ARTICLE IN BRIEF
In a randomized trial comparing standard medical therapy with deep brain stimulation, Parkinson's disease patients who had been diagnosed on average for 7.5 years scored significantly better in scales assessing quality of life, activities of daily living, movement disability, and levodopa-induced motor complications.
Parkinson's disease patients may benefit from deep brain stimulation (DBS) of the subthalamic nucleus in early stages of the disease process, according to a two-year international study. German and French scientists from 17 centers compared DBS with standard medical therapy alone and found that patients had a significant improvement in quality of life scores, activities of daily living, and mobility. Results of the EARLYSTIM study were published in the Feb. 14 issue of the New England Journal of Medicine.
Günther Deuschl, MD, of the University Hospital Schleswig–Holstein and the Christian-Albrechts University Kiel, co-lead investigator of the EARLYSTIM study, and his colleagues set out to study the benefits of DBS in patients who are just beginning to have obvious fluctuations of mobility. They randomized 251 patients — who had a mean age of 52 years old and had been diagnosed on average for 7.5 years — to medical treatment with or without neurostimulation and followed them for two years, assessing quality of life, activities of daily living, movement disability, and levodopa-induced motor complications.
At the end of the study, the neurostimulation group showed a 7.8-point improvement on the Parkinson's Disease Questionnaire (PDQ-39) compared with a 0.2 points worsening for those on medical therapy alone (p<0.002). [For the areas measured in the PDQ-39, see “More on PDQ-39.”] DBS was also superior to medical therapy in the United Parkinson's Disease Rating Scale (UPDRS) with respect to motor disability (p<0.001), activities of daily living (p<0.001), levodopa-induced motor complications (p<0.001), and time with good mobility and no dyskinesia (p=0.01).
DBS is federally approved for the treatment of advanced PD. This is the first controlled study comparing the best medical treatment to neurostimulation in patients at such an early stage of their disease, and Dr. Deuschl said “that it is very clear that quality of life among patients in the neurostimulation arm was very much improved.”
Dr. Deuschl was among the first researchers to conduct large, randomized trials of DBS for the treatment of advanced PD, the results of which were published in the New England Journal of Medicine in 2006. He said that they decided to test the benefits of neurostimulation on the heels of the so-called honeymoon phase and before more advanced symptoms, such as motor fluctuations and disturbances in sleep, set in. On average, the patients had the disease for only seven years and they had on and off periods for about 18 months. Many were still working.
The patients in the study received a variety of medical treatments, depending on their symptoms. They were assessed at five months, one year, and two years following the implantation of the device. Half the patients enrolled had best medical treatment and half had the addition of neurostimulation. Two neurologists reviewed the patients blindly and were shown videos of the patients before the start of the trial and two years later. They assessed over 2,000 tapes.
Patients in the DBS group scored 26 percent better on measures of quality of life than those patients who had received just medical treatment. Their motor scores in the medication-off condition (UPDRS III) were 53 percent better and the scores on the activities of daily living scale (UPDRS II, worst condition) was 30 percent better compared to a 12 percent decline in the medication group, according to Dr. Deuschl. The DBS group was able to decrease the dosage of their medications by 39 percent compared with a 21 percent increase in medication in those who did not have DBS and there was a 60 percent reduction in levodopa-induced complications (UPDRS IV) while the medication group worsened by 13 percent.
“These results tell us that if patients receive neurostimulation at an earlier stage you get a better overall result,” said Dr. Deuschl. Normally, patients have to wait a dozen or more years after diagnosis. There is a trend to operate earlier but it has not been proven that it is more beneficial than waiting until more advanced stages of the disease. Neurostimulation does not prevent the cognitive problems associated with PD and is not good at reducing problems with gait and speech over time.
Dr. Deuschl said that this trial may lead to changes in the guidelines and this option can now be discussed with patients.
