CMS Magnetic Resonance Guided Focused Ultrasound Surgery System (MRgFUS) for the treatment of neurologic conditions Form

Summary Of Evidence

Essential tremor (ET)

ET is the most common movement disorder as well as one of the most treated surgically. The prevalence of ET has been estimated at approximately 3% or 10 million people in the United States. While ET does not shorten life expectancy, the associated disabling symptoms, such as hand tremor, can greatly impact quality of life (functional ADLs, work activities, mood, and socialization).

Although there are no curative therapies, symptoms of ET are well managed medically in up to 70% of patients, with surgery reserved for medication-refractory severe impairments. Current surgical options include thalamotomy with radiofrequency (RF) ablation and deep-brain stimulation (DBS); both effectively suppress tremor but require intracranial surgery. Stereotactic radiosurgery (SRS), while non-operative, suffers from delay in tremor reduction (making intraoperative validation impossible), a greater than 10% cumulative risk of adverse events, and theoretical concerns about radiation side effects (6, 22). DBS is currently the intervention of choice, “because of its proven efficacy, reversibility, adjustability, and durability” ¹, with thalamotomy “a reasonable alternative….if DBS is not available or practical”² . This attribute of DBS in creating an adjustable “functional lesion” causes fewer adverse events than thalamotomy^3,4, and resulted in a general shift away from ablation methods⁵.

Neuromodulation with ultrasound energy also required craniotomy until recently; advances in ultrasound transducer design and high-resolution magnetic resonance imaging now allow precise transcranial delivery of high-intensity focused ultrasound. The ultrasound causes a local increase in temperature in the target tissue, resulting in coagulation necrosis while sparing the surrounding normal structures. In addition to providing location guidance, MRI provides real-time clinical monitoring of treatment intensity via thermal imagery. On 1/1/16, a CPT Category III tracking code (0398T) specific to MRgFUS treatment of movement disorder became effective. FDA PMA approval for the Magnetic Resonance Guided Focused Ultrasound Surgery System (MRgFUS) (ExAblate Model 4000, InSightec, Inc.) “for the unilateral thalamotomy treatment of idiopathic essential tremor patients with medication-refractory tremor” came on 7/11/16 ⁶.

Among the peer-reviewed clinical studies of MRgFUS for the treatment of medication-refractory ET, all but one were small, uncontrolled, pilot studies with short follow-up^7-14 . FDA approval for MRgFUS treatment of ET was based on its pivotal study, a prospective, double-blind, randomized, sham-controlled trial (RCT) of MRgFUS to create a unilateral thalamic ablation for the treatment of ET⁹ . Seventy-six patients with moderate-to-severe essential tremor refractory to at least two trials of medical therapy were randomized in a 3:1 ratio to either MRgFUS or a sham procedure. The primary endpoint, the CRST at 3 months, was significantly improved in the MRgFUS group (p<0.001). Secondary outcome measures, including disability and quality of life, were also significantly improved. However, both hand and total tremor scores steadily deteriorated over the year, 23% and 38% respectively. In fact, this drop in efficacy and the limited follow-up period were cited as major concerns in the accompanying editorial which advocates for much longer follow-up (2-5 years or more) to demonstrate sustained benefit¹⁵ . Another concern was persistent adverse neurologic effects in the MRgFUS group at 12 months, including gait disturbance (9%) or numbness (14%).

Two-year follow-up on sixty-seven of the patients demonstrated durable improvement in tremor at 1 year (53%; 8.9 ± 4.8; 70 patients) and at 2 years (56%; 8.8 ± 5.0; 67 patients). Disability score improved throughout this period, none of the adverse effects worsened, two resolved, and there were no new delayed complications¹⁶. 4 year data on 12 patients showed hand tremor score was sustained through the 4-year period after thalamotomy (5.3 ± 3.4 at 1 year and 7.7 ± 4.1 at 4 years, p=0.013)¹⁷.

The editorial concludes that “A head-to-head comparison with DBS would facilitate the direct comparison of the two approaches.” Some contend that a direct comparative trial between MRgFUS and DBS will be unlikely “due to the significant differences in invasiveness of the two procedures,” Interestingly, a letter to the editor agrees a direct comparative study isn’t warranted, but apparently for the opposite ethical reason, noting “that the high rate of adverse events that is consistently reported with thalamotomy of any kind suggests that equipoise does not exist”¹⁸. While it is true that MRgFUS is less invasive than DBS in terms of not requiring cranial penetration with hardware, it is more invasive than DBS in the creation of a fixed thalamic brain lesion, which can result in permanent neurologic deficit.

A recently published meta-analysis is meant to provide “an approximation of an RCT” head-to-head comparison between MRgFUS, DBS, and SRS; the authors claim an actual RCT is unlikely¹ . Pre- and postoperative tremor-related disability scores were collected from 32 studies involving 83 MRgFUS, 615 DBS, and 260 SRS cases. MRgFUS thalamotomy resulted in significantly higher utility scores (defined as quality of life and derived from percent change in functional disability) compared with DBS (P < 0.001) or SRS (P < 0.001). The authors conclude that “preliminary experience with MRgFUS supports its broad adoption for medically refractory ET.”

A retrospective analysis of 59 patients who underwent unilateral treatment for drug-resistant ET with RF thalamotomy (n=17), DBS (n=19), and MRgFUS (n=23) showed no statistical differences in tremor severity improvement at 1 month or 1-year follow-up (23). However, MRgFUS had a significantly lower complication rate (p < 0.01) at 1 year (4.4%) compared with RF (11.8%) and DBS (21.1%). The authors conclude that “MRgFUS is a promising therapy with the potential to replace DBS for patients who cannot tolerate DBS, the standard surgical treatment for ET,” but that “the long-term effects of MRgFUS should be systematically evaluated in a future prospective, randomized study in order to demonstrate whether MRgFUS provides superior management of ET symptoms⁵”.

