Longitudinal prospective cohort study to assess peripheral motor function with extensive electrophysiological techniques in patients with Spinal Muscular Atrophy (SMA): the SMA Motor Map protocol.

BACKGROUND: Hereditary spinal muscular atrophy (SMA) is a motor neuron disorder with a wide range in severity in children and adults. Two therapies that alter splicing of the Survival Motor Neuron 2 (SMN2) gene, i.e. nusinersen and risdiplam, improve motor function in SMA, but treatment effects vary. Experimental studies indicate that motor unit dysfunction encompasses multiple features, including abnormal function of the motor neuron, axon, neuromuscular junction and muscle fibres. The relative contributions of dysfunction of different parts of the motor unit to the clinical phenotype are unknown. Predictive biomarkers for clinical efficacy are currently lacking. The goals of this project are to study the association of electrophysiological abnormalities of the peripheral motor system in relation to 1) SMA clinical phenotypes and 2) treatment response in patients treated with SMN2-splicing modifiers (nusinersen or risdiplam). METHODS: We designed an investigator-initiated, monocentre, longitudinal cohort study using electrophysiological techniques ('the SMA Motor Map') in Dutch children (≥ 12 years) and adults with SMA types 1-4. The protocol includes the compound muscle action potential scan, nerve excitability testing and repetitive nerve stimulation test, executed unilaterally at the median nerve. Part one cross-sectionally assesses the association of electrophysiological abnormalities in relation to SMA clinical phenotypes in treatment-naïve patients. Part two investigates the predictive value of electrophysiological changes at two-months treatment for a positive clinical motor response after one-year treatment with SMN2-splicing modifiers. We will include 100 patients in each part of the study. DISCUSSION: This study will provide important information on the pathophysiology of the peripheral motor system of treatment-naïve patients with SMA through electrophysiological techniques. More importantly, the longitudinal analysis in patients on SMN2-splicing modifying therapies (i.e. nusinersen and risdiplam) intents to develop non-invasive electrophysiological biomarkers for treatment response in order to improve (individualized) treatment decisions. TRIAL REGISTRATION: NL72562.041.20 (registered at https://www.toetsingonline.nl . 26-03-2020).

Acute retigabine-induced effects on myelinated motor axons in amyotrophic lateral sclerosis.

Altered motor neuron excitability in patients with amyotrophic lateral sclerosis (ALS) has been suggested to be an early pathophysiological mechanism associated with motor neuron death. Compounds that affect membrane excitability may therefore have disease-modifying effects. Through which mechanism(s), these compounds modulate membrane excitability is mostly provided by preclinical studies, yet remains challenging to verify in clinical studies. Here, we investigated how retigabine affects human myelinated motor axons by applying computational modeling to interpret the complex excitability changes in a recent trial involving 18 ALS patients. Compared to baseline, the post-dose excitability differences were modeled well by a hyperpolarizing shift of the half-activation potential of slow potassium (K+ )-channels (till 2 mV). These findings verify that retigabine targets slow K+ -channel gating and highlight the usefulness of computational models. Further developments of this approach may facilitate the identification of early target engagement and ultimately aid selecting responders leading to more personalized treatment strategies.

Electrodiagnosis of Guillain-Barre syndrome in the International GBS Outcome Study: Differences in methods and reference values.

OBJECTIVE: To describe the heterogeneity of electrodiagnostic (EDx) studies in Guillain-Barré syndrome (GBS) patients collected as part of the International GBS Outcome Study (IGOS). METHODS: Prospectively collected clinical and EDx data were available in 957 IGOS patients from 115 centers. Only the first EDx study was included in the current analysis. RESULTS: Median timing of the EDx study was 7 days (interquartile range 4-11) from symptom onset. Methodology varied between centers, countries and regions. Reference values from the responding 103 centers were derived locally in 49%, from publications in 37% and from a combination of these in the remaining 15%. Amplitude measurement in the EDx studies (baseline-to-peak or peak-to-peak) differed from the way this was done in the reference values, in 22% of motor and 39% of sensory conduction. There was marked variability in both motor and sensory reference values, although only a few outliers accounted for this. CONCLUSIONS: Our study showed extensive variation in the clinical practice of EDx in GBS patients among IGOS centers across the regions. SIGNIFICANCE: Besides EDx variation in GBS patients participating in IGOS, this diversity is likely to be present in other neuromuscular disorders and centers. This underlines the need for standardization of EDx in future multinational GBS studies.

