Indications for Neuromuscular Ultrasound: Expert Opinion and Review of the Literature ⇑ Francis O

Clinical Neurophysiology xxx (2018) xxx–xxx

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Clinical Neurophysiology

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Indications for neuromuscular ultrasound: Expert opinion and review of the literature ⇑ Francis O. Walker a, , Michael S. Cartwright a, Katharine E. Alter b, Leo H. Visser c, Lisa D. Hobson-Webb d, Luca Padua e,f, Jeffery A. Strakowski g,h,i, David C. Preston j, Andrea J. Boon k, Hubertus Axer l, Nens van Alfen m, Eman A. Tawﬁk n, Einar Wilder-Smith o,p,q, Joon Shik Yoon r, Byung-Jo Kim s, Ari Breiner t, Jeremy D.P. Bland u, Alexander Grimm v, Craig M. Zaidman w a Department of Neurology at Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, USA b Department of Rehabilitation Medicine, National INeurolnstitutes of Health, Bethesda, MD 20892, USA c Departments of Neurology and Clinical Neurophysiology, Elisabeth-Tweesteden Hospital, Tilburg, The Netherlands d Department of Neurology, Neuromuscular Division, Duke University School of Medicine, Durham, NC, USA e Don Carlo Gnocchi ONLUS Foundation, Piazzale Rodolfo Morandi, 6, 20121 Milan, Italy f Department of Geriatrics, Neurosciences and Orthopaedics, Universita Cattolica del Sacro Cuore, Rome, Italy g Department of Physical Medicine and Rehabilitation, The Ohio State University, Columbus, OH, USA h Department of Physical Medicine and Rehabilitation, OhioHealth Riverside Methodist Hospital, Columbus, OH, USA i OhioHealth McConnell Spine, Sport and Joint Center, Columbus, OH, USA j Neurological Institute, University Hospitals, Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, USA k Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN, USA l Hans Berger Department of Neurology, Jena University Hospital, Jena 07747, Germany m Department of Neurology and Clinical Neurophysiology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands n Department of Physical Medicine & Rehabilitation, Faculty of Medicine, Ain Shams University, Cairo, Egypt o Department of Neurology, Yong Loo Lin School of Medicine, National University Singapore, Singapore p Department of Neurology, Kantonsspital Lucerne, Switzerland q Department of Neurology, Inselspital Berne, Switzerland r Department of Physical Medicine and Rehabilitation, Korea University Guro Hospital, Seoul, Republic of Korea s Department of Neurology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea t Division of Neurology, Department of Medicine, The Ottawa Hospital and University of Ottawa, Canada u Deparment of Clinical Neurophysiology, East Kent Hospitals University NHS Foundation Trust, Canterbury, Kent, UK v Department of Neurology, University Hospital Tuebingen, Tuebingen, Germany w Division of Neuromuscular Medicine, Department of Neurology, Washington University in St. Louis, 660 S. Euclid Ave, Box 8111, St. Louis, MO 63110, USA article info highlights

Article history: Experts routinely use ultrasound to evaluate both common and rare disorders of nerve and muscle. Accepted 2 September 2018 Accumulated evidence now puts diagnostic neuromuscular ultrasound on par with EMG and NCS. Available online xxxx Medical centers must acquire ultrasound equipment to keep electrodiagnostic laboratories current.

Keywords: Neuropathy abstract Myopathy Motor neuron disease Electromyography Over the last two decades, dozens of applications have emerged for ultrasonography in neuromuscular Nerve conduction studies disorders. We wanted to measure its impact on practice in laboratories where the technique is in fre- Diaphragm quent use. After identifying experts in neuromuscular ultrasound and electrodiagnosis, we assessed their use of ultrasonography for different indications and their expectations for its future evolution. We then

⇑ Corresponding author at: Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1078, USA. E-mail addresses: [email protected] (F.O. Walker), [email protected] (M.S. Cartwright), [email protected] (K.E. Alter), [email protected] (L.H. Visser), lisa. [email protected] (L.D. Hobson-Webb), [email protected] (L. Padua), [email protected] (J.A. Strakowski), [email protected] (D.C. Preston), [email protected] (A.J. Boon), [email protected] (H. Axer), [email protected] (N. van Alfen), Eman_Tawﬁ[email protected] (E.A. Tawﬁk), [email protected] (E. Wilder-Smith), [email protected] (J.S. Yoon), [email protected] (B.-J. Kim), [email protected] (A. Breiner), [email protected] (J.D.P. Bland), [email protected] (A. Grimm), [email protected] (C.M. Zaidman). https://doi.org/10.1016/j.clinph.2018.09.013 1388-2457/Ó 2018 Published by Elsevier B.V. on behalf of International Federation of Clinical Neurophysiology.

identified the earliest papers to provide convincing evidence of the utility of ultrasound for particular indications and analyzed the relationship of their date of publication with expert usage. We found that experts use ultrasonography often for inflammatory, hereditary, traumatic, compressive and neoplastic neuropathies, and somewhat less often for neuronopathies and myopathies. Usage significantly correlated with the timing of key publications in the field. We review these findings and the extensive evidence supporting the value of neuromuscular ultrasound. Advancement of the field of clinical neurophysiology depends on widespread translation of these findings. Ó 2018 Published by Elsevier B.V. on behalf of International Federation of Clinical Neurophysiology.

Contents

1. Introduction ...... 00 2. Methods ...... 00 2.1. Expert panel...... 00 2.2. Questionnaire ...... 00 2.3. Survey analysis ...... 00 2.4. Literature review ...... 00 2.5. Additional analysis of index papers ...... 00 3. Results...... 00 3.1. Indications ...... 00 3.2. Ultrasound first ...... 00 3.3. Usefulness of ultrasound components and future expectations for the field ...... 00 4. Discussion...... 00 5. The rationale underlying indications for neuromuscular ultrasound: A review...... 00 5.1. Generalized muscle disorders: ...... 00 5.1.1. Inclusion body myositis (52%/16%) ...... 00 5.1.2. Other inflammatory myopathies: dermatomyositis (51%/11%) and polymyositis (45%/11%) ...... 00 5.1.3. Muscular dystrophy (44%/11%) ...... 00 5.2. Muscle disorders, localized...... 00 5.2.1. Diaphragm paresis (66%/40%) ...... 00 5.2.2. Selective muscle atrophy (61%/30%) ...... 00 5.2.3. Intramuscular cysticercosis (50%/0%)** (Two asterisks mean that less than half the experts have seen patients with this indication, one asterisk means that 6–9 of the experts have not seen it)...... 00 5.2.4. Ultrasound guidance of chemodenervation (41%/24%)* ...... 00 5.2.5. Camptocormia (38%24%) ...... 00 5.3. Nerve disorders ...... 00 5.3.1. Regional or multifocal (primarily axonal) nerve disorders ...... 00 5.3.1.1. Nerve tumor or neuroma (89%/47%) (Beggs et al., 1999—index paper) ...... 00 5.3.1.2. Nerve torsion (81%/26%)* (Aryanyi et al., 2015—index paper) ...... 00 5.3.1.3. Thoracic outlet syndrome (75%/23%) (no index paper identified) ...... 00 5.3.1.4. Neurolymphomatosis (73%/33%)** (Vjayan et al., 2015—index paper) ...... 00 5.3.1.5. Brachial plexopathy (72%/24%) (Martinoli et al., 2002a—index paper) ...... 00 5.3.1.6. Neurofibroma (71%/48%) (Telleman et al., 2017a; 2017b—index papers) ...... 00 5.3.1.7. Lepromatous neuropathy (66%/26%)** (Martinoli et al., 2000—index paper) ...... 00 5.3.1.8. Brachial neuritis (63%/21%) (Arányi et al., 2015—index paper) ...... 00 5.3.1.9. Diabetic amyotrophy (28%/4%) (An et al., 2018—index paper) ...... 00 5.3.1.10. Cranial neuropathy (22%/6%) (Cartwright et al., 2009—index paper) ...... 00 5.3.1.11. Cervical radiculopathy (12%/6%) (Kim et al., 2015—index paper)...... 00 5.3.2. Focal nerve disorders ...... 00 5.3.2.1. Tarsal tunnel syndrome (89%/31%) (Nagaoka et al., 2005—index paper) ...... 00 5.3.2.2. Fibular neuropathy (88%/29%) (Visser 2006—index paper)...... 00 5.3.2.3. Ulnar neuropathy at the elbow (84%/31%) (Beekman et al., 2004—index paper) ...... 00 5.3.2.4. Carpal tunnel syndrome (82%/37%) (Buchberger et al., 1991—index paper) ...... 00 5.3.2.5. Other entrapment neuropathy (81%/29%) (no index paper identifiable) ...... 00 5.3.2.6. Traumatic neuropathy (81%/29%) (Cartwright et al., 2007—index paper) ...... 00 5.4. Generalized primarily demyelinating nerve disorders ...... 00 5.4.1. Charcot Marie Tooth (CMT) (76%/25%) (Martinoli et al., 2002b—index paper)...... 00 5.4.2. Chronic inflammatory demyelinating polyneuropathy (CIDP) (83%/19%) and multifocal motor neuropathy (MMN) (76%/19%) (Sugimoto et al., 2013; Zaidman et al., 2013b—index papers for CIDP; Beekman et al., 2005 index paper for MMN) ...... 00 5.4.3. Hereditary neuropathy with liability to pressure palsies (HNPP) (68%/23%) (Beekman et al., 2002—index paper) ...... 00 5.4.4. Guillain Barre syndrome/acute inflammatory demyelinating polyneuropathy (AIDP) (54%/9%) (Zaidman et al., 2009—index paper) 00 5.5. Generalized primarily axon/motor neuron loss disorders ...... 00 5.5.1. Motor neuron disease and amyotrophic lateral sclerosis (ALS) (77%/23%) (Arts et al., 2008—index paper)...... 00 5.5.2. Non-diabetic axonal polyneuropathy (32%/4%); diabetic polyneuropathy (27%/7%); toxic neuropathy (17%/8%) (Other-non-diabetic polyneuropathy—no index paper identifiable; diabetic polyneuropathy Severenson et al., 2007—index paper; toxic polyneuropathy Briani et al., 2013—index paper)...... 00 5.5.3. Sensory neuronopathy (22%/6%) (Pelosi et al., 2017—index paper)...... 00

