Revisiting distinct nerve excitability patterns in patients with amyotrophic lateral sclerosis.

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.

Increase of HCN current in SOD1-associated amyotrophic lateral sclerosis.

The clinical manifestations of sporadic amyotrophic lateral sclerosis (ALS) vary widely. However, the current classification of ALS is mainly based on clinical presentations, while the roles of electrophysiological and biomedical biomarkers remain limited. Herein, we investigated a group of patients with sporadic ALS and an ALS mouse model with superoxide dismutase 1 (SOD1)/G93A transgenes using nerve excitability tests (NET) to investigate axonal membrane properties and chemical precipitation, followed by enzyme-linked immunosorbent assay analysis to measure plasma misfolded protein levels. Six of 19 patients (31.6%) with sporadic ALS had elevated plasma misfolded SOD1 protein levels. In sporadic ALS patients, only those with elevated misfolded SOD1 protein levels showed an increased inward rectification in the current-threshold (I/V) curve and an increased threshold reduction in the hyperpolarizing threshold electrotonus (TE) in the NET study. Two familial ALS patients with SOD1 mutations also exhibited similar electrophysiological patterns of NET. For patients with sporadic ALS showing significantly increased inward rectification in the I/V curve, we noted an elevation in plasma misfolded SOD1 level, but not in total SOD1, misfolded C9orf72, or misfolded phosphorylated TDP43 levels. Computer simulations demonstrated that the aforementioned axonal excitability changes are likely associated with an increase in hyperpolarization-activated cyclic nucleotide-gated (HCN) current. In SOD1/G93A mice, NET also showed an increased inward rectification in the I/V curve, which could be reversed by a single injection of the HCN channel blocker, ZD7288. Daily treatment of SOD1/G93A mice with ZD7288 partially prevented the early motor function decline and spinal motor neuron death. In summary, sporadic ALS patients with elevated plasma misfolded SOD1 exhibited similar patterns of motor axonal excitability changes as familial ALS patients and ALS mice with mutant SOD1 genes, suggesting the existence of SOD1-associated sporadic ALS. The observed NET pattern of increased inward rectification in the I/V curve was attributable to an elevation in the HCN current in SOD1-associated ALS.

Morphofunctional characterisation of axonal damage in different rat models of chemotherapy-induced peripheral neurotoxicity: The role of nerve excitability testing.

BACKGROUND AND AIMS: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common and long-lasting adverse event of several anticancer compounds, for which treatment has not yet been developed. To fill this gap, preclinical studies are warranted, exploiting highly translational outcome measure(s) to transfer data from bench to bedside. Nerve excitability testing (NET) enables to test in vivo axonal properties and can be used to monitor early changes leading to axonal damage. METHODS: We tested NET use in two different CIPN rat models: oxaliplatin (OHP) and paclitaxel (PTX). Animals (female) were chronically treated with either PTX or OHP and compared to respective control animals. NET was performed as soon as the first injection was administered. At the end of the treatment, CIPN onset was verified via a multimodal and robust approach: nerve conduction studies, nerve morphometry, behavioural tests and intraepidermal nerve fibre density. RESULTS: NET showed the typical pattern of axonal hyperexcitability in the 72 h following the first OHP administration, whereas it showed precocious signs of axonal damage in PTX animals. At the end of the month of treatment, OHP animals showed a pattern compatible with a mild axonal sensory polyneuropathy. Instead, PTX cohort was characterised by a rather severe sensory axonal polyneuropathy with minor signs of motor involvement. INTERPRETATION: NET after the first administration demonstrated the ongoing OHP-related channelopathy, whereas in PTX cohort it showed precocious signs of axonal damage. Therefore, NET could be suggested as an early surrogate marker in clinical trials, to detect precocious changes leading to axonal damage.

Functional Characteristics of the Nav1.1 p.Arg1596Cys Mutation Associated with Varying Severity of Epilepsy Phenotypes.

