Paradoxical thinning of the diaphragm on ultrasound is a risk factor for requiring non-invasive ventilation in patients with neuromuscular diaphragmatic dysfunction.

INTRODUCTION/AIMS: Point-of-care ultrasound of the diaphragm is highly sensitive and specific in the detection of neuromuscular diaphragmatic dysfunction. In some patients with neuromuscular diaphragmatic dysfunction, paradoxical thinning of the diaphragm during inspiration is observed on ultrasound; however, its frequency, electrodiagnostic associations, and prognostic significance remain uncertain. METHODS: Medical records of patients presenting to two electrodiagnostic laboratories (Mayo Clinic, Rochester, Minnesota and University of Alberta, Edmonton, Alberta) from January 1, 2022 to December 31, 2022, for evaluation of suspected neuromuscular respiratory failure, were reviewed. RESULTS: 214 patients were referred and 19 patients excluded due to incomplete information. Of 195 patients (384 hemidiaphragms), 104 had phrenic neuropathy, 12 had myopathy, and 79 had no evidence of neuromuscular disease affecting the diaphragm. Paradoxical thinning occurred in 31 (27%) patients with neuromuscular diaphragmatic dysfunction and was unilateral in 30, the majority (83%) having normal contralateral ultrasound. Phrenic nerve conduction studies and diaphragm electromyography results did not distinguish patients with paradoxical thinning versus without. Most patients (71%) with paradoxical thinning required non-invasive ventilation (NIV), including 16 with unilateral paradoxical thinning. Paradoxical thinning and BMI ≥30 kg/m2 were risk factors for requiring NIV in multivariable logistic regression analysis, with odds ratios of 2.887 (95% CI:1.166, 7.151) and 2.561 (95% CI: 1.186, 5.532), respectively. DISCUSSION: Paradoxical thinning of the diaphragm occurs in patients with prominent neuromuscular diaphragmatic dysfunction, most commonly from phrenic neuropathy, and is a significant risk factor for requiring NIV. Unilateral paradoxical thinning is sufficient for needing NIV. BMI ≥30 kg/m2 additionally increases risk of requiring NIV in patients with neuromuscular diaphragmatic dysfunction.

Transforming the practice of medicine through team science.

BACKGROUND: The translation of biomedical research discoveries into clinical practice is marked by extended timelines (averaging 17 years) and multiple sequential process steps. However, even after a drug, device, diagnostic tool or unique therapeutic procedure successfully navigates through clinical testing to approval, real barriers remain in applying and scaling the innovation in practice. METHODS: Mayo Clinic initiated the Transform the Practice programme to facilitate multidisciplinary team and convergence science to continuously reinvent solutions to address unmet patient needs and accelerate the application of next-generation healthcare solutions. During a 5-year period, 24 programme teams received financial resources, barrier-removing engagement from clinical and research leadership, and enhanced administrative support, including dedicated project managers. RESULTS: The approach created value in facilitating consistent progress toward project objectives and resulted in multiple publications, new extramural funding sources, and implementation of new tests and services into the clinical practice. This report describes the concentrated institutional effort to accelerate the discovery-translation-application continuum in an academic medical centre and highlights successful applications and persistent obstacles. CONCLUSIONS: The Transform the Practice approach is effective in moving high-potential research discoveries closer to implementation in the clinical practice. Its concepts, including the application of structured project management methodology, may be quickly integrated to shorten an organisation's time to implementing its most important discoveries.

Compound muscle action potential duration in critical illness neuromyopathy.

INTRODUCTION: We sought to determine the specificity of compound muscle action potential (CMAP) durations and amplitudes in a large critical illness neuromyopathy (CINM) cohort relative to controls with other neuromuscular conditions. METHODS: Fifty-eight patients with CINM who had been seen over a 17-year period were retrospectively studied. Electrodiagnostic findings of the CINM cohort were compared with patients with axonal peripheral neuropathy and myopathy due to other causes. RESULTS: Mean CMAP durations were prolonged, and mean CMAP amplitudes were severely reduced both proximally and distally in all nerves studied in the CINM cohort relative to the control groups. The specificity of prolonged CMAP durations for CINM approached 100% if they were encountered in more than 1 nerve. DISCUSSION: Prolonged, low-amplitude CMAPs occur more frequently and with greater severity in CINM patients than in neuromuscular controls with myopathy and axonal neuropathy and are highly specific for the diagnosis of CINM. Muscle Nerve 57: 395-400, 2018.

