Clinical Utility and Diagnostic Yield of Genetic Testing for Inherited Neuromuscular Disorders in a Single, Large Neuromuscular Center.

Background and Objectives: Most published studies on the clinical utility of genetic testing for neuromuscular diseases (NMDs) focus on disease-specific cohorts and/or involve multiple centers. The aim of this study was to examine the clinical utility and diagnostic yield of genetic testing at a single, large neuromuscular center. Unlike previous studies, this study is unique in that it includes a broad array of patients at a single, large neuromuscular center, providing real-world data that may assist both neuromuscular specialists as well as general neurologists in decision-making regarding the need for genetic testing in patients with suspected NMDs. Methods: Genetic testing results were reviewed for all patients who underwent testing through a single genetic testing company for NMDs in this single laboratory at a large neuromuscular center from 2015 to 2020. Retrospective chart reviews were performed to determine whether genetic testing results conferred a specific NMD diagnosis, including cases where a variant of uncertain significance (VUS) was identified. Results: Genetic testing was pursued for 192 patients. A positive result, defined as a pathogenic mutation, a VUS, or both, was found in 77.1%. A definitive diagnosis was conferred in 35.9%. The most common testing indication was suspected neuropathy (53.3%), and the indication with the highest diagnostic yield was suspected myopathy (48.7%). Discussion: This study provides further evidence of the clinical utility of genetic testing for NMDs in a real-world setting with over one-third of patients tested receiving a definitive diagnosis. Over time, genetic testing will continue to become increasingly accessible, cost-effective, and sensitive, which will lead to even more utilization.

Neuromuscular Ultrasound in Polyneuropathies.

Neuromuscular ultrasound is a painless, radiation-free, high-resolution imaging technique for assessing the peripheral nervous system. It can accurately depict changes in the nerves and muscles of individuals with neuromuscular conditions, and it is therefore a robust diagnostic tool for the assessment of individuals with polyneuropathies. This review will outline the typical ultrasonographic changes found in a wide variety of polyneuropathies. In general, demyelinating conditions result in greater nerve enlargement than axonal conditions, and acquired conditions result in more patchy nerve enlargement compared to diffuse nerve enlargement in hereditary conditions. This review is data-driven, but more nuanced anecdotal findings are also described. The overall goal of this paper is to provide clinicians with an accessible review of the ultrasonographic approaches and findings in a wide variety of polyneuropathies.

Ultrahigh-frequency ultrasound of fascicles in the common fibular, superficial fibular, and sural nerves.

INTRODUCTION/AIMS: While ultrasound assessment of cross-sectional area and echogenicity has gained popularity as a biomarker for various neuropathies, there is a scarcity of data regarding fascicle count and density in neuropathies or even healthy controls. The aim of this study was to determine whether fascicles within select lower limb nerves (common fibular, superficial fibular, and sural nerves) can be counted in healthy individuals using ultrahigh-frequency ultrasound (UHFUS). METHODS: Twenty healthy volunteers underwent sonographic examination of the common fibular, superficial fibular, and sural nerves on each lower limb using UHFUS with a 48 MHz linear transducer. Fascicle counts and density in each examined nerve were determined by a single rater. RESULTS: The mean fascicle number for each of the measured nerves included the following: common fibular nerve 9.85 (SD 2.29), superficial fibular nerve 5.35 (SD 1.59), and sural nerve 6.73 (SD 1.91). Multivariate linear regression analysis revealed a significant association between cross-sectional area and fascicle count for all three nerves. In addition, there was a significant association seen in the common fibular nerve between fascicle density and height, weight, and body mass index. Age and sex did not predict fascicle count or density (all p > .13). DISCUSSION: UHFUS enabled the identification and counting of fascicles and fascicle density in the common fibular, superficial fibular, and sural nerves. Knowledge about normal values and normal peripheral nerve architecture is needed in order to further understand and identify pathological changes that may occur within each nerve in different disease states.

A case series evaluating patient perceptions after switching from nusinersen to risdiplam for spinal muscular atrophy.

