Neurostimulation Benefits Early Parkinson’s Disease

neuroSubthalamic nucleus deep brain stimulation (DBS) offers benefits earlier in the course of Parkinson’s disease (PD), before the appearance of severe disabling motor complications, according to results of a randomized controlled trial.

In a group of patients with relatively mild early motor complications of PD, subthalamic stimulation plus medical therapy was superior to medical therapy alone on several key measures of quality of life and motor function.

Results of the Controlled Trial of Deep Brain Stimulation in Early Patients with Parkinson’s Disease (EARLYSTIM) were published February 14 in the New England Journal of Medicine.

“The result of our study is that a new group of patients can do better with neurostimulation than with medication,” study investigator Gunther Deuschl, MD, from Christian Albrechts University in Kiel, Germany, told Medscape Medical News.

A Second Honeymoon?

Levodopa remains the most effective current treatment for parkinsonian motor symptoms. But after an initial “honeymoon” period, which may last several years, the beneficial effects are hampered by levodopa-induced motor complications, which progressively compromise quality of life, the researchers note. For patients with advanced PD with medically intractable motor fluctuations and dyskinesia, neurostimulation of the subthalamic nucleus effectively reduces motor disability and improves quality of life and has become an established treatment option.

The EARLYSTIM study suggests that neurostimulation “may be a therapeutic option for patients at an earlier stage than current recommendations suggest,” Dr. Deuschl and colleagues say.

In this 2-year trial, 251 patients with PD and early motor complications were randomly assigned to subthalamic nucleus stimulation plus medical therapy or medical therapy alone. The patients had a mean age of 52 years and had had PD for a mean of 7.5 years.

The intention-to-treat population included 124 patients assigned to neurostimulation (120 of whom underwent implantation and completed the study) and 128 assigned to medical therapy alone (125 underwent medical therapy and 123 completed the study).

In the intention-to-treat population, the primary outcome — Parkinson’s Disease Questionnaire (PDQ-39) summary index score — was improved from baseline to 24 months by 7.8 points (26%) in the neurostimulation group but worsened by 0.2 point (1%) in the medical therapy group.

In this population, the between-group difference in the mean change from baseline was 8.0% (95% confidence interval, 4.2% – 11.9%; P = .002), which was similar to the between-group differences in the per-protocol population.

Neurostimulation was also superior to medical therapy with respect to the major secondary outcomes, with significant mean differences achieved in parkinsonian motor disability, activities of daily living, levodopa-induced motor complications (all P < .001), and time with good mobility and no dyskinesia (P = .01).

An expert panel confirmed that medical therapy was consistent with practice guidelines for 96.8% of patients in the neurostimulation group and 94.5% in the medical therapy group.

It appears from this study, therefore, that neurostimulation in combination with medical therapy can “improve motor symptoms better than medical therapy alone at this earlier stage,” the authors say.

Monitor for Suicide

Serious adverse events occurred in 54.8% of patients in the neurostimulation group and in 44.1% of those in the medical therapy group. Serious adverse events related to surgical implantation or the neurostimulation device occurred in 17.7% of patients. A total of 26 serious adverse events were related directly to surgery or the implanted devices; 25 of them resolved completely, and 1 left a cutaneous scar.

The authors say serious adverse events in the medical therapy group were more often related to problems of mobility and adverse effects of medications, including 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 3 suicides in study patients (2 in the neurostimulation group and 1 in the medical therapy group), as well as 4 suicide attempts (2 in the neurostimulation group and 2 in the medical therapy group). The frequency of suicidal behavior, including suicide, was high but did not differ between treatment groups, the authors note.

The study “did not suggest that neurostimulation is associated with a higher risk of suicide than medical therapy,” they write. The authors hypothesize that the decision to eventually undergo neurostimulation may select a specific subgroup of patients with a higher risk for suicidal behavior than the general population. During the study, they established monitoring procedures for suicide, which they say may be useful in the future.

In a linked editorial, Caroline M. Tanner, MD, PhD, from the Parkinson’s Institute, Sunnyvale, California, and Stanford University School of Medicine, Palo Alto, California, points out that suicide has “previously been associated with stimulation of the subthalamic nucleus but less so with other surgical targets.”

Dr. Tanner says the EARLYSTIM study is one of the “most rigorously” conducted trials of neurostimulation, but she cautioned that patients in the trial do not match most patients with PD. All were 60 years of age or younger at the time of surgery, were in good general health, and had a good response to a levodopa challenge.

“Very few” patients with PD meet these criteria, she points out. Only 11% of cases of PD are diagnosed before age 60, and on average 30% of patients have dementia. “Whether these results would be obtained in older patients with PD or in less-experienced medical centers is not known,” she writes.

Potential Candidates

Dr. Tanner also notes that little is known about the long-term efficacy of neurostimulation. But she notes that a study published in Archives of Neurology in 2011 and reported by Medscape Medical News showed that motor improvement is sustained for as long as 10 years in a small number of selected patients. “This would argue in favor of using neurostimulation in carefully chosen, young patients with a recent onset of motor fluctuations,” Dr. Tanner says.

Dr. Deuschl told Medscape Medical News that potential candidates for earlier neurostimulation include patients beyond the first years when medications do very well and the patients are close to normal (honeymoon period). “They are in a disease stage which we call ‘intermediate period’ (followed many years later or decades later by the ‘late period’),” he explained.

The mobility of these patients has been fluctuating for about 1.5 years on average and dyskinesias are developing over that time, although they are still able to participate in activities related to work, family, and sports, he said. “These patients have on average a disease duration of 7.5 years and do better with DBS. I think age should also play a role and younger patients have most likely a lower risk to have complications due to the surgery,” Dr. Deuschl said.

The study was funded by the German Ministry of Research, the French Programme Hospitalier de Recherche Clinique National, and by Medtronic. Dr. Deuschl and several coauthors have disclosed financial relationships with Medtronic and other pharmaceutical companies. A complete list for study authors and Dr. Tanner can be found at

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