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A systematic review of the efficacy of globus pallidus stimulation in the treatment of Parkinson’s disease
Journal of Clinical Neuroscience 16 (2009) 877–881
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Review
A systematic review of the efficacy of globus pallidus stimulation in the treatment of Parkinson’s disease Pablo Andrade a,b,*, José D. Carrillo-Ruiz a,b, Fiacro Jiménez a,b a b
Unit of Functional Neurosurgery, Stereotactic and Radiosurgery, Mexico General Hospital, Mexico City, Mexico Anáhuac University, School of Medicine and Psychology, Mexico City, Mexico
a r t i c l e
i n f o
Article history: Received 24 September 2008 Accepted 26 November 2008
Keywords: GPi Deep brain stimulation Parkinson’s disease Meta-analysis Pallidal stimulation
a b s t r a c t The aim of this study was to systematically review the data published on deep brain stimulation (DBS) of the globus pallidus internus (GPi) in Parkinson’s disease (PD), and to determine its efficacy and optimal stimulation parameters. Only 22 of 4,648 articles fulfilled the inclusion and exclusion criteria of the study. The data were analysed using the Wilcoxon test. For 327 patients who underwent GPi-DBS, the preoperative baseline Unified Parkinson’s Disease Rating Scale (UPDRS) score, off-medication, mean was 52.7 (range 26.5–77.2). The postoperative UPDRS score, off-medication/on-stimulation, mean was 33.7 (range 18.7–46.2). The delta mean (the difference in mean UPDRS score between baseline and maximum follow-up) was 19.1 (range 2.2 to 36.5) (p < 0.001). When the electrical parameters were compared against the delta UPDRS score, the analysis showed that only frequency was correlated with motor improvement (R2 = 0.42, p < 0.05). Thus, GPi-DBS is a highly effective target for neuromodulation in PD. However, we found that significant clinical improvement (>50% delta UPDRS score) in PD is achieved at an amplitude of between 2.0 V and 3.5 V, a pulse-width between 75 ls and 300 ls and a frequency between 100 Hz and 190 Hz. Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction Stereotactic ablative surgery in the globus pallidus has been used to treat Parkinson’s disease (PD) since the end of the 1950s, when excellent results with improvement of rigidity and bradykinesia were obtained.1–3 During the 1970s and 1980s, surgical treatment of PD was replaced by pharmacotherapy with 3,4-dihydroxy-L-phenylalanine (L-dopa).4,5 Although the initial interest in surgery, based on promising results, had decreased because of new pharmacological alternatives, it was reconsidered in patients with low tolerance to medication during long-term therapy due to motor and non-motor side effects.6,7 At the same time, a renewed interest in PD surgery came about because of technical improvements in imaging and a broadened knowledge of the physiology and biochemistry of the basal ganglia. In 1994, Siegfried introduced deep brain stimulation (DBS) of the globus pallidus internus (GPi) as an alternative therapy to lesional surgery.8 Advantages of this treatment include its reversibility and potential to be used bilaterally. In addition, GPi-DBS can reduce the likelihood of permanent adverse effects by tailoring
* Corresponding author. Postal address: Mar de los Vapores no. 41, Colonia Ciudad Brisa, Naucalpan, Estado de México 53280, México. Tel.: +52 55 53640383; fax: +52 55 53642380. E-mail address: [email protected] (P. Andrade). 0967-5868/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2008.11.006
the stimulation parameters in specific programs to each patient. GPi-DBS also helps avoid the dyskinesias produced by L-dopa.9 There are now a number of different targets for DBS in PD, which include the subthalamic nucleus (STN),10 the ventralis intermedius nucleus of the thalamus (VIM),11 the prelemniscal radiation (Raprl),12 the pedunculus pontinus nucleus (PPN)13 as well as the GPi.1 Although STN-DBS has become the gold standard of PD surgical treatment, GPi-DBS remains a useful target because this procedure can improve motor symptoms with relatively fewer side effects.14 Targeting the GPi is also easier than the STN. Although many studies have demonstrated beneficial effects of GPi-DBS, to our knowledge there has not been a meta-analysis of patient outcome and stimulation parameters for this procedure. Thus, our main objective was to evaluate the efficacy of GPi-DBS using the Unified Parkinson’s Disease Rating Scale (UPDRS) score, find the most frequently used stimulation parameters and correlate them with the clinical response. Our hypothesis was that we would find positive or negative correlations with clinical symptoms when the parameters were manipulated and that these parameters could be divided into useful ranges.
2. Materials and methods We performed a systematic review of DBS and GPi. Articles were collected from PubMed by searching the following keywords
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Table 1 Demographic data for 327 patients from 22 studies who had undergone unilateral or bilateral deep brain stimulation of the globus pallidus internus and the electrical parameters as stated in the original article Study No.
Year
First author
Reference No.
No. patients
Procedure type
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
1997 1998 1998 1998 1998 1999 1999 1999 2000 2000 2000 2001 2001 2002 2002 2002 2003 2004 2004 2004 2005 2006
Gross, C. Ghika, J. Stanzione, P. Krack, P. Krack, P. Ardouin, C. Burchiel, K. Durif, F. Pillon, B. Kumar, R. Jahanshahi, M. Obeso, J.A. Peppe, A. Defebvre, L. Loher, T. Durif, F. Visser-Vandewalle, V. Peppe, A. Ogura, M. Volkmann, J. Anderson, V. Jimenez, F.
