Movement Disorders Moment: Focused Ultrasound in Movement Disorders: A Novel, Minimally Invasive Approach

Focused ultrasound is a novel, minimally invasive ablative procedure that is a current treatment option for essential tremor (ET) and Parkinson disease (PD). The most common intracranial targets are the ventral intermediate nucleus (VIM), subthalamic nucleus, and internal globus pallidus. As an incisionless procedure lacking the surgical and device-related adverse effects associated with deep brain stimulation (DBS), such as intracranial hemorrhage, infection, and device failure, focused ultrasound is an appropriate option to be considered along with the well-established procedures of DBS and stereotactic radiosurgery (SRS) for specific populations and needs.^1,2

MRI-guided focused ultrasound (MRgFUS) is approved by the Food and Drug Administration (FDA) for treatment of ET (approval received 2016) and tremor-predominant PD (approval received 2018), on the basis of evidence from 2 multicenter, sham-controlled randomized controlled trials (RCT).³ In November 2021 the FDA expanded MRgFUS approval for the treatment of individuals with advanced PD with mobility, rigidity, or dyskinesia symptoms.⁴ International regulatory approvals also exist for neuropathic pain and psychiatric disorders such as depression and obsessive-compulsive disorder.²

Background of Movement Disorder Management

The history of movement disorder management over the past century has included several revivals of lesioning procedures. Such procedures lost favor initially with the introduction of levodopa in the 1960s and for a second time with the advance of DBS, which is safer, reversible, and reprogrammable, if adverse effects related to stimulation develop. A third wave of revival came with SRS and gamma-ray ablative procedures, and, more recently, high-frequency focused ultrasound, which offers a less invasive means of ablation with certain advantages over SRS ablation.¹

Ultrasound for brain lesioning, first developed in the 1950s, was initially unsuccessful as an incisionless procedure. Craniotomy was required because ultrasound energy was unable to be transmitted through the skull.⁵ Technologic advances in focusing many ultrasound beams revived the procedure to overcome this disadvantage, which Moosa et al¹ likened to “a lens focusing the sun’s rays” (technically called “phase shifted multielement transducers”).⁵ MRgFUS combines the minimally invasive aspect of Gamma Knife surgery with the in-procedure monitoring used in DBS.⁶ With the help of stereotactic targeting, magnetic resonance thermography monitoring, and high-resolution MRI, new advances are reviving the previously abandoned procedure in several medical and surgical specialties—not only in the treatment of movement disorders, but also in the treatment of prostate cancer, glioblastoma, and uterine fibroids as well.

Description of MRgFUS Procedure

The procedure is performed with the patient awake on the MRI table. The first step is fitting of a stereotactic frame under local anesthesia. The target is identified anatomically with T2-weighted spin-echo sequences obtained with a 3T MRI scanner. The patient’s head is coupled to the focused ultrasound transducer (Exablate Neuro; Insightec Inc, Miami, FL) under proton resonance frequency-based magnetic resonance thermometry. Approximately 10 to 30 sonications ranging from 10 to 25 seconds of duration are made as the temperature is increased gradually from 40°C up to 64°C. Patients are assessed simultaneously for tremor severity and any neurologic adverse effects as the lesion is incrementally enlarged. Sonications are terminated when tremor control is achieved or adverse effects appear.⁷ Transient intraprocedural events are common, including dizziness, nausea, paresthesias, discomfort at the frame pin site, and feeling of warmth.⁸ The total duration of the procedure ranges from 3 to 6 hours.^2,8 This time includes frame fitting, target-beam coupling, planning with neuronavigation workstation, calibration, sonications, and repeat imaging after the lesioning.^5,7 Cooling of the elastic barrier between the patient’s head and the stereotactic frame to prevent overheating also adds to the total procedure time.⁵

MRgFUS Treatment for Essential Tremor

Over the course of the disease, medications for ET frequently lose efficacy, and up to one-third of individuals discontinue medications because of lack of efficacy or intolerable side effects.⁷ ET can be more disabling than PD for daily and social activities such as writing, eating, drinking, and social interactions.⁹ DBS is considered the standard surgical treatment of ET and has an abundance of data, experience, and greater safety profile compared with conventional approaches of thalamotomy. The advent of a novel approach to thalamotomy by focused ultrasound has ignited debate and has led to a small number of studies comparing the procedures.¹⁰