INTRODUCTION/AIMS: In 2016, nusinersen became the first disease-modifying medication approved by the U.S. Food and Drug Administration (FDA) for spinal muscular atrophy (SMA). With the later availability of risdiplam in 2020, individuals now have the option of switching from nusinersen to risdiplam. Limited published data exist to inform this decision. This study aims to evaluate the perceptions and experiences of adult participants and parents of minor participants who previously received nusinersen and switched to risdiplam for the treatment of SMA. METHODS: Institutional Review Board (IRB) approval was obtained from the Wake Forest IRB prior to the initiation of this study. A cross-sectional, observational study, with qualitative and quantitative data gathered via questionnaire and medical record review, was performed. Inclusion criteria included (1) prior diagnosis of SMA, (2) previous treatment with nusinersen, and (3) change to treatment with risdiplam. No participants were excluded based on age. RESULTS: Fourteen participants-eight adults and six children-were enrolled in the study. Respondents noted improvements in physical function with each medication. Overall, respondents reported worse satisfaction with the method of delivery of the intrathecally delivered nusinersen compared to the orally-delivered risdiplam, but no respondent reported negative overall satisfaction with either medication. A majority (78.6%) of respondents reported that switching from nusinersen to risdiplam was the correct decision. DISCUSSION: These results suggest that most patients are satisfied when switching from nusinersen to risdiplam, with the method of delivery being a primary factor.

Evaluation of Serum Neurofilament Light Chain and Nerve Ultrasound in Diabetic Neuropathy.

OBJECTIVE: To assess the role of serum neurofilament light chain (NfL) levels in individuals with diabetic polyneuropathy (DPN) compared with controls, as well as to highlight the different sonographic changes in DPN and determine if NfL correlates with sonographic, clinical, and functional parameters. METHODS: Diabetic individuals with signs or symptoms consistent with peripheral nerve involvement were recruited. They were evaluated by examination, functional neuropathy severity scores, laboratory assessments (including NfL), nerve conduction studies (NCS), and ultrasound. Ultrasound was performed of the bilateral median, ulnar, tibial, fibular, sural, and vagus nerves, and cervical roots 5 and 6. Results were compared with age, sex, and body mass index matched healthy controls. RESULTS: A total of 320 nerves from 20 patients and 480 nerves from 30 controls were evaluated. NfL was significantly elevated in those with diabetes with a mean and standard deviation of 6.95 ± 2.95 pg/mL in the diabetic group and 2.83 ± 0.77 pg/mL in controls (P < .001). Nerve cross-sectional area and serum NfL levels correlated significantly with clinical and functional parameters and with each other (P < .05). CONCLUSION: Individuals with DPN have significantly higher NfL levels than healthy controls, and NfL levels correlate with ultrasonographic parameters. These findings may be useful for the diagnosis, prognosis, and disease monitoring of those with DPN, though further exploration is needed.

Neuromuscular ultrasound in leprosy: A scanning protocol.

The diagnosis of leprosy neuropathies has been traditionally based on clinical findings and electrodiagnostic studies, but ultrasound has emerged as a new tool for use in clinical practice. We conducted a literature search on the subject and developed a pragmatic ultrasound scanning protocol for patients with confirmed or suspected leprosy neuropathy. We suggest scanning the ulnar, median, superficial radial, common fibular and sural nerves at specific sites and assessing cross-sectional area, vascularity, and epineural thickness. Our protocol is potentially useful in differentiating leprosy neuropathies from other demyelinating neuropathies, but its applicability and accuracy must be evaluated in different centers.

Exploration of Neurofilament Light Chain and Nerve Ultrasound in Leprotic Neuropathy.

OBJECTIVES: To explore neurofilament light chain (NfL) levels in leprotic neuropathy compared to controls, and to determine if the changes correlate with ultrasonographic nerve findings. METHODS: Individuals with leprosy with signs or symptoms suggestive of peripheral nerve involvement were recruited. They were evaluated by clinical examination, functional scores, laboratory assessments (including NfL), nerve conduction studies (NCS), and ultrasound. Ultrasound was conducted in bilateral median, ulnar, tibial, fibular, sural, and vagus nerves as well as cervical roots 5 and 6. Results were compared to age, sex, and body mass index matched healthy controls. RESULTS: A total of 320 nerves from 20 patients and 480 nerves from 30 controls were evaluated. NfL was significantly elevated in those with leprosy with a mean and standard deviation of 7.50 + 2.83 compared with 3.42 + 1.18 in controls (P < .001). Ultrasound showed focal enlargement of the nerves, particularly at entrapment sites. Additionally, there were noticeable changes in neural Doppler signal, echogenicity, and epineural thickness among the measured nerve sites. NfL levels in those with leprosy correlated closely with nerve cross-sectional area at all sites (P < .05). Functional and clinical assessment scores correlated with NfL and sonographic cross-sectional area as well (P ≤ .05). CONCLUSIONS: NfL is elevated in leprotic neuropathy. Ultrasound showed specific morphological changes in individuals with leprosy, and nerve enlargement correlated with NfL levels. Thus, both modalities may be useful for the diagnosis, prognosis, and disease monitoring in those with leprotic neuropathy, and further investigations are warranted.