Mutations of the SCN1A gene, which encodes the voltage-dependent Na+ channel's α subunit, are associated with diverse epileptic syndromes ranging in severity, even intra-family, from febrile seizures to epileptic encephalopathy. The underlying cause of this variability is unknown, suggesting the involvement of additional factors. The aim of our study was to describe the properties of mutated channels and investigate genetic causes for clinical syndromes' variability in the family of five SCN1A gene p.Arg1596Cys mutation carriers. The analysis of additional genetic factors influencing SCN1A-associated phenotypes was conducted through exome sequencing (WES). To assess the impact of mutations, we used patch clamp analysis of mutated channels expressed in HEK cells and in vivo neural excitability studies (NESs). In cells expressing the mutant channel, sodium currents were reduced. NESs indicated increased excitability of peripheral motor neurons in mutation carriers. WES showed the absence of non-SCA1 pathogenic variants that could be causative of disease in the family. Variants of uncertain significance in three genes, as potential modifiers of the most severe phenotype, were identified. The p.Arg1596Cys substitution inhibits channel function, affecting steady-state inactivation kinetics. Its clinical manifestations involve not only epileptic symptoms but also increased excitability of peripheral motor fibers. The role of Nav1.1 in excitatory neurons cannot be ruled out as a significant factor of the clinical phenotype.

Diagnostic accuracy of nerve excitability and compound muscle action potential scan derived biomarkers in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: The lack of reliable early biomarkers still causes substantial diagnostic delays in amyotrophic lateral sclerosis (ALS). The aim was to assess the diagnostic accuracy of a novel electrophysiological protocol in patients with suspected motor neuron disease (MND). METHODS: Consecutive patients with suspected MND were prospectively recruited at our tertiary referral centre for MND in Utrecht, The Netherlands. Procedures were performed in accordance with the Standards for Reporting of Diagnostic Accuracy. In addition to the standard diagnostic workup, an electrophysiological protocol of compound muscle action potential (CMAP) scans and nerve excitability tests was performed on patients' thenar muscles. The combined diagnostic yield of nerve excitability and CMAP scan based motor unit number estimation was compared to the Awaji and Gold Coast criteria and their added value was determined. RESULTS: In all, 153 ALS or progressive muscular atrophy patients, 63 disease controls and 43 healthy controls were included. Our electrophysiological protocol had high diagnostic accuracy (area under the curve [AUC] 0.85, 95% confidence interval [95% CI] 0.80-0.90), even in muscles with undetectable axon loss (AUC 0.78, 95% CI 0.70-0.85) and in bulbar-onset patients (AUC 0.85, 95% CI 0.73-0.95). Twenty-four of 33 (73%) ALS patients who could not be diagnosed during the same visit were correctly identified, as well as 8/13 (62%) ALS patients not meeting the Gold Coast criteria and 49/59 (83%) ALS patients not meeting the Awaji criteria during this first visit. CONCLUSIONS: Our practical and non-invasive electrophysiological protocol may improve early diagnosis in clinically challenging patients with suspected ALS. Routine incorporation may boost early diagnosis, enhance patient selection and generate baseline measures for clinical trials.

High-dose pharmaceutical-grade biotin in patients with demyelinating neuropathies: a phase 2b open label, uncontrolled, pilot study.

BACKGROUND: We proposed to investigate high-dose pharmaceutical-grade biotin in a population of demyelinating neuropathies of different aetiologies, as a proof-of-concept. METHODS: Phase IIb open label, uncontrolled, single center, pilot study in 15 patients (three groups of five patients) with chronic demyelinating peripheral neuropathy, i.e. chronic inflammatory demyelinating polyradiculoneuropathy, anti-myelin-associated glycoprotein neuropathy and Charcot-Marie-Tooth 1a or 1b. The investigational product was high-dose pharmaceutical-grade biotin (100 mg taken orally three times a day over a maximum of 52 weeks. The primary endpoint was a 10% relative improvement in 2 of the following 4 electrophysiological variables: motor nerve conduction velocity, distal motor latency, F wave latency, duration of the compound muscle action potential. The secondary endpoints included Overall Neuropathy Limitations Scale (ONLS) score, Medical Research Council (MRC) sum score, Inflammatory Neuropathy Cause and Treatment (INCAT) sensory sum score, 10-m walk test, 6-min walk test, posturography parameters, and nerve excitability variables. RESULTS: The primary endpoint was reached in one patient. In the full population analysis, some secondary endpoints parameters improved: MRC score, INCAT sensory sum score, 6-min walk distance, strength-duration time constant, and rheobase. There was a positive correlation between the improvement in the 6-min walk distance and the strength-duration time constant. Regarding the safety results, 42 adverse events occurred, of which three were of severe intensity but none was considered as related to the investigational product. CONCLUSIONS: Even if the primary endpoint was not met, administration of high-dose pharmaceutical-grade biotin led to an improvement in various sensory and motor parameters, gait abilities, and nerve excitability parameters. The tolerance of the treatment was satisfactory. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02967679; date 2016/12/05.

