In the fall, 2017 issue of MPDN we discussed focused ultrasound (FUS) (1), a specialized technique that was FDA approved to treat essential tremor (ET) in 2016. Parkinson disease (PD) tremor is not yet an FDA approved indication, but it seems likely that it will be in the future. Also mentioned in the MPDN article was a study of patients with PD who were given FUS. As that study was ongoing, no data was then available. That study is now complete and has been published in JAMA Neurology as discussed below, along with two other new scientific reports. Here we review the topic and briefly discuss the new findings and considerations.
FUS
Patients undergoing FUS experience a noninvasive MRI-guided procedure in which beams of acoustic energy (sound waves) are directed toward the same target in the brain from 1,024 tiny transducers worn around the head in a stereotactic frame. This energy combines on the target to generate friction and heat, which destroy the target. One could imagine an unwanted electrical signal being stopped in this way. There are a variety of potential targets in the brain.
VIM
For ET and most reported cases of PD, the target is the ventral intermediate nucleus (VIM) of the thalamus (a deep gray matter structure present on both sides of the brain). VIM in some ways functions as a relay for the signal which causes tremor and has been a target for deep brain stimulation (DBS), cautery, and gamma knife approaches to tremor. As with most parts of the brain, each side governs the opposite side of the body. FUS of the VIM is meant to cause a lesion which will stop or reduce tremor. As this heating up is taking place it is monitored by magnetic resonance thermometry. In other words, researchers are able to watch the lesion occur because the patient is inside of an MRI at that time. This provides confirmation that the correct target is being destroyed. There are multiple other parts of the thalamus nearby involving among other functions such as bodily sensation, hearing, and vision. And, there are neighboring structures involved in muscular strength, muscle tone, and balance. As of yet, with ET only one side of the brain is treated by FUS (under FDA approval). And, studies with PD have used FUS on only one side, which limits the risk of adverse events (AE) with the procedure. The most common AEs with VIM FUS are numbness on the side of the body tremor is being controlled and ataxia (the loss of coordination or control of bodily movements not due to weakness). With VIM FUS the goal is to control severe, medication-refractory tremor.
We previously referenced a small study which included 9 patients with Parkinson disease (2) with VIM FUS. In that study, the motor score (part III of the Unified Parkinson’s Disease Rating Scale, UPDRSIII) improved from 24.9 ± 8.0 to 16.4 ± 11 at one month, and 13.4 ± 9.2 at six months after treatment, a positive result (footnote).
A recently published study took place at two different academic centers (University of Virginia Health Sciences Center in Charlottesville, Virginia, and Swedish Neuroscience Institute, Seattle Washington), and sought to answer the questions as to how safe and efficacious FUS thalamotomy (VIM FUS) is for managing medically refractory, tremor-dominant PD (TDPD), and to ask the magnitude of the placebo response (3). Researchers identified TDPD patients from the database, and included patients whose disease was medication-refractory, severe, and disabling. Twenty-seven patients were randomized: 20 to FUS thalamotomy, and 7 to sham procedure. Twenty-six of the patients were male (96%), average age 67.8 years. The group receiving the sham procedure was offered open-label treatment after unblinding. Patients undergoing the study protocol were prepared by having their heads shaved and a stereotactic frame placed on their heads for MRI stereotactic planning. This meant that patients would each be placed in the MRI to localize the exact target before beginning the ultrasound treatment. Before beginning therapy, the treatment team was informed of whether each patient was to receive the sham or FUS. Ultrasound was administered with increasing energy and patients were clinically monitored after each sonication. Tremor was assessed at rest, posture, finger to nose, and drawing. Researchers noted that tremor did not tend to decrease until temperatures exceeded 50°C (122°F). The stated goal during the treatment was to reach tremor suppression “at an adequate thermal dose to the target.” During the treatment headache occurred in 65% and dizziness/vertigo and 42%. All of this resolved with completion of the procedure. Two patients had mild persistent hemiparesis (weakness on one side of the body) with gradual improvement. One patient had persistent mild ataxia. Patients returned for an MRI the next day and were then discharged from the hospital. Assessments of tremor were performed at one and three months. Neither the patient nor the evaluators were un-blinded until the 12 month assessment. Hand tremor was measured using a clinical rating scale for tremor (CRST) and revealed improvements of 62%, and was still present at the 12 month assessment. The more familiar UPDRSIII (motor subsection) revealed an overall 8 point benefit (from a baseline average of 23 points) , with 1.5 point improvement of resting tremor (from a baseline average of 4 points) and 1 point for postural tremor (from baseline average of 4 points). Three patients had inadequate improvement or even mild worsening of tremor scores. Sham treatment did not result in benefit. Six sham patients did go on to have the full treatment after unblinding. The most common thalamotomy related adverse events were finger tingling (39%), ataxia (35%), facial tingling (27%). At one year tingling persisted in 19% of patients and ataxia in 4%.