Focused Neuromuscular Ultrasound Approach for the Diagnosis of Chronic Inflammatory Demyelinating Polyneuropathy.

PURPOSE: Previous ultrasonographic studies of individuals with chronic inflammatory demyelinating polyneuropathy (CIDP) have shown nerve enlargement at several sites. This prospective study compares only the bilateral median and ulnar nerves of individuals with CIDP with reference values to determine the clinical usefulness of this focused approach as a diagnostic tool. METHODS: The cross-sectional area, echogenicity, and vascularity of the bilateral median and ulnar nerves of 25 subjects with CIDP were measured using ultrasound. Nineteen had typical CIDP based on the European Federation of Neurological Societies and the Peripheral Nerve Society guidelines, whereas six had atypical CIDP and were diagnosed based on clinical impression. RESULTS: Focal nerve enlargement was found in at least one segment in all subjects. Subjects with typical CIDP had larger cross-sectional areas compared with subjects with atypical CIDP. CONCLUSION: A focused ultrasound study, involving only the median and ulnar nerves, is sensitive for the detection of nerve enlargement in CIDP. Measuring the cross-sectional area of the median and ulnar nerves is clinically feasible and may help establish the diagnosis of CIDP.

Neuromuscular ultrasound standardized scanning techniques and protocols: Expert panel recommendations.

Neuromuscular ultrasound has become an integral part of the diagnostic workup of neuromuscular disorders at many centers. Despite its growing utility, uniform standard scanning techniques do not currently exist. Scanning approaches for similar diseases vary in the literature creating heterogeneity in the studies as reported in several meta-analysis. Moreover, neuromuscular ultrasound experts including the group in this study have different views with regards to technical aspects, scanning protocols, and the parameters that should be assessed. Establishing standardized neuromuscular scanning protocols is essential for the development of the subspeciality to ensure uniform clinical and research practices. Therefore, we aimed to recommend consensus-based standardized scanning techniques and protocols for common neuromuscular disorders using the Delphi approach. A panel of 17 experts participated in the study, which consisted of three consecutive electronic surveys. The first survey included voting on six scanning protocols addressing the general scanning technique and five common categories of suspected neuromuscular disorders. The subsequent surveys focused on refining the protocols and voting on new steps, rephrased statements, or areas of non-agreement. A high degree of consensus was achieved on the general neuromuscular ultrasound scanning technique and the scanning protocols for focal mononeuropathies, brachial plexopathies, polyneuropathies, amyotophic lateral sclerosis, and muscle diseases. In this study, a group of neuromuscular ultrasound experts developed six consensus-based neuromuscular ultrasound scanning protocols that may serve as references for clinicians and researchers. The standardized protocols could also aid in achieving high-quality uniform neuromuscular ultrasound practices.

Pearls & Oy-sters: Case of Atypical Peripheral Nerve Findings Following Paclitaxel for Breast Cancer.

Neuromuscular ultrasound (NMUS) is a valuable tool in establishing a diagnosis of carpal tunnel syndrome (CTS) and can be particularly helpful in patients with clinical CTS but normal nerve conduction studies (NCSs). This case involves the uncommon presentation of enlarged median nerves on NMUS with normal NCS in a patient with breast cancer who developed chemotherapy-induced peripheral neuropathy and CTS after taxane treatment. This case demonstrates that CTS should not be excluded based on electrodiagnostic studies alone, and comorbid CTS should be considered in patients receiving neurotoxic chemotherapy, even in the setting of normal NCS.

