Muscle ultrasound analysis: normal values and differentiation between myopathies and neuropathies

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.     

Ultrasound Imaging of Muscle Contraction of the Tibialis Anterior in Patients with Facioscapulohumeral Dystrophy

A need exists for biomarkers to diagnose, quantify and longitudinally follow facioscapulohumeral muscular dystrophy (FSHD) and many other neuromuscular disorders. Furthermore, the pathophysiological mechanisms leading to muscle weakness in most neuromuscular disorders are not completely understood. Dynamic ultrasound imaging (B-mode image sequences) in combination with speckle tracking is an easy, applicable and patient-friendly imaging tool to visualize and quantify muscle deformation. This dynamic information provides insight in the pathophysiological mechanisms and may help to distinguish the various stages of diseased muscle in FSHD. In this proof-of-principle study, we applied a speckle tracking technique to 2-D ultrasound image sequences to quantify the deformation of the tibialis anterior muscle in patients with FSHD and in healthy controls. The resulting deformation patterns were compared with muscle ultrasound echo intensity analysis (a measure of fat infiltration and dystrophy) and clinical outcome measures. Of the four FSHD patients, two patients had severe peroneal weakness and two patients had mild peroneal weakness on clinical examination. We found a markedly varied muscle deformation pattern between these groups: patients with severe peroneal weakness showed a different motion pattern of the tibialis anterior, with overall less displacement of the central tendon region, while healthy patients showed a non-uniform displacement pattern, with the central aponeurosis showing the largest displacement. Hence, dynamic muscle ultrasound of the tibialis anterior muscle in patients with FSHD revealed a distinctively different tissue deformation pattern among persons with and without tibialis anterior weakness. These findings could clarify the understanding of the pathophysiology of muscle weakness in FSHD patients. In addition, the change in muscle deformation shows good correlation with clinical measures and quantitative muscle ultrasound measurements. In conclusion, dynamic ultrasound in combination with speckle tracking allows the study of the effects of muscle pathology in relation to strength, force transmission and movement generation. Although further research is required, this technique can develop into a biomarker to quantify muscle disease severity.     

High-frequency ultrasonography of skeletal muscle in children with neuromuscular disease.

Ultrasonography of the thigh and calf was performed in 24 children who had primary neuromuscular disease and in 20 healthy children. The ultrasound image was clearly abnormal in all patients with progressive muscular dystrophy, and in the majority of children with benign myopathic disorders; the principal changes were increased muscular echogenicity and increased attenuation of ultrasound with a reduced bone surface echo. In 13 patients, the ultrasound findings were correlated with pathologic changes seen in muscle biopsy specimens: a clear correlation (r = .85) was found. Muscular dystrophies had a higher score of abnormal ultrasonographic and microscopic findings, while the more benign muscular diseases had a lower score.     

Electrical impedance in bovine skeletal muscle as a model for the study of neuromuscular disease

Electrical impedance myography (EIM) consists of a set of bioimpedance methods configured for neuromuscular disease assessment, in which high-frequency electrical current is applied to a limb and the consequent surface voltage pattern over a muscle is evaluated. Prior human work has shown that the EIM parameters of resistance, reactance and phase change in different neuromuscular disease states including neurogenic and myopathic conditions. These parameters are also sensitive to the angle at which current is applied and measured relative to muscle fiber direction, a characteristic known as anisotropy. In order to obtain insights into the impedance characteristics of mammalian skeletal muscle without the confounding effects of an overlying skin-fat layer, bone and irregular muscle shape, we performed EIM on three 'nearly ideal' round 16 cm diameter, 1 cm equal thickness pieces of bovine rectus abdominis muscle. Using a standardized tetrapolar electrode array with 50 kHz electrical current, we identified strong anisotropy in the measured reactance and phase, with weaker anisotropy identified for resistance. We also found that increasing amounts of muscle maceration, a rough model of myopathic or traumatic muscle fiber injury, reduced phase and muscle anisotropy when current was injected perpendicular to the muscle fibers. These findings support that EIM parameters, including muscle anisotropy, are likely to be sensitive to the pathological changes that occur in neuromuscular disease states.     

Musculoskeletal complications of neuromuscular disease in children

A wide variety of neuromuscular diseases affect children, including central nervous system disorders such as cerebral palsy and spinal cord injury; motor neuron disorders such as spinal muscular atrophy; peripheral nerve disorders such as Charcot-Marie-Tooth disease; neuromuscular junction disorders such as congenital myasthenia gravis; and muscle fiber disorders such as Duchenne's muscular dystrophy. Although the origins and clinical syndromes vary significantly, outcomes related to musculoskeletal complications are often shared. The most frequently encountered musculoskeletal complications of neuromuscular disorders in children are scoliosis, bony rotational deformities, and hip dysplasia. Management is often challenging to those who work with children who have neuromuscular disorders.     

