Tremor Suppression Devices: Comparison
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Tremors are the most prevalent movement disorder that interferes with the patient’s daily living, and physical activities, ultimately leading to a reduced quality of life. Due to the pathophysiology of tremor, developing effective pharmacotherapies, which are only suboptimal in the management of tremor, has many challenges. Thus, a range of therapies are necessary in managing this progressive, aging-associated disorder. Surgical interventions such as deep brain stimulation are able to provide durable tremor control. However, due to high costs, patient and practitioner preference, and perceived high risks, their utilization is minimized. Medical devices are placed in a unique position to bridge this gap between lifestyle interventions, pharmacotherapies, and surgical treatments to provide safe and effective tremor suppression.

  • tremor
  • medical devices
  • transcutaneous electrical nerve stimulation
  • electrical stimulation systems
  • wearable orthoses
  • assistive feeding devices

1. Introduction

Tremors, as defined by the task force of the International Parkinson and Movement Disorder Society (IPMDS), are an involuntary, rhythmic, oscillatory movement of a body part [1]. Essential tremor (ET) is recognized as the most prevalent pathological tremor among adults, affecting about 0.9% of the global population [2]. However, the true prevalence of ET may be higher, as it is believed that these patients may not seek medical attention [3]. Tremors, usually asymmetrically distributed, are frequently seen in patients with Parkinson’s disease (PD), which affects more than six million individuals worldwide [4]. The presence of resting tremor supports the diagnosis of PD [5]. Different clinical subtypes and classifications of tremor disorders have also been identified [1]. The etiologies of tremor include other neurodegenerative diseases such as Wilson’s disease, chromosomal aneuploidy, mitochondrial genetic disorders, infectious and inflammatory diseases, endocrine and metabolic disorders, neuropathies and spinal muscular atrophies, toxin-/drug-induced tremor pathology, and brain neoplasms and injury, as well as several environmental causes [1].

Tremors impact many aspects of the patient’s daily living and interfere with many physical activities at home and in the workplace [6][7][8][9][10]. One clinical-epidemiological study compared the quality of life, including physical and psychosocial aspects, between patients with ET and PD using the Quality of Life in Essential Tremor (QUEST) questionnaire [11]. Patients with ET had a higher QUEST total score and QUEST physical subscore than patients with PD (p < 0.05). This suggests that patients with ET suffers significantly more physical and psychosocial impairment than those with PD [11]. Additionally, among patients suffering from tremor, their psychological strain may be significantly more affected than their physical disabilities [6][12]. The psychological toll of tremor may extend beyond the patients themselves. The Clinical Pathological Study of Cognitive Impairment in Essential Tremor (COGNET), a longitudinal study that evaluates cognitive function in older adults with ET, reported that both patients with ET and those close to them suffer psychological stress [13]. In addition, patients may develop feelings of social isolation [11][14] and depression [6][11][13]. Due to the incredible burden put on individuals diagnosed with ET or PD, a multitude of approaches have been investigated to improve the symptoms and quality of life of those afflicted. These range from lifestyle interventions, pharmacotherapy, and surgical treatments.

Lifestyle interventions focusing on the use of weighted utensils can reduce the amplitude of tremor and alleviate the challenges patients face in their activities of daily living (ADLs) [15][16]. With additional weights, these utensils (e.g., spoon) can assist patients to eat and drink. In 2017, the National Institute for Health and Care Excellence (NICE) produced guidelines for the management of PD in adults [5]. Patients in the early stages of PD may benefit from physio- and occupational therapy if they experience motor symptoms or have difficulties with ADLs [5]. However, lifestyle and the nonpharmacological management of ET were not discussed in the guidelines produced by the American Academy of Neurology (AAN) and the IPMDS [17][18][19]. A systematic review of 19 studies found that physical therapy, limb cooling, vibration therapy, use of limb weights, bright light therapy, and transcranial magnetic stimulation were all examples of investigated treatments of tremor [20]. However, these studies mainly included convenience samples, and the long-term effectiveness of these interventions was not assessed [20].