5.6. Situational indications: ...... 00 5.6.1. Palpable masses (86%/47%) ...... 00 5.6.2. Variant anatomy (76%/34%) ...... 00 5.6.3. Phobic patients or patients unable to tolerate electrodiagnosis (67%/67%) ...... 00 6. The value of neuromuscular ultrasound and the likelihood of its continued evolution:...... 00 6.1. Validity and limitations of the expert survey ...... 00 6.2. Is there reason to expect that MRI will supersede ultrasound as a complementary routine test for neuromuscular evaluation? ...... 00 6.3. Relative growth of electrodiagnostic and ultrasound imaging technology ...... 00 6.4. Added value of instrumentation and ultrasound in practice ...... 00 6.5. Future expectations for neuromuscular ultrasound ...... 00 6.6. The nature of the current evidence ...... 00 7. Translational implications ...... 00 7.1. Re-envisioning electrodiagnosis ...... 00 Funding...... 00 Declarations of interest ...... 00 Appendix A. Supplementary material...... 00 References ...... 00

1. Introduction following criteria: (a) significant practical experience with the technique; (b) participation in national and international courses For much of the last fifty years, there has been remarkable uni- teaching neuromuscular ultrasound; and (c) multiple publications formity in electrodiagnostic practice. Aside from the rare patient in the fields of both electrodiagnostic medicine and neuromuscular who might need referral to a specialized center for a single fiber ultrasound (mean = 57 publications per expert, including 5 text- EMG study, patients have been able to receive consistent diagnos- books). The panel represented 9 different countries on 4 conti- tic evaluations with comparable results regardless of the size of the nents. Since the survey was in part designed to assess the laboratory or its geographic location. However, now a number of integration of ultrasound into electrodiagnostic practice, experts laboratories provide advanced ultrasound imaging in addition to in neuromuscular ultrasound whose primary specialty was radiol- standard electrophysiological assessment of nerve and muscle, a ogy or rheumatology were not included, although their contribu- trend that appears to be accelerating, and this is creating an tions to the field are cited throughout. unprecedented gap between ultrasound enhanced and standard clinical neurophysiology practice. 2.2. Questionnaire Over 25,000 papers have now been published in PubMed on diagnostic ultrasound of nerve and/or muscle. It accurately estab- The questionnaire was designed to estimate the frequency that lishes a diagnosis for a wide variety of neuromuscular disorders experts use ultrasound for different indications in their practice (Hobson-Webb et al., 2018, Pillen et al., 2016, Cartwright et al., and how often they used ultrasound prior to electrodiagnostic test- 2012). Furthermore, the technique has also changed the way we ing. Additional questions were directed at how experts saw the think and speak. In the past it was common parlance to say that future of the technology, how they characterized its diagnostic the nerves in chronic entrapment syndromes were ‘‘pinched,” but usefulness, and what aspects of instrumentation they found most now we have all seen how they can be focally or diffusely enlarged, helpful in their current practice. All the participant experts were subject to dynamic compression or internally distorted (Tagliafico given the opportunity to provide feedback on the questions prior 2016). The purpose of this study was to conduct a survey of experts to completing the survey. to see how neuromuscular ultrasound is changing electrodiagnosis, its scope of applications, and to determine to what extent ultra- 2.3. Survey analysis sound should be considered optional versus necessary in a modern clinical neurophysiology practice. It also looked to see how closely The survey on indications was intentionally worded with terms the date of publications on new indications for ultrasound corre- that assessed relative frequency of use. It focused on current lated with actual use of the technique, and finally, it reviewed usage--not intended usage in the future. Participants were asked the literature, to present the evidence on the use of ultrasound if they had patients referred for the indication specified and if so, for neuromuscular indications. had they used ultrasound always, often, sometimes, or never in evaluating such patients. Subsequently, the same indications were 2. Methods reviewed to evaluate the expert’s use of ultrasound as the initial diagnostic evaluation prior to electromyography (EMG) and nerve 2.1. Expert panel conduction studies (NCS), again, always, often, sometimes or never. For the purposes of analysis and data display, somewhat arbitrary Members of the expert panel were drawn from suggestions of units were assigned (always = 100%, often = 70%; sometimes = 30%, former journal editors and members of the governance of the Inter- never = 0%). For the portions of the survey assessing instrumenta- national Federation of Clinical Neurophysiology. They were tion impact and future expectations for the field, questions also selected from three specialties that routinely practice electrodiag- used qualitative terms. The assigned percentage values for these nostic medicine: Neurology, Clinical Neurophysiology, and Physi- terms is indicated in the figure legends, to help assist in informa- cal Medicine and Rehabilitation (PMR). Invitations were sent to tion display. For future expectations, the maximal likelihood score 22 identified individual experts of whom 19 agreed to participate; achievable was adjusted to 90%, to indicate the inherent limita- 2 who chose not to participate were no longer actively involved tions of prediction. with neuromuscular ultrasound and the third felt that expert sta- It is recognized that this approach to data display and analysis is tus had yet to be reached. There were 8 neurologists, 6 clinical neu- non-quantitative, but it was designed to provide a reasonably rophysiologists, and 5 PMR physicians. All participants met the accurate way to compare the relative usage of ultrasound across

Please cite this article in press as: Walker FO et al. Indications for neuromuscular ultrasound: Expert opinion and review of the literature. Clin Neurophysiol (2018), https://doi.org/10.1016/j.clinph.2018.09.013 4 F.O. Walker et al. / Clinical Neurophysiology xxx (2018) xxx–xxx multiple indications. Similarly, users of clinical rating scales by the expert panel was analyzed to determine if a correlation sometimes assign percentages to ordinal data to express relative was present. We hypothesized that the indications with longer severity of a disorder or relative change with treatment for primar- intervals since publication of the index paper would correlate with ily descriptive purposes. The experts were not allowed to discuss more experts using ultrasound for the given indication. with one another or see the results of others’ questionnaires until after all the data were collated and only one questionairre was 3. Results completed per laboratory. Also, the experts, while completing the survey, were unaware of the intention to compare their responses 3.1. Indications to the timing of the published literature. A few items had a fair to large number of experts who had not encountered that particular Experts use ultrasound for a large number of indications the indication (e.g. lepromatous neuropathy), and asterisks in the fig- majority of the time (Figs. 1–5). This ranges from about half of ures highlight these items. the time for inflammatory myopathies, to significantly more than half the time for diaphragm paresis, motor neuron disease, chronic 2.4. Literature review inflammatory and hypertrophic neuropathies, suspected masses or tumors, brachial plexopathy, entrapment and traumatic neu- The review of the literature, for papers cited in the discussion, ropathies, unexplained muscle atrophy, and those phobic or unable focused primarily on indications for neuromuscular ultrasound. to tolerate electrodiagnostic studies. Of the items queried, cervical These were selected based on clinical judgment of their relevance radiculopathy had the least usage, and the technique was used less to the field and the strength of the evidence contained. Once com- than half the time in common axonal neuropathies, diabetic amy- piled, the discussion and citations were circulated among the otrophy, camptocormia, cranial neuropathy, and Guillain Barre experts and they were encouraged to provide additional or alter- syndrome. nate references if they thought they provided equivalent or stron- Of interest, the association between years since the seminal ger evidence than those chosen, or if they addressed other unique publication on an indication and the frequency of use of ultrasound aspects of the indication. When available, evidence based reviews showed a moderate correlation with R = 0.56 and robust signifi- were included. All the expert participants reviewed a draft of the cance p = 0.004 (Fig. 6). manuscript and provided input at the draft stage and all were in agreement with the final draft of the manuscript. 3.2. Ultrasound first 2.5. Additional analysis of index papers Ultrasound first is a catchphrase and approach that refers to the We were curious to see if there was a relationship between the use of ultrasound as an initial study to facilitate diagnosis. For neu- timing of particularly informative papers published on specific romuscular ultrasound this sometimes refers to use in the clinic to indications for neuromuscular ultrasound and their application in evaluate patients with complex and undiagnosed muscular dystro- practice by this group of experts. For each specific indication for phy to guide the choice of subsequent gene tests (Bönnemann nerve disorders, the literature was searched for the earliest mean- et al., 2014). In this survey, we queried experts regarding the fre- ingful publication, and the frequency of neuromuscular ultrasound quency with which they have used ultrasound before performing use was correlated with this date. Not all indications had definitive either EMG or NCS studies for patients referred to their laboratory publications, mostly because certain categories were too non- (Figs. 1–5). We found that at least some of the surveyed experts specific (specifically: palpable masses, phobic patients, variant have used ultrasound first for virtually all the indications listed, anatomy, ‘other’ entrapment neuropathies, thoracic outlet syn- and the majority of experts believe that ultrasound first will drome, and ‘other’ axonal neuropathies.); but of the 30 nerve indi- become routine for a select group of disorders in the future. cations, surveyed, 24 items were specific enough to have identifiable single, early influential publications. These were deter- 3.3. Usefulness of ultrasound components and future expectations for mined first by searching Google Scholar (‘‘sonography” of the the field specific indication) and evaluating the top papers listed. The paper that was earliest, with the highest ranking, and that was suffi- One participant did not complete this portion of the survey, and ciently specific (e.g. mentioned the indication in the title or charac- several participants did not answer one or two of the questions in terized findings in a series of patients on that indication) was it because they were unsure how to respond. Therefore, each ques- chosen. This approach identified 18 of the 24 index papers, 12 tion in Figs. 7–9 indicates the number of respondents per item and (50%) of which were ranked #1 or #2 in Google Scholar, and the distribution of those responses. another 6 (25%) of which were ranked between #3–6. This method The most useful aspects of neuromuscular ultrasound, accord- did not identify index papers for the other 6 indications (multiple ing to the experts, are that it helps define anatomy, discovers unex- unrelated papers occupied the top ten citations). Those were pected findings, and complements electrodiagnostic testing selected by reviewing all papers in PubMed (‘‘sonography of x”) (Fig. 7). Experts also find modest to moderate added value in the and choosing the earliest descriptive series of patients that was ability of ultrasound to assess nerve movement, image real-time published on the topic that was sufficiently specific. One paper is blood flow in nerve and muscle, and display fascicular anatomy. a case report in press because no earlier publications are available. Of available ultrasound instrumentation, the experts find high- Once collated, the group of experts was given a chance to see if resolution transducers and color and power Doppler imaging to there were alternative papers, particularly if from earlier years, be of considerable benefit in daily practice (Fig. 8). Experts find that were superior or equivalent to the paper cited. For more moderate benefit from extended field of view ultrasound and details, see Appendix. An evaluation of indications for ultrasound quantitative gray scale analysis. Contrast agents, speckle tracking, in muscle disorders was not conducted because referrals for pri- elastography, and 3-D ultrasound are considered of limited benefit mary muscle disease make up only a small fraction of referrals in at this time, but it should be noted that these are new technologies electrodiagnostic practice. that are not widely available and have yet to be thoroughly studied Once this data was collected, years since publication of the (Gasparotti et al., 2017; Goutman et al., 2017; Motomiya et al., identified key indication paper and frequency of ultrasound use 2017; Dikici et al., 2017; Kwon et al., 2014).

