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Odekerken V, van Laar T, Staal M, et al. Subthalamic nucleus versus globus pallidus bilateral deep brain stimulation for advanced Parkinson’s disease (NSTAPS study): a randomised controlled trial. Lancet Neurol 2013;12:37-44.
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Bakker M, Esselink RA, Munneke M, Limousin-Dowsey P, Speelman HD, Bloem BR. Effects of stereotactic neurosurgery on postural instability and gait in Parkinson’s disease. Mov Disord 2004;19: 1092-1099.
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Rocchi L, Carlson-Kuhta P, Chiari L, Burchiel KJ, Hogarth P, Horak FB. Effects of deep brain stimulation in the subthalamic nucleus or globus pallidus internus on step initiation in Parkinson disease: laboratory investigation. J Neurosurg 2012;117:11411149.
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Nutt JG, Burchiel KJ, Comella CL, et al. Randomized, doubleblind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology 2003;60:69-73.
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Cowie D, Limousin P, Peters A, Hariz M, Day BL. Doorwayprovoked freezing of gait in Parkinson’s disease. Mov Disord 2012;27: 492-499.
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Buchthal F, Fernandez-Ballesteros ML. Electromyographic study of the muscles of the upper arm and shoulder during walking in patients with Parkinson’s disease. Brain 1965;88:875-896.
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Zampieri C, Salarian A, Carlson-Kuhta P, Aminian K, Nutt JG, Horak FB. The instrumented Timed Up and Go test: potential outcome measure for disease modifying therapies in Parkinson’s disease. J Neurol Neurosurg Psychiatry 2010;81:171-176.
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Rochester L, Hetherington V, Jones D, et al. Attending to the task: interference effects of functional tasks on walking in Parkinson’s disease and the roles of cognition, depression, fatigue, and balance. Arch Phys Med Rehabil 2004;85:1578-1585.
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Frank JS, Horak FB, Nutt J. Centrally initiated postural adjustments in parkinsonian patients on and off levodopa. J Neurophysiol 2000;84:2440-2448.
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Mak MK, Pang MY, Mak MKY, Pang MYC. Balance self-efficacy determines walking capacity in people with Parkinson’s disease. Mov Disord 2008;23:1936-1939.
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Mak MK, Pang MY, Mak MKY, Pang MYC. Balance confidence and functional mobility are independently associated with falls in people with Parkinson’s disease. J Neurol 2009;256: 742-749.
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St George RJ, Carlson-Kuhta P, Burchiel KJ, Hogarth P, Frank N, Horak FB. The effects of subthalamic and pallidal deep brain stimulation on postural responses in patients with Parkinson disease. J Neurosurg 2012;116:1347-1356.
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Sudhyadhom A, Bova FJ, Foote KD, et al. Limbic, associative, and motor territories within the targets for deep brain stimulation: potential clinical implications. Curr Neurol Neurosci Rep 2007;7: 278-289.
Deep Brain Stimulation in the Ventrolateral Thalamus/ Subthalamic Area in Dystonia With Head Tremor K. Amande M. Pauls, MD, PhD,1* Sven Hammesfahr,1 Elena Moro, MD, PhD,2 A. Peter Moore, MD,3 Ellen Binder, MD,1,4 Faycal El Majdoub, MD,5 Gereon R. Fink, MD, PhD,1,4 Volker Sturm, MD, PhD,5 Joachim K. Krauss, MD, PhD,6 Mohammad Maarouf, MD5 and Lars Timmermann, MD, PhD1 1
Department of Neurology, University Hospital Cologne, University of Cologne, Cologne, Germany; 2Division of Neurology, Toronto Western Hospital, University of Toronto, Toronto, Canada; 3The Walton Centre NHS Foundation Trust, Liverpool, United Kingdom. 4Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), €lich, Ju €lich, Germany; 5Department of Stereotaxy Research Centre Ju €ln, University of Cologne, and Functional Neurosurgery, Uniklinik Ko Cologne, Germany; 6Department of Neurosurgery, Medical School Hannover, Hannover, Germany
ABSTRACT Background: Pallidal deep brain stimulation (GPi-DBS) effectively ameliorates idiopathic dystonia, although approximately 15% of patients respond insufficiently. Although various thalamic and subthalamic targets have been suggested for dystonic tremor, no systematic studies have been published on thalamic DBS in dystonic tremor. We assessed the effect of thalamic/ subthalamic area DBS (Th-DBS) on dystonic head tremor and dystonia in a single-blind design. Methods: Dystonic head tremor and dystonia before and 3 months after surgery were quantified via blinded video-ratings using the Fahn-Tolosa-Marin-Tremor-
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Scale and the Burke-Fahn-Marsden-Dystonia-RatingScale in seven patients with idiopathic cervical or segmental dystonia, dystonic head tremor, and bilateral Th-DBS. Pain, side effects, adverse events, and stimulation parameters were assessed. Results: Th-DBS improved dystonic tremor and dystonia (P < 0.05; 57.1% and 70.4%, respectively). Head tremor amplitude and pain were also improved (P < 0.05; 77.5% and 90.0%, respectively). Side effects included dysarthria, gait disturbance, slowness of movement, and weight gain. Conclusion: Dystonic head tremor and dystonia can C 2014 International Parkinbe improved with Th-DBS. V son and Movement Disorder Society Key Words: dystonic tremor, treatment, pain, kinematic tremor analysis
eral low-frequency stimulation of the nucleus ventralis oralis anterior (Voa, or VLa), nucleus ventro-oralis internus, and the zona incerta.24 Improvement of dystonic tremor and writer’s cramp was reported with Vim/VLp DBS.15,16,25-28 Thus, thalamic DBS might be a useful alternative for subgroups of dystonia patients. However, no randomized or blinded studies have been published. Accordingly, this pilot study investigated the effect of thalamic/subthalamic area DBS (Th-DBS) on dystonic head tremor and dystonia in a single-blind trial. We hypothesized that dystonic head tremor, dystonia, and associated pain would be significantly reduced by Th-DBS. To our knowledge, this is the first singleblind study assessing the effects of Th-DBS, or any kind of DBS, on dystonic tremor.
