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Muscle ultrasound measurements and functional muscle parameters in nondystrophic myotonia suggest structural muscle changes
Abstract
Patients with non-dystrophic myotonias, including chloride (myotonia congenita) and sodium channelopathies (paramyotonia congenita/potassium aggravated myotonias), may show muscular hypertrophy in combination with some histopathological abnormalities. However, the extent of muscle changes has never been assessed objectively in a large group genetically confirmed patients. This study quantitatively determines echo intensities, thicknesses, ranges-of-motion and force of four skeletal muscles in 63 genetically confirmed patients. The main findings revealed elevated echo intensities in all muscles except the rectus femoris (+1.3-2.2SD, p<0.0001), and hypertrophy in the arms (+0.5-0.9SD, p<0.01). Muscle echo intensities were inversely correlated to the corresponding ranges-of-motion (biceps brachii: r= -0.43; p<0.001, forearm flexors: r= -0.47; p<0.001, rectus femoris: r= -0.40; p=0.001, and tibial anterior: r= -0.27; p=0.04) and correlated positively to age (r=0.22; p=0.05). The echo intensity of the forearm flexors was inversely correlated to their muscles' force (r= -0.30; p=0.02). Together, these data suggest that non-dystrophic myotonias may lead to structural muscle changes.
... According to the literature, myotonia in MC is not associated with structural changes in muscle [4,8,10]. However, evidence of pathological changes in the muscle tissue has been investigated in a few patients with MC using either magnetic resonance imaging (MRI) or ultrasound [8,12,13]. ...
... Only a few studies have described structural muscle changes with neuroimaging techniques in MC patients. A muscle ultrasound study on 34 individuals with MC found elevated echo intensities on the left biceps brachii, right flexor digitorum, and left tibialis anterior [13]. ...
... This confirms that the myotonic handgrip muscles in MC patients are structurally affected. Trip et al. found elevated ultrasound echo intensities in the flexor digitorum muscles, which were negatively correlated with their muscle force, and further, that the forearm muscles seem more affected than the calf and thigh muscles [13]. Our MRI findings support these conclusions and, as a more sensitive method for quantifying fat replacement of muscles, reveal that the fat replacement is confined to the profound flexor digitorum muscle. ...
Background and purpose
Myotonia congenita (MC) is a muscle channelopathy in which pathogenic variants in a key sarcolemmal chloride channel Gene (CLCN1) cause myotonia. This study used muscle magnetic resonance imaging (MRI) to quantify contractile properties and fat replacement of muscles in a Danish cohort of MC patients.
Methods
Individuals with the Thomsen (dominant) and Becker (recessive) variants of MC were studied. Isometric muscle strength, whole‐body MRI, and clinical data were collected. The degree of muscle fat replacement of thigh, calf, and forearm muscles was quantitively calculated on Dixon MRI as fat fractions (FFs). Contractility was evaluated as the muscle strength per contractile muscle cross‐sectional area (PT/CCSA). Muscle contractility was compared with clinical data.
Results
Intramuscular FF was increased and contractility reduced in calf and in forearm muscles compared with controls (FF = 7.0–14.3% vs. 5.3–9.6%, PT/CCSA = 1.1–4.9 Nm/cm² vs. 1.9–5.8 Nm/cm² [p < 0.05]). Becker individuals also showed increased intramuscular FF and reduced contractility of thigh muscles (FF = 11.9% vs. 9.2%, PT/CCSA = 1.9 Nm/cm² vs. 3.2 Nm/cm² [p < 0.05]). Individual muscle analysis showed that increased FF was limited to seven of 18 examined muscles (p < 0.05). There was a weak correlation between reduced contractility and severity of symptoms.
Conclusions
Individuals with MC have increased fat replacement and reduced contractile properties of muscles. Nonetheless, changes were small and likely did not impact clinically on their myotonic symptoms.
... Our observations are in accordance with data from most recent radiological (ultrasound and MRI) studies where evidence for structural muscle changes in MC as well as for relationship between severity of myopathy and duration of exposure to the symptom were established (Trip et al., 2009b;Morrow et al., 2013). Nowadays it is clear that muscle damage can occur in the non-dystrophic myotonias including myotonia congenita but its pathomechanism and frequency are unknown (Matthews et al., 2010). ...
... Nowadays it is clear that muscle damage can occur in the non-dystrophic myotonias including myotonia congenita but its pathomechanism and frequency are unknown (Matthews et al., 2010). In the study conducted by Trip et al. (2009b) echo intensity was significantly increased (what seemed to be caused by muscle changes such as fat and fibrosis) in all muscles, except for the rectus femoris muscle. The greatest ultrasound abnormalities were detected in forearm flexors of patients with chloride channelopathy and men. ...
... They reported also that the muscle echo intensities were negatively correlated with the corresponding range-ofmotion which may be the result of muscle shortening due to pathological processes in muscles. The range-of-motion in the work of Trip et al. (2009b) was significantly lower in chloride channelopathies. ...
Introduction:
Myotonia congenita (MC) is caused by pathogenic variants in the CLCN1 gene coding the chloride channel protein.
Methods:
To test the hypothesis that needle EMG could be helpful in distinguishing between the recessive and dominant MC, we performed EMG examination in 36 patients (23 men) aged 4-61 years with genetically proven MC: in 30 patients with autosomal recessive MC (Becker MC) and in 6 with autosomal dominant MC (Thomsen MC).
Results:
Myotonic discharges were recorded in 95.8% of examined muscles. For the whole MC group we observed a significant positive correlation between parameters of motor unit activity potentials (MUAPs) in vastus lateralis and tibialis anterior muscles and the duration of the disease. Similar correlation for biceps brachii also was found in Becker MC subgroup only.
Discussion:
EMG could still be helpful in diagnosis of MC and together with provocative tests might be useful in differentiation between recessive and autosomal MC.
... Trained individuals are hypothesized to present with lower EI due to an increase in hypoechoic muscle fber size relative to the volume of hyperechoic perimysium tissue [52][53][54][55]. In addition, the increase in muscle fber size produces a greater volume of tissue that an ultrasonographic Translational Sports Medicine 5 signal is required to penetrate. ...
... Te preferentially utilized type I muscle fbers demonstrate greater oxidative capacity in addition to greater intramuscular fat concentrations surrounding their muscle fber bundles and lipid content, possibly increasing the EI value [33,34]. Alternatively, increased hypoechoic capillarization within the muscle may decrease EI [52][53][54][55] and suggest a dynamic interplay on the EI value in endurance-trained individuals. In the current study, EI demonstrates no signifcant relationships with total knee extension repetitions performed at 50% 1RM. ...
Background. B-mode ultrasonography is an accessible and cost-effective method to assess muscle size and quality through muscle thickness (MT) and echo intensity (EI), respectively. Muscle thickness and EI have demonstrated relationships with maximal strength and local muscle endurance, providing a noninvasive and efficient modality to examine muscle fitness. However, these relationships have not been quantified in the individual quadriceps muscles of habitually endurance-trained populations, which may provide information to practitioners regarding rehabilitation and performance. Methods. Twenty-three participants (males: N = 10; females: N = 13) underwent B-mode ultrasonography to assess MT, EI, and adipose tissue thickness-corrected echo intensity (cEI) in the vastus intermedius (VI), vastus lateralis (VL), and rectus femoris (RF). Muscle fitness was evaluated through maximal strength (1RM) and local muscle endurance (4 sets to failure at 50% 1RM) during dynamic knee extension. Relationships between ultrasonography outcomes and muscle fitness were examined through stepwise multiple linear regression. Results. The results indicate that VI cEI is the strongest predictor of 1RM strength (r = −0.643), while no ultrasonography-derived measures significantly predicted local muscle endurance. Conclusion. The study demonstrates that ultrasonography, specifically measures of cEI in the VI, has the greatest association with maximal strength in endurance-trained individuals. These findings suggest monitoring VI muscle size and quality may benefit practitioners who aim to improve knee extension strength for performance or following injury. In addition, the findings support the use of EI examinations in trained populations.
... Quantitative diagnostic ultrasound (sonography) is a non-invasive, inexpensive method to assess muscle morphology that offers potential for rapid translation into rehabilitation clinics. Sonography can provide reliable and valid measures of 1) muscle thickness, which can be used to identify muscle atrophy and hypertrophy, and 2) tissue echogenicity measured via grayscale analysis, which can be used to identify alterations in muscle tissue composition such as fatty infiltration (Harris-Love et al., 2016;Trip et al., 2009). Sonography applications are increasingly used in clinical and research activities in patients with sarcopenia (Harris-Love et al., 2014). ...
... Similarly, an association between echogenicity and strength of the forearm flexors (r = -0.30) has been reported in persons with non-dystrophic myotonias (Trip et al., 2009). In addition to bivariate correlations, our study found that sonographic muscle morphology measures explained a significant amount of variance in muscle strength and power, suggesting that muscle loss and tissue changes may be important contributors to decreased muscle performance in PwMS. ...
Background:
Neurologically-based muscle weakness is a common symptom in people with multiple sclerosis MS (MS), who may also exhibit muscle morphology changes and intrinsic muscle dysfunction. Diagnostic ultrasound (sonography) is a non-invasive, inexpensive, and clinically feasible method to measure muscle morphology. The purpose of this study was to investigate possible asymmetries in lower limb muscle morphology and performance in people with MS, and to assess the relationships of muscle morphology measures with individual patient characteristics, muscle performance, and functional mobility.
Methods:
This cross-sectional study was conducted at the Washington, DC Veterans Affairs Medical Center. The study participants were 29 Veterans with MS (52% female, 79% African-American, 48.6 ± 11.2 years old, Mean Expanded Disability Status Scale: 3.6 ± 1.4) who completed seated knee extension isokinetic strength and power tests, functional assessments (Timed 25-Foot Walk - T25FW, 5-Times Sit-to-Stand - 5STS), and quantitative B-mode ultrasound image acquisition of the rectus femoris muscle to derive morphology measures (thickness and echogenicity). The limb with weaker knee extension strength was identified as the more-involved limb. Differences between the more and less-involved limb were quantified using a t-test for all muscle morphology and muscle performance measures. Relationships between muscle morphology and patient characteristics, muscle performance, and functional mobility were evaluated using bivariate and multivariate analyses.
Results:
The rectus femoris thickness from the more-involved limb was lower (p<0.001) than that of the less-involved limb, whereas echogenicity was not different between the two limbs (p=0.147). Rectus femoris thickness of the more-involved limb was directly related to age (r=-0.63, p<0.001), muscle strength (r=0.53, p=0.003) and power (r=0.53, p=0.003), and gait speed (r=0.42, p=0.024); whereas its echogenicity was positively associated only with muscle strength (r=-0.46, p=0.013) and power (r=-0.50, p=0.006). Together rectus femoris thickness and echogenicity of the more involved limb explained 44% and 48% of the variance in muscle strength and power, respectively (p<0.001).
Conclusion:
This study supports the ability of sonography to measure muscle morphology in people with MS, identify asymmetries, and quantify associations with important clinical correlates. Compared with more invasive and costly alternatives, sonography is a clinically feasible, relatively low-cost tool that can be used to assess muscle morphology in people with MS. Further research is warranted to determine the potential clinical utility of sonographic measures of muscle morphology in evaluating changes due to disease progression or therapeutic interventions in this population.
... 13,14 Muscle thickness (MT) and echo intensity (EI), an indicator of muscle quality, are related to muscle strength, physical function, and muscle mass measured using DXA or BIA. [15][16][17][18][19][20][21] The assessment of muscle quality is gaining increasing attention as a potentially more critical metric than simple muscle mass measurements. 22 Previous studies suggest that muscle quality may deteriorate before muscle mass and is independently associated with physical performance and survival. ...
... [26][27][28] The higher numerical value of EI reflects more fat and fibrous tissue in the body. 29,30 The majority of reports on muscle US have used the quadriceps femoris muscle (QFM) for measurement purposes, [13][14][15][16][17][18][19][20][21]26,27 but when performing QFM US in practice, it is necessary to expose and image the part above the knee, which makes it difficult to perform QFM US easily in clinical settings. To solve this problem, we previously investigated a method that uses the tibialis anterior muscle (TA) to determine whether US of this easier-to-approach site is useful to diagnose sarcopenia and evaluate muscle quality. ...
Purpose
Muscle mass, a key index for the diagnosis of sarcopenia, is currently assessed using the appendicular skeletal muscle mass index (ASMI) by bioelectrical impedance analysis (BIA). Muscle thickness (MT) assessed by ultrasonography (US) may be a better determinant and/or predictor of muscle condition than ASMI. Thus, we compared it to the ASMI determined by the BIA.
