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DBS Markedly Improves Parkinson Symptoms Earlier, French Trial Finds

Deep brain stimulation (DBS) significantly improved motor symptoms and quality of life in Parkinson patients treated much earlier than previously demonstrated, allowing younger patients to continue their careers, according to French researchers.

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Some experts say the finding of this new study on deep brain stimulation may make surgery the more ethical option for younger, less severely disabled patients.

In patients with symptoms for as little as five years, stimulation of the subthalamic nucleus dramatically improved motor fluctuations and dyskinesias that no longer responded to treatment with levodopa, according to lead author Michael Schüpbach, MD, a movement disorders investigator at the Center for Clinical Investigation at the Groupe Hospitalier Pitié-Salpêtrière.

He and his colleagues at the Salpêtrière University Hospital reported the findings online on Dec. 6 in advance of the Jan. 23 print edition of Neurology.

The team prospectively randomized 20 PD patients between ages 43 and 54 to have DBS, matching them with 20 similar subjects who received medical therapy alone. All of the subjects had mild to moderate motor symptoms that initially responded to levodopa but gradually worsened. Response was compared after six, 12, and 18 months.

Motor symptoms improved by 69 percent after 18 months in the DBS patients, levodopa-associated complaints fell 83 percent, and doses were reduced by 57 percent. In contrast, symptoms in the control group continued to worsen, by 29 percent (six months), 15 percent (12 months), and 12 percent (18 months).

DBS AS LAST RESORT FOR ADVANCED DISEASE

“Until now, DBS has been used as a last resort in patients only after their symptoms became advanced; even with medication, there was no other option,” Dr. Schüpbach told Neurology Today in a telephone interview. “We dared operating earlier to answer an important question: Can DBS work in milder disease in younger patients who still have professional careers ahead of them?”

Prior studies were almost exclusively conducted in patients with advanced disease for at least 15 years, when symptoms had become more severe and drugs did not help, he noted.

“Waiting five years is important because we had to ascertain a diagnosis of Parkinson disease,” Dr. Schüpbach said. “In our patients the disease was clear-cut. They had fluctuations and dyskinesia, but motor disability was less severe than in patients who are now candidates for DBS.”

Adverse events were mild or transient with surgery, while treatment improved not only motor scores but also helped anxiety and depression.

Surgical complications include asymptomatic intracranial bleed in 10 percent of procedures and symptomatic bleeding in 2 percent; seizures in 2 percent; headache in 25 percent; and infection in 4- to 6-percent. These infections are not life threatening, however, but do require immediate removal of the device.

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Dr. Michael Schüpbach: “Until now, DBS has been used as a last resort in patients only after their symptoms became advanced; even with medication, there was no other option.”

There is also the potential for device-related complications, most typically electrode lead replacement in 9 percent of procedures and repositioning in 8 percent. A 2006 study in 99 Parkinson patients who had DBS also suggested a risk of post-surgical decline in executive functions, including problems with speech, attention, and learning, as well as “psychiatric events” in about 9 percent of patients (Neurology 2006;66:1830–1836).

“Our results are in line with the degree of improvement reported in patients with more advanced disease, but many of our patients were in their 50s and even 40s,” Dr. Schüpbach said. “But this was also about improving quality of life. What we found was surgery also improved overall quality of life by 24 percent, which is also in line with the response in more advanced patients.”

Nonetheless, Dr. Schüpbach said the study needs to be replicated on a larger scale and his team is collaborating with DBS researchers in Germany and Great Britain to conduct the trial. “We have just started a multicenter trial called EARLYSTIM, and are in the pre-recruitment stage,” he said.

However, he also noted that in many countries the timing of DBS surgery is at the discretion of neurologists, and their patients and some younger patients with milder symptoms are already being treated.

“It's being done at some clinics, including ours. In France we didn't have restrictions for inclusion in terms of disease severity or duration until very recently. If EARLYSTIM confirms our findings, DBS-STN should be made available to more patients. DBS is still considered the very last option in the flowchart of treatment guidelines and restricted to a small percentage of patients, but if our findings are confirmed it will completely change that chart.”

‘UNNECESSARY’ DELAY?

EARLYSTIM will likely show similar benefits, commented David Riley, MD, professor of neurology at Case Western Reserve University School of Medicine and director of the Movement Disorders Center at the Neurological Institute at University Hospitals Case Medical Center in Cleveland.

“Although further research is clearly warranted, I'm not sure I'd wait for another trial,” he told Neurology Today in a telephone interview. “This study is in line with a trend that has been developing in recent years, particularly outside the US. Thus the results seem more like a confirmation of what we've suspected for some time, rather than a surprising, revolutionary conclusion.”

