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Keywords:

  • dystonia;
  • deep brain stimulation;
  • globus pallidus internus;
  • quality of life

Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. APPENDIX
  8. REFERENCES

As part of the first randomized, sham-timulation controlled trial on deep brain stimulation (DBS) in primary segmental or generalized dystonia, health-related quality of life (HRQoL) was assessed by SF-36. After the 3-month sham-controlled phase, significant HRQoL improvement occurred only in the active-stimulation group. The open-label extension phase resulted in a significant improvement in all SF-36 domains following 6 months of neurostimulation. These results demonstrate a favorable impact of DBS on HRQoL in primary dystonia. © 2007 Movement Disorder Society

Dystonia is one of the most prevalent movement disorders and has a significant negative impact on quality of life.1 Whereas local botulinum toxin (BTX) injections represent the treatment of choice in focal dystonia, more severely affected patients with segmental or generalized forms, often fail to respond to BTX and other pharmacological therapies.

Recently, trials of bilateral pallidal deep brain stimulation (DBS) have shown promising results in patients with medically refractory dystonia, but little is known about the effects of this treatment on health-related quality of life (HRQoL) and symptoms of psychological distress.

As part of the first randomized, sham-stimulation-controlled trial of DBS in primary dystonia2 we evaluated the impact of DBS on HRQoL, and symptoms of depression and anxiety.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. APPENDIX
  8. REFERENCES

A complete description of the parent study can be found elsewhere.2 In brief, 40 patients (27 male, 13 female, age 39.4 ± 13.5) with medically refractory primary generalized (n = 24) or segmental dystonia (n = 16) were implanted with electrodes into the internal globus pallidus for chronic high-frequency stimulation and randomized to either active or sham-stimulation for 3 months, followed by either 3 or 6 months of open-label treatment, for a total of 6 months of neurostimulation in each group.

Assessments were performed at baseline, at the end of the 3-months double-blind phase, and after 6-months of continuous neurostimulation in all patients. The following subsections describe the methods of the HRQoL study.

Outcome Measures

HRQoL was assessed by the Short Form 36 (SF-36), a 36-item generic measure that provides a profile assessment of HRQoL measuring eight multi-item variables: Physical function (PF), role limitations due to physical problems (RP), bodily pain (BP), general health (GH), vitality (VT), social function (SF), role limitations due to emotional problems (RE), and mental health (MH). A score from 0 (worst) to 100 (best possible health state) is generated for each of the eight dimensions.3

Depression was assessed with the Beck Depression Inventory (BDI), which covers cognitive as well as somatic and behavioral aspects of depression.4 Anxiety was assessed with the Beck Anxiety Inventory (BAI) and neuropsychiatric status with the Brief Psychiatric Rating Scale (BPRS).

Severity of dystonia was measured with the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) Movement score, and disability with the BFMDRS Disability score.5 In addition, global clinical impression (GCI) of dystonia and pain were assessed by a 0 to 10 visual analogue scale.

Statistical Analysis

We compared the score changes from baseline to 3 months between the neurostimulation-group and the sham control-group using the Mann-Whitney test. The individual scores after 6 months of DBS were compared to baseline using the Wilcoxon signed rank test for paired samples. SF-36 domain scores of individual patients were z-transformed and related to the percentile level of the age-matched German normal population.

Predictive factors for SF-36 improvement could not be studied with multivariate methods by using all eight SF-36 domain score changes as dependent variables because of the limited sample size. We therefore used the change of the SF-36 Physical Component Score (PCS) and Mental Component Score (MCS) from baseline to 6 months as dependent variables in separate multiple linear regression analyses.

Statistical analyses were performed using the JMP statistical package, version 6.0 (SAS Institute). The significance level was set at P < 0.05.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. APPENDIX
  8. REFERENCES

Baseline Scores

All SF-36 domain scores were significantly reduced in the patient group compared to data from a normal population reference sample (see Fig. 1), but did not differ significantly between the active and sham-stimulation group (Table 1). Patients with segmental dystonia differed from patients with generalized dystonia by having less disability (BFMDRS-disability scores, P = 0.001) and higher SF-36 PF scores (P = 0.02), but lower VT (P = 0.03) scores. BDI, BAI, or BPRS scores were not significantly different in the two groups.