Methods Dystonia is characterized by involuntary movements at rest or during voluntary movement.1 When pharmacotherapy is unsatisfactory, neurosurgical treatment can be considered. Deep brain stimulation (DBS) of the globus pallidus internus (GPi) has proved efficient in idiopathic primary dystonias2-7 and some secondary dystonias.8-10 However, 15% to 20% of patients with primary dystonia respond insufficiently, or side effects limit therapy.3,4,11 Hence, alternative stimulation targets may be of interest to provide further treatment options. Idiopathic dystonia can be accompanied by tremor or even manifest as monosymptomatic tremor.12,13 Dystonic tremor is sometimes improved by GPi-DBS, but may be refractory.14-16 The traditional DBS target in essential tremor and other tremor syndromes is the thalamic nucleus ventralis intermedius (Vim, or nucleus ventralis lateralis posterior [VLp]).15,17,18 DBS of the subthalamic area can also ameliorate tremor of various causes.18-22 The thalamus was the main target for dystonia in the pre-DBS era, and cervical dystonia patients benefitted from thalamic lesioning.23 Only a few studies have investigated thalamic/subthalamic area DBS in dystonia, with inconsistent results regarding efficacy. Mundinger24 reported improvements in torticollis patients after unilat-
-----------------------------------------------------------Additional Supporting Information may be found in the online version of this article.
€r Neuro*Correspondence to: Dr. Amande Pauls, Klinik und Poliklinik fu €ln, Kerpener Str. 62, 50924 Ko €ln, Germany; logie, Uniklinik Ko [email protected] Funding agencies: This study was supported by grants from Deutsche Forschungsgemeinschaft (DFG-grant KFO 219). Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Received: 7 August 2013; Revised: 28 January 2014; Accepted: 6 March 2014 Published online 21 April 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25884
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Seven subjects participated in this retrospective, singlecenter study. Inclusion criteria were: age 18 to 85 years, dystonia with prominent dystonic head tremor responding insufficiently to pharmacotherapy (benzodiazepines, anticholinergics, or botulinum toxin), continuous ThDBS of 3 months or longer, no other psychiatric/neurological disease or cognitive deficits, and patients’ informed consent. The study was approved by the local Ethics Committee (study number 09-150) and carried out in accordance with the Declaration of Helsinki. Details about target localization and surgical procedures can be found in the Supplementary Data. Thalamic DBS was chosen over pallidal DBS because of the presence of prominent head tremor. Because dystonia was also present, the more anteriorly located Voa/ VLa was targeted in addition to Vim/VLp. Electrode placement was confirmed by intraoperative stereotactic teleradiography (Fig. 1A) and postoperative nonstereotactic CT scans (Fig. 1B). Coordinates for the active contacts used for chronic stimulation were converted to stereotactic coordinates (Table 1). Device programming information is given in the Supplemental Data. We routinely videotape patients before surgery and during follow-up according to a standardized protocol.1 Additionally, three-dimensional movement analysis to quantify head tremor was carried out once between, 3 and 18 (median, 5) months postoperatively, with stimulation OFF, chronic stimulation settings (Th-DBS), only thalamic contact active, and only subthalamic contact active. Testing order was pseudorandomized. Nonchronic stimulation settings were applied 90 minutes or more before testing. Patients’ VAS ratings were obtained ON (Th-DBS) and OFF stimulation. Head tremor was assessed dually: We used a clinical scale modified from existing tremor assessment scales, consisting of three items with a score from 0 to 4 (analogous to existing tremor and dystonia rating scales)1,29
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FIG. 1. a: Intraoperative sagittal teleradiography showing position of burrholes and angle of the electrode trajectory; b: Postoperative computed tomography scout showing position of electrodes for chronic stimulation.
that were added to give a total score of 0 to 12. The scale (“mFTMTRS”) and details are given in the Supplemental Data. Clinical ratings were complemented by an observerindependent, ultrasound-based three-dimensional motion measurement system (CMS 20S, Zebris, Isny, Germany). Spatial coordinates of a position marker placed on the forehead were sampled for offline analysis while patients held their head in its spontaneous position without suppressing movement or tremor (for details, see Supplemental Data Methods and Supplemental Data Figure 1b). Two blinded external movement disorders specialists (E.M. and A.P.M.) rated head tremor and dystonia from the standardized videos using the mFTMTRS and the Burke-Fahn-Marsden-Dystonia-Rating-Scale Motor Score (BFMDRS-M).1 Primary outcome parameters were head tremor and severity of dystonia postoperatively versus preoperatively
(mean mFTMTRS and BFMDRS-M1 ratings of 2 blinded raters). Amplitude of dystonic head tremor and visual analog scale (VAS) pain ratings ON versus OFF were the secondary outcome measures. The Wilcoxon signed-rank test was used for significance testing with PASW 18.0. For the secondary outcome measures, we performed an alphacorrection (Holm-Bonferroni method). Adverse events were reviewed by K.A.M.P. and L.T. and classified as stimulation-related, device-related, or patient-related (for details, see Supplemental Data, Methods).