Changes in axonal and clinical function during intravenous and subcutaneous immunoglobulin therapy in chronic inflammatory demyelinating polyneuropathy.

BACKGROUND AND AIMS: Intravenous immunoglobulin (IVIg) has a rapid clinical effect which cannot be explained by remyelination during each treatment cycle in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). This study aimed to investigate axonal membrane properties during the IVIg treatment cycle and their potential correlation with clinically relevant functional measurements. METHODS: Motor nerve excitability testing (NET) of the median nerve was performed before and 4 and 18 days after initiation of an IVIg treatment cycle in 13 treatment-naïve (early) CIDP patients and 24 CIDP patients with long term (late) IVIg treatment, 12 CIDP patients treated with subcutaneous immunoglobulin (SCIg) and 55 healthy controls. Clinical function was measured extensively using the Six Spot Step test, 10-Meter Walk test, 9-Hole Peg test, grip strength, MRC sum score, Overall Neuropathy Limitations Score and Patient Global Impression of Change. RESULTS: Superexcitability and S2 accommodation decreased significantly in the early treatment group from baseline to day 4 and returned to baseline levels at day 18, suggesting temporary depolarization of the axonal membrane. A similar trend was observed for the late IVIg group. Substantial clinical improvement was observed in both early and late IVIg groups during the entire treatment cycle. No statistically significant correlation was found between clinical and NET changes. No change was found in NET or clinical function in the SCIg group or controls. INTERPRETATION: NET suggested temporary depolarization of the axonal membrane during IVIg treatment in treatment naïve CIDP patients. The relation to clinical improvement, however, remains speculative.

[Effects of repetitive transcranial magnetic stimulation on neuronal excitability and ion channels in hindlimb unloading mice].

Weightlessness in the space environment affects astronauts' learning memory and cognitive function. Repetitive transcranial magnetic stimulation has been shown to be effective in improving cognitive dysfunction. In this study, we investigated the effects of repetitive transcranial magnetic stimulation on neural excitability and ion channels in simulated weightlessness mice from a neurophysiological perspective. Young C57 mice were divided into control, hindlimb unloading and magnetic stimulation groups. The mice in the hindlimb unloading and magnetic stimulation groups were treated with hindlimb unloading for 14 days to establish a simulated weightlessness model, while the mice in the magnetic stimulation group were subjected to 14 days of repetitive transcranial magnetic stimulation. Using isolated brain slice patch clamp experiments, the relevant indexes of action potential and the kinetic property changes of voltage-gated sodium and potassium channels were detected to analyze the excitability of neurons and their ion channel mechanisms. The results showed that the behavioral cognitive ability and neuronal excitability of the mice decreased significantly with hindlimb unloading. Repetitive transcranial magnetic stimulation could significantly improve the cognitive impairment and neuroelectrophysiological indexes of the hindlimb unloading mice. Repetitive transcranial magnetic stimulation may change the activation, inactivation and reactivation process of sodium and potassium ion channels by promoting sodium ion outflow and inhibiting potassium ion, and affect the dynamic characteristics of ion channels, so as to enhance the excitability of single neurons and improve the cognitive damage and spatial memory ability of hindlimb unloading mice.

