INTRODUCTION
Tremor, the most common movement disorder, is characterized by an involuntary, rhythmic oscillation of a body part caused by the contractions of reciprocally innervated agonistic and antagonistic muscles, which are readily apparent and thus easily quantifiable [1,2]. Hence, numerous evaluation techniques, including simple clinical observation, standardized rating scales, accelerometers, and electromyography (EMG), have been used [3].
Ultrasound, a non-invasive, painless, and easily available technique, can be used to image muscle tissue with a resolution of up to 0.1 mm and has been used extensively to evaluate various neuromuscular disorders, including myopathy, lower motor neuron disease, and peripheral neuropathy [4,5]. Ultrasound also provides dynamic examination, allowing visualization of muscle movements across multiple regions. Furthermore, ultrasonography is more sensitive than clinical and electromyographic examinations in the detection of fasciculations and increased diagnostic sensitivity of amyotrophic lateral sclerosis [6-8]. Similarly, ultrasonography can detect tremors because these originate from muscle contractions. Furthermore, direct visualization of individual muscles using ultrasonography can evaluate tremor in depth. However, no studies have investigated the utilization of ultrasound for tremors, which are manifested by muscle movements, currently exist.
Botulinum toxin (BTX) is effective against tremors by dampening oscillations from the muscular to central nervous system levels [9,10]. BTX inhibits acetylcholine release at presynaptic terminals, leading to transient neuromuscular transmission block, ultimately inhibiting overactive muscle contraction. Moreover, it inhibits spinal cord input via the Ia afferent fibers and changes motor cortex excitability [11]. Hence, regarding BTX injection into tremors, various approaches, including surface anatomy, EMG, electrical stimulation, and kinematic analysis, have been used [12]. However, there is a lack of studies investigating how ultrasonography can assist in evaluating tremors and determining the optimal muscle for BTX injection. Any clinical differences depending on muscle-targeting techniques have not yet been proven in tremor treatment [12,13]. A narrative review on BTX injection for hand tremor demonstrated that it is not clear that technology-guided approaches including ultrasonography are linked to better outcomes, thus advocating BTX injection using surface anatomy for hand tremor treatment [9].
Herein, we report four cases of different types of tremors that were evaluated using ultrasonography and treated with an ultrasound-guided BTX type A injection.
METHODS
The ultrasonography of tremor was conducted in the muscle extremities using a 5–13-MHz linear array transducer (ACCUVIX XG; SAMSUNG MEDISON) with the patients in a supine position with their arms relaxed. Some patients were asked to move their arms to facilitate the detection of intention-tremor or provocation of tremor. Transverse sonography was performed on the muscle belly center using a 5–13-MHz linear array transducer. Ultrasonography setting parameters, such as contrast and gain, were kept constant during the day’s exam for each patient, while depth and focus were changed for each examination to observe whole thickness of each muscle.
We did not exert any undue pressure on the arm while scanning. B-mode scanning was primarily conducted to assess the muscles causing tremors and to measure the tremor frequency. During B-mode ultrasound examinations, tremors were identified by visual inspection of the sonographic images for the presence of involuntary muscular contractions. We identified tremor when any involuntary muscle contraction was detected although patients did not exert any voluntary contraction. When muscle contraction appeared too irregular or ambiguous to be conclusively defined as tremor, M-mode scanning was subsequently performed for precise quantification. We adopted the ultrasonographic determination of fasciculation to define involuntary muscle twitching, which is unrelated to voluntary muscle movement, as tremor [8]. In M-mode ultrasound examinations, tremors were defined by observing a previously flat line exhibiting abrupt vertical deviations, which were indicative of underlying tremor activity.
Sonography clips were recorded and independently assessed offline by two physicians, with potential disagreements resolved through discussion. To ensure consistency, the movements of each muscle were observed at least three times. The tremor frequency was then quantified by dividing the total number of tremor occurrences by the duration of the recorded clip. For example, 40 instances of tremor of a specific muscle during 20 seconds of recording corresponds to a frequency of 2 Hz. On the M-mode ultrasound image, peaks and troughs corresponding to the motion of the specific structure of interest were identified. The greatest height between the peaks and troughs was defined as the tremor amplitude. Patients were treated with BTX for tremors under ultrasonic guidance, and follow-up was performed. We performed M-mode scanning in two cases (Cases 3 and 4). The cases in this study were patients who were treated with BTX for tremor and had a follow-up. Patients who were cognitively impaired and could not follow physiatrists’ instructions were excluded.
Intramuscular injections of BTX were administered with each vial of 100 units of BTX (BTX, Botox; Allergan) diluted with 2 mL of normal saline. An expert physiatrist performed clinical evaluations and selected target muscles and dose according to the characteristics of the tremors. Subsequently, real-time ultrasound-guided injection was administered.