Patients and Methods
Our study included 165 ambulatory older adults (84 males, 81 females, mean age: 76.82 years). The ASMI by the BIA method, MT by US, and the distribution of body mass index (BMI) and body fat percentage (BFP) were examined using defined values for men and women. These were used as the basis for examining the association of MT and ASMI with handgrip strength (HGS), leg muscle strength (LMS), gait speed (GS), and echo intensity (EI). We compared HGS, LMS, GS, and EI for high and low ASMI among lower BMI or BFP. The same was also done for MT assessed by US.
Results
MT, as well as ASMI, was strongly associated with HGS and LMS. There was a correlation between MT and GS and EI but not between ASMI and GS and EI. There were significant differences in the prevalence between high ASMI and high MT or low ASMI and low MT in those with lower BMI or BFP. In non-overweight participants, HGS, LMS, GS, and EI were significantly higher in those with high MT than in those with low MT; however, there were no significant differences in them between those with high and low ASMI.
Conclusion
In the non-overweight group, the MT assessment by US showed a stronger relationship to muscle strength and muscle quality than the ASMI assessment by BIA. The MT assessment using US is a useful alternative to BIA-assessed ASMI, especially in non-overweight participants.
... Only a few studies have investigated associations between quantitative ultrasound parameters and muscle strength in NMDs, and these have reported ambiguous associations, depending on the muscles tested, patients studied, and methods used. 18,[23][24][25] In this study we sought to determine whether muscle ultrasound can distinguish muscles of patients with PPS from those of healthy controls and whether the severity of ultrasound abnormalities is related to muscle strength in this disorder. ...
... Previous studies in other NMDs (i.e., ALS, SMA, and non-dystrophic myotonia) reported no, weak, or moderate correlations between strength and EI, and between strength and MT. [23][24][25] These varying results may be explained by differences in the types of muscles tested, in disease-specific characteristics, and especially in the types of strength measurements used, namely manual muscle testing 23 and hand-held dynamometry, 24,25 rather than isometric strength assessment with fixed dynamometry. ...
... Whether pathological vacuoles in present patients also stem from perturbations of the autophagy flux is uncertain, but it would be highly interesting to investigate this in future studies and may lead to greater understanding of the pathogenesis of muscle degeneration.Other methods have previously been used to address muscular changes in patients with SCN4A mutations. Trip et al. used ultrasound to investigate a pooled group of SCN4A individuals and showed greater mean echo intensity indicating muscle degeneration25 . Morrow et al. used T1-weighted MRI and STIR (Short ...
Skeletal muscle sodium channel disorders give rise to episodic symptoms such as myotonia and/or periodic paralysis. Chronic symptoms with permanent weakness are not considered characteristic of the phenotypes. Muscle fat replacement represents irreversible damage that inevitably will impact on muscle strength. This study investigates muscle fat replacement and contractility in patients with pathogenic SCN4A variants compared to healthy controls. T1-weighted and 2-point Dixon MRI of the legs were conducted to assess fat replacement. Stationary dynamometry was used to assess muscle strength. Contractility was determined by maximal muscle contraction divided by cross-sectional muscle area. The average cross-sectional intramuscular fat fraction was greater in patients compared with controls by 2.5% in the calves (95% CI 0.74–4.29%, p = 0.007) and by 2.0% in the thighs (95% CI 0.75–3.2%, p = 0.003). Muscle contractility was less in patients vs. controls by 14–27% (p < 0.05). Despite greater fat fraction and less contractility, absolute strength was not significantly less. This study quantitatively documents greater fat fraction and additionally describes difference in muscle contractility in a large cohort of patients with skeletal muscle sodium channel disorders. The clinical impact of these abnormal findings is likely limited as muscle hypertrophy in the patients served to preserve absolute muscle strength. Subgroup analysis indicated significant difference in phenotype by genotype, however these findings lack statistical significance and serve as inspiration for future researchers to probe into the geno- phenotype relationship in these disorders.
Trial registration: The study was registered at http://clinicaltrials.gov (identifier: NCT04808388).
... SC, subcutaneous tissue; VL, vastus lateralis; VI, vastus intermedius; TA, tibialis anterior; EDL, extensor digitorum longus; IM, interosseous membrane evaluate the technique as a general screening tool, but it is assumed that sensitivity and specificity are similar to those in children. Besides studies that looked at muscle US use as a general (yes/no) screening tool for any neuromuscular disorder, there is further research showing muscle US changes in tissue echogenicity and muscle texture across the age span in different specific neuromuscular disorders such as Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA), Pompe disease, facioscapulohumeral dystrophy (FSHD), congenital myotonias, amyotrophic lateral sclerosis (ALS), and different forms of myositis [14][15][16][17][18][19][20][21][22]. In general, myopathic changes are characterized by granular fine increases in muscle Quantitative grayscale analysis in a healthy (A) and diseased muscle (B). ...
Purpose of review:
The purpose of this review is to critically discuss the use of ultrasound in the evaluation of muscle disorders with a particular focus on the emerging use in inflammatory myopathies.
Recent findings:
In myopathies, pathologic muscle shows an increase in echogenicity. Muscle echogenicity can be assessed visually, semi-quantitatively, or quantitatively using grayscale analysis. The involvement of specific muscle groups and the pattern of increase in echogenicity can further point to specific diseases. In pediatric neuromuscular disorders, the value of muscle ultrasound for screening and diagnosis is well-established. It has also been found to be a responsive measure of disease change in muscular dystrophies. In chronic forms of myositis like inclusion body myositis, ultrasound is very suitable for detecting markedly increased echogenicity and atrophy in affected muscles. Acute cases of muscle edema show only a mild increase in echogenicity, which can also reverse with successful treatment. Muscle ultrasound is an important imaging modality that is highly adaptable to study various muscle conditions. Although its diagnostic value for neuromuscular disorders is high, the evidence in myositis has only begun to accrue in earnest. Further systematic studies are needed, especially in its role for detecting muscle edema.
... One study that evaluated muscle ultrasound in a NDM cohort found elevated echo intensities in all muscles except the rectus femoris as well as muscle hypertrophy in the arms. 113 Muscle MRI evaluation in an NDM cohort showed hyperintensity within muscles on either T1-weighted or short-T1 inversion recovery (STIR) images in all patients. Edema was common in calf musculature especially in the medial gastrocnemius muscle (18/21 patients), where a fairly specific finding of a "central stripe" of STIR hyperintensity was observed in 10/11 CLCN1 patients and 3/10 SCN4A patients but no healthy volunteers. ...
The non‐dystrophic myotonias (NDMs) are rare muscle hyperexcitability disorders caused by gain‐of‐function mutations in the SCN4A gene or loss‐of‐function mutations in the CLCN1 gene. Clinically, they are characterized by myotonia, defined as delayed muscle relaxation after voluntary contraction, which leads to symptoms of muscle stiffness, pain, fatigue, and weakness. Diagnosis is based on history and examination findings, the presence of electrical myotonia on electromyography (EMG), and genetic confirmation. In the absence of genetic confirmation, the diagnosis is supported by detailed electrophysiological testing, exclusion of other related disorders, and analysis of a variant of uncertain significance (VUS) if present. Symptomatic treatment with a sodium channel blocker, such as mexiletine, is usually the first step in management, as well as educating patients about potential anesthetic complications.
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... In this study, we were able to detect both muscle atrophy and fatty replacement by MRI and CT imaging. An ultrasound study of 19 sodium channelopathy cases, including 10 PC cases, revealed increased echointensity in the biceps brachii and forearm exors [22]. Our study provides further detail by showing that exor digitorum super cialis and exor digitorum profundus muscles were strongly involved among forearm exors. ...
Introduction Paramyotonia congenita (PC; OMIM 168300) is a non-dystrophic myotonia caused by mutations in the SCN4A gene. Transient muscle stiffness, usually induced by exposure to cold and aggravated by exercise, is the predominant clinical symptom, and interictal persistent weakness is uncommon. Case presentation We report a family with a history of PC accompanied by persistent distal hand dominant muscle weakness with masticatory muscle involvement. Persistent weakness was exacerbated with age, and MR analysis showed marked atrophy of temporal, masseter, and finger flexor muscles with fatty replacement. Cases within the family harbor the prevalent PC causative mutation, T1313M, in the SCN4A gene. Administration of acetazolamide chloride improved clinical symptoms and the results of cold and short exercise tests. Phenotypic variation within the family was remarkable, as the two younger affected patients did not present with persistent weakness or muscle atrophy. Conclusions PC associated with the T1313M mutation is a possible cause of persistent distal hand weakness.
... (o paramiotonía) empeora conTrastornos del movimiento V. Propuesta de clasificación | NEUROLOGÍANEUROVET | 27 las acciones repetidas(Cannon 2006(Cannon , 2015) (video 4). Algunas formas de miotonía se asocian con hipertrofia mus- cular difusa(Trip et al. 2009b).Los trastornos del movimiento que se originan en el SNC incluyen un grupo de enfermedades en las que predo- minan las alteraciones en la forma y la velocidad de los movimientos corpora- les (Jiménez-Jiménez et al. 2015). En general, pueden distinguirse 2 catego- rías principales de MIs originados en el SNC; los síndromes rígido-acinéticos, y las hipercinesias (Abdo et al. 2010; Ji- ménez-Jiménez et al. 2015). ...
... The approach has been used to identify the presence and severity of many disorders. For instance, echointenisty is increased in Duchenne muscular dystrophy (Zaidman et al., 2010;Jansen et al., 2012;Rutkove et al., 2014), spinal muscular atrophy (Pillen et al., 2011), non-dystrophic myotonias (Trip et al., 2009) and late-onset acid maltase deficiency (Zaidman et al., 2011). It has also been shown to have high reproducibility (Zaidman et al., 2014). ...
Objectives:
In this study, we sought to determine whether quantitative ultrasound (QUS) could detect the impact of corticosteroids on muscle in the absence of frank weakness.
Methods:
QUS was performed on selected limb muscles of 20 brain tumor patients treated with dexamethasone and 30 healthy controls. Echointensity was quantified using gray scale level (GSL) analysis and compared between groups; correlation to corticosteroid exposure was also performed.
Results:
Average 4-muscle GSL (±standard deviation) was greater in patients compared to controls (35.5 ± 5.61 arbitrary units (AU) versus 30.4 ± 4.17 AU, p = 0.001), with the greatest differences in tibialis anterior. Average muscle GSL also correlated to length of corticosteroid therapy (rho = 0.52, p = 0.01).
Conclusions:
These findings suggest that QUS may be able to quantify skeletal muscle alterations associated with chronic corticosteroid use. Further study of this approach is warranted.
Significance:
The findings of this study may provide a tool to evaluate corticosteroid myopathy.
... However, in some patients, diffused affection and lost selectivity was also observed; also, we found no relation between the ultrasound findings and the age of patients, similar to Zaidman and his colleagues' (2011) findings [14]. This is in contrast to Trip and colleagues (2009), who found an increase in echo-intensity in the muscles with age, due to age-related replacement of muscle tissue by fat and fibrosis [20]. ...
Background
Selective involvement of certain muscles is an indicator for muscle diseases and helps to direct the diagnosis, but in some cases, it cannot be detected clinically; hence, the roles of muscle MRI and ultrasound are to detect this selectivity and facilitate the diagnosis.
Objectives
The possibility of using muscle ultrasound as a screening tool when muscle diseases are suspected and as an alternative to MRI.
Subjects and methods
This cross-sectional descriptive study included 38 patients presented with clinical manifestations suggestive of muscle diseases. The patients were selected over a period of 1 year. All patients were subjected to thorough clinical assessment and muscle ultrasound of the thigh and leg for all patients, while 15 were subjected to MRI. Clinical and radiological assessments were performed separately, followed by both clinical and radiological findings to assess the power of combining the clinical and radiological assessments for the diagnosis of muscle diseases.
Results
The clinical assessment reached a main provisional probable diagnosis in 53% cases, and radiological assessment blind to clinical data suggested diagnosis in 18 of the total cases, while the combination of both ultrasound and MRI could suggest diagnosis in 87% of the cases. The concordance ratio of ultrasound to MRI ranged between 78 and 100%.
Conclusion
The combination of clinical and radiological assessments of muscle diseases can suggest a main provisional probable diagnosis, especially when genetic diagnosis is not accessible, or to direct the genetic testing when it is available. Ultrasound can be used as a routine tool in screening and follow-up of muscle diseases.