Utility of ultrasound-guided surface electrode placement in lateral femoral cutaneous nerve conduction studies.

INTRODUCTION: Meralgia paresthetica is a common clinical complaint for which some patients ultimately undergo surgical treatment. The lateral femoral cutaneous nerve (LFCN) has been difficult to reliably test electrophysiologically, likely due to anatomic variability and lack of responses in asymptomatic obese subjects. METHODS: We compared a novel ultrasound-guided antidromic sensory nerve conduction study (NCS) with a technique described previously in a population of normal subjects, of whom 50% had body mass indices within the obese range (>27.5). RESULTS: Responses were obtained in at least 92% of subjects using either technique, and 92% of normal subjects had <60% interside variability using the ultrasound-guided technique. CONCLUSIONS: LFCN sensory nerve action potentials can be obtained in the vast majority of normal subjects, even in an obese population and can provide a useful sensory NCS for evaluation of mid-lumbar radiculopathy, plexopathy, or meralgia paresthetica.

Clinical Utility of Striational Antibodies in Paraneoplastic and Myasthenia Gravis Paraneoplastic Panels.

OBJECTIVE: To critically assess the clinical utility of striational antibodies (StrAbs) within paraneoplastic and myasthenia gravis serological evaluations. METHODS: All Mayo Clinic patients tested for StrAbs from January 1st 2012-December 31st 2018 utilizing Mayo's Unified Data Platform (UDP) were reviewed for neurological diagnosis and cancer. RESULTS: 38,502 unique paraneoplastic and 1,899 MG patients were tested. In paraneoplastic evaluations, the StrAbs positivity rate was higher in cancer vs without cancer (5% [321/6775] vs 4% [1154/31727]; p<0.0001; OR 1.35; CI=1.19-1.53) but ROC analysis indicated no diagnostic accuracy in cancer (AUC=0.505). No neurological phenotype was significantly associated with StrAbs in the paraneoplastic group. Positivity was more common in all MG cancers compared to paraneoplastic cancers (p<0.0001). In MG evaluations, the StrAbs positivity rate was higher in those with cancer vs without (46% [217/474] vs 26% [372/1425]; p<0.0001; OR 2.39, CI 1.9-2.96) with ROC analysis indicating poor diagnostic accuracy for thymic cancer (AUC 0.634, recommended cutoff=1:60, sensitivity=56%, specificity=71%), with worse accuracy for extrathymic cancers (AUC 0.543). In paraneoplastic or MG evaluations, the value of antibody positivity did not improve cancer predictions. Paraneoplastic evaluated patients were more likely with positive StrAbs to obtain computed tomography (CT) (p=0.0001) with 3% (12/468) cancer found. CONCLUSION: Despite a statistically significant association with cancer, an expansive review of performance in clinical service demonstrates that StrAbs are neither specific nor sensitive in predicting malignancy or neurological phenotypes. CT imaging is over utilized with positive StrAbs results. Removal of StrAbs from paraneoplastic or MG evaluations will improve the diagnostic characteristics of the current MG test. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the presence of StrAbs do not accurately identify patients with malignancy or neurological phenotypes.

Dok-7 myasthenia: phenotypic and molecular genetic studies in 16 patients.

OBJECTIVE: Detailed analysis of phenotypic and molecular genetic aspects of Dok-7 myasthenia in 16 patients. METHODS: We assessed our patients by clinical and electromyographic studies, by intercostal muscle biopsies for in vitro microelectrode analysis of neuromuscular transmission and quantitative electron microscopy EM of 409 end plates (EPs), and by mutation analysis, and expression studies of the mutants. RESULTS: The clinical spectrum varied from mild static limb-girdle weakness to severe generalized progressive disease. The synaptic contacts were single or multiple, and some, but not all, were small. In vitro microelectrode studies indicated variable decreases of the number of released quanta and of the synaptic response to acetylcholine; acetylcholine receptor (AChR) channel kinetics were normal. EM analysis demonstrated widespread and previously unrecognized destruction and remodeling of the EPs. Each patient carries 2 or more heteroallelic mutations: 11 in genomic DNA, 7 of which are novel; and 6 identifiable only in complementary DNA or cloned complementary DNA, 3 of which are novel. The pathogenicity of the mutations was confirmed by expression studies. Although the functions of Dok-7 include AChR beta-subunit phosphorylation and maintaining AChR site density, patient EPs showed normal AChR beta-subunit phosphorylation, and the AChR density on the remaining junctional folds appeared normal. INTERPRETATION: First, the clinical features of Dok-7 myasthenia are highly variable. Second, some mutations are complex and identifiable only in cloned complementary DNA. Third, Dok-7 is essential for maintaining not only the size but also the structural integrity of the EP. Fourth, the profound structural alterations at the EPs likely contribute importantly to the reduced safety margin of neuromuscular transmission.