Fig. 1. This figure is a summary slide describing expert usage for the indications listed. Although experts graded responses as no cases seen, never, sometimes, often, and always, the responses were assigned percentages to assist in information display: Never = 0%, Sometimes = 30%, Often = 70%, Always = 100%. The responses were designed to assess current usage, not anticipated future usage. The upper, top dark line represents how frequently they use ultrasound in evaluation of specific indications, the slightly lighter lower line, indicates the frequency with which they use ultrasound first, before other electrodiagnostic studies. NC stands for the number of experts who reported having seen no cases for that indication in their laboratory.

Fig. 2. This ﬁgure uses the same display strategies as in Fig. 1 but for different indications. The double asterisk indicates an indication with many experts who have never seen a case, and the single asterisk, an indication were a modest number of experts have not seen the indication in their laboratory.

The experts uniformly agree on the high likelihood that more 4. Discussion laboratories will adopt neuromuscular ultrasound, it will become a key element in training residents and fellows, its role in neuro- Experts who are already highly skilled in electrodiagnosis use muscular research will continue to expand, and the technology will neuromuscular ultrasound frequently for multiple indications. continue to improve (Fig. 9). Further, the consensus was strongly Once adopted for one indication, its usage quickly spreads across positive for every future application assessed. multiple indications. The discussion is designed to (A) summarize

Fig. 3. This ﬁgure uses the same display strategies outlined in Fig. 1 but for another group of indications.

Fig. 4. This ﬁgure uses the same display strategies as outlined in Fig. 1, for a different group of indications.

Fig. 5. This ﬁgure uses the same display strategies as outlined in Fig. 1. These indications are labeled as situational, as they are not tied to a speciﬁc diagnosis.

Fig. 6. This is a scatterplot showing years since publication of the index paper on the y-axis, and the frequency of usage of ultrasound by experts for the related indication on the x-axis. the evidence supporting the indications for neuromuscular ultra- of healthy myocytes and their replacement by fat and fibrous tis- sound (Section 5), (B) address the likelihood of the continued evo- sue (Reimers et al., 1993a; Pillen et al., 2009). It was noted early lution and value of neuromuscular ultrasound (Section 6) and (C) on that ultrasound was relatively insensitive in distinguishing characterize the translational implications of these findings (Sec- end stage muscle disease from end stage neurogenic disorders, tion 7). The first of these, Section 5, is, by necessity, the longest and that the interpretation of muscle ultrasound often takes place as it surveys the breadth of existing literature on neuromuscular in the context of broader clinical and laboratory assessments. ultrasound (note, less than 1% of the available literature is cited.) 5.1.1. Inclusion body myositis (52%/16%) 5. The rationale underlying indications for neuromuscular The percentages shown are the estimated use frequency from ultrasound: A review Figs. 1–5, first showing the usage of ultrasound for the disorder (52%), and second showing the usage of ultrasound first (prior to other This section highlights the published evidence to date on the electrodiagnostic studies) (16%). variety of indications or the use of neuromuscular ultrasound. Inclusion body myositis is one of the few common muscle dis- Many of the indications are related and most of the pathologic orders with a characteristic signature on ultrasound in which the changes described for nerve and muscle (e.g. muscle atrophy, flexor digitorum profundus is significantly more echogenic and nerve enlargement, and altered echogenicity) are common to mul- atrophic than the adjacent flexor carpi ulnaris. A single ultrasound tiple disorders. The selection of citations was designed to help the image of these adjacent muscles highlights this striking disparity interested reader find a few representative papers for each indica- (Vu and Cartwright 2016, Noto et al., 2014). In the majority of cases tion; an exhaustive review is beyond the scope of this paper. Those a similar disparity has been noted in the lower limb, with increased engaging in a more in depth search of these topics will find that the echogenicity in the gastrocnemius compared to the soleus muscle numbers of studies on neuromuscular ultrasound, the absence of (Nodera et al., 2016). In ALS or polymyositis, disorders commonly conflicting evidence and the consistency of findings further attests confused with inclusion body myositis, adjacent muscles are to its usefulness. almost always equally involved. It is not known to what extent other less common myopathies may show a pattern similar to that seen in inclusion body myositis, but this is a topic under active 5.1. Generalized muscle disorders: study. In affected patients, the distinguishing ultrasound findings, which can be acquired quickly without discomfort, help narrow The first indication ever discovered for neuromuscular ultra- the differential diagnosis and limit the number of additional elec- sound was for primary muscle diseases. (Heckmatt and trodiagnostic studies needed to establish a diagnosis. Dubowitz, 1980). The Heckmatt grading scale (Heckmatt et al., 1982), which rates echointensity of the muscle and the visibility of the signal of the subjacent bone into 4 levels, is still used for 5.1.2. Other inflammatory myopathies: dermatomyositis (51%/11%) grading ultrasound images of muscle involvement in a variety of and polymyositis (45%/11%) myopathic and neurogenic disorders. Quantitative assessment is In the acute phase, polymyositis and dermatomyositis are char- also possible (Scholten et al., 2003). The changes on ultrasound acterized by normal or increased muscle thickness, sometimes (and on MRI and CT) primarily reflect the gradual atrophy and loss with evidence of fasciitis manifest as increased fascial thickness,

Fig. 7. This ﬁgure demonstrates the self-reported assessment of how much each of the aspects of ultrasound imaging contributes to its diagnostic impact in practice. In parentheses is the absolute number of responses for each category by the 18 experts: Not at all = 0%, somewhat = 30%, A moderate amount = 70%, a great deal = 90%. Note that the highest possible score using this grading system would be 90%. Note that one participant did not address the survey questions in Figs. 7–9, and a few participants did not answer one or two of the questions because they were unsure as to how to best respond.

Fig. 8. This ﬁgure demonstrates the self-reported assessment by the experts of how much each of the instrumentation features added to the diagnostic value of ultrasound imaging. In parentheses is the absolute number of responses for each category: None = 0%, very little10%, somewhat30%, a moderate amount = 70%, or a great deal = 90%. Note that the highest possible score would be 90% using this grading system. (See Fig. 7 legend for additional details).

Fig. 9. This ﬁgure displays the self-reported assessment of how the experts view the future of neuromuscular ultrasound. In parentheses are the numbers of responses for each of the categories. Unlikely = 10%, possibly likely = 30%, Very likely = 90%. Note that the highest possible score using this grading system would be 90%. (US = neuromuscular ultrasound). (See Fig. 7 legend for additional details.)