... 14,29-31 As well, muscle ultrasound can detect a greater degree of muscle changes in patients with myotonic dystrophies and other non-dystrophic myotonic disorders, at times better than muscle MRI. 32,33 Improving the Diagnosis of Motor Neuron Diseases Ultrasound enhances the ability to detect fasciculations in 10% to 30% of muscles that may be subclinically involved or negative on EMG, thus increasing the diagnostic certainty for patients with motor neuron diseases and other neuromuscular disorders. [34][35][36][37] In addition to bilateral examination of the muscles as described in the standard muscle ultrasound protocol, screening of lower motor neuron disease usually involves additional scanning of the rectus abdominis, sternocleidomastoid, trapezius, masseter, first dorsal interosseous, and submental muscles, with fasciculation screening of up to 60-second scan time per muscle (see Figure 1D). ...
Advances in high-resolution ultrasound have provided clinicians with unique opportunities to study diseases of the peripheral nervous system. Ultrasound complements the clinical and electrophysiology exam by showing the degree of abnormalities in myopathies, as well as spontaneous muscle activities in motor neuron diseases and other disorders. In experienced hands, ultrasound is more sensitive than MRI in detecting peripheral nerve pathologies. It can also guide needle placement for electromyography exam, therapeutic injections, and muscle biopsy. Ultrasound enhances the ability to detect carpal tunnel syndrome and other focal nerve entrapment, as well as pathological nerve enlargements in genetic and acquired neuropathies. Furthermore, ultrasound can potentially be used as a biomarker for muscular dystrophy and spinal muscular atrophy. The combination of electromyography and ultrasound can increase the diagnostic certainty of amyotrophic lateral sclerosis, aid in the localization of brachial plexus or peripheral nerve trauma and allow for surveillance of nerve tumor progression in neurofibromatosis. Potential limitations of ultrasound include an inability to image deeper structures, with lower sensitivities in detecting neuromuscular diseases in young children and those with mitochondrial myopathies, due to subtle changes or early phase of the disease. As well, its utility in detecting critical illness neuromyopathy remains unclear. This review will focus on the clinical applications of neuromuscular ultrasound. The diagnostic values of ultrasound for screening of myopathies, neuropathies, and motor neuron diseases will be presented.
... Since it is highly unlikely that fibrous change can reverse at a later stage, an increased intramuscular fat component could be present in the FDS at an earlier stage. An ultrasonographic study in distinct, non-dystrophic myotonia showed a weak correlation between muscle changes and degree of muscle use [16]. This might suggest that the higher EIs of the FDS in patients with low mRS could be due to muscle overuse, in comparison to the patients with high mRS who were also bed-ridden and had low levels of physical activities. ...
Background and purpose:
In myotonic dystrophy type 1 (DM1), weakness of distal limb muscles affects quality of life. Non-invasive evaluation of muscular involvement by muscle sonography could be useful for characterizing muscle-specific involvement.
Methods:
Sonography of the lower leg and forearm was performed in 19 patients with DM1 and 10 control subjects. The mean echo intensities (EIs) of seven limb muscles were obtained by computer-assisted histogram analysis and compared within DM1 according to the overall clinical severity.
Results:
The EIs of the muscles were significantly higher in DM1 than in the controls (P < 0.01), except for the soleus (P = 0.4). Comparison of adjacent muscles showed the following: (i) greater EIs in flexor digitorum profundus than flexor carpi ulnaris (P < 0.01) and flexor digitorum superficialis (P = 0.02), and (ii) greater EIs in the medial head of the gastrocnemius than the soleus (P < 0.00001). In a subgroup analysis of DM1 according to the modified Rankin Scale (mRS), the more severe subgroup (mRS = 4-5) had lower mean EIs than the less severe subgroup (mRS from 1-3) (P = 0.01) in the flexor digitorum superficialis but not in other muscles.
Conclusions:
Preferential high echogenicity in the medial gastrocnemius and deep finger flexors is suggestive of DM1. Muscle echogenicity is not generally related to functional dysfunction in DM1.
... As described previously, for this registry we asked all Dutch neurologists and the Dutch Patient Association for Neuromuscular Diseases (Spierziekten Nederland), to notify us of patients with NDM. Patients (>18 years) were invited to our neurology outpatient clinic in Nijmegen, The Netherlands, for clinical assessment, needle-EMG, and collection of blood samples for genetic analysis [8,12,[26][27][28][29]. In 2007, the registry contained 62 NDM patients with a genetically confirmed NMD. ...
To obtain evidence for the clinical and cost-effectiveness of treatments for patients with rare diseases is a challenge. Non-dystrophic myotonia (NDM) is a group of inherited, rare muscle diseases characterized by muscle stiffness. The reimbursement of mexiletine, the expert opinion drug for NDM, has been discontinued in some countries due to a lack of independent randomized controlled trials (RCTs). It remains unclear however, which concessions can be accepted towards the level 1 evidence needed for coverage decisions, in rare diseases. Considering the large number of rare diseases with a lack of treatment evidence, more experience with innovative trial designs is needed. Both NDM and mexiletine are well suited for an N-of-1 trial design. A Bayesian approach allows for the combination of N-of-1 trials, which enables the assessment of outcomes on the patient and group level simultaneously.
We will combine 30 individual, double-blind, randomized, placebo-controlled N-of-1 trials of mexiletine (600 mg daily) vs. placebo in genetically confirmed NDM patients using hierarchical Bayesian modeling. Our results will be compared and combined with the main results of an international cross-over RCT (mexiletine vs. placebo in NDM) published in 2012 that will be used as an informative prior. Similar criteria of eligibility, treatment regimen, end-points and measurement instruments are employed as used in the international cross-over RCT.
The treatment of patients with NDM with mexiletine offers a unique opportunity to compare outcomes and efficiency of novel N-of-1 trial-based designs and conventional approaches in producing evidence of clinical and cost-effectiveness of treatments for patients with rare diseases.
ClinicalTrials.gov Identifier: NCT02045667.
... Analyzing the reflectivity via gray-scale analysis provides a useful low-cost, easily accessible, and safe method to evaluate the muscle quality [145]. Although some evidence suggests a relationship between muscle echo intensity and strength [146], our preliminary study did not find significant changes in muscle echo intensity with acute resistance exercise when significant strength changes occurred [122]. As skeletal muscle ultrasound applications to assessing muscle qualitative features is a newer approach, further studies are warranted to determine whether it may be a useful application for clinical incorporation. ...
Aging is often accompanied by declines in physical functioning which impedes older adults' quality of life, sense of independence, and ability to perform daily tasks. Age-related decreases in skeletal muscle quantity, termed sarcopenia, have traditionally been blamed for these physical decrements. However, recent evidence suggests that the quality of muscle tissue may be more functionally relevant than its quantity. 'Muscle quality' has been emerging as a means to elucidate and describe the intricate intramuscular changes associated with muscle performance in the context of aging and sarcopenia. While muscle quality has most commonly been defined in terms of muscle composition or relative strength, at the core, muscle quality really describes muscle's ability to function. Skeletal muscle displays a strong structure-function relationship by which several architectural characteristics factor into its functional capacity. This review describes the structural, physiological, and functional determinants of muscle quality at the tissue and cellular level, while also introducing other novel parameters such as sarcomere spacing and integrity, circulating biomarkers, and the muscle quality index. Muscle qualitative features are described from the perspective of how physical exercise may improve muscle quality in older adults. This broad, multidimensional perspective of muscle quality in the context of aging and sarcopenia offers comprehensive insights for consideration and integration in developing improved prognostic tools for research and clinical care, while also promoting translational approaches to the design of novel targeted intervention strategies designed to maintain function and mobility into late life.
... None of these hallmarks were detected in the age and sex-matched control sample (Fig. 5E and F). Thus, draggen mice show progressive muscle pathology, mimicking the muscle pathology seen in some myotonia and patients with periodic paralysis (Bradley et al., 1990;Tengan et al., 1994;Feng et al., 2009Feng et al., , 2011Luan et al., 2009;Trip et al., 2009). ...
Mutations in the skeletal muscle channel (SCN4A), encoding the Nav1.4 voltage-gated sodium channel, are causative of a variety of muscle channelopathies, including non-dystrophic myotonias and periodic paralysis. The effects of many of these mutations on channel function have been characterized both in vitro and in vivo. However, little is known about the consequences of SCN4A mutations downstream from their impact on the electrophysiology of the Nav1.4 channel. Here we report the discovery of a novel SCN4A mutation (c.1762A>G; p.I588V) in a patient with myotonia and periodic paralysis, located within the S1 segment of the second domain of the Nav1.4 channel. Using N-ethyl-N-nitrosourea mutagenesis, we generated and characterized a mouse model (named draggen), carrying the equivalent point mutation (c.1744A>G; p.I582V) to that found in the patient with periodic paralysis and myotonia. Draggen mice have myotonia and suffer from intermittent hind-limb immobility attacks. In-depth characterization of draggen mice uncovered novel systemic metabolic abnormalities in Scn4a mouse models and provided novel insights into disease mechanisms. We discovered metabolic alterations leading to lean mice, as well as abnormal AMP-activated protein kinase activation, which were associated with the immobility attacks and may provide a novel potential therapeutic target.
... [6] Paralysis periodica paramyotonica, a myotonic form of HyperPP, represents a mix of clinical features of HyperPP and PC. [7] Sodium channel myotonias generally present with isolated myotonia, and some of the pure sodium channel myotonias can manifest "warm-up effect," which is typically seen in MC. [4,8] While myotonia sets in after inactivity in MC, it develops soon after exercise in PC and 10-30 min post-exercise in sodium channel myotonias. [4] Based on the distinct electromyographic patterns, Fournier et al. [1,3] devised specialized neurophysiological protocols to guide genetic investigation. ...
Skeletal muscle sodium channelopathies (SMSCs) including hyperkalemic periodic paralysis (HyperPP), paramyotonia congenita (PC), and sodium channel myotonia are caused by sodium channel gene (SCN4A) mutations, with altered sarcolemal excitability, and can present as episodes of skeletal muscle weakness, paralysis, and myotonia. We report a teenage boy, who presented with features of HyperPP, PC, myotonia congenita, and sodium channel myotonia. His electromyography (EMG) revealed myopathic changes, myotonia, and Fournier EMG pattern I, and posed a diagnostic challenge. Genetic analysis showed Thr704Met mutation in SCN4A gene. While with typical clinical phenotypes, the electromyographic patterns can be used to direct genetic testing, atypical phenotypes may pose diagnostic dilemmas. Clinicians dealing with neuromuscular disorders in children need to be aware of the unusual clinical presentations of SMSC, so that focused genetic testing can be carried out.
... Imaging abnormalities are in keeping with the clinical observation that a proportion of these patients develop fixed weakness and muscle biopsy findings in these patients may show myopathic changes, tubular aggregates and vacuolar changes [3]. Our results are consistent with an ultrasound study of NDM patients which showed increased echogenicity suggestive of fatty infiltration or fibrosis of left biceps brachii, right forearm flexors and left tibialis anterior compared with healthy volunteers [13]. However, ultrasound examination is limited to superficial muscle groups and is operator dependent with relatively low inter-observer and intraobserver agreement [9]. ...
We assessed the presence, frequency and pattern of MRI abnormalities in non-dystrophic myotonia patients. We reviewed T1-weighted and STIR (short-tau-inversion-recovery) 3T MRI sequences of lower limb muscles at thigh and calf level in 21 patients with genetically confirmed non-dystrophic myotonia: 11 with CLCN1 mutations and 10 with SCN4A mutations, and 19 healthy volunteers. The MRI examinations of all patients showed hyperintensity within muscles on either T1-weighted or STIR images. Mild extensive or marked T1-weighted changes were noted in 10/21 patients and no volunteers. Muscles in the thigh were equally likely to be affected but in the calf there was sparing of tibialis posterior. Oedema was common in calf musculature especially in the medial gastrocnemius with STIR hyperintensity observed in 18/21 patients. In 10/11 CLCN1 patients this included a previously unreported "central stripe", also present in 3/10 SCN4A patients but no volunteers. Degree of fatty infiltration correlated with age (rho=0.46, p<0.05). Muscle MRI is frequently abnormal in non-dystrophic myotonia providing evidence of fatty infiltration and/or oedema. The pattern is distinct from other myotonic disorders; in particular the "central stripe" has not been reported in other conditions. Correlations with clinical parameters suggest a potential role for MRI as a biomarker.
... Moreover, there is a greater tendency to develop sarcopenia, which is related to increased age and intramuscular fat infiltration [20]. In patients with neuromuscular diseases, ultrasound has been used to evaluate muscle thickness in the upper and lower limbs, as a follow-up diagnosis, due to its advantages over other imaging methods discussed previously [21, 22]. This study aims to evaluate the thickness of the quadriceps femoris muscle and biceps brachii and brachialis muscles, bilaterally as well as the adjacent subcutaneous adipose tissue in patients undergoing Roux-en-Y gastric bypass. ...