15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
7 6 2 8 3 13 10 6 76 22 6 38 6 7 16 6 26 8 30 11 11 9
U B B U B B B U B U B B B B U U U B U B B U
&B
&B &B
&B &B
&B
Parametersà Frequency (Hz)
Pulse-width (ls)
Amplitude (V)
135–185 130–185 185 130 166 139.6 185 130 139.6 100–200 135.8 185 185 130 5–100 134.5 135 185 180 175.2 ± 19.8 135 130
90–120 75 150–200 60 110 78.5 158 ± 35 60 78.5 50–100 82.5 450 210 90 200–210 75 234 210 120 163.6 ± 85.2 75 300
2.4–7.2 3.5 2.5–3.5 0.5–3.6 3.6 3.1 2.8 ± 0.8 2.5 3.1 4.0 3.6 10.5 2.0–4.0 2.4 1.3–1.4 3.1 3.3 3.45 2.0 3.4 ± 0.6 3.0 2.5
B = bilateral, U = unilateral. U & B indicates that both procedures were reported on in the same study; treatment type was not specified for every patient in each study. à Electrical parameters were given as the mean, range or standard deviation.
and their combinations: ‘‘DBS”, ‘‘GPi”, ‘‘Parkinson”, ‘‘PD”, ‘‘electrical stimulation”, ‘‘globus pallidus”, ‘‘neuromodulation”, ‘‘pallidal stimulation” and ‘‘Parkinson’s disease”. The research was performed by two independent research teams who standardized the results according to the inclusion criteria, and the data were gathered by three independent researchers. The inclusion criteria were: original full-text articles (clinical trials, case series and case reports) and reviews written in English, French, German or Spanish between 1994 and July 2007. The analysis involved: therapy in humans; non-comparative data or comparison with GPi lesions or STN stimulation; unilateral or bilateral application; evaluation of baseline and post-surgical follow-up using the UPDRS; image-guided targeting method; and active contacts located by stereotactic coordinates. The exclusion criteria included: the absence of a standardized UPDRS score; absence of reported stimulation parameters; presence of co-morbidity (especially psychiatric illnesses except for depression); a previous ablative neurosurgical procedure; and non-specific reporting of UPDRS in on/off stimulation periods. A database was made up of articles that fulfilled all criteria. The information was then cross-referenced by aggregated variables such as use of microrecording or macrostimulation, and image type used for targeting (CT scan, MRI and ventriculography). Data were analysed using the non-parametric Wilcoxon test for clinimetric changes, in particular, for the UPDRS score quantities. A delta score improvement (maximum follow-up postsurgical score minus baseline values) was obtained from the data, and the correlation between stimulation parameters (amplitude, frequency and pulse-width) and the delta score was tested using Pearson’s test. Values of two or more standard deviations over the mean were excluded. An alpha level of p < 0.05 was considered significant. 3. Results From the primary search of 4,648 articles, which included the keywords either alone or combined, only 77 papers fulfilled the inclusion criteria. After applying the exclusion criteria, we obtained
23 articles: 30 were excluded for the absence of a standardized UPDRS score; 22 for not reporting stimulation parameters; 3 for co-morbidity; 1 for neurosurgical ablative antecedents; and 16 for non-specific reporting of UPDRS scores in on/off stimulation periods. One article was excluded for data repetition. Finally, 22 articles were selected for this study (Table 1). From the 327 patients who had undergone GPi-DBS, 13.6% had a unilateral procedure, 59.1% a bilateral procedure, and 27.3% of patients attended centers where both unilateral and bilateral procedures were conducted.15–36
Fig. 1. The Unified Parkinson’s Disease Rating Scale (UPDRS) score showing an evident improvement in patients’ motor outcome after deep brain stimulation (DBS) of the globus pallidus internus, with a mean difference (delta) of almost 20 points (**p < 0.0001), represented by the difference between the horizontal bars. In the left box, the baseline UPDRS score is reported for patients off medication (mean, 52.7 [horizontal bar], spread 26.5–77.2). The right box represents post-DBS UPDRS score reported for patients on stimulation/off medication at maximum follow-up (mean of 33.7 [horizontal bar], spread 18.7–46.2).
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The preoperative baseline UPDRS score, evaluated when patients were off-medication, was a mean of 52.7 (range 26.5–77.2) compared with a mean postoperative score of 33.7 (range 18.7– 46.2) (off-medication/on-stimulation) (p < 0.0001). The delta UPDRS score, between the baseline UPDRS and UPDRS at maxi-
mum follow-up, was 19.1 (range –2.2 to 36.5) (Fig. 1). Only one study reported an increased UPDRS score at maximum followup.31 The mean postoperative follow-up was 14.6 months (range 3–49) (Table 2). It was difficult to establish differences in the subcategories of tremor, rigidity and bradykinesia, because not all pa-
Table 2 Clinimetric changes in preoperative and postoperative UPDRS scores for 327 patients from 22 studies who had undergone unilateral or bilateral deep brain stimulation of the globus pallidus internus Study No.
Reference No.
UPDRS baseline
UPDRS post DBSà
Delta (%)§
Location–
Targeting method
Microrecording during surgery
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
53.4 66 69.5 ± 0.5 50 ± 11 50 48.5 ± 11.3 67 ± 24 36 ± 2 55.4 ± 8.5 50.1 ± 2.9 54.2 ± 9.2 50.8 ± 11.6 63.3 ± 4.8 50 ± 6 57.2 ± 13.7 34 ± 5 26.5 ± 9.2 67.4 ± 3.05 77.2 ± 11 30.1 ± 19.4 51 ± 22 53 ± 22
37 33 33 ± 6 34.1 ± 18.4 35.6 32.05 ± 12.9 40 ± 14 23 37.1 ± 13.3 35 ± 3.4 46.2 ± 8.7 33.9 ± 12.3 31.8 ± 5.6 31 ± 10 35.3 ± 6.9 26 ± 7 28.7 ± 7.6 38.3 ± 4.7 41.7 ± 17 18.7 ± 12.8 39 ± 23 31 ± 12
30.7 50 52.5 31.8 28.8 33.9 40.2 36.1 33.6 30.1 14.7 33.2 49.7 38 38.2 23.3 -8 43.1 45.9 37.9 23.5 41.5
P A P& P P& P& P& P& P P& P P P P P P P P A P& P& P
MRI & V MRI MRI MRI & V MRI & V MRI & V MRI & CT MRI & V MRI & V MRI & V MRI MRI, CT & V MRI, CT & V V MRI & CT MRI & V CT & V MRI, CT & V MRI & V CT & V MRI MRI & CT
Yes No Yes Yes Yes Yes No No Yes Yes No Yes Yes No Yes Yes No Yes Yes No Yes Yes
A A A A A A
A A
A = anteroventral, CT = CT scan, DBS = deep brain stimulation, GPi = globus pallidus internus, MRI = magnetic resonance imaging, P = posteroventral, UPDRS = Unified Parkinson’s Disease Rating Scale, V = ventriculography. Baseline score (mean or mean ± standard deviation) reported when patients were off medication. à Post-DBS score (mean or mean ± standard deviation) at ‘‘on stimulation/off medication” at maximum follow-up (range 3–49 months, mean 14.6). § Delta expressed as a percentage obtained from the difference between the UPDRS baseline score and the maximum postoperative score. – Location of effective contacts inside the GPi.