Results Seven dystonia patients (4 women, 4 cervical, 3 segmental; median age, 55.0 [23-76] years, median disease duration at surgery of 16.0 [2-32] years; for details, see Table 2) took part in the study. The median preoperative BFMDRS-M was 4.0 (2.25-22.25).
TABLE 1. Location of active electrode contactsa Left hemisphere
Sub-thalamic area
Median 6 SD Thalamic
Active contact
x
y
z
Active contact
x
Y
z
210.8 29.6 29.4 211.5 27.4 27.5 210.4 29.6 6 1.6 211.9 210.7 211.4 213.0 28.6 28.5 211.9 211.4 6 1.7
23.2 23.5 24.0 21.3 23.7 0.3 27.9 23.5 6 2.5 4.6 1.3 3.6 4.9 1.4 2.7 20.8 2.7 6 2.0
22.7 21.2 20.6 21.0 21.9 0.0 21.6 21.2 6 0.9 1.2 2.5 3.9 0.7 0.7 2.9 2.3 2.3 6 1.2
4 4 4 5 4 4 5
10.2 9.1 8.6 13.3 7.8 8.9 11.0 9.1 6 1.9 11.5 10.2 10.3 14.8 8.8 11.0 12.3 11.0 6 1.9
22.5 24.5 24.7 25.3 23.8 21.5 24.0 24.0 6 1.3 5.9 0.4 3.3 20.5 1.8 2.3 1.0 1.8 6 2.1
24.3 20.4 21.5 20.6 22.9 22.0 0.5 21.5 6 1.6 21.5 3.3 2.0 1.0 20.1 2.0 3.0 2.0 6 1.7
Pat. Pat. Pat. Pat. Pat. Pat. Pat.
1 2 3 4 5 6 7
0 0 0 1 0 1 0
Pat. Pat. Pat. Pat. Pat. Pat. Pat.
1 2 3 4 5 6 7
3 3 3 3 3 3 3
Median 6 SD
Right hemisphere
7 7 7 7 7 7 7
a
Stereotactic coordinates.
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TABLE 2. Patient characteristics Postoperative BFMDRS motor scorea,b
Type of dystonia
Current medicationc
At time of surgery: amitriptyline tetrazepam At time of surgery: mirtazapine clonazepam At time of surgery: primidone clonazepam -
Patient no.
Age
Sex
Disease duration
Preoperative BFMDRS motor scorea
1
62
f
32
13.25
4.75
Segmental
2
55
f
9
3.0
0.25
Cervical
3 4
41 76
m f
23 25
3.75 6.5
1.75 .5
Cervical Segmental
49 23 69 55.0 6 17.9
f m m 4w:3m
2 9 16 16.0 6 10.6
4.0 20.25 2.25 4.0 6 6.7
1.0 6.0 1.0 1.0 6 2.3
Cervical Segmental Cervical 4 Cervical 3 segmental
5 6 7 Median 6 SD
a
Mean of two raters. Three months FU. c Patients underwent a trial of anticholinergics, benzodiazepines, or botulinum toxin before DBS surgery. BFMDRS, Burke-Fahn-Marsden-Dystonia-Rating-Scale Motor Score. b
Severity of tremor (assessed with mFTMTRS) improved significantly during Th-DBS versus preoperatively (P < 0.05; median, 57.1% [18.5-100%], Fig. 2A). One patient’s tremor increased slightly. Severity of dystonia (assessed with BFMDRS-M) also improved significantly during chronic Th-DBS versus preoperatively (P < 0.05). The median improvement was 70.4% (53.3-92.3%, Fig. 2B). No patient showed increased dystonia postoperatively. One patient was lost to follow-up beyond 3 months and did not participate in the additional threedimensional tremor analysis. In the remaining 6 patients, tremor amplitude (assessed using three-dimensional movement analysis) showed a significant reduction ON versus OFF (P < 0.05). The median tremor amplitude reduction was 77.5% (11.7%-95.3%). Median pain ratings (assessed with VAS) improved significantly (4.5 OFF vs. 0.5 ON, P < 0.05), corresponding to a median improvement of 90.0%. To explore the differential effects of OFF versus thalamic versus subthalamic area stimulation versus ThDBS, an analysis of variance was performed on the three-dimensional head movement data. Tremor amplitude was significantly different in the four conditions (P < 0.05), with a trend for dystonic head movement over 10 seconds (P 5 0.064, Fig. 2C and D). Post-hoc t tests showed that thalamic stimulation alone was significantly inferior to Th-DBS in reducing head tremor (P < 0.05), whereas thalamic versus subthalamic area stimulation, or subthalamic area stimulation versus Th-DBS, did not differ. Stereotactic coordinates for chronically active stimulation contacts are given in Table 1. Information on
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the electrodes, generator, and stimulation settings can be found in Table 3. The most common stimulation-induced side effects were dysarthria, gait problems, and slowness of movement. Some patients experienced weight gain. Adverse events are listed in Supplemental Data Table 1.
