Opinion
EDITORIAL
Deep Brain Stimulation of the Subthalamic Nucleus Taking the Ouch Out of Parkinson Disease Pravin Khemani, MD; Richard B. Dewey Jr, MD
Parkinson disease (PD) is known to affect multiple neurotransmitter systems, resulting in both motor and nonmotor symptoms. Pain is an underrecognized but important nonmotor symptom of PD that may be very disabling and is known to Related article page 504 impair quality of life.1 While significant progress has been made in ameliorating motor symptoms using pharmacological, rehabilitative, and surgical treatments, the treatment of pain in this context has not received sufficient attention. A literature review2 noted a reported prevalence of pain in PD of 40% to 85%, yet only about half of patients with PD who felt pain took analgesics. Classifying PD-related pain into its subtypes3 is important for rational treatment, and the most common subtypes of pain in PD are musculoskeletal and dystonic, with central neuropathic pain being the least common.2 To address pain successfully in PD, an understanding of its pathogenesis is important, yet this has remained elusive, in part because its causes are protean. Just as certain motor symptoms of PD are more responsive to dopaminergic drugs and deep brain stimulation (DBS), some pain subtypes may respond better than others to pharmacological and surgical intervention. Dysfunction of both dopaminergic and nondopaminergic basal ganglia pathways are likely to be involved in PD-related pain, which may explain why some types of pain are responsive to levodopa and others are not.4 Deep brain stimulation of the subthalamic nucleus (STN) is now an established treatment of disabling motor symptoms in advanced PD, and it is therefore important to understand its effect on pain associated with PD. Previous reports5,6 on the effects of STN DBS on pain in PD show that the levels of musculoskeletal and dystonic pain decreased when assessed 1 year after surgery, but, to our knowledge, there is no existing information on the status of chronic pain. In this issue of JAMA Neurology, Jung and colleagues7 investigate the long-term effect of STN DBS on pain in 24 patients with PD who were observed for 8 years after undergoing the procedure for alleviating disabling motor symptoms. The beneficial effects of STN DBS in this cohort 3 months after surgery and 24 months after surgery have been previously published.8,9 The subtypes of pain were classified according to Ford.3 The severity and body distribution of pain were compared between presurgical and postsurgical states. Jung and colleagues7 noted significant improvement at 8 years in all pain types present preoperatively, regardless of whether the preoperative pain was responsive to levodopa or not. However, new pain, not present before surgery, developed in 75% of patients during prolonged follow-up. Musculoskeletal pain accounted for the majority of new pain cases. Although the mean severity of pain was less at jamaneurology.com
8 years than at baseline, more patients experienced pain at the end of the observation period than preoperatively. Because previous studies on pain following STN DBS for PD are of short duration, the durability of the procedure’s effect on pain is not well established. The chief strength of the work by Jung and colleagues7 is the long follow-up period, which suggests that, although DBS may relieve pain for a time, this is not a durable effect owing to the onset of new, primarily musculoskeletal pain. A recent report5 was concordant with the study by Jung and colleagues7 in showing the benefit of DBS on dystonic and musculoskeletal pain but was discordant in showing no effect of DBS on central and radicular pain. Methodological differences, the subjective classification of pain, and a much shorter observation period could account for these discrepant findings. The study by Jung and colleagues7 has several limitations that the authors acknowledge, including a small cohort without a control group that was treated medically, the lack of correlation of pain scores with motor Unified Parkinson’s Disease Rating Scale scores (especially rigidity, which can potentially impact musculoskeletal pain), the lack of measures of disability or effect