Pharmacotherapy for the treatment of ET is suboptimal and only treats the symptoms. Many patients do not respond to the existing medications indicated for ET and do not experience a significant improvement in their daily living. Currently, propranolol and primidone are the two first-line therapies [15][16][17][18][19][21]. Across randomized controlled trials (RCTs), propranolol and primidone monotherapy produce a mean reduction in the tremor amplitude of 54.1% and 59.9%, respectively, as measured by accelerometry [22]. Nonetheless, 56.3% of patients eventually discontinued the use of either medications [23]. Topiramate is also recommended as a first-line therapy by the guidelines of the Italian Movement Disorders Association (IMDA) [24] and is considered clinically useful at higher doses by the IPMDS task force [19]. However, it is recommended by the AAN guidelines as a second-line therapy [17][18]. Second-line medications have been reported to be less efficacious in reducing the amplitude of tremors. These include alprazolam, atenolol, gabapentin, and sotalol, as well as the aforementioned topiramate [17][18]. In contrast, there is no consensus in the management of PD tremors. The current NICE guidelines recommend levodopa as the first-line therapy for management of all motor symptoms in patients in the early stages of PD [5].

Deep brain stimulation (DBS), whose efficacy has been demonstrated through closed loop approaches [25][26] and interleaving stimulation [27], is the most common surgical treatment to date, providing durable tremor control, especially for patients with medically refractory ET or advanced PD. The effectiveness of DBS in ET and PD tremor is thought to be due to the direct electrical stimulation to the ventral intermediate nucleus (VIM) possibly disrupting the synchronous firing of thalamic neurons [28][29]. In addition to the VIM, the subthalamic nucleus, internal globus pallidus, and pedunculopontine nucleus are also effective targets for DBS in patients with PD tremors [30]. The use of DBS was approved by the Food and Drug Administration (FDA) for ET in 1997, for advanced PD in 2002, and for mid-stage PD in 2016. As of late, radiofrequency thalamotomy has become less favored. An RCT comparing DBS with thalamotomy in 68 patients with tremor due to ET, PD, or multiple sclerosis found that DBS results in fewer adverse effects (p = 0.024) and a greater increase in the Frenchay Activities Index score, which assess 15 ADLs. This suggests a greater improvement in the functional status when compared to thalamotomy [31]. Although surgical treatments for tremors, including DBS, stereotactic radiosurgery (SRS), and magnetic resonance-guided focused ultrasound (MRgFUS), are more efficacious than pharmacotherapy [32], the utilization of these procedures remains low. Limiting factors may include high surgical costs [33][34], access to care [35][36], and patient preference [35]. Other perceived barriers to DBS include practitioner preference [34][37], high resource and labor intensity [34][38], and perceptions of serious surgical risk [34][38][39].

Thus, a growing unmet need for safe and effective tremor control and suppression sets the stage for a range of therapies to bridge this gap between lifestyle modifications, pharmacotherapy, and surgical treatment. Using a variety of noninvasive suppression mechanisms, medical devices fit within this gap to provide effective tremor suppression at a lower risk than surgery. The increasing interest in this area has led to the birth of a new classification of external upper limb tremor stimulators. In 2018, the de novo classification request of Cala ONE (Cala Health, Burlingame, CA, USA) received FDA approval [40].

2. Tremor Suppression Devices: Place in Therapy

The onset of ET can occur early in childhood due to familial factors, but the majority of cases of ET appeared after the age of 40 [41]. One study investigated the correlation between the age of onset and the progression of ET in 115 patients [42]. Patients with an age of onset later than 60 years experienced a more rapid progression when compared to patients with a younger age of onset (p < 0.001) [42]. Since the onset of ET and PD tremors typically occurs in middle to late adulthood, aging-associated diseases such as dementia [43][44] and mild cognitive impairment [45][46][47] intersect with both of these conditions. These neurological disorders may further preclude patients from adhering to pharmacotherapies.

