Background
Cerebral palsy (CP) is a motor impairment caused by damage to the developing brain. Preterm and very low birth weight babies have the greatest risk of developing CP. Other common causes of CP include intrauterine growth restriction and infection, and intracranial hemorrhage [
1]. Spasticity is a common finding in children with upper motor neuron syndrome associated with CP. The management of children with CP requires a multidisciplinary team to meet the medical, social, psychological, educational, and therapeutic needs.
Rett syndrome is a disorder caused by mutations in X-linked methyl-CpG-binding protein 2 (
MECP2), with its late-stage neuromotor symptoms mimicking those of CP. Most patients have a history of normal early development, followed by a period of regression and hand apraxia. Their life course can be separated into four stages: stagnation (age 6–18 months), rapid regression (age 1–4 years), pseudostationary (age 2 years–potential life), and late motor deterioration (age 10 years–life). Characteristic symptoms include a decline in motor skills, repetitive hand movements, loss of acquired speech, breathing irregularities, and seizures [
2,
3].
Spasticity is a critical symptom of CP and late-stage Rett syndrome. Current therapies for spasticity include botulinum toxin injections, oral antispastic drugs, intrathecal baclofen injections, selective dorsal rhizotomies, and deep brain stimulation. Although these treatment modalities have been widely used in patients with CP, their treatment effects are usually subtle and may not be obvious. Regarding patients with Rett syndrome, few studies have emphasized the management of spasticity, with only one case reporting successful management with intrathecal baclofen [
4].
Extracorporeal shock wave therapy (ESWT) was first applied to patients in 1980 for the management of nephrolithiasis and later successfully employed for many orthopedic diseases such as nonunion of long bone fracture, plantar fasciitis, calcifying tendinitis of the shoulder, several inflammatory tendon diseases, myofascial pain syndrome, and treatment of spasticity after stroke [
5‐
8].The therapeutic effect of ESWT in patients with spastic CP has shown favorable results in literature reviews [
9‐
12]. However, its application in treating spasticity in Rett syndrome has never been reported.
Classical spasticity is thought to increase stiffness through an overactive velocity-dependent stretch reflex. Spasticity is diagnosed using the 5-point Modified Ashworth Scale (MAS), which requires no equipment; however, it is subjective and varies widely among muscle groups [
13].Various biomechanical changes within the skeletal muscle limit the validity and reliability of the MAS for evaluating spasticity associated with CP [
14,
15]. For example, the main limitation of spasticity assessment using the MAS is its inability to distinguish between neural and non-neural components. Therefore, other biomechanical measures that provide reliable quantitative information are required for routine clinical use.Gross Motor Function Measure (GMFM-88) is a clinical scale that separates gross motor functions into five fields: Lying and Rolling, Sitting, Crawling and Kneeling, Standing, and Walking/Running/Jumping [
16]. It is widely used to evaluate the gross motor function in patients with neuromuscular disorders and CP [
17,
18].
Recently, ultrasound elastography techniques have emerged as a promising tool for the evaluation of the mechanical properties of tissues, including skeletal muscle stiffness. It involves the principle of applying stress or force toward tissue, produced by external mechanical compression, vibration, or ultrasound “push” beam, and measuring the subsequent tissue deformation. Strain elastography, acoustic radiation force impulse imaging (ARFI), and shear-wave elastography are the three main techniques used to evaluate skeletal muscles [
19‐
22]. Few studies have investigated the utility of semi quantitative strain elastography in pediatric patients with CP as well as its feasibility for evaluating the severity of muscle stiffness and treatment effects [
23‐
25]. In addition, ARFI, which depicts tissue displacement induced by radiation force within a small region of interest, has been used to evaluate muscle stiffness in patients with CP [
26‐
28]. Shear-wave elastography shows good agreement in both phantoms and tissues, and is suitable for objectively quantifying muscle stiffness for individual muscles [
29‐
31].
Based on the clinical and ultrasonographic outcomes mentioned above, this study aimed to investigate the therapeutic effects of ESWT in Taiwanese children with CP and Rett syndrome.
Discussion
To the best of our knowledge, this is one of the first trials to evaluate the application of ESWT on patients with Rett syndrome. Moreover, previous studies on ESWT in patients with CP focused on clinical outcomes but seldom discussed ultrasonographic assessments [
33]. In this study, we used both clinical scores and ultrasound to evaluate the therapeutic effects. Our results showed that after 12 weeks of low-intensity ESWT, both patients with CP and those with Rett syndrome showed clinical improvement in total gross motor function (evaluated using the GMFM-88). In addition, patients with CP had improved spasticity (evaluated using MAS) and range of motion in ankles. On ultrasonographic assessment, patients with CP showed improved muscle stiffness after ESWT. Conversely, patients with Rett syndrome showed signs of increased muscle stiffness (illustrated by ARFI).
