Ultrasound Thalamotomy Benefits Essential Tremor

Pauline Anderson

August 15, 2013

Thalamotomy using high-intensity focused ultrasound, guided by MRI, improves tremor, particularly in the hand, and quality of life in patients with essential tremor, according to results of a small pilot study.

The novel aspect of this new study is that it used ultrasound therapeutically rather than diagnostically in the brain, said lead author W. Jeffrey Elias, MD, associate professor, neurosurgery, University of Virginia, Charlottesville.

The new thalamotomy approach was made possible with modern therapeutic techniques, said Dr. Elias. "There has always been this problem of sending sound waves through the skull, but now with modern technology and contemporary ultrasound devices we're able to focus over 1000 ultrasound beams to very precise points deep in the brain, in the thalamus."

He likened the procedure to interrupting a tremor circuit, or an aberrant circuit, or to correcting a cardiac arrhythmia.

Results of the phase 1 open-label uncontrolled trial are published in the August 15 issue of the New England Journal of Medicine.

Therapeutic Sonications

The study included 15 cognitively normal patients, mean age 66.6 years, who had severe, medication-refractory essential tremor. The patients, most of whom were male (67%), were right handed (80%), and had a family history of tremor (80%), had lived with the tremor for about 32 years.

Dr. W. Jeffrey Elias

Characterized by a rhythmic oscillation of agonist and antagonist muscle groups, essential tremor is the most common movement disorder, with a prevalence of up to 4%. Dr. Elias estimated that some 10 million Americans are affected by this condition.

Before entering the magnet, which was equipped with a guided focused ultrasound system, patients had their heads shaved and were fitted with a stereotactic head frame. An elastic diaphragm was attached to their scalp and connected to the ultrasound transducer so it could be filled with chilled, degassed water.

With MR thermography, clinicians used a series of low-power sonications that produced temperatures of 40°C to 45°C to confirm accurate focusing in 3 orthogonal planes. They then gradually escalated the power and monitored temperatures to reach therapeutic sonications of 10 to 20 seconds. Final sonication temperatures ranged from 55°C to 63°C. Patients communicated with clinicians throughout the treatment.

The procedure targeted the unilateral ventral intermediate nucleus of the thalamus. Only a unilateral treatment was performed because, as Dr. Elias explained, "this is early-stage research study, and the risk of side effects or complications goes way up for bilateral thalamotomy."

The treatment resulted in significant improvements. Over the course of a year of monitoring, the researchers observed initial improvements, then a slight recurrence of tremor, mostly within the first 3 months, after which "everything was stable," said Dr. Elias.

The greatest degree of tremor improvement was in the contralateral hand as shown by hand tremor subscores of the Clinical Rating Scale for Tremor (CRST), which decreased from a mean baseline score of 20.4 to a score of 5.2 at 12 months (a relative reduction of 75%; P = .001). Total CRST scores went from 54.9 at baseline to 24.3 at 12 months (a relative reduction of 56%; P = .001).

There was no significant difference in the tremor score for the ipsilateral hand (13.4 vs 13.5; P = .90).

Disability significantly improved, from a mean score of 18.2 to 2.8 on the relevant subsection of the CRST (P = .001) for a relative reduction of 85%. They also had improvements in quality of life (37% vs 12% on the Quality of Life in Essential Tremor Questionnaire; P = .001) and in physical performance, including better scores for the simulated eating task in which patients were rated on the speed of scooping 5 kidney beans from one small cup into another (from 29.4 seconds to 11.6 seconds; P = .001).

Patients were most pleased at being able to better carry out basic everyday life skills, such as drinking a cup of coffee, eating soup with a spoon, and brushing their teeth, according to Dr. Elias.

Thalamotomy for the treatment of essential tremor isn't new. In the past, physicians have used radiofrequency thalamotomy and deep-brain stimulation in this region, but these interventions are linked to serious adverse events, including intracerebral hemorrhage and neurologic impairment.

This new MRI-guided ultrasound version is theoretically safer because it doesn't involve a surgical opening or insertion of a probe, said Dr. Elias. In this study, only 1 serious adverse event occurred, a case of persistent dysesthesia on the tip of the dominant index finger. The most common adverse effects were paresthesias (2 in lips or tongue and 1 in finger).

"But we're not going to make any big claims because it's a small study," said Dr. Elias. "Even with a transcranial ultrasound thalamotomy like this, you could still have a complication; you have to be very precise, within a couple of millimeters."

If the target is missed, patients could have problems with weakness, numbness, or balance, he said.

The researchers plan to follow these study patients annually. They're also participating in a larger, multinational clinical trial that is to be launched later this year.

Among the limitations of the study were that it didn't include a control group or compare the procedure with other treatments. As well, comprehensive cognitive assessments weren't performed, although neither the researchers nor the patients noted any cognitive change following the procedure, according to Dr. Elias.

Natural Progression

Reached for a comment, Michael S. Okun, MD, national medical director, National Parkinson Foundation, and professor, Departments of Neurology, Neurosurgery, Neuroscience, Psychiatry, and History, University of Florida Center for Movement Disorders and Neurorestoration, Gainesville, said the study findings represent a natural progression.

"High intensity ultrasound was first utilized as a treatment for the brain in the 1940s and 1950s. Its rebirth should not be a surprise, as combining this technology with high field MRI scanning has the potential to lead to a powerful therapeutic tool."

Ultrasound therapy for essential tremor, and possibly for Parkinson's disease, holds great appeal for patients with these disorders because it doesn't require a scalp incision or a craniotomy, said Dr. Okun. "However, in this study several patients had a suboptimal result, likely due to lesion location."

Dr. Okun stressed that accurate lesion or lead placement is critical to the outcome of the procedure. "This is one challenge that ultrasound will have to overcome, especially since physiological guidance cannot be employed."

In the future, he said, it will be important to consider lesion-based therapies as alternatives to deep-brain stimulation, especially given issues of economics and availability. "However, there are important limitations, including serious risks of operating on both sides of the brain, and creating irreversible side effects."

The study was funded by Focused Ultrasound Surgery Foundation. Disclosure information for the authors is available at www.nejm.org.

N Engl J Med. 2013;369:640-648. Abstract

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