Beyond the holy grail of motor symptoms: deep brain stimulation for Parkinson’s disease
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《神经病学神经外科学杂志》
1 Department of Neurology, King’s College Hospital, London, UK
2 National Institutes of Neurological Disorders and Stroke, National Institute of Health, Bethesda, Maryland, USA
Correspondence to:
M Samuel
Department of Neurology, King’s College Hospital, Denmark Hill, London, SE5 9RS, UK; mike.samuel@kingsch.nhs.uk
Optimising non-dopaminergic and dopaminergic related motor responses, as well as cognitive and behavioural responses
Keywords: apathy; balance; behaviour; deep brain stimulation; Parkinson
At a recent international movement disorders meeting, a timely question was raised: "Is dopaminergic related gambling an indication or a contra-indication for subthalamic nucleus deep brain stimulation?" The question captures not only our curiosity on complex pathophysiology but also the very real uncertainties of our clinical practice.
Parkinson’s disease (PD) is a neurodegenerative disorder characterised by motor, cognitive, and behavioural symptoms. Bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) has been available for the treatment for advanced PD since 1993 and has demonstrated marked and sustained efficacy in motor symptoms.1 In this issue, the papers by Czernecki et al (pp 775), Colnat-Coulbois et al(pp 780), and Capecci et al (pp 769) expand the focus beyond the typical dopaminergic motor symptoms with reports on behavioural changes, balance, and overall functional improvement. These are relevant concepts to clinicians wanting to offer comprehensive advice to their patients and to health care providers who fund such resource intensive therapies.
Czernecki et al address the issue of aggravation of motivational changes following STN DBS by comparing non-demented, non-depressed PD patients 10 months following surgery with a matched non-surgical control group on levodopa using an apathy scale, reward sensitivity, and gambling tasks. As a group, there was no overall significant deterioration in apathy following acute DBS, despite 33% having significant apathy with DBS off. On the contrary, 9/18 patients of the DBS group had an improvement in apathy. Overall, both levodopa and DBS improved apathy grouped scores to the same extent. The study is limited by the lack of preoperative behavioural baseline measures, brevity of the off-stimulation period, and the lack of caregiver information. The DBS group was withdrawn from a relatively small amount of drug (133 mg of levodopa) in the "off" condition, compared with the levodopa group who were withdrawn from 982 mg. Despite these limitations, the study suggests that there is no significant evidence that STN stimulation per se acutely worsened apathy. Further, operated patients whose apathy improved differed from operated patients whose apathy did not improve in having shorter disease duration and less severe parkinsonism. Reward sensitivity and the gambling task measures did not change. These findings suggest that medial frontal and orbitofrontal function, as tapped by these assessments, can remain unaffected by STN DBS.
Colnat-Coulbois et al address the issue of balance control following STN DBS. Normal balance involves the central integration of inputs of proprioceptive, vestibular, and visual function to modulate the magnitude of the motor output (the motor response to the act of falling). In PD, it is hypothesised that the inputs are centrally misrepresented, thus resulting in impairments in the output to (rigid) muscles (impaired postural righting mechanisms). The response of axial symptoms to a preoperative levodopa challenge has been shown to be a good predictor for postoperative outcome of axial symptoms and postural stability.2 Colnat-Coulbois et al extend this observation by using prospective measurements of static and dynamic posturography in a cohort of STN DBS patients. The responses from a patient’s feet and muscles were recorded with the patient standing on a tilting platform while undergoing various experimental procedures designed to perturb balance. The authors showed that selective aspects of both static responses and dynamic adaptation improved following DBS. In particular, the postoperative outcome to the combined effect of DBS and a 30% reduction in levodopa was occasionally better than that of the preoperative outcome with levodopa alone. The authors hypothesise that the effect of DBS was synergistic with levodopa, possibly mediated via brainstem non-dopaminergic pathways. If indeed the case, it suggests that the current criteria for predicting the outcome of axial symptoms and posture may be too restrictive.