Motor unit integrity in multifocal motor neuropathy: A systematic evaluation with CMAP scans.

INTRODUCTION/AIMS: Progressive axonal loss in multifocal motor neuropathy (MMN) is often assessed with nerve conduction studies (NCS), by recording maximum compound muscle action potentials (CMAPs). However, reinnervation maintains the CMAP amplitude until a significant portion of the motor unit (MU) pool is lost. Therefore, we performed more informative CMAP scans to study MU characteristics in a large cohort of patients with MMN. METHODS: We derived the maximum CMAP amplitude (CMAPmax ), an MU number estimate (MUNE), and the largest MU amplitude stimulus current required to elicit 5%, 50%, and 95% of CMAPmax (S5, S50, S95) and relative ranges ([S95 - S5] × 100 / S50) from the scans. These metrics were compared with clinical, laboratory, and NCS results. RESULTS: Forty MMN patients and 24 healthy controls were included in the study. CMAPmax and MUNE were reduced in MMN patients (both P < .001). Largest MU amplitude as a percentage of CMAPmax was increased in MMN patients (P < .001). Disease duration and treatment duration were not associated with MUNE. Relative range was larger in patients with anti-GM1 antibodies than in those without anti-GM1 antibodies (P = .016) and controls (P < .001). The largest MU amplitudes were larger in patients without anti-GM1 antibodies than in patients with anti-GM1 antibodies (P = .037) and controls (P = .044). DISCUSSION: We found that MU loss is common in MMN and accompanied by enlarged MUs. Presence of anti-GM1 antibodies was associated with increased relative range of MU thresholds and reduction in largest MU amplitude. Our findings indicate that CMAP scans complement routine NCS, and may have potential for practical monitoring of treatment efficacy and disease progression.

Impact of stimulus duration on motor unit thresholds and alternation in compound muscle action potential scans.

OBJECTIVE: To investigate the impact of stimulus duration on motor unit (MU) thresholds and alternation within compound muscle action potential (CMAP) scans. METHODS: The stimulus duration (0.1, 0.2, 0.6, and 1.0 ms) in thenar CMAP scans and individual MUs of 14 healthy subjects was systematically varied. We quantified variability of individual MU's thresholds by relative spread (RS), MU thresholds by stimulus currents required to elicit target CMAPs of 5% (S5), 50% (S50) and 95% (S95) of the maximum CMAP, and relative range (RR) by 100*[S95-S5]/S50. We further assessed the strength-duration time constant (SDTC). Experimental observations were subsequently simulated to quantify alternation. RESULTS: RS, unaffected by stimulus duration, was 1.65% averaged over all recordings. RR increased for longer stimulus duration (11.4% per ms, p < 0.001). SDTC shortened with higher target CMAPs (0.007 ms per 10% CMAP, p < 0.001). Experiments and simulations supported that this may underlie the increased RR. A short compared to long stimulus duration recruited relative more MUs at S50 (more alternation) than at the tails (less alternation). CONCLUSIONS: The stimulus duration significantly affects MU threshold distribution and alternation within CMAP scans. SIGNIFICANCE: Stimulation settings can be further optimized and their standardization is preferred when using CMAP scans for monitoring neuromuscular diseases.

Electrophysiology of Guillain-Barré syndrome in Bangladesh: A prospective study of 312 patients.

