January 8, 2009 — Results of a randomized trial show that compared with best medical therapy (BMT), deep brain stimulation (DBS) increased "on" time without dyskinesias and improved motor function as well as quality of life at 6 months in patients with moderate to severe Parkinson's disease (PD), but at the cost of increased serious adverse events (SAEs).
"What we saw is that deep brain stimulation has the ability to shift these patients from the 'off' state to the 'on' state, and that was reflected in the quality-of-life measures," study author Kenneth Follett, MD, PhD, from the department of neurosurgery at the University of Nebraska Medical Center, in Omaha, told Medscape Neurology & Neurosurgery.
SAEs occurred in about 40% of DBS patients, including 1 death from cerebral hemorrhage, about a 4-fold increase over medical therapy, he noted. However, he noted, "by 6 months, almost all serious adverse events had resolved, and the incidence of permanent complication was very low."
The results are published in the January 7 issue of the Journal of the American Medical Association.
Widespread Use, Little Randomized Evidence
Widespread use of DBS for Parkinson's disease began during the 1990s, and acceptance has increased over the past 15 years, the authors write. Despite the increased use, there have been few randomized trials comparing surgery with best medical therapy. Recent reports outlining unexpected behavioral effects of DBS have highlighted this lack of randomized evidence, they note.
Only 1 other randomized trial has been done comparing these approaches, reported in 2006 (Deuschl G et al. N Engl J Med. 2006;355:896-908). It showed significant improvement in patient outcomes after DBS of the subthalamic nucleus "but also pointed out that not all patients who received deep brain stimulation improved," the authors note.
The current study compared 6-month outcomes among 255 patients with advanced PD (Hoehn & Yahr stage > 2 without medication) randomized to receive either DBS or BMT. Dr. Follett emphasized that BMT was also active management, with every patient followed by a movement-disorders specialist to provide optimal medical care.
Patients were stratified by age (<> 70 years) and by study site (7 Veterans Affairs and 6 university hospitals). Older patients were included in this study to more closely resemble the general population of patients with advanced PD, the authors note; 25% of patients were aged 70 years or older.
Patients randomized to DBS underwent a second randomization to receive bilateral stimulation of either the globus pallidus or the subthalamic nucleus. The best target for stimulation remains 1 of the "key clinical questions" in this area, Dr. Follett noted, and this second phase of the study will help to answer that question. For the purposes of this analysis, though, outcomes for all DBS patients represent pooled data. The data on this question are still blinded and are expected to be reported later in 2009, he said.
"The bottom line is that even with pooled data, those patients who underwent DBS had substantial and very statistically significant improvements in Parkinson's symptoms compared with those patients who continued on best medical therapy," Dr. Follett said.
On time without dyskinesia increased a mean of 4.6 hours per day in those receiving DBS vs no change (0 hours) in those on BMT. "So they went from about 6.5 hours per day in on time prior to surgery to almost 11 hours per day following surgery," Dr. Follett said. "That's most of the waking day; the hours when they need to be out and be active."
Time in the on state came from time previously spent in the off state, which decreased in the DBS groups from 6 hours prior to surgery to 3.4 hours after surgery, again vs no change in the medical-therapy group. Sleep time did not change significantly in either group.