Overall, adverse events were more frequent among patients receiving neurostimulation than those on medical therapy only. Serious events in the medical group were more often related to problems of mobility and side effects of medications (hallucinations and behavioral problems); whereas major depression occurred more often among patients with neurostimulation, despite an overall improvement in mood at the end of the trial. There were 26 serious adverse events related to surgery which all resolved after two years except for scarring.
A large team of health professionals has been keeping an eye on the patients in the study. One of the problems they were looking out for was an increase in suicide in those treated with DBS. In fact, the results did find a larger than expected number of suicides and attempts, but Dr. Deuschl said that it was evenly distributed in both treatment arms of the study. There were two suicides in the neurostimulation group and one in the medical-therapy group, as well as two suicide attempts in the neurostimulation group and two in the medical therapy group.
“It is not the neurostimulator,” he said. “We do think that people who seek out this treatment (whether they get it or not) may be more prone to a desperate attempt to end their lives,” said Dr. Deuschl. “This finding tells us that every patient that undergoes DBS must be carefully assessed for suicidal risks.”
“This is a terrific study,” said David Charles, MD, professor and vice chairman of neurology and chief medical officer at Vanderbilt Neuroscience Institute. “It will be transformative for the field.”
Dr. Charles is also conducting a DBS study on patients in the early stages of the disease, even before the fluctuations begin. The patients enrolled in the Vanderbilt study, which is also funded in part by Medtronic, the company that makes the DBS device, have been on medication for at least two years. That means they are at an even earlier stage than those in the European study.
They have completed the 30-patient pilot study and will be submitting the results for publication soon, said Dr. Charles. Meanwhile, he said that he believes that the new findings from the German and French researchers will “change physician recommendations to patients.”
Dr. Deuschl, Dr. Charles and others with experience providing DBS for PD patients say that the treatment can be offered if fluctuations occur and the patients have no contraindications, such as retained improvement following L-dopa, no dementia, and no special surgical risks. The risk-benefit ratio should be discussed, said Dr. Charles, and that includes the surgical risk, which according to several DBS studies is about one percent for a severe adverse event.
What scientists don't know is whether DBS used in the earliest stages of the disease will change the course of the disease or push back symptoms.
Michael S. Okun, MD, administrative director and co-director of the Center for Movement Disorders and Neurorestoration, and professor in the departments of neurology, neurosurgery, neuroscience, psychiatry, and history at the University of Florida College of Medicine, said it was not just that the European study was conducted on people earlier in the course of the disease but that they were almost a decade younger than those who are undergoing DBS today. “The results were better than anyone imagined,” said Dr. Okun. The DBS group fared better on every measure and there were no hemorrhages or side effects,” he added. “It may be because they are younger.”
“Potentially, patients could benefit from DBS much sooner in their disease,” he said. “In the early days, we tried everything to spare the patients surgery. Now, the threshold is starting to move earlier. I think it is a good thing.”
Addressing the adverse events, he added: “Certainly the surgical group in the study had more adverse events than the non-surgical group, but overall and compared to other studies the adverse events are much less.”
That said, Dr. Okun said that this study only speaks to a small group of patients in their 50s and does not address whether older patients in earlier stages would benefit. He said that his team will “offer DBS earlier because now there is data to support that.”
MORE ON PDQ-39
The Parkinson's Disease Questionnaire-39 is a survey designed to address aspects of functioning and well-being for those affected by Parkinson's disease. Patients are asked to think about their health and general well-being and to consider how often in the last month they have experienced certain events (for example, difficulty walking 100 yards). They are asked indicate the frequency of each event by selecting one of five options: never/occasionally/sometimes/often/always or cannot do at all.
Thirty-nine questions comprise eight distinct scales:
- mobility (10 items)
- activities of daily living (6 items)
- emotional well-being (6 items)
- stigma (4 items)
- social support (3 items)
- cognition (4 items)
- communication (3 items)
- bodily discomfort (3 items)
For more on the scale, see http://bit.ly/qwavcG.