Open-label pilot study of ranolazine for cramps in amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Neuronal hyperexcitability (manifested by cramps) plays a pathological role in amyotrophic lateral sclerosis (ALS), and drugs affecting it may help symptomatic management and slow disease progression. We aimed to determine safety and tolerability of two doses of ranolazine in patients with ALS and evaluate for preliminary evidence of drug-target engagement by assessing muscle cramp characteristics. METHODS: We performed an open-label dose-ascending study of ranolazine in 14 individuals with ALS in two sequential cohorts: 500 mg (cohort 1) and 1000 mg (cohort 2) orally twice daily. Each had a 2-week run-in period, 4-week drug administration, and 6-week safety follow-up. Primary outcome was safety and tolerability. Exploratory measures included cramp frequency and severity, fasciculation frequency, cramp potential duration, ALS Functional Rating Scale---Revised score, and forced vital capacity. RESULTS: Six and eight participants were enrolled in cohorts 1 and 2, respectively. There were no serious adverse events. Two subjects in cohort 2 discontinued the drug due to constipation. The most frequent drug-related adverse event was gastrointestinal (40%). Cramp frequency decreased by 54.8% (95% confidence interval [CI], 39%-70.8%) and severity decreased by 46.3% (95% CI, 29.5-63.3%), which appeared to be dose-dependent, with decreased awakening due to cramps. Other outcomes showed no change. DISCUSSION: Ranolazine was well tolerated in ALS up to 2000 mg/day, with gastrointestinal side effects being the most frequent. Ranolazine reduced cramp frequency and severity, supporting its investigation for muscle cramps in a future placebo-controlled trial.

Sodium-Calcium Exchanger 2: A Pivotal Role in Oxaliplatin Induced Peripheral Neurotoxicity and Axonal Damage?

Oxaliplatin (OHP)-induced peripheral neurotoxicity (OIPN) is a frequent adverse event of colorectal cancer treatment. OIPN encompasses a chronic and an acute syndrome. The latter consists of transient axonal hyperexcitability, due to unbalance in Na+ voltage-operated channels (Na+VOC). This leads to sustained depolarisation which can activate the reverse mode of the Na+/Ca2+ exchanger 2 (NCX2), resulting in toxic Ca2+ accumulation and axonal damage (ADa). We explored the role of NCX2 in in vitro and in vivo settings. Embryonic rat Dorsal Root Ganglia (DRG) organotypic cultures treated with SEA0400 (SEA), a NCX inhibitor, were used to assess neuroprotection in a proof-of-concept and pilot study to exploit NCX modulation to prevent ADa. In vivo, OHP treated mice (7 mg/Kg, i.v., once a week for 8 weeks) were compared with a vehicle-treated group (n = 12 each). Neurophysiological and behavioural testing were performed to characterise acute and chronic OIPN, and morphological analyses were performed to detect ADa. Immunohistochemistry, immunofluorescence, and western blotting (WB) analyses were also performed to demonstrate changes in NCX2 immunoreactivity and protein expression. In vitro, NCX inhibition was matched by ADa mitigation. In the in vivo part, after verifyingboth acute and chronic OIPN had ensued, we confirmed via immunohistochemistry, immunofluorescence, and WB that a significant NCX2 alteration had ensued in the OHP group. Our data suggest NCX2 involvement in ADa development, paving the way to a new line of research to prevent OIPN.

Impact of the metabolic syndrome on peripheral nerve structure and function in type 2 diabetes.

BACKGROUND AND PURPOSE: There is a strong association between the metabolic syndrome in diabetes and the development of peripheral neuropathy; however, the pathophysiological mechanisms remain unknown. METHODS: Participants with type 2 diabetes and metabolic syndrome (T2DM/MetS, n = 89) and type 2 diabetes alone (T2DM; n = 59) underwent median nerve ultrasound and excitability studies to assess peripheral nerve structure and function. A subset of T2DM/MetS (n = 24) and T2DM (n = 22) participants underwent confocal microscopy to assess central and inferior whorl corneal nerve structure. Neuropathy severity was assessed using the modified Toronto Clinical Neuropathy Score (mTCNS). Diabetes groups were similar for age, sex distribution, diabetes duration, hemoglobin A1c , insulin treatment, and renal function. Sixty healthy controls similar for age and sex distribution were recruited for comparison. RESULTS: Participants with T2DM/MetS manifested with a greater mTCNS compared to T2DM (p < 0.05). Median nerve cross-sectional area was larger in the T2DM/MetS group compared to the T2DM cohort (p < 0.05). Participants with T2DM/MetS had reductions in central (all p < 0.01) and inferior whorl (all p < 0.05) nerve measures. Compared to T2DM, the T2DM/MetS group demonstrated more severe changes in nerve excitability measures, which was due to reduced sodium channel permeability and sodium-potassium pump function. In comparison, only sodium channel permeability was reduced in the T2DM group. CONCLUSIONS: Compared to participants with type 2 diabetes alone, those with diabetes and metabolic syndrome manifested greater alterations in peripheral nerve structure and function, which may be due to reduced function of the sodium-potassium pump.