DBS patients also had significant and clinically meaningful improvements of motor function: 71% of DBS patients had improvements of 5 or more points on the United Parkinson's Disease Rating Score motor subscale, vs 32% of those on BMT (P < .001). Significant improvements were also seen in a summary measure of quality of life and on 7 of 8 PD quality-of-life scores, they add. Interestingly, outcomes among those 70 years of age and older were similar to those younger than 70 years, including both motor improvements and the incidence of SAEs. "Although sometimes we're a little leery about offering this surgery to older people, the study tells us in fact that age alone should not be a contraindication to surgery," Dr. Follett said. Increased Serious Adverse Events However, the improvements were not without some cost. At least 1 SAE occurred in 49 DBS patients compared with 15 medical-therapy patients (P < .001). Of SAEs in the surgical patients, 39 were related to the surgical procedure, most commonly infections, and there was 1 death secondary to cerebral hemorrhage. Other events included nervous system disorders, psychiatric disorders, and device-related complications. The incidence of SAEs was greater than that seen in the study by Deuschl et al, the authors note. "The greater number of serious adverse events in our trial is likely attributable to inclusion of an older cohort of patients and the fact that the trial was rigorously monitored for identification of all adverse events." Also of some concern were statistically significant treatment differences between baseline and follow-up in neurocognitive measures, including composite measures of working memory, processing speed, phonemic fluency, and delayed recall on the Brief Visuospatial Memory Test. Those on best medical therapy actually showed improvements of 1 to 2 points on some of these measures, while those in the DBS group showed 1- to 3.5-point decrements. The clinical significance of these cognitive changes and SAEs and the risk/benefit ratio in light of the motor-function and quality-of-life improvements remain to be seen, the authors conclude. "Caution should be exercised, however, against overstating or understating the risks of deep brain stimulation in patients with PD," they write. "Physicians must continue to weigh the potential short-term and long-term risks with the benefits of deep brain stimulation in each patient." Questions Remain Günther Deuschl, MD, PhD, from the department of neurology at the Universitätsklinikum Schleswig-Holstein, in Kiel, Germany, first author of the only other randomized trial comparing these modalities, wrote an editorial accompanying the article. He noted that these results are similar to their findings in terms of efficacy but underlined the higher incidence of SAEs seen in this trial, with at least 1 event occurring in 49 DBS patients vs 15 patients in the medical-therapy group. The cumulative risk for device-related problems was 10% at 6 months, and stimulation-related problems, which can mostly be corrected, were even more frequent, he writes. While, similar to other prospective studies, psychiatric adverse effects were not seen in this study to be more common with DBS than BMT, "cumulative data from 55 centers have shown that the suicide rate following deep brain stimulation was 13 times higher in the first postoperative year . . . and doubled after 4 years. Risk factors have been identified, but prevention algorithms still need to be developed." A variety of questions remain to be answered about this treatment, Dr. Deuschl writes, including the optimal timing to undertake surgery, replication of the finding of similar results in older and younger PD populations that is at odds with previous findings, and the best target for stimulation, insight on which will be provided by follow-up data from this study. "Overall, the results of this important study by Weaver et al have convincingly confirmed the 6-month efficacy of deep brain stimulation for advanced PD with the largest patient group studied thus far," Dr. Deuschl concludes. "However, this study, along with previous research on this therapy, shows that such progress cannot be made without costs in terms of adverse effects."
"What we saw is that deep brain stimulation has the ability to shift these patients from the 'off' state to the 'on' state, and that was reflected in the quality-of-life measures," study author Kenneth Follett, MD, PhD, from the department of neurosurgery at the University of Nebraska Medical Center, in Omaha, told Medscape Neurology & Neurosurgery.
SAEs occurred in about 40% of DBS patients, including 1 death from cerebral hemorrhage, about a 4-fold increase over medical therapy, he noted. However, he noted, "by 6 months, almost all serious adverse events had resolved, and the incidence of permanent complication was very low."
The results are published in the January 7 issue of the Journal of the American Medical Association.
Widespread Use, Little Randomized Evidence
Widespread use of DBS for Parkinson's disease began during the 1990s, and acceptance has increased over the past 15 years, the authors write. Despite the increased use, there have been few randomized trials comparing surgery with best medical therapy. Recent reports outlining unexpected behavioral effects of DBS have highlighted this lack of randomized evidence, they note.
Only 1 other randomized trial has been done comparing these approaches, reported in 2006 (Deuschl G et al. N Engl J Med. 2006;355:896-908). It showed significant improvement in patient outcomes after DBS of the subthalamic nucleus "but also pointed out that not all patients who received deep brain stimulation improved," the authors note.
The current study compared 6-month outcomes among 255 patients with advanced PD (Hoehn & Yahr stage > 2 without medication) randomized to receive either DBS or BMT. Dr. Follett emphasized that BMT was also active management, with every patient followed by a movement-disorders specialist to provide optimal medical care.
Patients were stratified by age (<> 70 years) and by study site (7 Veterans Affairs and 6 university hospitals). Older patients were included in this study to more closely resemble the general population of patients with advanced PD, the authors note; 25% of patients were aged 70 years or older.
Patients randomized to DBS underwent a second randomization to receive bilateral stimulation of either the globus pallidus or the subthalamic nucleus. The best target for stimulation remains 1 of the "key clinical questions" in this area, Dr. Follett noted, and this second phase of the study will help to answer that question. For the purposes of this analysis, though, outcomes for all DBS patients represent pooled data. The data on this question are still blinded and are expected to be reported later in 2009, he said.