5.2. Muscle disorders, localized tials (Walker and Macdonald, 2012). Ultrasound is often used by experts to evaluate unexplained focal muscle atrophy because it 5.2.1. Diaphragm paresis (66%/40%) helps the design of subsequent electrodiagnostic studies and may The experts most frequently use muscle ultrasound for the eval- facilitate pattern analysis of additional affected and unaffected uation of diaphragm paresis. In large part this relates to the chal- muscles before performing extensive electromyography. Ultra- lenges posed by electrodiagnostic study of this muscle. The sound can also help guide needle placement in an atrophic muscle diaphragm does not lend itself to belly-tendon electrode place- to ensure that the needle is not inserted into an uninvolved deeper ment for nerve conduction studies and co-stimulation artifact from muscle or other vital structure (Boon et al., 2014). the brachial plexus can further complicate interpretation. Further, needle electromyography (EMG) of the diaphragm poses a risk of 5.2.3. Intramuscular cysticercosis (50%/0%)** (Two asterisks mean that pneumothorax, which can be life threatening in a patient with less than half the experts have seen patients with this indication, one pre-existing respiratory dysfunction. Few electrodiagnostic labora- asterisk means that 6–9 of the experts have not seen it) tories routinely perform diaphragm studies. This is a rare disorder, and few of the experts have seen cases Ultrasound is sensitive and accurate for diagnosing diaphragm where this disorder was suspected. Ultrasound reveals a cystic paresis (Boon et al., 2014). It provides a non-invasive view of dia- structure in muscle, sometimes also demonstrating a calcified sco- phragm muscle thickness and echogenicity at rest and with maxi- lex (Nagaraju et al., 2015, Kanhere et al., 2015, Chaudhary, 2014), mal activation, and allows for reliable side-to-side comparison. It is which in the proper clinical setting is highly suggestive of the diag- superior to fluoroscopic evaluation for detecting paresis (Boon nosis. Because electrodiagnosis is uninformative in this disorder, et al., 2014). Furthermore, ultrasound is helpful for EMG studies neuromuscular ultrasound is of particular value. in that it can be used to guide needle placement or to estimate the depth and location of the diaphragm, thus substantially reduc- ing the risk of complications (Boon et al., 2008; Harper et al., 2013; 5.2.4. Ultrasound guidance of chemodenervation (41%/24%)* Shahgholi et al., 2014). It is a technique which may be used as the Ultrasound is a proven tool for guiding local anesthetic injec- first and/or only test for assessing diaphragm function in a clinical tions and soft tissue biopsies, so it is not surprising that ultrasound neurophysiology laboratory. is also effective for guiding botulinum toxin injections (Alter et al., Recent papers suggest a role for ultrasound in evaluating 2013; Alter and Karp 2017). The impact of ultrasound has been patients in the intensive care unit prior to extubation and for documented to result in better outcomes in spasticity and dystonia assessing the potential benefit of diaphragmatic pacing (Zambon for botulinum toxin injections (Picelli et al., 2012, Walter et al., et al., 2017; Sklasky et al., 2015). Given the vital importance of dia- 2018) and when combined with e-stimulation, for phenol injec- phragm function, further ultrasound indications are likely to tions as well (Matsumoto et al., 2017). Of interest, subspecialists evolve (Harlaar et al., 2018). in PMR, familiar with ultrasound guidance for joint injections, tended to be more likely users of this technique than clinical neu- 5.2.2. Selective muscle atrophy (61%/30%) rophysiologists or neurologists in this survey. Ultrasound guidance Occasionally patients present with unexplained muscle atro- of botulinum toxin also proves helpful in patients who have com- phy. Ultrasound can quantitate the degree of atrophy, and based plications from misplaced EMG needle guided injections (Hong on the echogenicity of the muscle, it can provide information et al., 2012). Ultrasound can assist in identifying the cricothyroid regarding its chronicity. Ultrasound screening can provide addi- membrane or muscle in patients requiring botulinum toxin for tional useful information regarding involvement of other affected voice disorders and spastic dysphonia (Siddiqui et al., 2015, Yang muscles as well, often providing insight into its cause. In extreme et al., 2015). For subjects in whom muscle localization is challeng- cases of profound atrophy the affected muscle may be electrically ing, ultrasound is attractive for injection guidance because it can be silent, showing neither insertional activity nor motor unit poten- used along with EMG needle guidance and electrical stimulation.

5.2.5. Camptocormia (38%24%) 5.3.1.4. Neurolymphomatosis (73%/33%)** (Vjayan et al., 2015—index Camptocormia refers to a syndrome in which patients have an paper). Cases of neurolymphomatosis have been seen by only a unusual bent-spine posture when upright which remits on becom- few of the surveyed experts. It may present as either polyneuropa- ing supine. Although rare, it can be seen in association with Parkin- thy or mononeuropathy with either diffuse of focal enlargement of son’s disease or neuromuscular disorders (Ghosh and Milone, nerves (Vijayan et al., 2015). A significant increase in intraneural 2015), its causes are disparate, either resulting from dystonic con- blood flow may be seen on power Doppler imaging which facili- traction of trunk flexors or from a myopathy affecting spine exten- tates diagnosis of this rare disorder (Walker and Cartwright 2015). sors (Sakai et al., 2017, Bertram and Colosimo, 2016, Bertram et al., 2015). Ultrasound is helpful in distinguishing these causes as it can 5.3.1.5. Brachial plexopathy (72%/24%) (Martinoli et al., 2002a—index identify hypertrophy of flexor muscles if they are dystonic and paper). Electrodiagnostic evaluation of plexus lesions is limited in atrophy and increased echogencity of extensor muscles if they that short segment motor or sensory nerve conduction studies are myopathic. Since the myopathy that causes camptocormia is are difficult and distal nerve conduction studies and needle EMG often atypical, using multiple modes of diagnostic evaluation (i.e. are suboptimal for precise localization. In contrast, ultrasound imaging and EMG) is often helpful in confirming its presence and can provide exquisite detail of the brachial plexus and its many assisting with proper biopsy guidance. Correct diagnosis of dys- branches as well as related structures in the neck that can con- tonic camptocormia can help determine if a trial of DBS or botuli- tribute to nerve compression (Martinoli et al., 2002a, Baute et al., num toxin might be appropriate, treatments that would be 2018). However, the brachial plexus is a challenging area in which unhelpful or pose risks if the disorder is caused by myopathy. to develop expertise in neuromuscular ultrasound (Somashekar, 2016, Smith et al., 2016). MR imaging is an alternative, albeit one 5.3. Nerve disorders with possibly lower sensitivity and specificity (Zaidman et al., 2013a). 5.3.1. Regional or multifocal (primarily axonal) nerve disorders 5.3.1.1. Nerve tumor or neuroma (89%/47%) (Beggs et al., 1999—index 5.3.1.6. Neurofibroma (71%/48%) (Telleman et al., 2017a; 2017b—index paper). Although electrodiagnosis can localize pathology to a seg- papers). Recent reports have suggested a potentially promising ment of nerve, it is insensitive for characterizing pathology within role for identifying and following neurofibromas in patients with this segment. Neuromuscular ultrasound is capable of identifying neurofibromatosis, tumors which may undergo malignant trans- tumors or neuromas, which may even occur at common entrap- formation (Telleman et al., 2018b, 2017a, 2017b; Winter et al., ment sites (Telleman et al., 2017a, 2017b, Zhang et al., 2016, 2017). The low cost and ease of use of ultrasound make it ideal Tahiri et al., 2013, Gruber et al., 2007 Hobson Webb and Walker as a screening tool, but further studies are needed to determine 2004, Beggs et al., 1999). Although not explored in this survey, how it can best be used in managing patients. recent studies have demonstrated the potential usefulness of ** intra-operative ultrasound in guiding surgical management of 5.3.1.7. Lepromatous neuropathy (66%/26%) (Martinoli et al., 2000— nerve tumors as well (Simon et al., 2014; Jose et al., 2014). Ultra- index paper). Few of the experts have seen cases of lepromatous sound can help distinguish affected from unaffected fascicles in neuropathy as it is rare in their geographic areas of practice. How- such cases, and can also be useful for screening multilocular ever, ultrasound can be quite helpful in diagnosis with nerve tumors as seen in neurofibromatosis (Winter et al., 2017; enlargement sometimes most prominent in the ulnar nerve just Telleman et al., 2018b, 2017a, 2017b). proximal to the medial epicondyle, often with increased vascularity. (Bathala et al., 2017, 2012; Jain et al., 2016; Martinoli. 2000). From a public health perspective, the portability of ultrasound 5.3.1.2. Nerve torsion (81%/26%)* (Aryanyi et al., 2015—index paper). devices, which can be battery or solar powered, makes them par- Of recent interest, has been the reported association of brachial ticularly attractive for screening individuals in areas without neuritis with nerve torsion, particularly in the radial nerve, which access to modern infrastructure who may be at increased risk for may develop acutely or chronically in association with brachial leprosy or cysticercosis. neuritis (Pan et al., 2014; Arányi et al., 2017, 2015; Shi et al., 2018; Samarawickrama et al., 2016a). Ultrasound reveals focal 5.3.1.8. Brachial neuritis (63%/21%) (Arányi et al., 2015—index acute constrictions or fascicular entwinement within a nerve paper). Imaging in brachial neuritis has been quite informative. which appear as beading. Although electrodiagnostic studies can Both by MR and ultrasound, this disorder can cause torsion or mul- identify severe axonal injury, only imaging studies such as ultra- tifocal abnormalities in peripheral nerves at multiple levels sound can identify the signature features of this disorder which throughout the upper limb (Arányi et al., 2017, 2015; Gruber may prompt urgent surgical evaluation. et al., 2017; Abraham et al., 2016; Lieba-Samal et al., 2016; Van Alfen 2017). In addition, the identification of focal enlargement 5.3.1.3. Thoracic outlet syndrome (75%/23%) (no index paper identi- of limb nerves or individual proximal nerve fascicles by ultrasound fied). The challenge of establishing a diagnosis and identifying provides evidence of this disorder. Such findings, in patients with patients likely to respond to surgery for thoracic outlet syndrome signs of anterior interosseous (or other focal) neuropathy but with is well known (Ferrante and Ferrante, 2017; Strakowski, 2013; a history suggestive of brachial neuritis, can help avoid the need for Simmons, 2013). Ultrasound offers several clues to its presence, surgical exploration for suspected entrapment. Ultrasound can also including the ability to identify cervical ribs or fibrous bands that identify patients for surgical intervention should they show evi- may impinge on the brachial plexus, and the ability to identify dence of nerve torsion with distal loss of function. focal swelling of nerve trunks or roots (Arányi et al., 2016, Mangrulkar et al., 2008). It also has a unique value for dynamic 5.3.1.9. Diabetic amyotrophy (28%/4%) (An et al., 2018—index assessment of potentially compressing muscles, such as the scale- paper). Clinical evaluation and electrodiagnostic testing are usu- nes and pectoralis minor with provocative clinical maneuvers ally definitive in diabetic amyotrophy. However, ultrasound can (Sucher 2012). Although well studied in other disorders of the bra- be of value in evaluating muscle involvement and chronicity. A chial plexus, neuromuscular ultrasound in neurogenic thoracic recent case suggests that proximal lower limb motor and sensory outlet syndrome has yet to be systematically studied, in part due nerves may show focal changes on ultrasound extending beyond to the lack of a gold standard for its diagnosis. the expected radiculoplexus distribution, but more studies are

