RESUMEN
Amyotrophic lateral sclerosis is a devastating neurodegenerative disease, characterized by loss of central and peripheral motor neurons. Although the disease is clinically and genetically heterogeneous, axonal hyperexcitability is a commonly observed feature that has been suggested to reflect an early pathophysiological step linked to the neurodegenerative cascade. Therefore, it is important to clarify the mechanisms causing axonal hyperexcitability and how these relate to the clinical characteristics of patients. Measures derived directly from a nerve excitability recording are frequently used as study end points, although their biophysical basis is difficult to deduce. Mathematical models can aid in the interpretation but are reliable only when applied to group-averaged recordings. Consequently, model estimates of membrane properties cannot be compared with clinical characteristics or treatment effects in individual patients, posing a considerable limitation in heterogeneous diseases, such as amyotrophic lateral sclerosis. To address these challenges, we revisited nerve excitability using a new pattern analysis-based approach (principal component analysis). We evaluated disease-specific patterns of excitability changes and established their biophysical origins. Based on the observed patterns, we developed new compound measures of excitability that facilitate the implementation of this approach in clinical settings. We found that excitability changes in amyotrophic lateral sclerosis patients (n = 161, median disease duration = 11 months) were characterized by four unique patterns compared with controls (n = 50, age and sex matched). These four patterns were best explained by changes in resting membrane potential (modulated by Na+/K+ currents), slow potassium and sodium currents (modulated by their gating kinetics) and refractory properties of the nerve. Consequently, we were able to show that altered gating of slow potassium channels was associated with, and predictive of, the rate of progression of the disease on the amyotrophic lateral sclerosis functional rating scale. Based on these findings, we designed four composite measures that capture these properties to facilitate implementation outside this study. Our findings demonstrate that changes in nerve excitability in patients with amyotrophic lateral sclerosis are dominated by four distinct patterns, each with a distinct biophysical origin. Based on this new approach, we provide evidence that altered slow potassium-channel function might play a role in the rate of disease progression. The magnitudes of these patterns, quantified using a similar approach or our new composite measures, have potential as efficient measures to study membrane properties directly in amyotrophic lateral sclerosis patients, and thus aid prognostic stratification and trial design.
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Esclerosis Amiotrófica Lateral , Neuronas Motoras , Esclerosis Amiotrófica Lateral/fisiopatología , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Neuronas Motoras/fisiología , Adulto , Potenciales de Acción/fisiología , Análisis de Componente Principal , Axones/fisiología , Potenciales de la Membrana/fisiologíaRESUMEN
Objective.To simulate progressive motor neuron loss and collateral reinnervation in motor neuron diseases (MNDs) by developing a dynamic muscle model based on human single motor unit (MU) surface-electromyography (EMG) recordings.Approach.Single MU potentials recorded with high-density surface-EMG from thenar muscles formed the basic building blocks of the model. From the baseline MU pool innervating a muscle, progressive MU loss was simulated by removal of MUs, one-by-one. These removed MUs underwent collateral reinnervation with scenarios varying from 0% to 100%. These scenarios were based on a geometric variable, reflecting the overlap in MU territories using the spatiotemporal profiles of single MUs and a variable reflecting the efficacy of the reinnervation process. For validation, we tailored the model to generate compound muscle action potential (CMAP) scans, which is a promising surface-EMG method for monitoring MND patients. Selected scenarios for reinnervation that matched observed MU enlargements were used to validate the model by comparing markers (including the maximum CMAP and a motor unit number estimate (MUNE)) derived from simulated and recorded CMAP scans in a cohort of 49 MND patients and 22 age-matched healthy controls.Main results.The maximum CMAP at baseline was 8.3 mV (5th-95th percentile: 4.6 mV-11.8 mV). Phase cancellation caused an amplitude drop of 38.9% (5th-95th percentile, 33.0%-45.7%). To match observations, the geometric variable had to be set at 40% and the efficacy variable at 60%-70%. The Δ maximum CMAP between recorded and simulated CMAP scans as a function of fitted MUNE was -0.4 mV (5th-95th percentile = -4.0 - +2.4 mV).Significance.The dynamic muscle model could be used as a platform to train personnel in applying surface-EMG methods prior to their use in clinical care and trials. Moreover, the model may pave the way to compare biomarkers more efficiently, without directly posing unnecessary burden on patients.