of pain on quality of life, and the lack of mood and cognitive assessments that can influence pain perception. In addition, an analysis of the effect of levodopa on preoperative pain vs the effect of DBS on pain was not performed. This would have been of interest in light of a previous report10 suggesting that the effects of DBS on pain can be predicted by measuring the effects of levodopa on pain. Despite its limitations, the study by Jung and colleagues7 provides a novel perspective on the durability of the pain-relieving properties of STN DBS in PD. The authors direct our attention to the fact that musculoskeletal pain may emerge years after DBS, warranting individualized treatment. The next step is to pursue a deeper understanding of the mechanism of pain in PD. Previous work11 with small numbers of participants has demonstrated altered pain processing in participants with PD who experienced pain compared with those who did not, such that STN DBS raises pain thresholds selectively in those who experience pain. Although there is a growing consensus that STN DBS decreases the level of pain in people with PD, the literature is mixed on the subtypes of pain that are responsive to DBS, and the study by Jung and colleagues7 shows that new pain arising years after the procedure is common. This underscores the importance of performing future trials with larger cohorts, longer observational periods, and standard methods to enable effective interpretation of outcomes. For now, we have learned that STN DBS does not take the ouch out of PD in the long run. (Reprinted) JAMA Neurology May 2015 Volume 72, Number 5
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of St. Andrews Library User on 05/16/2015
499
Opinion Editorial
ARTICLE INFORMATION Author Affiliations: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas. Corresponding Author: Richard B. Dewey Jr, MD, Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, 5323 Harry Hines, Dallas, TX 75390-9036 (richard [email protected]). Published Online: March 23, 2015. doi:10.1001/jamaneurol.2015.36. Conflict of Interest Disclosures: Dr Dewey reported serving as a consultant for Teva Pharmaceuticals, US WorldMeds, Lundbeck, Acadia, Merz, Xenoport, Impax, and GE Healthcare and receiving speakers fees from Teva Pharmaceuticals, US WorldMeds, Lundbeck, and UCB. No other disclosures are reported.
cross-sectional study. Parkinsonism Relat Disord. 2004;10(3):129-136. 2. Broen MP, Braaksma MM, Patijn J, Weber WE. Prevalence of pain in Parkinson’s disease: a systematic review using the modified QUADAS tool. Mov Disord. 2012;27(4):480-484. 3. Ford B. Pain in Parkinson’s disease. Mov Disord. 2010;25(suppl 1):S98-S103. 4. Berardelli A, Conte A, Fabbrini G, et al. Pathophysiology of pain and fatigue in Parkinson’s disease. Parkinsonism Relat Disord. 2012;18(suppl 1):S226-S228. 5. Cury RG, Galhardoni R, Fonoff ET, et al. Effects of deep brain stimulation on pain and other nonmotor symptoms in Parkinson disease. Neurology. 2014; 83(16):1403-1409.
REFERENCES
6. Oshima H, Katayama Y, Morishita T, et al. Subthalamic nucleus stimulation for attenuation of pain related to Parkinson disease. J Neurosurg. 2012;116(1):99-106.
1. Quittenbaum BH, Grahn B. Quality of life and pain in Parkinson’s disease: a controlled
7. Jung YJ, Kim H-J, Jeon BS, Park H, Lee W-W, Paek SH. An 8-year follow-up on the effect of subthalamic
nucleus deep brain stimulation on pain in Parkinson disease [published online March 23, 2015]. JAMA Neurol. doi:10.1001/jamaneurol.2015.8. 8. Kim HJ, Jeon BS, Lee JY, Paek SH, Kim DG. The benefit of subthalamic deep brain stimulation for pain in Parkinson disease: a 2-year follow-up study. Neurosurgery. 2012;70(1):18-23; discussion 23-24. 9. Kim HJ, Paek SH, Kim JY, et al. Chronic subthalamic deep brain stimulation improves pain in Parkinson disease. J Neurol. 2008;255(12):1889-1894. 10. Sürücü O, Baumann-Vogel H, Uhl M, Imbach LL, Baumann CR. Subthalamic deep brain stimulation versus best medical therapy for L-dopa responsive pain in Parkinson’s disease. Pain. 2013;154(8):14771479. 11. Dellapina E, Ory-Magne F, Regragui W, et al. Effect of subthalamic deep brain stimulation on pain in Parkinson’s disease. Pain. 2012;153(11):2267-2273.