The American Society for Stereotactic and Functional Neurosurgery published a position statement for MRgFUS for the treatment of ET in 2020.⁹ Indications are as follows:

1. Confirmed diagnosis of ET by a movement disorder specialist

2. Failure to respond to first-line therapies (primidone or propranolol)

3. Disabling appendicular tremor (defined as a score of 2 or greater on the disability subsection of the Clinical Rating Scale for Tremor)

4. Unilateral treatment (in December 2022, the procedure received FDA approval for treatment of the second side at least 9 months after treatment of the first side)

Contraindications are as follows:

1. Contraindication for MRI

2. Skull density ratio <0.40

A double-blind, sham-controlled RCT and several uncontrolled studies were used as guidance for the expert statement.⁹

A systematic review was published by Harary et al¹⁰ to compare unilateral MRgFUS thalamotomy, unilateral VIM DBS, and bilateral VIM DBS. Average percentage improvement in tremor severity was 61.2% in the bilateral DBS group, 55.6% in the MRgFUS group, and 56.4% in the unilateral DBS group. The review revealed that efficacy of bilateral DBS was superior to both unilateral DBS and MRgFUS in terms of improvement of tremor severity. No significant difference was found, however, between unilateral DBS and MRgFUS. Moreover, quality of life was greater in the MRgFUS group (percentage improvement 52.5% in the DBS group compared with 61.9% for MRgFUS).¹³ This could be a result of the frequent reprogramming visits and occasional surgical revisions needed after DBS, and an important point to consider from the patient perspective of management.^10,13

MRgFUS Treatment for Parkinson Disease

The first case series for MRgFUS VIM nucleus thalamotomy for tremor-predominant PD was performed as an unblinded prospective study by Schlesinger and colleagues with a mean follow-up time of 8 months. The reported total Unified Parkinson’s Disease Rating Scale (UPDRS) score decreased by 49.7% and the Parkinson’s Disease Questionnaire–39 score decreased by 48.9% from baseline to 1 week postoperatively.¹

For tremor-predominant PD, MRgFUS thalamotomy showed improvement in Clinical Rating Scale for Tremor A and B scores in 62% of individuals (22% sham) 3 months postoperatively in a double-blinded, prospective, sham-controlled RCT, and 8-point improvement in median motor UPDRS score. RCTs are underway for other surgical targets (subthalamic nucleus, globus pallidus, and pallidothalamic tract) for treatment of the cardinal features of PD.¹ One open subthalamotomy trial including 10 participants with PD showed 53% improvement in motor UPDRS score off medication 6 months postoperatively. A 24% decrease in levodopa dosage was achieved. One study reported an individual who received MRgFUS pallidotomy for levodopa-induced dyskinesias and showed 55% to 60% reduction in UPDRS part III score at 6 months.⁵ A limited number of studies with MRgFUS pallidotomy also showed favorable results. In comparison radiofrequency ablation of the same target results in permanent neurologic deficits in a small percentage of individuals.

Several clinical trials are underway examining the pallidothalamic tract as a target, which may result in fewer side effects and provide a path forward for a bilateral procedure. Bilateral subthalamic nucleus/internal globus pallidus lesioning is associated with greater speech deficit and gait and balance impairment, which may be mitigated by using the pallidothalamic tract, a much smaller target.¹⁴ The studies mentioned did not report intracranial hemorrhage or infection after focused ultrasound.¹

Complications

Different adverse effects are seen in DBS and MRgFUS. Side effects commonly reported with MRgFUS (Table 1) are gait disturbances, weakness, paresthesias, dysarthria, dysphagia, and nausea, whereas for DBS, side effects of speech disturbance and local symptoms predominate.^8,13 MRgFUS does not require a craniotomy or implanted hardware, but DBS can be reprogrammed to manage lesioning side effects.¹³ Because of the ablative nature of MRgFUS, persistent complications are more common in the MRgFUS group.¹³

