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Deep anterior cerebellar stimulation reduces symptoms of secondary dystonia in patients with cerebral palsy treated due to spasticity
Clinical Neurology and Neurosurgery 135 (2015) 62–68
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Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Deep anterior cerebellar stimulation reduces symptoms of secondary dystonia in patients with cerebral palsy treated due to spasticity a ´ Paweł Sokal a,∗ , Marcin Ruda´s a , Marek Harat b , Łukasz Szylberg c , Piotr Zielinski a
Department of Neurosurgery, 10th Military Research Hospital, Powstancow Warszawy 5, 85-681 Bydgoszcz, Poland Faculty of Health Sciences, Nicolaus Copernicus University, Jagielonska 13, 85-067 Bydgoszcz, Poland c Department of Pathology, Nicolaus Copernicus University, Jagielonska 13, 85-067 Bydgoszcz, Poland b
a r t i c l e
i n f o
Article history: Received 23 November 2014 Received in revised form 2 May 2015 Accepted 16 May 2015 Available online 23 May 2015 Keywords: Cerebellar neurostimulation Cerebral palsy Spasticity Dystonia
a b s t r a c t Introduction: Deep anterior cerebellar stimulation (DACS) is a neuromodulation therapy of spasticity. Bilateral DACS is applied in young patients with cerebral palsy (CP). In these patients symptoms of spasticity coexist with symptoms of focal or segmental dystonia, which can cause chronic pain. We performed the study to investigate the therapeutic effects of DACS in spasticity, secondary dystonia and pain. Methods: We examined 10 from 13 patients with CP treated with DACS due to spasticity in years 2006–2012. We compared Ashworth scores of spasticity, VAS scale of pain and UDRS (Unified Dystonia Rating Scale) score before DACS and after it in follow-up lasting from 2 to 11 years it in these patients basing on clinical examination and evaluating forms given by the patients or parents. Results: We received statistically significant reduction of spasticity in upper extremities (median: from 3 to 1,5 in Ashworth scale) in 8 patients (p = 0,01), in lower extremities in 7 patients (median: from 3 to 1,75) (p = 0,02). Symptoms of focal dystonia were reduced. Total score for the UDRS (median = 18,0 before surgery) after DACS decreased significantly (median = 10,3) (p = 0,043). Change in consecutive parts of UDRS before (median = 1,6) and after (median = 1,0) surgery in 7 patients had statistical significance (p = 0,0179). There were not significant changes in intensity of pain before and after surgery (p = 0,108). Discussion: Chronic bilateral DACS aimed for spasticity treatment not only decreases muscular tone in quadriplegic or paraplegic patients with CP but also is associated with reduction of symptoms of focal or segmental, secondary dystonia. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Cerebral palsy (CP) is a relatively rare condition (affecting approximately 2–3 in every 1,000 live births) [1,2]. Dystonic CP is caused by damage to the basal ganglia or cerebellum and causes symptoms such as involuntary movements and muscle spasms. It is estimated that dyskinetic CP has a prevalence of 0.27 per 1000 live births [3]. Dystonic forms with choreoathosis are met in up to 15% of patients with CP [1,4]. Patients with this type of CP have symptoms of spasticity which coexist with symptoms of focal or segmental dystonia. Pharmacological treatment of dystonic movements is unsatisfactory and is burden with side effects [5]. Surgical therapy for the secondary dystonias is generally perceived to be less effective than for primary disease [5–7]. In secondary dystonia effects of neurostimulation can be low [8–10]. Deep brain stimulation (DBS) of the globus pallidus internus (GPi)
∗ Corresponding author. Tel.: +48 523787093; fax: +48 523787094. E-mail address: [email protected] (P. Sokal). http://dx.doi.org/10.1016/j.clineuro.2015.05.017 0303-8467/© 2015 Elsevier B.V. All rights reserved.
has been described to be an effective and safe treatment in patients with primary generalized dystonia [11]. GPi stimulation is currently the mainstay surgical treatment for patients with dystonia, particularly for generalized dystonia [12,13]. In general in patients with primary dystonia, the improvement in Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) has been reported to be of 40–70% after GPi DBS, but in patients with secondary dystonia, the improvement in the BFMDRS has been reported to be of 10.6–41% [8,11,12]. Patients with secondary dystonia due to previous perinatal insults showed a mean improvement in BFMDRS of 41.9%, with better results in purely dyskinetic patients (mean improvement of 61.2%) [14]. Bilateral pallidal stimulation can also be an effective treatment in adult patients with dystonia-choreathosis CP [15]. DBS of GPi can produce 23.6% mean improvement in movement component of BFMDRS and 9,2% in disability component of BFMDRS in patients with dyskinetic CP according to results of meta-analysis recently published [16]. In the 1972 the electrical stimulation of the cerebellar cortex was used for the first time to treat abnormal motor disorders,
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Table 1 Characteristics of patients and results of Ashworth and VAS scores. Follow-up in years, age in years. No.
