Rationale for peripheral nerve stimulation in ET

ET is thought to involve the cerebello-thalamo-cortical loop. The oscillations possibly originate in the synaptic organization of the Purkinje cells [17, 18]. Although ET is central in origin; there is evidence to support a peripheral component in the pathophysiology, such as the mechanical properties of the arm, sensory feedback, and the sensorimotor reflex loop between the arm and the spinal cord [19, 20, 21]. While the mechanical factors have been found to mainly contribute to physiological tremor sensory feedback plays a crucial role in the pathogenesis of ET [22, 23, 24]. Previous studies found electrical stimulation of the median nerve evoked activity within the ventral intermedius nucleus (Vim) of the thalamus and other regions of the tremor network [25]. In one study, very-high-frequency oscillatory (VFO) activity in the range of 500 Hz was found to affect the activity recorded from the DBS contacts implanted within the Vim [25, 26]. The VFOs were thought to be generated in the sensory nucleus of the thalamus, inducing time-locked firing of neurons within the Vim subregion [27]. Modulation of these peripherally generated activities could potentially decrease the tremor amplitude.

In a physiological assessment, limb weighting that involves adding weights to the tremoring arm can isolate the peripheral component from the central component. Limb weighting likely affects the biophysical properties of the peripheral stretch reflexes. In the accelerometric and surface EMG recordings, adding weights can lead to the generation of two frequency peaks; one associated with the peripheral component and the other related to the central component [28, 29]. Besides limb weighting, limb cooling is another technique to modulate the tremor peripherally. Some studies found that surface cooling of the hand and forearm with an icepack or cold water can lower the tremor intensity [30, 31]. Limb cooling presumably reduces the conduction speed of peripheral nerves or affects the properties of muscle spindles sending afferent information [30, 32, 33]. Thus, various methods can modulate the peripheral tremor component (Figure 1).

Clinical evidence for Cala system

The initial open-labeled studies with sensory afferent stimulation in ET revealed promising findings (Table 1). Subsequently, a small (n = 23) randomized controlled study employed a single 40-min long session of median and radial nerve stimulation with a benchtop (Digitimer, England) device [46]. Stimulation between median and radial nerves alternated as per the tremor frequency of the individual. The primary outcome was blinded rating of the Archimedes spiral task item of the Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS). The study found that the spiral drawing in the real-stimulation group improved significantly by about 60% compared to baseline, whereas the sham group did not reveal improvements (1.01 ± 0.22 vs. 0.37 ± 0.22; p < 0.05) [46]. These initial studies had limitations of practical applicability as they did not employ a user-friendly wearable system such as the Cala device.

The Cala ONE device was examined for safety and efficacy in a randomized sham-controlled trial (n = 77) involving ET patients. (Table 2) In this pivotal trial, the primary outcome was the blinded rating of the TETRAS spiral item. With a single 40-min long stimulation session the spiral drawing did not improve significantly (p = 0.26). However, the secondary outcomes such as the blinded rating of Bain and Findley activities of daily living (ADL) items (42% vs. 28%; p = 0.001) and the unblinded scoring of the TETRAS upper limb item (49% vs. 27%; p = 0.017) revealed significant improvements [47]. A subsequent open-labeled PROSPECT trial that recruited 265 patients from 26 centers across North America assessed the longitudinal and long-term applicability of in-home use for the Cala Two device. Participants in the trial used the Cala device twice daily for three months [48]. The co-primary outcomes of the trial evaluated at one, two, and three months after stimulation were the clinician-rated TETRAS and patient-rated Bain and Findley ADL scale dominant hand scores. The secondary outcome was the accelerometer-based physiological assessment of tremor power. With a nearly 22% dropout, the study found significant improvements in the TETRAS dominant hand score and Bain and Findley ADL dominant hand scores at all follow-ups (p < 0.0001) [48]. After three months of the device use, there were 22% improvements in the TETRAS assessment and 28% improvements in the Bain and Findley ADL scores. The physiological data correlated significantly with the clinical ratings and there was a 50% reduction in tremor amplitude in nearly 54% of patients [48]. The investigators found that even though the magnitude of improvements on the TETRAS total score varied between patients, 62% of patients determined to have a “moderate to severe” tremor improved to a “mild” tremor category. Around 20% of patients reported skin irritations such as redness, itchiness, swelling, soreness or lesions that resolved using a topical ointment. Some patients complained of a stinging sensation, weakness, or burns that responded to a decrease in stimulation intensities. The adverse events were primarily mild to moderate in severity; overall, patients tolerated the device well [48].

The American Academy of Neurology follows a rigorous process rooted in evidence-based medicine methodology to review the evidence for an intervention efficacy. The risk of bias is measured using a four-tiered classification scheme with studies rated Class I are judged to have a low risk of bias, Class II is judged to have a moderate risk of bias, Class III, a moderately high risk of bias; and Class IV, a very high risk of bias. Based on the Class of evidence, adequacy of power, and consistency, practice recommendations with levels of certainty are formulated. Level A, the strongest level of recommendation, is employed if conclusive data is available from two Class I studies. Level B is the next level of recommendation if there is data from one Class I or two Class II studies. Level C is a recommendation with lower confidence level when data is available from one Class II study or two Class III studies. Level U indicates that the available evidence is insufficient to support or refute the efficacy of an intervention.