OBJECTIVE: To describe the electrophysiological features in relation to clinical and serological findings of Guillain-Barré syndrome (GBS) in the national neuroscience hospital in Bangladesh. This is one of the few studies that investigated GBS patients using standardized electrophysiology in low-income countries. METHODS: In a prospective and observational study, we investigated 312 GBS patients by standardized clinical, serological and electrophysiological methods. Unilateral motor and sensory nerve conduction studies (NCS) were performed within two weeks of onset of weakness. Follow up NCS were performed in 189 patients and classified according to eight sets of established GBS criteria. Serology included assessment of anti-GM1 antibodies and anti-campylobacter jejuni lipo-oligosaccharide (LOS) antibodies. RESULTS: Depending on the criteria used, 44-59% patients had axonal GBS with anti-GM1 antibodies being present in 55-58% and 9-42% patients had demyelinating GBS with anti-GM1 antibodies being present in 7-35%. Conduction block (CB) with demyelinative slowing in the same nerve segment was found in 24% (74/312) patients, and CB without demyelinative slowing in the same nerve segment was found in 18% (56/312) patients, of whom anti-GM1 antibodies were found in 27% and 57% patients respectively. Follow-up NCS showed a change in GBS classification in 11-26% of patients, mainly from demyelinating to axonal GBS. CONCLUSIONS: The predominant subtype of GBS in Bangladesh is axonal but demyelinating GBS also occurs with classification being strongly dependent on the applied criteria. SIGNIFICANCE: The present study demonstrates the importance of reaching international agreement on GBS criteria that should be based on the best evidence.

Excitability of motor and sensory axons in multifocal motor neuropathy.

OBJECTIVE: To assess excitability differences between motor and sensory axons of affected nerves in patients with multifocal motor neuropathy (MMN). METHODS: We performed motor and sensory excitability tests in affected median nerves of 20 MMN patients and in 20 age-matched normal subjects. CMAPs were recorded from the thenar and SNAPs from the 3rd digit. Clinical tests included assessment of muscle strength, two-point discrimination and joint position. RESULTS: All MMN patients had weakness of the thenar muscle and normal sensory tests. Motor excitability testing in MMN showed an increased threshold for a 50% CMAP, increased rheobase, decreased stimulus-response slope, fanning-out of threshold electrotonus, decreased resting I/V slope, shortened refractory period, and more pronounced superexcitability. Sensory excitability testing in MMN revealed decreased accommodation half-time and S2-accommodation and less pronounced subexcitability. Mathematical modeling indicated increased Barrett-Barrett conductance for motor fibers and increase in internodal fast potassium conductance for sensory fibers. CONCLUSIONS: Excitability findings in MMN suggest myelin sheath or paranodal seal involvement in motor fibers and, possibly, paranodal detachment in sensory fibers. SIGNIFICANCE: Excitability properties of affected nerves in MMN differ between motor and sensory nerve fibers.

Physiology of Myelinated Nerve Conduction and Pathophysiology of Demyelination.

Nerve conduction in myelinated axons is a fascinating subject due to the intricate structure and complex properties of the axon and its relation to the equally complex Schwann cells surrounding it. This chapter first deals with normal functional aspects of voltage-gated ion channels in the axon and Schwann cell membranes as well as their related proteins. Next, the pathophysiological alterations that are induced by experimental studies to mimic and study neuropathic disorders in humans are discussed. Finally, a link is made with human neuropathies associated with antibodies against gangliosides, and the putative mechanisms of axonal degeneration in demyelinating neuropathies are discussed. Although this chapter is relevant to understand symptoms in human neuropathies, the reader is referred to Franssen and Straver (Muscle Nerve 49:4-20, 2014) for a review of translational and clinical studies in human patients.

Neuropathy associated with immunoglobulin M monoclonal gammopathy: A combined sonographic and nerve conduction study.

INTRODUCTION: We assessed the specific sonographic pattern of structural nerve abnormalities in immunoglobulin M (IgM) neuropathy and disease controls. METHODS: We enrolled 106 incident patients-32 patients with IgM neuropathy, 42 treatment-naive patients with chronic inflammatory demyelinating polyneuropathy, and 32 patients with axonal neuropathies. All patients underwent standardized ancillary testing in addition to standardized sonography of the brachial plexus and the large arm and leg nerves bilaterally. RESULTS: We found widespread nerve enlargement in IgM neuropathy and chronic inflammatory demyelinating polyneuropathy (CIDP), with specific enlargement of brachial plexus and proximal segments of median nerve but not in axonal disease controls (P < .001). Sonographic nerve hypertrophy in IgM neuropathy was not associated with nerve conduction, clinical, or laboratory characteristics. DISCUSSION: Immunoglobulin M neuropathy is characterized by widespread nerve enlargement indistinguishable from CIDP. Our data provide evidence to confirm that the disease process is not confined to the more distal parts of nerves in either classical demyelinating or axonal variants of neuropathy with associated IgM.