This study was conducted according to the principles of the World Medical Association Declaration of Helsinki, revised in 2013 in Fortaleza, and approved by the Institutional Review Board of the National Rehabilitation Center (NRC-2014-05-014: 29 September 2014). The requirement of patient consent was waived because this study was a retrospective case report study.
RESULTS
Case 1: Holmes’ tremor
The first patient was a 32-year-old male with a history of sudden quadriparesis secondary to a left pontine hemorrhage. He developed continuous movement in his right wrist 6 months after stroke. His tremor was diagnosed as Holmes’ tremor, which occurs following lesions of the brainstem, cerebellum, or thalamus that affect the nigrostriatal and cerebellothalamic pathways [14]. Holmes’ tremor is characterized by non-rhythmic, low-frequency, flexion-extension oscillation at rest. Flexion-extension of the right fingers and wrist was presented at rest (1.0–1.5 Hz) upon visual inspection, which was aggravated during activity (1.5–2.0 Hz). B-mode ultrasonography at rest demonstrated the frequency of contraction of the following specific muscles: the right flexor pollicis longus (FPL, 1.8 Hz), right extensor pollicis longus (EPL, 1.5 Hz), and right second and third flexor digitorum superficialis (FDS2, 1.5 Hz; FDS3, 1.2 Hz).
Ultrasound-guided BTX injection was administered to the right EPL (40 U), FDS2 (20 U), and FDS3 (20 U). The tremors improved markedly, as did the upper extremity functions, including dressing of the upper limbs, bathing, and writing. Ultrasound revealed that the frequency and amplitude of involuntary muscle movement in the supine position decreased at the right EPL (0.6–1.0 Hz) and disappeared at the right FPL, FDS2, and FDS3 1 month after injection.
Case 2: Extremity tremor associated with palatal myoclonus
The second patient was a 36-year-old male who developed left-sided motor weakness due to a pontine cavernoma and hemorrhage. Three months after the hemorrhage, the patient developed action tremor of the right thumb (2.0–2.8 Hz), which only appeared during thumb movement, causing difficulty in using the right hand, such as while eating with a spoon or brushing teeth. Palatal myoclonus (1.5–2.0 Hz) also manifests as dysphagia and dysarthria. Ultrasonography revealed the frequency of involuntary twitching. Muscle movements of the right FPL at 2.3 Hz occurred during right thumb flexion and disappeared at rest. Fifteen units of BTX injections were administered at the right FPL. The right thumb tremor started to decrease 5 days after BTX injection and disappeared 1 month after injection. Functional activity of the right hand was regained despite mild thumb flexion weakness. Tremors resumed 3 months after injection; however, the amplitude of the tremors diminished with decreasing frequency, and the patient was satisfied with the ease of hand use. Ultrasonography confirmed a reduced frequency (0.7 Hz). Nevertheless, the palatal myoclonus did not change despite improved right FPL tremor.
Case 3: Dystonic tremor
The third patient was a 78-year-old male with involuntary tremor of the right upper limb, predominantly involving the right hand. His tremor was secondary to low-grade glioma tumor removal 9 months before the examination. He also complained of abnormal involuntary flexing of the right wrist, metacarpophalangeal joints, and finger flexors, including the thumb, and extended posturing of the metacarpal joint. Tremors were jerky and presented mainly during posturing; however, they were also observed at rest with decreased frequency. B-mode ultrasound revealed involuntary muscle contraction at the right FPL (5.3 Hz), FDS (3.4–3.6 Hz), and flexor digitorum profundus (FDP, 4.8–5.0 Hz), in which the frequency of tremors varied across muscles. In addition, it demonstrated involuntary right pronator teres (PT, 3.1 Hz) movement, which was invisible to the naked eye. After two weeks of oral medication, including clonazepam and propranolol, the tremors decreased slightly with differential effects on muscles: right FPL (4.4 Hz), right FDS (3.2–3.5 Hz), right FDP (4.3–4.6 Hz), and right PT (2.9 Hz). As the tremor of the right hand did not improve, ultrasound-guided BTX injections were administered at the right extensor digitorum communis (15 U), right FPL (10 U), right FDS2/3/4/5 (10 U, each), and right PT (20 U). The frequency of involuntary muscle contraction began to decrease 7 days after BTX injection. The frequencies of involuntary muscle contraction at 1 month (two weeks after BTX injection) were as follows: right FPL (0.2 Hz), right FDS (0.9–1.0 Hz), right FDP (0.6–0.7 Hz), and right PT (0.3 Hz). Fig. 1 depicts the change in M-mode scanning of the right forearm, including the finger flexors. The tremors of specific muscles identified by M-mode ultrasonography are presented in Table 1.