1 2 3 4 5 6 7 8 9 10
Initials
E.O E.K D.M E.Ł B.W E.Z J.M S.K A.O K.M
Sex
F F M F M F F M F F
Age
18 22 30 27 26 26 28 27 17 26
Follow-up
10 10 2 6 4 5 6 11 3 3
Ashworth before
Ashworth after
Upper
Lower
Upper
3 2 3 3 1 3 3 4 3 2
2 2 3 3 2 3 3 3 4 2
but with varying degrees of success. Cooper treated patients with muscular hypertonia in CP with the anterior lobe of cerebellum stimulation [17]. Several hundred patients with spasticity (mainly from CP) were operated in various centres by cortical cerebellar stimulation in the seventies [18–21]. Rose Davis, who has performed more than 600 operations, presented results of the cerebellar cortex stimulation and concluded that cerebellar stimulation reduces spasticity diminishing of hypertonus in muscles, co-contractions, spasms and athetoid movements in 85% of CP patients with various degree (marked 25%, moderate 34%) [20]. Schvarcz et al. reported positive effects of cerebellar dentate nucleus stimulation on spasticity, improvement in balance and posture of the patient [22]. High-frequency stimulation of the anterior lobe of the cerebellum was introduced by Galanda and has been designated as a neuromodulative method of treatment of spasticity. Instead of paddle type cortical electrodes, cylindrical ones for deep brain stimulation were placed in the region of the superior cerebellar peduncle. Intermittent stimulation was performed to decrease muscle tonus and general relaxation. As a result improvement in choreoathosis, in speech and mood was also observed [23,24]. Experience of Galanda et al. in treatment of CP with stereotactic stimulation of the anterior lobe of the cerebellum prompted us to conduct the study on the clinical effects of this method in diminishing symptoms of spasticity, secondary dystonia and pain. We introduced this method in 2003 in patients with CP. The study was performed to investigate the effects of DACS, in particular therapeutic effects in dystonic symptoms in these patients [25]. 2. Material and methods We examined 10 from 13 patients with CP treated with DACS in whom symptoms of focal or segmental dystonia occured. Three patients were excluded due to early postoperative infection in site of implantation. Retrospectively we scored them basing on the examination and interview of patients or their parents. A total 10 patients (3 men) were enrolled into the study with median age 26 (range 18–30) at the time of inclusion. Observational period lasted from 1 to 6 years (median 5,5) (Table 1). After ethics committee approval procedures of implantation of two electrodes into the anterior lobe of the cerebellum were conducted under general anaesthesia. Stereotactic frame was fixed to the head of patient and two burr holes were made in occipital area. Electrodes for DBS were implanted according to plan executed on MRI scans. Intraoperative CT was performed in an operating room before the surgery. CT scans were fused with MRI plan, then coordinates for stereotactic procedure were calculated. The planning of the operation was performed using a fusion CT/MRI (BrainLAB stereotactic frame and software) (Fig. 1). The quadripolar electrodes were implanted from the both sides. The enter points were placed in the suboccipital area below the transversus sinuses. Pulse generator (Activa
1,5 1,5 1,5 2 1 1 0 3 2 2
VAS
Lower 2 1,5 1,5 2 1,5 1 0 3 3 2
Before
After
Pain area
5 2 3 0 0 0 10 n/d n/d 8
4 2 1 0 0 0 0 n/d 1 8
Knees Knee hip Knee n/d n/d n/d Hands feet n/d Thighs Back
Kinetra, Medtronic, USA) or (Libra XP, St.Jude Medical, USA) was usually localized in subclavian area where extentions connecting to electrodes were inserted. Evaluation of the localization of the electrodes was performed intraoperatively with CT imaging in an operating room during the same procedure or after implantation the electrodes in the radiological department. We used two electrodes and bipolar intermittent (on 30 min, off 3,5 h) stimulation: the initial parameters of the stimulation were usually as follows: amplitude: 1,4–2,4 V; pulse width: 150–180 s; rate: 130 Hz; polarisation: 0 and 4 minus, 3 and 7 plus. We measured the results of muscle tone in Ashworth scale, involuntary movements in Unified Dystonia Rating Scale UDRS, and pain in VAS score before surgery and at the end of follow-up. UDRS consists of 11 components: subscales with scores from 0 (lack of involuntary movements) to 4 (the highest intensity of movements) on each. These components are duration of symptoms, intensity of symptoms in face, eyes, jaw, larynx, neck, shoulder, hand, trunk, pelvis and foot. We asked parents or caregivers to assess the effects of this treatment and fill out the forms with these scales. 2.1. Statistical analysis All statistical analyses were performed using Statistica version 10 (StatSoft) and Microsoft Excel 2007. The distribution of results differed from the normal distribution, the correlation analysis of the data was performed using the nonparametric Spearman’s test, and the comparative studies were analysed statistically using the nonparametric Mann–Whitney U test. To confirm the significance of differences between related variables the nonparametric Wilcoxon test was used. The p value <0,05 was considered statistically significant. 3. Results Spasticity in upper extremities measured in Ashworth scale decreased significantly (p = 0,01) in 8 patients (from median 3,0 to 1,5) (Fig. 2), in lower extremities spasticity was reduced in 7 patients (p = 0,01) (from median 3,0 to 1,75) (Fig. 3). We also noticed that reduction of spasticity was more expressed in elder patients over 26 years: in upper and lower extremities was 30% in comparison to patients younger than 26 years where the percentage of reduction was respectively 20 and 10%. There were not significant changes in intensity of pain before and after surgery (p = 0,108). Total score for the UDRS (median = 18,0 before surgery) after DACS decreased significantly (median = 10,3) (p = 0,043) (Fig. 4a). The most dominant and significant change in UDRS was observed in reduction of involuntary movements in neck, in hand, in pelvis and in duration of these symptoms (Table 2). Change in consecutive parts of UDRS before (median = 1,6) and after (median = 1,0) surgery in 7 patients had statistical significance in Wilcoxon test (p = 0,018) (Fig. 4b). In 3 patients we did not observed reduction of
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Fig. 1. (a–c) The target was set on in the deep region of anterior lobe in the midline sagittal section 8 mm from the fastigium rostrally, parallel to the floor of the 4th ventricle, then the target was moved 2 mm laterally from the midline.
