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doi: 10.1097/01.NT.0000436531.72054.b0
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Ultrasound Thalamotomy Reported to Be Promising Therapy for Essential Tremor

Rukovets, Olga

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ARTICLE IN BRIEF

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A small, pilot study in the Aug. 15 issue of theNew England Journal of Medicine(NEJM) found that performing focused ultrasound thalamotomy with the help of transcranial MRI reduced tremor in all 15 participants and improved their quality of life.

Medication alone does not control symptoms for nearly half of all patients with essential tremor (ET), the most common movement disorder. But, according to a small, pilot study in the Aug.15 issue of the New England Journal of Medicine (NEJM), MRI-guided focused ultrasound thalamotomy may be a promising, noninvasive treatment option for these individuals. (This procedure involves delivery of high-intensity focused ultrasound waves, or sonication, using MRI-guidance to pinpoint the targeted area for ablation — in this case, the ventralis intermedius nucleus of the thalamus.)

Researchers, led by W. Jeffrey Elias, MD, associate professor of neurological surgery and neurology director of stereotactic and functional neurosurgery at the University of Virginia School of Medicine, found that performing thalamotomy with the help of transcranial MRI reduced tremor in patients and improved their quality of life. The NEJM investigators reported a significant improvement in all 15 patients treated in this pilot study.

Study author Binit B. Shah, MD, assistant professor of neurology at the Parkinson's Disease and Movement Disorders Division at the University of Virginia, told Neurology Today: “Unlike other tissue throughout the body, the brain can be quite eloquent and exquisitely sensitive to certain treatments. From our standpoint, understanding both the immediate and the delayed safety profile [of this procedure] was important. What we found was that the majority of the fifteen patients showed improvement with no sustained adverse effects.”

Overall, he added, these results point to a potential and exciting new avenue for patients with essential tremor who have been unable to find relief with medications and prefer a non-incisional treatment approach.

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STUDY PROTOCOLS, FINDINGS

Over the course of one year, Dr. Shah and colleagues performed extensive testing and eventual thalamic ablation in 15 patients with severe medically intractable essential tremor with MRI guidance. Patients had all tried and failed at least two full courses of medications (one of which had to include propranolol or primidone) for ET.

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The 15 participants were predominantly men (67 percent) and were 66.6 years old on average. At each study visit, a movement-disorder neurologist conducted a complete neurologic and physical examination; any clinically relevant changes were reported as adverse events.

The hand tremor score, which was the primary outcome measure in these patients, improved significantly after treatment — from 20.4 at baseline to 5.2 after one year (p=0.001). At baseline, total tremor scores were 54.9, but improved to 24.3 at 12 months (p=0.001). There was also a significant improvement in disability scores from 18.2 at baseline to 2.8 after one year (p=0.001). Quality-of-life, according to self-reports, improved from 37 percent to 11 percent after 12 months (p=0.001). (For more information on these measures, see the sidebar: “Calculating Tremor Severity.”)

Adverse events in these patients included transient sensory, cerebellar, motor, and speech abnormalities; four patients had persistent paresthesias.

Dr. Shah told Neurology Today that the study was unique in that it not only measured tremor severity, but “broke that down to apply specifically to the hand being treated, since this was a unilateral, one-sided procedure. We also performed simulated eating tasks, where we were able to assess function other than our standard drawing of spirals, which may not correlate well to daily functioning for many patients with tremor. We showed benefit in simulated eating — using utensils, holding cups, and so on — which really impacted the patients' lives prior to the treatment,” he said.

Dr. Shah cited several study limitations, however, including the small sample size of 15 patients and the fact that the study was unblinded: the patients and clinicians were aware of the treatment, which could potentially introduce bias.

Still, the main goals of the pilot study — safety and efficacy — were met, according to Dr. Shah. “We were able to see treatment benefit almost immediately,” he said, and the only serious adverse event was a persistent dysesthesia in a patient's dominant index finger.

The investigators are now working on a multicenter, double-blinded study using MRI-guided ultrasound thalamotomy in ET patients. “Those who have the sham treatment will then be offered active treatment after some time. It'll be at seven sites throughout the US and the world,” Dr. Shah told Neurology Today. “Having larger numbers with a sham-controlled, double-blinded design will allow us to really compare what benefit we see, while controlling for blinding as well as for placebo effect,” he noted.

The pilot study was funded by the Focused Ultrasound Surgery Foundation (fusf.org).

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EXPERTS WEIGH IN

Independent commentators said the NEJM study shows promise for those individuals with tremor who may not want to have an invasive procedure, such as deep brain stimulation.

