DBS for Parkinson's Disease and Other Movement Disorders
DBS for Parkinson's Disease and Other Movement Disorders
Parkinson's disease is a neurodegenerative movement disorder characterized by disabling progressive motor and nonmotor symptoms. With a prevalence of 0.3%, and increasing age being a significant risk factor for its development, Parkinson's disease is projected to have a significant worldwide economic impact in the next several decades. Medical therapies, which are largely aimed at increasing the availability of dopamine within the central nervous system, are typically initiated when symptoms begin to impact a patient's function and/or quality of life, and are highly effective against the cardinal motor symptoms of the disease including rigidity, akinesia, and tremor. Unfortunately, the response to dopamine replacement therapy becomes less reliable and predictable over time, and is complicated by motor fluctuations and drug-induced dyskinesia as Parkinson's disease progresses, at which point DBS surgery is usually considered.
Several clinical trials have established that DBS targeting either the subthalamic nucleus (STN) or globus pallidus internus (GPi) is an effective treatment for moderate to severe Parkinson's disease ( Table 1 ). Typical surgical candidates are those patients in whom motor fluctuations and drug-induced dyskinesias have become significantly disabling, even though the cardinal symptoms of Parkinson's disease continue to respond to levodopa. These patients will have an excellent response of motor symptoms to DBS with the benefits of surgery remaining for years. Currently, the average time to surgical intervention is approximately 11–13 years after diagnosis.
Recently, Schuepbach and coworkers initiated the EARLYSTIM, multicenter randomized trial to test the hypothesis that DBS earlier in the course of the disease improves quality of life. Unlike typical patients undergoing surgery for more advanced Parkinson's disease, patients in this study were earlier in the disease course by an average of 5 years, and randomized either to best medical management or bilateral STN DBS. The study demonstrated significant benefit in the DBS group compared with best medical management alone in the primary outcome measure of quality of life as assessed by the Parkinson's Disease Questionnaire (PDQ-39) summary index, as well as in secondary outcomes including improved motor scores (UPDRS-III), activities of daily living, and mobility time. Significant reductions in motor complications and levodopa-equivalent medication dosage were also seen in the DBS group. The trial has been criticized because all patients in the surgical group had their DBS systems turned on for the duration of the trial, possibly introducing an expectation bias which could be avoided by randomizing patients to on or off stimulation conditions during an initial crossover phase within the trial. Furthermore, all patients were less than 60 years of age, and could represent a unique subgroup of younger Parkinson's disease patients. On the other hand, two major strengths of the study were that medical treatment was determined by an independent panel according to best available evidence, and all motor outcomes were assessed by independent reviewers blinded to patient identity and treatment group. Overall, the results of EARLYSTIM may change current practice: patients earlier in the disease course may have significantly more to gain from DBS if they obtain symptomatic benefit which allows independence to be maintained for a longer period of time. As a practical matter, this may impact the ability of Parkinson's disease patients to maintain productive employment, as they are known to stop working earlier due to the disease.
It is obvious that the ultimate goal of any therapy for Parkinson's disease is to alter the natural history of the disease, and current treatments including DBS are only thought to provide symptomatic benefit. Given the positive impact of early DBS, and in light of animal evidence for structural plasticity accompanying DBS, the hypothesis that DBS also changes the natural history of Parkinson's disease needs to be formally tested. Although no convincing neuroprotective response was demonstrated in EARLYSTIM, it may be that 24-month follow-up is insufficient to assess the trajectory of Parkinson's disease progression. Another pilot trial is underway that examines the potential benefit of early DBS in Parkinson's disease, in this case as early as 2 years after diagnosis. The results of this trial will provide further safety data to add to our understanding of the efficacy and possible disease-modifying capability of early DBS.
Although EARLYSTIM provides evidence to consider DBS surgery earlier in patients with Parkinson's disease, the only DBS target considered was the STN. As mentioned previously, the GPi has also been shown to be an excellent target in the treatment of advanced Parkinson's disease. Randomized trials have suggested that GPi is equally as effective as STN for the treatment of dyskinesias and levodopa-responsive motor symptoms of Parkinson's disease. Indeed, GPi has been thought by many to be a superior target compared with STN with respect to neuropsychological parameters such as cognition, mood, and behavioral problems. The latest episode in the STN versus GPi debate comes from the recent Netherlands Subthalamic and Pallidal Stimulation study (NSTAPS), which tested the hypothesis that bilateral GPi DBS should produce a greater improvement in a generic disability scale given the association between bilateral STN DBS and worsening cognitive, mood, and behavioral function. The study showed that STN and GPi DBS do not result in a significant difference in functional health measured by a self-reported disability scale, nor by a composite score assigned to various neuropsychological parameters. In fact, some secondary outcomes appeared to improve more markedly with STN DBS, including 'off'-drug motor score and a greater reduction in levodopa equivalent medication dosage. Conversely, the STN group did appear to have a higher incidence of dysphoria or even frank depression, which previous studies have suggested can lead to increased risk of suicide. Indeed, the EARLYSTIM trial suggested that the incidence of suicidal ideation might be higher than initially predicted. Taken together, these results suggest, at least for the time being, that the STN versus GPi debate goes on unresolved.