Fig. 2. Stimulation parameters correlation. A: Comparison between amplitude and UPDRS score delta does not show direct relation among these variables (p = 0.62, R2 = 0.11, M = 0.01). Significant improvement (over the mean) occurs between 2.0 and 3.5V. B: Comparison of pulse-width and UPDRS score delta, also does not show any direct correlation to motor outcome (p = 0.36, R2 = 0.2, M = 0.03). Clinical improvement occurs between 75 and 300 lsec. C: When frequency is compared to the UPDRS score delta, there is an improvement in motor outcome as the frequency parameters are increased. The maximum effect occurs between 100 and 190Hz in a significant manner (p < 0.05, R2 = 0.42, M = 0.17).
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pers reported both the basal and final values, or the values were absent. An analysis of anatomical positioning showed that the most common electrode position was the posteroventral GPi (54.5%), and the rest were located in the anteroventral GPi (45.5%). No article reported implantation in any other site. The mean UPDRS delta score for the posteroventral GPi was 30.81 compared to the mean anteroventral GPi score of 47.95, resulting in a difference between these two targets (p < 0.05). Various radiological tools and a mixture of techniques were used to identify the surgical target: ventriculography alone (4.5%), ventriculography and CT scan (9.0%); MRI alone (18.1%); and ventriculography with MRI (40.9%), the most frequent method of targeting. Microrecording assistance was performed in 68.1% of patients. None of the targeting procedures resulted in an improved clinical outcome (Table 2). However, treatment using bilateral procedures (n = 13 studies) showed a significant improvement against unilateral stimulation (n = 3 studies) (p < 0.05). Mean values (±standard deviation, SD) for the electrical parameters were: amplitude, 3.4 ± 1.8 V; frequency, 149.2 ± 31.0 Hz; and pulse-width, 145 ± 95.6 ls (Table 1). Only frequency was significantly correlated with the delta UPDRS score (Pearson test: p < 0.05; R2 = 0.42; M = 0.17) (Fig. 2). The correlation was poor for amplitude and pulse-width. The position of the electrodes (anteroventral or posteroventral portion of the GPi) did not affect the statistical significance of comparing frequency with delta values. There was a trend between increasing frequency and an improving delta UPDRS score.
4. Discussion GPi is the largest of the nuclei of the basal ganglia into which electrodes are implanted, compared to VIM, STN, zona incerta and the Raprl, even though only a specific area is utilized for surgical treatment. There are two main sites reported for implanting electrodes within the GPi: posteroventral and anteroventral. In this review we found 10 studies in which the anteroventral portion of the GPi was reported as a useful target. However, many caudal and ventral areas could be considered better targets. The posteroventral area is the most effective location for motor amelioration according to previously reported pallidotomy results.37 In the present study, the anteroventral area was associated with better clinical results from electrical stimulation;16,33 and although the number of the anteroventral studies is very small, (n = 2), the difference was also statistically significant (p < 0.05). Although both the posteroventral and anteroventral areas are located in the sensorimotor portion of the GPi, the mechanism of action of lesional and electrical stimulation procedures could differ depending on anatomical location. In addition, according to our results, it is not necessary to use microrecording to identify the neurons of the GPi during DBS to obtain a successful motor outcome. Thus, it might be possible to reduce surgical time and avoid the complications inherent to the microrecording procedure, including parenchymal hemorrhage, infection or cognitive deficits.38 Although STN-DBS is the gold standard of surgical treatment in PD, our personal experience and that reported from around the world suggests that GPi-DBS is an easier procedure because the area for stimulation is larger, microrecording is not absolutely necessary, and GPi-DBS has fewer side effects. According to our study, pallidal stimulation is still an effective neuromodulation treatment in PD. Almost a 20% decrease in UPDRS score was obtained 1 year after surgery. However, STNDBS is more effective in treating clinical signs of PD (40–60%) and in ameliorating the UPDRS score.1,3,10 Including other emer-
gent targets such as the PPN (32%),13 zona incerta (76%),39 and Raprl (65%)12 also significantly diminished the UPDRS scale. Issues related to tremor, rigidity, akinesia, bradykinesia and dyskinesia were either not well specified in the articles, or they were reported in an irregular form that complicated the relationship between basal data and their outcomes. Specific analysis of each symptom is important in order to select the best target to apply treatment. Additionally, GPi-DBS has been shown to decrease dyskinesias induced by L-dopa. This could not be comprehensively examined in our analysis due to the lack of a standardized data reporting system. Although some studies reported reduced L-dopa-carbidopa dosage, the quantity was not specified in all articles. One important question in brain neuromodulation studies is the mechanism of electrical stimulation in neuronal circuits to ameliorate motor signs. There are a number of theories that suggest that electricity modifies neurons depending on the central nervous system tissue type (nucleus or fibres) and thus stimulates or inhibits the membrane’s electrical properties; other explanations include ‘‘neural jamming” to understand the phenomenon.11 Certainly, the stimulation parameters are not homogeneous, and the ranges are very wide in some reports (e.g. 0.5–10.5 V, 5– 200 Hz and 50–450 ls).15–36. There is no global consensus about the initial parameters of DBS, nor is there a protocol for stimulation options in case of poor outcome. Overall, our review confirms that significant clinical improvement in PD (>50% in delta UPDRS score) is achieved when GPiDBS is applied at between 2.0 V and 3.5 V, 75 ls and 300 ls, and 100 Hz and 190 Hz. Outcome was correlated with stimulation frequency, but not amplitude or pulse width and interestingly, basic studies with isolated pallidal neurons exposed to electrical pulses showed that the most important parameter in neuronal stimulation was the frequency.40 Our review has also highlighted the evolution in stereotactic procedures. Initially ventriculography was the only technique used to find the target. Many groups have continued to use it. This classical technique can be used alone or combined with more recent tools, such as CT scans or MRI. We included 15 studies that reported the use of ventriculography as the sole targeting procedure, the remainder using mixed CT scans and MRI. No statistical differences were reported in the accuracy of methods, so it was considered not important. The only matter discussed in this regard is the ability to locate the electrode’s contacts clearly inside the GPi, in two and three dimensions with both CT scans and MRI; which is not possible to determine on X-ray. 5. Conclusions GPi-DBS is an important target with good outcomes in patients with PD. The best anatomical location is situated in the anteroventral zone of the nucleus. Bilateral is more effective than unilateral stimulation. The most important parameter in stimulation was the frequency compared to voltage or pulse-width. References 1. Volkmann J, Allert N, Voges J, et al. Safety and efficacy of pallidal or subthalamic nucleus stimulation in advanced PD. Neurology 2001;56:548–51. 2. Kern DS, Kumar R. Deep brain stimulation. Neurologist 2007;13:237–52. 3. Krause M, Fogel W, Heck A, et al. Deep brain stimulation for the treatment of Parkinson’s disease: subthalamic nucleus versus globus pallidus internus. J Neurol Neurosurg Psychiatry 2001;70:464–70. 4. Yahr MD. Levodopa. Ann Intern Med 1975;83:677–82. 5. Lloyd KG, Davidson L, Hornykiewicz O. The neurochemistry of Parkinson’s disease: effect of L-dopa therapy. J Pharmacol Exp Ther 1975;195:453–64. 6. Ludin HP, Bass-Verrey F. Study of deterioration in long-term treatment of parkinsonism with L-dopa plus decarboxylase inhibitor. J Neural Transm 1976;38:249–58. 7. Ahlskog JE. Beating a dead horse: dopamine and Parkinson disease. Neurology 2007;69:1701–11.
P. Andrade et al. / Journal of Clinical Neuroscience 16 (2009) 877–881 8. Siegfried J, Lippitz B. Bilateral chronic electrostimulation of ventroposterolateral pallidum: a new therapeutic approach for alleviating all parkinsonian symptoms. Neurosurgery 1994;35:1126–9. 9. Rodrigues JP, Walters SE, Watson P, et al. Globus pallidus stimulation in advanced Parkinson’s disease. J Clin Neurosci 2007;14:208–15. 10. Limousin P, Pollak P, Benazzouz A, et al. Bilateral subthalamic nucleus stimulation for severe Parkinson’s disease. Mov Disord 1995;10:672–4. 11. Benabid AL, Pollak P, Gao D, et al. Chronic electrical stimulation of the ventralis intermedius nucleus of the thalamus as a treatment of movement disorders. J Neurosurg 1996;84:203–14. 12. Carrillo-Ruiz JD, Velasco F, Jiménez F, et al. Bilateral electrical stimulation of prelemniscal radiations in the treatment of advanced Parkinson’s disease. Neurosurgery 2008;62:335–45. 13. Stefani A, Lozano AM, Peppe A, et al. Bilateral deep brain stimulation of the pedunculopontine and subthalamic nuclei in severe Parkinson’s disease. Brain 2007;130:1596–607. 14. Rodriguez-Oroz MC, Obeso JA, Lang AE, et al. Bilateral deep brain stimulation in Parkinson’s disease: a multicentre study with 4 years follow-up. Brain 2005;128:2240–9. 15. Gross C, Rougier A, Guehl D, et al. High-frequency stimulation of the globus pallidus internalis in Parkinon’s disease: a study of seven cases. J Neurosurg 1997;87:491–8. 16. Ghika J, Villemure JG, Fankhauser H, et al. Efficiency and safety of bilateral contemporaneous pallidal stimulation (deep brain stimulation) in levodoparesponsive patients with Parkinson’s disease with severe motor fluctuations: a 2-year follow-up review. J Neurosurg 1998;89:713–8. 17. Stanzione P, Mazzone P, Peppe A, et al. Antiparkinsonian and anti-levodopainduced dyskinesia effects obtained by stimulating the same site within the GPi in PD. Neurology 1998;51:1776–7. 18. Krack P, Pollak P, Limousin P, et al. Subthalamic nucleus or internal pallidal stimulation in young onset Parkinson’s disease. Brain 1998;121:451–7. 19. Krack P, Pollak P, Limousin P, et al. Opposite motor effects of pallidal stimulation in Parkinson’s disease. Ann Neurol 1998;43:180–92. 20. Ardouin C, Pillon B, Peiffer E, et al. Bilateral subthalamic or pallidal stimulation for Parkinson’s disease affects neither memory nor executive functions: a consecutive series of 62 patients. Ann Neurol 1999;46:217–23. 21. Burchiel KJ, Anderson VC, Favre J, et al. Comparison of pallidal and subthalamic nucleus deep brain stimulation for advanced Parkinson’s disease: results of a randomized, blinded pilot study. Neurosurgery 1999;45:1375–82. 22. Durif F, Lemaire JJ, Debilly B, et al. Acute and chronic effects of anteromedial globus pallidus stimulation in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1999;67:315–22. 23. Pillon B, Ardouin C, Damier P, et al. Neuropsychological changes between ‘‘OFF” and ‘‘on” STN or GPi stimulation in Parkinson’s disease. Neurology 2000;55:411–8. 24. Kumar R, Lang AE, Rodriguez-Oroz MC, et al. Deep brain stimulation of the globus pallidus pars interna in advanced Parkinson’s disease. Neurology 2000;55(12 Suppl. 6):S34–9.