Simulating perinodal changes observed in immune-mediated neuropathies: impact on conduction in a model of myelinated motor and sensory axons.

Immune-mediated neuropathies affect myelinated axons, resulting in conduction slowing or block that may affect motor and sensory axons differently. The underlying mechanisms of these neuropathies are not well understood. Using a myelinated axon model, we studied the impact of perinodal changes on conduction. We extended a longitudinal axon model (41 nodes of Ranvier) with biophysical properties unique to human myelinated motor and sensory axons. We simulated effects of temperature and axonal diameter on conduction and strength-duration properties. We then studied effects of impaired nodal sodium channel conductance and paranodal myelin detachment by reducing periaxonal resistance, as well as their interaction, on conduction in the 9 middle nodes and enclosed paranodes. Finally, we assessed the impact of reducing the affected region (5 nodes) and adding nodal widening. Physiological motor and sensory conduction velocities and changes to axonal diameter and temperature were observed. The sensory axon had a longer strength-duration time constant. Reducing sodium channel conductance and paranodal periaxonal resistance induced progressive conduction slowing. In motor axons, conduction block occurred with a 4-fold drop in sodium channel conductance or a 7.7-fold drop in periaxonal resistance. In sensory axons, block arose with a 4.8-fold drop in sodium channel conductance or a 9-fold drop in periaxonal resistance. This indicated that motor axons are more vulnerable to developing block. A boundary of block emerged when the two mechanisms interacted. This boundary shifted in opposite directions for a smaller affected region and nodal widening. These differences may contribute to the predominance of motor deficits observed in some immune-mediated neuropathies.NEW & NOTEWORTHY Immune-mediated neuropathies may affect myelinated motor and sensory axons differently. By the development of a computational model, we quantitatively studied the impact of perinodal changes on conduction in motor and sensory axons. Simulations of increasing nodal sodium channel dysfunction and paranodal myelin detachment induced progressive conduction slowing. Sensory axons were more resistant to block than motor axons. This could explain the greater predisposition of motor axons to functional deficits observed in some immune-mediated neuropathies.

Nerve ultrasound can identify treatment-responsive chronic neuropathies without electrodiagnostic features of demyelination.

INTRODUCTION: We present a case series of six treatment-naive patients with clinical phenotypes compatible with chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy without electrodiagnostic features of demyelination but with abnormal peripheral ultrasound findings who responded to treatment. METHODS: All six patients underwent a complete set of ancillary investigations, including extensive nerve conduction studies. We also performed standardized nerve ultrasound of median nerves and brachial plexus as part of a larger effort to evaluate diagnostic value of sonography. RESULTS: Nerve conduction studies did not show conduction block or other signs of demyelination in any of the six patients. Sonographic nerve enlargement was present in all patients and was most prominent in proximal segments of the median nerve and brachial plexus. Treatment with intravenous immunoglobulin resulted in objective clinical improvement. DISCUSSION: Our study provides evidence that nerve ultrasound represents a useful complementary diagnostic tool for the identification of treatment-responsive inflammatory neuropathies.

Warming nerves for excitability testing.

INTRODUCTION: The aim of this study was to find the best method of warming the median nerve before excitability testing to a standard temperature. METHODS: In 5 healthy subjects, the forearm and hand were warmed for 1 h to 37°C by infrared lamp, water blanket, or water bath. Recordings were performed before and during warming every 10 min. Excitability indices were fitted by exponential relations, thereby calculating the time needed to reach 95% of their asymptotic end value. RESULTS: Distal motor latency, refractory period, and superexcitability at 10 ms changed exponentially with time. Warming by water bath took the shortest time (24 min); this was followed by warming by infrared lamp (34 min) and water blanket (35 min). CONCLUSIONS: Warming by water bath is the quickest way. The other methods took only moderately more time. Future studies need to specify both warming method and warming time before excitability testing. Muscle Nerve, 2019.

Excitability tests using high-density surface-EMG: A novel approach to studying single motor units.

