Quantitative muscle ultrasound in adult spinal muscular atrophy. A pilot study.

INTRODUCTION/AIMS: Muscle ultrasound has been investigated in children with spinal muscular atrophy (SMA) and proposed as a potential biomarker of disease severity. We studied the ultrasound properties in adults with SMA to see whether they also have potential as markers of disease severity in older patients. METHODS: Thickness and quantitative echogenicity of muscle and subcutaneous tissue were compared between eight prospectively recruited adult patients with SMA and eight age, sex and body mass index-matched controls. Measurements were made in the dominant deltoid, biceps, triceps, forearm extensors, first dorsal interosseous, quadriceps, tibialis anterior, and gastrocnemius muscles. The muscle-to-subcutaneous (M:S) thickness and echogenicity ratios were also calculated. A mean value across all muscles as well as the individual values for each muscle were then calculated for each parameter in each subject and compared between the two groups. Significance was set at 0.05 after Bonferroni correction. RESULTS: In the SMA patients, mean muscle thickness was significantly smaller (1.3 vs. 1.9 cm), muscle echogenicity higher (106 vs. 67 on the grayscale level), and subcutaneous thickness larger (0.9 vs. 0.3 cm) than in controls; M:S echogenicity ratio was significantly increased and M:S thickness ratio reduced in the patients. The most abnormal scores were found in the nonambulatory patients and the least abnormal in the ambulatory patients. DISCUSSION: Ultrasound can detect and quantify the severity of muscle atrophy and structure in adult SMA, suggesting a potential role as a marker of disease severity, which will require validation by larger studies.

Neuromuscular ultrasound as a marker for inherited sensory neuronopathy.

A review and detailed analysis of the literature over the past two decades has revealed a unique ultrasound feature of pathologically "small" nerves in inherited sensory neuronopathies. Although sample sizes were limited, due to the rarity of these diseases, this characteristic ultrasound finding has been consistently reported across a variety of inherited diseases that affect the dorsal root ganglia. Direct comparisons with both acquired and inherited diseases that primarily affect the axons in the peripheral nerves showed that the ultrasound finding of abnormally "small" cross-sectional areas (CSAs) in mixed nerves of the upper limbs has a high diagnostic accuracy for inherited sensory neuronopathy. Based on this review, ultrasound CSA of the mixed upper limb nerves can be proposed as a marker for inherited sensory neuronopathy.

Ultrasound of peripheral nerves distinguishes inherited sensory neuronopathy of cerebellar ataxia with neuropathy and vestibular areflexia syndrome from inherited axonopathy.

Introduction/Aims Recent studies have shown that ultrasound of peripheral nerves can distinguish inherited sensory neuronopathy from acquired axonopathy with a high degree of accuracy. In this study we aimed to determine whether ultrasound can also distinguish inherited sensory neuronopathy from inherited axonopathy. Methods We compared the ultrasound cross-sectional areas (CSAs) of the median, ulnar, sural, and tibial nerves of retrospectively recruited patients with cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS), in whom sensory neuronopathy is a cardinal feature, with Charcot-Marie-Tooth type 2 (CMT2) disease patients, who have an inherited axonopathy, using the Kruskal-Wallis test and receiver-operating characteristic curves. Results There were 17 patients with CANVAS and 18 with CMT2. The upper limb nerve CSAs were significantly smaller in CANVAS than in CMT2 (P < .001), with the CSAs of the median nerve at mid-forearm and ulnar nerve at mid-arm being a third or less the size of those of the CMT2 patients. Nerve ultrasound reliably distinguished CANVAS from CMT2 with ROC areas under the curve between 0.97 and 0.99. The lower limb CSAs of the two patient groups were not significantly different. Discussion Ultrasound of the upper limb nerves distinguishes CANVAS sensory neuronopathy from inherited axonopathy with high accuracy and can therefore be proposed as a reliable additional tool in the investigation of these diseases.