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Figure 1. SF-36 domain scores of individual patients were z-transformed and related to the percentile level of the age-matched German normal population. Differences are considered relevant if they exceed one SD (z = ±1). PF, physical function; SF, social function; RP, role limitations due to physical problems; RE, role limitations due to emotional problems; MH, mental health; VT, vitality; BP, bodily pain; GH, general health.*P < 0.05, **P < 0.01.

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Table 1. Results of the 3-mo study phase
VariableBaseline3 MoChange from baseline to 3 moP value
StimulationSham stimulationStimulationSham stimulationStimulationSham stimulation
NMean ± SDNMean ± SDNMean ± SDNMean ± SDNMean ± SDNMean ± SD
  • a

    The total movement score of the Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS) is the sum of individual scores for each body region and represents the severity of symptoms of dystonia.

  • b

    A higher score on this scale indicates a higher level of function.

  • c

    A higher score on this scale indicates a greater severity of symptoms.

BFMDRS movement scorea2040.2 ± 24.92032.6 ± 24.32024.5 ± 22.81831.7 ± 25.220−15.8 ± 14.118−1.6 ± 4.0<0.001
BFMDRS disability score2010.4 ± 6.2209.6 ± 7.1206.5 ± 5.5198.5 ± 7.020−3.9 ± 2.919−0.8 ± 1.2<0.001
SF-36 domain scoresb             
 Physical function (PF)1839.9 ± 25.01938.7 ± 19.71867.2 ± 29.81842.5 ± 20.11827.3 ± 24.8183.0 ± 22.10.001
 Role physical (RP)1829.2 ± 40.41932.9 ± 35.41956.6 ± 35.21748.5 ± 39.01825.0 ± 44.61713.2 ± 34.40.20
 Bodily pain (BP)1949.8 ± 31.11938.6 ± 27.21972.5 ± 23.41846.9 ± 32.31922.7 ± 23.9189.7 ± 25.40.04
 General health (GH)1941.3 ± 16.41944.5 ± 16.01958.9 ± 18.31846.8 ± 15.51917.6 ± 20.7182.1 ± 17.20.02
 Vitality (VT)1946.8 ± 23.31943.9 ± 18.31961.6 ± 13.51846.4 ± 17.71914.7 ± 21.7182.0 ± 13.80.047
 Social function (SF)1947.4 ± 39.41971.1 ± 28.61968.4 ± 29.61872.9 ± 27.21921.1 ± 40.8180.7 ± 19.90.07
 Role emotional (RE)1961.4 ± 42.01963.2 ± 44.31986.0 ± 30.11772.5 ± 41.21924.6 ± 33.01713.7 ± 50.10.43
 Mental health (MH)1961.3 ± 22.01958.7 ± 17.91972.0 ± 16.11861.6 ± 17.31910.7 ± 25.5182.0 ± 11.90.54
 Physical component score (PCS)1733.9 ± 9.01733.5 ± 6.61844.1 ± 9.01837.7 ± 10.31710.1 ± 7.4163.8 ± 8.40.02
 Mental component score (MCS)1945.1 ± 15.11947.1 ± 11.71650.7 ± 11.31648.7 ± 11.6175.2 ± 15.0160.2 ± 8,70.39
Beck depression inventoryc1610.5 ± 7.3189.7 ± 5.8146.4 ± 8.91610.6 ± 10.114−5.1 ± 8.416−0.5 ± 10.20.42
Beck anxiety inventoryc1813.7 ± 11.01912.1 ± 10.5168.0 ± 6.51710.5 ± 7.416−6.9 ± 10.219−2.4 ± 11.40.10
Brief psychiatric rating scalec1927.0 ± 7.31927.8 ± 8.01821.4 ± 4.61924.8 ± 5.518−5.9 ± 6.319-3.0 ± 8.40.09

Randomized Study Period

Active stimulation as compared to sham-stimulation resulted in significant reductions of BFMDRS Movement score, BFMDRS Disability score, and of GCI dystonia and pain scores after 3 months.2 Significant improvement of HRQoL was observed in the active stimulation group only, and included the following SF-36 domains: PF (P = 0.001), BP (P = 0.04), GH (P = 0.02), VT (P = 0.047) (Table 1). BDI, BAI, and BPRS scores had not changed significantly in either group at month 3 compared to baseline.