dystonic symptoms, in 2 others improvement was nearly marked, but in 7 patients (70%) decrease in intensity of dystonia measured in UDRS was significant ranging from 13,6% to 35% (mean 18,9%) including 5 patients (50%) with mean reduction of 25,4%. There was no correlation of the outcome measured in UDRS with the sex of patient (p = 0,49) nor the age (p = 0,5) and longevity of follow–up (p = 0,18). To summarize in one half of patients symptoms of secondary dystonia were reduced over one fourth. 3.1. Complications We have had 3 infectious complications after stimulator implantation, which were the reason of removal the stimulating system. 4. Discussion DACS serves for treatment of spasticity [24,25]. During 10 years experience we have noticed beneficial effects of DACS
associated with the reduction of symptoms of dyskinetic forms of CP. Evaluation of the questionnaires sent to parents revealed interesting findings. Basing on these results we received reduction of muscle tone measured in Ashworth scale in upper and lower extremities and a significant decrease in involuntary movements determined in UDRS. In some patients pain relief was also noted. Outcome of functional surgery in dystonia can be measured with BFMDRS movement score, in Unified Dystonia Rating Score or in Global Dystonia Rating Scale [16,26]. To facilitate the evaluation forms with have chosen the second one. The reliability of BFMDRS and UDRS is similar [27]. In patients with mixed movement disorders, BFMDRS has low sensitivity to hyperkinetic movements in limbs [16]. The important advantage of this study is the fact that the assessment was predominantly done by parents and caregivers who are very critical in regard of effects of medical management, and who spend long hours with these patients and present objective opinion. This study has limitation: the small number of subjects,
Table 2 Percentage of reduction of symptoms, and amount of patients with this reduction in consecutive components of UDRS. Neck No. of patiens % reduction
5 45,0
Duration 5 40,0
Hand
Pelvis
5 40,0
4 37,5
Shoulder 4 31,3
Eyes
Face
4 25,0
3 33,3
Foot 3 33,3
Trunk 3 25,0
Jaw 3 25,0
Larynx 2 37,5
P. Sokal et al. / Clinical Neurology and Neurosurgery 135 (2015) 62–68
Fig. 2. (a) Reduction of spasticity in upper extremities measured in Ashworth scale. (b) Changes in spasticity in upper extremities in 10 consecutive patients.
non-homogenous group of patients (segmental or focal form of dystonia with different intensity) and no predetermined data collection with different observational period. DACS is reversible and not ablative procedure. Bilateral or unilateral DACS is a stereotactically guided implantation of electrodes with minimal invasiveness. It produces substantial improvement in spasticity, diminishing of pain and reduction of involuntary movements and disability in patients with CP. The reduction of spasticity is crucial in effective motor rehabilitation and gives the chance to mobilize the bedridden patients. The important disadvantage of this procedure is a high risk of infection in the place of the wound where electrode was inserted. The occipital area with wounds is predominantly threatened with the pressure of the head in patients with spasticity and retrocollis. DACS has to influence on cerebello-cortical tract which tonizes pyramidal and afferent tracts leading to reduction of muscular tone in extremities. The stimulation of the cerebellar cortex of the anterior lobe produces release from spasticity by electric stimulation acting through orthodromic excitation of Purkinje cells, via antidromic activation of the brain stem and the spinal neurons
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Fig. 3. (a) Reduction of spasticity in lower extremities measured in Ashworth scale. (b) Changes in spasticity in lower extremities in 10 consecutive patients.