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25. Jahanshahi M, Ardouin CM, Brown RG, et al. The impact of deep brain stimulation on executive function in Parkinson’s disease. Brain 2000;123:1142–54. 26. The Deep Brain Stimulation for Parkinson´s Disease Study Group. Deep brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson’s disease. N Engl J Med 2001;345:956–63. 27. Peppe A, Pierantozzi M, Altibrandi M, et al. Bilateral GPi DBS is useful to reduce abnormal involuntary movements in advanced Parkinson’s disease patients, but its action is related to modality and site of stimulation. Eur J Neurol 2001;8:579–86. 28. Defebvre LJ, Krystkowiak P, Blatt JL, et al. Influence of pallidal stimulation and levodopa on gait and preparatory postural adjustments in Parkinson’s disease. Mov Disord 2002;17:76–83. 29. Loher TJ, Burgunder JM, Pohle T, et al. Long-term pallidal deep brain stimulation in patients with advanced Parkinson disease: 1-year follow-up study. J Neurosurg 2002;96:844–53. 30. Durif F, Lemaire JJ, Debilly B, et al. Long-term follow-up of globus pallidus chronic stimulation in advanced Parkinson’s disease. Mov Disord 2002;17:803–7. 31. Visser-Vandewalle V, van der Linden C, Temel Y, et al. Long-term motor effect of unilateral pallidal stimulation in 26 patients with advanced Parkinson disease. J Neurosurg 2003;99:701–7. 32. Peppe A, Pierantozzi M, Bassi A, et al. Stimulation of the subthalamic nucleus compared with the globus pallidus internus in patients with Parkinson disease. J Neurosurg 2004;101:195–200. 33. Ogura M, Nakao N, Nakai E, et al. The mechanism and effect of chronic electrical stimulation of the globus pallidus for treatment of Parkinson disease. J Neurosurg 2004;100:997–1001. 34. Volkmann J, Allert N, Voges J, et al. Long-term results of bilateral pallidal stimulation in Parkinson’s disease. Ann Neurol 2004;55:871–5. 35. Anderson VC, Burchiel KJ, Hogarth P, et al. Pallidal vs subthalamic nucleus deep brain stimulation in Parkinson disease. Arch Neurol 2005;62:554–60. 36. Jiménez F, Velasco F, Carrillo-Ruiz JD, et al. Comparative evaluation of the effects of unilateral lesion versus electrical stimulation of the globus pallidus internus in advanced Parkinson’s disease. Stereotact Funct Neurosurg 2006;84:64–71. 37. Guridi J, Lozano AM. A brief history of pallidotomy. Neurosurgery 1997;41:1169–80. 38. Hariz MI, Fodstad H. Do microelectrode techniques increase accuracy or decrease risks in pallidotomy and deep brain stimulation? A critical review of the literature. Stereotact Funct Neurosurg 1999;72:157–69. 39. Plaha P, Ben-Shlomo Y, Patel NK, et al. Stimulation of the caudal zona incerta is superior to stimulation of the subthalamic nucleus in improving contralateral parkinsonism. Brain 2006;129:1732–47. 40. Birdno MJ, Grill WM. Mechanisms of deep brain stimulation in movement disorders as revealed by changes in stimulus frequency. Neurotherapeutics 2008;5:14–25.
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Review
A systematic review of the efficacy of globus pallidus stimulation in the treatment of Parkinson’s disease Pablo Andrade a,b,*, José D. Carrillo-Ruiz a,b, Fiacro Jiménez a,b a b
Unit of Functional Neurosurgery, Stereotactic and Radiosurgery, Mexico General Hospital, Mexico City, Mexico Anáhuac University, School of Medicine and Psychology, Mexico City, Mexico
a r t i c l e
i n f o
Article history: Received 24 September 2008 Accepted 26 November 2008
Keywords: GPi Deep brain stimulation Parkinson’s disease Meta-analysis Pallidal stimulation
a b s t r a c t The aim of this study was to systematically review the data published on deep brain stimulation (DBS) of the globus pallidus internus (GPi) in Parkinson’s disease (PD), and to determine its efficacy and optimal stimulation parameters. Only 22 of 4,648 articles fulfilled the inclusion and exclusion criteria of the study. The data were analysed using the Wilcoxon test. For 327 patients who underwent GPi-DBS, the preoperative baseline Unified Parkinson’s Disease Rating Scale (UPDRS) score, off-medication, mean was 52.7 (range 26.5–77.2). The postoperative UPDRS score, off-medication/on-stimulation, mean was 33.7 (range 18.7–46.2). The delta mean (the difference in mean UPDRS score between baseline and maximum follow-up) was 19.1 (range 2.2 to 36.5) (p < 0.001). When the electrical parameters were compared against the delta UPDRS score, the analysis showed that only frequency was correlated with motor improvement (R2 = 0.42, p < 0.05). Thus, GPi-DBS is a highly effective target for neuromodulation in PD. However, we found that significant clinical improvement (>50% delta UPDRS score) in PD is achieved at an amplitude of between 2.0 V and 3.5 V, a pulse-width between 75 ls and 300 ls and a frequency between 100 Hz and 190 Hz. Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction Stereotactic ablative surgery in the globus pallidus has been used to treat Parkinson’s disease (PD) since the end of the 1950s, when excellent results with improvement of rigidity and bradykinesia were obtained.1–3 During the 1970s and 1980s, surgical treatment of PD was replaced by pharmacotherapy with 3,4-dihydroxy-L-phenylalanine (L-dopa).4,5 Although the initial interest in surgery, based on promising results, had decreased because of new pharmacological alternatives, it was reconsidered in patients with low tolerance to medication during long-term therapy due to motor and non-motor side effects.6,7 At the same time, a renewed interest in PD surgery came about because of technical improvements in imaging and a broadened knowledge of the physiology and biochemistry of the basal ganglia. In 1994, Siegfried introduced deep brain stimulation (DBS) of the globus pallidus internus (GPi) as an alternative therapy to lesional surgery.8 Advantages of this treatment include its reversibility and potential to be used bilaterally. In addition, GPi-DBS can reduce the likelihood of permanent adverse effects by tailoring
* Corresponding author. Postal address: Mar de los Vapores no. 41, Colonia Ciudad Brisa, Naucalpan, Estado de México 53280, México. Tel.: +52 55 53640383; fax: +52 55 53642380. E-mail address: [email protected] (P. Andrade). 0967-5868/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2008.11.006
