Daniel M. Keller, PhD

June 30, 2016

BERLIN — For patients with essential tremor (ET), unilateral focused ultrasound thalamotomy improves contralateral hand tremor, avoids use of an operating room and invasion of the skull, and requires only minimal recovery time, giving it some advantages over deep-brain stimulation (DBS), researchers report.

In a poster presentation here at the 20th International Congress of Parkinson's Disease and Movement Disorders, William Ondo, MD, director of the movement disorders clinic at Houston Methodist Neurological Institute in Texas, described a study of 76 patients with severe, medication-refractory ET randomly assigned to MRI-guided unilateral focused ultrasound (n = 56) or to a sham procedure (n = 20), with an open-label extension.

MRI guidance of focused ultrasound allows the creation of precise stereotactic thalamic lesions through an intact skull. Ultrasound transducers converge energy onto a spot, heating it to 55 to 60 degrees Celsius for 10 to 30 seconds.

A core group of neurologists, blinded to the procedure type, assessed tremor according to videotapes of patients made preoperatively and at months 1, 3, 6, and 12.

Groups were well matched for age (approximately 71 years), sex (66% to 75% male), and race (about three quarters white, one quarter Asian). Each group had had ET symptoms for 28 years, were about 17 years from initial diagnosis, and had been receiving medical therapy for about 14 years. Overall and dominant-hand tremor scores were also similar.

Improvements in Tremor, Quality of Life, Disability

The difference in contralateral upper-limb tremor at 3 months, the study's primary endpoint, was significantly greater for the focused ultrasound group than the sham- treated group (P < .001).

Tremor was reduced by about half at 3 months and maintained at 12 months among the actively treated thalamotomy group, but there was no change at 3 months in the sham-treated group. Functional measures of disability and quality of life also improved for the active treatment group.

For the extension phase, 19 of 20 sham patients crossed over to ultrasound thalamotomy at month 3, and those who originally were treated with focused ultrasound also continued to be followed.

Table. Change in Dominant-Hand Tremor

Time Mean CRST Score in Focused Ultrasound Group (n = 56) Mean CRST Score in Sham Group (n = 20) P Value Between Groups P Value Within Ultrasound Group vs Baseline Mean CRST Score in Ultrasound Group, Open-Label Extension
Baseline 18.09 ± 4.81 16.00 ± 4.42 16.5 ± 4.21
Month 1 8.84 ± 4.67 16.05 ± 3.68 .001 7.75 ± 4.06
Month 3 9.55 ± 5.06 15.75 ± 4.90 .001 .001 7.43 ± 3.88
Month 6 10.13 ± 5.33 .001 8.00 ± 3.86
Month 12 10.89 ± 4.86 .001 6.71 ± 4.7

CRST = Clinical Rating Scale for Tremor (32 points maximum).

 

From a baseline of 42 for both groups, Quality of Life in Essential Tremor Questionnaire score improved to 23 at 3 months and 21 at 12 months for the ultrasound group, whereas the score was unchanged at 3 months for the sham procedure group.

Similarly, disability scores improved from a mean of about 16 for both groups to 6 at 3 and 12 months for the ultrasound group, with no change at 3 months for the sham group.

The investigators reported that adverse effects (AEs) were mostly transient or mild. AEs related to thalamotomy were mainly sensory (paresthesia or numbness: 24 of 56 transient; 10 of 56 at 12 months) and "unsteadiness" (18 of 56 transient; 10 of 56 at 12 months) vs 1 of 20 transient "unsteadiness" for the sham procedure group.

Transient sonication-related AEs of headache, nausea/vomiting, or dizziness also occurred in the ultrasound group, and a minority of patients in each group reported transient bruising/bleeding, facial edema, or pain related to the stereotactic frame.

Focused Ultrasound vs DBS

The investigators said MRI-guided focused ultrasound can have several advantages over DBS. No incision is required, an operating suite is not needed, the procedure takes 3 to 6 hours, cost is lower, and recovery time is minimal. Real-time thermal imaging with MRI allows improved accuracy and safety of lesioning, and the effect of lesions can be seen in real time.

Benjamin Walter, MD, director of the Parkinson's disease and movement disorders center at University Hospitals and assistant professor of neurology at Case Western Reserve University in Cleveland, Ohio, told Medscape Medical News that the use of focused ultrasound is an interesting new way of performing thalamotomy, an operation that has been around for a long time as an open stereotactic ablative procedure and was subsequently replaced by DBS.

"Now we're coming back to it because there's this newer, noninvasive approach to doing it," he said. He noted the investigators got "a moderate response, not as good as they saw before in their open-label study, of course."

He said unilateral procedures will not improve head or axial tremors much, so the goal is to improve one hand. The advantage is that a focused ultrasound procedure can be accomplished without surgery. "It's still a destructive lesion, [and] you still have limitations probably how far you can go with it, unilateral vs bilateral [procedure], and adverse events," he said. "It's not reversible. Deep brain stimulation is adjustable and reversible." Too large a lesion with thalamotomy is a permanent condition.

Another thalamotomy procedure is the use of gamma knife, but there is no immediate feedback as to the size of the lesion and the scope of the clinical effects. And the lesions expand over several months.

The advantage of focused ultrasound is that with MRI thermography "they're able to actually image the heating of the brain and get an idea about how big" the lesion is going to be, Dr Walter said, "and you're able to see the clinical effects when you do it." Using MRI thermography with ultrasound also offers the possibility of doing functional MRI at the same time.

Because people do not routinely do gamma knife thalamotomy, he said the most useful comparison for ultrasound will be with DBS.

Compared with DBS, focused ultrasound thalamotomy "is not adjustable, and it's not reversible. It is, however, low upkeep as far as the long-term effects," he said. "There is no need to replace a battery, the patient is not undergoing brain surgery…. But instead of having a hole in your skull, you have a hole in your brain."

The study was funded by InSightec Ltd, Israel; the Israel-U.S. Binational Industrial Research and Development Foundation; and the Focused Ultrasound Foundation. Dr. Ondo has received compensation as a speaker and consultant for Teva, Ipsen, UCB, Merz, and Lundbeck.

20th International Congress of Parkinson's Disease and Movement Disorders. Abstract 133. Presented June 20, 2016.

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