The changing role of pediatric electrodiagnosis

Electrodiagnosis is one of several useful diagnostic tests in infants and children who have anterior horn cell disease, neuropathy, neuromuscular junction disorders, or myopathy. It is also used for intraoperative monitoring in children. For hypotonic infants and for older children with a nonspecific presentation of weakness, EDX may provide direction for more specific diagnostic testing, such as DNA testing with or without muscle biopsy. Genetic testing has an increasingly important role in the diagnosis of children with neuromuscular disorders. Future improvements in motor unit quantitation, which do not require active patient cooperation and require less time than current methodologies, may make EDX more specific and useful for diagnosing neuromuscular disease in children.     

Muscle Ultrasound Quantifies Segmental Neuromuscular Outcome in Pediatric Myelomeningocele

In pediatric spina bifida aperta (SBA), non-invasive assessment of neuromuscular integrity by muscle ultrasound density (MUD) could provide important information about the clinical condition. We therefore aimed to determine the association between pediatric SBA MUD and segmental neurologic function. We included 23 children (age range: 1–18 y) with SBA with L4–5 lesions, and we associated SBA MUD with control values and segmental neuromuscular function. Results revealed that MUD outcomes in the lower extremities: (i) are independent of age, (ii) exceed control values, (iii) differ intra-individually (i.e., between the left and right sides in the same individual) in association with segmental neuromuscular function. We concluded that SBA leg MUD can quantify the segmental neuromuscular condition throughout childhood.     

Clinical value of electrodiagnostic studies in neuromuscular disorders

EMG and conduction studies provide the physician with a precise means of defining the multiple diseases affecting the peripheral motor-sensory unit. These studies frequently provide clues that may be useful in arriving at the appropriate therapeutic decisions and in determining prognosis. Normal results may also support a suspected clinical diagnosis of inorganic illness, providing no evidence of central nervous system disease can be defined. Like any other test, however, results of EMG may be false-negative in bona fide neuromuscular disorders. This is particularly true early in a disease process; in neuropathies restricted primarily to small, unmyelinated nerve fibers; and in certain of the less virulent diseases of muscle and muscle energy metabolism.     

Objective parameters in magnetic resonance imaging (MRI) for neuromuscular diagnosis: preliminary findings.

T1 relaxation time (T1 time), T2 relaxation time (T2 time), and proton (rho) density in the thigh muscles of 20 normal healthy volunteers and three patients with muscle atrophy in the lower extremity were measured in order to select the useful MRI parameters for neuromuscular diagnosis. Since the standard deviation (SD) of both T1 and T2 times in each muscle was found to be within a relatively small range, these values were expected to be useful MRI parameters for neuromuscular diagnosis. On the contrary, rho density was not a valid parameter for diagnosis, as it was demonstrated to have large SDs in the muscles. The differences of these parameters in the three patients also supported the fact that MRI was useful for discriminating between the various types of muscular abnormalities based on relaxation times. The longer T1 and T2 times in women suggested that the content of water in skeletal muscle was higher in women than in men. Moreover, the T1 time in the dominant limbs was found to be shorter than in the non-dominant limbs for rectus femoris only in both men and women, while there were no differences in T2 time in these muscles.     

Reliability of quantitative muscle testing in healthy children and in children with Duchenne muscular dystrophy using a hand-held dynamometer

The purpose of this study was to examine intratester and test-retest reliability using a hand-held dynamometer for the measurement of isometric muscle strength in 28 healthy children and children with Duchenne muscular dystrophy. The Dystrophic Group consisted of 14 children diagnosed with Duchenne muscular dystrophy, and the Healthy Group consisted of 14 age-matched children with no history of orthopedic or neuromuscular disorders. One physical therapist tested hip and knee extension, elbow flexion, and shoulder abduction in each child bilaterally. A two-way analysis of variance for repeated measures was used to analyze differences between measurements taken within and across the testing sessions. Pearson product-moment correlation coefficients were determined on mean values across the testing sessions for each variable. No significant differences (p greater than .05) between measurements taken within or across testing sessions were found in either the Dystrophic Group or the Healthy Group. Correlation coefficients for the Dystrophic Group ranged from .83 to .99 for the variables tested. Correlation coefficients for the Healthy Group ranged from .74 to .99. The results suggest that the hand-held dynamometer can be used as a reliable instrument in measuring the isometric strength of selected muscles in children.     