the stimulation parameters in specific programs to each patient. GPi-DBS also helps avoid the dyskinesias produced by L-dopa.9 There are now a number of different targets for DBS in PD, which include the subthalamic nucleus (STN),10 the ventralis intermedius nucleus of the thalamus (VIM),11 the prelemniscal radiation (Raprl),12 the pedunculus pontinus nucleus (PPN)13 as well as the GPi.1 Although STN-DBS has become the gold standard of PD surgical treatment, GPi-DBS remains a useful target because this procedure can improve motor symptoms with relatively fewer side effects.14 Targeting the GPi is also easier than the STN. Although many studies have demonstrated beneficial effects of GPi-DBS, to our knowledge there has not been a meta-analysis of patient outcome and stimulation parameters for this procedure. Thus, our main objective was to evaluate the efficacy of GPi-DBS using the Unified Parkinson’s Disease Rating Scale (UPDRS) score, find the most frequently used stimulation parameters and correlate them with the clinical response. Our hypothesis was that we would find positive or negative correlations with clinical symptoms when the parameters were manipulated and that these parameters could be divided into useful ranges.
2. Materials and methods We performed a systematic review of DBS and GPi. Articles were collected from PubMed by searching the following keywords
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Table 1 Demographic data for 327 patients from 22 studies who had undergone unilateral or bilateral deep brain stimulation of the globus pallidus internus and the electrical parameters as stated in the original article Study No.
Year
First author
Reference No.
No. patients
Procedure type
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
1997 1998 1998 1998 1998 1999 1999 1999 2000 2000 2000 2001 2001 2002 2002 2002 2003 2004 2004 2004 2005 2006
Gross, C. Ghika, J. Stanzione, P. Krack, P. Krack, P. Ardouin, C. Burchiel, K. Durif, F. Pillon, B. Kumar, R. Jahanshahi, M. Obeso, J.A. Peppe, A. Defebvre, L. Loher, T. Durif, F. Visser-Vandewalle, V. Peppe, A. Ogura, M. Volkmann, J. Anderson, V. Jimenez, F.
15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
7 6 2 8 3 13 10 6 76 22 6 38 6 7 16 6 26 8 30 11 11 9
U B B U B B B U B U B B B B U U U B U B B U
&B
&B &B
&B &B
&B
Parametersà Frequency (Hz)
Pulse-width (ls)
Amplitude (V)
135–185 130–185 185 130 166 139.6 185 130 139.6 100–200 135.8 185 185 130 5–100 134.5 135 185 180 175.2 ± 19.8 135 130
90–120 75 150–200 60 110 78.5 158 ± 35 60 78.5 50–100 82.5 450 210 90 200–210 75 234 210 120 163.6 ± 85.2 75 300
2.4–7.2 3.5 2.5–3.5 0.5–3.6 3.6 3.1 2.8 ± 0.8 2.5 3.1 4.0 3.6 10.5 2.0–4.0 2.4 1.3–1.4 3.1 3.3 3.45 2.0 3.4 ± 0.6 3.0 2.5
B = bilateral, U = unilateral. U & B indicates that both procedures were reported on in the same study; treatment type was not specified for every patient in each study. à Electrical parameters were given as the mean, range or standard deviation.
and their combinations: ‘‘DBS”, ‘‘GPi”, ‘‘Parkinson”, ‘‘PD”, ‘‘electrical stimulation”, ‘‘globus pallidus”, ‘‘neuromodulation”, ‘‘pallidal stimulation” and ‘‘Parkinson’s disease”. The research was performed by two independent research teams who standardized the results according to the inclusion criteria, and the data were gathered by three independent researchers. The inclusion criteria were: original full-text articles (clinical trials, case series and case reports) and reviews written in English, French, German or Spanish between 1994 and July 2007. The analysis involved: therapy in humans; non-comparative data or comparison with GPi lesions or STN stimulation; unilateral or bilateral application; evaluation of baseline and post-surgical follow-up using the UPDRS; image-guided targeting method; and active contacts located by stereotactic coordinates. The exclusion criteria included: the absence of a standardized UPDRS score; absence of reported stimulation parameters; presence of co-morbidity (especially psychiatric illnesses except for depression); a previous ablative neurosurgical procedure; and non-specific reporting of UPDRS in on/off stimulation periods. A database was made up of articles that fulfilled all criteria. The information was then cross-referenced by aggregated variables such as use of microrecording or macrostimulation, and image type used for targeting (CT scan, MRI and ventriculography). Data were analysed using the non-parametric Wilcoxon test for clinimetric changes, in particular, for the UPDRS score quantities. A delta score improvement (maximum follow-up postsurgical score minus baseline values) was obtained from the data, and the correlation between stimulation parameters (amplitude, frequency and pulse-width) and the delta score was tested using Pearson’s test. Values of two or more standard deviations over the mean were excluded. An alpha level of p < 0.05 was considered significant. 3. Results From the primary search of 4,648 articles, which included the keywords either alone or combined, only 77 papers fulfilled the inclusion criteria. After applying the exclusion criteria, we obtained
23 articles: 30 were excluded for the absence of a standardized UPDRS score; 22 for not reporting stimulation parameters; 3 for co-morbidity; 1 for neurosurgical ablative antecedents; and 16 for non-specific reporting of UPDRS scores in on/off stimulation periods. One article was excluded for data repetition. Finally, 22 articles were selected for this study (Table 1). From the 327 patients who had undergone GPi-DBS, 13.6% had a unilateral procedure, 59.1% a bilateral procedure, and 27.3% of patients attended centers where both unilateral and bilateral procedures were conducted.15–36
Fig. 1. The Unified Parkinson’s Disease Rating Scale (UPDRS) score showing an evident improvement in patients’ motor outcome after deep brain stimulation (DBS) of the globus pallidus internus, with a mean difference (delta) of almost 20 points (**p < 0.0001), represented by the difference between the horizontal bars. In the left box, the baseline UPDRS score is reported for patients off medication (mean, 52.7 [horizontal bar], spread 26.5–77.2). The right box represents post-DBS UPDRS score reported for patients on stimulation/off medication at maximum follow-up (mean of 33.7 [horizontal bar], spread 18.7–46.2).