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Enfermedad de la Neurona Motora , Músculo Esquelético , Humanos , Músculo Esquelético/fisiología , Potenciales de Acción/fisiología , Neuronas Motoras/fisiología , Electromiografía/métodos , Enfermedad de la Neurona Motora/diagnóstico , Enfermedad de la Neurona Motora/patología , Degeneración Nerviosa/patologíaRESUMEN
Objective: Electrophysiological techniques are emerging as an aid in identifying prognostic or therapeutic biomarkers in patients with spinal muscular atrophy (SMA), but electrophysiological assessments may be burdensome for patients. We, therefore, assessed feasibility and tolerability of multimodal peripheral non-invasive electrophysiological techniques in a cohort of patients with SMA. Methods: We conducted a single center, longitudinal cohort study investigating the feasibility and tolerability of applying multimodal electrophysiological techniques to the median nerve unilaterally. Techniques consisted of the compound muscle action potential scan, motor nerve excitability tests, repetitive nerve stimulation and sensory nerve action potential. We assessed tolerability using the numeric rating scale (NRS), ranging from 0 (no pain) to 10 (worst possible pain), and defined the protocol to be tolerable if the NRS scoreâ¯≤â¯3. The protocol was considered feasible if it could be performed according to test and quality standards. Results: We included 71 patients with SMA types 1-4 (median 39â¯years; range 13-67) and 63 patients at follow-up. The protocol was feasible in 98% of patients and was well-tolerated in up to 90% of patients. Median NRS score was 2 (range 0-6 at baseline and range 0-4 at follow-up (pâ¯<â¯0.01)). None of the patients declined follow-up assessment. Conclusions: Multimodal, peripheral, non-invasive, electrophysiological techniques applied to the median nerve are feasible and well-tolerated in adolescents and adults with SMA types 1-4. Significance: Our study supports the use of non-invasive multimodal electrophysiological assessments in adolescents and adults with SMA types 1-4.
RESUMEN
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).
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Atrofia Muscular Espinal , Humanos , Estudios Longitudinales , Estudios Prospectivos , Atrofia Muscular Espinal/terapia , BiomarcadoresRESUMEN
BACKGROUND: Given the large genetic heterogeneity in amyotrophic lateral sclerosis (ALS), it seems likely that genetic subgroups may benefit differently from treatment. An exploratory meta-analysis identified that patients homozygous for the C-allele at SNP rs12608932, a single nucleotide polymorphism in the gene UNC13A, had a statistically significant survival benefit when treated with lithium carbonate. We aim to confirm the efficacy of lithium carbonate on the time to death or respiratory insufficiency in patients with ALS homozygous for the C-allele at SNP rs12608932 in UNC13A. METHODS: A randomized, group-sequential, event-driven, double-blind, placebo-controlled trial will be conducted in 15 sites across Europe and Australia. Patients will be genotyped for UNC13A; those homozygous for the C-allele at SNP rs12608932 will be eligible. Patients must have a diagnosis of ALS according to the revised El Escorial criteria, and a TRICALS risk-profile score between -6.0 and -2.0. An expected number of 1200 patients will be screened in order to enroll a target sample size of 171 patients. Patients will be randomly allocated in a 2:1 ratio to lithium carbonate or matching placebo, and treated for a maximum duration of 24 months. The primary endpoint is the time to death or respiratory insufficiency, whichever occurs first. Key secondary endpoints include functional decline, respiratory function, quality of life, tolerability, and safety. An interim analysis for futility and efficacy will be conducted after the occurrence of 41 events. DISCUSSION: Lithium carbonate has been proven to be safe and well-tolerated in patients with ALS. Given the favorable safety profile, the potential benefits are considered to outweigh the burden and risks associated with study participation. This study may provide conclusive evidence about the life-prolonging potential of lithium carbonate in a genetic ALS subgroup. TRIAL REGISTRATION: EudraCT number 2020-000579-19 . Registered on 29 March 2021.
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Esclerosis Amiotrófica Lateral , Insuficiencia Respiratoria , Humanos , Esclerosis Amiotrófica Lateral/diagnóstico , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/genética , Carbonato de Litio/efectos adversos , Polimorfismo de Nucleótido Simple , Alelos , Calidad de Vida , Insuficiencia Respiratoria/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto , Metaanálisis como AsuntoRESUMEN
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.
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Esclerosis Amiotrófica Lateral , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Axones/fisiología , Carbamatos , Humanos , Neuronas Motoras , Fenilendiaminas/farmacología , Fenilendiaminas/uso terapéuticoRESUMEN
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.