Our study demonstrated a significant decrease in the MAS score of the lower limb flexors after ESWT in the CP group and a trend of decrement in the Rett group. In addition, the CP group showed significantly increased PROM of the ankles after ESWT. Randomized controlled trials in adults with stroke have shown similar effects of ESWT with significantly decreased MAS; however, the results differ regarding the alteration of PROM [
34,
35]. Previous studies on patients with CP have revealed compatible results of significant improvements in both the MAS and PROM of the ankle [
10,
12,
17,
18,
36,
37]. In addition, ESWT has been shown to be more effective than conventional physical therapies [
38], and the combination of ESWT with botulism toxin A injection provided better improvement in MAS and PROM than botulism injection alone [
6,
39].
After ESWT, our study showed a significant improvement in walking/running/jumping function in the CP group and in total function in both groups. The gross motor function of the lower extremities in adults with stroke have shown significant improvement after ESWT [
34,
35].In addition, patients with CP have shown significantly increased GMFM-88 scores after ESWT, especially in the Standing and Walking/Running/Jumping functions [
17,
18]. To summarize, most trials have concluded that ESWT has promising clinical effects in patients with CP and stroke. Moreover, our study revealed its benefits in improving gross motor function and spasticity in patients with Rett syndrome, although it was more effective in patients with CP (Additional file
2).
However, the changes in muscle thickness were not consistent with those of previous studies. Although muscle thickness and spasticity decreased after ESWT in adults with stroke [
34], there were no significant changes in post-therapeutic muscle thickness in our study. In our hypothesis, this may have been caused by the rapid muscle growth in our pediatric patients. Previous studies on ESWT in patients with CP did not discuss the alterations in muscle thickness.
ARFI has been used as a non-invasive and feasible method to evaluate the muscle stiffness of patients with CP [
23,
26] and the effects of botulinum toxin injection [
27,
40]. In our study, the CP group showed a significantly decreased shear wave speed after ESWT in the GCM-M but not in the SOL or GCM-L. We supposed that this was caused by the penetration of the shock wave and depth of the muscles. In this study, we used a hand piece with a short penetration depth of 15 mm and a focal zone of 30 mm; thus, the superficial muscle was more vulnerable to shockwave therapy. Picelli et al. used sonography to measure muscle stiffness and revealed a significantly greater reduction in muscle hardness percentage, which indicated a greater reduction in muscle stiffness when applying additional ESWT to conventional botulinum injection therapy for patients with CP [
33]. Their conclusion corroborated our finding of decreased shear wave velocity on ARFI elastography after ESWT in patients with CP. The strain elastography data were highly related to the pressure applied by the manipulator to the targeted tissue. Therefore, the unremarkable elastography index results were likely caused by the lack of cooperation and voluntary movement of our pediatric patients.
In our result, the baseline MAS is significantly higher in Rett group than CP group, however, the baseline shear wave velocity in ARFI imaging is significanly higher in CP group than Rett group. We provided the possible explanation for the discrepancy results herein. In ARFI, an ultrasound transducer generates a push beam to apply stress, after which the same transducer measures the tissue displacement along the push beam. ARFI measurements are more reliable than traditional strain elastography measurements because tissue displacement with ARFI is caused by fixed ultrasound waves, rather than by tissue compression by the sonographer and thus was less likely interfered by manipulative error. MAS is a clinical measurement performed by an occupational therapist, who measures the degree of resistance to passive movement of the ankle plantar-flexor muscles and classifies the spasticity into five scores. In addition, the ARFI indicated microscopic muscle stiffness in one single muscle while the MAS referred to gross muscle tone of ankle plantar-flexors. From this point of view, ARFI elastography and MAS are quite different tool for assessing muscular spasticity. We also demonstrated the similar result as previous research [
41], which showed a weak correlation between the clinical MAS and the shear wave velocity of biceps brachii muscle in ARFI imaging. Thus, these two parametersdo not necessarily have positive correlation in clinical application.