In an editorial accompanying the study, Dr. Riley and Andres Lozano. MD, PhD, the Ronald R. Tasker chair in functional neurosurgery at the University of Toronto and Toronto Western Hospital, pointed out that by significantly reducing fluctuations and dyskinesias at an earlier stage, the study indicates that many PD patients not currently considered candidates for surgery might benefit from DBS. Treating younger patients before symptoms become disabling should help many remain productive longer than without surgery, according to the editorial.

“This is not for patients whose symptoms are well managed with medication, but for those for whom drugs have started to fail and no longer provide predictable results,” Dr. Riley told Neurology Today. “I don't believe patients should be kept from surgery any longer than necessary. Even though the outlook for these patients isn't dire, the problem is that medication produces increasingly inconsistent results and they lose ability to function at times. Surgery provides more stability.”

By excluding patients with symptoms of less than five years, the study also conforms with recommendations of an ad hoc consensus committee of Parkinson experts. In 2006 they concluded that five years is a sufficient period to allow atypical parkinsonism to appear, enhancing diagnostic certainty.

“The study suggests that it is possible to identify such patients earlier in the course of PD, and that it is unnecessary to postpone the benefits they might receive from DBS,” he said. “If patients continue to fit diagnostic criteria for PD five years after onset of symptoms, and respond well to levodopa but spend more than 25 percent of their time in the ‘off’ state, they should be considered for DBS.”

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Dr. Alim-Louis Benabid: “For years, Ive been asking for a study in younger patients to see if it can change the evolution of the disease. Even in this trial, where the mean duration of PD was six to eight years, that question was not addressed. There have been many patients around the world who had surgery within this time span, and some sooner. So why dont we go to an early study?”

THE ETHICAL OPTION

Nonethless, it remains important “to strike a proper balance” between maximizing the opportunity for DBS in patients who are eventually going to require surgery, while not exposing patients to unnecessary risk of surgical complications when their symptoms can be managed satisfactorily otherwise, he added.

Dr. Riley told Neurology Today that while larger trials in younger patients are welcome, most patients meeting the study's criteria should be made aware of the findings and have the option to have DBS.

Editorial co-author Dr. Lozano also told Neurology Today in a telephone interview that the findings may invert the current DBS paradigm as a treatment of last resort and make surgery the more ethical option for younger, less severely disabled patients.

“This study demonstrates that there's a price to pay for delaying surgery when medication no longer works. Waiting means only that their symptoms will get worse,” he said.

In the US, DBS is seldom performed on PD patients when motor fluctuations still respond to levodopa to any degree, he observed. But in Canada, France, and elsewhere, physicians have already started performing DBS at earlier stages, especially when symptoms interfere with work — whether they are artisans or musicians.

CENTRAL QUESTION UNANSWERED

Alim-Louis Benabid, MD, PhD, professor of biophysics at Joseph Fourier University in Grenoble, France, who directs stereotactic and functional neurosurgery at Grenoble University Hospital, told Neurology Today in a telephone interview that while the results are encouraging and the study well-designed, it failed to address the central question of whether early intervention has a neuroprotective effect that can change progression of the disease in a fundamental way.

Dr. Benabid pioneered the use of DBS for movement disorders and was the first to show that surgery could help symptoms in levodopa-resistant PD. “For years, I've been asking for a study in younger patients to see if it can change the evolution of the disease,” he said. “Even in this trial, where the mean duration of PD was six to eight years, that question was not addressed. There have been many patients around the world who had surgery within this time span, and some sooner. So why don't we go to an early study?”

Although the course of the disease varies with individual patients, it is possible to identify candidates sooner than six or eight years, he said, suggesting a trial in patients with three years duration of refractory dyskinesias, with parallel PET evaluation.

“This is the only way we will know if there is neuroprotection or not. If there is, it might be possible to change the natural history of the disease and make it evolve more slowly.”

Dr. Benabid said he has tried unsuccessfully to garner support for such a study, although his team is about to publish data from 89 PD patients showing a 20 percent improvement in symptoms when they were off both medication and stimulation, including some who were stable for three or more years.

“This data may reflect long-lasting benefits of DBS in at least 20 percent of patients,” he told Neurology Today.

ARTICLE IN BRIEF

  • ✓ In patients with symptoms for as little as five years, stimulation of the subthalamic nucleus dramatically improved motor fluctuations and dyskinesias that no longer responded to treatment with levodopa.