with axons terminating in the cortex [24]. In children with CP more complex mechanism could be responsible for spasticity associated with symptoms of dystonia. Basing on studies conducted in the seventies Davies attained different grades of reduction in spasticity in 85% from 600 patients with cerebellar stimulation and in two thirds of them marked improvement in athetoid movements occurrence [20]. Chronic cerebellar stimulation of the cortex of the anterior lobe was also effective in intractable epilepsy [17,20]. Electrode pads were placed over the bilateral superior-medial cortices of the cerebellum (paleocerebellum) parasagitally through the bilateral enlarged, occipital burr holes [20]. In cerebellar cortical stimulation only around 15% of the surface of the cortex was accessible for stimulation due to large sulcal surface and electrodes were migrating [24]. In order to potentiate the effects produced by cortical stimulation of the anterior lobe of the cerebellum and to reduce the risk of electrode dislocation, Galanda introduced the method of deep cerebellar stimulation of the region of the superior cerebellar peduncle. The targets are situated in the deep region of the anterior lobe in white matter in the midline sagittal section 8 mm from the fastigium rostrally, parallel to the floor of the 4th ventricle, 2 mm laterally from the midline. Instead of cortical surface, subcortical structures of the
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Fig. 4. (a) Changes in total UDRS p = 0,04. (b) Changes in median values of components of UDRS p = 0,018.
anterior lobe are stimulated where the majority of pathway fibers pass out from subcortical nuclei toward the brainstem (Fig. 1 and Fig. 5). Multiple efferents from these nuclei projects to the basal ganglia which in turn project to the neocortical areas of cerebral cortex influencing on generation and control of movements [28]. Galanda observed that apart from the immediate reduction of spasticity a gradual improvement in choreoathethoid movements after several days or weeks. Other functions as speech, swallowing and posture were also improved [24]. Cerebellum plays important role in the etiology of dystonia [33]. Pathophysiology of dystonia is associated with dysfunction of the cerebellum in the cortico-ponto-cerebello-thalamo-cortical loop [34]. Dystonia may arise from abnormal communication between nodes in the network consisting of motor cortex, basal ganglia, brainstem and cerebellum or dysfunction of two nodes in this
Fig. 5. (a and b) Post op X-ray images (A-P and lateral) with deep cerebellar electrodes pointed out with arrows.
network [33]. The reorganization of neural circuits in basal ganglia and cerebellum might be involved in disinhibition of motor cortical activity causing dystonic movements. The cerebellum exerts also an inhibitory effect on the thalamus and the cerebral cortex through the synaptic action of Purkinje cells and its efferent fibers traveling via the superior cerebellar peduncle what plays substantial a role in antiepileptic activity during cerebellar stimulation. Cerebellum has inhibitory effect on basal ganglia through reticular formation
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and leads to decreased activity of thalamocortical projections [35]. Temporal attenuation of dystonic symptoms one can achieve with transcranial stimulation of the cerebellum or with the use of transcranial direct current stimulation what effects on cerebellar-brain inhibition [36,37]. Patients with CP constitute heterogeneous group in terms of age, the extent of brain damage, etiology and advancement of movement disorder. The most prominent symptoms are paresis, spasticity and involuntary movements. The term secondary dystonia refers to symptoms which occur with another recognizable disorder as in the course of CP. Treatment of secondary dystonia in CP is difficult. Classical targets for lesional surgery of dystonic symptoms in CP were thalamus and internal segment of globus pallidus and dental nuclei of the cerbellum. Results were disappointing [29]. According to Martinez patients in the CP group should receive an ITB (Intrathecal Baclofen) trial as a first step, continuing progressively higher doses. Patients not responding to the ITB trial should be treated with DBS. When a tonic component predominates, GPi is the first target [14]. According to Marks et al. DBS may offer an effective treatment option for cerebral palsy-related dystonia, especially in those treated before skeletal maturity [30]. Trials with combined stereotactic treatment (stimulation and lesioning) were also positive [31]. Bilateral pallidal stimulation is the most commonly chosen neuromodulative method but the outcome is variable [7,32]. Metaanalysis on efficacy of deep brain stimulation mostly in dyskinetic CP conducted by Koy revealed positive moderate but significant effects of GPi stimulation of 64 patients. The other targets were STN (subthalamic nucleus) or VIM (ventral-intermediate nucleus). This meta-analysis did not show correlation between age of the patient and the outcome whereas there was a strong negative correlation between severity of symptoms and outcome. Severity of symptoms decreased 23% considering comparison of BFMDRS score before and 12 month after surgery. Suboptimal effects of pallidal stimulation in the secondary dystonia especially in CP are associated with the presence of irreversible, focal brain lesions and striatal or pallidal atrophy occurring in the course of neurodegenerative or ischemic processes [32]. In patients with dystonic form of CP after bilateral GPi stimulation the improvement ranges from 21% to 55% in over 60% of patients in <20% there is little benefit and in −7.4% deterioration [15]. Our study shows that DACS is not only a neuromodulation therapy of spasticity but also has a great impact on dystonic movements in patients with CP. In our opinion patients with CP who have predominant symptoms of spasticity with the presence of secondary dystonia should be candidates for DACS while the cases with involuntary, dyskinetic movements without severe muscle hypertonia are amenable for pallidal stimulation. This is a preliminary study. The more detailed investigation is necessary to elucidate therapeutic mechanism of DACS to prove the feasibility of this method in patients with dystonia and CP.
5. Conclusions The results of DACS are encouraging. Chronic bilateral DACS aimed for spasticity treatment not only decreases muscular tone in quadriplegic or paraplegic patients with CP but also is associated with reduction of symptoms of focal or segmental, secondary dystonia. Significant arguments for consideration of DACS in the treatment of CP are suboptimal effects of pallidal stimulation in secondary dystonia in CP and coexistence of spasticity and
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involuntary movements in patients with CP. This method helps to reduce both symptoms.