OBJECTIVE: To study excitability of single motor units (MUs) using high-density surface-EMG. METHODS: Motor unit action potentials (MUAPs) were evoked by submaximal stimulation of the median nerve at the wrist and recorded with a 9 × 14 electrode grid on the skin overlying the thenar muscles. For excitability tests of single MUs, the most optimal specific single-channel surface-EMG signal was selected based on the spatiotemporal profile of single MUs. RESULTS: Axonal excitability measures were successfully obtained from 14 single MUs derived from ten healthy subjects. Selecting the optimal single-channel surface-EMG signals minimized interference from other single MUs and improved signal-to-noise ratio. The muscle fiber conduction velocity (MFCV) could also be derived from the unique spatiotemporal profile of single MUs. CONCLUSION: High-density surface-EMG helps to isolate single MUAP responses, making it a suitable technique for assessing excitability in multiple single motor axons per nerve. SIGNIFICANCE: Our method enables the reliable study of ion-channel dysfunction in single motor axons of nerves without any requirement for specific conditions, such as prominent MU loss or enlarged MUAPs due to collateral sprouting.

Acute Effects of Riluzole and Retigabine on Axonal Excitability in Patients With Amyotrophic Lateral Sclerosis: A Randomized, Double-Blind, Placebo-Controlled, Crossover Trial.

Increased excitability of motor neurons in patients with amyotrophic lateral sclerosis (ALS) may be a relevant factor leading to motor neuron damage. This randomized, double-blind, three-way crossover, placebo-controlled study evaluated peripheral motor nerve excitability testing as a biomarker of hyperexcitability and assessed the effects of riluzole and retigabine in 18 patients with ALS. We performed excitability testing at baseline, and twice after participants had received a single dose of either 100 mg riluzole, 300 mg retigabine, or placebo. Between- and within-day repeatability was at least acceptable for 14 out of 18 recorded excitability variables. No effects of riluzole on excitability testing were observed, but retigabine significantly decreased strength-duration time-constant (9.2%) and refractoriness at 2 ms (10.2) compared to placebo. Excitability testing was shown to be a reliable biomarker in patients with ALS, and the acute reversal of previously abnormal variables by retigabine justifies long-term studies evaluating the impact on disease progression and survival.

Sodium-potassium pump assessment by submaximal electrical nerve stimulation.

OBJECTIVE: Sodium-potassium pump dysfunction in peripheral nerve is usually assessed by determining axonal hyperpolarization following maximal voluntary contraction (MVC) or maximal electrical nerve stimulation. As MVC may be unreliable and maximal electrical stimulation too painful, we assessed if hyperpolarization can also be induced by submaximal electrical nerve stimulation. METHODS: In 8 healthy volunteers different submaximal electrical stimulus trains were given to the median nerve at the wrist, followed by 5 min assessment of thresholds for compound muscle action potentials of 20%, 40% or 60% of maximal. RESULTS: Threshold increase after submaximal electrical nerve stimulation was most prominent after an 8 Hz train of at least 5 min duration evoking submaximal CMAPs of 60%. It induced minimal discomfort and was not painful. Threshold increase after MVC was not significantly higher than this stimulus train. CONCLUSIONS: Submaximal electrical stimulation evokes activity dependent hyperpolarization in healthy test subjects without causing significant discomfort. SIGNIFICANCE: Sodium-potassium pump function may be assessed using submaximal electrical stimulation.

Comparing excitability at 37°C versus at 20°C: Differences between motor and sensory axons.

INTRODUCTION: In some peripheral nervous system disorders, cold induces symptoms of muscle weakness without loss of sensation. To understand this selective effect on motor function, it is first essential to delineate the effects of cooling in motor and sensory axons of healthy subjects. METHODS: In 17 healthy volunteers, we performed excitability and clinical tests of median nerve motor and sensory axons at 37°C and at 20°C. Clinical tests consisted of assessing thenar muscle strength, 2-point discrimination, and joint position sense of the third finger. RESULTS: Excitability tests showed that cooling induced opposite changes to hyperpolarizing current in threshold electrotonus (motor, decreased threshold change; sensory, increased threshold change) and current-voltage relation slopes (motor, steepening; sensory, less steep). Clinical tests showed worsening in motor function but no consistent changes in sensory function. DISCUSSION: Cooling induces changes in motor axons consistent with depolarization and more complicated changes in sensory axons, possibly related to differences in hyperpolarization-activated cyclic nucleotide-gated channel expression. Muscle Nerve 57: 574-580, 2018.