Open-Label Study Extension

After 6 months of continuous DBS, the average BFMDRS Movement score reduction was significant both in generalized (−42%) and segmental dystonia (−53%). Comparisons of baseline and 6-month data for the entire group showed significant improvements in all SF-36 domains (Table 2), without significant differences between the two types of dystonia.

Table 2. Results of the open-label extension phase
VariableBaseline6 MoChange from baseline to 6 moP value
NMean ± SDNMean ± SDNMean ± SD
  • a

    The total movement score of the Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS) is the sum of individual scores for each body region and represents the severity of symptoms of dystonia.

  • b

    A higher score on this scale indicates a higher level of function.

  • c

    A higher score on this scale indicates a greater severity of symptoms.

BFMDRS movement scorea4036.4 ± 24.63620.2 ± 18.036−16.7 ± 13.0<0.001
BFMDRS disability score4010.0 ± 6.6365.9 ± 5.636−4.1 ± 3.6<0.001
SF-36 domain scoresb       
 Physical function (PF)3739.3 ± 22.13463.1 ± 27.53323.1 ± 25.7<0.001
 Role physical (RP)3731.1 ± 37.53463.2 ± 39.03331.1 ± 39.0<0.001
 Bodily pain (BP)3844.2 ± 29.43469.8 ± 26.23421.8 ± 25.1<0.001
 General health (GH)3842.9 ± 16.03461.0 ± 21.73419.2 ± 21.5<0.001
 Vitality (VT)3845.4 ± 20.73459.3 ± 20.73412.9 ± 23.60.003
 Social function (SF)3859.2 ± 36.03479.0 ± 26.83418.0 ± 35.50.009
 Role emotional (RE)3862.3 ± 42.63482.4 ± 33.13424.5 ± 40.50.005
 Mental health (MH)3860.0 ± 19.83474.0 ± 19.13414.2 ± 18.6<0.001
 Physical component score (PCS)3633.7 ± 7.73444.1 ± 9.13410.6 ± 9.9<0.001
 Mental component score (MCS)3646.2 ± 13.23451.8 ± 11.8344.0 ± 12.90.01
Beck depression inventoryc3410.1 ± 6.5317.1 ± 6.729−3.1 ± 5.70.008
Beck anxiety inventoryc3712.9 ± 10.7329.4 ± 7.634−3.5 ± 10.50.09
Brief psychiatric rating scalec3827.4 ± 7.63325.3 ± 7.133−2.0 ± 7.00.19

Among the patients with abnormal baseline SF-36 domain scores (z < −1), the following proportion entered the normal age-matched range after 6 months of neurostimulation: 14 of 34 patients for PF, 16 of 28 for RP, 15 of 28 for BP, 17 of 27 for GH, 11 of 23 for VT, 12 of 20 for SF, 11 of 18 for RE, and 11 of 16 for MH.

Six months of continuous DBS also resulted in a significant improvement of the BDI score, whereas BAI and BPRS scores did not change significantly (Table 2).

According to regression analyses, BFMDRS Movement score reduction was the only significant predictor of SF-36 PCS improvement after 6 months of neurostimulation (P = 0.003). GCI pain score reduction was weakly associated with improvement of the SF-36 MCS (P = 0.05) after 6 months of continuous DBS. None of the baseline factors tested (age, gender, disease severity, disease duration, type of dystonia, GCI pain, BDI, BAI scores) were predictive of SF-36 PCS or MCS improvement at 6 months.

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. APPENDIX
  8. REFERENCES

This first sham-controlled DBS trial in dystonia proves a positive effect on health-related quality of life in patients with medically refractory segmental and generalized dystonia. Three months of active stimulation resulted in significant improvement of the severity of dystonia, and physical aspects of HRQoL, compared to sham stimulation. Notably, none of the SF-36 dimensions improved with sham-stimulation. The clinical benefit was sustained after 6 months of continuous DBS, and the symptomatic benefit translated into a significant improvement of all SF-36 domains, as well as of depression scores measured by the BDI.

Patients with segmental and generalized dystonia showed similar improvements in SF-36 physical and mental dimensions following 6 months of continuous DBS, despite some differences regarding disability, PF, and VT scores at baseline. This suggests that both types of dystonia are equally likely to respond favorably to DBS.