Case 4: Tremor associated with dystonia secondary to hypoxic brain injury
The fourth patient was a 51-year-old male who had survived cardiac arrest 1 year before this study and presented with a 6-month history of bilateral upper extremity and neck tremors combined with cervical dystonia. The tremor of the bilateral distal upper limb was symmetric and correlated with neck flexor dystonia. Ultrasound revealed a tremor of 2.0–2.2 Hz among the bilateral sternocleidomastoid muscles (SCM) and forearm flexors (0–1.2 Hz of FDP and 0.3–0.4 Hz of FDS). The tremors decreased following clonazepam administration at a dose of 1 mg and BTX injection into the bilateral SCM (right, 30 U; left, 25 U). Thus, ultrasound revealed that bilateral SCM tremors decreased to 0.5–0.7 Hz and bilateral FDP and FDS tremors disappeared 2 weeks after BTX injection. Tremors of the bilateral SCM decreased to 0.3–0.4 Hz, tremors of the bilateral FDS were not visible 10 weeks after BTX injection, and bilateral FDP tremors aggravated to 0.2 Hz. Fig. 2 shows the changes in the tremors of the bilateral SCM and forearm flexors visualized using M-mode ultrasonography. Table 2 shows the frequency and amplitude of tremors in individual muscles obtained using M-mode ultrasonography.
DISCUSSION
Ultrasonography has demonstrated its clinical role in various neuromuscular diseases involving the dynamic features of muscles, such as fibrillation and fasciculation [15,16]. In this study, we demonstrated the role of ultrasonography in tremor in four patients with upper limb tremor secondary to various disorders. Direct visualization of the muscles using ultrasonography is advantageous for assessment, intervention, and follow-up of tremors.
Ultrasonography, as a non-invasive imaging modality, offers a unique advantage in visualizing muscle activity and structural changes in real-time, distinguishing it from EMG and accelerometry, which primarily provide indirect assessments of tremor characteristics. Ultrasonography can easily assist in determining which muscles affect tremors, as tremors are attributed to the movement of specific muscles using a non-invasive method. Furthermore, ultrasonography provides spatial information regarding surrounding structures simultaneously because of its large sampling area. Accelerometry or gyroscopic measurements cannot depict the action of specific muscles, despite being used to measure tremors. While accelerometry or gyroscopic measurements excel in quantifying the amplitude and frequency of tremors with high temporal resolution, they lack the ability to provide anatomical context, a gap that ultrasonography effectively fills by enabling the visualization of muscle contractions as they occur. EMG has been used to identify tremors, but the accuracy of muscle needle placement using a blinded technique is unreliable. Furthermore, the scope of surface EMG is limited to superficial muscles [17,18]. Unlike EMG (EMG), ultrasonography allows for a more detailed examination of both superficial and deep muscle, potentially offering insights into the origins of tremor that cannot be captured by surface electrodes alone. Similarly, ultrasonography is easier to implement and more sensitive than EMG for the detection of fasciculations [19,20]. Therefore, ultrasonography can be used to measure detailed tremor frequencies in individual muscle movements. Similarly in cervical dystonia, ultrasonography is helpful in BTX injections and also in detecting tremor [21].
Ultrasonography demonstrates different frequencies of specific muscle movements; tremors are typically described at their frequency, which originates from the gross movement of the body part. Detailed visualization of individual muscles through ultrasonography allowed us to observe an interesting finding in Case 1, in which FPL tremor disappeared despite the lack of BTX injection into the FPL. As reported in a previous case study, ultrasonography allows us to monitor changes in the frequency of specific muscle contractions before and after injection [22]. Motion transducers or EMG has been used to measure the frequency of tremors; however, ultrasonography is more accessible and less complicated to perform than other methods. Body distribution has been documented simply based on visual observation; however, it is classified as critical and requires careful documentation [1]. In Case 3, the patient only complained of hand tremor; however, ultrasonography revealed minute movement of the PT, which was not evident during visual observation. Thus, ultrasonography can detect tremors with high sensitivity due to its high resolution and large sampling area.
Real-time dynamic ultrasonography can also identify activation conditions by visualizing the changing pattern of muscle movement depending on the conditions, such as posture and activity. Thus, ultrasonography can help classify resting and action tremors, and kinetic, postural, and isometric tremors. For example, the FPL movement in Case 2 was observed during voluntary movement and disappeared at rest, suggesting action tremor. FPL movement was evident among action tremors during voluntary movement, but not with posture against gravity, indicating kinetic rather than postural tremor. Therefore, ultrasonography can be used to define tremor characteristics, including activation conditions, tremor frequency, and body distribution. However, identifying tremors during various activities is challenging because the probe must remain fixed on the patient's limb while they move. In Case 2, action tremors could be readily examined because they were elicited by thumb flexion rather than gross movement of the upper limb. The development of attachable probes or improved attachment methods will enable stable image acquisition and facilitate deeper investigation of tremors.
