; Cerebellum; Acquired Dystonia
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Abbreviations BFMDRS, Burke-Fahn-Marsden Dystonia Rating Scale; BFMDRS-M, BFMDRS-Motor scale; BFMDRS-D, BFMDRS-Disability scale; SF-36, 36-Item Short Form Survey; DBS, Deep Brain Stimulation; CP, Cerebral
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palsy; GPi, Globus Pallidus Internus.
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ACCEPTED MANUSCRIPT Abstract Cerebral palsy (CP) is a heterogeneous group of syndromes that cause a non-progressive disorder of early onset, with abnormal control of movement and posture. Various aetiologies can cause the CP clinical spectrum, but all have a disruption of motor control in common. CP can be divided into four major types
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based on the motor disability: predominant spastic, dyskinetic, ataxic and mixed form. Dyskinetic CP (DCP) is the most common cause of acquired dystonia in children. The treatment of DCP is challenging because most individuals have mixed degrees of chorea, athetosis and dystonia. Pharmacological treatment is often
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unsatisfactory. Functional neurosurgery, in particular deep brain stimulation targeting the basal ganglia or the cerebellum, is emerging as a promising therapeutic approach in selected patients with DCP. We
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evaluated herein the effects of DBS on patients with DCP in a review of published patient data in the largest
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available studies.
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ACCEPTED MANUSCRIPT 1. Introduction Cerebral palsy (CP) is a heterogeneous group of syndromes that cause a non-progressive disorder of early onset, with abnormal control of movement and posture.1,2 The incidence of CP is between 1.5 and 2.5 per
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1000 live births and the risk is higher in low birth weight infants and in twins’ pregnancies.3 Various aetiologies can cause the CP clinical spectrum1 but all have a disruption of motor control in common. In addition to prematurity, other known aetiologies include developmental defects of the brain,
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perinatal stroke, hypoxia, shock, and foetal or neonatal inflammation or infection.4 Among others, genetic factors,5 maternal disease, preterm birth, low birthweight and birth asphyxia are associated with an
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increased risk of CP.6 However, CP may also occur in low-risk children for whom there is no obvious aetiology or risk factor.4
The physical impairment is often accompanied by disturbances in cognition and perception. CP is often accompanied by comorbidities such as seizures, communication deficits, hearing and vision deficits, and
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intellectual disability. There is a wide spectrum of motor dysfunction and of functional outcomes from normal educational, career, and social activities to complete disability and dependence.4 Most often, the pathology of CP in preterm infants can be ascribed to periventricular leukomalacia or peri-
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or intraventricular haemorrhage. Some cases of CP in infants born at term are caused by birth asphyxia or
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neonatal arterial infarction, but often a clear underlying pathology is not found.7 CP can be divided into four major types based on the motor disability: predominant spastic, dyskinetic, ataxic and mixed form.2 Dyskinetic CP is the most common cause of acquired dystonia in children.8 The dyskinetic CP is characterized by the presence of the involuntary movements as chorea, athetosis and dystonia. Abnormal movements usually involve all four extremities, with prominent involvement of the upper body. The phenomenology of cerebral palsy is heterogeneous, and frequently both dystonic and non-dystonic features might co-exist in the same patient, leading to variable causes of functional impairment. 9
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ACCEPTED MANUSCRIPT The treatment of dyskinetic CP is challenging because most individuals have mixed degrees of chorea, athetosis and dystonia.9-11 Pharmacological treatment is often unsatisfactory.12-16 The general approach to therapy is to target the dyskinetic movement that is causing the greatest difficulty. Therapeutic trials are largely empiric and responses often individualized. During the last decade, several case reports and case
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series have been published about the therapeutic outcome of surgical approaches 17-21 or more recently on deep brain stimulation (DBS) in patients with dyskinetic CP, reporting that basal ganglia or cerebellar targeting can be an effective treatment option for dyskinetic CP.22,23 The precise mechanism of action of
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DBS is far from clear: stimulation should create a signal modification in the target nuclei or replace a physiological signal into an aberrant output from the target nuclei.24
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We evaluated herein the effects of DBS on patients with dyskinetic CP in a review of published patient data in the largest available studies.