Please cite this article in press as: Walker FO et al. Indications for neuromuscular ultrasound: Expert opinion and review of the literature. Clin Neurophysiol (2018), https://doi.org/10.1016/j.clinph.2018.09.013 F.O. Walker et al. / Clinical Neurophysiology xxx (2018) xxx–xxx 11 needed (An et al., 2018). The deep location of the lumbosacral 5.3.2.2. Fibular neuropathy (88%/29%) (Visser 2006—index plexus makes it inaccessible to routine ultrasound imaging; here paper). Fibular neuropathy at the knee provides a compelling MRI is the preferred technique. rationale for the use of ultrasound for diagnosis because ultrasound sometimes demonstrates a surgically correctible intraneural 5.3.1.10. Cranial neuropathy (22%/6%) (Cartwright et al., 2009—index ganglion cyst (Spinner et al., 2008). This finding is more common in paper). Cranial neuropathies are an emerging area of investigation patients lacking another cause for the disorder such as leg crossing, by ultrasound in part because of the recent improvements in ultra- squatting or weight loss (Visser 2006, Cartwright and Walker 2013, sound resolution and in part because of the challenge of evaluating Visser et al., 2013). Electrophysiological findings alone cannot cranial nerves with electrophysiology (Smith, 2018, Stino and exclude the presence of such a cyst, and given the higher resolution Smith, 2018). Cranial nerves 1, 3, 4, 5, 6, 8, 9 are difficult to visual- of ultrasound than MRI, ultrasound appears more sensitive for ize on ultrasound (Tawfik et al., 2015). The optic nerve is readily their detection (Wilson et al., 2017). The common fibular nerve imaged, but caution should be taken to ensure that power settings can also be severely injured from knee dislocations and other on the instrument (and use of color flow imaging) are limited to trauma in that region. The anatomic correlation provided by ultra- avoid inadvertent injury to the eye. As it is often considered part sound in these types of injuries includes nerve stretch, compres- of the CNS, it is not discussed further in this review (Tawfik sion from hematoma, transection, projectile penetration or et al., 2015). The vagus, if enlarged in AIDP, may be associated with muscle tear and can assist with proper diagnosis and management an increased risk of autonomic instability (Grimm et al., 2014a; (Zywiel et al., 2011, Marciniak 2013, Grant et al., 2015). Ultrasound Knappertz et al., 1998). It also can be enlarged in patients with can also help identify variant fibular nerve anatomy that may com- CMT 1B, and decreased in size in patients with diabetes mellitus plicate interpretation of nerve conduction studies (Luchetta et al., (Tawfik et al., 2017, Cartwright et al., 2009). The facial and 2011). hypoglossal nerves are visible with ultrasound to some extent (Meng et al., 2016; Tawfik et al., 2015). The spinal accessory nerve, which is vulnerable to minor procedures in the neck, is amenable 5.3.2.3. Ulnar neuropathy at the elbow (84%/31%) (Beekman et al., to imaging, and a recent study suggests that ultrasound is sensitive 2004—index paper). Ultrasound also provides a particularly useful for the detection of transection of this nerve (Cesmebasi et al., assessment of the ulnar nerve at the elbow (Yoon et al., 2010; 2015a; Cesmebasi and Spinner, 2015). At this time expert use of Yoon et al., 2008; Beekman et al., 2004a). Nerve conduction studies ultrasound for evaluating cranial neuropathies is limited, but with are less sensitive for diagnosing this disorder than carpal tunnel increasing experience with the technique new indications may syndrome. One complicating factor is subluxation or dislocation evolve. of the ulnar nerve over the medial epicondyle with elbow flexion in some individuals. In such cases, the measurement of the 5.3.1.11. Cervical radiculopathy (12%/6%) (Kim et al., 2015—index expected course of the ulnar nerve around the elbow over- paper). A few publications have suggested that ultrasound can estimates the true length of the nerve, which leads to a nerve con- identify nerve enlargement in cervical spinal nerves just as they duction velocity calculation that may miss true slowing (Childress, exit the neural foramen in radiculopathy (Takeuchi et al., 2017; 1975; Kim et al., 2005, 2008). Recent papers have suggested that Metin Ökmen et al., 2018; Kim et al., 2015), but further studies dislocation, in which the nerve completely pivots around the med- are needed. Expert use of ultrasound is limited in this area, but ial epicondyle may be protective, whereas, subluxation, where it expertise in imaging the spinal nerves in a common disorder such rises up on the medial epicondyle, but does not dislocate, may as cervical radiculopathy could have additional value in helping place the nerve just deep to the skin adjacent to the medial epi- electrodiagnosticians acquire skill in brachial plexus imaging. condyle where it is vulnerable to pressure at the elbow (Leis et al., 2017). However, the extent to which subluxation actually 5.3.2. Focal nerve disorders puts the nerve at risk is debated. (Van Den Berg et al., 2013). Ultra- Ultrasound is helpful in entrapment neuropathies in a variety of sound imaging, with a bit of practice, provides a more precise ways. It provides anatomic confirmation of focal neuropathy which assessment of this type of nerve movement than palpation, partic- is particularly useful when electrophysiological studies are border- ularly in obese patients or in those who have had previous ulnar line or non-localizing. It also can identify unexpected anatomic nerve surgery. It also can be used to assess the influence of the lesions that can cause nerve compression, such as cysts, foreign medial triceps brachii muscles on subluxation and compression bodies or tumors, which may be electrodiagnostically indistin- of the nerve (Jacobson et al., 2001). guishable from common entrapment. Ultrasound also provides Reference values for the ulnar nerve show consistency across additional physiologic information, such as nerve vascularity and multiple studies (Fink et al., 2017; Terayama et al., 2018). Of addi- mobility that may be of help in evaluating pathophysiological tional interest, ultrasound can help pinpoint the lesion to the mechanisms (Park et al., 2018; Dejaco et al., 2013). retroepicondylar groove (sulcus olecrani), most often seen in desk workers, or the humeroulnar arcade (cubital tunnel proper) below 5.3.2.1. Tarsal tunnel syndrome (89%/31%) (Nagaoka et al., 2005— the attachment of the flexor carpi ulnaris muscle just distal to the index paper). Some studies suggest electrodiagnostic techniques elbow, more commonly seen in manual workers (Omejec and have relatively poor accuracy for identifying tibial neuropathy at Podnar, 2016). Ultrasound is effective for detection of anatomic the tarsal tunnel (Doneddu et al., 2017). Ultrasound can be used variations such as an anconeus epitrochlearis muscle that can pre- to identify anatomic structures in the tarsal tunnel that could pre- dispose to nerve compression, particularly in younger individuals dispose to neuropathy such as lipomas, varicosities, ganglion cysts (Lee et al., 2016; De Maeseneer et al., 2015). Further, ultrasound or tenosynovitis. In addition, it provides a direct evaluation of the is helpful in identifying ulnar nerve pathology in symptomatic size and fascicular anatomy of the tibial nerve (Nagaoka et al., patients in whom electrodiagnosis is normal (Yoon et al., 2010) 2005, Tawfik et al., 2016). A recent review concludes that imaging and, in conjunction with nerve conduction studies, may also help may be more informative than electrodiagnosis in this disorder predict the results of surgical intervention (Beekman et al., likely accounting for expert interest in the technique (Doneddu 2004b). Ultrasound also is useful for assessing post-surgical prob- et al., 2017; Iborra et al., 2018). In one recently reported series, lems, as it can identify undesired positioning of the nerve, exces- ultrasound was abnormal in all cases of electrophysiologically ver- sive mobility or subluxation, kinking, persistent focal notching ified tarsal tunnel syndrome (Samarawickrama et al., 2016b). and post-surgical scarring (Gruber et al., 2015, Duetzmann et al.,

2016). Further investigation of how ultrasound can enhance man- are uses of ultrasound for evaluating bowel and bladder dysfunc- agement and outcomes is needed (Cartwright et al., 2015). tion an area of active ongoing research (Tagliaﬁco et al., 2014).

