Figure 1
Peripheral interventions for treating essential tremor.
Table 1
Clinical studies employing sensory afferent stimulation in ET.
| STUDY | STUDY DESIGN | N | AGE IN YEARS | SEX (MALES) | STIM DEVICE | STIM LOCATION & STRATEGY | STIM DESIGN | STIM SETTINGS | STIM DURATION | OUTCOME MEASURES | TIMING OF OUTCOME ASSESSMENT | OUTCOME | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| STIM AMPLITUDE | PULSE WIDTH | FREQUENCY IN HZ | ||||||||||||
| Dosen et al 2013 | open labeled with objective physiology | 2 | 72 | Not avail | Axelgaard electrodes | wrist & fingers | closed loop | 7.8 mA | 300 | 100 | 2 sec | tremor power | real time | 35%–48% reduction |
| Heo et al 2015 | open labeled; physiology | 18 | 68.8 ± 7.7 | 8 | Cybermedic stimulator | arm & forearm | closed loop | 0.2 mA | 300 | 100 | 15 sec | angular velocity, peak power & frequency | real time & 5 min after | improvements in RMS & power with no change in frequency during and after |
| Lin et al 2018 | randomized controlled; blinded & unblinded outcomes | 23 | 70 | 11 | Digitimer DS5 | median & radial at wrist | open loop | 5.9 ± 1.2 mA | 300 | 150 | single session; 40-min | TETRAS spiral item | immediately after | 37% improvement in spiral |
| Yu et al 2020 | open labeled; objective physiology | 15 | 69.6 ± 10.2 | 9 | Digitimer DS5 | median & radial at wrist | open loop | not available | 300 | 150 | single session; 40-min | FTM-CRS & tremor power | real time, immediately after, 30 & 60min after | FTM-CRS score improved for 60min for 80% of patientsTremor power improved 60 min for 70% of patients. |
| Kim et al 2020 | open labeled but study outcomes objective | 9 | 67.6 ± 11.6 | 4 | custom-built constant voltage mode stimulator | radial at wrist | open & closed loop | 3.6 – 17.3 V | 200 | 50, 100, 200 | single session; 9 trials; 10-sec each | tremor power & peak frequency, qualitative assessment | real time monitoring | |
| Pascual-Valdunciel et al 2020 | blinded & objective assessment | 9 | 70.3 | 5 | intramuscular thin film multichannel & surface Axelgaard stimulation | wrist flexors & extensors; intramuscular & surface stimulation | open & closed loop (out-of-phase & in-phase | 2.4mA intramuscular; 5mA surface | 200 | 100 | 30-sec each trial | Kinematics of wrist, elbow, shoulder & FTM-CRS | immediately after & 24 hrs after | closed loop intramuscular stimulation led to > 30% tremor reduction during & after; 4 patients 24 hr benefits |
Table 2
Clinical studies employing Cala device in ET.
| STUDY | STUDY DESIGN | N ENROLLED | AGE IN YEARS | SEX (MALES) | STIM DEVICE | STIM LOCATION & STRATEGY | STIM DESIGN | STIM SETTINGS | STIM DURATION | OUTCOME MEASURES | TIMING OF OUTCOME ASSESSMENT | OUTCOME | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| STIM AMPLITUDE | PULSE WIDTH | FREQUENCY IN HZ | ||||||||||||
| Pahwa et al 2018 | randomized controlled; blinded and unblinded outcomes | 93 (77 completed) | 70.2 ± 10.6 | 45 | Cala - one | median & radial sensory at wrist | open loop | 5.4 ± 2.9 mA (average) | 300 | 150 | single session; 40-min | Primary: TETRAS spiral item; Secondary: TETRAS upper limb subscore, ADL and CGI-I | immediately after | Spiral score did not improve; upper limb tremor score improved (42 vs 28%), subject rated ADL scores improved (49 vs 27%) |
| Isaacson et al 2020 | open labeled; outcomes also included objective physiology | 263 (205 completed) | 72.2 ± 8.6 | 126 | Cala - two | median & radial sensory at wrist | open loop | not available | 300 | 150 | twice daily; 40-min per session; 3 months | Primary: TETRAS upper limb subscore, ADL & CGI-I; Secondary: tremor power | immediately after, at monthly in-clinic follow-up visits & at three months for long-term | Patients rated “Severe” or “Moderate” improved from 49.3% (TETRAS) and 64.8% (BF-ADL) at visit 1 pre-stimulation visit to 21.0% (TETRAS) and 23.0% (BF-ADL) at visit 3 post-stimulation and 54% had > 50% tremor reduction |
Figure 2
Possible peripheral and central mechanisms underlying the use of Cala device. In the peripheral mechanism, sensory afferents with median and radial nerve stimulation relayed to the spinal cord modulate the excitability of spinal motor neurons. Median nerve afferents increase flexor motor neuron excitability and radial nerve afferents increase extensor neuron excitability. Pattern of tremor bursts and phase and timing of afferent stimulation whether in-phase or out-of-phase will be important for control of tremor amplitude.