ARTICLE IN BRIEF:
Deep brain stimulation of the ventral thalamic nucleus ameliorated severe essential tremor in the short-term, but its efficacy waned over the course of 10 years.
The effects of deep brain stimulation (DBS) on essential tremor appear to diminish over time, according to a report appearing in the February 20 online edition of Neurology.
Although the study is small, non-randomized, and uncontrolled, experts who reviewed the report for Neurology Today said the findings align with their clinical experience: that the effectiveness of DBS wanes as patients age, either because of the natural progression of the disease, or because of “habituation.”
The authors of the paper and expert reviewers also agreed that although the waning effectiveness is an important clinical consideration in weighing risks and benefits of treatment options, DBS continues to provide significant tremor improvement even ten years out.
“Within the limitations of a monocentric follow-up study the present data strongly suggest that there is a habituation of the efficacy over a 10-year period,” lead author Gunther Deuschl, MD, of the department of neurology at Christian-Albrechts-University in Kiel, Germany, told Neurology Today. “But still after 10 years these patients do have a positive, albeit lower stimulation effect. There is a disease worsening for this group as suggested by many studies, and we have proposed an estimation of the contribution of habituation to be above 10 percent. This needs confirmation by larger cohorts.”
A total of 51 patients with severe, medically intractable essential tremor underwent bilateral DBS surgery between 2003 and 2011. Twenty patients were included in the final, follow-up analysis.
In the surgery, electrodes were implanted bilaterally into the thalamic ventral intermediate nucleus (Vim) of the thalamus with contacts extending into the subthalamic area of the zona incerta. Stereotactic MRI was used to define the target coordinates and the trajectories and up to five microelectrodes were used for intraoperative target localization. The final stimulation site was determined as the best compromise between good therapeutic response and high threshold side effects.
The primary outcome measure was tremor severity as assessed by the essential tremor rating scale (TRS). The patients were assessed between 32 months (short-term) and 120 months (long-term) after surgery with a full examination including the TRS rating scale, activities of daily living scale and quantitative tremor assessment with accelerometry, among others. Patients were tested in the Vim-stimulation on- and off-condition.
Dr. Deuschl and colleagues found that tremor severity in the stimulation-off condition worsened from an average of 56.3 points at baseline to 76.5 points at long-term follow-up. In the stimulation-on condition, tremor severity worsened from a mean of 20.9 at short-term follow up to 43.2 at long-term follow-up.
Yet, importantly, in the on condition, DBS provided significant benefit over baseline at short and long-term follow-up.
In comments to Neurology Today, Dr. Deuschl said that patients who do not respond sufficiently to medication and are severely impaired should still consider DBS. “The benefit-risk balance is well-known,” he said. “This has not changed, but new stimulation paradigms and possibly new targets need to be studied to counter the habituation we have found in our study.”
He added that there are few alternatives to DBS. Focused ultrasound lesioning, recently introduced, can only be applied unilaterally and patients with axial tremor (head, voice, titubation) do not sufficiently respond to unilateral lesioning. Moreover, long-term effects of this treatment are unknown.
Daniel Leventhal, MD, PhD, assistant professor of neurology and biomedical engineering at the University of Michigan, who reviewed the report said the evidence is convincing that, at least in essential tremor patients in their 60s, the benefits of DBS diminish over time. Although it is a small, uncontrolled study, the results “match well with my anecdotal clinical experience,” he said.
“Blinding the raters and using multiple outcome measures, which all more or less gave the same answer, support this finding,” Dr. Leventhal said.
However, he cited some caveats: patients in this study were an average of 66.6 years old when implanted so it is not clear if the same results would also apply to younger patients. And it is unclear how the tremor rating scale translates to disability and/or quality of life.
“Notably, the activities of daily living scales were improved on stimulation at long-term follow-up compared to baseline,” he said. “For that matter, every single outcome measure was improved at long-term follow-up on stimulation compared to baseline. One important question that the study does not address is whether the patients feel that, despite waning benefit, the surgery was worth it in terms of their quality of life.”
Dr. Leventhal said patients should be screened by an experienced DBS team and fully informed about known potential risks and benefits. The evaluation usually includes neuropsychometric testing, a brain scan, a formal tremor evaluation, and presurgical evaluations. Patients should have failed a reasonable trial of tremor medications (or have a contraindication to the medication).
“The major impact of this study will be the way I counsel patients—that there may be diminishing returns over time, which they need to take into account when deciding whether to pursue DBS,” he said. “However, in my experience, even patients that still have significant disability on stimulation years after surgery are almost completely incapacitated with their stimulator off.”
Theresa A. Zesiewicz, MD, professor of neurology and director of the University of South Florida Ataxia Research Center, agreed. “The results of the study, which reported diminished effectiveness of DBS over a long-term period, would not negatively influence the decision to use DBS if patients suffered disabling and refractory tremor that greatly interfered with their quality of life,” she told Neurology Today. “Moreover, the real question is whether we can improve on target areas and methods of neuromodulation in the future that can improve on these long-term results for patients.”
She added: “Both pharmacotherapy and neuromodulation like DBS have a place in essential tremor therapy. The decision to choose DBS must take into account patient response to medications, quality of life, and comorbid conditions. It is understandable that DBS loses some efficacy over the long term, as essential tremor is a progressive condition. However, DBS has been shown to be a very effective way to control essential tremor with an impressive magnitude of effect. Hopefully, newer DBS techniques will prolong its efficacy in the future.”
Dr. Deuschl said clinicians should advise patients about the likelihood of habituation over time but explain that DBS is still a treatment of choice.
Dr. Leventhal agreed. “The take-home message for clinicians is that the therapeutic benefit of DBS is likely to wane over time largely due to disease progression, but also possibly due to `habituation.' However, DBS continues to provide significant tremor improvement even 10 years out, and the decision of whether to pursue DBS remains a personal choice for patients weighing the impact of their tremor against the risks of DBS (mostly risks associated with the surgery itself).”
“This study gives us important additional information for patients to consider when making that decision,” he said.
Dr. Deuschl has received lecture fees and has been serving as a consultant for Boston Scientific. He received royalties from Thieme Publishers; he is a government employee and receives through his institution funding for his research from the German Research Council, the German Ministry of Education and Research, and Medtronic. Drs. Leventhal and Zesiewicz had no disclosures.