5.3.2.4. Carpal tunnel syndrome (82%/37%) (Buchberger et al., 1991— 5.3.2.6. Traumatic neuropathy (81%/29%) (Cartwright et al., 2007— index paper). Neuromuscular ultrasound is supported by level A index paper). Perhaps the most persuasive outcomes evidence for recommendation for the diagnosis of carpal tunnel syndrome the use of neuromuscular ultrasound is in suspected traumatic (Cartwright et al., 2012). Further, neither NCS nor ultrasound have neuropathy (Renna et al., 2012; Chin et al., 2017; Burks et al., been shown convincingly to be diagnostically superior to one 2017; Lauretti et al., 2015). In these cases, ultrasound modifies another; rather they are essentially of equivalent value. Of interest, the diagnosis and treatment plan in up to 58% of studies (Padua up to 25% of false negative ultrasound studies in CTS may result et al., 2013, 2012). Discoverable pathology ranges from transection, from isolated enlargement of the median nerve in the distal carpal to scar tissue formation, to bony entrapment of nerves in fractures tunnel or palm instead of the wrist, and this should be taken into or callous. Transection is of particular importance, as electrodiag- account in any future studies comparing the two approaches nostic studies alone cannot distinguish between transection and (Paliwal et al., 2014; Csillik et al., 2016). Ultrasound evaluation of acute complete neurapraxia or chronic complete axonotmesis the median nerve in suspected carpal tunnel syndrome should (Bianchi et al., 2014; Walker, 2017; Cartwright et al., 2007). Delay- include, at a minimum, distal and proximal portions of the nerve ing surgery, even by a few weeks, to repair transection results in in the hand; blood flow imaging may also be of benefit (Karahan worse outcomes so the ability to detect transection early is of prog- et al., 2018). nostic significance. Furthermore, ultrasound can help identify Ultrasound imaging of the median nerve in CTS adds value to nerve lesions distant from the trauma site, for example posterior NCS in several ways. First, it provides anatomic evidence of focal interosseous neuropathy may develop in patients with radial nerve enlargement that is independent of electrophysiological findings. compression from humeral fractures (Erra et al., 2016). Finally, Second, it provides a structural baseline for subsequent studies, ultrasound may help in management and prognostication after complemting the physiological baseline provided by NCS should traumatic neuroma (Coraci et al., 2015). Distinguishing lesioned patients need to be restudied for treatment failure. For example, from unlesioned fascicles and extraneural from intraneural scar- ultrasound can identify focal pathology in the recurrent branch ring, fibrosis or hematoma can help guide surgical intervention. of the median nerve a structure sometimes injured during surgery Not surprisingly, a majority of the experts frequently use ultra- (Smith et al., 2017; Riegler et al., 2017). Third, it sometimes iden- sound in suspected nerve trauma. tifies unexpected causes or contributing factors not evident by electrodiagnosis including tumor, accessory muscles, or thrombo- 5.4. Generalized primarily demyelinating nerve disorders sis of a persistent median artery (DeFranco et al., 2014; Walker et al., 2012; Rzpecka-Wejs et al., 2012; Padua et al., 2006). Fourth, 5.4.1. Charcot Marie Tooth (CMT) (76%/25%) (Martinoli et al., 2002b— it can identify variants, such as Martin-Gruber anastomosis, which index paper) can complicate interpretation of nerve conduction studies (Gans Ultrasound demonstrates striking, diffuse, nerve enlargement in and van Alfen, 2017); Fifth, ultrasound of carpal tunnel syndrome, CMT type 1, the most common form of hereditary hypertrophic the best understood, easiest to image, and most frequently encoun- neuropathy. The abnormality is present from a very young age, is tered focal neuropathy, helps practitioners hone and maintain more prominent proximally, and is associated with significant ultrasound imaging skills in identifying neuromuscular pathology. enlargement of individual nerve fascicles (Telleman et al., 2018a; These include changes in echogenicity and nerve shape that Yiu et al., 2015; Martinoli et al., 2002b). A quick ultrasound scan, accompany entrapment, atypical nerve branching, persistent med- even of one or two nerves is highly informative, and can be used ian arteries, anomalous tendon, nerve and muscle anatomy, loss of to screen family members of affected patients. Given the harm that normal nerve sliding and movement relative to the tendons with chemotherapy can cause in such patients, a quick and painless wrist/finger flexion and extension, increased nerve vascularity, screening tool for patients suspected of having the disorder is of and neurogenic atrophy and hyperechogenicity in muscles inner- value. Of note, the absence of profound nerve enlargement does vated by the median nerve. not exclude axonal forms of CMT, but nerves may be moderately enlarged in these disorders as well (Padua et al., 2018; Schreiber 5.3.2.5. Other entrapment neuropathy (81%/29%) (no index paper et al., 2013). A recent report also suggests that nerve enlargement identifiable). When relatively uncommon entrapments are sus- may be seen in children with Dejerine-Sottas disease (Hobbelink pected, most of the experts find ultrasound of benefit in part et al., 2018), and is prominent in CMT1B (Cartwright et al., 2009). because unexpected anatomic pathology is likely to be more often found in such disorders. Furthermore, in many less common neu- 5.4.2. Chronic inflammatory demyelinating polyneuropathy (CIDP) ropathies, short segment nerve conduction studies are not always (83%/19%) and multifocal motor neuropathy (MMN) (76%/19%) possible. In such cases, ultrasound could be used to enhance near (Sugimoto et al., 2013; Zaidman et al., 2013b—index papers for CIDP; nerve studies, should they be desired (Deimel et al., 2013). Patients Beekman et al., 2005 index paper for MMN) anxious to find the cause of their symptoms, particularly if electro- These two disorders are discussed together because a number diagnostic studies are negative, are often reassured by ultrasound, of recent neuromuscular ultrasound papers include both disorders. even if it too yields negative results. Of note, this survey did not In both, ultrasound typically demonstrates significant, multifocal specifically address the use of ultrasound in meralgia paresthetica, nerve enlargement particularly in the proximal median and ulnar posterior interosseous neuropathy, or other disorders of smaller nerves and brachial plexus, not always associated with clinical dys- nerves, specific indications for which there is increasing evidence function in the same distribution. Several grading scales and proto- of its value. (Walker, 2017; Kim et al., 2017; Hung et al., 2016; cols for determining abnormality have been proposed (Grimm Moritz et al., 2013; Diemel et al., 2013; Aravindakannan and et al., 2016a; Kerasnoudis et al., 2016; Padua et al., 2014; Jang Wilder-Smith, 2012; Kim et al., 2012). Of particular interest is et al., 2014) and perhaps the simplest of these is most attractive ‘‘double crush” syndromes in which ultrasound can rapidly screen (Goedee et al., 2017). Given the risk and expense of treating CIDP for a second focal neuropathy in a patient with compression at a and MMN with steroids, IVIG, or chemotherapeutic agents it makes distal or proximal site of the same nerve (Dietz et al., 2016; Erra sense to use both imaging and electrophysiology to establish a et al., 2016; Lee et al., 2016). Also not addressed in this report, diagnosis. Furthermore, ultrasound may help differentiate suba-

5.5. Generalized primarily axon/motor neuron loss disorders 5.5.3. Sensory neuronopathy (22%/6%) (Pelosi et al., 2017—index paper) 5.5.1. Motor neuron disease and amyotrophic lateral sclerosis (ALS) While nerves typically enlarge and become hypoechoic in most (77%/23%) (Arts et al., 2008—index paper) neuropathies (Walker 2017), recent studies have shown that in Ultrasound is a particularly sensitive tool for detecting fascicu- some sensory neuronopathies, particularly cerebellar ataxia, neu- lations in muscle (Walker et al., 1990). Now that the Awaji criteria ropathy, vestibular areflexia syndrome (CANVAS), nerve thinning include fasciculations as part of the diagnostic criteria for amy- can be seen (Pelosi et al., 2018, 2017). Ultrasound in Friedereich’s otrophic lateral sclerosis (ALS), adding ultrasound to the clinical ataxia, another, somewhat more complicated and possibly mixed exam has proven to be useful for establishing this diagnosis in form of sensory neuronopathy, shows that some nerves may show patients (Grimm et al., 2015, Boekestein et al., 2012, Misawa enlargement in this disorder, so additional work is needed (Mulroy et al., 2011, O’gorman et al., 2017). Ultrasound can also be used et al., 2017). In Wartenberg’s migrant sensory neuritis, an idio- to assess the split hand index, using echointensity ratios of the the- pathic, patchy, pure sensory neuropathy ultrasound reveals diffuse nar and hypothenar muscles (Seok et al 2018). For those seeking multifocal nerve enlargement which includes pure sensory and electrodiagnostic confirmation of ALS, ultrasound, by identifying mixed nerves (Herraets et al., 2017). At this time, most experts promising muscles for EMG sampling, can reduce the number of are not routinely using ultrasound to evaluate pure sensory disor- muscles that need to be tested for diagnosis (Caress 2017). Of note, ders, but further investigation seems promising. recent studies have suggested that fasciculations may be the earliest manifestation of amyotrophic lateral sclerosis, and, that as this 5.6. Situational indications: disease spreads to uninvolved limbs, fasciculations may be the heralding feature. It is possible therefore, that fasciculations could 5.6.1. Palpable masses (86%/47%) also serve as a biomarker of the disorder (de Carvahalo et al., 2017; It is not uncommon for patients to describe palpable lumps or Eisen and Vucic, 2013). bumps during an electrodiagnostic evaluation. Ultrasound is quite Nerve ultrasound in ALS may also be of diagnostic benefit helpful in these cases. It can demonstrate to the patient that noth- because motor nerves tend to be slightly smaller than normal. This ing is apparent by ultrasound which can be quite reassuring; alter- is likely due to gradual motor axonal loss (Schreiber et al., 2016; natively, it can identify lesions which sometimes are not apparent Cartwright et al., 2011). Multifocal motor neuropathy (MMN), by clinical examination. Common palpable findings include benign which can be confused clinically with motor neuron disease, often enlarged lymph nodes, lipomas and ganglion cysts. However ultra- shows enlargement of nerves, and as such, the presence of nerve sound can identify a wide variety of other pathologic changes enlargement may be a useful additional discriminating factor in including scar tissue, neuromas, tumors, calcifications, aneurysms, distinguishing between MMN and ALS (Jongbloed et al., 2016). arteritis, aberrant muscles or tendons, musculoskeletal disorders Spinal muscular atrophy, a now treatable disorder, also shows and bony malformations. The sonoacoustic properties of unex- characteristic changes on ultrasound, with hyperechoic, atrophic pected peripheral masses may also be useful in discriminating muscles and a correspondingly hypertrophic layer of subcutaneous between various peripheral nerve associated tumors and changes fat. The striking contrast between the hypoechoic fat and hypere- on color Doppler may even help in the diagnosis temporal arteritis choic muscle provides a useful yardstick for assessing its presence (Ryu et al., 2015, Nescher et al., 2002). The neuromuscular sonog-