Prolonged compound muscle action potential duration in critical illness myopathy.

Critical illness myopathy (CIM) is a frequent cause of generalized weakness in the intensive care unit. Prolonged compound muscle action potential (CMAP) durations have been described in this patient population, and this study presents further data on CMAP duration in normal controls and patients with CIM. The findings highlight the importance of testing multiple nerve muscle combinations in weak, critically ill patients. Recognition of this pattern, which has not been widely described, can facilitate the diagnosis of CIM.

The mayo clinic model of clinical integration.

The multi-campus Academic Health Center (AHC) of the future will need to be system-based and committed to clinical integration to continue to meet institutional goals and serve the needs of its patients. The key tactics we describe to accomplish this are.

Triple Furrowed Atrophic Tongue of Myasthenia Gravis.

The authors present a case and image of a patient with refractory tongue weakness and characteristic triple furrowed pattern of atrophy due to autoimmune myasthenia gravis.

Monotonicity of nerve tests in diabetes: subclinical nerve dysfunction precedes diagnosis of polyneuropathy.

OBJECTIVE: The objective of this study was to test whether monotone worsening of nerve function, attributable to diabetes, can be demonstrated before criteria for diabetic sensorimotor polyneuropathy (DSPN) have been met. Which nerve tests are best? RESEARCH DESIGN AND METHODS: From a prevalence cohort of 504 individuals in the Rochester Diabetic Neuropathy study (RDNS), we identified 238 individuals (group 1) who at first examination were without polyneuropathy (DSPN) by a sum score of the normal deviates (from percentiles) of five attributes of nerve conduction of the legs (i.e., their five nerve conduction normal deviate values were <97.5th percentile) and were followed longitudinally two or more times. Of these 238, 90 (group 2) were followed six or more times at yearly or bi-yearly intervals. We compared different nerve tests for the ones most sensitive and reliable in showing latent nerve dysfunction and monotone (the extent to which a variable measured repeatedly over time reveals a significant trend of worsening or improvement). RESULTS: In group 1 patients, the mean sum score of five attributes of nerve conduction (sigma 5 NC nds) at baseline was 1.08 and at the last examination (only patients with Sigma 5 NC nds <97.5th percentile) was 3.63, markedly higher than that in healthy subjects (only of individuals with Sigma 5 NC nds <97.5th percentile) (-0.12), indicating a subtle latent shift of nerve conduction tests toward abnormality. Serial evaluations of many individual and especially sum scores of nerve conduction tests in group 2 patients showed statistically significant worsening with time, even when nerve conduction tests were still well within normal limits. Neurologic signs also worsened but barely to significant levels; however, symptoms and quantitative sensation tests did not. Considering the composite score sigma 5 NC nds, 42 (of 90 group 2 patients) showed significant worsening, 22 were still without DSPN by nerve conduction test criteria, and some were even below the 50th percentile at the last evaluation. CONCLUSIONS: Subtle and latent functional worsening of nerve conduction can be demonstrated even before nerve conduction test criteria for DSPN have been met. For demonstrating monotone worsening, the order (from best to worst) of tests was: some composite scores of nerve conduction and individual attributes of nerve conduction. We did not show monotone worsening of symptoms or of quantitative sensation test results. In multivariate analysis of risk factors and their association with worsening sigma 5 NC nds, 24-h microalbuminuria (a marker of microvessel disease) was found to be a significant covariate, an indication that the asymptomatic alterations of nerve conduction are meaningful.