... While both qualitative and quantitative ultrasound assessments of skeletal muscle are effective in identifying neuromuscular pathology, quantitative ultrasonography offers superior inter-rater reliability and greater sensitivity for detecting pathology (Heckmatt et al. 1989;Zuberi et al. 1999;Maurits et al. 2003;Pillen et al. 2006;Brockmann et al. 2007). Quantification of the amount of muscle pathology using ultrasound provides a sensitive, noninvasive measure of disease severity from varied pathologies including Duchenne muscular dystrophy (Zaidman et al. 2010;Jansen et al. 2011), late-onset acid maltase deficiency (Zaidman et al. 2011), spinal muscular atrophy (Wu et al. 2010) and nondystrophic myotonias (Trip et al. 2009) and is of sufficient sensitivity to detect differences between steroid treated and untreated dystrophic mice ). Although quantitative ultrasound offers advantages over qualitative assessments, widespread implementation of quantitative ultrasonography in the clinical setting is limited by an inability to replicate results between different ultrasound systems. ...
Widespread implementation of quantitative muscle ultrasonography in assessing skeletal muscle pathology is limited by an inability to replicate results between different ultrasound systems. We have developed a measurement of skeletal muscle pathology, calibrated muscle backscatter (cMB), which should be reproducible between different ultrasound systems. We compared the reliability of grayscale and cMB measurements between different ultrasound systems, configurations and region-of-interest (ROI) sizes. cMB of skeletal muscle was reliably measured (intraclass correlation coefficient [ICC] ≤0.98) despite very dissimilar grayscale levels (ICC ≤0.54). cMB reliability was highest between systems using similar settings (ICC: 0.82-0.98) and was lowest when transducer type varied (ICC: 0.47-0.71). Reliability was better from ROIs spanning a narrow range of depths compared with larger ranges. cMB measurements are more reliable than grayscale between different ultrasound systems and configurations. Measuring cMB could improve widespread implementation of quantitative ultrasound in assessments of skeletal muscle pathology.
... A number of studies have highlighted the need to compare ultrasound and MRI data with histological findings. 8 Detailed sonographic assessment of the healing process requires more precise knowledge of the correlation between sonographic images and the events taking place at the tissue level. The degeneration-regeneration process involves a well-established sequence of major mi-croscopic changes. ...
In this study we correlated ultrasound findings with histological changes taking place during experimentally induced degeneration-regeneration in rat skeletal muscle.
Gastrocnemius muscles were injected with mepivacaine, and the progress of the muscle injury was monitored by ultrasound from day 1 to day 20. Muscles were extracted on the same days for histological examination.
The degenerative phase was characterized by increased echogenicity in the injured area; thereafter, echogenicity gradually diminished during the regenerative phase, attaining normal levels by 20 days postinjection. By this stage, histological examination revealed that regeneration was complete. The heteroechoic texture observed from day 4 to day 10 appeared to reflect the coexistence of degenerative and regenerative processes.
The results suggest that the degenerative and regenerative phases of muscle injury may be distinguished sonographically through differences in echogenicity and echotexture and, using Doppler ultrasound, differences in the degree of vascularization.
... Muscle ultrasound is a non-invasive technique for detecting the presence and extent of changes in muscle structure and muscle thickness in various parts of the body [8,9]. Muscle thickness can be decreased, normal, or increased in muscles affected by a neuromuscular disorder [10,11]. Furthermore, affected muscles have increased echo intensity, i.e. the muscles appear whiter [12][13][14][15]. ...
This study determines the presence and extent of muscle changes in 31 myotonic dystrophy type 2 (DM2) patients detected by muscle ultrasound. Results were compared to 31 adult-onset myotonic dystrophy type 1 patients (DM1) and healthy controls. Furthermore, we tested the hypothesis that structural muscle changes correlate with age, quantitative muscle force and serum creatine kinase in both disorders. In DM2 all seven examined muscles (right masseter muscle, right and left biceps brachii, right and left forearm flexors, right rectus femoris, and left tibialis anterior muscle) showed increased mean echo intensities (p ≤ 0.001). Atrophy of the masseter muscle and rectus femoris were both found in 23% of DM2 patients. Muscle thickness was significantly more decreased in the elbow flexors in DM2 compared to DM1. Echo intensity sum score correlated positively with age in DM2 (r=0.57, p=0.001) and negatively with muscle force (r=0.36, p=0.048). We conclude that all tested muscles are affected and structurally abnormal in DM2 patients. Proximal arm muscles are more affected in DM2 compared to DM1, which corresponds to clinical findings.
... Sustained electrical activity (myotonia) and muscle contractions associated with chloride and sodium channelopathies can lead to dramatic muscle hypertrophy in the nondystrophic myotonias. 106,107 Spontaneous discharges in dystrophin-deficient muscle may occur because of altered ion currents across the damaged muscle cell membrane, with an associated shift in the resting membrane potential. Sustained muscle contraction would presumably augment muscle size, just as it does in myotonia. ...
Mutations in the dystrophin gene cause Duchenne and Becker muscular dystrophy in humans and syndromes in mice, dogs, and cats. Affected humans and dogs have progressive disease that leads primarily to muscle atrophy. Mdx mice progress through an initial phase of muscle hypertrophy followed by atrophy. Cats have persistent muscle hypertrophy. Hypertrophy in humans has been attributed to deposition of fat and connective tissue (pseudohypertrophy). Increased muscle mass (true hypertrophy) has been documented in animal models. Muscle hypertrophy can exaggerate postural instability and joint contractures. Deleterious consequences of muscle hypertrophy should be considered when developing treatments for muscular dystrophy.
... Moreover, there is a greater tendency to develop sarcopenia, which is related to increased age and intramuscular fat infiltration [20]. In patients with neuromuscular diseases, ultrasound has been used to evaluate muscle thickness in the upper and lower limbs, as a follow-up diagnosis, due to its advantages over other imaging methods discussed previously [21, 22]. This study aims to evaluate the thickness of the quadriceps femoris muscle and biceps brachii and brachialis muscles, bilaterally as well as the adjacent subcutaneous adipose tissue in patients undergoing Roux-en-Y gastric bypass. ...
This study aims to evaluate the thickness of the femoral quadriceps and biceps brachii and brachialis muscles bilaterally and the adjacent subcutaneous fat in patients undergoing gastric bypass Roux-en-Y before and after surgery, using ultrasound as the diagnostic method of choice.
We studied 12 patients undergoing this surgical method preoperatively and during the first, third, and sixth postoperative months. During these periods, patients were evaluated by ultrasound to determine the thickness of subcutaneous adipose tissue and muscle of the upper and lower limbs.
Postoperatively, these patients showed a reduction in the thickness of the upper and lower extremities muscle and adipose tissue as compared to their preoperative values. There was a significant difference in the loss of muscle thickness in all postoperative months and in the thickness of fatty tissue in the sixth month after surgery, compared to the preoperative muscle and fatty tissue thickness.
Ultrasound can be considered as the diagnostic method of choice when assessment of the fat and lean body mass is required in morbidly obese patients before and after bariatric surgery.
... First, this study only investigated the influence of muscle quality assessed from EI on the muscle strength of the quadriceps femoris. However, studies in patients with non-dystrophic myotonia, showed that the EIs of the biceps brachii and tibialis anterior were not correlated with muscle strength, although the EI of the forearm flexors was significantly correlated with grip strength (Trip et al. 2009). This indicates that the influence of muscle quality assessed from EI on strength may differ between muscles. ...
Enhanced echo intensity (EI) on an ultrasound image of skeletal muscle indicates changes in muscle quality, including increases in intramuscular fibrous and adipose tissues. However, it is not known whether muscle quality assessed from the EI of computer-aided gray-scale analysis of an ultrasound image is associated with the muscle strength or body composition of a subject. The objectives of this study were to investigate whether muscle quality assessed from EI measured using gray-scale analysis is associated with muscle strength independently of age or muscle thickness (MT), and to examine the relationship between muscle EI and body composition. Ninety-two healthy women with a mean age of 70.4 ± 5.5 years (range, 51-87 years) dwelling in Kyoto, Japan, participated in the study. The MT, subcutaneous fat thickness (FT), and EI of the quadriceps femoris on the right extremity were assessed from transverse ultrasound images. Knee extensor isometric strength was used as a measure of the quadriceps femoris muscle strength. EI was significantly correlated with quadriceps strength independently of age or MT, and stepwise regression analysis revealed that MT and EI were independently associated with quadriceps strength. Importantly, EI showed no significant correlations with FT, percentage of body fat (%BF), or body mass index (BMI), while FT, BMI, and %BF did not significantly influence muscle strength. These data suggest that muscle quantity (i.e., MT) and muscle quality assessed from EI measured using computer-aided gray-scale analysis independently contribute to muscle strength in middle-aged and elderly persons.
... This change was most marked in the forearm flexors where the increased echogenicity correlated negatively with muscle power. There was no positive correlation between echo intensity and age for individual muscles except the rectus femoris although the sum of the scores did show a significant positive correlation (Trip et al., 2009c). Recently, a mouse model of hyperkalaemic periodic paralysis has been engineered by introducing the murine equivalent of the SCN4A mis-sense mutation M1592V (Hayward et al., 2008). ...
The non-dystrophic myotonias are an important group of skeletal muscle channelopathies electrophysiologically characterized by altered membrane excitability. Many distinct clinical phenotypes are now recognized and range in severity from severe neonatal myotonia with respiratory compromise through to milder late-onset myotonic muscle stiffness. Specific genetic mutations in the major skeletal muscle voltage gated chloride channel gene and in the voltage gated sodium channel gene are causative in most patients. Recent work has allowed more precise correlations between the genotype and the electrophysiological and clinical phenotype. The majority of patients with myotonia have either a primary or secondary loss of membrane chloride conductance predicted to result in reduction of the resting membrane potential. Causative mutations in the sodium channel gene result in an abnormal gain of sodium channel function that may show marked temperature dependence. Despite significant advances in the clinical, genetic and molecular pathophysiological understanding of these disorders, which we review here, there are important unresolved issues we address: (i) recent work suggests that specialized clinical neurophysiology can identify channel specific patterns and aid genetic diagnosis in many cases however, it is not yet clear if such techniques can be refined to predict the causative gene in all cases or even predict the precise genotype; (ii) although clinical experience indicates these patients can have significant progressive morbidity, the detailed natural history and determinants of morbidity have not been specifically studied in a prospective fashion; (iii) some patients develop myopathy, but its frequency, severity and possible response to treatment remains undetermined, furthermore, the pathophysiogical link between ion channel dysfunction and muscle degeneration is unknown; (iv) there is currently insufficient clinical trial evidence to recommend a standard treatment. Limited data suggest that sodium channel blocking agents have some efficacy. However, establishing the effectiveness of a therapy requires completion of multi-centre randomized controlled trials employing accurate outcome measures including reliable quantitation of myotonia. More specific pharmacological approaches are required and could include those which might preferentially reduce persistent muscle sodium currents or enhance the conductance of mutant chloride channels. Alternative strategies may be directed at preventing premature mutant channel degradation or correcting the mis-targeting of the mutant channels.
Introduction:
Skeletal muscle channelopathies (SMCs) are a heterogenous group of disorders, caused by mutations in skeletal ion channels leading to abnormal muscle excitability, resulting in either delayed muscle relaxation (myotonia) which characterizes non-dystrophic myotonias (NDMs), or membrane transient inactivation, causing episodic weakness, typical of periodic paralyses (PPs).
Areas covered:
SMCs include myotonia congenita, paramyotonia congenita, and sodium-channel myotonia among NDMs, and hyper-normokalemic, hypokalemic, or late-onset periodic paralyses among PPs. When suspecting an SMC, a structured diagnostic approach is required. Detailed personal and family history and clinical examination are essential, while neurophysiological tests should confirm myotonia and rule out alternative diagnosis. Moreover, specific electrodiagnostic studies are important to further define the phenotype of de novo cases and drive molecular analyses together with clinical data. Definite diagnosis is achieved through genetic testing, either with Sanger sequencing or multigene next-generation sequencing panel. In still unsolved patients, more advanced techniques, as exome-variant sequencing or whole-genome sequencing, may be considered in expert centers.
Expert opinion:
The diagnostic approach to SMC is still mainly based on clinical data; moreover, definite diagnosis is sometimes complicated by the difficulty to establish a proper genotype-phenotype correlation. Lastly, further studies are needed to allow the genetic characterization of unsolved patients.