Electrophysiological investigation of motor axonal excitability in a mouse model of nerve constriction injury.

Peripheral nerve injuries caused by focal constriction are characterised by local nerve ischaemia, axonal degeneration, demyelination, and neuroinflammation. The aim of this study was to understand temporal changes in the excitability properties of injured motor axons in a mouse model of nerve constriction injury (NCI). The excitability of motor axons following unilateral sciatic NCI was studied in male C57BL/6J mice distal to the site of injury at the acute (6 hours-1 week) and chronic (up to 20 weeks) phases of injury, using threshold tracking. Multiple measures of nerve excitability, including strength-duration properties, threshold electrotonus, current-threshold relationship, and recovery cycle were examined using the automated nerve excitability protocol (TRONDNF). Acutely, injured motor axons developed a pattern of excitability characteristic of ischemic depolarisation. In most cases, the sciatic nerve became transiently inexcitable. When a liminal compound muscle action potential could again be recorded, it had an increase in threshold and latency, compared to both pre-injury baseline and sham-injured groups. These axons showed a greater threshold change in response to hyperpolarising threshold electrotonus and a significant upward shift in the recovery cycle. Mathematical modelling suggested that the changes seen in chronically injured axons involve shortened internodes, reduced myelination, and exposed juxtaparanodal fast K+ conductances. The findings of this study demonstrate long-term changes in motor excitability following NCI (involving alterations in axonal properties and ion channel activity) and are important for understanding the mechanisms of neurapraxic injuries and traumatic mononeuropathies.

Neu-horizons: neuroprotection and therapeutic use of riluzole for the prevention of oxaliplatin-induced neuropathy-a randomised controlled trial.

TRIAL DESIGN: Peripheral neuropathy is a commonly reported adverse effect of oxaliplatin treatment, representing a significant limitation which may require discontinuation of effective therapy. The present study investigated the neuroprotective potential of riluzole in patients undergoing oxaliplatin treatment in a randomised-controlled trial comparing riluzole and placebo-control. METHODS: Fifty-two patients (17 females, 58.1 ± 12.7 years) receiving oxaliplatin treatment were randomised into either a treatment (50 mg riluzole) or lactose placebo group. The primary outcome measure was the total neuropathy score-reduced (TNSr). Secondary outcome measures include nerve excitability measures, 9-hole pegboard and FACT-GOG NTX questionnaire. Patients were assessed at baseline, pre-cycle 10 or 12, 4-week and 12-week post-treatment. RESULTS: Both the treatment and placebo groups developed objective and patient reported evidence of neurotoxicity over the course of oxaliplatin treatment, although there were no significant differences across any parameters between the two groups. However, across follow-up assessments, the treatment group experienced greater neuropathy, represented by a higher TNSr score at 4-week post-chemotherapy of 8.3 ± 2.7 compared with 4.6 ± 3.6 (p = 0.032) which was sustained at 12-week post-treatment (p = 0.089). Similarly, patients in the treatment group reported worse symptoms with a FACT-GOG NTX score of 37.4 ± 10.2 compared with 43.3 ± 7.4 (p = 0.02) in the placebo group at 4-week post-treatment. CONCLUSION: This study is the first to provide an objective clinical investigation of riluzole in oxaliplatin-induced peripheral neuropathy employing both functional and neurophysiological measures. Although the recruitment target was not reached, the results do not show any benefit of riluzole in minimising neuropathy and may suggest that riluzole worsens neuropathy associated with oxaliplatin treatment.

Altered sensory nerve excitability in fibromyalgia.