Howard Hurtig, MD, Elliott professor of neurology at the University of Pennsylvania School of Medicine, who was not involved in the research, told Neurology Today that the authors did a nice job of showing the potential of this treatment, but were also careful not to overgeneralize the results of the small study.

“We know that medical treatment for essential tremor is very unsatisfactory. On the other hand, many patients learn to live with tremor and many will choose not to take the big step of having brain surgery. If ultrasound can be shown to be safe in a larger study, then this provides a good option for those who are reluctant to have a bigger procedure and have hardware planted in their body. So, I think the outcome remains to be tested and this pilot study shows some promise,” Dr. Hurtig told Neurology Today.

The finding might have been more robust, he added, if the clinical evaluations of the progression and severity of the tremor were blinded. “They could have done that with a blinded grader evaluating each patient or alternatively they could have done a blinded videotaped assessment.”

Additionally, due to the small sample size, Dr. Hurtig pointed out, “there's no way to know what the serious risk might be in a larger group. Four out of 15 is a substantial number [of adverse events] even though the four only had sensory symptoms. I think the authors were careful to conclude that a larger study was needed before any broad conclusions could be made.”

Andres Lozano, MD, chairman of neurosurgery at the University of Toronto and senior scientist in the Division of Brain Imaging & Behaviour Systems at Neuroscience Toronto Western Research Institute in Canada, said: “Unlike the other available options for this group of medically intractable patients, this treatment may be attractive to patients because there is no incision being made.”

“What this means is that many of the patients with ET who are shut in at home, who don't want to go out, who are confined by social embarrassment now may want to receive this treatment because they don't consider it as dangerous or as invasive as conventional surgery,” he explained. Those patients who had otherwise accepted their ET and its associated limitations are now re-examining the possibility of treatment with this technique, he said. [Earlier this year, Dr. Lozano and colleagues published a proof-of-concept study in The Lancet Neurology, reporting benefits of ultrasound thalamotomy in four patients with ET.]

However, unlike deep brain stimulation — where electrodes can be removed from patients in the case of infection or adverse reaction to treatment — the side effects of thalamotomy may not be reversible, said Dr. Hurtig. “For those patients (nearly 50 percent) who do not respond to medications for essential tremor, ultrasound thalamotomy may offer promise. However, because tremor is not a fatal illness, some individuals may not choose to seek any treatment at all,” he said.

In the future, ultrasound thalamotomy may hold promise for treating a number of other conditions, Dr. Lozano said, including other movement disorders, central pain disorders, epilepsy, brain tumors, and “an exciting area will be using focused ultrasound to open up the blood-brain barrier to allow the delivery of chemotherapeutic agents or antibodies for Alzheimer's disease or Parkinson's disease.” From animal models, he said, “it looks like disrupting the blood-brain barrier temporarily with focused ultrasound, you can significantly increase the delivery of antibodies to the brain with the same dose,” he told Neurology Today.

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CALCULATING TREMOR SEVERITY

In this New England Journal of Medicine pilot study, Binit B. Shah, MD, assistant professor of neurology at the Parkinson's Disease and Movement Disorders Division at the University of Virginia, and colleagues calculated tremor severity using the Clinical Rating Scale for Tremor (ranging from 0 to 160), hand subscore (primary outcome, ranging from 0 to 32), and disability subscore (ranging from 0 to 32), with higher scores indicating worse tremor. See the scale here: http://bit.ly/19LfA6f.

Quality of life was measured by patients' responses to the Quality of Life in Essential Tremor Questionnaire (ranging from 0 to 100%, where higher scores mean greater perceived disability). The questionnaire is available here: http://bit.ly/1diaov8.

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LISTEN IN: In a promising pilot study in the Aug. 15 New England Journal of Medicine, investigators reported improvement in 15 essential tremor patients after MRI-guided focused ultrasound thalamotomy. Study author Binit B. Shah, MD, assistant professor of neurology at the Parkinson's Disease and Movement Disorders Division at the University of Virginia, spoke with Neurology Today about the potential implications of this small study for neurologists and essential tremor patients: http://bit.ly/rCBryX.

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LINK UP FOR MORE INFORMATION:

•. Elias WJ, Huss D, Wintermark M, et al. A pilot study of focused ultrasound thalamotomy for essential tremor. N Engl J Med. 2013; 369:640–8.

•. Lipsman N, Schwartz ML, Lozano AM. MR-guided focused ultrasound thalamotomy for essential tremor: a proof-of-concept study. Lancet Neurol. 2013; 12:(5): 462–468.

•. Neurologyarchive on essential tremor: http://bit.ly/1e7miIM.

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