"The bottom line is that even with pooled data, those patients who underwent DBS had substantial and very statistically significant improvements in Parkinson's symptoms compared with those patients who continued on best medical therapy," Dr. Follett said.
On time without dyskinesia increased a mean of 4.6 hours per day in those receiving DBS vs no change (0 hours) in those on BMT. "So they went from about 6.5 hours per day in on time prior to surgery to almost 11 hours per day following surgery," Dr. Follett said. "That's most of the waking day; the hours when they need to be out and be active."
Time in the on state came from time previously spent in the off state, which decreased in the DBS groups from 6 hours prior to surgery to 3.4 hours after surgery, again vs no change in the medical-therapy group. Sleep time did not change significantly in either group.
DBS patients also had significant and clinically meaningful improvements of motor function: 71% of DBS patients had improvements of 5 or more points on the United Parkinson's Disease Rating Score motor subscale, vs 32% of those on BMT (P < .001). Significant improvements were also seen in a summary measure of quality of life and on 7 of 8 PD quality-of-life scores, they add. Interestingly, outcomes among those 70 years of age and older were similar to those younger than 70 years, including both motor improvements and the incidence of SAEs. "Although sometimes we're a little leery about offering this surgery to older people, the study tells us in fact that age alone should not be a contraindication to surgery," Dr. Follett said. Increased Serious Adverse Events However, the improvements were not without some cost. At least 1 SAE occurred in 49 DBS patients compared with 15 medical-therapy patients (P < .001). Of SAEs in the surgical patients, 39 were related to the surgical procedure, most commonly infections, and there was 1 death secondary to cerebral hemorrhage. Other events included nervous system disorders, psychiatric disorders, and device-related complications. The incidence of SAEs was greater than that seen in the study by Deuschl et al, the authors note. "The greater number of serious adverse events in our trial is likely attributable to inclusion of an older cohort of patients and the fact that the trial was rigorously monitored for identification of all adverse events." Also of some concern were statistically significant treatment differences between baseline and follow-up in neurocognitive measures, including composite measures of working memory, processing speed, phonemic fluency, and delayed recall on the Brief Visuospatial Memory Test. Those on best medical therapy actually showed improvements of 1 to 2 points on some of these measures, while those in the DBS group showed 1- to 3.5-point decrements. The clinical significance of these cognitive changes and SAEs and the risk/benefit ratio in light of the motor-function and quality-of-life improvements remain to be seen, the authors conclude. "Caution should be exercised, however, against overstating or understating the risks of deep brain stimulation in patients with PD," they write. "Physicians must continue to weigh the potential short-term and long-term risks with the benefits of deep brain stimulation in each patient." Questions Remain Günther Deuschl, MD, PhD, from the department of neurology at the Universitätsklinikum Schleswig-Holstein, in Kiel, Germany, first author of the only other randomized trial comparing these modalities, wrote an editorial accompanying the article. He noted that these results are similar to their findings in terms of efficacy but underlined the higher incidence of SAEs seen in this trial, with at least 1 event occurring in 49 DBS patients vs 15 patients in the medical-therapy group. The cumulative risk for device-related problems was 10% at 6 months, and stimulation-related problems, which can mostly be corrected, were even more frequent, he writes. While, similar to other prospective studies, psychiatric adverse effects were not seen in this study to be more common with DBS than BMT, "cumulative data from 55 centers have shown that the suicide rate following deep brain stimulation was 13 times higher in the first postoperative year . . . and doubled after 4 years. Risk factors have been identified, but prevention algorithms still need to be developed." A variety of questions remain to be answered about this treatment, Dr. Deuschl writes, including the optimal timing to undertake surgery, replication of the finding of similar results in older and younger PD populations that is at odds with previous findings, and the best target for stimulation, insight on which will be provided by follow-up data from this study. "Overall, the results of this important study by Weaver et al have convincingly confirmed the 6-month efficacy of deep brain stimulation for advanced PD with the largest patient group studied thus far," Dr. Deuschl concludes. "However, this study, along with previous research on this therapy, shows that such progress cannot be made without costs in terms of adverse effects."
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