Nerve ultrasound detects abnormally small nerves in patients with spinal and bulbar muscular atrophy.

INTRODUCTION/AIMS: Sensory impairment secondary to dorsal root ganglion neuronopathy is common, although often subclinical, in X-linked spinal and bulbar muscular atrophy (SBMA). We investigated the hypothesis that nerves of SBMA patients show the same morphological changes on ultrasound as other inherited sensory neuronopathies and that these changes are distinct from those in axonal neuropathy. METHODS: We compared the ultrasound cross-sectional areas (CSAs) of median, ulnar, sural, and tibial nerves of prospectively recruited SBMA patients with those of patients with acquired axonal neuropathy and healthy controls. We also compared the individual nerve CSAs of SBMA and neuropathy patients with our laboratory reference values. RESULTS: There were 7 SBMA patients, 18 neuropathy patients, and 42 healthy controls. The nerve CSAs of the SBMA patients were significantly smaller than those of patients in the other two groups. The changes were most prominent in the upper limbs (p < .001), with the nerves of the SBMA patients being on average approximately half the size of the controls and a third the size of the neuropathy patients. On individual analysis, the ultrasound abnormality was sufficiently characteristic to be detected in all but one SBMA patient. DISCUSSION: These ultrasound changes are similar to those reported in other inherited sensory neuronopathies and clearly different from the ultrasound findings in axonal neuropathy. Smaller nerves are possibly a distinctive finding in SBMA that may distinguish it from other motor neuron syndromes. Further studies are warranted to confirm this and determine the optimal sonographic protocol.

Utility of neuromuscular ultrasound in the investigation of common mononeuropathies in everyday neurophysiology practice.

INTRODUCTION: In everyday clinical neurophysiology practice, mononeuropathies are evaluated primarily by traditional electrodiagnostic testing. We sought to assess the additional benefit of neuromuscular ultrasound (US) in this scenario. METHODS: All consecutive mononeuropathies undergoing combined US and electrodiagnostic evaluation over a 23-mo period at a single neurophysiology practice were reviewed. Three independent examiners assessed how often US was: (a) "contributory" - enabling a definite diagnosis not made by electrophysiology alone and/or impacting on the therapeutic decision, (b) "confirmatory" of the electrodiagnostic findings, but not adding further diagnostic or therapeutic information, or (c) "negative" - missed the diagnosis. RESULTS: There were 385 studies included. US was "contributory" in 36%, "confirmatory" in 61% and "negative" in 3%. DISCUSSION: In this study of everyday neurophysiology practice, neuromuscular US contributed significant diagnostic or therapeutic information in over 1/3 of the investigations for common mononeuropathies. False negative US studies were uncommon in this setting.

A Maori specific RFC1 pathogenic repeat configuration in CANVAS, likely due to a founder allele.

Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) is a recently recognized neurodegenerative disease with onset in mid- to late adulthood. The genetic basis for a large proportion of Caucasian patients was recently shown to be the biallelic expansion of a pentanucleotide (AAGGG)n repeat in RFC1. Here, we describe the first instance of CANVAS genetic testing in New Zealand Maori and Cook Island Maori individuals. We show a novel, possibly population-specific CANVAS configuration (AAAGG)10-25(AAGGG)exp, which was the cause of CANVAS in all patients. There were no apparent phenotypic differences compared with European CANVAS patients. Presence of a common disease haplotype among this cohort suggests this novel repeat expansion configuration is a founder effect in this population, which may indicate that CANVAS will be especially prevalent in this group. Haplotype dating estimated the most recent common ancestor at ∼1430 ce. We also show the same core haplotype as previously described, supporting a single origin of the CANVAS mutation.

Carpal tunnel syndrome in advanced age: A sonographic and electrodiagnostic study.