2. Search strategy and selection criteria
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The MEDLINE database (1966 to November 2017) was searched for articles describing the effect of DBS in patients affected by CP. Searches used a combination of text words and MeSH terms that combine "Cerebral Palsy" and "Deep Brain Stimulation" [or “DBS”]. The bibliographies of all eligible articles were also
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examined for relevant studies. We selected studies according to the following inclusion criteria: 1) clinical trials or observational studies with at least 5 patients treated; 2) articles written in English; 3) publications
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which reported individual clinical outcome data of the patients affected by CP. Studies which reported clinical outcome data on series of patients affected by different aetiologies, such as other causes of secondary dystonia as metabolic or neurodegenerative diseases, were excluded. All articles were reviewed for pertinent patient data. Information on aetiology of dystonia, age at operation, target of operation, duration of follow-up, stimulation parameters, adverse events, and outcome measures was obtained.
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ACCEPTED MANUSCRIPT 3. Results The original database search revealed 72 articles. After selecting only those reports according to inclusion/exclusion criteria, 13 eligible articles corresponding to twelve studies were identified [Table 1], assessing a total of 124 patients with dyskinetic CP who underwent bilateral GPi DBS in all or in almost all
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patients.25-35 In one study,36,37 bilateral GPi DBS was compared with the effect of DBS in bilateral GPi plus unilateral Vo thalamotomy. Available studies were eight case series observational studies,25-27,29,32,33,36,37 two cohort studies,28,31 one cross sectional study,34 one uncontrolled trial 35 and one registry.30 The age at
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DBS implant was variable, including both paediatric and adult patients (overall range 3.5-47 years). These studies are quite different for the considered follow up after surgery, that was very variable ranging from 2
3.1. Efficacy of DBS on dystonia
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months to 11 years. All studies used BFMDRS as primary outcome measure.
Bilateral GPi DBS was reported to be effective in reduction of motor symptoms of dystonia in all studies,
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however the magnitude of such effect was reported to be very variable between the different studies, ranging from a mean percentage reduction of 1.2% to 49.5% of motor score of BFMDRS [Figure 1]. The effect of GPi DBS on disability was very variable [Figure 2], in five studies an improvement of disability score
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of BFMDRS was reported ranging from -0.5% to 32%,31,32,34-37 and in two of them a significant improvement of SF-36 was also observed.34,35 In two other studies a slight worsening of disability score was reported.25,29
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A clear benefit of pallidal DBS in speech and swallowing was found in only two studies,27,34 whereas no significant improvement was reported in the study of Vidailhet 35 and in one study stimulation ‘on’ and ‘off’ did not lead to any significant clinical changes.29 The responsiveness of dystonia to DBS treatment is reported to be less beneficial than in patients with dystonia due to DYT1 gene mutation in two comparative studies,28,31 because DYT1 patients demonstrated continued improvement with ongoing pallidal stimulation during the follow up which was not observed in cerebral palsy patients, who showed sustained benefit after first months of treatment. A possible time-
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ACCEPTED MANUSCRIPT effect of DBS after implant for DCP, was however proposed in a larger follow up study that reported progressive improvements in motor and disability scores later than one/two years after implant .34 In a study the effect of bilateral GPi DBS was compared with bilateral GPi DBS plus unilateral thalamotomy; 36,37
the authors did not find significant difference in overall BFMDRS scores between the two treatments,
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however they suggest that unilateral thalamotomy could be useful in reducing movements of the contralateral upper extremities and associated with a better health-related quality of life.
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3.2. DBS parameters
DBS programming basically relies on the adjustments of four parameters: contacts configuration,
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amplitude, pulse width, and frequency of stimulation. Extensive programming sessions are reported in many studies to define the most optimal stimulation parameters, with variable amplitude (range, 1-6.5 V), pulse width (range, 60-240 µs) and frequency (range, 30–185 Hz), so the analyses revealed a wide spectrum of stimulation parameters used probably mainly rely only on neurologist’s experience [Table 1].
