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Spinal muscular atrophy (SMA) is associated with developmental disruption of motor axons in ventral roots of the spinal cord alongside motor axon degeneration. The pathogenesis of peripheral axonal change during development is pertinent to understand treatment response. Nerve excitability techniques, stimulating the median motor nerve at the wrist, were utilised to investigate axonal change during neurodevelopment in 24 children with SMA, compared with 71 age-matched controls. Longitudinal axonal response to nusinersen treatment in 18 children was also investigated. Significant differences in axonal development were noted in the youngest children with SMA, signified by reduced compound muscle action potential (CMAP) (P = 0.030), higher axonal threshold (P = 0.016), rheobase (minimal current amplitude of infinite duration, required to generate an action potential) (P = 0.012) and greater changes in depolarising and hyperpolarising threshold electrotonus. Subexcitability increased in all children with SMA, compared to controls. With treatment, nerve excitability changes were observed prominently in young children, with increases in CMAP, reduction in axonal threshold, fanning-in of threshold electrotonus, increase in resting current-threshold slope and reduction in subexcitability. Whilst motor axons continue to mature in SMA, developmental delays in passive and active membrane properties occur especially in early childhood. Concurrently, motor axons actively undergo degeneration. Nusinersen restores the developmental trajectory of motor axons reducing degeneration, especially in children with early treatment initiation. Our findings move the field forward in understanding the developmental aspect of childhood-onset motor neurone diseases and changes in axonal function associated with disease modification. KEY POINTS: Pathomechanisms in spinal muscular atrophy involve concurrent neurodevelopmental and neurodegenerative processes. The greatest delays in maturation of the passive and active properties of the peripheral motor axon are seen in early childhood. Nusinersen facilitates developmental recovery of the motor axon whilst also reducing neurodegeneration. Axonal dysfunction is reversed with SMN repletion particularly when intervention occurs early in development.

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.

ObjectivesTo elucidate the motor unit response to intrathecal nusinersen in children with symptomatic spinal muscular atrophy (SMA) using a novel motor unit number estimation technique.MethodsMScanFit MUNE studies were sequentially undertaken from the abductor pollicis brevis muscle after stimulation of the median nerve in a prospective cohort of symptomatic children with SMA, undergoing intrathecal treatment with nusinersen at a single neuromuscular centre from June 2017 to August 2019. Electrophysiological measures included compound muscle action potential (CMAP), motor unit number estimation (MUNE), motor unit number contributing to 50%–100% of CMAP (N50) and measures of collateral reinnervation including largest single motor unit potential (LSMUP) and amplitude of the smallest unit contributing to N50 (A50).ResultsTwenty children (median age 99 months, range 4–193) were followed for a median of 13.8 (4–33.5) months. Therapeutic intervention was an independent and significant contributor to an increase in CMAP (p = 0.005), MUNE (p = 0.001) and N50 (p = 0.04). The magnitude of this electrophysiological response was increased in children with shorter disease durations (pInterpretationNusinersen therapy facilitated functional innervation in SMA through recovery of smaller motor units. Delineation of biomechanisms of therapeutic response may be the first step in identifying potential novel targets for disease modification in this and other motor neuropathies. MScanFit MUNE techniques may have a broader role in establishing biomarkers of therapeutic response in similar adult-onset diseases.

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. 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. 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. 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.

Objective The present study investigates the peripheral neuropathy in Primary Sjögren's syndrome (pSS) using the nerve excitability test to further elucidate how peripheral nerves are affected by the autoantibodies. Methods Each patient received clinical evaluation, examination for anti‐SSA/Ro and anti‐SSB/La antibodies titer, paired motor and sensory nerve excitability test, thermal quantitative sensory test (QST), and nerve conduction study (NCS). Results A total of 40 pSS patients wasenrolled. Motor axonal study of the pSS with positive anti‐SSA/Ro or anti‐SSB/La antibodies (n = 28) was found to have increased stimulus for 50% compound muscle action potential (CMAP) (P

Introduction: A spectrum of non-motor manifestations in amyotrophic lateral sclerosis (ALS) patients has been increasingly recognized, with cognitive and behavioral impairments the most prominent. Evidence suggests that ALS overlaps on a pathological, genetic, and clinical level with frontotemporal dementia (FTD), thereby suggesting a frontotemporal spectrum disorder (ALS-FTSD). Cognitive impairment has been reported in up to 75% of ALS patients, whilst the rate of behavioral dysfunction ranges up to 50%.Areas covered: The present review explores the current understanding of cognitive and behavioral changes in ALS with a particular emphasis on its implications on prognosis and survival.Expert commentary: Further longitudinal studies are needed to clarify the evolution of cognitive impairment in ALS and how this may ultimately influence survival. Improving understanding of cognitive changes has important implications toward the capacity of patients in making critical medical decisions. There is a need to develop a universally accepted and validated cognitive assessment tool to be administered in a multidisciplinary clinic that is efficient and sensitive, as well as being integrated into the design and analysis of future ALS drug trials. In addition, revision of the ALS diagnostic criteria is critically needed that should accommodate cognitive and behavioral symptoms in addition to motor manifestations.