Often by the time a patient with Parkinson's disease is offered DBS, significant nonlevodopa responsive symptoms such as cognitive impairment, gait instability, speech impairment, mood alterations, and autonomic dysfunction become paramount and may limit the overall benefit derived from DBS. Furthermore, neuropsychiatric and cognitive symptoms may occasionally be worsened by surgery, as may gait. Current work is examining potential targets to address nonlevodopa-responsive symptoms in Parkinson's disease. Much of this work has focused on gait impairment and postural instability that put many Parkinson's disease patients at high risk for falls. Dysfunction perhaps secondary to enhanced inhibition of the locomotor pedunculopontine nucleus (PPN) may contribute to gait disturbance in Parkinson's disease. Accordingly, recent work has been undertaken to test whether DBS of the PPN may improve gait; to date 100 patients have had PPN electrodes implanted. Interestingly, blinded assessment in several of these patients has not demonstrated objective motor improvement in the stimulation 'on' versus 'off' condition, but has shown a sustained reduction in falls and freezing. More recent studies are testing the hypothesis that PPN stimulation combined with either STN DBS or DBS of the caudal zona incerta may provide additive benefit to the Parkinson's disease patient by treating motor and gait issues simultaneously.
As with gait, some have suggested that DBS can be used to counteract cognitive deterioration in Parkinson's disease. Recently, one group has explored the possibility of stimulating the nucleus basalis of Meynert (NBM) in the basal forebrain with the aim of overcoming the potential memory impairment from STN DBS, and improving cognitive function in Parkinson's disease altogether. In two case reports, they describe a patient treated with bilateral STN DBS who went on to develop Parkinson's disease dementia. The patient then underwent implantation of bilateral NBM DBS electrodes, which when turned on produced improvements in attention, alertness, and capacity for concentration. There was also improvement in a severe nonaphasic apraxia that had developed along with disease progression. The authors attribute these promising cognitive improvements to an enhancement of cholinergic outflow to the cortical mantle from the basal forebrain in response to NBM DBS. Similarly, it has been suggested that DBS within motor circuits could be combined with fornix stimulation in patients with cognitive compromise.
Deep Brain Stimulation for Parkinson's Disease
Parkinson's disease is a neurodegenerative movement disorder characterized by disabling progressive motor and nonmotor symptoms. With a prevalence of 0.3%, and increasing age being a significant risk factor for its development, Parkinson's disease is projected to have a significant worldwide economic impact in the next several decades. Medical therapies, which are largely aimed at increasing the availability of dopamine within the central nervous system, are typically initiated when symptoms begin to impact a patient's function and/or quality of life, and are highly effective against the cardinal motor symptoms of the disease including rigidity, akinesia, and tremor. Unfortunately, the response to dopamine replacement therapy becomes less reliable and predictable over time, and is complicated by motor fluctuations and drug-induced dyskinesia as Parkinson's disease progresses, at which point DBS surgery is usually considered.
Several clinical trials have established that DBS targeting either the subthalamic nucleus (STN) or globus pallidus internus (GPi) is an effective treatment for moderate to severe Parkinson's disease ( Table 1 ). Typical surgical candidates are those patients in whom motor fluctuations and drug-induced dyskinesias have become significantly disabling, even though the cardinal symptoms of Parkinson's disease continue to respond to levodopa. These patients will have an excellent response of motor symptoms to DBS with the benefits of surgery remaining for years. Currently, the average time to surgical intervention is approximately 11–13 years after diagnosis.
Recently, Schuepbach and coworkers initiated the EARLYSTIM, multicenter randomized trial to test the hypothesis that DBS earlier in the course of the disease improves quality of life. Unlike typical patients undergoing surgery for more advanced Parkinson's disease, patients in this study were earlier in the disease course by an average of 5 years, and randomized either to best medical management or bilateral STN DBS. The study demonstrated significant benefit in the DBS group compared with best medical management alone in the primary outcome measure of quality of life as assessed by the Parkinson's Disease Questionnaire (PDQ-39) summary index, as well as in secondary outcomes including improved motor scores (UPDRS-III), activities of daily living, and mobility time. Significant reductions in motor complications and levodopa-equivalent medication dosage were also seen in the DBS group. The trial has been criticized because all patients in the surgical group had their DBS systems turned on for the duration of the trial, possibly introducing an expectation bias which could be avoided by randomizing patients to on or off stimulation conditions during an initial crossover phase within the trial. Furthermore, all patients were less than 60 years of age, and could represent a unique subgroup of younger Parkinson's disease patients. On the other hand, two major strengths of the study were that medical treatment was determined by an independent panel according to best available evidence, and all motor outcomes were assessed by independent reviewers blinded to patient identity and treatment group. Overall, the results of EARLYSTIM may change current practice: patients earlier in the disease course may have significantly more to gain from DBS if they obtain symptomatic benefit which allows independence to be maintained for a longer period of time. As a practical matter, this may impact the ability of Parkinson's disease patients to maintain productive employment, as they are known to stop working earlier due to the disease.