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3.3. Post-operative neuropsychological issues
Neuropsychological features were analysed in only two studies, which reported that cognition and mood were not affected after surgery.34,35 In a study, cognitive measures were reported to be stable without
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clinically relevant neuropsychological complications after a long term follow up. 34 Moreover, improvement
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of some aspects of psychological distress, particularly regarding interpersonal sensitivity, depression, paranoid ideation, and psychotic symptoms, was also reported.35
3.4. DBS Safety
Data regarding safety are scanty. Only few studies clearly reported adverse events, which were almost all described as serious adverse events. The most frequent post-operative complications were hardware infection that was reported in 7 patients and dysarthria that was reported in 7 patients. In one study,35 four patients developed a worsening of dystonia after surgery. Death unrelated to DBS procedure, due to acute
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ACCEPTED MANUSCRIPT cardiac failure, was reported in only one patient.34 Table 2 lists post-operative adverse events that can be assigned to individual CP patients.
4. Discussion
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The studies considered in this review have established that pallidal DBS is mostly effective in the treatment of dystonia in patients affected by CP. The results of these studies were very variable, with an overall better response when considering the measures of motor symptoms of dystonia than the measures of disability.
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In a recent systematic review, a meta-analysis of individual patient data showed a significant improvement in the BFMDRS-M of 23.6% and an overall improvement of BFMDRS-D of 9.2%.22
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The difference between the motor improvement and functional improvement after DBS could be related to the presence of disability due to symptoms other than dystonia in CP patients, because cerebral palsy can cause functional impairment in many ways, affecting patients’ posture, balance and ability to move, communicate, eat, sleep and learn.26,29,38,39 It is also likely that studies reporting no significant improvement
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of disability after DBS could have included patients with ataxic features, that usually determine a severe functional impairment and cannot improve after GPi-DBS. 9 It is remarkable that improvement in disability is higher in the studies that had inclusion criteria suitable to select patients with disabling dystonia.31,34,35
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Another possibility is that clinical scales, commonly used to evaluate disability in CP patients, as the BFMDRS-D, are unable to detect meaningful qualitative change in relevant functional areas for these
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patients.26 It was proposed that a documented multidimensional assessment pre- and post- DBS in CP is needed to elucidate what DBS offers to patients in terms of function, participation, care, comfort and quality of life, particularly in the paediatric population.25 The responsiveness of dystonia to DBS treatment in CP is usually considered less beneficial than in patients with idiopathic or genetic dystonias, who have substantial improvement of motor symptoms and disability with pallidal stimulation.40,41 However, in the only two available comparative studies between genetic dystonia and CP, severity of dystonia was generally worse at baseline among patients with cerebral palsy
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ACCEPTED MANUSCRIPT than those with genetic dystonias, and patients with cerebral palsy presented with a baseline disability that was significantly more severe than patients with genetic dystonia.28,31 Differences between genetic dystonias and cerebral palsy in the response to GPi-DBS could be due to differences in pathophysiological mechanisms. 11 In inherited and idiopathic dystonias pathophysiological
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deficits include reduced inhibition at many levels of the motor system, including spinal cord, brainstem and motor cortex, enhanced synaptic plasticity and cerebellar deficits. 11,42 These deficits were not
demonstrated in dystonia caused by structural brain lesions. 43 Thus therapeutic interventions that could
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modify motor cortex plasticity might be less useful in patients with acquired dystonia due to cerebral palsy.
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43,44
The findings about treatment of speech and swallowing in CP are controversial and a clear benefit on these outcomes was reported in only two studies.27,34 Further studies, which consider the treatment of speech and swallowing impairment as primary outcome, are needed to define the effect of DBS on these relevant
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clinical problems.