BACKGROUND/PURPOSE: To investigate nerve excitability changes in patients with fibromyalgia and the correlation with clinical severity. METHODS: We enrolled 20 subjects with fibromyalgia and 22 sex and age-matched healthy subjects to receive nerve excitability test and nerve conduction study to evaluate the peripheral axonal function. RESULTS: In the fibromyalgia cohort, the sensory axonal excitability test revealed increased superexcitability (%) (P = 0.029) compared to healthy control. Correlational study showed a negative correlation between increased subexcitability (%) (r = -0.534, P = 0.022) with fibromyalgia impact questionnaire (FIQ) score. Computer modeling confirmed that the sensory axon excitability pattern we observed in fibromyalgia cohort was best explained by increased Barrett-Barrett conductance, which was thought to be attributed to paranodal fast K+ channel dysfunction. CONCLUSION: The present study revealed that paranodal sensory K+ conductance was altered in patients with fibromyalgia. The altered conductance indicated dysfunction of paranodal fast K+ channels, which is known to be associated with the generation of pain.

Altered peripheral nerve structure and function in latent autoimmune diabetes in adults.

AIM: The present study was undertaken to investigate mechanisms of peripheral nerve dysfunction in latent autoimmune diabetes in adults (LADA). MATERIALS AND METHODS: Participants with LADA (n = 15) underwent median nerve ultrasonography and nerve excitability to examine axonal structure and function, in comparison to cohorts of type 1 diabetes (n = 15), type 2 diabetes (n = 23) and healthy controls (n = 26). The LADA group was matched for diabetes duration, glycaemic control, and neuropathy severity with the type 1 and type 2 diabetes groups. A validated mathematical model of the human axon was utilized to investigate the pathophysiological basis of nerve dysfunction. RESULTS: The most severe changes in nerve structure and function were noted in the LADA group. The LADA cohort demonstrated a significant increase in nerve cross-sectional area compared to type 1 participants and controls. Compared to type 1 and 2 diabetes, measures of threshold electrotonus, which assesses nodal and internodal conductances, were significantly worse in LADA in response to both depolarising currents and hyperpolarising currents. In the recovery cycle, participants with LADA had a significant increase in the relative refractory period. Mathematical modelling of excitability recordings indicated the basis of nerve dysfunction in LADA was different to type 1 and 2 diabetes. CONCLUSIONS: Participants with LADA exhibited more severe changes in nerve function and different underlying pathophysiological mechanisms compared to participants with type 1 or 2 diabetes. Intensive management of risk factors to delay the progression of neuropathy in LADA may be required.

Cold aggravates abnormal excitability of motor axons in oxaliplatin-treated patients.

INTRODUCTION: Cold allodynia is often seen in the acute phase of oxaliplatin treatment, but the underlying pathophysiology remains unclear. METHODS: Patients scheduled for adjuvant oxaliplatin for colorectal cancer were examined with quantitative sensory testing and nerve excitability tests at baseline and after the second or third oxaliplatin cycle at different skin temperatures. RESULTS: Seven patients were eligible for examination. All patients felt evoked pain and tingling when touching something cold after oxaliplatin infusion. Oxaliplatin decreased motor nerve superexcitability (P < .001), increased relative refractory period (P = .011), and caused neuromyotonia-like after-activity. Cooling exacerbated these changes and prolonged the accommodation half-time. DISCUSSION: The findings suggest that a combined effect of oxaliplatin and cooling facilitates nerve excitability changes and neuromyotonia-like after-activity in peripheral nerve axons. A possible mechanism is the slowing in gating of voltage-dependent fast sodium and slow potassium channels, which results in symptoms of cold allodynia.

Reducing glucose variability with continuous subcutaneous insulin infusion is associated with reversal of axonal dysfunction in type 1 diabetes mellitus.

INTRODUCTION: We assess whether improvement in control of type 1 diabetes mellitus (T1DM) with continuous subcutaneous insulin infusion (CSII) can protect peripheral nerve function. METHODS: Twelve patients with T1DM treated with multiple daily insulin injections were assessed with nerve excitability testing prior to and 3 months after initiation of CSII. RESULTS: Although commencing treatment with CSII for 3 months improved mean glycosylated hemoglobin, it did not significantly alter nerve excitability or glycemic variability (GV). In four patients, some deterioration in GV was observed, while eight patients had improvement in SD and mean amplitude of glycemic excursions. For these eight patients, there was normalization of depolarizing and hyperpolarizing threshold electrotonus and recovery cycle superexcitablity. DISCUSSION: When CSII initiation is able to reduce glycemic variability in T1DM, reversal of axonal dysfunction is seen, likely due to normalization of sodium-potassium pump function and restoration of transaxonal membrane potential.