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The preoperative baseline UPDRS score, evaluated when patients were off-medication, was a mean of 52.7 (range 26.5–77.2) compared with a mean postoperative score of 33.7 (range 18.7– 46.2) (off-medication/on-stimulation) (p < 0.0001). The delta UPDRS score, between the baseline UPDRS and UPDRS at maxi-
mum follow-up, was 19.1 (range –2.2 to 36.5) (Fig. 1). Only one study reported an increased UPDRS score at maximum followup.31 The mean postoperative follow-up was 14.6 months (range 3–49) (Table 2). It was difficult to establish differences in the subcategories of tremor, rigidity and bradykinesia, because not all pa-
Table 2 Clinimetric changes in preoperative and postoperative UPDRS scores for 327 patients from 22 studies who had undergone unilateral or bilateral deep brain stimulation of the globus pallidus internus Study No.
Reference No.
UPDRS baseline
UPDRS post DBSà
Delta (%)§
Location–
Targeting method
Microrecording during surgery
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
53.4 66 69.5 ± 0.5 50 ± 11 50 48.5 ± 11.3 67 ± 24 36 ± 2 55.4 ± 8.5 50.1 ± 2.9 54.2 ± 9.2 50.8 ± 11.6 63.3 ± 4.8 50 ± 6 57.2 ± 13.7 34 ± 5 26.5 ± 9.2 67.4 ± 3.05 77.2 ± 11 30.1 ± 19.4 51 ± 22 53 ± 22
37 33 33 ± 6 34.1 ± 18.4 35.6 32.05 ± 12.9 40 ± 14 23 37.1 ± 13.3 35 ± 3.4 46.2 ± 8.7 33.9 ± 12.3 31.8 ± 5.6 31 ± 10 35.3 ± 6.9 26 ± 7 28.7 ± 7.6 38.3 ± 4.7 41.7 ± 17 18.7 ± 12.8 39 ± 23 31 ± 12
30.7 50 52.5 31.8 28.8 33.9 40.2 36.1 33.6 30.1 14.7 33.2 49.7 38 38.2 23.3 -8 43.1 45.9 37.9 23.5 41.5
P A P& P P& P& P& P& P P& P P P P P P P P A P& P& P
MRI & V MRI MRI MRI & V MRI & V MRI & V MRI & CT MRI & V MRI & V MRI & V MRI MRI, CT & V MRI, CT & V V MRI & CT MRI & V CT & V MRI, CT & V MRI & V CT & V MRI MRI & CT
Yes No Yes Yes Yes Yes No No Yes Yes No Yes Yes No Yes Yes No Yes Yes No Yes Yes
A A A A A A
A A
A = anteroventral, CT = CT scan, DBS = deep brain stimulation, GPi = globus pallidus internus, MRI = magnetic resonance imaging, P = posteroventral, UPDRS = Unified Parkinson’s Disease Rating Scale, V = ventriculography. Baseline score (mean or mean ± standard deviation) reported when patients were off medication. à Post-DBS score (mean or mean ± standard deviation) at ‘‘on stimulation/off medication” at maximum follow-up (range 3–49 months, mean 14.6). § Delta expressed as a percentage obtained from the difference between the UPDRS baseline score and the maximum postoperative score. – Location of effective contacts inside the GPi.
Fig. 2. Stimulation parameters correlation. A: Comparison between amplitude and UPDRS score delta does not show direct relation among these variables (p = 0.62, R2 = 0.11, M = 0.01). Significant improvement (over the mean) occurs between 2.0 and 3.5V. B: Comparison of pulse-width and UPDRS score delta, also does not show any direct correlation to motor outcome (p = 0.36, R2 = 0.2, M = 0.03). Clinical improvement occurs between 75 and 300 lsec. C: When frequency is compared to the UPDRS score delta, there is an improvement in motor outcome as the frequency parameters are increased. The maximum effect occurs between 100 and 190Hz in a significant manner (p < 0.05, R2 = 0.42, M = 0.17).
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pers reported both the basal and final values, or the values were absent. An analysis of anatomical positioning showed that the most common electrode position was the posteroventral GPi (54.5%), and the rest were located in the anteroventral GPi (45.5%). No article reported implantation in any other site. The mean UPDRS delta score for the posteroventral GPi was 30.81 compared to the mean anteroventral GPi score of 47.95, resulting in a difference between these two targets (p < 0.05). Various radiological tools and a mixture of techniques were used to identify the surgical target: ventriculography alone (4.5%), ventriculography and CT scan (9.0%); MRI alone (18.1%); and ventriculography with MRI (40.9%), the most frequent method of targeting. Microrecording assistance was performed in 68.1% of patients. None of the targeting procedures resulted in an improved clinical outcome (Table 2). However, treatment using bilateral procedures (n = 13 studies) showed a significant improvement against unilateral stimulation (n = 3 studies) (p < 0.05). Mean values (±standard deviation, SD) for the electrical parameters were: amplitude, 3.4 ± 1.8 V; frequency, 149.2 ± 31.0 Hz; and pulse-width, 145 ± 95.6 ls (Table 1). Only frequency was significantly correlated with the delta UPDRS score (Pearson test: p < 0.05; R2 = 0.42; M = 0.17) (Fig. 2). The correlation was poor for amplitude and pulse-width. The position of the electrodes (anteroventral or posteroventral portion of the GPi) did not affect the statistical significance of comparing frequency with delta values. There was a trend between increasing frequency and an improving delta UPDRS score.