Overall, we found cognitive measures stable or mildly improved in two studies. 34-36 Cognitive and psychiatric safety after bilateral pallidal stimulation is in keeping with earlier reports on idiopathic and
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symptomatic dystonia patients treated with DBS. 45-47 However, cognitive changes with transient deteriorations were previously reported in individual patients, 46 thus more studies are needed to identify
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predictors for postsurgical cognitive outcome. The data on DBS in dyskinetic CP patients have some limitations and important questions remain unanswered. Because of heterogeneity in outcome and lack of established eligibility criteria, selection of suitable patients is often difficult.39 On one side there is the question of the best timing for DBS implantation: CP patients have absent or reduced chance for a normal motor development and an early DBS may facilitate overcoming maladaptive neuroplasticity and learning processes. There was a significant negative correlation between severity of dystonia and clinical outcome;22 fixed skeletal deformities or cervical myelopathy are associated with a 10
ACCEPTED MANUSCRIPT poorer outcome. Moreover, the precise description of motor phenotype, radiological imagines and neurophysiological measurements contribute to identify prognostic factors for therapy response.38 A better outcome and further improvement probably can depend on the homogeneity of patients and procedures, as reported in a recent study.34
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On the other side, DBS in CP can be complicated by adverse events, transient, persistent, occurring during surgical procedures, device-related and stimulation-induced. The risk of adverse events due to DBS seems to be higher in paediatric patients than in adult, especially in patients aged less than 10 years,39 even
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though recently was reported a multistage surgical plan for paediatric CP patients undergoing DBS that helps to reduce the risk of infection.48 The safety issue could indicate the way for a post-implant
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management strategy in these patients. At last, data regarding disability, quality of life and pain are poor. Functional impairment in cerebral palsy is due to variable causes, regarding both dystonic and non-dystonic features, thus selection of candidates for DBS should be made focusing on specific goals, related to
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dystonia and potentially achievable, to increase the probability of success.
In summary, because of the large variability of the reported effect of the GPi DBS in patients effected by CP, it is of utmost importance the proper selection of candidates for this treatment, identifying those patients
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who are affected by prominent and disabling dystonia, without or with only minimal occurrence of other neurological manifestations, such as spasticity or ataxia.
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In conclusion, severity of dystonia influence surgery outcome, but the role of age at onset, duration of symptoms or age at time of surgery should be elucidated. For this reason, there is a need for more reliable markers that will help to accurately select CP patients who will benefit from DBS. There is a need for welldesign trials with a longer-term (5–10 years) follow up and an accurate data collection to increase knowledge on results in CP patients treated with DBS and to establish the clinical predictive factors of favourable outcome.
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Acknowledgment
numbers GR-2009-1594645 and GR-2009-1607326].
Conflict of Interest
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The authors declare that they have no conflict of interest.
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Authors were partly sustained (A.E.E., C.B., F.M.F, L.M.R.) by the Italian National Institutes of Health [grant
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ACCEPTED MANUSCRIPT
Vidailhet et al. 35 2009
Uncontrolled trial
Number of patients
Bilateral GPi
Mean age at surgery (years)
32.6 ±8.6 (range 20-44)
13
Follow up (months)
(High quality)
Outcome measures
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V: variable
BFMDRS-D
(range, 2-3.8 V)
SF-36 SCL-90
Case series #
(Moderate quality)
Bilateral GPi in 13 patients; unilateral GPi in 1 patient.
15 (14 evaluated, 1 patient required removal of hardware because of
BFMDRS-M: -24.3 ±21.1
BFMDRS-D: -13.3 ±31.1 PW: variable SF-36: 15 SCL-90: -34.9 F: 130 Hz
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32
Main results with dystonia score variation (%) at last FU
(range, 60-150 µs)
14.4 ±5.9 (range 7–26)
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Marks et al. 2011
Stimulation parameters**
BFMDRS-M
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#
Target
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Design
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Study (reference)
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Table 1 - Observational studies and trials evaluating bilateral GPi (±other brain targets) deep brain stimulation for patients affected by dystonic/dyskinetic cerebral palsy.