Discussion Our study shows that Th-DBS can ameliorate dystonic head tremor and dystonia. Tremor amplitude and pain ratings also improved. Few studies examined DBS effects on head tremor or dystonic tremor. In essential tremor, previous studies reported tremor reductions of 55%, and head tremor reductions of 45%, although bilaterally stimulated patients’ head tremor improved from 2.22 to 0.33 points.30 GPi-DBS reduced segmental and generalized dystonia by 46% and 51%,3,4 and cervical dystonia between 40% and 60%.5-7,31 Hence, the reductions in dystonia after Th-DBS reported here are comparable to those for GPi-DBS, but tremor reductions appear somewhat inferior to the results with bilateral Vim/VLp DBS in essential head tremor.32 Previous studies regarding thalamic DBS do not allow any conclusions as to whether Voa/VLa24,27 or Vim/ VLp21,26 yield better results in (tremulous) dystonia. Based on limitations in image resolution for thalamic visualization, we cannot be sure that we indeed placed electrode contacts in VLa, VLp, and subthalamic areas in each patient, and thus we referred to thalamic versus subthalamic stimulation instead. The optimal thalamic target for dystonic tremor remains to be established.
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FIG. 2. Severity of (a) dystonic head tremor (mFTTRS) and (b) dystonia (BFMDRS-M) pre- vs. 3 months postoperatively with chronic stimulation settings. (c) Tremor amplitude and (d) total dystonic movement over 10 sec in different stimulation settings measured using three-dimensional movement analysis.
Some limitations of our study should be discussed. Although seven patients constitute a rather small cohort, the results were significant. Second, the analysis was carried out retrospectively. However, we obtained blinded video ratings from standardized videos by external movement disorders specialists, thereby eliminating observer bias. Third, we had to
No consensus has been reached on optimal stimulation settings in dystonia.32 Previous studies reported stimulation parameters of 130 to 170 Hz, and 3.1 to 3.7 V,3-5,31 pulse widths of up to 450 mm, and one or two active contacts per lead.3,5,31 Overall, stimulation settings used in the present study are comparable to those reported for GPi-DBS.
TABLE 3. Device information and chronic stimulation settings Patient no.
Hemisphere
1
Left Right Left Right Left Right Left Right Left Right Left Right Left Right Left Right
2 3 4 5 6 7 Median
Electrode
3387 3387 3389 3389 3387 3387 3387 3387 3389 3389 3389 3389 3387 3387
Generator
Kinetra Activa PC Kinetra Kinetra Activa RC Kinetra Kinetra
Active contacts
04040415041405-
37373737373737-
case case case case case case case case case case case case case case
1 1 1 1 1 1 1 1 1 1 1 1 1 1
Amplitude (V)
Pulse duration (ms)
Frequency (Hz)
2.4 2.3 1.4 1.4 3.1 2.5 2.3 2.3 1.5 1.5 3.0 2.8 1.9 2.2 2.3 6 0.7 2.3 6 0.5
90 90 90 90 60 60 150 150 60 60 90 90 60 60 90.0 6 32.1 90.0 6 32.1
160 160 130 130 130 130 130 130 130 130 130 130 200 200 130.0 6 27.0 130.0 6 27.01
PC, Precharge; RC, Recharge.
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use the BFMDRS-M because of heterogeneity in dystonia severity. Despite this heterogeneity in extent and severity of dystonia, the improvements in dystonia and tremor were statistically significant, suggesting that Th-DBS is efficient for dystonic tremor and dystonia regardless of severity and type. However, a comparison of thalamic versus subthalamic area stimulation in a larger patient cohort is necessary for a more definitive statement on the optimal stimulation site. Available dystonia rating scales neglect tremor as an independent symptom. We therefore assessed tremor using a modified clinical scale and three-dimensional movement recording to minimize observer bias. Both measures showed a significant reduction in head tremor after thalamic/subthalamic DBS. Th-DBS side effects appeared somewhat more frequently than with GPi-DBS. Most common side effects were dysarthria, slowness of movement, and unsteadiness of gait, all of which were dependent on stimulation settings and reversible and did not limit patients’ everyday activities. Dysarthria and unsteadiness of gait have been described in previous studies of DBS of the subthalamic area.33 Weight gain also has been reported in patients with subthalamic nucleus DBS, GPi-DBS, and thalamic DBS.34 Potential side effect profiles need to be taken into account when choosing an appropriate DBS target. In summary, we demonstrated in a single-blind design that Th-DBS can improve dystonic head tremor and dystonia and thus may constitute an alternative to GPi-DBS in patients with insufficient response to GPiDBS, dystonia patients with severe tremor,16 or possibly patients with severe damage to the GPi. Future studies need to define the optimal thalamic/subthalamic area target and define side effect profiles. Larger prospective controlled studies are needed to compare efficacy and side effects of Th-DBS and GPi-DBS. Acknowledgments: We thank all patients who participated in this study. The study was supported by Deutsche Forschungsgemeinschaft (DFG-grant KFO 219).
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Limousin P, Speelman JD, Gielen F, Janssens M. Multicentre European study of thalamic stimulation in parkinsonian and essential tremor. J Neurol Neurosurg Psychiatry 1999;66:289-296.
