Assessing pulmonary function in ALS using electrical impedance tomography.

Objective: We sought to determine whether thoracic electrical impedance tomography (EIT) could characterize pulmonary function in amyotrophic lateral sclerosis (ALS) patients, including those with facial weakness. Thoracic EIT is a noninvasive, technology in which a multi-electrode belt is placed across the chest, producing real-time impedance imaging of the chest during breathing. Methods: We enrolled 32 ALS patients and 32 age- and sex-matched healthy controls (HCs) without underlying lung disease. All participants had EIT measurements performed simultaneously with standard pulmonary function tests (PFTs), including slow and forced vital capacity (SVC and FVC) in upright and supine positions and maximal inspiratory and expiratory pressures (MIPs and MEPs, respectively). Intraclass correlation coefficients (ICCs) were calculated to assess the immediate reproducibility of EIT measurements and Pearson's correlations were used to explore the relationships between EIT and PFT values. Results: Data from 30 ALS patients and 27 HCs were analyzed. Immediate upright SVC reproducibility was very high (ICC 0.98). Correlations were generally strongest between EIT and spirometry measures, with R values ranging from 0.64 to 0.82 (p < 0.001) in the ALS cohort. There were less robust correlations between EIT values and both MIPs and MEPs in the ALS patients, with R values ranging from 0.33 to 0.44. There was no significant difference for patients with and without facial weakness. There were no reported adverse events. Conclusion: EIT-based pulmonary measures hold the promise of providing an alternative approach for lung function assessment in ALS patients. Based on these early results, further development and study of this technology are warranted.

A study of flex miniaturized coils for focal nerve magnetic stimulation.

BACKGROUND: Peripheral magnetic stimulation (PMS) is emerging as a complement to standard electrical stimulation (ES) of the peripheral nervous system (PNS). PMS may stimulate sensory and motor nerve fibers without the discomfort associated with the ES used for standard nerve conduction studies. The PMS coils are the same ones used in transcranial magnetic stimulation (TMS) and lack focality and selectiveness in the stimulation. PURPOSE: This study presents a novel coil for PMS, developed using Flexible technologies, and characterized by reduced dimensions for a precise and controlled targeting of peripheral nerves. METHODS: We performed hybrid electromagnetic (EM) and electrophysiological simulations to study the EM exposure induced by a novel miniaturized coil (or mcoil) in and around the radial nerve of the neuro-functionalized virtual human body model Yoon-Sun, and to estimate the current threshold to induce magnetic stimulation (MS) of the radial nerve. Eleven healthy subjects were studied with the mcoil, which consisted of two 15 mm diameter coils in a figure-of-eight configuration, each with a hundred turns of a 25 µm copper-clad four-layer foil. Sensory nerve action potentials (SNAPs) were measured in each subject using two electrodes and compared with those obtained from standard ES. The SNAPs conduction velocities were estimated as a performance metric. RESULTS: The induced electric field was estimated numerically to peak at a maximum intensity of 39 V/m underneath the mcoil fed by 70 A currents. In such conditions, the electrophysiological simulations suggested that the mcoil elicits SNAPs originating at 7 mm from the center of the mcoil. Furthermore, the numerically estimated latencies and waveforms agreed with those obtained during the PMS experiments on healthy subjects, confirming the ability of the mcoil to stimulate the radial nerve sensory fibers. CONCLUSION: Hybrid EM-electrophysiological simulations assisted the development of a miniaturized coil with a small diameter and a high number of turns using flexible electronics. The numerical dosimetric analysis predicted the threshold current amplitudes required for a suprathreshold peripheral nerve sensory stimulation, which was experimentally confirmed. The developed and now validated computational pipeline will be used to improve the performances (e.g., focality and minimal currents) of new generations of mcoil designs.

Effects of mexiletine on hyperexcitability in sporadic amyotrophic lateral sclerosis: Preliminary findings from a small phase II randomized controlled trial.