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BFMDRS-M
V: variable
BFMDRS-D
(range 2–6.5 V)
BFMDRS-M: -5.46 ±23.97
BADS PW: 210 µs
BFMDRS-D: -8.95 ±13.42
F: variable
BADS: -1.73 ±19.29
infection)
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(range, 30–185 Hz) 36
Bilateral GPi (group 1, 4 patients)
BFMDRS-M:
Case series
26.8 ±5.1 (range 18–37)
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Case series #
(Low quality)
Bilateral GPi plus unilateral Vo thalamotomy (group 2, 6 patients)
Bilateral GPi
31.8 ±24.9 (range 12– 86)
6
9.8 ±3.4 (range 513)
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V: 2.15 V BFMDRS-D:
BFMDRS-M
-14.3 for group 1 PW: 139.9 µs
BFMDRS-D
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(Low quality)
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#
BFMDRS-M: -31.5 for group 2 F: 95.9 Hz
BFMDRS-D: -0.18 for group 2 BFMDRS-M
Not reported
BFMDRS-M: -5.9 ±2.9
BFMDRS-D CPCHILD
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Gimeno et al. 25 2012
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BFMDRS-D: 0.5 ±4.5
PPP/NRS
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Kim et al. 2011 37 and 2012 , B
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-32.0 for group 1
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Kim et al. 2011 37 and 2012 , A
COPM
CPCHILD: -22.6 ±28.5
GAS PPP/NRS: Significant reduction in perceived pain
14
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31
Cohort
Bilateral GPi
#
11.02 ±3.09 (range 7.9-15.9)
37.12 ±12.05 (range 2156)
BFMDRS-M
GAS: In all cases at least 60% of GAS goals achieved V: Not reported
BFMDRS-M: -21.8 ±19.3
PW: Not reported
BFMDRS-D: -15.8 ±29.1
F: 76.7 ±34.1 Hz (range 30-135)
BADS:
BFMDRS-D BADS GMCS for ambulation
TE D
(Moderate quality)
12 (3 excluded because hardware removal due to infection or unilateral disease) compared with 8 patients with DYT1 dystonia
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Marks et al. 2013
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COPM: Clinically significant improvement
-15.8 ±15.4
33
Olaya et al. 2013
Case series #
(Low quality)
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EP
GMCS for ambulation:
Bilateral GPi (8 patients)
9
unchanged for the CP group
16.3 ±5.1 (range 6-20)
3.8 ±3.3 (range 0.5-9)
BFMDRS BADS
Bilateral GPi plus bilateral STN (1
Not reported
BFMDRS: -10.5 ±15.8
BADS:
15
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patient) Case series
Bilateral GPi
8.9 ±4.1 (range 3.5-18)
14
#
Case series
Kim et al. 2014
28
11.4 ±4.2 (range 8–17)
5
(Low quality)
Cohort
26.6 ±15.6 (range 2–42)
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#
Bilateral GPi
Bilateral GPi
#
Not reported
7 (compared with 5 patients affected by DYT1 or idiopathic dystonia)
COPM COPM: Significant improvement in individualised goal attainment
BFMDRS-M
V: variable
BADS
(range 1–4.7 V)
Case series #
Bilateral GPi
8
BADS: -16,3 ±12.5
BFMDRS: -27.9 ±13.2 PW: 120 µs
29.0 ±4.4 (range 21-34)
24
BFMDRS-M BFMDRS-D
Not reported
BFMDRS-M: -39.2 ±11.2
SSS BFMDRS-D: -0.5 ±6.6
AC C 29
Koy et al. 2014
BFMDRS-M: -3.5 ±7.9
F: 180 Hz
EP
(Moderate quality)
TE D
27
Keen et al. 2014
BFMDRS-M
RI PT
(Moderate quality)
8.9 ±3.9 (range 3.518.25)
SC
Gimeno et al. 26 2014
-7.9 ±12.1
SSS: decreased satisfaction 26.1 ±6.5 (range 16.1-33.8)
(Low quality)
16
44.5 ±27.2 (range 8-83)
AIMS
V: variable
BFMDRS-M
(range 1.2–3.8 V)
BFMDRS-M: -1.2 ±17.9
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BFMDRS-D
Cross sectional
Romito et al. 34 2015
Bilateral GPi
29.8 ±9.5 (range 15-47)
15
(Moderate quality)
Registry #
10
13.3 ±3.8 (range not available)
AC C
EP
(Moderate quality)
Bilateral GPi in 9 and VIM in 1 patient
TE D
30
Koy et al. 2017
52.8 ±21.6 (range 2484)
M AN U
#
SC
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PW: variable (range, 90-240 µs)
* Percentage improvement in primary outcome (motor score), mean (SD); ** Best stimulation parameters at last FU
17
2.3
BFMDRS-M