The medical devices described above offer alternative options for the suppression of tremors (Table 1), especially in patients who are not eligible for surgical interventions (i.e., DBS, SRS, and MRgFUS). However, the use of these devices is patient specific. For example, although Cala Trio has an aesthetic design that will likely not pose any social concerns, wearable orthoses may be a better option if the patient has any contraindication to the use of electrical stimulation systems. Depending on the patient’s needs, assistive feeding devices may be a useful addition to the patient’s daily living. Most of the devices that are available for use are subjected to the FDA’s Class I general control for safety and efficacy assurance. In addition to the general control, Cala ONE requires Class II special control for its performance standards and special prescriber labeling.

Table 1. Summary of the tremor suppression devices and study results.

Type of Device Study Participants (n) Efficacy Risks Refs
Electrical Stimulation Systems: Transcutaneous Electrical Nerve Stimulators
Cala ONE ‡ ET (77)
  • Improved upper limb TETRAS tremor scores (p = 0.017)
  • Improved subject-rated BF-ADL scores (p = 0.001)
  • Skin irritations (redness, itchiness, and swelling)
  • Soreness or lesions
  • Discomfort (stinging and sensation of weakness) or burns
 [48]
Cala Trio * ET (205)
  • Improved upper limb TETRAS tremor scores (p < 0.0001)
  • Improved subject-rated BF-ADL scores (p < 0.0001)
 [49]
Electrical Stimulation Systems: Functional Electrical Stimulators
MOTIMOVE ET (3); PD tremor (4) 67% tremor suppression Muscle fatigue [50]
TREMOR neurorobot ET (4); PD tremor (2) 52% tremor suppression [51]
Tremor’s glove PD tremor (30) Reduced UPDRS score (p = 0.001) [52]
Wearable Orthoses: Active Orthoses
WOTAS exoskeleton ET (7); MS tremor (1); Posttraumatic tremor (1); Mixed tremor (1) 40% tremor suppression [53] Not reported [54][55][56][53]
Pneumatic actuator-based orthosis ET (5) §; PD tremor (5) § 98.1% tremor suppression [57] [58][59][57]
PMLM-based orthosis PD tremor (5) § 97.6% tremor suppression [60]
Voluntary-driven elbow orthosis ET (1) § 99.8% tremor suppression [61]
MMS-based WTSG Not reported Not reported [62]
Myoelectric-controlled orthosis ET (2); Healthy (4) Not reported [63][64][65][66]
Myoelectric-controlled orthosis (ver. 2) Healthy (1) 50–80% tremor suppression [67] [68][67]
BSN-based orthosis Healthy (6) § 77% tremor suppression [69]
Wearable Orthoses: Semi-Active Orthoses
Double viscous beam orthosis Not reported Not reported Not reported [70]
MR damper-based orthosis Not reported Not reported [71][72][73][74]
SETS system Not reported Not reported [75]
Electromagnetic brake-based orthosis Healthy (3) § 88% tremor suppression [76]
Pneumatic hand cuff ET (1) 30% tremor suppression [77]
Wearable Orthoses: Passive Orthoses
Tremelo * PD tremor (1) 85% tremor suppression Not reported [78]
Steadi-One * Lab simulation 85–90% tremor suppression [79]
Readi-Steadi * ET (20); Healthy (40) 50% tremor suppression [80]
Task-Adjustable Passive Orthosis PD tremor (1)
  • 82% tremor suppression while drinking (p = 0.03)
  • 79% tremor suppression while pouring (p = 0.03)
  • 74% tremor suppression while drawing a spiral (p = 0.03)
 [81]
Particle Damper Not reported Not reported [82]
Vib-Bracelet PD tremor (1) § 85% tremor suppression [83][84]
Air-dashpot-based orthosis Healthy (1)
  • 20–62% tremor suppression in the wrist
  • 82% tremor suppression in the elbow
 [85]
Assistive Feeding Devices
Neater Eater * Not reported Not reported Not reported [86]
Liftware Steady * ET (15)
  • Improved FTM-TRS while holding, eating, and transferring objects (p = 0.001)
  • 73% tremor suppression
 [87]
Gyenno Spoon * Not reported 85% tremor suppression (claimed) [88]
Gyroscopic Stabilizers
GyroGlove * Not reported Not reported Not reported [89]
Haptic Stimulation Systems
Emme Watch Not reported Not reported Not reported  
BF-ADL, Bain and Findley Activities of Daily Living; BSN, body senor network; ET, essential tremor; FTM-TRS, Fahn-Tolosa-Marin Tremor Rating Scale; MMS, multi-channel mechatronic splitter; MS, multiple sclerosis; PMLM, permanent magnet linear motor; SETS, soft exoskeleton for tremor suppression; TETRAS, Tremor Research Group Essential Tremor Rating Assessment Scale; PD, Parkinson’s disease; UPDRS, Unified Parkinson’s Disease Rating Scale; WOTAS, Wearable Orthosis for Tremor Assessment and Suppression; and WTSG, wearable tremor suppression gloves. * FDA-registered; Class I medical device. ‡ FDA-approved; Class II medical device. § Test bench simulation. Induced muscle contraction.
 