A standardized ultrasound approach in neuralgic amyotrophy.

Neuralgic amyotrophy (NA), also referred to as idiopathic brachial plexitis and Parsonage-Turner syndrome, is a peripheral nerve disorder characterized by acute severe shoulder pain followed by progressive upper limb weakness and muscle atrophy. While NA is incompletely understood and often difficult to diagnose, early recognition may prevent unnecessary tests and interventions and, in some situations, allow for prompt treatment, which can potentially minimize adverse long-term sequalae. High-resolution ultrasound (HRUS) has become a valuable tool in the diagnosis and evaluation of NA. Pathologic HRUS findings can be grouped into four categories: nerve swelling, swelling with incomplete constriction, swelling with complete constriction, and fascicular entwinement, which may represent a continuum of pathologic processes. Certain ultrasound findings may help predict the likelihood of spontaneous recovery with conservative management versus the need for surgical intervention. We recommend relying heavily on history and physical examination to determine which nerves are clinically affected and should therefore be assessed by HRUS. The nerves most frequently affected by NA are the suprascapular, long thoracic, median and anterior interosseous nerve (AIN) branch, radial and posterior interosseous nerve (PIN) branch, axillary, spinal accessory, and musculocutaneous. When distal upper limb nerves are affected (AIN, PIN, superficial radial nerve), the lesion is almost always located in their respective fascicles within the parent nerve, proximal to its branching point. The purpose of this review is to describe a reproducible, standardized, ultrasonographic approach for evaluating suspected NA, and to share reliable techniques and clinical considerations when imaging commonly affected nerves.

Sonographic reference values of nerve size in children: A systematic review and meta-analysis.

INTRODUCTION/AIMS: Nerve ultrasound is useful in the diagnosis and follow-up of peripheral nerve disorders in children. The aim of this study was to explore and analyze the current literature on nerve cross-sectional area (CSA) in healthy children, with the goal of presenting reference values and discussing their implications. METHODS: We performed a systematic review and meta-analysis of studies that reported ultrasound measurements of the upper or lower limb nerves in healthy children through a search of Web of Science, PubMed, Embase, and Scopus. RESULTS: Sixteen studies with measurements of 10 nerves covering a total of 5149 nerves measured in 823 healthy children (445 boys and 378 girls) were included. Mean nerve CSA increased with age in the median nerve at the middle and lower third of the upper arm, mid-forearm, and distal wrist crease, the ulnar nerve at the middle third of the upper arm and elbow, the radial nerve at the spiral groove, and the tibial nerve at the popliteal fossa. Growth charts for nerve CSA for different age groups were developed. DISCUSSION: This meta-analysis provides robust reference values for nerve CSA at different sites in children, and this can inform clinical practice and assist in identifying nerve enlargement. Moreover, it identifies the strength and quality of the current published data. We recommend future studies divide their samples into smaller age subgroups and standardize the anatomic site of measurement.

Short-term educational value of online neuromuscular ultrasound courses.

INTRODUCTION/AIMS: We have previously reported that online neuromuscular ultrasound courses are feasible and were found to be useful by most survey respondents. However, our previous report lacked objective assessment of the educational value of the courses. Therefore, we aimed in this study to evaluate the learning outcomes of online neuromuscular ultrasound courses. METHODS: Each of the basic and advanced courses featured one pre- and two post-course online knowledge tests. The percentage of corrected answers and the participants' scores in the three tests were calculated and compared. RESULTS: A total of 153 out of 277 course participants answered the course test. The mean percentage of correct answers were significantly higher in the second and first post-course tests compared to the pre-course test (Basic course test: 80.2 ± 14.8%, 75.5 ± 15.9%, 64.3 ± 19.1%, respectively; Advanced course test: 80.9 ± 20.1, 78.9 ± 15.2%, 69.5 ± 20.2%, respectively). The mean scores of the participants in the basic course test significantly improved in the first and second post-course tests (from 66.6% to 77.5% and from 67.2% to 80.2%, respectively) whereas those of the participants in the advanced course test significantly improved in the first post-course test only (from 76.3% to 85.4%). DISCUSSION: This report demonstrates the capability of online neuromuscular ultrasound courses, particularly the basic-level courses, to enhance knowledge. This information can further help integrate virtual neuromuscular ultrasound teaching as a standard complementary educational format together with supervised in-person or remote hands-on training.