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Kupsch A, Tagliati M, Vidailhet M, et al. Early postoperative management of DBS in dystonia: programming, response to stimulation, adverse events, medication changes, evaluations, and troubleshooting. Mov Disord 2011;26(Suppl 1):S37-S53.
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Shivitz N, Koop MM, Fahimi J, et al. Bilateral subthalamic nucleus deep brain stimulation improves certain aspects of postural control in Parkinson’s disease, whereas medication does not. Mov Disord 2006;21:1088-1097.
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Fahn S, Elton R. Unified Parkinson’s Disease Rating Scale. Florham Park, NJ: Macmillan Healthcare Information; 1987.
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Bakker M, Esselink RA, Munneke M, Limousin-Dowsey P, Speelman HD, Bloem BR. Effects of stereotactic neurosurgery on postural instability and gait in Parkinson’s disease. Mov Disord 2004;19: 1092-1099.
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Rocchi L, Carlson-Kuhta P, Chiari L, Burchiel KJ, Hogarth P, Horak FB. Effects of deep brain stimulation in the subthalamic nucleus or globus pallidus internus on step initiation in Parkinson disease: laboratory investigation. J Neurosurg 2012;117:11411149.
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Cowie D, Limousin P, Peters A, Hariz M, Day BL. Doorwayprovoked freezing of gait in Parkinson’s disease. Mov Disord 2012;27: 492-499.
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Buchthal F, Fernandez-Ballesteros ML. Electromyographic study of the muscles of the upper arm and shoulder during walking in patients with Parkinson’s disease. Brain 1965;88:875-896.
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Zampieri C, Salarian A, Carlson-Kuhta P, Aminian K, Nutt JG, Horak FB. The instrumented Timed Up and Go test: potential outcome measure for disease modifying therapies in Parkinson’s disease. J Neurol Neurosurg Psychiatry 2010;81:171-176.
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Rochester L, Hetherington V, Jones D, et al. Attending to the task: interference effects of functional tasks on walking in Parkinson’s disease and the roles of cognition, depression, fatigue, and balance. Arch Phys Med Rehabil 2004;85:1578-1585.
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Frank JS, Horak FB, Nutt J. Centrally initiated postural adjustments in parkinsonian patients on and off levodopa. J Neurophysiol 2000;84:2440-2448.
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Powell LE, Myers AM. The Activities-specific Balance Confidence (ABC) Scale. J Gerontol A Biol Sci Med Sci 1995;50A: M28-M34.
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Mak MK, Pang MY, Mak MKY, Pang MYC. Balance self-efficacy determines walking capacity in people with Parkinson’s disease. Mov Disord 2008;23:1936-1939.
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Mak MK, Pang MY, Mak MKY, Pang MYC. Balance confidence and functional mobility are independently associated with falls in people with Parkinson’s disease. J Neurol 2009;256: 742-749.
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St George RJ, Carlson-Kuhta P, Burchiel KJ, Hogarth P, Frank N, Horak FB. The effects of subthalamic and pallidal deep brain stimulation on postural responses in patients with Parkinson disease. J Neurosurg 2012;116:1347-1356.
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Sudhyadhom A, Bova FJ, Foote KD, et al. Limbic, associative, and motor territories within the targets for deep brain stimulation: potential clinical implications. Curr Neurol Neurosci Rep 2007;7: 278-289.
Deep Brain Stimulation in the Ventrolateral Thalamus/ Subthalamic Area in Dystonia With Head Tremor K. Amande M. Pauls, MD, PhD,1* Sven Hammesfahr,1 Elena Moro, MD, PhD,2 A. Peter Moore, MD,3 Ellen Binder, MD,1,4 Faycal El Majdoub, MD,5 Gereon R. Fink, MD, PhD,1,4 Volker Sturm, MD, PhD,5 Joachim K. Krauss, MD, PhD,6 Mohammad Maarouf, MD5 and Lars Timmermann, MD, PhD1 1
Department of Neurology, University Hospital Cologne, University of Cologne, Cologne, Germany; 2Division of Neurology, Toronto Western Hospital, University of Toronto, Toronto, Canada; 3The Walton Centre NHS Foundation Trust, Liverpool, United Kingdom. 4Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), €lich, Ju €lich, Germany; 5Department of Stereotaxy Research Centre Ju €ln, University of Cologne, and Functional Neurosurgery, Uniklinik Ko Cologne, Germany; 6Department of Neurosurgery, Medical School Hannover, Hannover, Germany
ABSTRACT Background: Pallidal deep brain stimulation (GPi-DBS) effectively ameliorates idiopathic dystonia, although approximately 15% of patients respond insufficiently. Although various thalamic and subthalamic targets have been suggested for dystonic tremor, no systematic studies have been published on thalamic DBS in dystonic tremor. We assessed the effect of thalamic/ subthalamic area DBS (Th-DBS) on dystonic head tremor and dystonia in a single-blind design. Methods: Dystonic head tremor and dystonia before and 3 months after surgery were quantified via blinded video-ratings using the Fahn-Tolosa-Marin-Tremor-
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Scale and the Burke-Fahn-Marsden-Dystonia-RatingScale in seven patients with idiopathic cervical or segmental dystonia, dystonic head tremor, and bilateral Th-DBS. Pain, side effects, adverse events, and stimulation parameters were assessed. Results: Th-DBS improved dystonic tremor and dystonia (P < 0.05; 57.1% and 70.4%, respectively). Head tremor amplitude and pain were also improved (P < 0.05; 77.5% and 90.0%, respectively). Side effects included dysarthria, gait disturbance, slowness of movement, and weight gain. Conclusion: Dystonic head tremor and dystonia can C 2014 International Parkinbe improved with Th-DBS. V son and Movement Disorder Society Key Words: dystonic tremor, treatment, pain, kinematic tremor analysis
eral low-frequency stimulation of the nucleus ventralis oralis anterior (Voa, or VLa), nucleus ventro-oralis internus, and the zona incerta.24 Improvement of dystonic tremor and writer’s cramp was reported with Vim/VLp DBS.15,16,25-28 Thus, thalamic DBS might be a useful alternative for subgroups of dystonia patients. However, no randomized or blinded studies have been published. Accordingly, this pilot study investigated the effect of thalamic/subthalamic area DBS (Th-DBS) on dystonic head tremor and dystonia in a single-blind trial. We hypothesized that dystonic head tremor, dystonia, and associated pain would be significantly reduced by Th-DBS. To our knowledge, this is the first singleblind study assessing the effects of Th-DBS, or any kind of DBS, on dystonic tremor.