A Call for New Thoughts About What Might Influence Human Brain Aging Aging, Apolipoprotein E, and Amyloid Charles DeCarli, MD
The wiser mind mourns less for what age takes away than what it leaves behind. William Wordsworth, The Fountain
As a greater proportion of the world’s population live beyond age 65 years, there is increasing awareness of age-related differences in cognitive ability and a rising interest in finding ways to maintain healthy brain aging with the hope to avoid demenRelated article page 511 tia. Although conventional wisdom stresses the inevitable decline of cognitive ability with age, seminal work by Wilson et al1 finds that individual trajectories of cognitive ability vary greatly, suggesting that at least some of the age-related differences in cognitive ability are due to incipient disease. Conventional wisdom also stresses that incipient or clinically expressed Alzheimer disease (AD) explains most cognitive decline and incident dementia among older individuals. The negative impact of incipient AD on cognitive ability among apparently cognitively normal older individuals is further supported by the long prodromal period of the AD process. The advent of in vivo amyloid imaging (and even eventually tau imaging) has stimulated intense interest regarding the role of incipient AD in relationship to cognitive aging. Early reports suggest a strong relationship between memory performance and cortical amyloid retention in a group of individuals with various degrees of cognitive ability. Later studies also found that increased cerebral amyloid burden, which is highly associated with 500
age and the apolipoprotein E ε4 (APOE ε4) genotype2 among cognitively normal individuals, is associated with subtle declines in cognitive performance 3 and increased risk for future dementia.4 This work and the increasing availability of biological markers of AD pathology have led to a proposed biological cascade model of AD5 and reevaluation of diagnostic criteria for AD.6 If one ascribes religiously to the concept that a large proportion of cognitive differences with age are driven by incipient disease, then one might expect that memory performance—a cognitive ability that changes most dramatically with age and is common to AD—would follow increasing levels of associated cerebral amyloid and be strongly associated with hippocampal atrophy. In their article, Jack et al7 present new information that challenges the notion that amyloid accumulation explains memory performance across the entire age range. Importantly, this work does not only address the likely highly significant impact of cerebral amyloid accumulation on dementia risk, but also extends current knowledge relating to the impact of the aging process across the spectrum of ages 30 to 95 years to brain structure, amyloid accumulation, and memory performance among cognitively normal individuals. Their study7 details cross-sectional associations between age; memory performance using the auditory-verbal learning test, a common memory task; hippocampal volume; and the extent of cerebral amyloidosis for a group of more than 1200 men and women, ranging from age 30 to 95 years. A number of important findings come from this seminal study. One par-
JAMA Neurology May 2015 Volume 72, Number 5 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of St. Andrews Library User on 05/16/2015
jamaneurology.com
EDITORIAL
Deep Brain Stimulation of the Subthalamic Nucleus Taking the Ouch Out of Parkinson Disease Pravin Khemani, MD; Richard B. Dewey Jr, MD
Parkinson disease (PD) is known to affect multiple neurotransmitter systems, resulting in both motor and nonmotor symptoms. Pain is an underrecognized but important nonmotor symptom of PD that may be very disabling and is known to Related article page 504 impair quality of life.1 While significant progress has been made in ameliorating motor symptoms using pharmacological, rehabilitative, and surgical treatments, the treatment of pain in this context has not received sufficient attention. A literature review2 noted a reported prevalence of pain in PD of 40% to 85%, yet only about half of patients with PD who felt pain took analgesics. Classifying PD-related pain into its subtypes3 is important for rational treatment, and the most common subtypes of pain in PD are musculoskeletal and dystonic, with central neuropathic pain being the least common.2 To address pain successfully in PD, an understanding of its pathogenesis is important, yet this has remained elusive, in part because its causes are protean. Just as certain motor symptoms of PD are more responsive to dopaminergic drugs and deep brain stimulation (DBS), some pain subtypes may respond better than others to pharmacological and surgical intervention. Dysfunction of both dopaminergic and nondopaminergic basal ganglia pathways are likely to be involved in PD-related pain, which may explain why some types of pain are responsive to levodopa and others are not.4 Deep brain stimulation of the subthalamic nucleus (STN) is now an established treatment of disabling motor symptoms in advanced PD, and it is therefore important to understand its effect on pain associated with PD. Previous reports5,6 on the effects of STN DBS on pain in PD show that the levels of musculoskeletal and dystonic pain decreased when assessed 