Capecci et al reported a prospective study utilising three different clinician-rated and patient-rated measures of functional status in a cohort of PD patients assessed 1 and 2 years after STN DBS. The results were compared with a matched control group who opted for medical therapy. The authors reported significant improvements in two of the functional scales compared to preoperative baseline measures in the surgical group. In comparison to the control group, the surgical group had significant improvements on all three measures of functional status following surgery due to the decline in function in the control group. The authors argue that in a medically treated group, it may have been unethical to delay by up to 2 years: "treatment whose efficacy in controlling motor symptoms is firmly established". Despite non-blinding, this study highlights not only an outcome clinically relevant to both patients and caregivers, but also the role of control groups in the optimal assessment of postoperative outcomes.
These papers contribute to the ongoing refinement of the practice of STN DBS for advanced PD. Beyond the known improvement of motor signs of PD, the evidence is limited regarding the impact of STN DBS on issues of quality of life, caregiver burden, social outcomes, non-motor symptoms, medication-induced behavioural symptoms, and other non-dopaminergic symptoms. Methodological issues addressed include the need for appropriate control groups and difficulties in achieving blinding and randomisation. Implicit within these, is the need to control for the multiple factors involved in the aetiology of these symptoms (which, as highlighted in these papers, include the non-dopaminergic aetiology of symptoms, STN stimulation, the role of medications, functional neuroanatomy of the STN, or the progression of PD). Currently, despite patient selection based on standard DBS inclusion criteria,3 DBS clinicians are sometimes faced post-operatively with patients who have had an excellent motor response, no major change in cognition, and yet feel unsatisfied. There are many unanswered non-motor and motor issues relating to DBS. These three studies allow more focused discussion on the increasingly complex issue of optimising not only the dopaminergic related motor responses, but also non-dopaminergic related motor responses, as well as cognitive and behavioural responses.
REFERENCES
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.
Welter ML, Houeto JL, Tezenas du MS, et al. Clinical predictive factors of subthalamic stimulation in Parkinson’s disease. Brain 2002;125:575–83.
Lang AE, Widner H. Deep brain stimulation for Parkinson’s disease: patient selection and evaluation. Mov Disord 2002;17 (Suppl 3) :S94–101.(M Samuel1 and V Voon2)
2 National Institutes of Neurological Disorders and Stroke, National Institute of Health, Bethesda, Maryland, USA
Correspondence to:
M Samuel
Department of Neurology, King’s College Hospital, Denmark Hill, London, SE5 9RS, UK; mike.samuel@kingsch.nhs.uk
Optimising non-dopaminergic and dopaminergic related motor responses, as well as cognitive and behavioural responses
Keywords: apathy; balance; behaviour; deep brain stimulation; Parkinson
At a recent international movement disorders meeting, a timely question was raised: "Is dopaminergic related gambling an indication or a contra-indication for subthalamic nucleus deep brain stimulation?" The question captures not only our curiosity on complex pathophysiology but also the very real uncertainties of our clinical practice.
Parkinson’s disease (PD) is a neurodegenerative disorder characterised by motor, cognitive, and behavioural symptoms. Bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) has been available for the treatment for advanced PD since 1993 and has demonstrated marked and sustained efficacy in motor symptoms.1 In this issue, the papers by Czernecki et al (pp 775), Colnat-Coulbois et al(pp 780), and Capecci et al (pp 769) expand the focus beyond the typical dopaminergic motor symptoms with reports on behavioural changes, balance, and overall functional improvement. These are relevant concepts to clinicians wanting to offer comprehensive advice to their patients and to health care providers who fund such resource intensive therapies.
Czernecki et al address the issue of aggravation of motivational changes following STN DBS by comparing non-demented, non-depressed PD patients 10 months following surgery with a matched non-surgical control group on levodopa using an apathy scale, reward sensitivity, and gambling tasks. As a group, there was no overall significant deterioration in apathy following acute DBS, despite 33% having significant apathy with DBS off. On the contrary, 9/18 patients of the DBS group had an improvement in apathy. Overall, both levodopa and DBS improved apathy grouped scores to the same extent. The study is limited by the lack of preoperative behavioural baseline measures, brevity of the off-stimulation period, and the lack of caregiver information. The DBS group was withdrawn from a relatively small amount of drug (133 mg of levodopa) in the "off" condition, compared with the levodopa group who were withdrawn from 982 mg. Despite these limitations, the study suggests that there is no significant evidence that STN stimulation per se acutely worsened apathy. Further, operated patients whose apathy improved differed from operated patients whose apathy did not improve in having shorter disease duration and less severe parkinsonism. Reward sensitivity and the gambling task measures did not change. These findings suggest that medial frontal and orbitofrontal function, as tapped by these assessments, can remain unaffected by STN DBS.