BACKGROUND: To collect preliminary data on the effects of mexiletine on cortical and axonal hyperexcitability in sporadic amyotrophic lateral sclerosis (ALS) in a phase 2 double-blind randomized controlled trial. METHODS: Twenty ALS subjects were randomized to placebo and mexiletine 300 or 600 mg daily for 4 wk and assessed by transcranial magnetic stimulation and axonal excitability studies. The primary endpoint was change in resting motor threshold (RMT). RESULTS: RMT was unchanged with 4 wk of mexiletine (combined active therapies) as compared to placebo, which showed a significant increase (P = .039). Reductions of motor evoked potential (MEP) amplitude (P = .013) and accommodation half-time (P = .002), secondary outcome measures of cortical and axonal excitability, respectively, were also evident at 4 wk on mexiletine. CONCLUSIONS: The relative stabilization of RMT in the treated subjects was unexpected and could be attributed to unaccounted sources of error or chance. However, a possible alternative cause is neuromodulation preventing an increase. The change in MEP amplitude and accommodation half-time supports the reduction of cortical and axonal hyperexcitability with mexiletine.

Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.

Importance: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor nervous system. Clinical studies have demonstrated cortical and spinal motor neuron hyperexcitability using transcranial magnetic stimulation and threshold tracking nerve conduction studies, respectively, although metrics of excitability have not been used as pharmacodynamic biomarkers in multi-site clinical trials. Objective: To ascertain whether ezogabine decreases cortical and spinal motor neuron excitability in ALS. Design, Setting, and Participants: This double-blind, placebo-controlled phase 2 randomized clinical trial sought consent from eligible participants from November 3, 2015, to November 9, 2017, and was conducted at 12 US sites within the Northeast ALS Consortium. Participants were randomized in equal numbers to a higher or lower dose of ezogabine or to an identical matched placebo, and they completed in-person visits at screening, baseline, week 6, and week 8 for clinical assessment and neurophysiological measurements. Interventions: Participants were randomized to receive 600 mg/d or 900 mg/d of ezogabine or a matched placebo for 10 weeks. Main Outcomes and Measures: The primary outcome was change in short-interval intracortical inhibition (SICI; SICI-1 was used in analysis to reflect stronger inhibition from an increase in amplitude) from pretreatment mean at screening and baseline to the full-dose treatment mean at weeks 6 and 8. The secondary outcomes included levels of cortical motor neuron excitability (including resting motor threshold) measured by transcranial magnetic stimulation and spinal motor neuron excitability (including strength-duration time constant) measured by threshold tracking nerve conduction studies. Results: A total of 65 participants were randomized to placebo (23), 600 mg/d of ezogabine (23), and 900 mg/d of ezogabine (19 participants); 45 were men (69.2%) and the mean (SD) age was 58.3 (8.8) years. The SICI-1 increased by 53% (mean ratio, 1.53; 95% CI, 1.12-2.09; P = .009) in the 900-mg/d ezogabine group vs placebo group. The SICI-1 did not change in the 600-mg/d ezogabine group vs placebo group (mean ratio, 1.15; 95% CI, 0.87-1.52; P = .31). The resting motor threshold increased in the 600-mg/d ezogabine group vs placebo group (mean ratio, 4.61; 95% CI, 0.21-9.01; P = .04) but not in the 900-mg/d ezogabine group vs placebo group (mean ratio, 1.95; 95% CI, -2.64 to 6.54; P = .40). Ezogabine caused a dose-dependent decrease in excitability by several other metrics, including strength-duration time constant in the 900-mg/d ezogabine group vs placebo group (mean ratio, 0.73; 95% CI, 0.60 to 0.87; P < .001). Conclusions and Relevance: Ezogabine decreased cortical and spinal motor neuron excitability in participants with ALS, suggesting that such neurophysiological metrics may be used as pharmacodynamic biomarkers in multisite clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT02450552.

Quantitative ultrasound of muscle can detect corticosteroid effects.