Tremor-Dominant Parkinson’s disease (TDPD)

Tremor is a common motor feature of Parkinson disease (PD), and TDPD is a clinical subtype distinct from the akinesia/rigidity (AR) and postural instability/gait disorder subtypes. This subtype may be more resistant to dopamine-replacement therapy than other motor symptoms. DBS and traditional thalamic lesioning are accepted treatments of motor symptoms of PD. Several small observational studies also demonstrated efficacy of MRgFUS thalamotomy in TDPD out to one year^19-21.

A small prospective, sham-controlled RCT looked at the safety and efficacy of unilateral MRgFUS thalamotomy at 3 and 12 months in patients with TDPD²² (28). Twenty-seven patients (median age 67.8 years; interquartile range [IQR], 62.1-73.8) were randomized (2:1) to MRgFUS (20) vs. sham (7). Predefined primary outcomes were safety and difference in improvement between groups at 3 months in the on-medication treated hand tremor CRST subscore. Secondary outcomes included descriptive results of UPDRS scores and quality of life measures. Three-month on-medication median tremor scores improved 62% (17 to 4.5; IQR, 22%-79%) in the treatment group, and 22% (23 to 17; IQR, −11% to 29%) in the sham group (P = .04). Secondary outcomes showed non-statistical improvement trends in the treatment group. At 3 months, 6 sham patients crossed-over to MRgFUS treatment. Three months after crossover the median baseline CRST score improved from 21 to 5.5, similar to the 3 months outcomes in the group originally allocated to treatment. One-year follow-up of 14 treatment and 5 sham crossover patients demonstrated CRST score maintenance. Early in the study, heating of the internal capsule resulted in 2 cases (8%) of mild hemiparesis, which improved and prompted monitoring of an additional axis during magnetic resonance thermometry. Other persistent adverse events were orofacial paresthesia (20%), finger paresthesia (5%), and ataxia (5%). A sub-analysis reported no change in cognitive, mood, or behavioral perspective at 3 and 12 months²³.

On 12/16/2018, the Exablate MRgFUS device FDA indication was expanded to include unilateral thalamotomy (ventralis intermedius) treatment of TDPD with medication-refractory tremor in patients at least age 30²⁴ . UpToDate recommends consideration of MRgFUS thalamotomy in selected TDPD patients who are not candidates for DBS²⁵..

Analysis of Evidence

In summary, MRgFUS is a promising new treatment approach that has attributes, positive and negative, distinct from both traditional thalamotomy and DBS. However, long-term effectiveness and safety remain uncertain^2,5 and warrant a direct comparison with DBS, the current surgical standard.

However, given the support for traditional thalamotomy, generally, as an alternative “if DBS is not available or practical”, and the support for MRgFUS thalamotomy, specifically, as an alternative in patients “who are not a candidate for DBS” by the American Association of Neurological Surgeons (AANS), Congress of Neurological Surgeons (CNS) and the American Association of Stereotactic and Functional Neurosurgery (ASSFN)²⁶, CGS considers MRgFUS reasonable and necessary in that context.

This LCD addresses use of Magnetic Resonance Guided Focused Ultrasound Surgery System (MRgFUS) for the treatment of neurologic conditions.

MRgFUS unilateral thalamotomy is considered medically reasonable and necessary in patients with all following:

1. Medication refractory (ONE)

1. Essential Tremor (ET)- defined as refractory to at least two trials of medical therapy, including at least one first-line agent
2. Tremor-Dominant Parkinson’s disease (TDPD) (BOTH)
   1. refractory (or intolerant) to levodopa or levodopa equivalent daily dosage (LEDD) ≥ 900 mg
   2. On-medication Unified Parkinson’s Disease Rating Scale (UPDRS) ratio of the mean score for tremor items (items 16, 20, and 21) to the mean postural instability/gait disorder score (items 13-15, 29, and 30) of ≥ 1.5

2. Moderate to severe postural or intention tremor of the dominant hand (defined by a score of ≥2 on the Clinical Rating Scale for Tremor (CRST)
3. Disabling tremor (defined by a score of ≥2 on any of the eight items in the disability subsection of the CRST
4. Not a surgical candidate for deep-brain stimulation (DBS) (e.g., advanced age, anticoagulant therapy, or surgical comorbidities)

Limitations (not covered)

1. Treatment of head or voice tremor
2. Bilateral thalamotomy
3. Conditions

1. other neurodegenerative condition
2. unstable cardiac disease
3. untreated coagulopathy
4. risk factors for deep-vein thrombosis
5. severe depression (defined by a score ≥20 on Patient Health Questionnaire 9 (PHQ-9), or Beck Depression Inventory score (BDI-II) >14)
6. cognitive impairment (defined by a score of <24 on the Mini–Mental State Examination, or Montreal Cognitive Assessment (MoCA) score ≤21)
7. previous brain procedure (transcranial magnetic stimulation, DBS, stereotactic lesioning, or electroconvulsive therapy)
8. a skull density ratio (of cortical to cancellous bone) <0.45 ± 0.05 as calculated from the screening CT
9. MRI contraindicated
10. Drug-induced Parkinsonism
11. history of seizures, brain tumor, intracranial aneurysm or arteriovenous malformation requiring treatment.