Real-world Adherence to Nusinersen in Adults with Spinal Muscular Atrophy in the US: A Multi-site Chart Review Study.

Limited evidence exists on real-world adherence to nusinersen for the treatment of spinal muscular atrophy (SMA). Data are presented from a multi-site retrospective chart review of 86 adults with SMA initiating nusinersen at nine US centers between January 2017 and February 2019. Seventy-nine (92%) adults remained on nusinersen during the study; 454 (92%) of 493 total nusinersen doses were received on time. Fifty-eight (67%) adults received all nusinersen doses on time. The majority of patients with at least one nonadherent dose resumed nusinersen on time. Most patients followed the dosing schedule across the loading and maintenance dose periods.

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.

Evidence-based guideline: Neuromuscular ultrasound for the diagnosis of ulnar neuropathy at the elbow.

INTRODUCTION/AIMS: The purpose of this literature review is to develop an evidence-based guideline for the use of neuromuscular ultrasound in the diagnosis of ulnar neuropathy at the elbow (UNE). The proposed research question was: "In patients with suspected UNE, does ulnar nerve enlargement as measured with ultrasound accurately identify those patients with UNE?" METHODS: A systematic review and meta-analysis was performed, and studies were classified according to American Academy of Neurology criteria for rating articles for diagnostic accuracy. RESULTS: Based on Class I evidence in four studies, it is probable that neuromuscular ultrasound measurement of the ulnar nerve at the elbow, either of diameter or cross-sectional area (CSA), is accurate for the diagnosis of UNE. RECOMMENDATION: For patients with symptoms and signs suggestive of ulnar neuropathy, clinicians should offer ultrasonographic measurement of ulnar nerve cross-sectional area or diameter to confirm the diagnosis and localize the site of compression (Level B).

A Retrospective Study of Ultrasound Accuracy for the Diagnosis of Chronic Inflammatory Demyelinating Polyneuropathy.

INTRODUCTION: Ultrasound is emerging as a useful tool for the evaluation of immune-mediated neuropathies because it can provide high-resolution anatomic information to complement electrodiagnostic data. Nerve enlargements are commonly found in chronic inflammatory demyelinating polyneuropathy (CIDP), and their presence likely useful in diagnosis, particularly if multifocal. METHODS: In this study, the authors undertook a retrospective chart review to identify ultrasound findings in patients with CIDP previously studied in a single busy neurodiagnostic laboratory. RESULTS: Of the 50 cases identified from 2000 to 2017, individuals with a confirmed diagnosis of CIDP (21 cases) were more likely to have multiple sites of enlargement, as well as more pronounced nerve enlargement, than patients who were subsequently found to have an alternate cause of neuropathy (22 cases). The presence of any moderately enlarged nerve segment predicted definite CIDP with sensitivity of 81% and specificity 77%. CONCLUSION: This study demonstrates that ultrasound can be of diagnostic utility in patients with suspected CIDP, even when conducted in a nonstandardized real-world setting.

Neuromuscular Ultrasound: Indications in the Electrodiagnostic Laboratory.

ABSTRACT: Accurate assessment of neuromuscular disorders is critical to facilitate timely treatment and achieve the best outcomes. Historically, electrodiagnostic studies have filled this role, but recently, neuromuscular ultrasound is being used in the electrodiagnostic laboratory. This review discusses the uses of neuromuscular ultrasound in the electrodiagnostic laboratory that have strong evidence, emphasizing those that could be adopted in a typical electrodiagnostic laboratory with a reasonable level of equipment and training. The evidence currently supports using neuromuscular ultrasound to diagnose carpal tunnel syndrome and ulnar neuropathies at the elbow and as a supplementary test when electrodiagnostic studies are suspected to be falsely negative or in axonal nonlocalizing lesions. Neuromuscular ultrasound can identify the causes of focal mononeuropathies, which can change treatment in specific cases. It is sensitive at identifying fasciculations and providing complementary evidence of autoimmune demyelinating polyneuropathies. It is particularly helpful in assessing nerves after trauma. Neuromuscular ultrasound is likely to prove even more useful in the electrodiagnostic laboratory as the technology continues to advance.