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Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Deep anterior cerebellar stimulation reduces symptoms of secondary dystonia in patients with cerebral palsy treated due to spasticity a ´ Paweł Sokal a,∗ , Marcin Ruda´s a , Marek Harat b , Łukasz Szylberg c , Piotr Zielinski a
Department of Neurosurgery, 10th Military Research Hospital, Powstancow Warszawy 5, 85-681 Bydgoszcz, Poland Faculty of Health Sciences, Nicolaus Copernicus University, Jagielonska 13, 85-067 Bydgoszcz, Poland c Department of Pathology, Nicolaus Copernicus University, Jagielonska 13, 85-067 Bydgoszcz, Poland b
a r t i c l e
i n f o
Article history: Received 23 November 2014 Received in revised form 2 May 2015 Accepted 16 May 2015 Available online 23 May 2015 Keywords: Cerebellar neurostimulation Cerebral palsy Spasticity Dystonia
a b s t r a c t Introduction: Deep anterior cerebellar stimulation (DACS) is a neuromodulation therapy of spasticity. Bilateral DACS is applied in young patients with cerebral palsy (CP). In these patients symptoms of spasticity coexist with symptoms of focal or segmental dystonia, which can cause chronic pain. We performed the study to investigate the therapeutic effects of DACS in spasticity, secondary dystonia and pain. Methods: We examined 10 from 13 patients with CP treated with DACS due to spasticity in years 2006–2012. We compared Ashworth scores of spasticity, VAS scale of pain and UDRS (Unified Dystonia Rating Scale) score before DACS and after it in follow-up lasting from 2 to 11 years it in these patients basing on clinical examination and evaluating forms given by the patients or parents. Results: We received statistically significant reduction of spasticity in upper extremities (median: from 3 to 1,5 in Ashworth scale) in 8 patients (p = 0,01), in lower extremities in 7 patients (median: from 3 to 1,75) (p = 0,02). Symptoms of focal dystonia were reduced. Total score for the UDRS (median = 18,0 before surgery) after DACS decreased significantly (median = 10,3) (p = 0,043). Change in consecutive parts of UDRS before (median = 1,6) and after (median = 1,0) surgery in 7 patients had statistical significance (p = 0,0179). There were not significant changes in intensity of pain before and after surgery (p = 0,108). Discussion: Chronic bilateral DACS aimed for spasticity treatment not only decreases muscular tone in quadriplegic or paraplegic patients with CP but also is associated with reduction of symptoms of focal or segmental, secondary dystonia. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Cerebral palsy (CP) is a relatively rare condition (affecting approximately 2–3 in every 1,000 live births) [1,2]. Dystonic CP is caused by damage to the basal ganglia or cerebellum and causes symptoms such as involuntary movements and muscle spasms. It is estimated that dyskinetic CP has a prevalence of 0.27 per 1000 live births [3]. Dystonic forms with choreoathosis are met in up to 15% of patients with CP [1,4]. Patients with this type of CP have symptoms of spasticity which coexist with symptoms of focal or segmental dystonia. Pharmacological treatment of dystonic movements is unsatisfactory and is burden with side effects [5]. Surgical therapy for the secondary dystonias is generally perceived to be less effective than for primary disease [5–7]. In secondary dystonia effects of neurostimulation can be low [8–10]. Deep brain stimulation (DBS) of the globus pallidus internus (GPi)
∗ Corresponding author. Tel.: +48 523787093; fax: +48 523787094. E-mail address: [email protected] (P. Sokal). http://dx.doi.org/10.1016/j.clineuro.2015.05.017 0303-8467/© 2015 Elsevier B.V. All rights reserved.
has been described to be an effective and safe treatment in patients with primary generalized dystonia [11]. GPi stimulation is currently the mainstay surgical treatment for patients with dystonia, particularly for generalized dystonia [12,13]. In general in patients with primary dystonia, the improvement in Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) has been reported to be of 40–70% after GPi DBS, but in patients with secondary dystonia, the improvement in the BFMDRS has been reported to be of 10.6–41% [8,11,12]. Patients with secondary dystonia due to previous perinatal insults showed a mean improvement in BFMDRS of 41.9%, with better results in purely dyskinetic patients (mean improvement of 61.2%) [14]. Bilateral pallidal stimulation can also be an effective treatment in adult patients with dystonia-choreathosis CP [15]. DBS of GPi can produce 23.6% mean improvement in movement component of BFMDRS and 9,2% in disability component of BFMDRS in patients with dyskinetic CP according to results of meta-analysis recently published [16]. In the 1972 the electrical stimulation of the cerebellar cortex was used for the first time to treat abnormal motor disorders,
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Table 1 Characteristics of patients and results of Ashworth and VAS scores. Follow-up in years, age in years. No.