Objective Gene silencing treatments for hereditary transthyretin amyloidosis (ATTRv) have recently been developed with dramatic improvements observed in patient outcomes. However, the optimal time to initiate treatment is not yet known. The aim of this study is to explore the pathophysiological progression of neuropathic features of ATTRv using nerve excitability and motor unit number estimation. Methods We prospectively recruited 14 symptomatic patients and 7 asymptomatic carriers and with varied TTR mutations and compared these to 21 healthy controls. Nerve excitability properties of ulnar motor and sensory axons, and ulnar-ADM motor unit number estimation was collected. Results ‘Fanning in’ of threshold electrotonus was observed in the motor axons of symptomatic ATTRv patients, suggestive of membrane depolarisation. Motor unit number estimation demonstrated a significant reduction in mean unit number between symptomatic and asymptomatic ATTRv patients (p =0.04), with declines seen according to FAP stage and PND score. Significantly increased hyperpolarising current/threshold gradients were seen in sensory axons between symptomatic ATTRv patients and healthy controls (p=0.002), suggesting that upregulation of inwardly rectifying conductance may underlie sensory symptoms and neuropathic pain in ATTRv amyloidosis. Conclusions These findings suggest that ulnar nerve excitability and motor unit number estimation could be used as a tool to identify early nerve disease in ATTRv and monitor progression.

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.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.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.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.

Understanding of maturational properties of sensory and motor axons is of central importance for determining the impact of nerve changes in health and in disease in children and young adults.This study investigated maturation of sensory axons using axonal excitability parameters of the median nerve in 47 children, adolescents and young adults (25 males, 22 females; age range 1-25 years) and compared them to concurrent motor studies.The overall pattern of sensory maturation was similar to motor maturation demonstrating prolongation of the strength duration time constant (P 0.001), reduction of hyperpolarising threshold electrotonus (P = 0.002), prolongation of accommodation half-time (P = 0.005), reduction in hyperpolarising current-threshold slope (P = 0.03), and a shift to the right of the refractory cycle curve (P 0.001), reflecting changes in passive membrane properties and fast potassium channel conductances. Sensory axons, however, had a greater increase in strength duration time constant and more attenuated changes in depolarising threshold electrotonus and current-threshold parameters, attributable to a more depolarised resting membrane potential evident from early childhood and maintained in adults. Peak amplitude was established early in sensory axons whereas motor amplitude increased with age (P 0.001), reflecting non-axonal motor unit changes.Maturational trajectories of sensory and motor axons were broadly parallel in children and young adults, but sensory-motor differences were initiated early in maturation.Identifying the evolution of biophysical changes within and between sensory and motor axons through childhood and adolescence is fundamental to understanding developmental physiology and interpreting disease-related changes in immature nerves.

INTRODUCTION Given recent findings of subclinical sensory deficits in colorectal cancer patients before oxaliplatin treatment, in the current study we aimed to identify evidence of subclinical peripheral neuropathy on multimodal testing before chemotherapy commencement. METHODS Clinical, functional, and neurophysiological assessments were undertaken in 93 colorectal cancer patients before chemotherapy. RESULTS There was no neurophysiological evidence of neuropathy, with 92 of 93 sural sensory values within normative reference values for age and no significant abnormalities detected in nerve conduction or nerve excitability studies. Clinical neurological assessment revealed 75.9% of patients with no signs or symptoms, 10.3% with reduction in distal vibration or pinprick sensitivity, and 6.9% with reduction in ankle reflexes only. There was no difference in manual dexterity (using the 9-hole peg-board test) compared with normative data. DISCUSSION The present study has established a low likelihood of significant distal symmetrical polyneuropathy in colorectal cancer patients before initiation of chemotherapy. Muscle Nerve 57: 615-621, 2018.