The value of elecromyography in the aetiological diagnosis of hypotonia in infants and toddlers

IntroductionDuring the first two years of life, hypotonia may be the only symptom of a central or peripheral nervous system disorder. We propose to assess the sensitivity of electroneuromyography (ENMG) in the aetiological diagnosis of hypotonia of neuromuscular origin in infants and toddlers.MethodThis is a retrospective, single-centre study with revision of the files of the 37 children aged between zero and 24 months who, between 1994 and 2006, underwent an ENMG in the etiological approach of their hypotonia and had a final diagnosis of neuromuscular disease.ResultsAll the 13 patients with spinal muscular atrophy or Charcot Marie-Tooth disease displayed neurogenic alterations on the electromyography (EMG). Among the 24 children ultimately diagnosed with myopathies, five only displayed myogenic alterations when tested before the age of two. Sixteen had normal EMG results and three showed neurogenic alterations.Discussion and conclusionIn infants presenting with hypotonia, ENMG is useful for the diagnosis of peripheral neuropathy. Normal ENMG is relatively common for confirmed muscle disorders in infants whereas myogenic alterations seem more unusual, so that muscle biopsy appears unquestionable. In a few cases, early onset myopathies may present with a neurogenic ENMG pattern. Such a result should not invalidate the clinically presumed diagnosis of myopathy and would indicate on the contrary the need for a muscle biopsy.     

Sonographically guided percutaneous muscle biopsy in diagnosis of neuromuscular disease: a useful alternative to open surgical biopsy.

OBJECTIVE: The purpose of this study was to evaluate the feasibility of sonographically guided percutaneous muscle biopsy in the investigation of neuromuscular disorders. METHODS: Sonographically guided percutaneous needle biopsy of skeletal muscle was performed with a 14-gauge core biopsy system in 40 patients over a 24-month period. Patients were referred from the Department of Neurology under investigation for neuromuscular disorders. Sonography was used to find suitable tissue and to avoid major vascular structures. A local anesthetic was applied below skin only. A 3- to 4-mm incision was made. Three 14-gauge samples were obtained from each patient. All samples were placed on saline-dampened gauze and sent for neuropathologic analysis. As a control, we retrospectively assessed results of the 40 most recent muscle samples acquired via open surgical biopsy. RESULTS: With the use of sonography, 32 (80%) of 40 patients had a histologic diagnosis made via percutaneous needle biopsy. This included 26 (93%) of 28 patients with acute muscular disease and 6 (50%) of 12 patients with chronic disease. In the surgical group (all acute disease), 38 (95%) of 40 patients had diagnostic tissue attained. CONCLUSIONS: Sonographically guided percutaneous 14-gauge core skeletal muscle biopsy is a useful procedure, facilitating diagnosis in acute muscular disease. It provides results comparable with those of open surgical biopsy in acute muscular disease. It may also be used in chronic muscular disease but repeated or open biopsy may be needed.     

Genetics of neuromuscular disorders

Neuromuscular disorders affect the peripheral nervous system and muscle. The principle effect of neuromuscular disorders is therefore on the ability to perform voluntary movements. Neuromuscular disorders cause significant incapacity, including, at the most extreme, almost complete paralysis. Neuromuscular diseases include some of the most devastating disorders that afflict mankind, for example motor neuron disease. Neuromuscular diseases have onset any time from in utero until old age. They are most often genetic. The last 25 years has been the golden age of genetics, with the disease genes responsible for many genetic neuromuscular disorders now identified. Neuromuscular disorders may be inherited as autosomal dominant, autosomal recessive, or X-linked traits. They may also result from mutations in mitochondrial DNA or from de novo mutations not present in the peripheral blood DNA of either parent. The high incidence of de novo mutation has been one of the surprises of the recent increase in information about the genetics of neuromuscular disorders. The disease burden imposed on families is enormous including decision making in relation to presymptomatic diagnosis for late onset neurodegenerative disorders and reproductive choices. Diagnostic molecular neurogenetics laboratories have been faced with an ever-increasing range of disease genes that could be tested for and usually a finite budget with which to perform the possible testing. Neurogenetics has moved from one known disease gene, the Duchenne muscular dystrophy gene in July 1987, to hundreds of disease genes in 2011. It can be anticipated that with the advent of next generation sequencing (NGS), most, if not all, causative genes will be identified in the next few years. Any type of mutation possible in human DNA has been shown to cause genetic neuromuscular disorders, including point mutations, small insertions and deletions, large deletions and duplications, repeat expansions or contraction and somatic mosaicism. The diagnostic laboratory therefore has to be capable of a large number of techniques in order to identify the different mutation types and requires highly skilled staff. Mutations causing neuromuscular disorders affect the largest human proteins for example titin and nebulin. Successful molecular diagnosis can make invasive and expensive diagnostic procedures such as muscle biopsy unnecessary. Molecular diagnosis is currently largely based on Sanger sequencing, which at most can sequence a small number of exons in one gene at a time. NGS techniques will facilitate molecular diagnostics, but not for all types of mutations. For example, NGS is not good at identifying repeat expansions or copy number variations. Currently, diagnostic molecular neurogenetics is focused on identifying the causative mutation(s) in a patient. In the future, the focus might move to prevention, by identifying carriers of recessive diseases before they have affected children. The pathobiology of many of the diseases remains obscure, as do factors affecting disease severity. The aim of this review is to describe molecular diagnosis of genetic neuromuscular disorders in the past, the present and speculate on the future.     