Loss of MUNC13-1 function causes microcephaly, cortical hyperexcitability, and fatal myasthenia.

OBJECTIVE: To identify the molecular basis of a fatal syndrome of microcephaly, cortical hyperexcitability, and myasthenia. METHODS: We performed clinical and in vitro microelectrode studies of neuromuscular transmission, examined neuromuscular junctions cytochemically and by electron microscopy (EM), and searched for mutations by Sanger and exome sequencing. RESULTS: Neuromuscular transmission was severely compromised by marked depletion of the readily releasable pool of quanta, but the probability of quantal release was normal. Cytochemical and EM studies revealed normal endplate architecture. Exome sequencing identified a homozygous nonsense mutation in the N-terminal domain of MUNC13-1 (UNC13A) truncating the protein after 101 residues. CONCLUSIONS: Loss of Munc13-1 function predicts that syntaxin 1B is consigned to a nonfunctional closed state; this inhibits cholinergic transmission at the neuromuscular junction and glutamatergic transmission in the brain. Inactivation of syntaxin 1B likely accounts for the patient's cortical hyperexcitability because mutations of syntaxin 1B cause febrile seizures with or without epilepsy, haploinsufficiency of the STX1B is associated with myoclonic astatic epilepsy, and antisense knockdown of stx1b in zebrafish larvae elicits epileptiform discharges. A very recent publication also shows that syntaxin 1B has a separate obligatory role for maintenance of developing and mature neurons and illustrates impaired brain development in syntaxin 1A/1B double knockout mice. We therefore attribute our patient's microcephaly to the truncating homozygous Munc13-1 mutation that consigns syntaxin 1B to a permanently closed nonfunctional state akin to a knockout.

Preoperative and intraoperative electrophysiologic assessment of brachial plexus injuries.

Preoperative and intraoperative electrophysiologic studies complement one another and complement information obtained from clinical and imaging studies in brachial plexus injury. The information provided by electrodiagnostic studies helps to better define the number, location, and severity of plexus lesions. In addition, establishing the presence or absence of nerve root continuity and early regeneration through postganglionic lesions helps to direct surgical therapy.

Regenerative Medicine Build-Out.

UNLABELLED: Regenerative technologies strive to boost innate repair processes and restitute normative impact. Deployment of regenerative principles into practice is poised to usher in a new era in health care, driving radical innovation in patient management to address the needs of an aging population challenged by escalating chronic diseases. There is urgency to design, execute, and validate viable paradigms for translating and implementing the science of regenerative medicine into tangible health benefits that provide value to stakeholders. A regenerative medicine model of care would entail scalable production and standardized application of clinical grade biotherapies supported by comprehensive supply chain capabilities that integrate sourcing and manufacturing with care delivery. Mayo Clinic has rolled out a blueprint for discovery, translation, and application of regenerative medicine therapies for accelerated adoption into the standard of care. To establish regenerative medical and surgical service lines, the Mayo Clinic model incorporates patient access, enabling platforms and delivery. Access is coordinated through a designated portal, the Regenerative Medicine Consult Service, serving to facilitate patient/provider education, procurement of biomaterials, referral to specialty services, and/or regenerative interventions, often in clinical trials. Platforms include the Regenerative Medicine Biotrust and Good Manufacturing Practice facilities for manufacture of clinical grade products for cell-based, acellular, and/or biomaterial applications. Care delivery leverages dedicated interventional suites for provision of regenerative services. Performance is tracked using a scorecard system to inform decision making. The Mayo Clinic roadmap exemplifies an integrated organization in the discovery, development, and delivery of regenerative medicine within a growing community of practice at the core of modern health care. SIGNIFICANCE: Regenerative medicine is at the vanguard of health care poised to offer solutions for many of today's incurable diseases. Accordingly, there is a pressing need to develop, deploy, and demonstrate a viable framework for rollout of a regenerative medicine model of care. Translation of regenerative medicine principles into practice is feasible, yet clinical validity and utility must be established to ensure approval and adoption. Standardized and scaled-up regenerative products and services across medical and surgical specialties must in turn achieve a value-added proposition, advancing intended outcome beyond current management strategies.

Reversible myelopathy in a 34-year-old man with vitamin B12 deficiency.