INTRODUCTION: After noting inconsistent sonographic median nerve cross-sectional area (CSA) enlargement at the wrist in very elderly patients with carpal tunnel syndrome (CTS), we systematically reviewed ultrasound, electrodiagnostic, and clinical data collected over a 12-month period in patients from 2 age groups: 80-95 years and 40-65 years old. METHODS: Clinical and electrodiagnostic CTS severity, sensitivity of ultrasound CSA (against both electrodiagnostic and clinical reference standards), and correlations between ultrasound CSA and clinical and electrodiagnostic severity were compared in both groups. RESULTS: In very elderly patients, despite a higher prevalence of severe CTS, nerve ultrasound was less sensitive than in the younger group (54% vs. 87%, using clinical reference standard), and did not correlate with clinical (r = 0.28, P = 0.10) or electrodiagnostic (r = 0.09, P = 0.60) severity. DISCUSSION: Median nerve ultrasound CSA at the wrist is not a sensitive marker of CTS in very elderly populations. In this work we detail and discuss potential pathophysiological underpinnings of this unexpected finding. Muscle Nerve, 2019.

Spinocerebellar ataxia type 2-neuronopathy or neuropathy?

INTRODUCTION: Use of peripheral nerve ultrasound alongside standard electrodiagnostic tests may help to gain insight into the pathophysiology of peripheral nerve involvement in type 2 spinocerebellar ataxia (SCA2). METHODS: Twenty-seven patients with SCA2 underwent ultrasound cross-sectional area (CSA) measurement of median, ulnar, sural and tibial nerves, and motor (median, ulnar, tibial) and sensory (median, ulnar, radial, sural) nerve conduction studies. RESULTS: Twenty patients had pathologically small-nerve CSAs, suggestive of sensory neuronopathy. In these patients, electrophysiology showed non-length-dependent sensory neuropathy (14 of 20), "possible sensory neuropathy" (1 of 20), or normal findings (5 of 20). Four different patients had length-dependent sensory neuropathy on electrophysiology, and 1 had enlarged nerve CSAs. Regression analysis showed an inverse relationship between ataxia scores and upper limb nerve CSA (P < 0.03). DISCUSSION: Our findings suggest that a majority of patients with SCA2 (74%) have a sensory neuronopathy and this correlates with disability. A minority of patients have findings consistent with axonal neuropathy (18%). Muscle Nerve, 2019.

Peripheral nerve ultrasound in Friedreich ataxia.

INTRODUCTION: Sensory impairment in Friedreich ataxia (FRDA) is generally accepted as being due to a ganglionopathy. The degree of contribution from axonal pathology remains a matter of debate. Nerve ultrasound may be able to differentiate these processes. METHODS: The ultrasound cross-sectional area of median, ulnar, tibial, and sural nerves of 8 patients with FRDA was compared with 8 age- and gender-matched healthy controls and with reference values in our population. RESULTS: The nerves of the patients with FRDA were significantly larger than those of healthy controls at all upper limb sites (P < 0.05) but not significantly different in the lower limbs. DISCUSSION: Our findings add additional weight to the theory that dorsal root ganglionopathy is not the sole cause of peripheral sensory loss in FRDA. Peripheral neuropathic processes are also likely to play a role. Muscle Nerve 57: 852-856, 2018.

Peripheral nerve ultrasound findings in mucolipidosis type 3.

PURPOSE: The mucolipidoses are rare autosomal recessive lysosomal storage disorders. Neurologic involvement in these conditions is generally thought to be limited to cognitive delay and entrapment neuropathies (primarily carpal tunnel syndrome). We sought to evaluate peripheral nerves in this condition using nerve ultrasound. METHODS: We performed peripheral nerve ultrasound in two siblings with genetically confirmed mucolipidosis type 3 (alpha/beta). RESULTS: Peripheral nerves in mucolipidosis type 3 (alpha/beta) exhibit multifocal enlargement. CONCLUSION: The peripheral nerve ultrasound has a role in the evaluation of this, and possibly other lysosomal storage disorders.

Peripheral nerve ultrasound in cerebellar ataxia neuropathy vestibular areflexia syndrome (CANVAS).

