Hypothesis 1: could the intraoperative clinical assessment possible in FUS be more attractive to functional neurosurgeons than SRS workflow?

Both FUS and SRS allow the generation of lesions without skin incision, burr hole and brain penetration. A significant advantage of FUS over SRS is that it allows graded, incremental lesions that can be titrated to the clinical effects seen during the procedure. FUS lesions are created through successive sonication of increasing power between which the awake patient is typically assessed for efficacy and side effects. This is akin to progressively increasing lesions during conventional RF thalamotomy procedures. With SRS, on the other hand, GK requires acceptance that the lesion and its effect will be delayed, as its effect only appears after a median of 4 months, sometimes up to a year.12 16 19–24 To some patients and functional neurosurgeons, this might be suboptimal, given the highly variable response that can be observed with both modalities (figure 4).

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Figure 4

Typical response patterns after left ventral intermediate (VIM) thalamotomy with either focused ultrasound (FUS) or Gamma Knife (GK). Representative fluid-attenuated inversion recovery sequence of responses obtained 24 hours (for FUS) or 12 months (for GK) after left VIM thalamotomy for essential tremor. The protocol used was the same for all treatments of the same modality, highlighting the variability of individual responses.

Hypothesis 2: could FUS be more effective than SRS for tremor?

There is no study directly comparing the outcomes of FUS versus SRS thalamotomies. In the most recent review of surgical outcomes in ET, the rate of tremor control at 12 months was 35%–75% for FUS versus 48%–63% for SRS.1 These compare to a 49%–100% historical rate for RF thalamotomies.

The highest-quality study on FUS is an international randomised, sham-controlled trial.11 Seventy-six patients with medically refractory ET were assigned to either a unilateral VIM thalamotomy or a sham treatment and followed for 12 months. Crossover was allowed after 3 months for the sham patients. The primary outcome was the between-group difference in the change from baseline to 3 months in hand tremor. Thalamotomy patients showed significantly better tremor reduction (47% improvement vs 0.1%), improvement in activities of daily living (62% improvement vs 3%) and quality of life (46% improvement vs 3%). These results were sustained at the 3-year follow-up.25 While the goal of this trial was to test FUS lesions specifically, it also provided the highest level of evidence yet for the use of thalamotomies in ET (OCEBM level 2).

All SRS thalamotomy data in ET are from single-arm GK series. The highest-quality study is a prospective cohort of 50 patients who underwent unilateral VIM thalamotomy and were followed for 12 months.12 Blinded video assessment demonstrated a tremor score improvement of 54%. Activities of daily living improved by 72%.

While the current evidence convincingly demonstrates that thalamotomies are effective at reducing tremor, the superiority of one modality over the other cannot be established. Because all techniques appear to produce similar improvements, the rapid rate of adoption of FUS is not related to improved outcomes.

Hypothesis 3: could FUS be safer than SRS?

As for efficacy, there are no studies comparing the safety of FUS versus SRS thalamotomies. In the FUS pivotal trial, adverse events included gait disturbance (36%), paresthesia or numbness (38%) and haemiparesis (4%) that persisted at 12 months in 9%, 14% and 2% of patients, respectively.11 The median rate of permanent gait disturbance, paresthesia and haemiparesis across all FUS series was 4%, 8% and 2%, respectively.1 These side effects are similar to those reported for historical RF treatments, which included transient paresthesias (42%), transient paresis (34%) and transient dysarthria (29%).1 For SRS series, the median rate of adverse events was 2% (range 0%–9%) for transient symptoms and 0% (range 0%–18%) for permanent symptoms.1 In the highest-quality SRS study, no permanent adverse event occurred and a single case of transient haemiparesis (2%) was documented.12 Because most SRS studies are retrospective, adverse events might be underreported. However, even when considering only the prospective studies, the complication rate of FUS treatments appears substantially higher than for GK. The accelerated adoption of FUS over GK cannot be explained on the basis of safety.

Hypothesis 4: could FUS deliver a better patient experience?

