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Focused Ultrasound Thalamotomy Is Found to Reduce Hand Tremor in Essential Tremor

ARTICLE IN BRIEF

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DR. JEFFREY ELIAS, of the University of Virginia, led the study, which enrolled enrolled 76 patients who had disabling moderate-to-severe essential hand tremor that had been refractory for treatment.

In a randomized, blinded, controlled study, transcranial focused ultrasound thalamotomy led to a nearly 50 percent reduction in hand tremor for patients with medication-refractory essential tremor compared to a sham procedure. Experts agreed that focused ultrasound should join deep brain stimulation in the portfolio of treatment options for patients with essential tremor, but further study is needed to measure a benefit beyond a few years.

Transcranial focused ultrasound thalamotomy with magnetic resonance imaging (MRI) guidance led to a significant reduction in hand tremor at three months compared to a sham procedure, and the improvement persisted for a 12-month study period, according to the results of a randomized, controlled study published in the August 25 edition of the New England Journal of Medicine.

Lesioning procedures, including thalamotomy, are used to treat medication-refractory essential tremor, but unlike traditional radiofrequency thalamotomy, focused ultrasound thalamotomy does not require the use of a probe to enter the cranium. Patients are placed in a stereotactic head frame coupled with an MRI-compatible ultrasound transducer. After sterotactic targeting with MRI, acoustic energy is sequentially titrated to temperatures sufficient to ablate the tissue.

One of the study authors, William G. Ondo, MD, FAAN, director of the Movement Disorders Clinic at the Houston Methodist Neurological Institute, said the success of the study may be due to the accuracy of the imaging method used to guide the procedure. “The accuracy is greater than the older thermal thalamotomy, because you can see where the lesion will be on the MRI in real time. MRI guidance is accurate.”

In addition, he said, MRI guidance allows doctors to test areas of the brain before lesioning. “During the procedure, you heat up the area slightly, and if there is even a millimeter of error, you can correct that using software [before lesioning].”

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DR. WILLIAM G. ONDO said the success of the study may be due to the accuracy of the imaging method used to guide the procedure. “The accuracy is greater than the older thermal thalamotomy, because you can see where the lesion will be on the MRI in real time. MRI guidance is accurate.” In addition, he said, MRI guidance allows doctors to test areas of the brain before lesioning. “During the procedure, you heat up the area slightly, and if there is even a millimeter of error, you can correct that using software [before lesioning].”

The ultrasound energy creates discrete intracranial lesions to reduce symptoms of essential tremor. Although the procedure is considered less invasive than other treatment options for medication-refractory essential tremor, such as deep brain stimulation (DBS), the study authors noted that it does create a thalamic lesion, which can result in permanent neurologic deficits. In the study, a number of adverse events occurred in the thalamotomy group, the researchers noted, including gait disturbance in 36 percent of patients and parethesias or numbness in 38 percent of patients.

Dr. Ondo said that thalamotomy can be repeated, if not reversed. “The procedure can be repeated if there is waning of effect [although there are no data on repeat procedures]. It actually costs less to perform this procedure again than DBS.”

“The procedure can be successful on a wide range of patients. It doesn't require anesthesia and there is no medical clearance, so people with comorbidities would not be excluded.”

STUDY FINDINGS, METHODOLOGY

For their analysis, the researchers, led by W. Jeffrey Elias, MD, professor of neurological surgery at the University of Virginia Health System, enrolled 76 patients who had disabling moderate-to-severe essential hand tremor – defined by a score of at least 2 on the Clinical Rating Scale for Tremor (CRST), with scores ranging from 0 to 4 and higher scores indicating more severe tremor. The patients had not responded to at least two trials of medical therapy.

The researchers randomized study participants at eight international centers in a 3:1 ratio to undergo unilateral focused ultrasound thalamotomy or a sham procedure. At one, three, six, and 12 months, the researchers administered the CRST and the Quality of Life in Essential Tremor questionnaire to assess changes in the participants' functional status.

To ensure blinding, the assessments were videotaped and were rated by an independent group of neurologists who were not involved in the study treatments and were unaware of the treatment assignments or the follow-up time periods.

The researchers' primary end point measure was a between-group difference in the change in hand tremor from baseline to three months. The tremor score was derived from the CRST, Part A (which measures resting, postural, and action or intention components of hand tremor) and the CSRT, Part B (which measures five tasks involving handwriting, drawing, and pouring).

The mean score for hand tremor in the thalamotomy group improved by 47 percent (from 18.1 points at baseline to 9.6) at three months compared with 0.1 percent in the sham-procedure group (from 16.0 points at baseline to 15.8 points); the between-group difference in the mean change was 8.3 points (p<0.001), corresponding to greater improvement after focused ultrasound thalamotomy than after the sham procedure.

Additionally, the improvement in hand tremor scores in the patients who underwent focused ultrasound thalamotomy persisted throughout the 12-month study period (7.2-point change in the tremor score from baseline to 12 months, p<0.001), which represented a 40 percent overall improvement in hand tremor. The sham group did not continue beyond three months.

The study authors noted that in an unblinded cohort of 21 participants who were treated after the three-month blinded assessment period, the improvement in tremor was similar to that seen in the patients in the blinded thalamotomy group; the mean score for hand tremor in the hand contralateral to the thalamotomy improved by 55 percent at three months (p<0.001) and by 52 percent at six months (p<0.001) in these patients.

EXPERTS COMMENT

In an accompanying editorial, Elan D. Louis, MD, professor of neurology at the Yale University School of Medicine, said the findings of the study were promising, writing that the scores for hand tremor and two of the secondary end points — disability and quality of life — improved significantly in the thalamotomy group.