Methods Dystonia is characterized by involuntary movements at rest or during voluntary movement.1 When pharmacotherapy is unsatisfactory, neurosurgical treatment can be considered. Deep brain stimulation (DBS) of the globus pallidus internus (GPi) has proved efficient in idiopathic primary dystonias2-7 and some secondary dystonias.8-10 However, 15% to 20% of patients with primary dystonia respond insufficiently, or side effects limit therapy.3,4,11 Hence, alternative stimulation targets may be of interest to provide further treatment options. Idiopathic dystonia can be accompanied by tremor or even manifest as monosymptomatic tremor.12,13 Dystonic tremor is sometimes improved by GPi-DBS, but may be refractory.14-16 The traditional DBS target in essential tremor and other tremor syndromes is the thalamic nucleus ventralis intermedius (Vim, or nucleus ventralis lateralis posterior [VLp]).15,17,18 DBS of the subthalamic area can also ameliorate tremor of various causes.18-22 The thalamus was the main target for dystonia in the pre-DBS era, and cervical dystonia patients benefitted from thalamic lesioning.23 Only a few studies have investigated thalamic/subthalamic area DBS in dystonia, with inconsistent results regarding efficacy. Mundinger24 reported improvements in torticollis patients after unilat-
-----------------------------------------------------------Additional Supporting Information may be found in the online version of this article.
€r Neuro*Correspondence to: Dr. Amande Pauls, Klinik und Poliklinik fu €ln, Kerpener Str. 62, 50924 Ko €ln, Germany; logie, Uniklinik Ko [email protected] Funding agencies: This study was supported by grants from Deutsche Forschungsgemeinschaft (DFG-grant KFO 219). Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Received: 7 August 2013; Revised: 28 January 2014; Accepted: 6 March 2014 Published online 21 April 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25884
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Seven subjects participated in this retrospective, singlecenter study. Inclusion criteria were: age 18 to 85 years, dystonia with prominent dystonic head tremor responding insufficiently to pharmacotherapy (benzodiazepines, anticholinergics, or botulinum toxin), continuous ThDBS of 3 months or longer, no other psychiatric/neurological disease or cognitive deficits, and patients’ informed consent. The study was approved by the local Ethics Committee (study number 09-150) and carried out in accordance with the Declaration of Helsinki. Details about target localization and surgical procedures can be found in the Supplementary Data. Thalamic DBS was chosen over pallidal DBS because of the presence of prominent head tremor. Because dystonia was also present, the more anteriorly located Voa/ VLa was targeted in addition to Vim/VLp. Electrode placement was confirmed by intraoperative stereotactic teleradiography (Fig. 1A) and postoperative nonstereotactic CT scans (Fig. 1B). Coordinates for the active contacts used for chronic stimulation were converted to stereotactic coordinates (Table 1). Device programming information is given in the Supplemental Data. We routinely videotape patients before surgery and during follow-up according to a standardized protocol.1 Additionally, three-dimensional movement analysis to quantify head tremor was carried out once between, 3 and 18 (median, 5) months postoperatively, with stimulation OFF, chronic stimulation settings (Th-DBS), only thalamic contact active, and only subthalamic contact active. Testing order was pseudorandomized. Nonchronic stimulation settings were applied 90 minutes or more before testing. Patients’ VAS ratings were obtained ON (Th-DBS) and OFF stimulation. Head tremor was assessed dually: We used a clinical scale modified from existing tremor assessment scales, consisting of three items with a score from 0 to 4 (analogous to existing tremor and dystonia rating scales)1,29
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FIG. 1. a: Intraoperative sagittal teleradiography showing position of burrholes and angle of the electrode trajectory; b: Postoperative computed tomography scout showing position of electrodes for chronic stimulation.
that were added to give a total score of 0 to 12. The scale (“mFTMTRS”) and details are given in the Supplemental Data. Clinical ratings were complemented by an observerindependent, ultrasound-based three-dimensional motion measurement system (CMS 20S, Zebris, Isny, Germany). Spatial coordinates of a position marker placed on the forehead were sampled for offline analysis while patients held their head in its spontaneous position without suppressing movement or tremor (for details, see Supplemental Data Methods and Supplemental Data Figure 1b). Two blinded external movement disorders specialists (E.M. and A.P.M.) rated head tremor and dystonia from the standardized videos using the mFTMTRS and the Burke-Fahn-Marsden-Dystonia-Rating-Scale Motor Score (BFMDRS-M).1 Primary outcome parameters were head tremor and severity of dystonia postoperatively versus preoperatively
(mean mFTMTRS and BFMDRS-M1 ratings of 2 blinded raters). Amplitude of dystonic head tremor and visual analog scale (VAS) pain ratings ON versus OFF were the secondary outcome measures. The Wilcoxon signed-rank test was used for significance testing with PASW 18.0. For the secondary outcome measures, we performed an alphacorrection (Holm-Bonferroni method). Adverse events were reviewed by K.A.M.P. and L.T. and classified as stimulation-related, device-related, or patient-related (for details, see Supplemental Data, Methods).