Please cite this article in press as: Walker FO et al. Indications for neuromuscular ultrasound: Expert opinion and review of the literature. Clin Neurophysiol (2018), https://doi.org/10.1016/j.clinph.2018.09.013 14 F.O. Walker et al. / Clinical Neurophysiology xxx (2018) xxx–xxx rapher, even if not sure about the exact nature of the change, can performed, and it is possible that inaccuracies resulted from this often determine if it is causing focal compression of nerve or mus- approach; however, given the variation in responses from partici- cle and describe it in a manner that helps the referring physician pant to participant, and significant variations in practice suggest decide if further imaging (e.g. MR) is warranted (DiDomenico that there was no universal trend in over or underreporting ultra- et al., 2014). A recent report suggests that extra-neural findings sound usage. It should be noted, however, that the overall relation- are not uncommon in routine neuromuscular ultrasound examina- ship between the publication date of evidence and the actual usage tions (Bignotti et al., 2018). of ultrasound (Fig. 6) suggests that expert practice is responsive to the published literature and thus, less likely to be reflective of 5.6.2. Variant anatomy (76%/34%) internal or systematic bias. Variant anatomy can sometimes be anticipated, for example, in Another limitation of the manuscript is that it does not address patients with congenital malformations, severe trauma, or who have the skill level required to perform neuromuscular ultrasound, nor undergone reconstructive surgery or nerve transposition. In others, the requisite sophistication of ultrasound equipment to address cer- anatomic variation is discovered during their laboratory evaluation. tain conditions. Similarly, appropriate requirements for instrumen- In either case, ultrasound can be of value in helping to guide EMG tation for each indication have yet to be defined, but this reflects the and NCS studies for nerves or muscles in unusual locations and for evolving nature and standardization of ultrasound devices. The time evaluating pathology secondary to the variant anatomy (Zhu et al., required for physicians in electrodiagnostic practice to acquire 2011; Erra et al., 2013; Enhesari et al., 2014; Cesmebasi et al., expert ultrasound imaging and interpretation skills is unknown 2015b; Gans et al., 2017; Grigoriu et al., 2015). For example, persis- because many of the experts learned ultrasound through the ineffi- tent median arteries can thrombose causing acute symptoms sug- cient process of trial and error. However, the degree to which gestive of carpal tunnel syndrome or nerves can be entrapped in thoughtful instruction can speed up learning is significant in that instrumentation used to secure displaced fractures (Walker et al., reliable large muscle ultrasound measurement skills can be 2013; Peer et al., 2001). Identifying variant anatomy also may help acquired with less than one hour’s training, and reliable upper guide interventions around vital structures. Ultrasound can also be extremity nerve imaging skills can be acquired in two months of res- used to identify anatomic variants suggested by unusual NCS find- idency training in an electrodiagnostic laboratory with ultrasound ings such as Martin-Gruber anastomoses or accessory fibular nerves equipment (Zaidman et al., 2014a, Garcia-Santibanez et al., 2018). (Gans and van Alfen, 2017; Luchetta et al., 2011). Other possible limitations of neuromuscular ultrasound unad- dressed in this manuscript include the overlap in presentation of musculoskeletal (MSK) disorders with neuromuscular disorders. 5.6.3. Phobic patients or patients unable to tolerate electrodiagnosis Not all physicians skilled in neuromuscular ultrasound can evalu- (67%/67%) ate for MSK disorders. It is also possible that ultrasound could con- A small percentage of patients referred for electrodiagnostic test- tribute to the costs of neurodiagnostic evaluations. However, once ing are unable to tolerate the procedure. Small children and infants expertise in neuromuscular ultrasound and an instrument are present special challenges in this regard and an unknown number acquired, the marginal cost of ultrasound is quite modest. An anal- are never referred for testing even when it might be appropriate. ysis of the cost of ultrasound in practice is beyond the scope of this At the request of the parents, sedation is sometimes used which review, but preliminary work suggests ultrasound is cost-effective has other risks and drawbacks. As a third component of the neurodi- (Cartwright et al., 2015). agnostic evaluation, ultrasound offers an intermediate step in the evaluation of such individuals. It assesses nerves and muscles in a 6.2. Is there reason to expect that MRI will supersede ultrasound as a patient friendly manner, which in itself, may be sufficient for diag- complementary routine test for neuromuscular evaluation? nosis in some disorders or suitably informative to obviate the need for EMG or nerve conduction studies. For example, there is evidence The experts were not specifically asked this question, but the that ultrasound, by assessing the echointensity ratio of differentially investment in ultrasound and optimism for its future clearly indi- innervated muscles, may be helpful in quantitating the extent of cates that this is not felt to be likely. To date, for the few published axonal loss in distal hand muscles without the discomfort of EMG comparisons of MRI with neuromuscular ultrasound, ultrasound (Kim et al., 2016). Sometimes, after performing an ultrasound, has proven to be an equal or somewhat superior diagnostic tech- enough trust is built with the examiner to allow for limited addi- nique (Bignotti et al., 2017; Smith et al., 2016; Jannsen et al., tional electrodiagnostic studies. Ultrasound may also help in deter- 2014; Zaidman et al., 2013a; Gabmarota et al., 2007). This is not mining if there is a need for other types of testing. surprising as ultrasound has significantly better resolution than MRI (Cartwright et al., 2017, Gambarota et al., 2007), and the com- 6. The value of neuromuscular ultrasound and the likelihood of puter driven technology that has contributed to improved MR res- its continued evolution: olution over the last few decades is similar to the technology that continues to improve ultrasound resolution. The lower cost, porta- 6.1. Validity and limitations of the expert survey bility, and availability without scheduling of ultrasound are fixed advantages of the technique. Nonetheless, MRI offers specific This study has several limitations. It should be reiterated that advantages including contrast enhancement, tractography and the self-reporting component regarding expert usage is non- access to nerves throughout the body—information unavailable quantitative and the translation of terms such as ‘sometimes, often through ultrasound making MRI a valuable tool for research, vali- and frequent’ can vary across different individuals. It is further pos- dation of ultrasound findings and direct evaluation of patients. Of sible that participant enthusiasm for ultrasound may have biased note, ultrasound and MRI measurements of nerve size correlate the results. Hidden bias in a survey of this type cannot be com- quite well (Pitarokoili et al., 2018). pletely excluded, although a number of steps were taken to avoid or minimize it. The geographic and specialty representation among 6.3. Relative growth of electrodiagnostic and ultrasound imaging the experts is well balanced and there was, reassuringly, a consen- technology sus among the experts on the selection of representative publications cited in this report. The survey involves self-reporting and Although ultrasound and electrodiagnosis both evolved from recall instead of a monitored retrospective analysis of all studies oscilloscope technology (Walker, 2007), electrodiagnostic technol-

