Assistant Professor of Clinical Neurology, Weill Cornell Medical College; Assistant Attending Neurologist, New York Presbyterian Hospital

Dr. Sarva reports no financial relationships relevant to this field of study.

SYNOPSIS: This study comparing 20 individuals who received MRI-guided focused ultrasound thalamotomy with seven individuals who received sham treatment showed improvements in Parkinson’s disease tremor. Side effects were similar to prior studies of this technology for essential tremor, with ataxia and limb/orofacial paresthesias being most common.

SOURCE: Bond AE, Shah BB, Huss DS, et al. Safety and efficacy of focused ultrasound thalamotomy for patients with medication-refractory, tremor-dominant Parkinson’s disease: A randomized clinical trial. JAMA Neurol 2017; Oct. 30. doi:10.1001/jamaneurol.2017.3098. 

This was a randomized, sham-controlled pilot study to assess the safety and efficacy of MRI-guided focused ultrasound (FUS) thalamotomy for the treatment of medically refractory tremor in tremor-predominant Parkinson’s disease (PD). The patients were blinded for the first three months, after which those who received sham treatment were offered FUS. They were all followed unblinded for one year. All patients were prepared the same way. For the first three months, the patients and examiners were blinded. Those with tremor-predominant PD with severe, disabling, medication-refractory tremor were included. The FUS was planned and performed as in the previous essential tremor studies. The primary endpoint was a change in the Clinical Rating Scale for Tremor (CRST) Section A (assesses resting, postural, and action tremor) and Section B (assesses tremor while performing tasks such as handwriting) in the “on” medication state. Twenty-seven patients were enrolled, 20 in the treatment arm and seven in the sham procedure arm. The treated arm had a 62% reduction in the CRST scores from baseline whereas the sham arm had a 22% reduction from baseline. Secondary endpoints, such as improvements in the Unified Parkinson’s Disease Rating Scale, were greater in the thalamotomy arm as opposed to the sham group. Thalamotomy and procedure-related adverse events were noted. In the thalamotomy group, ataxia and limb and orofacial paresthesias were the most common. At the one-year mark, 19% had persistent paresthesia and 4% had ataxia. Two had mild, transient hemiparesis. The common procedure-related adverse events were headache and vertigo. All patients were available for the three-month follow-up but after unblinding, six of the seven who received sham treatment received the FUS thalamotomy. Six of the original 20 treated subjects did not have follow-up at one year. Of the six who later received the treatment after unblinding, two had very good tremor control, one had marginal control, and three had inadequate tremor control. Of the 14 of the original 20 from the treatment cohort, 13 reported a positive outcome.

COMMENTARY

Deep brain stimulation (DBS) has been an effective surgical treatment for PD motor symptoms for more than a decade. However, implantable hardware, insufficient numbers of neurologists with DBS programming experience, and the invasiveness of the surgery make FUS lesioning a promising option to treat medically refractory PD symptoms. For those who have cognitive or medical contraindications to DBS, FUS offers a means of improving quality of life. The rationale for lesioning the ventral intermedius nucleus (VIM) thalamus is clear, as the tremor circuitry in PD likely involves the dentato-rubro-thalamic tracts. However, while tremor can be treated by lesioning this target, remaining PD symptoms would not respond to thalamic lesioning. Subthalamic nucleus (STN) and globus pallidus interna (GPi) would be the preferred targets, and studies of those targets are required in PD. An important consideration is that FUS is still a lesioning procedure, and in PD, both sides would need to be treated to obtain adequate symptom control. However, lesioning of bilateral targets, GPi, STN, or VIM would lead to unwanted side effects (dysarthria, ataxia, corticospinal tract involvement).

Thus, DBS remains a better option when bilateral surgical treatment is warranted. Another benefit of DBS over FUS is the use of electrophysiology in targeting the specific nuclei, but with the use of more advanced MRI technology such as tractography, visualization of the nuclei during FUS procedures is evolving. Despite the small sample size, this is still a promising study and opens the door for consideration of FUS in the treatment of PD, enabling better treatment of patients with medically refractory motor symptoms who cannot have DBS.