1 2 3 4 5 6 7 8 9 10
Initials
E.O E.K D.M E.Ł B.W E.Z J.M S.K A.O K.M
Sex
F F M F M F F M F F
Age
18 22 30 27 26 26 28 27 17 26
Follow-up
10 10 2 6 4 5 6 11 3 3
Ashworth before
Ashworth after
Upper
Lower
Upper
3 2 3 3 1 3 3 4 3 2
2 2 3 3 2 3 3 3 4 2
but with varying degrees of success. Cooper treated patients with muscular hypertonia in CP with the anterior lobe of cerebellum stimulation [17]. Several hundred patients with spasticity (mainly from CP) were operated in various centres by cortical cerebellar stimulation in the seventies [18–21]. Rose Davis, who has performed more than 600 operations, presented results of the cerebellar cortex stimulation and concluded that cerebellar stimulation reduces spasticity diminishing of hypertonus in muscles, co-contractions, spasms and athetoid movements in 85% of CP patients with various degree (marked 25%, moderate 34%) [20]. Schvarcz et al. reported positive effects of cerebellar dentate nucleus stimulation on spasticity, improvement in balance and posture of the patient [22]. High-frequency stimulation of the anterior lobe of the cerebellum was introduced by Galanda and has been designated as a neuromodulative method of treatment of spasticity. Instead of paddle type cortical electrodes, cylindrical ones for deep brain stimulation were placed in the region of the superior cerebellar peduncle. Intermittent stimulation was performed to decrease muscle tonus and general relaxation. As a result improvement in choreoathosis, in speech and mood was also observed [23,24]. Experience of Galanda et al. in treatment of CP with stereotactic stimulation of the anterior lobe of the cerebellum prompted us to conduct the study on the clinical effects of this method in diminishing symptoms of spasticity, secondary dystonia and pain. We introduced this method in 2003 in patients with CP. The study was performed to investigate the effects of DACS, in particular therapeutic effects in dystonic symptoms in these patients [25]. 2. Material and methods We examined 10 from 13 patients with CP treated with DACS in whom symptoms of focal or segmental dystonia occured. Three patients were excluded due to early postoperative infection in site of implantation. Retrospectively we scored them basing on the examination and interview of patients or their parents. A total 10 patients (3 men) were enrolled into the study with median age 26 (range 18–30) at the time of inclusion. Observational period lasted from 1 to 6 years (median 5,5) (Table 1). After ethics committee approval procedures of implantation of two electrodes into the anterior lobe of the cerebellum were conducted under general anaesthesia. Stereotactic frame was fixed to the head of patient and two burr holes were made in occipital area. Electrodes for DBS were implanted according to plan executed on MRI scans. Intraoperative CT was performed in an operating room before the surgery. CT scans were fused with MRI plan, then coordinates for stereotactic procedure were calculated. The planning of the operation was performed using a fusion CT/MRI (BrainLAB stereotactic frame and software) (Fig. 1). The quadripolar electrodes were implanted from the both sides. The enter points were placed in the suboccipital area below the transversus sinuses. Pulse generator (Activa
1,5 1,5 1,5 2 1 1 0 3 2 2
VAS
Lower 2 1,5 1,5 2 1,5 1 0 3 3 2
Before
After
Pain area
5 2 3 0 0 0 10 n/d n/d 8
4 2 1 0 0 0 0 n/d 1 8
Knees Knee hip Knee n/d n/d n/d Hands feet n/d Thighs Back
Kinetra, Medtronic, USA) or (Libra XP, St.Jude Medical, USA) was usually localized in subclavian area where extentions connecting to electrodes were inserted. Evaluation of the localization of the electrodes was performed intraoperatively with CT imaging in an operating room during the same procedure or after implantation the electrodes in the radiological department. We used two electrodes and bipolar intermittent (on 30 min, off 3,5 h) stimulation: the initial parameters of the stimulation were usually as follows: amplitude: 1,4–2,4 V; pulse width: 150–180 s; rate: 130 Hz; polarisation: 0 and 4 minus, 3 and 7 plus. We measured the results of muscle tone in Ashworth scale, involuntary movements in Unified Dystonia Rating Scale UDRS, and pain in VAS score before surgery and at the end of follow-up. UDRS consists of 11 components: subscales with scores from 0 (lack of involuntary movements) to 4 (the highest intensity of movements) on each. These components are duration of symptoms, intensity of symptoms in face, eyes, jaw, larynx, neck, shoulder, hand, trunk, pelvis and foot. We asked parents or caregivers to assess the effects of this treatment and fill out the forms with these scales. 2.1. Statistical analysis All statistical analyses were performed using Statistica version 10 (StatSoft) and Microsoft Excel 2007. The distribution of results differed from the normal distribution, the correlation analysis of the data was performed using the nonparametric Spearman’s test, and the comparative studies were analysed statistically using the nonparametric Mann–Whitney U test. To confirm the significance of differences between related variables the nonparametric Wilcoxon test was used. The p value <0,05 was considered statistically significant. 3. Results Spasticity in upper extremities measured in Ashworth scale decreased significantly (p = 0,01) in 8 patients (from median 3,0 to 1,5) (Fig. 2), in lower extremities spasticity was reduced in 7 patients (p = 0,01) (from median 3,0 to 1,75) (Fig. 3). We also noticed that reduction of spasticity was more expressed in elder patients over 26 years: in upper and lower extremities was 30% in comparison to patients younger than 26 years where the percentage of reduction was respectively 20 and 10%. There were not significant changes in intensity of pain before and after surgery (p = 0,108). Total score for the UDRS (median = 18,0 before surgery) after DACS decreased significantly (median = 10,3) (p = 0,043) (Fig. 4a). The most dominant and significant change in UDRS was observed in reduction of involuntary movements in neck, in hand, in pelvis and in duration of these symptoms (Table 2). Change in consecutive parts of UDRS before (median = 1,6) and after (median = 1,0) surgery in 7 patients had statistical significance in Wilcoxon test (p = 0,018) (Fig. 4b). In 3 patients we did not observed reduction of
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Fig. 1. (a–c) The target was set on in the deep region of anterior lobe in the midline sagittal section 8 mm from the fastigium rostrally, parallel to the floor of the 4th ventricle, then the target was moved 2 mm laterally from the midline.