Please cite this article in press as: Walker FO et al. Indications for neuromuscular ultrasound: Expert opinion and review of the literature. Clin Neurophysiol (2018), https://doi.org/10.1016/j.clinph.2018.09.013 F.O. Walker et al. / Clinical Neurophysiology xxx (2018) xxx–xxx 15 ogy is in an evolutionary plateau at this time and is relatively the experts foresee curtailment of their use of the technology unchanged in the last few decades. Motor unit quantitation has and all foresee a high likelihood for more indications, better quality improved with newer programs, but the impact of computerized instruments, more research, and better diagnosis. All see it as a EMG analysis has been, at best, modest. In contrast, ultrasound part of routine clinical neurophysiology training and practice in has evolved considerably and this survey shows a unanimous the future. Also, given the increasing use of ultrasound in medical expert consensus as to continued improvements in ultrasound schools, it seems likely that prospective residents and fellows will technology. Furthermore, instrumentation is becoming more expect training programs to be able to instruct them in neuromus- adaptable, with remarkable miniaturization of some ultrasound cular ultrasound. Point of care ultrasound is becoming an integral devices, some now the size of a cellular telephone. Image resolu- part of many medical specialties as well. The experts are optimistic tion continues to improve with modifications in transducers and about increasing pediatric indications for neuromuscular ultra- signal analysis, and over the last few decades, the entry level cost sound and the use of ultrasound first for certain indications. The of an effective instrument has dropped considerably. Currently, at only area where there is significantly less agreement by experts least two companies have developed combined ultrasound/EMG is the likelihood of lower cost- ultrasound instruments. instruments that can simultaneously display ultrasound and EMG data. Standard options on ultrasound instruments have also 6.6. The nature of the current evidence increased, with extended field of view, 3-D and 4-D imaging, elastography, and other advanced programs becoming more available The rate of discovery of new indications for neuromuscular ultra- on smaller instruments. Ultra-high frequency transducers have sound, the endurance of previously discovered indications, the con- been developed that offer unprecedented visualization of superifi- tinued evolution of instrumentation, its non-invasiveness, and the cal peripheral nerves and surrounding structures (Cartwright et al., growing use of ultrasound for different neuromuscular disorders 2017). Training in neuromuscular ultrasound is now much more by experts in electrodiagnostic medicine makes a compelling case widespread than a decade ago. The evolution of ultrasound is for imaging in clinical neurophysiology laboratories. We encourage accelerating and recognition of this trend has led to training med- rigorous attention to design in future studies of neuromuscular ical students and residents in clinical applications of ultrasound, ultrasound to help facilitate its acceptance by those outside the field and in a few countries, neuromuscular ultrasound certification pro- of electrodiagnosis. Similarly, readers interested in formal levels of grams are active or in development. There is also rapidly growing evidence are encouraged to explore the literature and report their interest in the use of ultrasound guidance for enhancing existing findings. However, for those readers who practice electrodiagnosis techniques such as steroid injections, diagnostic anesthetic blocks and who wish to form an independent opinion on the usefulness and pre-operative localization of nerves, as well as in the develop- of neuromuscular ultrasound, we suggest that they borrow an ment of new techniques such as needle fenestration for carpal tun- instrument and simply look for themselves. nel syndrome, hydrodissection of entrapped nerves and regenerative procedures (Hanna et al., 2017, Tudose et al., 2017, Cass, 2016, Strakowski, 2016, Tagliafico et al., 2016, McShane 7. Translational implications et al., 2012). Expertise with ultrasound is a prerequisite for would-be innovators in these areas and for those testing the clini- For decades, electrodiagnostic medicine has been based on a cal value of new approaches. fairly equal assignment of importance to EMG and NCS in the evaluation of patients referred for a neuromuscular evaluation. This is 6.4. Added value of instrumentation and ultrasound in practice because the need for one or both procedures cannot be determined until an expert in the laboratory sees the patient and initial test The majority of the focus of neuromuscular ultrasound over the results are available. A laboratory that only performed one of these last few decades has been on resolving the anatomy of nerves, tests would be of limited value. muscles, blood vessels and the surrounding tissues (Figs. 7 and Neuromuscular ultrasound has now become, in addition to EMG 8). Experts have thus placed the highest value, in their current and NCS, a third component of a neurodiagnostic evaluation. This is equipment, on the high resolution transducers and color flow because the need for any combination of EMG, NCS or ultrasound imaging—the features most helpful for assessing anatomy, comple- cannot be determined until an expert sees the patient and some menting electrodiagnostic findings, and in identifying unexpected preliminary test results are available (Tables 1 and 2). What makes pathology. Quantitative gray scale analysis and extended field of the interplay of the three studies of interest is that some informa- view, techniques which can further assist in anatomic resolution tion provided by EMG and NCS cannot be replicated by ultrasound are rated next most helpful. Contrast agents, speckle tracking, elas- including selective motor versus sensory impairment in the same tography and 3D ultrasound are more recent innovations in ultra- nerve, sensory localization with respect to the dorsal root ganglion, sound technology that have been the subject of relatively few and some aspects of prognosis and severity. On the other hand, publications, and not all experts have access to these innovations. ultrasound diagnoses common entrapment neuropathies with an Understandably, they are rated less important at this time, as the accuracy comparable to that of electrodiagnosis, localizes other potential usefulness of these technologies has not been fully nerve problems when NCS alone cannot (e.g. when responses are explored. Given the added time required to use these techniques absent, when inching is not possible, or when nerve dysfunction and the greater complexity involved in assessing physiology com- is not severe enough to be detected electrically). Furthermore, pared to anatomy (e.g. changes in anatomy over time), it can be ultrasound provides information beyond localization unavailable assumed that their integration into routine practice will take by EMG or NCS regarding the presence or absence of intrinsic or longer than the immediate benefits of high-resolution transducers extrinsic nerve pathology (e.g. tumors, cysts etc.) or chronic muscle and blood flow assessment. disease and it provides this information quickly, safely, and without discomfort. 6.5. Future expectations for neuromuscular ultrasound 7.1. Re-envisioning electrodiagnosis The most compelling results of the survey relate to the unanim- ity of opinion by experts on the continued expansion for indica- Fifty year ago, the approach in an electrodiagnostic laboratory tions and use of neuromuscular ultrasound in the future. None of was to perform all possibly helpful diagnostic studies at the initial

Table 1 Added value of ultrasound in focal neuropathy.

(A) Suspected focal neuropathy already localized by electrodiagnosis (EDX) 1. Confirms or further refines localization (e.g. in long segments, such as median nerve in the forearm). 2. Excludes unexpected intrinsic or extrinsic anatomic pathology (e.g. ganglion cyst in fibular neuropathy at the knee, or focal nerve tumor/neuroma). 3. May be used to exclude a second entrapment of the nerve at a distal or proximal site (e.g. double crush). 4. Identification of nerve torsion (brachial neuritis). 5. Establishment of anatomic baseline for future comparison in anticipation of medical or surgical treatment. 6. Muscle ultrasound, by using echointensity ratios, may provide insight into relative axonal loss in distal muscles. 7. Helps identify variant nerve anatomy that complicates interpretation of nerve conduction studies (Martin-Gruber or accessory fibular nerve). (B) Suspected focal neuropathy unable to be further localized by EDX (absent motor/sensory responses) 1. Localizes the lesion to a specific site along the nerve. 2. In the presence of trauma, confirms nerve continuity or identifies transection and assesses for hematoma, bone injury, or other contributing factors. (C) Suspected focal neuropathy with borderline EDX 1. Can help support or refute the presence of focal nerve pathology. (D) Suspected focal neuropathy with normal EDX 1. May identify focal nerve pathology not apparent by EDX, or present in nerve branches not suitable for EDX testing. 2. May identify dislocation of the ulnar nerve with elbow flexion, which may account for false negative NCS findings. 3. May identify a proximal fascicular lesion masquerading as a distal entrapment as in brachial neuritis.

Table 2 Added value in other neuromuscular disorders.

(A) Suspected polyneuropathy (before or after EDX) 1. Helps support or refute the presence of hypertrophic polyneuropathies (CMT, MMN, CIDP, HNPP, and AIDP). 2. Distinguishes CMT and HNPP from CIDP and MMN. 3. Increased power Doppler signal may identify lepromatous neuropathy or neurolymphomatosis. 4. Evaluates distal muscle atrophy/increased echogenicity indicative of a chronic neurogenic process. 5. Demonstrates nerve thinning in CANVAS or enlargement in Wartenberg’s migrant sensory neuritis. (B) Suspected motor neuron disease: prior to EMG 1. Identification of fasciculations to help diagnose ALS using modified Awaji criteria, or to enhance muscle selection for EMG examination. 2. Distinction, based on location, size and frequency, of benign from pathological fasciculations. 3. May provide evidence, using relative muscle echointensity and thickness, of split-hand syndrome which may be seen in ALS. 4. The absence of enlarged nerves (and the presence of slightly smaller nerves) may help distinguish motor neuron disease from MMN. (C) Suspected muscle disorder prior to EMG 1. Provide a rapid screen for inclusion body myositis. 2. Identifies muscles involved in unexplained myopathy or camptocormia, aiding clinical diagnosis. 3. Identifies calcification and/or cysts indicative of prior inflammation, hemorrhage or infection. 4. Identifies muscles most suitable for EMG or biopsy, particularly in mild or severe myopathies. 5. Evaluates diaphragm function and provides guidance, if needed, for EMG needle insertion. 6. Quantitative muscle ultrasound may help distinguish central and peripheral etiologies in infants and small children, and helps guide choice of further testing. (D) Other 1. Evaluates nerve and muscle in those unable to tolerate EDX. 2. Assesses variant anatomy from surgery, trauma, or congenital anomalies. 3. May be used to guide chemodenervation, steroid injections, near nerve needle placement, or phenol injections, or nerve biopsy. 4. May be used to map the course of nerves (e.g. spinal accessory) prior to surgical intervention to prevent injury.

Abbreviations, CMT = Charcot Marie Tooth, MMN (Multifocal motor neuropathy), CIDP = chronic inflammatory demyelinating polyneuropathy, HNPP = Hereditary neuropathy with liability to pressure palsy, AIDP = acute inflammatory demyelinating polyneuropathy. CANVAS = cerebellar ataxia, neuropathy, vestibular areflexia syndrome). EMG = electromyography.

encounter because patients were often reluctant to return and optimize clinical helpfulness and diagnostic yield (Te Riele et al. because, at that time, alternative studies of the peripheral nervous 2017). system were typically invasive and not always informative. Since Those interested in staying current in clinical neurophysiology then, testing alternatives have evolved. Instead of spinal myelogra- need to ﬁrst acquire a high-resolution ultrasound device and then phy to rule out radiculopathy, patients may now undergo an MRI, develop skill in its use. At this time, many laboratories do not have instead of nerve biopsy to evaluate small ﬁber pathology, patients access to ultrasound; for example, in Canada at this time there are may now undergo a skin biopsy, instead of muscle biopsy to fur- fewer than 10 centers in the country with ultrasound access. This is ther evaluate a myopathy, patients may now undergo a wide vari- no longer tenable and it is the responsibility of hospitals and aca- ety of genetic and antibody tests. Over this time period, the demic medical centers to promptly address this issue. The second approach to diagnosis in a patient with suspected neuromuscular step does not require immediate mastery of all potential applica- disorders has thus shifted away from conducting all possibly help- tions, but rather, it need only begin with one individual mastering ful studies to conducting those that are least invasive and most one indication along with one nerve segment and relevant mus- useful for guiding patient care. As discussed above and as shown cles. Once this is done, the technique can gradually spread to more in Tables 1 and 2, neuromuscular ultrasound is instrumental in this nerve segments, muscles, indications and members in a laboratory. regard, painlessly adding information that is otherwise unobtain- For each of the experts surveyed, the technique was mastered one able. The inclusion of neuromuscular ultrasound with EMG and nerve, one muscle, and one indication at a time, and now, there are NCS across testing centers will eventually lead practitioners to ample courses and literature to guide newcomers to acquire exper- develop protocols for sequencing these three types of studies to tise relatively quickly. The gap in best practices between experts

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