In this review we summarise the key techniques of muscle ultrasound as they apply to hereditary muscle disease. We review the diagnostic utility of muscle ultrasound including its role in guiding electromyography and muscle biopsy sampling. We summarize the different patterns of sonographic muscle involvement in the major categories of genetic muscle disorders and discuss the limitations of the technique. We hope to encourage others to adopt ultrasound in their care for patients with hereditary muscle diseases.
Background:
Paramyotonia congenita (PC; OMIM 168300) is a non-dystrophic myotonia caused by mutations in the SCN4A gene. Transient muscle stiffness, usually induced by exposure to cold and aggravated by exercise, is the predominant clinical symptom, and interictal persistent weakness is uncommon.
Case report:
We report a family with a history of PC accompanied by persistent hand muscle weakness with masticatory muscle involvement. Persistent weakness was exacerbated with age, and MR analysis showed marked atrophy of temporal, masseter, and finger flexor muscles with fatty replacement. The PC causative mutation T1313M in the SCN4A gene was prevalent in the family. Administration of acetazolamide chloride improved clinical symptoms and the results of cold and short exercise tests. Phenotypic variation within the family was remarkable, as the two younger affected patients did not present with persistent weakness or muscle atrophy.
Conclusions:
PC associated with the T1313M mutation is a possible cause of persistent distal hand weakness.
Objectives
Sarcopenia is diagnosed on the basis of skeletal muscle mass and muscle strength/function; however, simpler and more accurate measures for muscle mass and muscle strength/function should be explored using ultrasonography. This study aimed to investigate a new screening method using ultrasonography to diagnose sarcopenia of lower leg muscles in older males.
Design
Cross-sectional study.
Setting and subjects
A total of 60 males, aged 65 years or older, participated in this study.
Measures
The muscle thickness (MT) and echo intensity (EI) of the lower leg muscles were measured using ultrasonography, and the physical functions were examined. The MT and EI values of the lower leg muscles for predicting low appendicular skeletal muscle mass index (ASMI) and low grip strength were analyzed using receiver operating characteristic curve analysis and significant cutoff values were observed. A binary logistic regression analysis was performed with an MT below the cutoff value or an EI above the cutoff value as the independent variable, and with sarcopenia according to the Asian Working Group for Sarcopenia criterion as the dependent variable.
Results
Using the optimal cutoff points of MT and EI for predicting a low ASMI and low grip strength, the MT of the tibialis anterior (TA), the EI of the TA and gastrocnemius, and the MT/EI index of the TA and soleus were found to be associated with sarcopenia after adjusting for age, body mass index, calf circumference, presence of diabetes mellitus, and statin use in the binary logistic regression model. In addition, the combined MT and EI of the TA showed predictability with respect to sarcopenia.
Conclusions/Relevance
Ultrasonographic assessment of lower leg muscles might be useful as a convenient approach for detecting sarcopenia. In particular, the determination of both MT and EI of the TA should be considered as an alternative method of screening for sarcopenia.
Introduction: The Muscle Ultrasound examination (MUS) is a non‐invasive and inexpensive technique for evaluating neuromyopathies. Standardized MUS normative data are incomplete in paediatric subjects.
Methods: We performed a MUS study with 120 healthy children (59 males; mean age 10.44; age range 2–16 years). We measured the width and the echogenicity bilaterally in the following muscles: biceps brachii and brachialis, brachioradialis, forearm‐flexors, rectus femori sand vastus intermedius, tibialis anterior, extensor hallucis longus, lateral and medial gastrocnemius .
Results: The muscle thickness increased with age for all muscles. Confidence limits were set for each age group muscle width. Echogenicity increased with age only in some muscles.
Discussion: Our MUS study provides new data on physiological muscle structural changes in healthy children to address the limited available references in this age group. This article is protected by copyright. All rights reserved.
Introduction
Ultrasound (US) has an important role in musculoskeletal (MSK) evaluation, allowing the study of muscle morphology and function. Muscle thickness (MT) and muscle echo-intensity (EI) are two important parameters that may quantify muscle structural adaptations to a variety of stimuli. The aim was to explore the potential of quantitative US imaging for assessing the adaptations and responses of the muscle tissue to increased contractile activity using B-mode US. This study was centred on the quadriceps femoris muscle contractile activity on MT and EI.
Methods and materials
Twenty-eight young male adults participated in the study, divided in a control group and two training groups performing concentric or eccentric strength training, respectively. The effect of a 15-week strength program was studied on MT and EI in several regions of the heads of the quadriceps femoris using B-mode US. All images acquisitions and measurements were done by the same experience sonographer.
Results
Strength training resulted in an increase of MT at all muscles and sites (p < 0.05), except the VM. Strength training failed in changing EI in most of the quadriceps femoris, except in the VI and some regions of the VL. No statistically significant differences were observed in our quantitative US parameters between concentric and eccentric training (p > 0.05).
Conclusion
These results emphasise the value of MT as a quantifiable muscle US method for evaluating muscle adaptation to exercise training. However, the inconsistency of the EI values indicates that more studies are needed to develop it as an accurate diagnostic tool.
Muscle ultrasound is an ideal imaging modality that allows for noninvasive, radiation-free point-of-care neuromuscular imaging. There are many potential applications of muscle ultrasound, including identification of abnormal muscle movements such as fasciculations, evaluation of muscle trauma, identification of physiologic parameters such as pennation angle, accurate performance of chemodenervation, and improved accuracy of challenging electrodiagnostic studies such as phrenic nerve conduction studies or needle electromyogram (EMG) of the diaphragm. Tissue Doppler imaging can be used to help identify inflammatory myopathies. With computer-assisted quantification, muscle ultrasound has high sensitivity and specificity in the diagnosis of pediatric neuromuscular disease and amyotrophic lateral sclerosis, and is a valuable addition to other diagnostic techniques for neuromuscular disease. When used as a first-line screening tool it can obviate the need for more invasive procedures such as EMG or muscle biopsy in certain patients. This chapter provides an overview of the fundamentals, clinical applications, and validation of muscle ultrasound for patients with neuromuscular disorders.
The myotonic disorders are a heterogeneous group of genetically determined diseases that are unified by the presence of myotonia, which is defined as failure of muscle relaxation after activation. The presentation of these disorders can range from asymptomatic electrical myotonia, as seen in some forms of myotonia congenita (MC), to severe disability with muscle weakness, cardiac conduction defects, and other systemic features as in myotonic dystrophy type I (DM1). In this review, we describe the clinical features and pathophysiology of the different myotonic disorders, their laboratory and electrophysiologic findings and briefly review the currently available treatments.
Introduction:
Skeletal muscle channelopathies are rare disorders of muscle membrane excitability. Their episodic nature may result in diagnostic difficulty and delays in diagnosis. Advances in diagnostic clinical electrophysiology combined with DNA-based diagnosis have improved diagnostic accuracy and efficiency. Ascribing pathogenic status to identified genetic variants in muscle channel genes may be complex and functional analysis, including molecular expression, may help with this. Accurate clinical and genetic diagnosis enables genetic counselling, advice regarding prognosis and aids treatment selection.
Areas covered:
An approach to accurate and efficient diagnosis is outlined. The importance of detailed clinical evaluation including careful history, examination and family history is emphasised. The role of specialised electrodiagnostics combined with DNA testing and molecular expression is considered. New potential biomarkers including muscle MRI using MRC Centre protocols are discussed.
Expert opinion:
A combined diagnostic approach using careful clinical assessment, specialised neurophysiology and DNA testing will now achieve a clear diagnosis in most patients with muscle channelopathies. An accurate diagnosis enables genetic counselling and provides information regarding prognosis and treatment selection. Genetic analysis often identifies new variants of uncertain significance. In this situation, functional expression studies as part of a diagnostic service will enable determination of pathogenic status of novel genetic variants.
Although the diagnostic work-up for myopathies can be difficult, it should be carried out for medical and financial reasons if the suspicion is supported by evidence. The diagnosis is based on the history, neurological investigation, blood chemical investigations at rest and under stress, electromyography, muscle MRI, biopsy, the in-vitro coffeine-halothan contracture test, and molecular genetic studies. There is some role for muscle enzyme determinations in the diagnostic work-up, although these values are frequently multifactorial. However, if muscle enzymes are repeatedly increased without explanation but in the presence of muscular symptoms, the diagnostic work-up should be initiated. Stress tests can be of some additional help. Needle electromyography may be normal, myogenic, neurogenic or non-specifically abnormal. Muscle MRI may show trophic disturbances, and may guide one to the muscle most adequate for biopsy. A muscle biopsy may be taken for a number of further investigations and may lead to the correct diagnosis. Only if there is a profound suspicion for a certain genetic defect, molecular genetic investigations should be initiated. In the case that a pathogenic mutation is found, genetic counselling, and assessment of the prognosis, and therapy can be initiated. For diagnostic, therapeutic and prognostic implications, diagnostic work-up should be carried out as soon as possible if myopathy is suspected.
Chapter 1 gives a general introduction to non-dystrophic myotonic syndromes (NDMs). Chapter 2 comprises a systematic review about drug treatment for myotonia. Three small crossover studies evaluated myotonia in myotonic dystrophy. Unfortunately, for the treatment of myotonia in NDMs we were unable to find valid, separate data. Chapter 3 gives the outline of this thesis. In Chapter 4 we determine the genetic profiles of 54 probands by analysing CLCN1 and SCN4A in tandem. We established CLCN1 mutations in 32 families (59%) and SCN4A mutations in 22 families (41%), reflecting a high-level of mutation ascertainment. In Chapter 5 we describe three NDM patients with a genotype-phenotype mismatch. In Chapter 6 we redefine the non-dystrophic myotonic syndromes. Bedside tests revealed a higher incidence and longer relaxation times of myotonia in the leg muscles for chloride channelopathies and in eyelid muscles for the sodium channelopathies. Multivariate logistic regression analyses allowed us to develop clinical guidelines for genetic testing. In Chapter 7 describes the health-status of patients with a NDM. Sixty-two patients, all off treatment, completed a standardised interview, the Fatigue Assessment Scale, and the 36-item Short-Form health survey. All physically oriented SF-36 domains were substantially lower in both channelopathy groups compared to the Dutch community scores. Fatigue proved to be the strongest predictor of low general-health perceptions, while painful myotonia best predicted low overall physical functioning. In Chapter 8 we systematically analyse the changes in and thickness of four limb muscles from genetically confirmed NDM patients by ultrasound. The results showed elevated echo intensities in all muscles except the rectus femoris, and hypertrophy in the arm muscles. In correlation with functional measurements these readings suggest structural muscle changes in NDMs. If muscle biopsies will also show structural changes, the designation non-dystrophic myotonic syndromes would be open to debate.
Introduction:
We studied ultrasound features of muscle after nerve injury.
Methods:
We evaluated ultrasound measurements of muscle thickness and backscatter in injured and contralateral uninjured elbow flexors of 51 children with newborn brachial plexus palsy (NBPP) and compared the results to elbow flexor function (Active Movement Scale), defined as normal, moderate, or severe.
Results:
Compared with uninjured limbs, muscle in injured arms was 15% thinner with severe impairment, 17% thicker with moderate impairment, and no different with normal function. Relative to uninjured limbs, moderately impaired muscle was thicker than both severely impaired and normal strength muscle. Backscatter was higher in injured than in uninjured limbs regardless of function. In 17 patients with sequential measures, muscle thickness, but not backscatter, increased with function over time.
Conclusions:
Muscle thickness differentiates moderate from severe impairment after NBPP and increases with recovery over time. Muscle backscatter identifies prior injury regardless of function.
The aim is to review the recent findings in relation to the genetics, pathophysiology, clinical phenotypes, investigation and treatment of the nondystrophic myotonias (NDMs) and periodic paralyses.
The number of pathogenic mutations causing NDMs and periodic paralyses in known genes continues to expand. In addition, a mutation has been identified in the ryanodine receptor gene manifesting as an atypical periodic paralysis phenotype. Another recent study indicated that thyrotoxic hypokalaemic periodic paralysis is determined by mutations in a novel gene encoding an inwardly rectifying potassium channel, Kir2.6. Work studying molecular mechanisms indicates that 90% of the known mutations causing hypokalaemic periodic paralysis (HypoPP) result in loss of positively charged arginine residues in the S4 segments of either SCN4A or CACNA1S, possibly creating a gating-pore current that may be important in the pathogenesis of HypoPP. Recent studies evaluating clinical features and health status in NDM patients have provided more detailed insights into the significant morbidity associated with these diseases. Ultrasound has been successfully used to demonstrate muscle abnormalities in NDM patients and magnetic resonance spectroscopy studies applied to HypoPP patients suggest that this technique can demonstrate both disease-related and treatment-related changes.