dystonic symptoms, in 2 others improvement was nearly marked, but in 7 patients (70%) decrease in intensity of dystonia measured in UDRS was significant ranging from 13,6% to 35% (mean 18,9%) including 5 patients (50%) with mean reduction of 25,4%. There was no correlation of the outcome measured in UDRS with the sex of patient (p = 0,49) nor the age (p = 0,5) and longevity of follow–up (p = 0,18). To summarize in one half of patients symptoms of secondary dystonia were reduced over one fourth. 3.1. Complications We have had 3 infectious complications after stimulator implantation, which were the reason of removal the stimulating system. 4. Discussion DACS serves for treatment of spasticity [24,25]. During 10 years experience we have noticed beneficial effects of DACS
associated with the reduction of symptoms of dyskinetic forms of CP. Evaluation of the questionnaires sent to parents revealed interesting findings. Basing on these results we received reduction of muscle tone measured in Ashworth scale in upper and lower extremities and a significant decrease in involuntary movements determined in UDRS. In some patients pain relief was also noted. Outcome of functional surgery in dystonia can be measured with BFMDRS movement score, in Unified Dystonia Rating Score or in Global Dystonia Rating Scale [16,26]. To facilitate the evaluation forms with have chosen the second one. The reliability of BFMDRS and UDRS is similar [27]. In patients with mixed movement disorders, BFMDRS has low sensitivity to hyperkinetic movements in limbs [16]. The important advantage of this study is the fact that the assessment was predominantly done by parents and caregivers who are very critical in regard of effects of medical management, and who spend long hours with these patients and present objective opinion. This study has limitation: the small number of subjects,
Table 2 Percentage of reduction of symptoms, and amount of patients with this reduction in consecutive components of UDRS. Neck No. of patiens % reduction
5 45,0
Duration 5 40,0
Hand
Pelvis
5 40,0
4 37,5
Shoulder 4 31,3
Eyes
Face
4 25,0
3 33,3
Foot 3 33,3
Trunk 3 25,0
Jaw 3 25,0
Larynx 2 37,5
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Fig. 2. (a) Reduction of spasticity in upper extremities measured in Ashworth scale. (b) Changes in spasticity in upper extremities in 10 consecutive patients.
non-homogenous group of patients (segmental or focal form of dystonia with different intensity) and no predetermined data collection with different observational period. DACS is reversible and not ablative procedure. Bilateral or unilateral DACS is a stereotactically guided implantation of electrodes with minimal invasiveness. It produces substantial improvement in spasticity, diminishing of pain and reduction of involuntary movements and disability in patients with CP. The reduction of spasticity is crucial in effective motor rehabilitation and gives the chance to mobilize the bedridden patients. The important disadvantage of this procedure is a high risk of infection in the place of the wound where electrode was inserted. The occipital area with wounds is predominantly threatened with the pressure of the head in patients with spasticity and retrocollis. DACS has to influence on cerebello-cortical tract which tonizes pyramidal and afferent tracts leading to reduction of muscular tone in extremities. The stimulation of the cerebellar cortex of the anterior lobe produces release from spasticity by electric stimulation acting through orthodromic excitation of Purkinje cells, via antidromic activation of the brain stem and the spinal neurons
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Fig. 3. (a) Reduction of spasticity in lower extremities measured in Ashworth scale. (b) Changes in spasticity in lower extremities in 10 consecutive patients.
with axons terminating in the cortex [24]. In children with CP more complex mechanism could be responsible for spasticity associated with symptoms of dystonia. Basing on studies conducted in the seventies Davies attained different grades of reduction in spasticity in 85% from 600 patients with cerebellar stimulation and in two thirds of them marked improvement in athetoid movements occurrence [20]. Chronic cerebellar stimulation of the cortex of the anterior lobe was also effective in intractable epilepsy [17,20]. Electrode pads were placed over the bilateral superior-medial cortices of the cerebellum (paleocerebellum) parasagitally through the bilateral enlarged, occipital burr holes [20]. In cerebellar cortical stimulation only around 15% of the surface of the cortex was accessible for stimulation due to large sulcal surface and electrodes were migrating [24]. In order to potentiate the effects produced by cortical stimulation of the anterior lobe of the cerebellum and to reduce the risk of electrode dislocation, Galanda introduced the method of deep cerebellar stimulation of the region of the superior cerebellar peduncle. The targets are situated in the deep region of the anterior lobe in white matter in the midline sagittal section 8 mm from the fastigium rostrally, parallel to the floor of the 4th ventricle, 2 mm laterally from the midline. Instead of cortical surface, subcortical structures of the
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Fig. 4. (a) Changes in total UDRS p = 0,04. (b) Changes in median values of components of UDRS p = 0,018.