INTRODUCTION: We report preliminary findings of nerve ultrasound in patients with cerebellar ataxia neuropathy vestibular areflexia syndrome (CANVAS) who have sensory impairment due to dorsal root ganglionopathy. METHODS: The ultrasound cross-sectional area (CSA) of median and ulnar nerves of 7 CANVAS patients was compared with 7 age- and gender-matched controls and with the mean CSA of our reference population. RESULTS: The nerve CSA of CANVAS patients was significantly smaller than that of controls at all sites (P < 0.01). All but 1 individual measurement of CSA at the mid-forearm level in the CANVAS patients fell outside the normal control range and was >2 standard deviations below the reference mean. CONCLUSIONS: The small nerves in CANVAS probably reflect nerve thinning from axonal loss secondary to ganglion cell loss. Our data show a role for ultrasound in the diagnosis of CANVAS ganglionopathy. This may also be applicable to ganglionopathy from other causes. Muscle Nerve 56: 160-162, 2017.

Carpal tunnel syndrome: updated evidence and new questions.

Carpal tunnel syndrome is the most common entrapment neuropathy, affecting quality of life for many people. Although it is a well recognised condition, new insights into epidemiology, diagnosis, and treatment have emerged in the past 6 years. The availability of disease-modifying treatments for rare systemic disorders associated with carpal tunnel syndrome (eg, amyloidosis) should alert clinicians to these diagnostic possibilities. Besides clinical evaluation and electrophysiology, the role of ultrasonography as a diagnostic tool has been confirmed and new ultrasound techniques have been applied, the clinical use and feasibility of which require further investigation. Surgical and non-surgical interventions are beneficial for the treatment of carpal tunnel syndrome and several treatment options are now available, giving clinicians the possibility to choose the best approach for every patient. New diagnostic and therapeutic techniques require further validation.

Expert consensus on the combined investigation of carpal tunnel syndrome with electrodiagnostic tests and neuromuscular ultrasound.

Expert consensus was sought to guide clinicians on the use of electrodiagnostic tests (EDX) and neuromuscular ultrasound (NMUS) in the investigation of suspected carpal tunnel syndrome (CTS). Consensus was achieved using the Delphi method via three consecutive anonymised surveys of 15 experts and was defined as rating agreement ≥ 80%. The panel agreed that combining EDX and NMUS is more informative than using each modality alone. NMUS adds value in patients with clinically suspected CTS with non-localizing or normal EDX, atypical EDX, failed CTS surgery, polyneuropathy, and CTS suspected to be secondary to structural pathology. The median nerve cross-sectional area should be measured at the site of maximal nerve enlargement, and the nerve should be scanned from mid-forearm to the palm. The group also identified those situations where the wrist-to-forearm area ratio and longitudinal scans of the median nerve should also be obtained. EDX should always be performed to quantify CTS severity and in individuals over age 70. This document is an initial step to guide clinicians on the combined investigation of CTS using EDX and NMUS, to be updated regularly with the emergence of new research.

Expert consensus on the combined investigation of ulnar neuropathy at the elbow using electrodiagnostic tests and nerve ultrasound.

The addition of ultrasound (US) to electrodiagnostic (EDX) tests can significantly enhance the accuracy of testing for ulnar neuropathy at the elbow (UNE). We aimed to obtain expert consensus to guide clinicians on the combined use of EDX and US in UNE investigation. Consensus was achieved using the Delphi method. Two consecutive anonymised questionnaires were submitted to 15 experts, who were asked to choose their level of agreement with each statement. Consensus was pre-defined as ≥ 80% rating agreement. The experts concluded that all investigations of UNE should include both nerve conduction studies and US. There was consensus that US should include cross-sectional area measurement and assessment of nerve mobility at the elbow, and that the entire ulnar nerve should be imaged. This study defined expert opinion on the 'core' techniques that should be used routinely in the UNE investigation using EDX and US. Areas with lack of consensus highlighted some controversial issues in the current use of these diagnostic modalities and the need for future research. This document is an initial step to guide clinicians on the combined investigation of UNE using EDX and US, to be regularly updated as new research emerges.