Recent discoveries in the skeletal muscle channelopathies have increased our understanding of the genetics and pathophysiology of these diseases. Studies reporting imaging techniques raise the possibility of improved disease monitoring and better outcome measures for clinical trials. Randomized controlled trials to establish an evidence base upon which to recommend standard treatments are required.
To redefine phenotypical characteristics for both chloride (ClCh) and sodium channelopathies (NaCh) in non-dystrophic myotonic syndromes (NDM).
In a cross-sectional, nationwide study, standardised interviews and clinical bedside tests were performed in 62 genetically confirmed NDM patients, 32 ClCh and 30 NaCh.
Standardised interviews revealed that ClCh reported a higher frequency of muscle weakness (75 vs 36.7%; p<0.01), the warm-up phenomenon (100 vs 46.7%; p<0.001), and difficulties in standing up quickly (90.6 vs 50.0%; p<0.001), running (90.6% vs 66.7; p<0.05) and climbing stairs (90.6 vs 63.3%; p = 0.01). Patients with NaCh reported an earlier onset (4.4 vs 9.6 years; p<0.001), and higher frequencies of paradoxical (50.0 vs 0%; p<0.001) and painful myotonia (56.7 vs 28.1%; p<0.05). Standardised clinical bedside tests showed a higher incidence and longer relaxation times of myotonia in the leg muscles for ClCh (100 vs 60%; mean duration of chair tests 12.5 vs 6.3 s; p<0.001), and in eyelid muscles for NaCh (96.7 vs 46.9%; mean relaxation time of 19.2 vs 4.3 s; p<0.001). Transient paresis was only observed in ClCh (62.5%) and paradoxical myotonia only in NaCh (30.0%). Multivariate logistic regression analyses allowed clinical guidelines to be proposed for genetic testing.
This study redefined the phenotypical characteristics of NDM in both ClCh and NaCh. The clinical guidelines proposed may help clinicians working in outpatient clinics to perform a focused genetic analysis of either CLCN1 or SCN4A.
Hereditary muscle channelopathies are caused by dominant mutations in the genes encoding for subunits of muscle voltage-gated ion channels. Point mutations on the human skeletal muscle Na+ channel (Nav1.4) give rise to hyperkalemic periodic paralysis, potassium aggravated myotonia, paramyotonia congenita and hypokalemic periodic paralysis type 2. Point mutations on the human skeletal muscle Ca2+ channel give rise to hypokalemic periodic paralysis and malignant hyperthermia. Point mutations in the human skeletal chloride channel CIC-1 give rise to myotonia congenita. Point mutations in the inwardly rectifying K+ channel Kir2.1 give rise to a syndrome characterized by periodic paralysis, severe cardiac arrhythmias and skeletal alterations (Andersen's syndrome). Involvement of the same ion channel can thus give rise to different phenotypes. In addition, the same mutation can lead to different phenotypes or similar phenotypes can be caused by different mutations on the same or on different channel subtypes. Bearing in mind, the complexity of this field, the growing number of potential channelopathies (such as the myotonic dystrophies), and the time and cost of the genetic procedures, before a biomolecular approach is addressed, it is mandatory to apply strict diagnostic protocols to screen the patients. In this study we propose a protocol to be applied in the diagnosis of the hereditary muscle channelopathies and we demonstrate that muscle biopsy studies and muscle cell cultures may significantly contribute towards the correct diagnosis of the channel involved. DNA-based diagnosis is now a reality for many of the channelopathies. This has obvious genetic counselling, prognostic and therapeutic implications.
The measurement of human muscle size is essential when assessing the effects of training, disuse and ageing. The considered 'gold standard' for cross-sectional area measurements of muscle size is magnetic resonance imaging (MRI). However, MRI is costly and often inaccessible. The aim of the present study was to test the reproducibility and validity of a more accessible alternative method using ultrasonography (ULT). We examined the cross-sectional areas in the vastus lateralis muscle of six individuals. Axial-plane ULT scans were taken at given levels along the entire muscle length. The ULT scanning was repeated on different days (reliability) and validated against MRI-based measurements. Mean intraclass correlation coefficients were 0.998 for the reliability of ULT and 0.999 for the validity of ULT against MRI. The coefficient of variation values for cross-sectional area measurements assessed by six different experimenters were 2.1% and 0.8% for images obtained with ULT and MRI, respectively. The ULT method is a valid and reliable alternative tool for assessing cross-sectional areas of large individual human muscles. The present findings justify the application of the ULT method for the detection of changes throughout large muscles in response to training, disuse or as a consequence of sarcopenia.
In this report we present three patients who had complaints primarily related to joints and flexibility. Two had no specific diagnosis and one was thought to have ankylosing spondylitis. Extensive evaluation revealed Emery-Dreifuss muscular dystrophy (EDMD) in all. EDMD is a muscular dystrophy where joint contractures and spinal limitation occur before any overt muscle weakness, and the syndrome may be combined with serious cardiac pathology. We wish to call the attention of professionals involved in rheumatology and physical medicine to the existence of this syndrome, which may only present with joint contractures and spinal limitation but which may end with fatal cardiac problems if not diagnosed in time.
To prospectively examine whether sodium 23 (23Na) magnetic resonance (MR) imaging can be used to visualize acute intracellular Na+ accumulation and the effects of specific therapy in patients with paramyotonia congenita (PC).
Ethics committee approval and informed consent were obtained. Sixteen patients (four women, 12 men; mean age, 46.7 years +/- 16.7 [standard deviation]) with confirmed PC and 10 healthy volunteers (three women, seven men; mean age, 26.6 years +/- 3) were examined by using a 1.5-T MR system with a 16.8-MHz surface coil. 23Na MR imaging was performed before and after local cooling of the nondominant lower leg and exercising, with experimentally induced weakness scored by a neurologist. The 23Na MR examination was repeated in 13 patients and all volunteers after 3 days and, additionally, in seven patients after 4 days of oral administration of mexiletine, which blocks Na+ channels. The 23Na MR protocol comprised two-dimensional (2D) fast low-angle shot (FLASH), 2D radial, and free induction decay (FID) sequences. The FID data were fitted to a biexponential decay curve to evaluate the slow and fast components of the T2 relaxation time. Fast and slow components were assigned to intra- and extracellular Na+ concentrations, respectively. Radial and FLASH MR images were evaluated by means of a region-of-interest analysis by using 0.3% saline solution for reference. T1- and T2-weighted MR imaging were also performed. Data were analyzed by using a parametric t test.
After exercising, all patients developed considerable weakness exclusively in the cooled lower leg; no weakness was observed in volunteers. In patients, all 23Na MR images showed a significant increase in 23Na signal intensity in the cooled lower leg (P < .001) in comparison with nonsignificant findings in volunteers. After treatment with mexiletine, cooling and exercise induced almost no muscle weakness and no changes in 23Na MR signal intensity in patients.
23Na MR imaging enables visualization of muscular Na+ accumulation associated with muscle weakness in patients with PC, and effects of specific therapy can be detected.
Non-dystrophic myotonias (NDMs) are caused by mutations in CLCN1 or SCN4A. The purpose of the present study was to optimize the genetic characterization of NDM in The Netherlands by analysing CLCN1 and SCN4A in tandem. All Dutch consultant neurologists and the Dutch Patient Association for Neuromuscular Diseases (Vereniging Spierziekten Nederland) were requested to refer patients with an initial diagnosis of NDM for clinical assessment and subsequent genetic analysis over a full year. Based on clinical criteria, sequencing of either CLCN1 or SCN4A was performed. When previously described mutations or novel mutations were identified in the first gene under study, the second gene was not sequenced. If no mutations were detected in the first gene, the second gene was subsequently also analysed. Underlying NDM mutations were explored in 54 families. In total, 20% (8 of 40) of our probands with suspected chloride channel myotonia showed no CLCN1 mutations but subsequent SCN4A screening revealed mutations in all of them. All 14 probands in whom SCN4A was primarily sequenced showed a mutation. In total, CLCN1 mutations were identified in 32 families (59%) and SCN4A in 22 (41%), resulting in a diagnostic yield of 100%. The yield of mutation detection was 93% with three recessive and three sporadic cases not yielding a second mutation. Among these mutations, 13 in CLCN1 and 3 in SCN4A were novel. In conclusion, the current results show that in tandem analysis of CLCN1 and SCN4A affords high-level mutation ascertainment in families with NDM.
An 20 Patienten mit einer Myotonia congenita wurden die elektrischen und mechanischen Phänomene der Myotonie untersucht. Zuerst wurden die Parameter der myotonen Entladungssalven bestimmt, dann die EMG-Aktivität bei mäßiger und maximaler Willkürinnervation beurteilt und schließlich die Elektromyogramme und Mechanogramme nach indirekter Muskelreizung simultan aufgezeichnet. Die Ergebnisse machten deutlich, daß zwischen der myotonen Faseraktivität und den EMG- und Mechanogrammbefunden Zusammenhänge bestehen, die von den Untersuchungsbedingungen, d.h. von der Reizfrequenz bzw. der Kontraktionsstärke, abhängen. Bei der Einzelreizung unterschieden sich die Muskelkenngrößen zwischen Patienten und Gesunden nicht. Tetanische Reizserien (15 Hz) führten bei den Myotoniepatienten zu einem Amplitudenabfall im EMG, der einsetzte, sobald myotone Schauer auftraten; im Mechanogramm imponierte ein verzögerter Kontraktionsablauf, der sowohl die Kontraktionsphase als auch die Erschlaffungsphase betraf. Bei Erhöhung der Reizfrequenz (30 Hz) nahmen der Amplitudenabfall zu, die Kontraktions- und Erschlaffungszeiten dagegen ab. Die Befunde werden anhand tierexperimenteller Versuchsergebnisse interpretiert und in Zusammenhang mit der Chloridhypothese diskutiert.
ABSTRACT – In 12 patients with paramyotonia congenita, percutaneous needle biopsies from the brachial biceps muscle were performed. Muscle fibre area, distribution of muscle fibre types I, II-A and II-B and capillarization were not different from healthy controls. Signs of myopathy with central nuclei in the muscle cells were noted in 9 of the patients. 4 of these patients also had small areas with degeneration and, in one, vacuoles were observed. Quantitative determination of muscle glycogen, water and protein content were within normal range as were enzyme activities for hexokinase, lactate dehydrogenase, citrate synthetase and 3-hydroxy-acyl-CoA dehydrogenase.
In this study, we examined the correlation between muscle ultrasound and muscle structure. Echo intensity (EI) of 14 muscles of two golden retriever muscular dystrophy dogs was correlated to the percentage interstitial fibrous tissue and fat in muscle biopsy. A significant correlation between interstitial fibrous tissue and EI was found (r = 0.87; p < 0.001). The separate influence of interstitial fat on muscle EI could not be established as only little fat was present. We conclude that fibrous tissue causes increased muscle EI. The high correlation between interstitial fibrous tissue and EI makes ultrasound a reliable method to determine severity of structural muscle changes. (E-mail: [email protected]
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We have investigated the muscle biopsies of 8 patients with myotonia congenita. There were 2 families with autosomal recessive inheritance (5 cases), 1 with autosomal dominant inheritance, and 2 sporadic cases. Mild abnormalities were seen with routine pathological preparations which were nondiagnostic. Histochemical studies of fiber subtypes demonstrated a complete absence of Type 2B muscle fibers in all of our patients regardless of the type of inheritance. this is the first reporot of an entity in which there is a consistent absence of a muscle fiber type, and some speculation has been made as to the possible causes.
In thirteen major muscle groups of 50 healthy females and 50 males, aged 20-60 years, maximum voluntary contraction was measured with a hand-held dynamometer. The intrasession variation, the left-right variation, and the fifth and fiftieth centile values were calculated. The ratio of two observations within one session ranged from 0.85 to 1.18 and the ratio of left to right ranged from 0.82 to 1.22 (95% reference limits). In 20 volunteers the repeatability was tested after one week. The ratio of averages of three measurements in two successive weeks ranged from 0.82 to 1.23 (95% reference limits). There were only small differences between muscle groups concerning these ratios. A significant relation with age and weight/Quetelet Index could be demonstrated in some muscle groups. The mean strength of females is approximately two thirds of the strength of males. The data may be useful as reference values in the application of hand-held myometry.
Guided by ultrasonography percutaneous needle biopsy of skeletal muscle was performed in 24 patients, using the one hand held Biopty system and a 2 mm Tru-Cut needle. The specimens were graded with regard to diagnostic quality and utility and almost all specimens (96%) were of highest quality. The use of ultrasonography was helpful in selecting a suitable area for the biopsy and vascular structures could be avoided. The procedure was well tolerated and easy to perform, and no complications were recorded.