 
 
 

ET is associated with a staggering cost of direct medical expenses, indirect productivity and income losses, nonmedical expenses, and disability benefits. The unemployment rate increases to about 88% in patients whose ET progresses from mild to severe

[90]

, leading to forced early retirements. Collectively, patients with mild ET have a 1.83-year average loss of employment, corresponding to a $280 billion in income loss

[90]

. In patients with moderate to severe tremors, the average loss of employment is 6.5 years

[90]

. ET and PD tremors likely increase the economic burden more than currently estimated due to their progressive natures and the underreported cases. The development of a medical device for tremor suppression is an under-researched area. Most of the investigational devices discussed were abandoned before entering the market. However, it is imperative that the search for safe and effective tremor suppression devices continues, given the overall economic burden of tremors. Given that most of the currently available devices are based on preliminary data, more investigation is needed to understand the safety and efficacy of these devices before their use in clinical practice can be supported. Cost-effectiveness data are necessary and important to convince insurance programs to provide coverage, alleviating the financial constraints on patients and caregivers.

3. Future Perspectives

The devices currently studied have employed distinctive mechanistic approaches. The weight of evidence supporting their efficacy challenges the notion that tremors originate from a single, dominant pathway. Additional pathological insights, such as the loss of Purkinje cells in ET [91][92] and increased central oscillator synchronization in the basal ganglia in PD tremors [93], along with several mechanistic targets of tremor suppression devices, highlight the advances in our understanding of how tremors may be generated. Perhaps the most pertinent pathway implicated in tremors is the cortico-ponto-cerebello-thalamo-cortical loop, which serves as the basis for successful surgical interventions [21]. These findings suggest an integrative multi-pathway model for tremor pathogenesis. The relevance of these pathways necessitates a further clarification of the complexities and inter-related causes of tremors, which is central to spur the future development of safer and more effective devices for tremor suppression.

The lack of consensus on the characterization and electrophysiology of tremor previously represented two major diagnostic pitfalls [94]. However, in 2018, the IPMDS task force reviewed the vast uncertainties to update its consensus classification criteria for tremor disorders [1]. Besides ET and PD tremors, it is important to recognize that a wide range of other tremor conditions also affect the upper limbs with varying clinical features and etiologies [1]. Future studies could investigate whether the efficacy of these devices is generalizable to other tremor conditions. As seen in the pivotal Cala ONE trial [48], tremor suppression can, in part, be attributed to the surgical placebo effect. Since the studies of most of these devices were descriptive in design, sham-controlled randomized trials are warranted to confirm their efficacy. Lastly, evaluating the concurrent use of one or more devices, along with pharmacotherapy/lifestyle interventions, may derive insightful data to explain the benefits and overall impact of a multimodal strategy in the management of tremors.

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