Results Seven dystonia patients (4 women, 4 cervical, 3 segmental; median age, 55.0 [23-76] years, median disease duration at surgery of 16.0 [2-32] years; for details, see Table 2) took part in the study. The median preoperative BFMDRS-M was 4.0 (2.25-22.25).
TABLE 1. Location of active electrode contactsa Left hemisphere
Sub-thalamic area
Median 6 SD Thalamic
Active contact
x
y
z
Active contact
x
Y
z
210.8 29.6 29.4 211.5 27.4 27.5 210.4 29.6 6 1.6 211.9 210.7 211.4 213.0 28.6 28.5 211.9 211.4 6 1.7
23.2 23.5 24.0 21.3 23.7 0.3 27.9 23.5 6 2.5 4.6 1.3 3.6 4.9 1.4 2.7 20.8 2.7 6 2.0
22.7 21.2 20.6 21.0 21.9 0.0 21.6 21.2 6 0.9 1.2 2.5 3.9 0.7 0.7 2.9 2.3 2.3 6 1.2
4 4 4 5 4 4 5
10.2 9.1 8.6 13.3 7.8 8.9 11.0 9.1 6 1.9 11.5 10.2 10.3 14.8 8.8 11.0 12.3 11.0 6 1.9
22.5 24.5 24.7 25.3 23.8 21.5 24.0 24.0 6 1.3 5.9 0.4 3.3 20.5 1.8 2.3 1.0 1.8 6 2.1
24.3 20.4 21.5 20.6 22.9 22.0 0.5 21.5 6 1.6 21.5 3.3 2.0 1.0 20.1 2.0 3.0 2.0 6 1.7
Pat. Pat. Pat. Pat. Pat. Pat. Pat.
1 2 3 4 5 6 7
0 0 0 1 0 1 0
Pat. Pat. Pat. Pat. Pat. Pat. Pat.
1 2 3 4 5 6 7
3 3 3 3 3 3 3
Median 6 SD
Right hemisphere
7 7 7 7 7 7 7
a
Stereotactic coordinates.
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TABLE 2. Patient characteristics Postoperative BFMDRS motor scorea,b
Type of dystonia
Current medicationc
At time of surgery: amitriptyline tetrazepam At time of surgery: mirtazapine clonazepam At time of surgery: primidone clonazepam -
Patient no.
Age
Sex
Disease duration
Preoperative BFMDRS motor scorea
1
62
f
32
13.25
4.75
Segmental
2
55
f
9
3.0
0.25
Cervical
3 4
41 76
m f
23 25
3.75 6.5
1.75 .5
Cervical Segmental
49 23 69 55.0 6 17.9
f m m 4w:3m
2 9 16 16.0 6 10.6
4.0 20.25 2.25 4.0 6 6.7
1.0 6.0 1.0 1.0 6 2.3
Cervical Segmental Cervical 4 Cervical 3 segmental
5 6 7 Median 6 SD
a
Mean of two raters. Three months FU. c Patients underwent a trial of anticholinergics, benzodiazepines, or botulinum toxin before DBS surgery. BFMDRS, Burke-Fahn-Marsden-Dystonia-Rating-Scale Motor Score. b
Severity of tremor (assessed with mFTMTRS) improved significantly during Th-DBS versus preoperatively (P < 0.05; median, 57.1% [18.5-100%], Fig. 2A). One patient’s tremor increased slightly. Severity of dystonia (assessed with BFMDRS-M) also improved significantly during chronic Th-DBS versus preoperatively (P < 0.05). The median improvement was 70.4% (53.3-92.3%, Fig. 2B). No patient showed increased dystonia postoperatively. One patient was lost to follow-up beyond 3 months and did not participate in the additional threedimensional tremor analysis. In the remaining 6 patients, tremor amplitude (assessed using three-dimensional movement analysis) showed a significant reduction ON versus OFF (P < 0.05). The median tremor amplitude reduction was 77.5% (11.7%-95.3%). Median pain ratings (assessed with VAS) improved significantly (4.5 OFF vs. 0.5 ON, P < 0.05), corresponding to a median improvement of 90.0%. To explore the differential effects of OFF versus thalamic versus subthalamic area stimulation versus ThDBS, an analysis of variance was performed on the three-dimensional head movement data. Tremor amplitude was significantly different in the four conditions (P < 0.05), with a trend for dystonic head movement over 10 seconds (P 5 0.064, Fig. 2C and D). Post-hoc t tests showed that thalamic stimulation alone was significantly inferior to Th-DBS in reducing head tremor (P < 0.05), whereas thalamic versus subthalamic area stimulation, or subthalamic area stimulation versus Th-DBS, did not differ. Stereotactic coordinates for chronically active stimulation contacts are given in Table 1. Information on
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the electrodes, generator, and stimulation settings can be found in Table 3. The most common stimulation-induced side effects were dysarthria, gait problems, and slowness of movement. Some patients experienced weight gain. Adverse events are listed in Supplemental Data Table 1.