Ultrasonography can identify necessary tremor interventions and help determine treatment. Oral medication is preferable to BTX injection in cases in which no definite contractions of specific muscles are present. In contrast, BTX could be considered as a first option for tremors manifesting by focal muscle contraction, as observed in the present cases. During BTX injection, the accuracy of muscle needle placement using a blinded technique is not reliable [17,18]. Although BTX injections have been widely employed for the treatment of tremors, a lack of studies on the method of injection currently exists [23,24]. A review on hand tremor based on authors’ experiences demonstrated that it is not clear that technology-guided approaches such as EMG, ultrasonography, and kinematic-guided analysis are linked to better outcomes [9]. However, they suggested that technology-guided injection is useful when identifying the target muscles for hand tremor is difficult. Ultrasound provides a completely accurate injection and better clinical outcomes for spasticity [25,26]. Similarly, it may be beneficial as a guidance tool for tremor intervention with BTX. In a clinical setting, ultrasonography can provide real-time feedback during assessment and BTX injection, offering a comprehensive approach that could enhance diagnostic accuracy and treatment planning. However, ultrasonography may have a limitation in detecting the main oscillation generators of tremors compared with EMG; thus, further studies are warranted to determine the optimal administration methods of BTX.
Moreover, ultrasonography allows us to compare the tremor amplitude, which is measured based on the muscle movement amplitude. Considering the argument that patients are more affected by amplitude than frequency, this information is helpful in determining the intervention target [27,28]. For instance, the decision to inject BTX into the muscles is based on the amplitude of the muscle movement. BTX is retained for movements that are relatively larger on ultrasonography, and the amount of toxin administered is based on the amplitude of the muscle movement. This approach can reduce the risk of weakness secondary to BTX injection, which may increase the efficacy of the injection. Additionally, ultrasound has the safety advantage of avoiding vessels or nerves, especially in patients at high bleeding risk, such as those on anticoagulants. It could also be used for detailed follow-up after the intervention.
However, the reliance on operator skill in ultrasonography and the potential for variability in image interpretation are challenges that must be considered, especially when compared to the more standardized and objective outputs of EMG and accelerometry; thus, setting a uniform protocol is important and challenging. Therefore, we suggest the following protocol: (1) scan the middle of the corresponding muscle belly in the transverse plane over 30 seconds twice to assess specific muscle movements; (2) assess muscle action during both resting and affected limb movement and kinetic, postural, and isometric conditions in cases of action tremor for tremor classification; and (3) use both B-mode and M-mode scanning. The B-mode is optimal for exploring the corresponding muscle for tremor and the surrounding structure, while the M-mode is more helpful for tremor measurements because it enables the detection of minute muscle movements and the measurement of tremor amplitude based on the twitching amplitude of the muscle.
Therefore, B-mode scanning is an improved method of guiding BTX injection, whereas M-mode scanning is better for quantifying tremors and is more sensitive than B-mode scanning for detecting minor muscle movements and is thus useful for research purposes. The M-mode is particularly useful for the definition and quantification of tremors caused by continuous irregular muscle contractions. We determined tremors using several irregular repetitive involuntary muscle contractions without time limitation, with reference to a previous study on fasciculation [8].
A more uniform definition of tremor should be established. Reimers et al. [29] determined fasciculation by irregular movements of small parts of the muscle that lasted for approximately 0.2–0.5 seconds. We established an ultrasonographic definition of tremor by adopting this definition. In addition, we modified the tremor duration to >0.1 seconds because a brisk muscle contraction resulted in tremor. Moreover, the integration of ultrasonography with other instruments may offer a more holistic approach to tremor assessment, combining the strengths of each method to better understand the underlying mechanisms and develop more effective interventions.
The limitations of our study were as follows. First, we evaluated tremor only with ultrasonography not but with other modalities such as accelerometry, gyroscopic measurements, or EMG. Thus, we could not compare the tremor depending on measurement instruments. Second, we did not assess tremor in Cases 1 and 2 with M-mode scanning, as the authors did not consider M-mode ultrasonography for tremor assessment.
Conclusions
The present study showed that ultrasonography has the potential for quantitative assessment of tremor and for detecting muscles with tremors, allowing further information regarding tremor characteristics with high sensitivity to be discovered. Ultrasonography also helps determine the treatment and guide the exact intervention with BTX and follow-up. Further investigations of various tremors in larger populations, including those with concomitant use of EMG, are warranted to elucidate the reliability of ultrasound.
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