Peripheral immunity plays a key role in maintaining homeostasis and conferring crucial neuroprotective effects on the injured nervous system, while at the same time may contribute to increased vulnerability to neuropathic pain. Little is known about the reciprocal relationship between entrapment neuropathy and peripheral immunity. This study investigated immune profile in patients with carpal tunnel syndrome (CTS), the most prevalent entrapment neuropathy. All patients exhibited neurophysiological abnormalities in the median nerve, with the majority reporting neuropathic pain symptoms. We found a significant increase in serum CCL5, CXCL8, CXCL10 and VEGF, and in CD4+ central and effector memory T cells in CTS patients, as compared to healthy controls. CCL5 and VEGF were identified as having the highest power to discriminate between patients and controls. Interestingly, and contrary to the prevailing view of CCL5 as a pro-nociceptive factor, the level of circulating CCL5 was inversely correlated with neuropathic pain intensity and median nerve motor latency. In contrast, the level of central memory T cells was positively associated with abnormal neurophysiological findings. These results suggest that entrapment neuropathy is associated with adaptive changes in the homeostasis of memory T cells and an increase in systemic inflammatory modulating cytokines/chemokines, which potentially regulate neuropathic symptoms.

Diabetes may impair the capacity for neuroplasticity such that patients experience a slower and poorer recovery after stroke. The current study investigated changes in cortical function in stroke patients with diabetes to determine how this comorbidity may affect poststroke cortical plasticity and thereby functional recovery. From a cohort of 57 participants, threshold-tracking transcranial magnetic stimulation was used to assess cortical function over the ipsilateral and contralesional hemispheres in 7 patients with diabetes after an acute stroke compared with 12 stroke patients without diabetes. Cortical function was also assessed in 8 patients with diabetes without stroke and 30 normal control subjects. After acute stroke, short-interval intracortical inhibition (SICI) was reduced over both motor cortices in stroke patients without diabetes compared with normal control patients, while in stroke patients with diabetes, SICI was only reduced over the contralesional but not the ipsilesional cortex compared with control patients with diabetes. In addition, SICI was significantly reduced in the control patients with diabetes compared with normal control patients. These results have demonstrated the absence of ipsilesional cortical excitability change after diabetic strokes, suggesting impaired capacity for neuroplasticity over this hemisphere as a consequence of a “double-hit” phenomenon because of preexisting alterations in cortical function in nonstroke patients with diabetes. The reliance on reorganization over the contralesional cortex after stroke will likely exert influence on poststroke recovery in patients with diabetes.

To gain insights into erythromelalgia disease pathophysiology, this study elucidated changes in peripheral axonal excitability and influences of temperature and mexiletine on axonal function., Erythromelalgia (EM) is a rare neurovascular disorder characterized by intermittent severe burning pain, erythema, and warmth in the extremities on heat stimuli. To investigate the underlying pathophysiology, peripheral axonal excitability studies were performed and changes with heating and therapy explored. Multiple excitability indices (stimulus–response curve, strength–duration time constant (SDTC), threshold electrotonus, and recovery cycle) were investigated in 23 (9 EMSCN9A+ and 14 EMSCN9A−) genetically characterized patients with EM stimulating median motor and sensory axons at the wrist. At rest, patients with EM showed a higher threshold and rheobase (P < 0.001) compared with controls. Threshold electrotonus and current–voltage relationships demonstrated greater changes of thresholds in both depolarizing and hyperpolarizing preconditioning electrotonus in both EM cohorts compared with controls in sensory axons (P < 0.005). When average temperature was raised from 31.5°C to 36.3°C in EMSCN9A+ patients, excitability changes showed depolarization, specifically SDTC significantly increased, in contrast to the effects of temperature previously established in healthy subjects (P < 0.05). With treatment, 4 EMSCN9A+ patients (4/9) reported improvement with mexiletine, associated with reduction in SDTC in motor and sensory axons. This is the first study of primary EM using threshold tracking techniques to demonstrate alterations in peripheral axonal membrane function. Taken together, these changes may be attributed to systemic neurovascular abnormalities in EM, with chronic postischaemic resting membrane potential hyperpolarization due to Na+/K+ pump overactivity. With heating, a trigger of acute symptoms, axonal depolarization developed, corresponding to acute axonal ischaemia. This study has provided novel insights into EM pathophysiology.

Objective To explore the benefits of modified-release fampridine on walking distance in MS. Methods This was a randomised double-blind, placebo-controlled crossover trial of fampridine in 25 MS patients. The primary outcome measure was the six minute walk test (6MWT). A p -value Results The pre-specified criterion for statistical significance was met, with a 17m improvement in 6MWT in the treatment arm. In addition, baseline S2 accommodation, a nerve excitability parameter that reflects slow K + channel activity, modified the effect of fampridine. For patients who had abnormally high S2 accommodation values, there was a 28m improvement in the 6MWT ( p =0.04). In contrast, for patients with low S2 values, a 0m improvement was noted ( p =1.0). Conclusion The study provides evidence that fampridine may improve walking distance. Nerve excitability assessment may be useful in selecting those patients who are most likely to gain benefit from fampridine. Significance Fampridine may improve walking distance in MS. Nerve excitability assessment may assist in identifying those patients most likely to respond to fampridine.