1 year after surgery, but, to our knowledge, there is no existing information on the status of chronic pain. In this issue of JAMA Neurology, Jung and colleagues7 investigate the long-term effect of STN DBS on pain in 24 patients with PD who were observed for 8 years after undergoing the procedure for alleviating disabling motor symptoms. The beneficial effects of STN DBS in this cohort 3 months after surgery and 24 months after surgery have been previously published.8,9 The subtypes of pain were classified according to Ford.3 The severity and body distribution of pain were compared between presurgical and postsurgical states. Jung and colleagues7 noted significant improvement at 8 years in all pain types present preoperatively, regardless of whether the preoperative pain was responsive to levodopa or not. However, new pain, not present before surgery, developed in 75% of patients during prolonged follow-up. Musculoskeletal pain accounted for the majority of new pain cases. Although the mean severity of pain was less at jamaneurology.com
8 years than at baseline, more patients experienced pain at the end of the observation period than preoperatively. Because previous studies on pain following STN DBS for PD are of short duration, the durability of the procedure’s effect on pain is not well established. The chief strength of the work by Jung and colleagues7 is the long follow-up period, which suggests that, although DBS may relieve pain for a time, this is not a durable effect owing to the onset of new, primarily musculoskeletal pain. A recent report5 was concordant with the study by Jung and colleagues7 in showing the benefit of DBS on dystonic and musculoskeletal pain but was discordant in showing no effect of DBS on central and radicular pain. Methodological differences, the subjective classification of pain, and a much shorter observation period could account for these discrepant findings. The study by Jung and colleagues7 has several limitations that the authors acknowledge, including a small cohort without a control group that was treated medically, the lack of correlation of pain scores with motor Unified Parkinson’s Disease Rating Scale scores (especially rigidity, which can potentially impact musculoskeletal pain), the lack of measures of disability or effect of pain on quality of life, and the lack of mood and cognitive assessments that can influence pain perception. In addition, an analysis of the effect of levodopa on preoperative pain vs the effect of DBS on pain was not performed. This would have been of interest in light of a previous report10 suggesting that the effects of DBS on pain can be predicted by measuring the effects of levodopa on pain. Despite its limitations, the study by Jung and colleagues7 provides a novel perspective on the durability of the pain-relieving properties of STN DBS in PD. The authors direct our attention to the fact that musculoskeletal pain may emerge years after DBS, warranting individualized treatment. The next step is to pursue a deeper understanding of the mechanism of pain in PD. Previous work11 with small numbers of participants has demonstrated altered pain processing in participants with PD who experienced pain compared with those who did not, such that STN DBS raises pain thresholds selectively in those who experience pain. Although there is a growing consensus that STN DBS decreases the level of pain in people with PD, the literature is mixed on the subtypes of pain that are responsive to DBS, and the study by Jung and colleagues7 shows that new pain arising years after the procedure is common. This underscores the importance of performing future trials with larger cohorts, longer observational periods, and standard methods to enable effective interpretation of outcomes. For now, we have learned that STN DBS does not take the ouch out of PD in the long run. (Reprinted) JAMA Neurology May 2015 Volume 72, Number 5
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of St. Andrews Library User on 05/16/2015
499
Opinion Editorial
ARTICLE INFORMATION Author Affiliations: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas. Corresponding Author: Richard B. Dewey Jr, MD, Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, 5323 Harry Hines, Dallas, TX 75390-9036 (richard [email protected]). Published Online: March 23, 2015. doi:10.1001/jamaneurol.2015.36. Conflict of Interest Disclosures: Dr Dewey reported serving as a consultant for Teva Pharmaceuticals, US WorldMeds, Lundbeck, Acadia, Merz, Xenoport, Impax, and GE Healthcare and receiving speakers fees from Teva Pharmaceuticals, US WorldMeds, Lundbeck, and UCB. No other disclosures are reported.
cross-sectional study. Parkinsonism Relat Disord. 2004;10(3):129-136. 2. Broen MP, Braaksma MM, Patijn J, Weber WE. Prevalence of pain in Parkinson’s disease: a systematic review using the modified QUADAS tool. Mov Disord. 2012;27(4):480-484. 3. Ford B. Pain in Parkinson’s disease. Mov Disord. 2010;25(suppl 1):S98-S103. 4. Berardelli A, Conte A, Fabbrini G, et al. Pathophysiology of pain and fatigue in Parkinson’s disease. Parkinsonism Relat Disord. 2012;18(suppl 1):S226-S228. 5. Cury RG, Galhardoni R, Fonoff ET, et al. Effects of deep brain stimulation on pain and other nonmotor symptoms in Parkinson disease. Neurology. 2014; 83(16):1403-1409.