It is obvious that the ultimate goal of any therapy for Parkinson's disease is to alter the natural history of the disease, and current treatments including DBS are only thought to provide symptomatic benefit. Given the positive impact of early DBS, and in light of animal evidence for structural plasticity accompanying DBS, the hypothesis that DBS also changes the natural history of Parkinson's disease needs to be formally tested. Although no convincing neuroprotective response was demonstrated in EARLYSTIM, it may be that 24-month follow-up is insufficient to assess the trajectory of Parkinson's disease progression. Another pilot trial is underway that examines the potential benefit of early DBS in Parkinson's disease, in this case as early as 2 years after diagnosis. The results of this trial will provide further safety data to add to our understanding of the efficacy and possible disease-modifying capability of early DBS.
Although EARLYSTIM provides evidence to consider DBS surgery earlier in patients with Parkinson's disease, the only DBS target considered was the STN. As mentioned previously, the GPi has also been shown to be an excellent target in the treatment of advanced Parkinson's disease. Randomized trials have suggested that GPi is equally as effective as STN for the treatment of dyskinesias and levodopa-responsive motor symptoms of Parkinson's disease. Indeed, GPi has been thought by many to be a superior target compared with STN with respect to neuropsychological parameters such as cognition, mood, and behavioral problems. The latest episode in the STN versus GPi debate comes from the recent Netherlands Subthalamic and Pallidal Stimulation study (NSTAPS), which tested the hypothesis that bilateral GPi DBS should produce a greater improvement in a generic disability scale given the association between bilateral STN DBS and worsening cognitive, mood, and behavioral function. The study showed that STN and GPi DBS do not result in a significant difference in functional health measured by a self-reported disability scale, nor by a composite score assigned to various neuropsychological parameters. In fact, some secondary outcomes appeared to improve more markedly with STN DBS, including 'off'-drug motor score and a greater reduction in levodopa equivalent medication dosage. Conversely, the STN group did appear to have a higher incidence of dysphoria or even frank depression, which previous studies have suggested can lead to increased risk of suicide. Indeed, the EARLYSTIM trial suggested that the incidence of suicidal ideation might be higher than initially predicted. Taken together, these results suggest, at least for the time being, that the STN versus GPi debate goes on unresolved.
Often by the time a patient with Parkinson's disease is offered DBS, significant nonlevodopa responsive symptoms such as cognitive impairment, gait instability, speech impairment, mood alterations, and autonomic dysfunction become paramount and may limit the overall benefit derived from DBS. Furthermore, neuropsychiatric and cognitive symptoms may occasionally be worsened by surgery, as may gait. Current work is examining potential targets to address nonlevodopa-responsive symptoms in Parkinson's disease. Much of this work has focused on gait impairment and postural instability that put many Parkinson's disease patients at high risk for falls. Dysfunction perhaps secondary to enhanced inhibition of the locomotor pedunculopontine nucleus (PPN) may contribute to gait disturbance in Parkinson's disease. Accordingly, recent work has been undertaken to test whether DBS of the PPN may improve gait; to date 100 patients have had PPN electrodes implanted. Interestingly, blinded assessment in several of these patients has not demonstrated objective motor improvement in the stimulation 'on' versus 'off' condition, but has shown a sustained reduction in falls and freezing. More recent studies are testing the hypothesis that PPN stimulation combined with either STN DBS or DBS of the caudal zona incerta may provide additive benefit to the Parkinson's disease patient by treating motor and gait issues simultaneously.
As with gait, some have suggested that DBS can be used to counteract cognitive deterioration in Parkinson's disease. Recently, one group has explored the possibility of stimulating the nucleus basalis of Meynert (NBM) in the basal forebrain with the aim of overcoming the potential memory impairment from STN DBS, and improving cognitive function in Parkinson's disease altogether. In two case reports, they describe a patient treated with bilateral STN DBS who went on to develop Parkinson's disease dementia. The patient then underwent implantation of bilateral NBM DBS electrodes, which when turned on produced improvements in attention, alertness, and capacity for concentration. There was also improvement in a severe nonaphasic apraxia that had developed along with disease progression. The authors attribute these promising cognitive improvements to an enhancement of cholinergic outflow to the cortical mantle from the basal forebrain in response to NBM DBS. Similarly, it has been suggested that DBS within motor circuits could be combined with fornix stimulation in patients with cognitive compromise.
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