- Email: [email protected]
Deep brain stimulation versus best medical therapy for advanced Parkinson's disease
Reflection and Reaction
Deep brain stimulation versus best medical therapy for advanced Parkinson’s disease
www.thelancet.com/neurology Vol 8 March 2009
10% of patients in the surgical group had hardwarerelated complications, which is much higher than in the German study.2 Although Weaver and co-workers’ study1 was well designed and thorough, this work involved only 6 months of follow-up, which is too short a time to assess the outcome of treatment for a chronic progressive disease such as PD. All surgical studies (including ablative and DBS techniques) in PD that conform to the strict rules of a randomised controlled trial have undoubtedly shown that, at 6 months, surgery is better than no surgery for this group of patients. This is the case for pallidotomy,3,4 with follow-up reaching up to 24 months in some patients.4 At present, at least five open-label studies have been published that describe the outcome of DBS in the STN at 4–5 years,5–9 all of which show better results than baseline, mainly on appendicular motor symptoms, with a persistent decrease in levodopa-induced dyskinesias. Although these studies were not randomised controlled trials, they provide clinical support for the longerterm benefit of DBS in the STN for some symptoms of advanced PD. The clinical evidence for the benefits of surgery in the context of advanced PD (assuming proper selection
BSIP, ASTIER-CHRU-Lille/Science Photo Library
Although deep brain stimulation (DBS) in the subthalamic nucleus (STN) and the globus pallidus internus (GPi) is well established and routinely used worldwide for surgical treatment of advanced Parkinson’s disease (PD), few of the several hundred reports on DBS published in the past 15 years qualify as evidencebased medicine (ie, prospective randomised controlled studies with masked outcome assessments). Therefore, the North American multicentre study recently published in JAMA1 is a welcome contribution. This study reported the 6-month masked outcomes for 255 patients (25% of whom were aged ≥70 years), with 134 randomly assigned to receive best medical therapy and 121 to receive DBS (60 in the STN and 61 in the GPi). The primary outcome was time spent in the “on” state (“good motor control with unimpeded motor function”) without dyskinesia. Motor and cognitive functions, quality of life, and adverse events were also monitored. Patients who received DBS gained a mean of 4·6 h per day of “on” time, whereas patients who received medical therapy had no benefit. There was a clinical motor improvement in 71% of patients who received DBS and in 32% of patients who received medical therapy. Furthermore, the DBS group had improved quality of life measurements and cognition was generally unaffected. Severe side-effects were more common in the patients who received surgery than in those who received medical treatment (falls, depression, infections related to DBS hardware, and one fatal haemorrhage). The authors concluded that, at 6 months, DBS was more effective than best medical therapy, but at the cost of serious adverse events. An earlier German multicentre study that used a similar protocol arrived at the same conclusion.2 The North American study differs from the German trial in that patients included were up to 83 years old: patients with PD who are older than 70–75 years of age are seldom offered DBS surgery. Another difference is that the German study used DBS only in the STN, whereas the American trial used DBS in either the STN or the GPi. All centres involved in the North American study were chosen because of their track records in experienced use of DBS for PD. Nevertheless, about
A patient being prepared for DBS surgery
223
Reflection and Reaction
of patients) is so convincing that doing randomised studies between surgery and non-surgery groups with a long follow-up over several years would be ethically impossible. In fact, Weaver and co-workers state in their study that “results indicated that randomization to the best medical therapy group could be discontinued”. This ethical problem indicates the dilemma of the idea of evidence-based medicine: would a randomised trial with a follow-up of 6 months carry more scientific weight than repetitive non-randomised trials from across the world with much longer follow-up, which all provide concurring conclusions—namely that surgery is efficacious for patients with advanced PD? What we learn from the JAMA paper is that, at 6 months of follow-up, patients with advanced PD who receive DBS have better outcomes than those who do not receive DBS. One of the ongoing debates in DBS today is focused on the timing of the surgery. In a pilot study from France, patients with PD were randomly assigned to groups that received DBS in the STN earlier than usual (ie, after 5–7 years of disease duration and before establishment of motor complications) or that continued on best medical therapy. The surgical group had better results on all scores at 18 months’ follow-up than did the patients who received best medical therapy.10 A similar European multicentre study is underway with follow-up intended to extend for several years.