Reliability,validity, and norms of the 2-min walk test in children with and without neuromuscular disorders aged 6–12

Purpose: The 2-min walk test may be more appropriate functional exercise test for young children. This study aimed to examine the 2-min walk test’s reliability; validity; and minimal clinically important difference; and to establish norms for children aged 6–12.

Methods: Sixty-one healthy children were recruited to examine the 2-min walk test’s reliability. Forty-six children with neuromuscular disorders (63% cerebral palsy) were recruited to test the validity. The normative study involved 716 healthy children without neuromuscular disorders (male?=?51%, female?=?49%). They walked at a self-selected speed for 2?min along a smooth, flat path 15 m in length.

Results: The mean distance covered in the 2-min walk test was 152.8 m (SD?=27.5). No significant difference was found in the children’s test-retest results (p?>?0.05). The intra- and inter-rater reliability were high (all intra-class correlation coefficients >0.8). All children, except one with neuromuscular disorders, completed the 2-min walk test, of which the minimal clinically important difference at 95% confidence interval was 23.2 m for the entire group, 15.7 m for children walking with aids, and 16.6 m for those walking independently.

Conclusions: The 2-min walk test is a feasible, reliable, and valid exercise test for children with and without neuromuscular disorders aged 6–12. The first normative references and minimal clinically important difference for children with neuromuscular disorders were established for children of this age group.

• Implications for rehabilitation

• The 2-min walk test is a feasible, safe, reliable, and valid time-based walk test for children aged 6–12 years.

• Normative references have been established for healthy children aged 6–12 years.

• Minimal clinically important difference at 95% confidence interval were calculated for children with neuromuscular disorders who walked without aids (i.e., independent and stand-by supervision) and those who walked with aids equal to 16.6 and 15.7 m, respectively.

• Distance covered by the healthy children in the 2?min did not correlate with age, gender, height, and weight of the children.

     

Visual Screening of Muscle Ultrasound Images in Children

In children, non-invasive muscle ultrasound (MU) imaging has become increasingly important for the detection of neuromuscular pathology, by either quantitative or visual assessment. MU quantification requires time, expertise and equipment. If application of visual MU screening provides reliable results, ubiquitous application could be advocated. Previously, we found that visual MU screening can reliably detect segmental neuromuscular alterations within a patient. Analogously, we reasoned that visual MU screening could discern pathologic MU images from healthy controls. We therefore investigated visual screening results by 20 clinical observers (involving 100 MU images, with [n = 53] and without [n = 47] neuromuscular pathology). MU screening revealed adequate sensitivity, specificity and negative predictive value (85%, 75% and 82%, respectively). MU-experienced observers revealed higher specificity than MU-inexperienced observers (86% vs. 69%, p = 0.005). We conclude that clinical observers can identify neuromuscular pathology by visual screening. To enhance specificity, a secondary view by an expert appears advisory.     