A progressive degenerative myopathy has been well described in hypokalemic periodic paralysis but is not as widely recognized in hyperkalemic periodic paralysis. We studied four families with the latter disease in which some members developed a progressive myopathy. Episodes of paralysis were prolonged, lasting for months in some cases, and in one case paralysis was sufficiently severe to require ventilatory support. The progressive myopathy tended to develop at a time when attacks of paralysis were decreasing in frequency. Muscle biopsy specimens showed variability in fiber size, internal nuclei, and fibers with vacuoles. Electron microscopy showed myofibrillary degeneration and tubular aggregates. An abnormal biopsy specimen was more common in older patients. Our experience suggests that a progressive myopathy is as common in hyperkalemic periodic paralysis as it is in the hypokalemic disorder.
The histochemical ATPase fibre type pattern was examined in muscle biopsy samples obtained from patients with recessive myotonia, paramyotonia and from one patient with dominant myotonia. Absence (less than or equal to 5%) of 2B fibres was a genuine finding in the minority of the cases. In additional cases of recessive myotonia, a deficiency (less than or equal to 15%) of 2B fibres was observed. Absence or deficiency of 2B fibres was not related to the minor myopathic alterations or to (para-)myotonic activity. It is hypothesised that absence of 2B fibres is a dominant or a recessive autosomal trait, and deficiency of 2B fibres is a recessive trait. Reported findings and our own observations suggest the possibility of a genetic combination of myotonia and absence/deficiency of 2B fibres. Implications of these hypotheses are proposed.
A reproducible ultrasound imaging technique is described for measurement of midthigh muscle and subcutaneous tissue thickness. We studied 276 children including those attending hospital outpatient clinics with non-neurological disorders, newborn babies on the obstetric wards, and children attending a local primary school. There was no significant difference in muscle depth between girls and boys, but girls had a significantly greater subcutaneous tissue depth than boys. The results of this study provide a basis for the study of muscle atrophy and hypertrophy in neuromuscular disease.
Ultrasound imaging of the thigh in a 6-year-old girl with limb girdle muscular dystrophy showed striking focal involvement of the vastus intermedius and vastus lateralis muscles, with sparing and hypertrophy of the rectus femoris muscle. This was confirmed on needle muscle biopsy, using the Bergstrom needle, which showed normal histology in the rectus femoris and severe dystrophic change in the vastus intermedius. In neuromuscular disease, it is important to be aware of the possibility of focal muscle involvement, which can be screened for by ultrasound imaging and more effectively investigated by needle than by open muscle biopsy.
A comparative study of the ultrasound appearances of the thigh with the static B scan showed consistent differences in 10 children with muscular dystrophy compared with 40 healthy controls. This non-invasive technique could be useful in assessing the extent of pathological change in dystrophic patients and could prove a valuable diagnostic aid.
Electrical and mechanical investigations in myotonia were investigated in 20 patients with myotonia congenita. At first the parameters of the myotonic muscle fiber discharges were determined, than the EMG-activity was estimated during slight and maximal force of voluntary muscle contraction and finally the electromyogram and the mechanogram were simultaneously registered after indirect stimulation of the muscle. The results show, that there is a correlation between the myotonic muscle fiber discharges and the EMG- and mechanical findings depending on the frequency of stimulation and the force of contraction. The parameters of muscles did not differ between the patients and the health persons after single stimulation. Repetitive supramaximal stimuli (15 Hz) showed a rapid decline of EMG-amplitude in the patients with myotonia congenita. The fall of amplitude was observed, as soon as myotonia fiber discharges occured. The duration of contraction was longer both in the phase of contraction and in the phase of relaxation. When the frequency of stimulation was increased (30 Hz), the fall of EMG-amplitude was more increased whereas the contraction and relaxation time decreased. The findings are interpreted by means of the author's own experimental results and are discussed in connection with the chloride-hypothesis.
A comparative study has been done of the static B-scan ultrasound appearance of the quadriceps muscle of the thigh in 60 new patients attending our muscle clinic and in 60 control children. In the control subjects there was good visualization of bone and fascia, which stood out clearly against the background of echo-free muscle tissue. Striking change was found in children with neuromuscular disease. Muscular dystrophies were associated with an increase in the intensity of echo reflected from the muscle substance, with corresponding loss of bone echo. Spinal muscular atrophies and neuropathies also showed an increase in muscle echo along with atrophy of the muscle and increase in depth of subcutaneous tissue. Various congenital myopathies also showed changes. Infants with hypotonia from nonneuromuscular causes had normal scans. Severity of change on the scan did not relate to functional disability, and some children had good function yet strikingly abnormal scans. Three degree of change on the scan correlated with the degree of disruption of muscle architecture on biopsy. Ultrasound imaging has proved to be a useful, noninvasive screening tool in the investigation of children with neuromuscular disease.
Clinical and electrophysiological data have outlined a spectrum of similar yet distinct periodic paralyses, including potassium-sensitive (hyperkalemic periodic paralysis [HYPP]) and temperature-sensitive (paramyotonia congenita [PC]) forms. Recent work has revealed that these disorders result from allelic defects in the alpha-subunit of the adult, human skeletal muscle sodium channel. We report an additional mutation, a leucine-->arginine substitution in the S3 segment of domain 4 (L1433R), that results in the PC phenotype. Five other HYPP and PC families have been ascertained, and previously reported sodium channel mutations have been identified in each. Characterization of these mutations and phenotypic variations in such families will contribute to the understanding of sodium channel structure and function relationships, as well as channel malfunction in the periodic paralyses.
In skeletal muscle sonography high echogenicities have proved to be of diagnostic value. The following study examines whether these echointensities are caused mainly by interstitial fat or fibrosis. Consequently, the echogenicities of 86 muscles, their diameters, and the thickness of subcutaneous fat layers superficial to these muscles were measured and compared for content of fat and connective tissue, which were assessed by morphometry and biochemical testing in the corresponding muscle biopsy samples. The results indicate that fat replacement constitutes the main cause of increased muscle echogenicity, whereas intramuscular fibrosis did not significantly affect the muscles' echogenicity.
To evaluate the value of myosonography in inflammatory myopathies ultrasound of skeletal muscles was performed in 70 patients, aged 21-82 years, suffering from histologically proven polymyositis (n = 30), dermatomyositis (n = 18), granulomatous myositis (n = 9), inclusion body myositis (n = 13), and in 102 control persons. The sensitivity of muscle ultrasound in detecting histopathologically proven disease (82.9%) was not significantly different from electromyography (92.4%) or serum creatine kinase activity (68.7%). The positive predictive value of ultrasound was 95.1%, the negative predictive value 89.2%, and the accuracy 91.3%. The different types of inflammatory myopathies presented with typical, but not specific ultrasound features. Polymyositis showed atrophy and increased echointensity predominantly of lower extremity muscles, whereas in dermatomyositis clear muscle atrophy was rare and echointensities were highest in forearm muscles. Echointensities were lower in dermatomyositis compared to poly- and granulomatous myositis. Granulomatous myositis was characterized by the highest echointensities and a tendency towards muscle hypertrophy. Severe muscle atrophy was the most impressive feature in the majority of patients with inclusion body myositis. Comparison of ultrasound and histopathological findings indicates that muscle lipomatosis has a much greater impact on muscular echointensity than does muscle fibrosis. Ultrasound of myositis improved clinical assessment of patients by supplying differential diagnostic clues based on precise muscle size measurements and identification of mesenchymal abnormalities, particularly muscle lipomatosis.
The hereditary disorders of muscle excitability are now recognized to be caused by defects in the genes encoding muscle ion channels. This led to a new classification of this disease group. The pathophysiology of these disorders has been elucidated on the molecular level to an extent that exceeds the understanding of the disease mechanisms of most other neuromuscular diseases. The seemingly minor variants of the symptom of myotonia were found to be caused by the remarkable difference that either chloride or sodium channel function is impaired. Even more surprising, the basic defects for hyper- and hypokalemic periodic paralysis, often clinically very difficult to distinguish, turned out to be in the sodium and calcium channels, respectively; these channels are considered to have very different functions in muscle physiology. Three new types of myotonic disease, that is, myotonia, fluctuans, myotonia permanens and proximal myotonic myopathy were discovered. An explanation has been provided as to why myotonia congenita may be transmitted as a dominant or recessive trait.
Sodium channel disorders include hyperkalemic periodic paralysis (hyperPP), paramyotonia congenita (PC) and potassium-aggravated myotonia (PAM). PC is a myotonic syndrome characterized by cold-induced muscle stiffness and weakness. In this paper, we report two families. The first is affected by PC with cold-induced stiffness and no weakness, in addition to hyperPP. This family displays the Arg1448Cys mutation in the sodium channel gene originally described in pure PC families. The fact that families with the same mutation present distinct phenotypes indicates that other factors, genetic or environmental, may modulate the expression of the disease in sodium channel disorders. The second family was unusual because patients presented cold-induced weakness without stiffness. A mutation was found in the sodium channel gene that changed an isoleucine into a threonine at position 693. These two families demonstrate that sodium channel mutations may cause either cold-induced stiffness or weakness.
Calf hypertrophy is a typical clinical feature in neuromuscular diseases such as X-linked muscular dystrophies of Duchenne and Becker type and can be seen as an atypical feature in numerous other diseases. The diagnosis of calf hypertrophy usually is based on subjective visual assessment. The aim of this prospective study was to examine the prevalence of calf hypertrophy in a large number of patients with various neuromuscular diseases based on quantitative ultrasound measurement of calf muscle thickness. Additionally, true and pseudohypertrophy should be distinguished according to the absence or presence of abnormal muscle echointensities caused by infiltration of fat tissue. Fifty adult normal controls and 350 patients with various neuromuscular diseases were investigated. Absolute calf hypertrophy was diagnosed if the combined thickness of the gastrocnemius and soleus muscles exceeded the mean value of the control persons by at least 3.0 standard deviations (SD). Relative calf hypertrophy was diagnosed when the ratio of the combined thicknesses of the gastrocnemius and soleus muscles divided by the combined thicknesses of the rectus femoris and vastus intermedius muscles lay at least 3.0 SD below the mean value of the controls. Pseudohypertrophy was present if the echointensities of the gastrocnemius and soleus muscles reached or exceeded 3.0 SD above the mean value of the controls. An absolute hypertrophy of the calves was detected in 80 patients (= 22,9%; 64 true and 16 pseudohypertrophies), 16 patients exhibited a relative hypertrophy of the calves (= 4.6%; 12 true and 4 pseudohypertrophies). A significantly increased portion of both absolute calf hypertrophies and pseudohypertrophies as compared to the control group were found in juvenile proximal spinal muscular atrophy type 3, central core disease, centronuclear myopathy, benign X-linked muscular dystrophy of Becker type, autosomal recessive limb girdle muscular dystrophy, acid maltase deficiency, polymyositis, and granulomatous myositis. A significantly increased number of relative calf hypertrophies was present in juvenile proximal spinal muscular atrophy type 3, facioscapulohumeral muscular dystrophy, and inclusion body myositis. In the majority of the diseases included in the study, calf hypertrophy occurred in at least some patients. In conclusion, calf hypertrophy is a frequent and unspecific clinical feature in many neuromuscular diseases. Ultrasound is a convenient method for the exact definition of calf hypertrophy.
In adults, the volume of quadriceps femoris muscle decreases with age, whereas the impact of increasing age on the size of other extremity muscles was hardly studied. This study was conducted to examine whether age-related muscle atrophy is a general phenomenon, whether it is accompanied by increasing subcutaneous fat and whether physical activity can compensate age-related muscle atrophy. One hundred and two female and 101 male subjects (aged 19-86 years), with common physical activity, as well as 29 women and 38 men (aged 20-81 years) regularly performing sports at least 3 h per week for several years (mean, 10 years in women and 14 years in men, respectively), were examined. Both in athletes and control subjects, the thickness of thigh muscles significantly decreased with age (-15(-)-21% from age 20 to age 70), whereas diameter of upper arm muscles remained nearly unchanged. Diameters of the calf muscle decreased with advancing age only in the control group. In male control subjects, the tibialis anterior muscle shrunk as well. Except for the vastus lateralis muscle in women, the relative loss of muscle thickness was more evident in control subjects than in athletes. Thickness of the subcutaneous fat layers remained almost unchanged. In summary, not all extremity muscles exhibit age-related decrease in size. Regular physical activity can ease off muscle atrophy.