224
Marwan Hariz Unit of Functional Neurosurgery, Institute of Neurology, Queen Square, London WC1N 3BG, UK [email protected] I have occasionally received honoraria and travel expenses from Medtronic for giving lectures at meetings. 1
2
3
4
5
6
7
8
9
10
Weaver FM, Follett K, Stern M, et al; CSP 468 Study Group. Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. JAMA 2009; 301: 63–73. Deuschl G, Schade-Brittinger C, Krack P, et al. German Parkinson Study Group, Neurostimulation Section. A randomized trial of deep-brain stimulation for Parkinson’s disease. N Engl J Med 2006; 355: 896–908. de Bie RM, de Haan RJ, Nijssen PC, et al. Unilateral pallidotomy in Parkinson’s disease: a randomised, single blind, multicentre trial. Lancet 1999; 354: 1665–69. Vitek JL, Bakay RA, Freeman A, et al. Randomized trial of pallidotomy versus medical therapy for Parkinson’s disease. Ann Neurol 2003; 53: 558–69. Krack P, Batir A, Van Blercom N, et al. Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 2003; 349: 1925–34. Rodriguez-Oroz MC, Obeso JA, Lang AE, et al. Bilateral deep brain stimulation in Parkinson’s disease: a multicenter study with 4 years follow-up. Brain 2005; 128: 2240–49. Schüpbach WM, Chastan N, Welter ML, et al. Stimulation of the subthalamic nucleus in Parkinson’s disease: a 5 year follow up. J Neurol Neurosurg Psychiatry 2005; 76: 1640–44. Østergaard K, Aa Sunde N. Evolution of Parkinson’s disease during 4 years of bilateral deep brain stimulation of the subthalamic nucleus. Mov Disord 2006; 21: 624–31. Wider C, Pollo C, Bloch J, Burkhard PR, Vingerhoets FJ. Long-term outcome of 50 consecutive Parkinson’s disease patients treated with subthalamic deep brain stimulation. Parkinsonism Relat Disord 2008; 14: 114–19. Schüpbach WM, Maltête D, Houeto JL, et al. Neurosurgery at an earlier stage of Parkinson’s disease: a randomized, controlled trial. Neurology 2007; 68: 267–71.
www.thelancet.com/neurology Vol 8 March 2009
Deep brain stimulation versus best medical therapy for advanced Parkinson’s disease
www.thelancet.com/neurology Vol 8 March 2009
10% of patients in the surgical group had hardwarerelated complications, which is much higher than in the German study.2 Although Weaver and co-workers’ study1 was well designed and thorough, this work involved only 6 months of follow-up, which is too short a time to assess the outcome of treatment for a chronic progressive disease such as PD. All surgical studies (including ablative and DBS techniques) in PD that conform to the strict rules of a randomised controlled trial have undoubtedly shown that, at 6 months, surgery is better than no surgery for this group of patients. This is the case for pallidotomy,3,4 with follow-up reaching up to 24 months in some patients.4 At present, at least five open-label studies have been published that describe the outcome of DBS in the STN at 4–5 years,5–9 all of which show better results than baseline, mainly on appendicular motor symptoms, with a persistent decrease in levodopa-induced dyskinesias. Although these studies were not randomised controlled trials, they provide clinical support for the longerterm benefit of DBS in the STN for some symptoms of advanced PD. The clinical evidence for the benefits of surgery in the context of advanced PD (assuming proper selection
BSIP, ASTIER-CHRU-Lille/Science Photo Library
Although deep brain stimulation (DBS) in the subthalamic nucleus (STN) and the globus pallidus internus (GPi) is well established and routinely used worldwide for surgical treatment of advanced Parkinson’s disease (PD), few of the several hundred reports on DBS published in the past 15 years qualify as evidencebased medicine (ie, prospective randomised controlled studies with masked outcome assessments). Therefore, the North American multicentre study recently published in JAMA1 is a welcome contribution. This study reported the 6-month masked outcomes for 255 patients (25% of whom were aged ≥70 years), with 134 randomly assigned to receive best medical therapy and 121 to receive DBS (60 in the STN and 61 in the GPi). The primary outcome was time spent in the “on” state (“good motor control with unimpeded motor function”) without dyskinesia. Motor and cognitive functions, quality of life, and adverse events were also monitored. Patients who received DBS gained a mean of 4·6 h per day of “on” time, whereas patients who received medical therapy had no benefit. There was a clinical motor improvement in 71% of patients who received DBS and in 