Only few previous studies have assessed HRQoL in smaller series of patients with dystonia and DBS using a variety of outcome measures.6–8 Different from our study, Vidailhet et al. reported improvement of only two of the physical SF-36 domains 12 months following surgery in their series of patients with generalized dystonia, despite a comparable degree of BFMDRS Movement score improvement.8 This discrepancy might in part be attributable to the smaller sample size of that study, but clearly indicates the need for more data to better delineate the effects of DBS on HRQoL and identify predictors of HRQoL improvement in dystonia patients treated with DBS.

The present data indicate that symptomatic improvement of dystonia by means of BFMDRS movement score reduction represents the most important predictor of HRQoL improvement. Our results further indicate that neither age of onset, duration of disease, gender nor distribution of dystonia, exhibit any relation to HRQoL improvement.

Another important observation of the present study is that mild to moderate depression at baseline was not a negative predictor of outcome, and even improved with DBS. Patients with depression may therefore not necessarily need to be excluded from pallidal DBS despite some recent concern about an increased risk of suicidality with this treatment.9

In conclusion, pallidal DBS in primary segmental and generalized dystonia induces a rapid and pronounced improvement of HRQoL that is indicative of early postoperative psychosocial adaptation even in patients with long-standing and severe disease. This first sham-controlled trial thus proofs a favorable impact of DBS on HRQoL in severe primary dystonia which is at least comparable to the effect of neurostimulation on HRQoL in other movement disorders such as Parkinson's disease or essential tremor.10

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. APPENDIX
  8. REFERENCES

The study was supported by an unrestricted research grant from Medtronic Inc. to JV and RB. Additional funding was obtained from the universities involved and from the German Ministry of Research and Technology (FK: 01GI0201). The sponsors had no influence on the design, data collection or analysis of the trial. The following authors have served as paid speakers for Medtronic: Guenther Deuschl, Wilhelm Eisner, Martin Krause, Andreas Kupsch, Martin Krause, Marcus O. Pinsker; Gerd-Helge Schneider, Alfons Schnitzler, Volker Tronnier, Thomas Trottenberg, Jan Vesper, Jürgen Voges, Jens Volkmann. The following authors have served as paid consultants for Medtronic: Günther Deuschl, Geir Ketil Roeste, Lars Timmermann, Volker Tronnier, Jens Volkmann, Lars Woitecki. The following authors have received research grants (>$10,000) from Medtronic: Reiner Benecke, Günther Deuschl, Martin Krause, Andreas Kupsch, Jens Volkmann.

APPENDIX

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. APPENDIX
  8. REFERENCES

Members of the Deep Brain Stimulation for Dystonia Study Group are listed below according to their function in the trial: Study Design and Principle Investigators: R. Benecke, J. Volkmann; Statistical Advisor: Lothar Gierl (deceased), Institute for Medical Informatics and Statistics, University of Rostock, Rostock, Germany; External Raters: K.P. Bathia, Institute of Neurology, Queen Square, London, UK, and J.L. Vitek, Center for Neurological Restoration, Cleveland Clinic, Ohio, USA; Neurosurgical Monitoring: M. H. Mehdorn, Department of Neurosurgery, Christian-Albrechts-University, Kiel, Germany; Investigators (in alphabetical order by center and last name): Berlin: Doreen Gruber, Anatol Kivi, Andrea A. Kühn, Andreas Kupsch, Thomas Trottenberg, Gerd-Helge Schneider; Düsseldorf/Cologne: Alfons Schnitzler, Volker Sturm, Lars Timmermann, Jürgen Voges, Lars Wojtecki; Freiburg: Guido Nikkah, Thomas Prokop, Jan Vesper; Heidelberg: Manja Kloss, Martin Krause, Volker Tronnier; Innsbruck: Wilhelm Eisner, Thomas Fiegele, Jöerg Müeller, Werner Poewe; Kiel: Güenther Deuschl, Jan Herzog, Maximilian M. Mehdorn, Marcus O. Pinsker, Monika Pötter, Frank Steigerwald, Jens Volkmann; Münster: Hans-Werner Boothe, Angela Brentrup, Juliane Vollmer-Haase; Oslo: Geir Ketil Roeste, Inger Marie Skogseid; Rostock: Reiner Benecke, Jan-Uwe Müller, Matthias Wittstock, Alexander Wolters; Würzburg: Markus Naumann, Axel Schramm.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. APPENDIX
  8. REFERENCES