Discussion Our study shows that Th-DBS can ameliorate dystonic head tremor and dystonia. Tremor amplitude and pain ratings also improved. Few studies examined DBS effects on head tremor or dystonic tremor. In essential tremor, previous studies reported tremor reductions of 55%, and head tremor reductions of 45%, although bilaterally stimulated patients’ head tremor improved from 2.22 to 0.33 points.30 GPi-DBS reduced segmental and generalized dystonia by 46% and 51%,3,4 and cervical dystonia between 40% and 60%.5-7,31 Hence, the reductions in dystonia after Th-DBS reported here are comparable to those for GPi-DBS, but tremor reductions appear somewhat inferior to the results with bilateral Vim/VLp DBS in essential head tremor.32 Previous studies regarding thalamic DBS do not allow any conclusions as to whether Voa/VLa24,27 or Vim/ VLp21,26 yield better results in (tremulous) dystonia. Based on limitations in image resolution for thalamic visualization, we cannot be sure that we indeed placed electrode contacts in VLa, VLp, and subthalamic areas in each patient, and thus we referred to thalamic versus subthalamic stimulation instead. The optimal thalamic target for dystonic tremor remains to be established.
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FIG. 2. Severity of (a) dystonic head tremor (mFTTRS) and (b) dystonia (BFMDRS-M) pre- vs. 3 months postoperatively with chronic stimulation settings. (c) Tremor amplitude and (d) total dystonic movement over 10 sec in different stimulation settings measured using three-dimensional movement analysis.
Some limitations of our study should be discussed. Although seven patients constitute a rather small cohort, the results were significant. Second, the analysis was carried out retrospectively. However, we obtained blinded video ratings from standardized videos by external movement disorders specialists, thereby eliminating observer bias. Third, we had to
No consensus has been reached on optimal stimulation settings in dystonia.32 Previous studies reported stimulation parameters of 130 to 170 Hz, and 3.1 to 3.7 V,3-5,31 pulse widths of up to 450 mm, and one or two active contacts per lead.3,5,31 Overall, stimulation settings used in the present study are comparable to those reported for GPi-DBS.
TABLE 3. Device information and chronic stimulation settings Patient no.
Hemisphere
1
Left Right Left Right Left Right Left Right Left Right Left Right Left Right Left Right
2 3 4 5 6 7 Median
Electrode
3387 3387 3389 3389 3387 3387 3387 3387 3389 3389 3389 3389 3387 3387
Generator
Kinetra Activa PC Kinetra Kinetra Activa RC Kinetra Kinetra
Active contacts
04040415041405-
37373737373737-
case case case case case case case case case case case case case case
1 1 1 1 1 1 1 1 1 1 1 1 1 1
Amplitude (V)
Pulse duration (ms)
Frequency (Hz)
2.4 2.3 1.4 1.4 3.1 2.5 2.3 2.3 1.5 1.5 3.0 2.8 1.9 2.2 2.3 6 0.7 2.3 6 0.5
90 90 90 90 60 60 150 150 60 60 90 90 60 60 90.0 6 32.1 90.0 6 32.1
160 160 130 130 130 130 130 130 130 130 130 130 200 200 130.0 6 27.0 130.0 6 27.01
PC, Precharge; RC, Recharge.
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use the BFMDRS-M because of heterogeneity in dystonia severity. Despite this heterogeneity in extent and severity of dystonia, the improvements in dystonia and tremor were statistically significant, suggesting that Th-DBS is efficient for dystonic tremor and dystonia regardless of severity and type. However, a comparison of thalamic versus subthalamic area stimulation in a larger patient cohort is necessary for a more definitive statement on the optimal stimulation site. Available dystonia rating scales neglect tremor as an independent symptom. We therefore assessed tremor using a modified clinical scale and three-dimensional movement recording to minimize observer bias. Both measures showed a significant reduction in head tremor after thalamic/subthalamic DBS. Th-DBS side effects appeared somewhat more frequently than with GPi-DBS. Most common side effects were dysarthria, slowness of movement, and unsteadiness of gait, all of which were dependent on stimulation settings and reversible and did not limit patients’ everyday activities. Dysarthria and unsteadiness of gait have been described in previous studies of DBS of the subthalamic area.33 Weight gain also has been reported in patients with subthalamic nucleus DBS, GPi-DBS, and thalamic DBS.34 Potential side effect profiles need to be taken into account when choosing an appropriate DBS target. In summary, we demonstrated in a single-blind design that Th-DBS can improve dystonic head tremor and dystonia and thus may constitute an alternative to GPi-DBS in patients with insufficient response to GPiDBS, dystonia patients with severe tremor,16 or possibly patients with severe damage to the GPi. Future studies need to define the optimal thalamic/subthalamic area target and define side effect profiles. Larger prospective controlled studies are needed to compare efficacy and side effects of Th-DBS and GPi-DBS. Acknowledgments: We thank all patients who participated in this study. The study was supported by Deutsche Forschungsgemeinschaft (DFG-grant KFO 219).
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