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Polineuropatías , Potenciales de Acción/fisiología , Estudios de Cohortes , Progresión de la Enfermedad , Humanos , Conducción Nerviosa/fisiología , Polineuropatías/diagnóstico por imagenRESUMEN
OBJECTIVE: To determine which compound muscle action potential (CMAP) scan-derived electrophysiological markers are most sensitive for monitoring disease progression in amyotrophic lateral sclerosis (ALS), and whether they hold value for clinical trials. METHODS: We used four independent patient cohorts to assess longitudinal patterns of a comprehensive set of electrophysiological markers including their association with the ALS functional rating scale (ALSFRS-R). Results were translated to trial sample size requirements. RESULTS: In 65 patients, 225 thenar CMAP scan recordings were obtained. Electrophysiological markers showed extensive variation in their longitudinal trajectories. Expressed as standard deviations per month, motor unit number estimation (MUNE) values declined by 0.09 (CI 0.07-0.12), D50, a measure that quantifies CMAP scan discontinuities, declined by 0.09 (CI 0.06-0.13) and maximum CMAP by 0.05 (CI 0.03-0.08). ALSFRS-R declined fastest (0.12, CI 0.08 - 0.15), however the between-patient variability was larger compared to electrophysiological markers, resulting in larger sample sizes. MUNE reduced the sample size by 19.1% (n = 388 vs n = 314) for a 6-month study compared to the ALSFRS-R. CONCLUSIONS: CMAP scan-derived markers show promise in monitoring disease progression in ALS patients, where MUNE may be its most suitable derivate. SIGNIFICANCE: MUNE may increase clinical trial efficiency compared to clinical endpoints.
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Potenciales de Acción , Esclerosis Amiotrófica Lateral/fisiopatología , Adulto , Anciano , Esclerosis Amiotrófica Lateral/diagnóstico , Ensayos Clínicos como Asunto , Electromiografía/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/inervación , Músculo Esquelético/fisiopatologíaRESUMEN
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.
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Potenciales de Acción , Fibras Musculares Esqueléticas/fisiología , Estimulación Eléctrica Transcutánea del Nervio/métodos , Adulto , Electromiografía/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Contracción Muscular , TiempoRESUMEN
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.
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Potenciales de Acción/fisiología , Axones/fisiología , Neuronas Motoras/fisiología , Conducción Nerviosa/fisiología , Polineuropatías/fisiopatología , Células Receptoras Sensoriales/fisiología , Adulto , Anciano , Estimulación Eléctrica , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: To assess motor unit (MU) changes in patients with spinal muscular atrophy (SMA) using compound muscle action potential (CMAP) scans. METHODS: We performed CMAP scan recordings in median nerves of 24 treatment-naïve patients (median age 39; range 12-75 years) with SMA types 2-4. From each scan, we determined maximum CMAP amplitude (CMAPmax), a motor unit number estimate (MUNE), and D50 which quantifies the largest discontinuities within CMAP scans. RESULTS: Median CMAPmax was 8.1 mV (range 0.9-14.6 mV), MUNE was 29 (range 6-131), and D50 was 25 (range 2-57). We found a reduced D50 (<25) in patients with normal CMAPmax (n = 12), indicating MU loss and enlarged MUs due to reinnervation. Lower D50 values were associated with decreased MUNE (P < 0.001, r = 0.68, n = 43). CMAPmax, MUNE and D50 values differed between SMA types (P < 0.001). Lower motor function scores were related to patients with lower CMAPmax, MUNE and D50 values (P < 0.001). CONCLUSIONS: The CMAP scan is an easily applicable technique that is superior to routine assessment of CMAPmax in SMA. SIGNIFICANCE: The detection of pathological MU changes across the spectrum of SMA may provide important biomarkers for evaluating disease course and monitoring treatment efficacy.
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Potenciales de Acción/fisiología , Nervio Mediano/fisiopatología , Neuronas Motoras/fisiología , Músculo Esquelético/fisiopatología , Atrofia Muscular Espinal/fisiopatología , Unión Neuromuscular/fisiopatología , Adolescente , Adulto , Anciano , Niño , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
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.
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Axones/fisiología , Modelos Biológicos , Neuronas Motoras/fisiología , Fibras Nerviosas Mielínicas/fisiología , Conducción Nerviosa/fisiología , Nódulos de Ranvier/fisiología , Células Receptoras Sensoriales/fisiología , Canales de Sodio/fisiología , Animales , Enfermedades Desmielinizantes/fisiopatología , Humanos , Enfermedades del Sistema Inmune/fisiopatologíaRESUMEN
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.