OBJECTIVES: In this study, we sought to determine whether quantitative ultrasound (QUS) could detect the impact of corticosteroids on muscle in the absence of frank weakness. METHODS: QUS was performed on selected limb muscles of 20 brain tumor patients treated with dexamethasone and 30 healthy controls. Echointensity was quantified using gray scale level (GSL) analysis and compared between groups; correlation to corticosteroid exposure was also performed. RESULTS: Average 4-muscle GSL (±standard deviation) was greater in patients compared to controls (35.5 ±â€¯5.61 arbitrary units (AU) versus 30.4 ±â€¯4.17 AU, p = 0.001), with the greatest differences in tibialis anterior. Average muscle GSL also correlated to length of corticosteroid therapy (rho = 0.52, p = 0.01). CONCLUSIONS: These findings suggest that QUS may be able to quantify skeletal muscle alterations associated with chronic corticosteroid use. Further study of this approach is warranted. SIGNIFICANCE: The findings of this study may provide a tool to evaluate corticosteroid myopathy.

Provisional best practices guidelines for the evaluation of bulbar dysfunction in amyotrophic lateral sclerosis.

INTRODUCTION: Universally established comprehensive clinical bulbar scales objectively assessing disease progression in amyotrophic lateral sclerosis (ALS) are currently lacking. The goal of this working group project is to design a best practice set of provisional bulbar ALS guidelines, available for immediate implementation within all ALS clinics. METHODS: ALS specialists across multiple related disciplines participated in a series of clinical bulbar symposia, intending to identify and summarize the currently accepted best practices for the assessment and management of bulbar dysfunction in ALS Results: Summary group recommendations for individual speech, Augmentative and Alternative Communication (AAC), and swallowing sections were achieved, focusing on the optimal proposed level of care within each domain. DISCUSSION: We have identified specific clinical recommendations for each of the 3 domains of bulbar functioning, available for incorporation within all ALS clinics. Future directions will be to establish a formal set of bulbar guidelines through a methodological and evidence-based approach. Muscle Nerve 59:531-531, 2019.

Ultra-focal Magnetic Stimulation Using a µTMS coil: a Computational Study.

A new miniaturized figure-of-eight coil (µCoil) for TMS applications has been developed taking advantage of the Flex circuit technology. First experiments on volunteers demonstrated the ability of the µCoil to elicit sensorial action potentials of the peripheral nervous system. The necessity of reducing the size of standard TMS stimulator arises from the poor spatial resolution of the latter. This study aims to model the µCoil and study the electromagnetic fields induced inside the arm during peripheral nerve stimulation. Results confirmed that the µCoil is capable of inducing a focalized electric field inside the tissues with amplitudes up to 70V/m consistent with the observed peripheral nerve stimulation in healthy volunteers.

Best practices protocol for the evaluation of bulbar dysfunction: summary recommendations from the NEALS bulbar subcommittee symposium.

OBJECTIVE: The aim of this Symposium was to develop a consensus based, bulbar assessment protocol for implementation within NEALS clinics. METHODS: A one-day symposium, held in April 2017, was organized into Speech and Swallowing sections to establish summary recommendations for the assessment of bulbar dysfunction within each group. RESULTS: Summary recommendations included speech referrals and AAC evaluations at initial visit, CNS-BFS, maximum sustained phonation, and speaking rate. Dysarthria evaluation included the speech subsystem involvement of respiration, phonation, resonance, and articulation. Specific recommendations for swallowing were established for each of the following domains: dietary/oral intake, airway defense physiologic capacity, swallow safety screen, patient-reported swallow-related outcomes, oral sensorimotor exam, and pulmonary function. Practice parameters focused upon patient education and unresolved questions included the use of videofluoscopy, monitoring diet progression, and swallow safety screening. CONCLUSIONS: The working goal is to establish a clinical bulbar protocol, designed to be incorporated within ALS clinics and ultimately to formulate a best practice set of bulbar ALS guidelines, available for implementation throughout the international ALS community.

Optimizing electrical impedance myography of the tongue in amyotrophic lateral sclerosis.