If safety and efficacy are comparable, neurologists and neurosurgeons could choose the modality that provides the best patient experience. This is a highly subjective, yet important outcome. FUS but not SRS requires complete head shaving. Both FUS and GK require the application of a stereotactic frame. For FUS, the patient is next brought into the MRI suite where he needs to stay in the magnet for usually 2–3 hour. This can be challenging for patients with claustrophobia, obesity, kyphosis or back pain. During the sonication, a scalp heating sensation can be felt. In a small number, this heating reaches a level of 10/10 or unbearable pain. SRS procedures only last 1 hour, do not require hair shaving, are less claustrophobic and the treatment does not generate any physical sensations. Some patients may be reluctant to receive radiation perhaps due to a perceived associated delayed risk. On the current level of analysis, it would appear that FUS procedures are more involved, take longer and can produce more discomfort than SRS thalamotomies. Their rapid adoption is not due to improved tolerability of the procedure.

Hypothesis 5: is FUS less expensive than GK?

Adoption of a new treatment could be driven by its lower cost. It is, however, difficult to generalise and estimate the total costs and cost per case of FUS versus SRS because of the large variability in the usage of these modalities across centres. This is largely related to the fact that FUS is restricted to one approved indication while SRS is used primarily for oncology, trigeminal neuralgia and arteriovenous malformations rather than movement disorders. Both procedures require specialised personnel and service and are associated with significant capital costs and, in the case of GK, replacement costs of the radioactive sources every 5 years. The costs analysis thus has to be individualised and will likely be driven in large part by the volume of ET cases relative to other indications. The assessment of the cost effectiveness of FUS and SRS for ET will require a separate analysis. Interestingly, both lesioning modalities have been suggested to be more cost-effective than DBS,15 and both are probably comparable or more expansive than conventional RF.

Hypothesis 6: could FUS have better marketing than SRS for ET?

Because tremor is currently the only approved indication for cerebral FUS, manufacturers have higher incentives to aggressively promote and focus on ET. In contrast, ET represents only 0.3% of annual GK cases26 and receives correspondingly little attention from the manufacturer. This is evident in the direct patient outreach performed by the FUS foundation27 which has no equivalent in the SRS world. This interest also translates into more funding for clinical trials. As of 20 April 2020, Insightec was documented as a sponsor of 12 of 155 studies on ET registered on clinicaltrial.gov compared with 0 for Elekta, which explains the higher quality of evidence for FUS. Indeed, while performing a modern, randomised, sham-controlled trial of RF thalamotomy might be ethically challenging, there is no obvious reason other than funding and sponsor interest explaining why such a trial was never performed for SRS. Quality studies, in turn, can generate further interest in the field. An additional factor may be related to leadership and direction of therapeutic programmes. In Canada for example, all four FUS centres are led by functional neurosurgeons, compared with only one of the six GK centres where oncological neurosurgeons and radiation oncologists are predominant. The oversight of FUS programmes by functional neurosurgeons and their close interactions with movement disorder neurologists might further drive the adoption of this technology.

What happened to RF?

The lack of registry for RF thalamotomies (as opposed to Insightec’s FUS registry and the Leksell Gamma Knife Society’s GK registry) did not allow us to reliably estimate the number of RF thalamotomies performed annually (figure 3). Based on the number of publications, however, it is unlikely that RF thalamotomies experienced a resurgence as significant as the rise of FUS (figure 2). It is paradoxical that RF was abandoned two decades ago because DBS was shown to be safer, while FUS is now expanding despite a side effect profile in the 36%–38% range.11 It is clear that not all patients desire a permanent implant or are eligible for it. The resurrection of lesioning modalities now provides options to this population who might have been underserved in the ‘DBS-only’ era. From a cost-effectiveness and accessibility standpoints, RF probably remains advantageous. Whether this modality will keep its relevance in the face of FUS and SRS, which both forgo the need for incision, burr hole and brain penetration remains to be seen.

Limitations

The discussion of the drivers of the adoption of FUS and SRS for ET is based on the best available data for each modality. Because there is no prospective trial directly comparing SRS and FUS, conclusions regarding efficacy, safety, patient experience and cost might be influenced by the selection bias of each study. For instance, when analysing the studies selected in the latest systematic review of surgical ET management,1 the weighted mean (SD) age of patients in the FUS studies11 25 28–33 was 69.2 (3.2) versus 79.4 (3.4) for GK12 16 19–24 (unpaired t-test p=0.0131). GK patients were not only older, but also used anticoagulant medication in up to 26% of cases,19 whereas this is currently a contraindication to FUS. Interestingly, one would expect these differences to increase the morbidity of GK relative to FUS. The prospective and controlled nature of the FUS pivotal trial,11 which is also the largest FUS study, might have counterbalanced this selection bias by better ascertainment of adverse events compared with GK retrospective series.