32% of patients who received medical therapy. Furthermore, the DBS group had improved quality of life measurements and cognition was generally unaffected. Severe side-effects were more common in the patients who received surgery than in those who received medical treatment (falls, depression, infections related to DBS hardware, and one fatal haemorrhage). The authors concluded that, at 6 months, DBS was more effective than best medical therapy, but at the cost of serious adverse events. An earlier German multicentre study that used a similar protocol arrived at the same conclusion.2 The North American study differs from the German trial in that patients included were up to 83 years old: patients with PD who are older than 70–75 years of age are seldom offered DBS surgery. Another difference is that the German study used DBS only in the STN, whereas the American trial used DBS in either the STN or the GPi. All centres involved in the North American study were chosen because of their track records in experienced use of DBS for PD. Nevertheless, about
A patient being prepared for DBS surgery
223
Reflection and Reaction
of patients) is so convincing that doing randomised studies between surgery and non-surgery groups with a long follow-up over several years would be ethically impossible. In fact, Weaver and co-workers state in their study that “results indicated that randomization to the best medical therapy group could be discontinued”. This ethical problem indicates the dilemma of the idea of evidence-based medicine: would a randomised trial with a follow-up of 6 months carry more scientific weight than repetitive non-randomised trials from across the world with much longer follow-up, which all provide concurring conclusions—namely that surgery is efficacious for patients with advanced PD? What we learn from the JAMA paper is that, at 6 months of follow-up, patients with advanced PD who receive DBS have better outcomes than those who do not receive DBS. One of the ongoing debates in DBS today is focused on the timing of the surgery. In a pilot study from France, patients with PD were randomly assigned to groups that received DBS in the STN earlier than usual (ie, after 5–7 years of disease duration and before establishment of motor complications) or that continued on best medical therapy. The surgical group had better results on all scores at 18 months’ follow-up than did the patients who received best medical therapy.10 A similar European multicentre study is underway with follow-up intended to extend for several years.
224
Marwan Hariz Unit of Functional Neurosurgery, Institute of Neurology, Queen Square, London WC1N 3BG, UK [email protected] I have occasionally received honoraria and travel expenses from Medtronic for giving lectures at meetings. 1
2
3
4
5
6
7
8
9
10
Weaver FM, Follett K, Stern M, et al; CSP 468 Study Group. Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. JAMA 2009; 301: 63–73. Deuschl G, Schade-Brittinger C, Krack P, et al. German Parkinson Study Group, Neurostimulation Section. A randomized trial of deep-brain stimulation for Parkinson’s disease. N Engl J Med 2006; 355: 896–908. de Bie RM, de Haan RJ, Nijssen PC, et al. Unilateral pallidotomy in Parkinson’s disease: a randomised, single blind, multicentre trial. Lancet 1999; 354: 1665–69. Vitek JL, Bakay RA, Freeman A, et al. Randomized trial of pallidotomy versus medical therapy for Parkinson’s disease. Ann Neurol 2003; 53: 558–69. Krack P, Batir A, Van Blercom N, et al. Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 2003; 349: 1925–34. Rodriguez-Oroz MC, Obeso JA, Lang AE, et al. Bilateral deep brain stimulation in Parkinson’s disease: a multicenter study with 4 years follow-up. Brain 2005; 128: 2240–49. Schüpbach WM, Chastan N, Welter ML, et al. Stimulation of the subthalamic nucleus in Parkinson’s disease: a 5 year follow up. J Neurol Neurosurg Psychiatry 2005; 76: 1640–44. Østergaard K, Aa Sunde N. Evolution of Parkinson’s disease during 4 years of bilateral deep brain stimulation of the subthalamic nucleus. Mov Disord 2006; 21: 624–31. Wider C, Pollo C, Bloch J, Burkhard PR, Vingerhoets FJ. Long-term outcome of 50 consecutive Parkinson’s disease patients treated with subthalamic deep brain stimulation. Parkinsonism Relat Disord 2008; 14: 114–19. Schüpbach WM, Maltête D, Houeto JL, et al. Neurosurgery at an earlier stage of Parkinson’s disease: a randomized, controlled trial. Neurology 2007; 68: 267–71.
www.thelancet.com/neurology Vol 8 March 2009