4. Discussion GPi is the largest of the nuclei of the basal ganglia into which electrodes are implanted, compared to VIM, STN, zona incerta and the Raprl, even though only a specific area is utilized for surgical treatment. There are two main sites reported for implanting electrodes within the GPi: posteroventral and anteroventral. In this review we found 10 studies in which the anteroventral portion of the GPi was reported as a useful target. However, many caudal and ventral areas could be considered better targets. The posteroventral area is the most effective location for motor amelioration according to previously reported pallidotomy results.37 In the present study, the anteroventral area was associated with better clinical results from electrical stimulation;16,33 and although the number of the anteroventral studies is very small, (n = 2), the difference was also statistically significant (p < 0.05). Although both the posteroventral and anteroventral areas are located in the sensorimotor portion of the GPi, the mechanism of action of lesional and electrical stimulation procedures could differ depending on anatomical location. In addition, according to our results, it is not necessary to use microrecording to identify the neurons of the GPi during DBS to obtain a successful motor outcome. Thus, it might be possible to reduce surgical time and avoid the complications inherent to the microrecording procedure, including parenchymal hemorrhage, infection or cognitive deficits.38 Although STN-DBS is the gold standard of surgical treatment in PD, our personal experience and that reported from around the world suggests that GPi-DBS is an easier procedure because the area for stimulation is larger, microrecording is not absolutely necessary, and GPi-DBS has fewer side effects. According to our study, pallidal stimulation is still an effective neuromodulation treatment in PD. Almost a 20% decrease in UPDRS score was obtained 1 year after surgery. However, STNDBS is more effective in treating clinical signs of PD (40–60%) and in ameliorating the UPDRS score.1,3,10 Including other emer-
gent targets such as the PPN (32%),13 zona incerta (76%),39 and Raprl (65%)12 also significantly diminished the UPDRS scale. Issues related to tremor, rigidity, akinesia, bradykinesia and dyskinesia were either not well specified in the articles, or they were reported in an irregular form that complicated the relationship between basal data and their outcomes. Specific analysis of each symptom is important in order to select the best target to apply treatment. Additionally, GPi-DBS has been shown to decrease dyskinesias induced by L-dopa. This could not be comprehensively examined in our analysis due to the lack of a standardized data reporting system. Although some studies reported reduced L-dopa-carbidopa dosage, the quantity was not specified in all articles. One important question in brain neuromodulation studies is the mechanism of electrical stimulation in neuronal circuits to ameliorate motor signs. There are a number of theories that suggest that electricity modifies neurons depending on the central nervous system tissue type (nucleus or fibres) and thus stimulates or inhibits the membrane’s electrical properties; other explanations include ‘‘neural jamming” to understand the phenomenon.11 Certainly, the stimulation parameters are not homogeneous, and the ranges are very wide in some reports (e.g. 0.5–10.5 V, 5– 200 Hz and 50–450 ls).15–36. There is no global consensus about the initial parameters of DBS, nor is there a protocol for stimulation options in case of poor outcome. Overall, our review confirms that significant clinical improvement in PD (>50% in delta UPDRS score) is achieved when GPiDBS is applied at between 2.0 V and 3.5 V, 75 ls and 300 ls, and 100 Hz and 190 Hz. Outcome was correlated with stimulation frequency, but not amplitude or pulse width and interestingly, basic studies with isolated pallidal neurons exposed to electrical pulses showed that the most important parameter in neuronal stimulation was the frequency.40 Our review has also highlighted the evolution in stereotactic procedures. Initially ventriculography was the only technique used to find the target. Many groups have continued to use it. This classical technique can be used alone or combined with more recent tools, such as CT scans or MRI. We included 15 studies that reported the use of ventriculography as the sole targeting procedure, the remainder using mixed CT scans and MRI. No statistical differences were reported in the accuracy of methods, so it was considered not important. The only matter discussed in this regard is the ability to locate the electrode’s contacts clearly inside the GPi, in two and three dimensions with both CT scans and MRI; which is not possible to determine on X-ray. 5. Conclusions GPi-DBS is an important target with good outcomes in patients with PD. The best anatomical location is situated in the anteroventral zone of the nucleus. Bilateral is more effective than unilateral stimulation. The most important parameter in stimulation was the frequency compared to voltage or pulse-width. References 1. Volkmann J, Allert N, Voges J, et al. Safety and efficacy of pallidal or subthalamic nucleus stimulation in advanced PD. Neurology 2001;56:548–51. 2. Kern DS, Kumar R. Deep brain stimulation. Neurologist 2007;13:237–52. 3. Krause M, Fogel W, Heck A, et al. Deep brain stimulation for the treatment of Parkinson’s disease: subthalamic nucleus versus globus pallidus internus. J Neurol Neurosurg Psychiatry 2001;70:464–70. 4. Yahr MD. Levodopa. Ann Intern Med 1975;83:677–82. 5. Lloyd KG, Davidson L, Hornykiewicz O. The neurochemistry of Parkinson’s disease: effect of L-dopa therapy. J Pharmacol Exp Ther 1975;195:453–64. 6. Ludin HP, Bass-Verrey F. Study of deterioration in long-term treatment of parkinsonism with L-dopa plus decarboxylase inhibitor. J Neural Transm 1976;38:249–58. 7. Ahlskog JE. Beating a dead horse: dopamine and Parkinson disease. Neurology 2007;69:1701–11.
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