Vitamin B12 deficiency is common, with most patients lacking classic features of advanced severe deficiency. Early diagnosis and treatment prevent severe anemia and irreversible damage to the nervous system. We describe a 34-year-old man with pernicious anemia who presented with clinical and radiologic features of early myelopathy and borderline low serum levels of vitamin B12. Prompt diagnosis based on the measurement of serum methylmalonic acid and treatment with cyanocobalamin injections led to rapid resolution of clinical manifestations and magnetic resonance imaging abnormalities. We review the literature of magnetic resonance imaging in vitamin B12 deficiency myelopathy and discuss the issues relating to diagnosis and early treatment of this potentially reversible condition.

Intraoperative electromyographic monitoring of the recurrent laryngeal nerve in reoperative thyroid and parathyroid surgery.

BACKGROUND: Injury to the recurrent laryngeal nerve (RLN) is a rare complication of initial thyroid and parathyroid surgery, but the prevalence is much higher in the reoperative setting. The use of continuous, intraoperative electromyographic monitoring of the RLN has been suggested to improve the safety of cervical explorations. METHODS: Outcomes of a group of reoperative thyroid and parathyroid cases that used EMG monitoring with endoscopically applied hook-wire electrodes were compared with a group of cervical reoperations without monitoring. Office laryngoscopy (indirect or fiberoptic) was used to evaluate and follow suspected RLN complications. RESULTS: Electromyography was used in 52 cervical reexploration procedures. Patients averaged 1.8 previous explorations (range, 1-7 explorations) and underwent procedures for parathyroid (31%) and/or thyroid (77%) disease (overall, 72% malignant). The non-monitored group had 59 patients with similar characteristics. Only 1 permanent nerve complication in each group was unintended (electromyography, 1.9%; non-electromyography, 1.7%). Seven false-negative and 2 false-positive electromyographic findings occurred. No complications resulted from placement of the electromyography electrodes. CONCLUSIONS: Intraoperative electromyographic monitoring of the RLN in reoperative neck surgery can be performed safely but did not decrease RLN complications in this study. Experience and routine nerve exposure remain crucial to the minimization of RLN complications.

Regenerative medicine blueprint.

Regenerative medicine, a paragon of future healthcare, holds unprecedented potential in extending the reach of treatment modalities for individuals across diseases and lifespan. Emerging regenerative technologies, focused on structural repair and functional restoration, signal a radical transformation in medical and surgical practice. Regenerative medicine is poised to provide innovative solutions in addressing major unmet needs for patients, ranging from congenital disease and trauma to degenerative conditions. Realization of the regenerative model of care predicates a stringent interdisciplinary paradigm that will drive validated science into standardized clinical options. Designed as a catalyst in advancing rigorous new knowledge on disease causes and cures into informed delivery of quality care, the Mayo Clinic regenerative medicine blueprint offers a patient-centered, team-based strategy that optimizes the discovery-translation-application roadmap for the express purpose of science-supported practice advancement.

Ultrasound applications in electrodiagnosis.

This review article discusses the current scope of high-resolution diagnostic ultrasound in the diagnosis of neuromuscular disease, both as a complementary tool to electrodiagnosis and in some cases as a stand-alone imaging modality. Indications, limitations, potential for research, and training and credentialing are discussed. Indications include needle guidance for nerve conduction studies and needle electromyography, diagnosis of nerve entrapment, diagnostic muscle imaging via grayscale analysis, and dynamic real-time imaging, including sonopalpation, to provide additional diagnostic information. The role of neuromuscular ultrasound in research is discussed, including the need to evaluate the sensitivity, specificity, positive and negative predictive value, and cost-effectiveness of these techniques when they are used alone or in combination. Training and credentialing are reviewed, specifically noting the challenge of the lack of formal training programs and the relatively long, flat learning curve of diagnostic ultrasound.

The Mayo Clinic Value Creation System.

The authors present Mayo Clinic's Value Creation System, a coherent systems engineering approach to delivering a single high-value practice. There are 4 tightly linked, interdependent phases of the system: alignment, discovery, managed diffusion, and measurement. The methodology is described and examples of the results to date are presented. The Value Creation System has been demonstrated to improve the quality of patient care while reducing costs and increasing productivity.