REFERENCES
6. Oshima H, Katayama Y, Morishita T, et al. Subthalamic nucleus stimulation for attenuation of pain related to Parkinson disease. J Neurosurg. 2012;116(1):99-106.
1. Quittenbaum BH, Grahn B. Quality of life and pain in Parkinson’s disease: a controlled
7. Jung YJ, Kim H-J, Jeon BS, Park H, Lee W-W, Paek SH. An 8-year follow-up on the effect of subthalamic
nucleus deep brain stimulation on pain in Parkinson disease [published online March 23, 2015]. JAMA Neurol. doi:10.1001/jamaneurol.2015.8. 8. Kim HJ, Jeon BS, Lee JY, Paek SH, Kim DG. The benefit of subthalamic deep brain stimulation for pain in Parkinson disease: a 2-year follow-up study. Neurosurgery. 2012;70(1):18-23; discussion 23-24. 9. Kim HJ, Paek SH, Kim JY, et al. Chronic subthalamic deep brain stimulation improves pain in Parkinson disease. J Neurol. 2008;255(12):1889-1894. 10. Sürücü O, Baumann-Vogel H, Uhl M, Imbach LL, Baumann CR. Subthalamic deep brain stimulation versus best medical therapy for L-dopa responsive pain in Parkinson’s disease. Pain. 2013;154(8):14771479. 11. Dellapina E, Ory-Magne F, Regragui W, et al. Effect of subthalamic deep brain stimulation on pain in Parkinson’s disease. Pain. 2012;153(11):2267-2273.
A Call for New Thoughts About What Might Influence Human Brain Aging Aging, Apolipoprotein E, and Amyloid Charles DeCarli, MD
The wiser mind mourns less for what age takes away than what it leaves behind. William Wordsworth, The Fountain
As a greater proportion of the world’s population live beyond age 65 years, there is increasing awareness of age-related differences in cognitive ability and a rising interest in finding ways to maintain healthy brain aging with the hope to avoid demenRelated article page 511 tia. Although conventional wisdom stresses the inevitable decline of cognitive ability with age, seminal work by Wilson et al1 finds that individual trajectories of cognitive ability vary greatly, suggesting that at least some of the age-related differences in cognitive ability are due to incipient disease. Conventional wisdom also stresses that incipient or clinically expressed Alzheimer disease (AD) explains most cognitive decline and incident dementia among older individuals. The negative impact of incipient AD on cognitive ability among apparently cognitively normal older individuals is further supported by the long prodromal period of the AD process. The advent of in vivo amyloid imaging (and even eventually tau imaging) has stimulated intense interest regarding the role of incipient AD in relationship to cognitive aging. Early reports suggest a strong relationship between memory performance and cortical amyloid retention in a group of individuals with various degrees of cognitive ability. Later studies also found that increased cerebral amyloid burden, which is highly associated with 500
age and the apolipoprotein E ε4 (APOE ε4) genotype2 among cognitively normal individuals, is associated with subtle declines in cognitive performance 3 and increased risk for future dementia.4 This work and the increasing availability of biological markers of AD pathology have led to a proposed biological cascade model of AD5 and reevaluation of diagnostic criteria for AD.6 If one ascribes religiously to the concept that a large proportion of cognitive differences with age are driven by incipient disease, then one might expect that memory performance—a cognitive ability that changes most dramatically with age and is common to AD—would follow increasing levels of associated cerebral amyloid and be strongly associated with hippocampal atrophy. In their article, Jack et al7 present new information that challenges the notion that amyloid accumulation explains memory performance across the entire age range. Importantly, this work does not only address the likely highly significant impact of cerebral amyloid accumulation on dementia risk, but also extends current knowledge relating to the impact of the aging process across the spectrum of ages 30 to 95 years to brain structure, amyloid accumulation, and memory performance among cognitively normal individuals. Their study7 details cross-sectional associations between age; memory performance using the auditory-verbal learning test, a common memory task; hippocampal volume; and the extent of cerebral amyloidosis for a group of more than 1200 men and women, ranging from age 30 to 95 years. A number of important findings come from this seminal study. One par-
JAMA Neurology May 2015 Volume 72, Number 5 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of St. Andrews Library User on 05/16/2015
jamaneurology.com