Upper and lower limb motor axons demonstrate differential excitability and accommodation to strong hyperpolarizing currents during induced hyperthermia.

Length-dependent peripheral neuropathy typically involves the insidious onset of sensory loss in the lower limbs before later progressing proximally. Recent evidence proposes hyperpolarization-activated cyclic nucleotide-gated (HCN) channels as dysfunctional in rodent models of peripheral neuropathy, and therefore differential expression of HCN channels in the lower limbs was hypothesized as a pathophysiological mechanism accounting for the pattern of symptomatology within this study. We studied six healthy participants, using motor axon excitability including strong and long [-70% and -100% hyperpolarizing threshold electrotonus (TEh)] hyperpolarizing currents to preferably study HCN channel function from the median and tibial nerves from high (40%) and low (20%) threshold. This was recorded at normothermia (~32°C) and then repeated during hyperthermia (~40°C) as an artificial hyperpolarizing axon stress. Significant differences between recovery cycle, superexcitability, accommodation to small depolarizing currents, and alterations in late stages of the inward-rectifying currents of strongest (-70% and -100% TEh) currents were observed in the lower limbs during hyperthermia. We demonstrate differences in late IH current flow, which implies higher expression of HCN channel isoforms. The findings also indicate their potential inference in the symptomatology of length-dependent peripheral neuropathies and may be a unique target for minimizing symptomatology and pathogenesis in acquired disease. NEW & NOTEWORTHY This study demonstrates nerve excitability differences between the upper and lower limbs during hyperthermia, an experimentally induced axonal stress. The findings indicate that there is differential expression of slow hyperpolarization-activated cyclic nucleotide-gated (HCN) channel isoforms between the upper and lower limbs, which was demonstrated through strong, long hyperpolarizing currents during hyperthermia. Such mechanisms may underlie postural control but render the lower limbs susceptible to dysfunction in disease states.

Parameters derived from compound muscle action potential scan for discriminating amyotrophic lateral sclerosis-related denervation.

INTRODUCTION: The objective of this study was to determine compound muscle action potential (CMAP) scan parameters and MScanFit motor unit number estimation (MUNE) in patients with amyotrophic lateral sclerosis (ALS) and to compare the results in the abductor pollicis brevis (APB) to those in the abductor digiti minimi (ADM). METHODS: CMAP scans were recorded from the APB and ADM in 35 patients with ALS and 21 controls. MScanFit MUNE, neurophysiological index (NI), step%, returner%, and D50 were calculated. RESULTS: CMAP scan parameters including the returner%, MScanFit MUNE, and NI can distinguish ALS with high sensitivity and specificity. The electrophysiological parameters, with the exception of D50 (the number of largest consecutive differences of recorded responses generating 50% of maximum CMAP), showed more pronounced changes in the APB than in the ADM, even though most of the patients had normal APB/ADM amplitude ratios. DISCUSSION: CMAP scan parameters and MScanFit MUNE can be used in the evaluation of denervation and reinnervation and may herald the "split hand" in ALS.

Altered axonal excitability properties in facial palsy.

INTRODUCTION: Axonal excitability measures give insight into the biophysical properties of peripheral nerve axons. In this study we applied these techniques to the study of facial palsy. METHODS: Thirty patients with established facial palsy due to unresolved Bell's palsy or herpes zoster (>6 months duration), tumor invasion of the facial nerve, or traumatic facial nerve injury were assessed using facial nerve excitability techniques. RESULTS: Full recordings were obtained in 23 patients (15 unrecovered Bell's palsy or herpes zoster, 5 trauma, 3 tumor-related). Compared with normal controls, the facial palsy group demonstrated changes in stimulus response properties, threshold electrotonus, refractoriness, superexcitability, and I/V slope. Depolarizing threshold electrotonus distinguished between viral and non-viral etiologies on subgroup analysis. DISCUSSION: In this cross-sectional study, established facial palsy demonstrated findings similar to those seen in studies of regenerated axons. The improved understanding of underlying axonal characteristics offered by the technique may guide future treatment. Muscle Nerve 57: 268-272, 2018.