Focused Ultrasound vs Deep Brain Stimulation

The reversibility of neurologic adverse effects from DBS provides an important advantage over MRgFUS in addition to the abundance of experience that exists with DBS. DBS, on the other hand, comes with risks associated with an open craniotomy, with rates of intracerebral hemorrhage resulting in severe neurologic deficits approaching 1% to 2% across studies, hardware complications in 10%, and infections in 5% to 10%.^2,7 Risks associated with general anesthesia based on cardiopulmonary comorbidities also should be considered.²

Points to consider are frequent follow-up visits and the possibility of reoperations for hardware-related complications or implantable pulse generator exchange in DBS versus higher chance of persistent neurologic adverse effects in MRgFUS and limitation to unilateral lesioning in the case of PD.¹⁰ Ablative procedures should be strongly considered if a person is expected to have difficulty with follow-up visits.^8,9 Other considerations might be individuals with increased risk of intracranial bleeding, history of infection with DBS, thin scalp, scalp lesions, or unwillingness to undergo open neurosurgery. These factors limit surgical options for many individuals with PD or ET.⁹ The patient also must be informed that MRgFUS requires shaving the entire head, as opposed to DBS, which usually is performed with shaving along the incision areas.⁸

Focused Ultrasound vs Stereotactic Radiosurgery

The main advantage of MRgFUS over SRS is real-time monitoring performed intraoperatively by initially assessing for effects with low-temperature stimulation for targeting. Individuals who are awake can report symptoms immediately. Furthermore, magnetic resonance thermometry is used intraoperatively to guide lesioning.¹⁰ Clinical benefits also can be seen immediately, as opposed to SRS, where clinical benefit may be delayed from weeks to months. Lack of patient feedback intraoperatively and delayed effect makes SRS lesions unpredictable. Tremor suppression is detectable with MRgFUS during the procedure while the patient is in the scanner.⁷ High complication rates ranging from 2% to 46% are also reported for SRS, which includes intracranial hemorrhage.²

Maintenance of Clinical Benefits

A meta-analysis of 21 studies of MRgFUS for ET (395 patients total) reported 61.5% improvement of hand tremor score (score of 19.2 to 7.4); this was mildly decreased at 36 months (hand tremor score 9.1; 8.8% reduction). There were 4 studies with follow-up beyond 24 months (hand tremor score 9.0). Chang et al and Halpern et al demonstrated persistent benefit up to 36 months and for Park et al up to 48 months (hand tremor score 7.7). These 3 studies were follow-up of a study cohort from RCTs performed by Elias et al in 2016.¹⁵

A current issue reported with MRgFUS is the possible loss of clinical benefit over time, which was attributed to shrinkage of lesions appreciable in imaging. In their review of 37 individuals treated with MRgFUS thalamotomy, Miller et al¹⁵ reported a small trend in decreased clinical benefit over 2 years, measured by the tremor subscore of the Clinical Rating Score for Tremor. The clinical benefit nevertheless remained significant, with 42.4% improvement reported at 1 year and 43.4% at 2 years.⁸

Predictors of outcome of MRgFUS for ET by analysis of 189 individuals were age, disease duration, peak temperature, and number of sonications.¹¹

Conclusions and Future Directions

MRI-guided focused ultrasound is an effective treatment for essential tremor and tremor-predominant PD. Thoughtful patient selection based on individual characteristics and preferences is crucial to securing a good outcome.

Future directions might be to investigate the safety of bilateral lesioning for PD, explore different anatomic targets, consider diffusion tensor imaging–based targeting approaches for subcortical white matter tracts, and treat PD earlier given the minimally invasive nature of the procedure.¹ Another line of novel research is using focused ultrasound to open the blood–brain barrier transiently for delivery of gene-targeted or immunomodulatory therapeutics for neurodegenerative diseases, such as antibodies against α-synuclein.³ DBS and SRS techniques have been honed over the past 40 years, leading to fewer adverse effects and yielding better outcomes. As physicians gain real-world experience with MRgFUS, outcomes are similarly likely to improve over time.^10,13