Currently, the efficacy data for the Cala system is available from a single open-labeled (Class IV) and a single randomized clinical trial (Class II). As evident in the results of the randomized clinical trial the primary outcomes did not reveal a significant change but the secondary analysis of blinded ADL ratings by patients and the unblinded upper limb tremor ratings by clinicians revealed significant improvements indicating an inconsistency in support of efficacy. Based on this efficacy data, there is currently insufficient evidence (level U) to support the use of the Cala device for control of the ET symptoms. Future studies with robust designs and conclusive evidence could lead to upgrading the practice level of recommendation. Nevertheless, the FDA has provided a Class II Medical Device clearance status, which means the manufacturer has shown that Cala is “substantially equivalent to another (similar) legally marketed device” that already has FDA clearance or approval. The Cala device, currently available only in the United States, is costly (around 3200 US dollars; with a return policy if ineffective), lacks the insurance coverage, and cannot be prescribed to patients with a DBS system. However, the clinical community could leverage the user-friendly nature and the established safety data to augment benefits from pharmacological therapies in ET.

Potential mechanisms underlying clinical benefits with Cala device

In an 18F-fluorodeoxyglucose PET/CT study involving five ET patients, brain metabolism was measured at baseline and after 90 days following 40-min open-labeled stimulation sessions employed twice daily using the Cala device [49]. Tremor power and frequency were measured using an onboard three-axis accelerometer before and after all the transcutaneous afferent patterned stimulation was completed. Following 90 days of stimulation, the FDG PET/CT revealed increased metabolism in the ipsilateral and decreased metabolism in the contralateral cerebellar hemisphere. The pre-post kinematic measurement decreased tremor power, but there was no change in the tremor frequency [49].

As the cerebellum is a key pathogenic node in the ET network, these changes in metabolism were offered as the potential underlying mechanism to explain benefits from the Cala device. The authors speculated that an increased glucose utilization in the ipsilateral cerebellar cortex was related to alteration of Purkinje cell activity [49]. The study also found a decrease in metabolism of the ipsilateral pre- and post- central areas, occipital lobe, insula, cuneus, anterior cingulate, and inferior parietal cortex which cannot be attributed to functioning of tremor network. Furthermore, the study did not examine the relationship between brain metabolism change and tremors. Thus, these findings from a small open-labeled study sample that did not correct for multiple statistical comparisons cannot be interpreted with certainty. Further investigations are warranted to understand the brain adaptation response relevant to ET pathophysiology.

Another potential mechanism for Cala therapy is the peripheral modulation of tremor oscillations. The Cala device alternately activates the sensory afferent fibers of the median and radial nerves. The A-alpha sensory afferent stimulation supposedly carries the proprioceptive information from the muscle spindles and the Golgi tendon organs, leading to an increase in the excitability of the agonist spinal motor neurons and decrease in the excitability of antagonist spinal motor neurons [50]. When the agonist and antagonist muscles co-contract, the impedance at the oscillating joints increases, and when they contract out of the phase, the oscillating movements receive counteractive forces. Thus, the net result of the afferent input from the median nerve will activate the wrist flexors, and the radial nerve will activate wrist extensors. Whether the intrinsic pattern of tremor discharge is alternating or synchronous and whether the afferents are stimulated in-phase or out-of-phase will determine the final effects. These potential peripheral mechanisms have not been examined yet (Figure 2).

Other devices & techniques that could be applied peripherally

Prochazka and colleagues around the 1990s first pioneered FES that directly triggers muscle contractions of the peripheral arms. FES was observed to result in nearly 70% tremor improvement [36, 51]. Although direct intramuscular stimulation could lead to more significant tremor suppression, practically, it may not be viable. Thus, transcutaneous FES is more appealing and has shown promising data in multiple small cohort studies. Some studies have used real-time monitoring with EMG-based sensing algorithms to allow precise delivery of electrical pulses to the muscle stimulation [51]. A few devices for potential in-home use include the TREMOR neurorobot and a special glove adopting a co-contraction stimulation strategy to increase the stiffness of the limb via continuous stimulation of antagonistic flexor and extensor muscles of the arm [16]. On the other hand, the MOTIMOVE system (Belgrade, Serbia) with CE Marketing consists of a multichannel stimulator for out-of-phase stimulation [38]. FES commonly leads to side effects such as hand numbness, burning sensation, and muscle fatigue due to continuous active muscle contraction and joint activation. These side effects are essential as they can potentially limit long-term practical use.

Wearable orthotic systems are another group of devices for peripheral control of tremor [52]. These devices work on the principles of active force generation to counteract the involuntary movement related to tremor or passively suppress the oscillatory movements through dissipation of energy [16]. While the active systems may not be practical for day to day use as they are bulky, the passive systems such as the Viscous Beam system, Tremelo (Five Microns, Fresno, CA, USA), Steadi-One (Steadiwear, Toronto, ON, Canada), and Readi-Steadi (Readi-Steadi, Gonzales, LA, USA) are promising but do not have the aesthetic advantages of Cala [16]. Furthermore, safety and efficacy data from large sham-controlled randomized trials are currently lacking.