In the Rett group, despite clinical improvement of muscle spasticity and gross motor function in MAS and GMFM-88 assessment, the muscle stiffness seemed to get worse after ESWT in the ARFI elastography. We can provide the possible explanation for the contradictory results. First, being a neurodevelopmental disorder, patients with Rett syndrome have regressive course in motor functions, spasticity, and muscle stiffness time-by-time, which may be the reason why the shear wave velocity in ARFI imaging was progressively higher after ESWT. Second, the MAS was not positively correlated with ARFI just as we stated. Thus, patients with Rett syndrome showed decrement in MAS score after ESWT may not lead to decrease shear wave velocity in ARFI imaging. We gave a conclusion that ESWT ameliorated the clinical spasticity, but not muscle stiffness in patients with Rett syndrome. However, the disappointed result may contribute to the low shock wave energy used in our study. Beside our study, sonoelastography has also been utilized in a few studies to monitor muscle stiffness in patients with genetic entity such as Duchenne muscular dystrophy [
42]. In the future, it might be a useful tool for monitoring the precise microstructural alterations in patients with a genetic etiology.
In the late stages, the motor function and spasticity of Rett syndrome mimic those of CP. However, whether the mechanisms underlying spasticity in CP and Rett syndrome are similar remain unknown. In this study, we attempted to manage muscular spasticity using ESWT in the same setting and investigated the therapeutic response in these two diseases. Our data revealed that the therapeutic responses to ESWT between CP and Rett was quite different. After ESWT, there was a significant improvement in spasticity, ankle joint range of motion, and gross motor function in the CP group compared with the Rett group. These results indicated that patients with CP were more responsive to ESWT than those with Rett syndrome. A possible explanation could be that the baseline spasticity was more severe in the Rett group, which needed a higher shock wave energy than the CP group. In addition, we supposed that patients with CP and Rett syndrome share different mechanisms of muscular spasticity; therefore, they show different responses to ESWT.
Previous research revealed several possible mechanisms of ESWT reducing muscle spasticity, such as (1) by acting directly on fibrous tissue to alter the rheological properties, e.g. muscle elasticity and extensibility [
43,
44], (2) by inducing nitric oxide production to reduce intramuscular connective tissue stiffness [
45], (3) by inhibiting transmission at neuromuscular junctions and inducing degeneration of acetylcholine receptors [
46], and (4) by enhancing growth of axonal regeneration followed by partial destruction [
47]. The pathophysiology of spasticity and muscle tissue in Rett syndrome were rarely discussed in previous study, but generally, the brain circuitry related to hypertonia included cholinergic, dopaminergic, GABAergic, and glutaminergic pathways [
48]. Among these mechanisms, anticholinergics such as Trihexylphenidyl had shown effectiveness in management of hypertonia/dystonia on patients with Rett syndrome [
49] but not on those with CP [
50]. This finding provided a clue that the third mechanism of ESWT mentioned above, inducing degeneration of acetylcholine receptors, may act a more important role in Rett syndrome. Animal studies on rats found a minimal requirement of energy flux densities (EFD) at 0.09 mJ/mm
2 with total exposure of 360 mJ to inhibit the transmission in neuromuscular junction [
51]; they also found the time to recovery from inhibition to be 8 weeks after ESWT [
46]. Based on these findings, our current protocol of 1500 pulses with EFD at 0.1 mJ/mm
2 might be insufficient for patients with Rett syndrome. For further quantitative study, a protocol of 3600 pulses with EFD at 0.1 mJ/mm
2 or 4000 pulses with EFD at 0.09 mJ/mm
2 and a post-therapeutic follow-up of at least 8 weeks should be considered.
Our study has some limitations. First, as Rett syndrome being a rare disease, the small sample size provided a limited quality of evidence; thus, a systematic review, meta-analysis, or a multicenter study with large-scale, well-designed trials is required to provide convincing conclusions. Second, our study lacked a comparison with conventional therapeutic interventions, such as physical therapy or botulinum injections. Third, the observation period provided only intra-therapeutic outcomes, but not long-term effects, after the completion of ESWT. Previous meta-analyses revealed that MAS was significantly reduced for only one month after ESWT, but spasticity-associated factors (e.g., ankle ROM) could persist for over three months and the outcomes were not dependent on shock wave doses [
52,
53]. Despite the above limitations, this is a pivotal study that evaluated the application of ESWT in patients with Rett syndrome. Furthermore, the measurement of both clinical and ultrasonographic outcomes after ESWT in children could be a good reference for associated research. Being a less invasive, less painful, and more cost-effective therapeutic option than botulinum injection, the utility of ESWT on pediatric population is highly valuable.
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