However, he noted that the follow-up was limited to 12 months, and it is unknown whether the benefit was sustained beyond two years. Moreover, the procedure did not achieve large improvements in everyone, with less than a 20 percent change in tremor score in nine patients. He pointed out that a loss of efficacy between months one and 12 — when the hand tremor score for patients in the thalamotomy group increased by only 23 percent — may indicate disease progression.

Commenting on the study, Anthony Lang, MD, FAAN, professor of neurology and director of the Morton and Gloria Shulman Movement Disorders Centre at the University of Toronto, said he thought the editorial “overemphasized” the so-called loss of effect between months one and 12, however.

“Most of the loss of effect was between one and three months, not between three and 12,” he said. “With any lesioning procedure, there is an immediate effect — plus additional edema and changes in tissues that will naturally resolve with time. The immediate effect of a lesion is not always sustained, but that's not because the disease is progressing.”

“The study was very well conducted,” he added. “The patients were widely representative of a group of individuals disabled by a relatively common disorder... Many of them can benefit from this procedure. However, the relative benefit from this procedure versus DBS or even the older radiofrequency thalamotomy is unknown.”

While the nearly 50 percent reduction in hand tremor is significant, the clinical meaning of a partial reduction in tremor is a somewhat controversial issue, said Mark Hallett, MD, FAAN, chief of the human motor control section at the National Institute of Neurological Disorders and Stroke. “If you have a big hand tremor and you can't eat soup on a spoon, and you cut [the tremor] down by 50 percent, you still can't eat soup on a spoon. You have to consider the activities people want to do. It's similar to treating someone with epilepsy — if you can reduce seizures by 50 or even 80 percent, they still can't drive. So that makes the assessment of the phenomenon tricky — is a 50 percent reduction good?”

He noted, however, that the researchers found significant improvements on disability and quality-of-life scales for those in the thalamotomy group, which showed the procedure can in fact benefit many patients, and it is particularly important here since the patients investigated are those who have not responded to medical therapy. those who have not responded to medical therapy.

The method of blinding was one of the study's greatest strengths, said Mark Stacy, MD, FAAN, professor of neurology and vice dean of clinical research at Duke University Medical Center. “The raters looked at videos that were remote from the patient, and they were careful to make appropriate statistical powering for the study.”

However, he said, “It was unfortunate that they didn't continue the sham evaluations until 12 months. [The researchers found] no change in efficacy in the sham group at three months, but the active group had a decline in tremor control over 12 months. I would have liked to see a statistical difference between the sham procedure and thalamotomy at 12 months.”

Since the benefit of thalamotomy beyond a few years is not yet known, the ideal candidate for the procedure may be older, said Dr. Stacy. “If I have a patient who is 35, and has severe tremor, DBS would seem to be a much better approach. Even though it's invasive at the start, electrodes can treat patients for many years. But if patient is 75 and has other medical issues like heart disease and diabetes, focused ultrasound may be a better option if that's a treatment that only works for three years.”

As for how focused ultrasound thalamotomy compares with DBS, Dr. Lang commented that focused ultrasound is a good option for patients who do not want an open surgical procedure, which is what DBS requires.

However, he cautioned against the perception that ultrasound thalamotomy is non-invasive or non-operative. “It is invasive. It is an operation,” he said. “It is a lesion to the brain, and there can be permanent consequences to any lesion. But there are additional consequences of DBS — patients can have hemorrhages from the passage of electrodes through tissue. With DBS, they have hardware implanted, which raises the possibility of infections and erosions. The batteries need to be replaced.”

While he agreed that DBS may have a higher risk of adverse events, Dr. Ondo noted that DBS has been “very successful.”

Among the unique advantages to DBS, he said, “It's adjustable, and it can be moved somewhat and expanded.” That may be preferable for some patients, he said, adding that he hopes there will be a head-to-head trial of the two procedures in the future.

EXPERTS: ON FOCUSED ULTRASOUND THALAMOTOMY FOR ESSENTIAL TREMOR

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DR. MARK HALLETT said the clinical meaning of a partial reduction in tremor is a controversial issue. “If you have a big hand tremor and you cant eat soup on a spoon, and you cut [the tremor] down by 50 percent, you still cant eat soup on a spoon. You have to consider the activities people want to do.”

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DR. ANTHONY LANG: “[Focused ultrasound thalamotomy] is invasive. It is an operation. It is a lesion to the brain, and there can be permanent consequences to any lesion. But there are additional consequences of DBS – patients can have hemorrhages from the passage of electrodes through tissue. With DBS, they have hardware implanted, which raises the possibility of infections and erosions. The batteries need to be replaced.”

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DR. MARK STACY: “It was unfortunate that they didnt continue the sham evaluations until 12 months. [The researchers found] no change in efficacy in the sham group at three months, but the active group had a decline in tremor control over 12 months. I would have liked to see a statistical difference between the sham procedure and thalamotomy at 12 months.”

LINK UP FOR MORE INFORMATION:

•. Elias WJ, Lipsman N, Ondo WG, et al. A randomized trial of focused ultrasound thalamotomy for essential tremor http://www.nejm.org/doi/full/10.1056/NEJMoa1600159#t=article. N Engl J Med 2016; 375(8): 730–739.
    •. Louis ED. Editorial: Treatment of medically refractory essential tremor http://www.nejm.org/doi/full/10.1056/NEJMe1606517?af=R&rss=currentIssue#t=article. N Engl J Med 2016; 375(8): 792–793.