BFMDRS-D (difference between switched “on” and “off”): 4.2 ±11.8
F: 130 Hz
AIMS (difference between switched “on” and “off”): 3.7 ±20.1
V: 3.1 ±0.7 V
BFMDRS-M: -49.5 ±19.0
PW: 111.4 ±38.1 µs
BFMDRS-D: -32.6 ±18.4
F: 132.6 ±19.5 Hz
SF-36: 82.3 ±31.4
Wide spectrum of stimulation
BFMDRS-M: -14 (Mean postoperative
parameters (mean values: V: 2.7 V [range 1-6.5 V]; current: 3.0 mA [2.0-3.8], F: 133 Hz [60-210]; PW: 136 µs [60 -450]). The two ventralmost contacts were used in most GPi DBS patients
Improvement of 9.8 ±10.3)
BFMDRS-D SF-36
BFMDRS-M
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Abbreviations: GPi, Globus Pallidus Internus; BFMDRS, Burke-Fahn-Marsden Dystonia Rating Scale; BFMDRS-M, BFMDRS-Motor scale; BFMDRS-D, BFMDRS-Disability scale; SF-36, 36-Item Short Form Survey; SCL-90, Symptom Checklist-90; BADS, Behavioural Assessment of the Dysexecutive Syndrome; CPCHILD, Caregiver Priorities and Child Health Index of Life with Disabilities questionnaire; PPP/NRS, Paediatric Pain Profile/ Numerical Rating Scale; COPM, Canadian Occupational Performance Measure; GAS, Goal Attainment Scaling; GMCS for ambulation, Gross Motor Functional Classification System for ambulation; SSS, Subjective satisfaction scale; AIMS, Abnormal involuntary movement scale; UDRS, Unified Dystonia Rating Scale. V, Voltage; PW, Pulse width; F, Frequency.
EP
TE D
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SC
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Levels of evidence are adapted from EFNS guidance and GRADE system. 49
AC C
#
18
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Table 2. Adverse events reported in bilateral GPi (±other brain targets) DBS studies on dystonic CP.
Vidailhet et al. 2009
Adverse events
35
Number of dropped out
Worsening of dystonia (n = 4), deterioration after 1 year/cervical myelopathy (n = 1), sub-clavicular pain (n = 1), stimulation
32
Infection (n = 1)
36
37
Kim et al. 2011 and 2012 25
31
Infection (3)
33
Olaya et al. 2013
Gimeno et al. 2014
Not reported
TE D
Marks et al. 2013
Dysarthria, hemiparesis (n = 3)
Not reported 26
27
Infections (n = 2)
0 3
0 2
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Keen et al. 2014
Not reported
0
0
EP
Gimeno et al. 2012
1
M AN U
Marks et al. 2011
0
SC
arrest/magnetic field (n = 1)
RI PT
Study (reference)
28
Not reported
29
Revision of the electrodes because of hardware breakage (n = 1)
0
Fever (2), seizure (1), spasms of pharynx (1), dysphagia and
0
Kim et al. 2014 Koy et al. 2014
34
Romito et al. 2015
0
hypophonia (1), hypophonia (1), dysarthria (4), local pain (2),
19
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paraesthesia (2), muscular strain (1), visual disturbance (1), extracranial lead damage (1), sub-clavear seroma (1), unexplained
hardware infection (1), death for acute cardiac failure (1) Not reported (authors reported 42 adverse events reported in a
Not reported (authors reported 13 dropped out among a whole series of 44 patients, 10 of them affected by CP)
EP
TE D
M AN U
SC
whole series of 44 patients, 10 of them affected by CP)
AC C
30
Koy et al. 2017
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implantable pulse generator switching-off (1), lead migration (1),
20
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AC C
EP
TE D
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SC
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Figure 1. BFMRS-Motor scales variations in the individual studies on bilateral GPi (±other brain targets) deep brain stimulation in cerebral palsy. Negative values represent improvement. Standard error bars are showed.
21
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AC C
EP
TE D
M AN U
SC
RI PT
Figure 2. BFMRS-Disability scale variations in the individual studies on bilateral GPi (±other brain targets) deep brain stimulation in cerebral palsy. Negative values represent improvement. Standard error bars are showed.
22
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