Contractures are exceedingly common impairments in selected progressive NMD conditions, particularly those with excessive fibrosis and fatty infiltration into muscle (i.e., dystrophic myopathies) and more severe NMD conditions, resulting in significant weakness and wheel-chair reliance, such as SMA. Less than antigravity strength produces an inability to achieve full active range of motion. Static positioning of limbs (generally in flexion) and lack of weight bearing results in fixed contractures. This article has reviewed the prevalence and distribution of contractures in specific NMD conditions. Aggressive rehabilitation strategies, including stretching, positioning, splinting, upright weight bearing, and orthopaedic surgical management may help minimize the degree of disability in NMD patients with contractures.
Since muscle force and functional ability are not related linearly; maximum force can be reduced while functional ability is still maintained. For diagnostic and therapeutic reasons loss of muscle force should be detected as early and accurately as possible. Because of growth factors, maximum muscle force in children varies with age, which makes detection of force loss difficult. The purpose of this study was to establish reference values for muscle force in children aged 4-16 years, obtained by hand-held dynamometry in 11 muscle groups. In boys muscle force was predicted best by weight whereas in girls weight and age were best predictors. At age 14 boys become significantly stronger for nearly all tested muscle groups. These age-related reference values can be used to quantify muscle weakness in individual muscle groups in children aged 4-16 years and to evaluate the effects of therapy.
Pure non-syndromic, non-dystrophic myotonia in humans is caused by mutations in the genes coding for the skeletal muscle sodium channel (SCN5A) or the skeletal muscle chloride channel (CLCN1) with similar phenotypes. Chloride-channel myotonia can be dominant (Thomsen-type myotonia) or recessive (Becker-type myotonia). More than 60 myotonia-causing mutations in the CLCN1 gene have been identified, with only a few of them being dominant. A common phenotype of dominant mutations is a dominant negative effect of mutant subunits in mutant-WT heterodimers, causing a large shift of the steady-state open probability voltage-dependence towards more positive, unphysiological voltages. The study of the properties of disease causing mutations has helped in understanding the functional properties of the CLC-1 channel that is part of a nine-member gene family of chloride channels. The large body of knowledge obtained for CLC-1 may also help to better understand the other CLC channels, three of which are also involved in genetic diseases.
Ullrich congenital muscular dystrophy (UCMD) is a form of merosin-positive congenital muscular dystrophy characterized by proximal contractures, distal laxity, rigidity of the spine, and respiratory complications. Recently, a deficiency of collagen VI on muscle and skin biopsy together with recessive mutations in the collagen 6A2 gene were reported in three families with UCMD. However, the clinical spectrum, frequency, and level of heterogeneity of this disorder are not known. Subjects and Methods: The authors studied 15 patients (aged 3 to 23.6 years) with a clinical diagnosis of UCMD. Linkage analysis to the three collagen VI genes was performed in all informative families (n = 7), whereas immunohistochemical analysis of collagen VI expression in muscle was performed in the remaining cases.
An immunocytochemical reduction of collagen VI was observed in six patients. Three of the six patients belonged to informative families, and haplotype analysis clearly suggested linkage to the COL6A1/2 locus in two cases and to the COL6A3 loci in the third case. In the remaining nine patients, primary collagen VI involvement was excluded based on either the linkage analysis (four families) or considered unlikely based on normal immunolabeling of collagen VI. Age and presentation at onset, the distribution and severity of weakness and contractures, and the frequency of nonambulant patients were similar in the patients with and without collagen VI involvement. Distal laxity, rigidity of the spine, scoliosis, failure to thrive, and early and severe respiratory impairment were found in all patients by the end of the first decade of life, irrespective of their maximum motor functional ability or their collagen status.
These results suggest that collagen VI involvement is relatively common in UCMD (40%); however, the role of this molecule was excluded in a number of cases, suggesting genetic heterogeneity of this condition.
In this study, 145 healthy adults (20 to 94 years old, 69 women) were examined using ultrasound (US) imaging to obtain reference values of muscle parameters that were previously not available. We measured biceps and quadriceps sizes and subcutaneous fat thickness. To quantify muscle aspect, we defined and calculated the muscle aspect parameters muscle density, inhomogeneity and white-area index by digital image analysis. All muscle aspect parameters were found to increase with age, which may be due to age-related muscle replacement by fatty tissue and collagen. Other age-, weight- and gender-dependencies are also discussed. The complete set of muscle parameters was used to differentiate between typical myopathies and neuropathies in a group of 32 patients (24 to 79 years old, 18 women). We were successful in almost completely separating the two types of disorders based on abnormality of muscle aspect parameters alone. These preliminary results show that this set of normal muscle parameters can be used to help diagnose neuromuscular disorders. It will also facilitate follow-up in disease progression and therapy.
We determined prospectively the diagnostic value of quantitative ultrasonography in detecting neuromuscular disorders in children. Ultrasonographic scans of four muscles were made in 36 children with symptoms or signs suggestive of neuromuscular disease, such as muscle weakness and hypotonia. The muscle thickness, ratio of muscle thickness to subcutaneous fat thickness, and echo intensity were determined in each muscle. The echo intensity was measured using computer-assisted gray-scale analysis. Thirteen of the 36 patients had a neuromuscular disorder (6 a myopathy and 7 a neuropathy). Differentiation between neuromuscular diseases and nonneuromuscular diseases could be made on the basis of echo intensities with a sensitivity of 92%, a specificity of 90%, a positive predictive value of 86%, and a negative predictive value of 95%. We conclude that computer-assisted quantitative analysis of muscle echo intensity is a reliable method to discriminate between neuromuscular and nonneuromuscular diseases in children.
The purpose of this study was to establish normal values of muscle thickness, ratio of muscle thickness to subcutaneous fat thickness, and muscle echo intensity in children between 11 weeks and 16 years of age. Transverse scans of four muscles were made by standardized real-time ultrasound examination. The scans were digitized, and mean echo intensity was measured using gray-scale analysis. A multiple regression equation was used to study which independent parameter (age, height, weight, or sex) influenced the variables for each muscle. Muscle thickness depended on the child's weight. The other parameters did not significantly influence muscle thickness after correction for weight. The ratio of muscle thickness to subcutaneous fat thickness depended on age. Echo intensity showed no correlation with either of the variables. As a result, all normal values, including the equation to calculate them, are described. These normal data may help to determine the diagnostic value of muscle ultrasound in children with suspected neuromuscular disease.
Mutations in CLCN1, the gene encoding the ClC-1 chloride channel in skeletal muscle, lead to myotonia congenita. The effects on the intramembranous channel forming domains have been investigated more than that at the intracellular C-terminus. We have performed a mutation screen involving the whole CLCN1 gene of patients with myotonia congenita by polymerase chain reaction (PCR), single-strand conformation polymorphism studies, and sequencing. Two unrelated patients harbored the same homozygous G-to-T mutation on the donor splice site of intron 17. This led to the skipping of exon 17, as evidenced by the reverse transcriptase PCR. When the exon 17-deleted CLCN1 was expressed in Xenopus oocytes, no chloride current was measurable. This function could be restored by coexpression with the wild-type channel. Our data suggest an important role of this C-terminal region and that exon 17 skipping resulting from a homozygous point mutation in CLCN1 can lead to recessive myotonia congenita.
Myotonia congenita is a hereditary chloride channel disorder characterized by delayed relaxation of skeletal muscle (myotonia). It is caused by mutations in the skeletal muscle chloride channel gene CLCN1 on chromosome 7. The phenotypic spectrum of myotonia congenita ranges from mild myotonia disclosed only by clinical examination to severe and disabling myotonia with transient weakness and myopathy. The most severe phenotypes are seen in patients with two mutated alleles. Heterozygotes are often asymptomatic but for some mutations heterozygosity is sufficient to cause pronounced myotonia, although without weakness and myopathy. Thus, the phenotype depends on the mutation type to some extent, but this does not explain the fact that severity varies greatly between heterozygous family members and may even vary with time in the individual patient. In this review, existing knowledge about phenotypic variability is summarized, and the possible contributing factors are discussed.
Joint contractures are the second major impairment affecting the locomotor system of children with Duchenne muscular dystrophy (DMD). While the negative influence of joint contractures has been documented, the passive moments produced by joint contractures could benefit the gait of patients with muscle weakness. We describe a biomechanical model that quantifies the mechanical contribution of ankle and hip flexion contractures to the gait of DMD children. Kinematic and kinetic parameters were measured under the same experimental conditions during the gait and passive resistance assessment of two subjects: one healthy child as a control, and one child with DMD. The child with DMD had a plantar flexion contracture and a greater ankle stiffness coefficient than the control child. During gait, the contribution of the ankle passive moment to the net moment was more important for the child with DMD than for the control child. At the hip, passive joint moments and passive moment contribution were more important for the control child but this was not related to the presence of hip flexion contracture. These preliminary results suggest the model might be used to evaluate contractures effect on a larger cohort of subjects.
Muscle sodium-channel disorders cover a spectrum of rare myotonic diseases. In a German family with 17 affected individuals in four generations, we identified a heterozygous missense mutation in exon 24 A1481D (c.4442 C>A) of the voltage-gated sodium channel gene (SCN4A) alpha subunit. Phenotypes of 12 family members were characterized by a mild myotonia with cold sensitivity but without paramyotonia. The index patient presented with fluctuating cold- and exercise-induced stiffness of ocular, facial, and distal muscles. The myotonia became more severe at the age of 22 years. His father had had cold- and exercise-induced periodic weakness with fluctuating myotonia since age 10. Later he developed a more severe, purely exercise- and cold-aggravated myotonia of arms, hands, and facial muscles. The father's mother presented with cold-induced myotonia until age 65, when progressive weakness of proximal limb muscles developed. Her muscle biopsies revealed considerable myopathic changes with a variety of fine structural alterations. This study presents a family with cold-aggravated myotonia and progression of myopathic changes in the muscle biopsy with increasing age. In older patients, sodium channelopathies may mimic the phenotypic features of myotonic dystrophy type 2.
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In this study we investigated the diagnostic value of quantitative skeletal muscle ultrasonography in 150 consecutively referred children with symptoms suspect for a neuromuscular disorder. Muscle thickness and quantitatively determined echo intensity of four muscles and the distribution of these variables within the body were examined.
Results:
Patients with and without a neuromuscular disorder could be discriminated with a positive predictive value of 91% and a negative predictive value of 86%. Patients with a neurogenic disorder could be distinguished from myopathies and non-neuromuscular disorders with a positive predictive value of 86% and a negative predictive of 84%, using the pattern of distribution of pathology within the body.
Conclusions:
Skeletal muscle ultrasound is a good, practical and non-invasive aid in the diagnosis of neuromuscular disorders in children, that is able to discriminate between children with and without a neuromuscular disorder and between neurogenic disorders and myopathies with high predictive values.
In this study, we examined whether quantitative muscle ultrasonography can detect structural muscle changes in early-stage amyotrophic lateral sclerosis (ALS). Bilateral transverse scans were made of five muscles or muscle groups (sternocleidomastoid, biceps brachii/brachialis, forearm flexor group, quadriceps femoris and anterior tibialis muscles) in 48 patients with ALS. Twenty-five patients were also screened for fasciculations. Quantitative analysis revealed a significant increase in echo intensity in all muscles and a decrease in muscle thickness of the biceps brachii, forearm flexors and quadriceps femoris on both sides. Fasciculations were easy to detect in multiple muscles of all screened patients except one. We conclude that quantitative ultrasonography can be used to detect muscle changes caused by ALS in an early phase of the disease. (E-mail: [email protected]
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Muscle ultrasound is a useful tool in the diagnosis of neuromuscular disorders, as these disorders result in muscle atrophy and intramuscular fibrosis and fatty infiltration, which can be visualized with ultrasound. Several prospective studies have reported high sensitivities and specificities in the detection of neuromuscular disorders. Although not investigated in large series of patients, different neuromuscular disorders tend to show specific changes on muscle ultrasound, which can be helpful in differential diagnosis. For example, Duchenne muscular dystrophy results in a severe, homogeneous increase of muscle echo intensity with normal muscle thickness, whereas spinal muscular atrophy shows an inhomogeneous increase of echo intensity with severe atrophy. A major advantage of muscle ultrasound, compared to other imaging techniques, is its ability to visualize muscle movements, such as muscle contractions and fasciculations. This study reviews the possibilities and limitations of ultrasound in muscle imaging and its value as a diagnostic tool in neuromuscular disorders.
Measurement of joint motion a guide to goniometry
- C C Norkin
- D J White
Norkin CC, White DJ. Measurement of joint motion a guide to goniometry. In:
Davis FA, editor. Philadelphia, 1995.