Skeletal muscle ultrasonography: Visual versus quantitative evaluation

In this study, we compared the sensitivity and specificity of visual versus quantitative evaluation of skeletal muscle ultrasound in children suspected of having a neuromuscular disorder (NMD). Ultrasonography (US) scans of four muscles (biceps brachii, forearm flexors, quadriceps femoris, anterior tibial muscle) were made in 76 children. All images were visually evaluated using the Heckmatt criteria and quantitatively evaluated with computer-assisted grey-scale analysis of muscle echo intensity. Visual evaluation could achieve a sensitivity up to 71%, with a specificity of 92%. With quantification, a sensitivity of 87% accompanied by a specificity of 67% was found, but other diagnostic values could be achieved, depending on the cut-off point. Quantification resulted in a higher interobserver agreement (kappa 0.86) compared with visual evaluation (kappa 0.53). We conclude that quantification of echo intensity is a more objective and accurate method. Because it can achieve higher sensitivities, it is better-suited for the screening task in the diagnostic phase of children with a NMD.     

Neuromuscular-blocking drugs. Use and misuse in the intensive care unit.

The use of NMB agents for more than 24 to 48 hours in critically ill patients is associated with many potential complications. Neuromuscular-blocking drugs should be used only when their use is essential for optimal patient care. The indications for neuromuscular blockade must be defined clearly, and patients should be evaluated during treatment for the need for continued muscle relaxation. The smallest doses of NMB agents that will accomplish clinical goals should be used. This dosage can be determined through clinical evaluations and peripheral nerve monitoring. It is essential that all patients treated with NMB drugs receive appropriate sedation and analgesia. Myopathies, neuropathies, and alterations of the neuromuscular junction can occur in the ICU setting, and nondepolarizing muscle relaxants seem to be involved in the development of these disorders. Clinicians should be aware of risk factors that may predispose certain patients to neuromuscular complications, including sepsis and the use of high-dose steroids. Neuromuscular-blocking agents should be avoided in these patients if possible. Although not proved, early recognition and treatment of iatrogenic neuromuscular complications may improve patient outcome.     

Mechanisms of ventilator dependence in children with neuromuscular and respiratory control disorders identified by monitoring diaphragm electrical activity

Objectives

To report on the monitoring of diaphragm electrical activity (Edi) using neurally adjusted ventilator assist (NAVA) technology to investigate the mechanisms of ventilator dependence in children with neuromuscular and respiratory control disorders.

Patients and methods

Using NAVA technology, electrical activity of the diaphragm (Edi) was monitored at the lowest achievable level of respiratory support in six ventilator-dependent patients with neuromuscular and respiratory control disorders, aged 6?weeks to 12?years, admitted to a tertiary paediatric intensive care unit between 2009 and 2011.

Results

Edi monitoring identified markedly abnormal respiratory dynamic patterns that were not always apparent clinically. These were associated with disorders of central respiratory control, muscle weakness and diaphragm pathology.

Conclusions

Edi monitoring using NAVA technology is a valuable, minimally invasive, diagnostic adjunct in children with neuromuscular and respiratory control disorders who are ventilator-dependent.     

High-frequency chest-wall oscillation in a noninvasive-ventilation-dependent patient with type 1 spinal muscular atrophy

With the recent increased use of noninvasive ventilation, the prognoses of children with neuromuscular disease has improved significantly. However, children with muscle weakness remain at risk for recurrent respiratory infection and atelectasis. We report the case of a young girl with type 1 spinal muscular atrophy who was dependent on noninvasive ventilation, and in whom conventional secretion-clearance physiotherapy became insufficient to clear secretions. We initiated high-frequency chest-wall oscillation (HFCWO) as a rescue therapy, and she had improved self-ventilation time. This is the first case report of HFCWO for secretion clearance in a severely weak child with type 1 spinal muscular atrophy. In a patient with neuromuscular disease and severe respiratory infection and compromise, HFCWO can be used safely in combination with conventional secretion-clearance physiotherapy.     

Restless legs syndrome in Behçet's disease

The prevalence of restless legs syndrome (RLS) and its association with the clinical features of Beh?et's disease (BD) has not previously been elucidated. The inflammatory character, central nervous system involvement and neuropathies of BD led to this investigation of RLS risk in BD patients. A total of 116 BD patients and 104 healthy control subjects were included; seven BD patients were excluded because of concurrent diseases, pregnancy or alcohol misuse that might cause RLS symptoms, and the remaining 109 BD patients were included in the analysis. The prevalence of RLS was significantly higher in patients with BD (32/109; 29.4%) than in controls (5/104; 4.8%). No significant differences were found between BD patients with and without RLS with regard to the clinical features of BD. RLS severity positively correlated with age in BD patients. In conclusion, BD-related RLS should be considered in symptomatic RLS secondary to rheumatological disorders and BD patients should be examined for RLS. Further studies are needed to clarify the pathogenetic mechanisms underlying BD-related RLS.