Benefit of DBS for Essential Tremor Fades Over Time

Deep brain stimulation (DBS) can be an effective treatment for severe refractory essential tremor but new research suggests its efficacy fades over time.

In a small study that followed patients for up to 10 years, investigators found the beneficial effects of DBS of the ventral intermediate thalamic nucleus (Vim) declined over time. This may be due to habituation, which is a gradual adaptation to a stimulus that is tied to a decreasing response. It's also possible that the efficacy fades because the condition progresses.

"We have to counsel our patients that habituation can happen. This does not mean that we should not treat them with Vim-DBS," study coauthor Günther Deuschl, MD, PhD, of the Department of Neurology at Christian-Albrechts-University in Kiel, Germany, told Medscape Medical News. "This is currently the best and most established treatment for them — even if there is habituation."

The study was published online February 20 in Neurology.

Long-Term Efficacy Unclear

Although many patients respond to drug treatment for essential tremor, others do not; it's then that more aggressive options like DBS are considered. Vim-DBS treatment is the most established invasive approach but its long-term efficacy is less clear.

Deuschl said his team has been treating essential tremor patients with DBS for two decades and have anecdotally observed a worsening of the condition in their patients as time goes on.

To learn more, and to distinguish any difference in DBS efficacy due to habituation vs tremor progression, the investigators assessed symptom severity in both stimulation-on and stimulation-off conditions over time.

In theory, comparing tremor severity in the "off" condition at two time points should reflect only disorder progression, the researchers note. In contrast, symptom severity in the "on" condition is determined by both disorder progression and the effect of stimulation, including possible habituation.

The study included patients with medically intractable essential tremor who were assessed following bilateral DBS surgery between 2003 and 2011. The 11 men and 9 women had a stable initial response to DBS implantation.

Baseline assessment for surgery included a full neurologic exam, medication history, and tests to exclude other diagnoses. Trained movement disorder specialists conducted the preimplantation assessment as well as a short-term follow-up examination at approximately 1 year postsurgery.

Study participants returned for an additional visit between 2013 and 2015. At this time, they were assessed using the Tremor Rating Scale (TRS), Archimedes spiral scale, activities of daily living scale, and quantitative tremor assessment with accelerometry.

Medication Increase

Two experienced tremor specialists independently reviewed videotaped TRS assessments. The videos were presented in a random order regarding patients, visits, and the "on" or "off" stimulation conditions.

The majority of participants — 17 of 20 — took additional medication at the time of baseline assessment. These medications included primidone, propranolol, gabapentin, and topiramate. At long-term follow-up, there were an additional four prescriptions for propranolol and three for primidone.

To increase precision of measuring tremor severity in the DBS "off" condition, the researchers controlled for a rebound effect. Patients who rebound following cessation of stimulation typically show a sudden spike in tremor amplitude, followed by a gradual decrease over time.

The investigators assumed the rebound effect would wear off by 1 hour, at which point TRS clinical subscores would more accurately reflect disorder progression only.

A total of 7 participants demonstrated this rebound effect out of a subset of 17 participants specifically tested for it.

"The major finding is the reduction of the stimulation effect observed over the time interval of 2 to 10 years," the researchers note.

Clinical severity indicated by TRS total score in the stimulation-off condition, for example, worsened from a mean 56 points at baseline to 77 points at long-term follow-up. TRS scores range from 0 to 144, with higher scores indicating worse tremor.

The TRS total score also worsened in the stimulation-on condition from a mean 21 points at short-term follow-up to 43 at long-term follow-up.

"Profound Reduction"

The decrease of DBS treatment effect at long-term follow-up measured with the TRS total score in the stimulation-off vs the stimulation-on condition was negatively associated with the time since surgery (Spearman ρ = −0.78, P < .001). Spiral scores and activity of daily living scores similarly worsened over time.

"Thus, the stimulation effect showed a clear decrement for all tremor severity and functional outcome parameters over the long-term course in this cohort," the researchers note.

When comparing decreases in TRS scores per month over time, the investigators found 13% (95% confidence interval [CI], −28% to 53%) of the worsening of the score in the stimulation-on condition was caused by habituation and 87% (95% CI, 47% to 128%) was due to progression.

Currently, said Deuschl, there is no evidence that repositioning the DBS electrodes would improve patient response.

The "profound reduction" of the clinical effect of vim-DBS over the long-term "may indeed be of relevance for shared and informed decision-making for DBS treatment between patient and physician," the researchers note.

The need for future research is urgent, Deuschl said. Studies examining different electrode positions and new stimulation protocols — including whether switching off the stimulator at night provides value — should be investigated further, he added.

Deuschl's team and other investigators, in fact, "are currently working on the analysis of the electrode position, which will probably show us what the best placement is," he said.

"Not a Cure"

Commenting on the findings for Medscape Medical News, Atom Sarkar, MD, PhD, of the Global Neurosciences Institute, LLC and Drexel Neurosciences Institute at Drexel University College of Medicine in Philadelphia noted that "DBS is one of the most significant surgical additions" in combating neurological afflictions.

"Its FDA-approved indications are fundamentally for movement disorders, the two most frequent being Parkinson's disease as well as essential tremor," added Sarkar, who was not involved with the current study.

"DBS surgery offers safe, effective, personalized care solutions for essential tremor patients," Sarkar said. "That being said, like many things in medicine, it is not a cure, as the therapy necessarily improves the symptoms of those disabled by essential tremor, but it is not necessarily addressing the etiology of the disorder."

The German Research Foundation supported Deuschl's role in this study. Deuschl 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. Sarkar has disclosed no relevant financial relationships.

Neurology. Published online February 20, 2019. Abstract

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