anterior lobe are stimulated where the majority of pathway fibers pass out from subcortical nuclei toward the brainstem (Fig. 1 and Fig. 5). Multiple efferents from these nuclei projects to the basal ganglia which in turn project to the neocortical areas of cerebral cortex influencing on generation and control of movements [28]. Galanda observed that apart from the immediate reduction of spasticity a gradual improvement in choreoathethoid movements after several days or weeks. Other functions as speech, swallowing and posture were also improved [24]. Cerebellum plays important role in the etiology of dystonia [33]. Pathophysiology of dystonia is associated with dysfunction of the cerebellum in the cortico-ponto-cerebello-thalamo-cortical loop [34]. Dystonia may arise from abnormal communication between nodes in the network consisting of motor cortex, basal ganglia, brainstem and cerebellum or dysfunction of two nodes in this
Fig. 5. (a and b) Post op X-ray images (A-P and lateral) with deep cerebellar electrodes pointed out with arrows.
network [33]. The reorganization of neural circuits in basal ganglia and cerebellum might be involved in disinhibition of motor cortical activity causing dystonic movements. The cerebellum exerts also an inhibitory effect on the thalamus and the cerebral cortex through the synaptic action of Purkinje cells and its efferent fibers traveling via the superior cerebellar peduncle what plays substantial a role in antiepileptic activity during cerebellar stimulation. Cerebellum has inhibitory effect on basal ganglia through reticular formation
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and leads to decreased activity of thalamocortical projections [35]. Temporal attenuation of dystonic symptoms one can achieve with transcranial stimulation of the cerebellum or with the use of transcranial direct current stimulation what effects on cerebellar-brain inhibition [36,37]. Patients with CP constitute heterogeneous group in terms of age, the extent of brain damage, etiology and advancement of movement disorder. The most prominent symptoms are paresis, spasticity and involuntary movements. The term secondary dystonia refers to symptoms which occur with another recognizable disorder as in the course of CP. Treatment of secondary dystonia in CP is difficult. Classical targets for lesional surgery of dystonic symptoms in CP were thalamus and internal segment of globus pallidus and dental nuclei of the cerbellum. Results were disappointing [29]. According to Martinez patients in the CP group should receive an ITB (Intrathecal Baclofen) trial as a first step, continuing progressively higher doses. Patients not responding to the ITB trial should be treated with DBS. When a tonic component predominates, GPi is the first target [14]. According to Marks et al. DBS may offer an effective treatment option for cerebral palsy-related dystonia, especially in those treated before skeletal maturity [30]. Trials with combined stereotactic treatment (stimulation and lesioning) were also positive [31]. Bilateral pallidal stimulation is the most commonly chosen neuromodulative method but the outcome is variable [7,32]. Metaanalysis on efficacy of deep brain stimulation mostly in dyskinetic CP conducted by Koy revealed positive moderate but significant effects of GPi stimulation of 64 patients. The other targets were STN (subthalamic nucleus) or VIM (ventral-intermediate nucleus). This meta-analysis did not show correlation between age of the patient and the outcome whereas there was a strong negative correlation between severity of symptoms and outcome. Severity of symptoms decreased 23% considering comparison of BFMDRS score before and 12 month after surgery. Suboptimal effects of pallidal stimulation in the secondary dystonia especially in CP are associated with the presence of irreversible, focal brain lesions and striatal or pallidal atrophy occurring in the course of neurodegenerative or ischemic processes [32]. In patients with dystonic form of CP after bilateral GPi stimulation the improvement ranges from 21% to 55% in over 60% of patients in <20% there is little benefit and in −7.4% deterioration [15]. Our study shows that DACS is not only a neuromodulation therapy of spasticity but also has a great impact on dystonic movements in patients with CP. In our opinion patients with CP who have predominant symptoms of spasticity with the presence of secondary dystonia should be candidates for DACS while the cases with involuntary, dyskinetic movements without severe muscle hypertonia are amenable for pallidal stimulation. This is a preliminary study. The more detailed investigation is necessary to elucidate therapeutic mechanism of DACS to prove the feasibility of this method in patients with dystonia and CP.
5. Conclusions The results of DACS are encouraging. Chronic bilateral DACS aimed for spasticity treatment not only decreases muscular tone in quadriplegic or paraplegic patients with CP but also is associated with reduction of symptoms of focal or segmental, secondary dystonia. Significant arguments for consideration of DACS in the treatment of CP are suboptimal effects of pallidal stimulation in secondary dystonia in CP and coexistence of spasticity and
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involuntary movements in patients with CP. This method helps to reduce both symptoms.
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