INTRODUCTION: Electrical impedance myography (EIM) can quantify muscle health at a range of frequencies, including that most commonly employed, 50 kHz. However, disease-related changes in EIM data suggest the distinction between normal and patient EIM values could be more apparent at frequencies of >50 kHz. We investigated at what other selected frequencies tongue EIM may differentiate healthy individuals and amyotrophic lateral sclerosis (ALS) patients, remain reliable, and correlate with a standard metric of bulbar function. METHODS: Tongue EIM phase data from 30 volunteers and 11 ALS patients were analyzed at 6 discrete frequencies from 50 to 500 kHz. RESULTS: Of the frequencies assessed, EIM demonstrated maximal separation and reliability at 100 kHz, where phase value was also significantly correlated with the bulbar subscore on the revised version of the ALS Functional Rating Scale. CONCLUSIONS: One hundred kilohertz could serve as an optimal frequency at which to measure EIM phase values of the tongue in ALS. Muscle Nerve 55: 539-543, 2017.

Tongue electrical impedance in amyotrophic lateral sclerosis modeled using the finite element method.

OBJECTIVE: Electrical impedance myography (EIM) of the tongue has demonstrated alterations in patients with amyotrophic lateral sclerosis (ALS) compared to normal subjects. Whether these differences are due to reduced tongue size or diseased-associated alterations in the electrical characteristics of intrinsic tongue muscles is uncertain. METHODS: We employed computer simulations using the finite element method, inputting data from healthy and ALS mouse muscle, to help answer that question, comparing our modeled results to human data. RESULTS: The models revealed that much of the electrical current flows superficially in the tongue and that tongue thickness only begins to have a major impact on the measured impedance when substantial atrophy is present. Modeled values paralleled the human tongue data. CONCLUSIONS: These findings suggest that the observed changes in tongue impedance in ALS are mainly due to alterations in the electrical properties of the tongue and are not a mere consequence of tongue volume loss. SIGNIFICANCE: Further development of EIM for evaluation of bulbar dysfunction in ALS may provide useful information on drug efficacy and could serve as a biomarker in future clinical trials.

Critical appraisal of the use of alpha lipoic acid (thioctic acid) in the treatment of symptomatic diabetic polyneuropathy.

BACKGROUND: The most common of the neuropathies associated with diabetes mellitus, diabetic sensorimotor polyneuropathy (DSPN) is a syndrome of diffuse, length-dependent, symmetric nerve dysfunction. The condition is linked with substantial morbidity, frequent healthcare utilization, and compromised quality of life due to related discomfort. Correspondingly, antidepressants, anticonvulsants, and opioids are regularly prescribed with the goal of pain control. However, the agents rarely provide complete pain relief and fail to address progression of the disorder. Whereas strict blood glucose control can slow the onset and worsening of DSPN, near-normoglycemia is not easily attainable. Evidence implicating oxidative processes in the pathogenesis of DSPN offers one potentially important therapeutic avenue. Due to its properties as a potent antioxidant, alpha lipoic acid (ALA) could mitigate the development of DSPN and attenuate resultant symptoms and signs. Approved for treatment of DSPN in Germany, the agent is not more widely used due to uncertainty about its efficacy and reported adverse effects. Here we review the effectiveness and tolerability of ALA in the treatment of symptomatic DSPN. METHODS: The MEDLINE, EMBASE, and Cochrane Library databases were searched for English-language literature on the topic. Randomized, blinded studies comparing parenteral and oral ALA with placebo in the treatment of peripheral neuropathy in diabetic adults were selected. Analysis included studies with a level of evidence of at least 2b. RESULTS: The current appraisal summarizes data from 1160 participants in the ALADIN, SYDNEY, ORPIL, SYDNEY 2, and ALADIN III trials. In four of the studies, ALA provided significant improvement in manifestations of DSPN. CONCLUSION: Treatment with ALA 600 mg iv daily for 3 weeks represents a well-tolerated and effective therapy for DSPN. An oral dose of 600 mg daily administered for up to 5 weeks could offer benefits in symptoms and signs of DSPN without significant side effects.