Diagnostic value of sonography in treatment-naive chronic inflammatory neuropathies.

OBJECTIVE: To determine the diagnostic value of high-resolution ultrasound (HRUS) for detection of chronic inflammatory demyelinating polyneuropathy (CIDP), Lewis-Sumner syndrome (LSS), and multifocal motor neuropathy (MMN). METHODS: Between January 2013 and January 2015, we enrolled 75 consecutive treatment-naive patients with chronic inflammatory neuropathies and 70 disease controls. We performed extensive nerve conduction and standardized HRUS studies bilaterally of large arm and leg nerves and brachial plexus. We determined optimal sonographic cutoff values of nerve size and used receiver operating characteristic analysis and logistic regression models to identify nerve combinations with optimal diagnostic performance. RESULTS: Enlargement of median nerve at forearm >10 mm2, upper arm >13 mm2, and any trunk of brachial plexus >8 mm2 was 99% specific for chronic inflammatory neuropathies. A shortened HRUS protocol for detecting this abnormal nerve enlargement showed high sensitivity (83%-95%), positive predictive value (100%), and negative predictive value (98%) in discriminating CIDP, LSS, and MMN from clinical mimics. CONCLUSIONS: Sonographic enlargement of proximal median nerve segments in the arms and brachial plexus is a key feature of chronic inflammatory neuropathies, which helps to reliably distinguish them from axonal neuropathies and amyotrophic lateral sclerosis. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, in absence of clinical features that suggest a hereditary demyelinating neuropathy, sonographic enlargement of proximal median nerve segments and brachial plexus accurately identifies patients with chronic inflammatory neuropathies.

The potential and limitations of quantitative electromyography in equine medicine.

This review discusses the scope of using (quantitative) electromyography (EMG) in diagnosing myopathies and neuropathies in equine patients. In human medicine, many EMG methods are available for the diagnosis, pathophysiological description and evaluation, monitoring, or rehabilitation of patients, and some of these techniques have also been applied to horses. EMG results are usually combined with other neurophysiological data, ultrasound, histochemistry, biochemistry of muscle biopsies, and clinical signs in order to provide a complete picture of the condition and its clinical course. EMG technology is commonly used in human medicine and has been subject to constant development and refinement since its introduction in 1929, but the usefulness of the technique in equine medicine is not yet widely acknowledged. The possibilities and limitations of some EMG applications for equine use are discussed.

Complement activity is associated with disease severity in multifocal motor neuropathy.

OBJECTIVE: To investigate whether high innate activity of the classical and lectin pathways of complement is associated with multifocal motor neuropathy (MMN) and whether levels of innate complement activity or the potential of anti-GM1 antibodies to activate the complement system correlate with disease severity. METHODS: We performed a case-control study including 79 patients with MMN and 79 matched healthy controls. Muscle weakness was documented with Medical Research Council scale sum score and axonal loss with nerve conduction studies. Activity of the classical and lectin pathways of complement was assessed by ELISA. We also determined serum mannose-binding lectin (MBL) concentrations and polymorphisms in the MBL gene (MBL2) and quantified complement-activating properties of anti-GM1 IgM antibodies by ELISA. RESULTS: Activity of the classical and lectin pathways, MBL2 genotypes, and serum MBL concentrations did not differ between patients and controls. Complement activation by anti-GM1 IgM antibodies was exclusively mediated through the classical pathway and correlated with antibody titers (p < 0.001). Logistic regression analysis showed that both high innate activity of the classical pathway of complement and high complement-activating capacity of anti-GM1 IgM antibodies were significantly associated with more severe muscle weakness and axonal loss. CONCLUSION: High innate activity of the classical pathway of complement and efficient complement-activating properties of anti-GM1 IgM antibodies are determinants of disease severity in patients with MMN. These findings underline the importance of anti-GM1 antibody-mediated complement activation in the pathogenesis and clinical course of MMN.