Colnat-Coulbois et al address the issue of balance control following STN DBS. Normal balance involves the central integration of inputs of proprioceptive, vestibular, and visual function to modulate the magnitude of the motor output (the motor response to the act of falling). In PD, it is hypothesised that the inputs are centrally misrepresented, thus resulting in impairments in the output to (rigid) muscles (impaired postural righting mechanisms). The response of axial symptoms to a preoperative levodopa challenge has been shown to be a good predictor for postoperative outcome of axial symptoms and postural stability.2 Colnat-Coulbois et al extend this observation by using prospective measurements of static and dynamic posturography in a cohort of STN DBS patients. The responses from a patient’s feet and muscles were recorded with the patient standing on a tilting platform while undergoing various experimental procedures designed to perturb balance. The authors showed that selective aspects of both static responses and dynamic adaptation improved following DBS. In particular, the postoperative outcome to the combined effect of DBS and a 30% reduction in levodopa was occasionally better than that of the preoperative outcome with levodopa alone. The authors hypothesise that the effect of DBS was synergistic with levodopa, possibly mediated via brainstem non-dopaminergic pathways. If indeed the case, it suggests that the current criteria for predicting the outcome of axial symptoms and posture may be too restrictive.
Capecci et al reported a prospective study utilising three different clinician-rated and patient-rated measures of functional status in a cohort of PD patients assessed 1 and 2 years after STN DBS. The results were compared with a matched control group who opted for medical therapy. The authors reported significant improvements in two of the functional scales compared to preoperative baseline measures in the surgical group. In comparison to the control group, the surgical group had significant improvements on all three measures of functional status following surgery due to the decline in function in the control group. The authors argue that in a medically treated group, it may have been unethical to delay by up to 2 years: "treatment whose efficacy in controlling motor symptoms is firmly established". Despite non-blinding, this study highlights not only an outcome clinically relevant to both patients and caregivers, but also the role of control groups in the optimal assessment of postoperative outcomes.
These papers contribute to the ongoing refinement of the practice of STN DBS for advanced PD. Beyond the known improvement of motor signs of PD, the evidence is limited regarding the impact of STN DBS on issues of quality of life, caregiver burden, social outcomes, non-motor symptoms, medication-induced behavioural symptoms, and other non-dopaminergic symptoms. Methodological issues addressed include the need for appropriate control groups and difficulties in achieving blinding and randomisation. Implicit within these, is the need to control for the multiple factors involved in the aetiology of these symptoms (which, as highlighted in these papers, include the non-dopaminergic aetiology of symptoms, STN stimulation, the role of medications, functional neuroanatomy of the STN, or the progression of PD). Currently, despite patient selection based on standard DBS inclusion criteria,3 DBS clinicians are sometimes faced post-operatively with patients who have had an excellent motor response, no major change in cognition, and yet feel unsatisfied. There are many unanswered non-motor and motor issues relating to DBS. These three studies allow more focused discussion on the increasingly complex issue of optimising not only the dopaminergic related motor responses, but also non-dopaminergic related motor responses, as well as cognitive and behavioural responses.
REFERENCES
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.
Welter ML, Houeto JL, Tezenas du MS, et al. Clinical predictive factors of subthalamic stimulation in Parkinson’s disease. Brain 2002;125:575–83.
Lang AE, Widner H. Deep brain stimulation for Parkinson’s disease: patient selection and evaluation. Mov Disord 2002;17 (Suppl 3) :S94–101.(M Samuel1 and V Voon2)