There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.
Abstract
Neuromuscular ultrasound (NMUS) is a rapidly evolving technique used in neuromuscular
medicine to provide complimentary information to standard electrodiagnostic studies.
NMUS provides a dynamic, real time assessment of anatomy which can alter both diagnostic
and management pathways in peripheral nerve disorders. This review describes the current
and future techniques used in NMUS and details the applications and developments in
the diagnosis and monitoring of compressive, hereditary, immune-mediated and axonal
peripheral nerve disorders, and motor neuron diseases. Technological advances have
allowed the increased utilisation of ultrasound for management of peripheral nerve
disorders; however, several practical considerations need to be taken into account
to facilitate the widespread uptake of this technique.
Late-onset ataxia is common, often idiopathic, and can result from cerebellar, proprioceptive, or vestibular impairment; when in combination, it is also termed cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). We used non-parametric linkage analysis and genome sequencing to identify a biallelic intronic AAGGG repeat expansion in the replication factor C subunit 1 (RFC1) gene as the cause of familial CANVAS and a frequent cause of late-onset ataxia, particularly if sensory neuronopathy and bilateral vestibular areflexia coexist. The expansion, which occurs in the poly(A) tail of an AluSx3 element and differs in both size and nucleotide sequence from the reference (AAAAG)11 allele, does not affect RFC1 expression in patient peripheral and brain tissue, suggesting no overt loss of function. These data, along with an expansion carrier frequency of 0.7% in Europeans, implies that biallelic AAGGG expansion in RFC1 is a frequent cause of late-onset ataxia.
Summary Background A substantial impediment to progress in trials of new therapies in neuromuscular disorders is the absence of responsive outcome measures that correlate with patient functional deficits and are sensitive to early disease processes. Irrespective of the primary molecular defect, neuromuscular disorder pathological processes include disturbance of intramuscular water distribution followed by intramuscular fat accumulation, both quantifiable by MRI. In pathologically distinct neuromuscular disorders, we aimed to determine the comparative responsiveness of MRI outcome measures over 1 year, the validity of MRI outcome measures by cross-sectional correlation against functionally relevant clinical measures, and the sensitivity of specific MRI indices to early muscle water changes before intramuscular fat accumulation beyond the healthy control range. Methods We did a prospective observational cohort study of patients with either Charcot-Marie-Tooth disease 1A or inclusion body myositis who were attending the inherited neuropathy or muscle clinics at the Medical Research Council (MRC) Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, London, UK. Genetic confirmation of the chromosome 17p11·2 duplication was required for Charcot-Marie-Tooth disease 1A, and classification as pathologically or clinically definite by MRC criteria was required for inclusion body myositis. Exclusion criteria were concomitant diseases and safety-related MRI contraindications. Healthy age-matched and sex-matched controls were also recruited. Assessments were done at baseline and 1 year. The MRI outcomes—fat fraction, transverse relaxation time (T2), and magnetisation transfer ratio (MTR)—were analysed during the 12-month follow-up, by measuring correlation with functionally relevant clinical measures, and for T2 and MTR, sensitivity in muscles with fat fraction less than the 95th percentile of the control group. Findings Between Jan 19, 2010, and July 7, 2011, we recruited 20 patients with Charcot-Marie-Tooth disease 1A, 20 patients with inclusion body myositis, and 29 healthy controls (allocated to one or both of the 20-participant matched-control subgroups). Whole muscle fat fraction increased significantly during the 12-month follow-up at calf level (mean absolute change 1·2%, 95% CI 0·5–1·9, p=0·002) but not thigh level (0·2%, −0·2 to 0·6, p=0·38) in patients with Charcot-Marie-Tooth disease 1A, and at calf level (2·6%, 1·3–4·0, p=0·002) and thigh level (3·3%, 1·8–4·9, p=0·0007) in patients with inclusion body myositis. Fat fraction correlated with the lower limb components of the inclusion body myositis functional rating score (ρ=–0·64, p=0·002) and the Charcot-Marie-Tooth examination score (ρ=0·63, p=0·003). Longitudinal T2 and MTR changed consistently with fat fraction but more variably. In muscles with a fat fraction lower than the control group 95th percentile, T2 was increased in patients compared with controls (regression coefficients: inclusion body myositis thigh 4·0 ms [SE 0·5], calf 3·5 ms [0·6]; Charcot-Marie-Tooth 1A thigh 1·0 ms [0·3], calf 2·0 ms [0·3]) and MTR reduced compared with controls (inclusion body myositis thigh −1·5 percentage units [pu; 0·2], calf −1·1 pu [0·2]; Charcot-Marie-Tooth 1A thigh −0·3 pu [0·1], calf −0·7 pu [0·1]). Interpretation MRI outcome measures can monitor intramuscular fat accumulation with high responsiveness, show validity by correlation with conventional functional measures, and detect muscle water changes preceding marked intramuscular fat accumulation. Confirmation of our results in further cohorts with these and other muscle-wasting disorders would suggest that MRI biomarkers might prove valuable in experimental trials. Funding Medical Research Council UK.
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.
Brain and Mind Research Centre, University of Sydney, Camperdown 2050, NSW, Australia
Department of Neurology, Westmead Hospital, University of Sydney, Westmead 2145, NSW,
Australia
Department of Neurology, St Vincent’s Hospital, Sydney, Darlinghurst 2010, NSW, Australia
Northern Clinical School, University of Sydney, Frenchs Forest 2086, NSW, Australia.
neil@
123456nbneuro.com.au
Author notes
Author contributions: Carroll AS was involved in the design, data acquisition, writing
of the original draft manuscript, creation of figures and editing; Simon NG was involved
in conceptualization, review of manuscript, creating of figures and editing. All authors
have read and approve the final manuscript.
Supported by
Brain Foundation of Australia.
Corresponding author: Neil G Simon, FRACP, MBBS, PhD, Doctor, Senior Lecturer, Northern
Clinical School, The University of Sydney, Northern Beaches Hospital, Suite 14A, Frenchs
Forest 2086, NSW, Australia.
neil@
123456nbneuro.com.au
This article is an open-access article which was selected by an in-house editor and
fully peer-reviewed by external reviewers. It is distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits
others to distribute, remix, adapt, build upon this work non-commercially, and license
their derivative works on different terms, provided the original work is properly
cited and the use is non-commercial.
scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.