VOP
A single case report from a 73 year-old Japanese patient with refractory right-sided tremor (4). The patient could not tolerate higher doses of levodopa or dopamine agonists due to hallucinations and excessive daytime sleepiness. He was given FUS to ablate both the VIM and the ventro oralis posterior (VOP) nuclei of the thalamus (4). By including the VOP, investigators hoped to improve muscular rigidity (increased tone). Right-side resting tremor and rigidity were “abolished immediately following 10 sonications with an average maximum sonication time of 13.0 ± 3.4 seconds (range 10-17 seconds).” Temperatures inside of the thalamus reached a maximum of 60°C (140°F). No adverse events occurred during sonications. However, bradykinesia (slowness of movement) was exacerbated after thalamotomy and was reportedly due to local swelling of brain tissue. The patient was given steroids and the bradykinesia resolved after two weeks.
STN
Another target to consider is the subthalamic nucleus (STN). This is the more common site used for DBS in PD because of several factors, including the benefit that not only tremor, but bradykinesia (slowness of movement) and rigidity might be improved.
An open-label pilot study (not blinded, patients knew they were getting the treatment) was done at CINAC (Centro Integral de Neurociencias), UniversityHospital HM Puerta del Sur in Madrid, Spain (5). Ten PD patients with markedly asymmetric parkinsonism poorly controlled with medications were included. FUS subthalamotomy was targeted with several sonications above 55°C and adjusted according to clinical response. Total number of sonications given ranged from 17-31, though the average number of sonications above 55°C was 9. Time spent receiving sonication ranged from 144-337 seconds. There were pauses between sonications, and thus time spent from first sonication to completion ranged from 83-174 minutes, thus the longest time under therapy was just under 3 hours. The goal was to safely change the motor status of the treated side of the body in both off-medication and on-medication states at 6 months.
By the 6 month follow-up, 38 non-serious AEs had been recorded, though only 7 were still present. Three AEs were directly related to subthalamotomy: off-medication dyskinesia, on-medication dyskinesia, and subjective speech disturbance. Four of the adverse events present at 6 months were related to medical management, and included anxiety, fatigue, and weight gain. The most frequent AEs were transient gait ataxia (6 patients), transient head pain related to the head frame (6 patients), and transient high blood pressure during the procedure (5 patients). During the procedure back pain was reported, likely due to position in the MRI (2 patients), “warm cranial sensations (2 patients), and nausea (4 patients). Transient facial asymmetry (1 patient) and moderate impulsivity (2 patients) were also noted. At six months the average motor score in the treated side of the body improved by 53% in the off-medication state and 47% in the on-medication state.
Gpi
Globus pallidus interna is a target for DBS leads. Surgical lesions of the GPi have been shown to improve tremor, bradykinesia, rigidity, and dyskinesias. As yet there do not appear to be any published cases regarding Gpi FUS. However, a trial is recruiting (NCT02003248) in Seoul, Korea to study safety and effectiveness of Gpi FUS in the treatment of dyskinesia (6). Another trial (NCT03319485) with locations in Maryland, New York, and Ohio is also recruiting to evaluate the safety and efficacy of unilateral focused ultrasound pallidotomy in the management of dyskinesia or motor fluctuations for medication refractory, advanced PD (7). A third trial (NCT02263885) is active, not recruiting, in multiple U.S. sites including California, Maryland, Massachusetts, Ohio, and Virgina (8). This study is designed to evaluate the safety, and initial efficacy of unilateral lesion in the globus pallidus as an adjunct to PD medications in medication-refractory PD.
PPN
Pedunculopontine nucleus (PPN) is an experimental target for DBS in the treatment of freezing and other gait dysfunction. As yet no studies or articles are available approaching this target.
Footnote: Recall that UPDRSIII is a 108 point scale which measures motor functions such as tremor, stiffness, slowness, gait, etc.
REFERENCES
- https://mainepdnews.org/2017/09/28/how-close-are-we-to-focused-ultrasound-for-pd-in-maine/
- Zaaroor, et al. Magnetic resonance-guided focused ultrasound thalamotomy for tremor: a report of 30 Parkinson’s disease and essential tremor cases. J Neurosurg. 2017 Feb 24:1-9.
- Bond, et al. Safety and efficacy of focused ultrasound thalamotomy for patients with medication-refractory, tremor-dominant Parkinson disease. A randomized clinical trial. JAMA Neurol. 2017;74 (12): 1412-1418.
- Ito, et al. Magnetic Resonance Imaging-guided Focused Ultrasound Thalamotomy for Parkinson’s Disease: A Case Report.Intern Med. 2017 Dec 21. .9586-17.
- Martínez-Fernández, et al. Focused ultrasound subthalamotomy in patients with asymmetric Parkinson’s disease: a pilot study. Lancet Neurol 2018; 17: 54–63
- https://clinicaltrials.gov/ct2/show/NCT02003248?term=focused+ultrasound&cond=Parkinson+Disease&rank=2
- https://clinicaltrials.gov/ct2/show/NCT03319485?term=focused+ultrasound&cond=Parkinson+Disease&rank=9
- https://clinicaltrials.gov/ct2/show/NCT02263885?term=focused+ultrasound&cond=Parkinson+Disease&rank=10