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Hipotermia/fisiopatología , Nervio Mediano/fisiopatología , Piel/fisiopatología , Temperatura , Adulto , Femenino , Humanos , Masculino , Tejido Nervioso/fisiopatología , Factores de TiempoRESUMEN
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 9â¯×â¯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.
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Electromiografía/métodos , Potenciales Evocados Motores/fisiología , Reclutamiento Neurofisiológico/fisiología , Potenciales de Acción/fisiología , Adolescente , Adulto , Estimulación Eléctrica/instrumentación , Estimulación Eléctrica/métodos , Femenino , Mano/inervación , Mano/fisiología , Humanos , Masculino , Adulto JovenRESUMEN
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.
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Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Axones/efectos de los fármacos , Carbamatos/administración & dosificación , Potenciales Evocados Motores/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Neuronas Motoras/efectos de los fármacos , Fármacos Neuroprotectores/administración & dosificación , Fenilendiaminas/administración & dosificación , Riluzol/administración & dosificación , Adulto , Anciano , Esclerosis Amiotrófica Lateral/patología , Esclerosis Amiotrófica Lateral/fisiopatología , Axones/patología , Carbamatos/efectos adversos , Carbamatos/farmacocinética , Estudios Cruzados , Método Doble Ciego , Electromiografía , Antagonistas de Aminoácidos Excitadores/efectos adversos , Antagonistas de Aminoácidos Excitadores/farmacocinética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neuronas Motoras/patología , Países Bajos , Fármacos Neuroprotectores/efectos adversos , Fármacos Neuroprotectores/farmacocinética , Fenilendiaminas/efectos adversos , Fenilendiaminas/farmacocinética , Periodo Refractario Electrofisiológico/efectos de los fármacos , Riluzol/efectos adversos , Riluzol/farmacocinética , Factores de Tiempo , Resultado del TratamientoRESUMEN
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 8â¯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.
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Nervio Mediano/fisiología , Contracción Muscular/fisiología , ATPasa Intercambiadora de Sodio-Potasio/fisiología , Adulto , Estimulación Eléctrica/métodos , Femenino , Humanos , MasculinoRESUMEN
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.
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Axones/fisiología , Mano , Neuronas Motoras/fisiología , Fuerza Muscular/fisiología , Propiocepción/fisiología , Células Receptoras Sensoriales/fisiología , Temperatura , Tacto/fisiología , Adulto , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Umbral Sensorial , Adulto JovenRESUMEN
INTRODUCTION: The aim of this study was to determine whether electrically evoked multiplet discharges (MDs) are related to severity of clinical deterioration in motor neuron disease (MND). METHODS: Stimulated high-density surface electromyographic (HDsEMG) recordings were performed in thenar muscles. Data were collected from 31 MND patients. MDs from the HDsEMG recordings were determined at baseline. ALSFRS-R scores were obtained at baseline and at a maximum of 16 weeks follow-up. RESULTS: The presence of MDs was associated with progressive deterioration of ALSFRS-R score (P = 0.02) and fine motor function (FMF) (P < 0.001). Patients who had a higher number of motor units that generated MDs (r = 0.61, P < 0.001) and patients who had a higher number of MDs (as percentage of applied stimuli) (r = 0.59, P = 0.001) had a more severe decline in FMF. CONCLUSIONS: Electrically evoked MDs are associated with more marked clinical deterioration in patients with MND.
Asunto(s)
Potenciales de Acción/fisiología , Enfermedad de la Neurona Motora/fisiopatología , Adulto , Anciano , Electromiografía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/fisiopatología , Índice de Severidad de la EnfermedadRESUMEN
INTRODUCTION: Fasciculations, the spontaneous activity of single motor units (MUs) are characteristic, but nonspecific for motor neuron disease (MND). We aimed to identify MU discharge properties to optimally differentiate MND patients from healthy controls. METHODS: High-density surface electromyography recordings were performed in the thenar muscles during 10 min of rest. MU discharges were classified as "isolated" when the interspike intervals (ISIs) before and after were > 250 ms, "continual" when both ISIs were ≤ 250 ms, or as "other". RESULTS: In patients (n = 30) compared with controls (n = 14), more MUs were active (9 vs. 3, P < 0.001) and generated relatively more isolated discharges (35% vs. 10%, P = 0.01). Two or more MUs with isolated discharges occurred more frequently in patients compared with controls (24% vs. <1% of 10-s windows, P < 0.001). CONCLUSIONS: More frequent occurrence of multiple MUs showing isolated discharges may improve identification of patients with MND.