Guided Ultrasound Thalamotomy Decreases Hand Tremor in Patients With Essential Tremor

Deborah Brauser

August 25, 2016

Ultrasound thalamotomy guided by MRI is effective and relatively safe when used to treat patients with essential tremor (ET), a randomized trial suggests.

Initial findings of the 76-person study were presented in a poster at this year's International Congress of Parkinson's Disease and Movement Disorders, as reported by Medscape Medical News.

In addition, it was the basis for the recent approval from the US Food and Drug Administration (FDA) for the first focused ultrasound device (ExAblate Neuro, InSightec) to treat ET when other treatments have been unsuccessful.

Now, full study results are published in the August 25 issue of the New England Journal of Medicine. It shows that patients with ET who underwent MRI-guided focused ultrasound thalamotomy had a 47% improvement 3 months later in composite hand tremor scores compared with a 0.1% improvement in those who underwent a sham procedure.

This outcome was still significant at 1 year, slipping to just 40% improvement at 1 year for those who received the active treatment.

Quality-of-life and disability scores were also significantly improved for the thalamotomy group. However, gait disturbance affected 36% of these patients and paresthesias/numbness affected 38% — with 9% and 14%, respectively, still having these adverse events (AEs) at 1-year follow-up.

Principal investigator W. Jeffrey Elias, MD, professor of neurosurgery and neurology at the University of Virginia in Charlottesville, told Medscape Medical News that none of the AEs were unexpected and that the field of neurosurgery and patient groups are still welcoming this type of procedure because it's perceived as being noninvasive, unlike deep-brain stimulation (DBS), and has a shorter recovery time.

Dr W. Jeffrey Elias

"This is a good match of the technology to the clinical problem," said Dr Elias.

He added that he wasn't surprised by the overall findings because the earlier pilot studies "were very powerful and effective." But he was pleased to see that results were still strong after a more rigorously designed trial.

In an accompanying editorial, Elan D. Louis, MD, Center for Neuroepidemiology and Clinical Neurological Research at Yale School of Medicine, New Haven, Connecticut, noted several limitations of the study, including that it had a limited follow-up period, but called the results promising.

"Even with these concerns and caveats, pros and cons, the procedure will take its place among other surgical procedures for medically refractory essential tremor," writes Dr Louis.

Eliminates Need for Craniotomy

Thalamotomy is an old procedure that was replaced by DBS, which is now the surgical standard for treating medication-resistant ET.

However, the "subsequent introduction of phased-array transducers" in focused ultrasound thalamotomy "eliminated the need for a craniotomy, and high-resolution imaging allows real-time, image-guided lesioning," explain the researchers.

In the procedure, energy is converged onto a spot that is heated to approximately 55 to 60°C for 10 to 30 seconds.

For the study, the 76 participants (68% men; mean age, 71 years) with moderate-to-severe ET (a score of 2 or greater on the Clinical Rating Scale for Tremor [CRST]) were enrolled between August 2013 and September 2014 in 8 centers in the United States, Canada, Sweden, Japan, and South Korea.

All had previously gone through at least two medical therapy trials and had not responded to treatment. The mean time from initial diagnosis was 16.8 years, and mean time from initial ET symptoms was 28 years.

The patients were randomly assigned 3:1 to unilateral focused ultrasound thalamotomy using the ExAblate Neuro system (n = 56) or to a sham procedure, "in which no acoustic energy was delivered" (n = 20).

Videos of the patients at 1-, 3-, 6-, and 12-month follow-ups were viewed and evaluated by a blinded group of neurologists. At each of these visits, the Quality of Life in Essential Tremor Questionnaire (QUEST) was also administered, and functional status was determined by using the disability subsection of the CRST.

Primary Outcome Goal Met

The primary outcome was change from baseline to 3 months in composite hand tremor scores, with higher scores representing more severe tremor.

At baseline, the composite hand-tremor score was 18.1 for the focused thalamotomy group and 16.0 for the sham group. At the 3-month follow-up, the scores were 9.6 and 15.8, respectively (group difference in mean change, P < .001).

At this point, the sham group was offered the opportunity to cross over to receive the active treatment, which 19 of the 20 individuals agreed to. For those who crossed over, hand-tremor scores were significantly reduced at 3- and 6-month postprocedure assessments (both P < .001).

The hand-tremor score was 10.9 at 12 months for the group originally assigned to the thalamotomy procedure (mean change from baseline, 7.2 points; P < .001).

When examining functional improvements, the investigators found a 62% reduction in disability scores from baseline to 3 months (from 16.5 to 6.2) for the thalamotomy group vs a 3% reduction (from 16.0 to 15.6) for the sham procedure group (P < .001). And the treatment's group score was sustained at 1 year (6.3).

The QUEST quality-of-life scores also improved significantly for this group at 3 months compared with the sham group (46% vs 3% score reduction from baseline, respectively). Interestingly, "the largest improvement was in the psychosocial domain," note the investigators.

"Million Dollar Question"

Regarding adverse events, numbness or paresthesia was reported in the face for 8 patients, in the hand for 6, and in both locations for 6, "presumably from involvement of the adjacent ventral posterolateral (sensory) nucleus," write the researchers.

Overall, "the results show that tremor reduction was related to treatment, not a placebo effect."

They add that past studies have shown that medications can reduce tremors by approximately 50% in patients, but these were conducted during the early stages of ET. "The current trial shows that focused ultrasound thalamotomy can further control tremor when it has become advanced and resistant to medication," they write.

Limitations cited, however, included that the active treatment was not compared with DBS in this study.

"It's kind of a million dollar question: which one of these is better? And my answer is that each has different side effect profiles or issues," said Dr Elias. "So they provide different options."

Although a head-to-head comparison would be interesting, "that would be hard to do. The more invasive an intervention becomes, the more unlikely that patients are to randomly select one or the other in a clinical trial," he said. "They would have to be compared in a nonrandomized fashion."

He reported that the current study's participants have been asked to continue in a 5-year follow-up study, which will conduct yearly assessments.

Risks of Both Procedures

Dr Louis notes in his editorial that ET affects about 7 million individuals in the United States and that "effective pharmacotherapies…have been elusive."

DBS has become the go-to procedure for this disease, but it is associated with risk for intracranial bleeding and infection, "as well as malpositioned electrodes, the need to replace the battery periodically, and hardware issues such as lead breakage," he writes.

Although the patients in the current study who underwent focused ultrasound thalamotomy showed significant improvements in hand tremors, function, and quality of life, this procedure has its own risks and limitations, writes Dr Louis. For example, it is associated with the AE of altered sensation, and it creates a fixed brain lesion.

In addition, not all patients are suitable candidates. "The procedure did not achieve large improvements in everyone; the percentage change in tremor was less than 20% in 9 of 56 patients," he writes.

The investigators note that this could be because of acoustic wave properties, such as frequency, and/or individual cranial characteristics.

"Skull thickness presents a problem is some cases," adds Dr Louis.

Still, because this approach is perceived as less invasive than others "because it does not involve burr holes and intracerebral electrodes, as well as the evidence that patients with essential tremor are perhaps particularly harm avoidant, [it] may allow more patients to avail themselves of a surgical option for the treatment of this often disabling disease," he concludes.

The study was funded by InSightec, the Focused Ultrasound Foundation, and the Binational Industrial Research and Development Foundation. Dr Elias reports receiving grant support from InSightec and the Focused Ultrasound Foundation. Disclosures for the coauthors are in the original paper.

N Engl J Med. 2016;375:730-739, 792-793. Abstract  Editorial

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