Utility of nerve ultrasound in ulnar neuropathy with abnormal non-localizing electrophysiology in diabetes mellitus.

We studied the utility of ultrasound in the diagnostic workup of ulnar neuropathy with abnormal non-localizing electrophysiology (NL-UN) in patients with diabetes. Eighteen ulnar nerves (15 patients) were scanned from wrist to mid-upper arm. Ultrasound showed: (a) focal nerve enlargement at the elbow (8/18 nerves), either alone (6) or superimposed upon diffuse nerve abnormality (2); (b) diffuse nerve enlargement without focal abnormality (8/18); (c) segmental abnormality in upper-arm or forearm without extrinsic nerve compression (2/18). This study shows a pivotal role for ultrasound in the classification of NL-UN in patients with diabetes, which can facilitate critical therapeutic decisions.

Diagnostic sensitivity of electrophysiology and ultrasonography in ulnar neuropathies of different severity.

OBJECTIVE: To assess the diagnostic performance of electrophysiology and nerve ultrasound in ulnar neuropathies of varying clinical severity in 135 consecutive patients. METHODS: Clinical severity of ulnar neuropathy was graded on a 4 point scale from very mild (symptoms only) to severe (marked atrophy of intrinsic hand muscles). Sensitivity and localization ability of electrophysiology and nerve ultrasound were assessed for each point of the scale. RESULTS: Ultrasound had higher sensitivity than electrophysiology in clinically very mild (20% and 3% for ultrasound and electrophysiology, respectively) and mild (62% and 47% for ultrasound and electrophysiology, respectively) neuropathies, had greater localizing ability in axonal ulnar neuropathies, and identified nerve hypermobility. Ultrasound nerve cross-sectional area had strong positive correlation with both clinical and electrophysiological severity scores, but with significant overlap across the severity groups. CONCLUSION: The diagnostic work-up of ulnar neuropathies was improved by using both electrophysiology and ultrasound at all levels of clinical severity. Ultrasound increased the diagnostic yield in very mild and mild neuropathies, localized all the ulnar neuropathies with abnormal non-localizing electrophysiology and identified nerve hypermobility. SIGNIFICANCE: This is the first detailed analysis of the diagnostic performance of electrophysiology and ultrasound in ulnar neuropathies of varying severity.

Nerve ultrasound as a diagnostic tool for sensory neuronopathy in spinocerebellar ataxia syndrome.

OBJECTIVE: The objective was to assess if nerve ultrasound has a role in diagnosing sensory neuronopathy in spinocerebellar ataxia syndrome (SCA) by examining if proposed diagnostic cut-off criteria of ultrasound in sensory neuronopathy caused by cerebellar ataxia neuropathy vestibular areflexia syndrome (CANVAS) were also discriminatory for SCA-related sensory neuronopathy. METHODS: Optimal diagnostic cut-off criteria for nerve size measured by diagnostic ultrasound were developed in 14 patients with CANVAS and 42 healthy controls using six peripheral nerve sites; and logistic regression and receiver operating characteristic (ROC) curves. These proposed cut-off values were tested in seven patients with spinocerebellar ataxia type 2 (SCA2) patients with sensory neuronopathy. RESULTS: Ultrasound of upper limb nerves was highly accurate in differentiating between CANVAS and healthy controls with areas under the ROC curves between 0.97 and 0.99. Optimal cut-off measurements from the CANVAS patients also accurately diagnosed sensory neuronopathy in all patients with SCA2. CONCLUSIONS: Upper limb ultrasound is a sensitive tool for detecting sensory neuronopathy in established cases of CANVAS and SCA2. SIGNIFICANCE: Ultrasound could aid the diagnosis of sensory neuronopathy in spinocerebellar ataxias.