Recent unprecedented advances in treatment for spinal muscular atrophy (SMA) enabled patients to access the first approved disease modifying therapy for the condition. There are however many uncertainties, regarding timing of treatment initiation, response to intervention, treatment effects and long-term outcomes, which are complicated by the evolving phenotypes seen in the post-treatment era for patients with SMA. Biomarkers of disease, with diagnostic, prognostic, predictive, and pharmacodynamic value are thus urgently required, to facilitate a wider understanding in this dynamic landscape. A spectrum of these candidate biomarkers, will be evaluated in this review, including genetic, epigenetic, proteomic, electrophysiological, and imaging measures. Of these, SMN2 appears to be the most significant modifier of phenotype to date, and its use in prognostication shows considerable clinical utility. Longitudinal studies in patients with SMA highlight an emerging role of circulatory markers such as neurofilament, in tracking disease progression and response to treatment. Furthermore, neurophysiological biomarkers such as CMAP and MUNE values show considerable promise in the real word setting, in following the dynamic response and output of the motor unit to therapeutic intervention. The specific value for these possible biomarkers across diagnosis, prognosis, prediction of treatment response, efficacy, and safety will be central to guide future patient-targeted treatments, the design of clinical trials, and understanding of the pathophysiological mechanisms of disease and intervention.

Aims/Introduction To elucidate whether axonal changes arise in the prediabetic state and to find a biomarker for early detection of neurophysiological changes. Materials and Methods We enrolled asymptomatic diabetes patients, as well as prediabetic and normoglycemic individuals to test sensory nerve excitability, and we analyzed those findings and their correlation with clinical profiles. Results In nerve excitability tests, superexcitability in the recovery cycle showed increasing changes in the normoglycemic, prediabetes and diabetes cohorts (−19.09 ± 4.56% in normoglycemia, −22.39 ± 3.16% in prediabetes and −23.71 ± 5.15% in diabetes, P = 0.002). Relatively prolonged distal sensory latency was observed in the median nerve (3.12 ± 0.29 ms in normoglycemia, 3.23 ± 0.38 ms in prediabetes and 3.45 ± 0.43 ms in diabetes, P = 0.019). Superexcitability was positively correlated with fasting plasma glucose (r = 0.291, P = 0.009) and glycated hemoglobin (r = 0.331, P = 0.003) in all participants. Conclusions Sensory superexcitability and latencies are the most sensitive parameters for detecting preclinical physiological dysfunction in prediabetes. In addition, changes in favor of superexcitability were positively correlated with glycated hemoglobin for all participants. These results suggest that early axonal changes start in the prediabetic stage, and that the monitoring strategy for polyneuropathy should start as early as prediabetes., We explored early changes of axonal function in prediabetes using axonal excitability test. The changes progressed from normoglycemia, prediabetes and early diabetes. Superexcitability is the most sensitive parameter for sensory axonal dysfunction. Fasting sugar and glycated hemoglobin were correlated with superexcitability in all participants.

To investigate the effects of fampridine on nerve excitability, the present study utilized peripheral axonal excitability techniques in 18 MS patients receiving treatment with fampridine.Studies were performed at baseline and repeated 3months after institution of fampridine at standard dosing.Following treatment with fampridine there were significant changes in axonal excitability for those parameters associated with fast K(+) channels that shifted towards normal control values. Specifically, increases were noted in the peak superexcitability of recovery cycle (fampridine, -25.6±1.6%; baseline -22.8±1.7%; p0.004), peak depolarizing threshold electrotonus (fampridine, 69.1±1.0%; baseline 67.0±1.4%; p0.004), and depolarizing threshold electrotonus between 40 and 60ms after onset of depolarization (fampridine, 52.8±1.3%; baseline 49.9±1.4%; p=0.02).The present study has established that fampridine at standard doses exerts effects on peripheral nerve function that may be mediated by reduction of fast K(+) conductances.Modulation of fast K(+) conductances by fampridine may contribute to the improvement observed in MS symptoms including motor fatigue.

Objectives Diabetic neuropathy is a debilitating complication of diabetes. Animal models of type 1 diabetes (T1DM) suggest that functional and structural changes, specifically axo-glial dysjunction, may contribute to neuropathy development. The present study sought to examine and characterise early sensory axonal function in T1DM patients in the absence of clinical neuropathy. Methods Thirty patients with T1DM (15M:15F) without neuropathy underwent median nerve sensory and motor axonal excitability studies to examine axonal function. A verified mathematical model of human motor and sensory axons was used to elucidate the underlying causes of observed alterations. Results Compared to controls (NC), T1DM patients demonstrated significant axonal excitability abnormalities in sensory and motor axons. These included marked reductions in sensory and motor subexcitability during the recovery cycle (T1DM 7.9 ± 0.4:10.4 ± 0.6%, NC 10.4 ± 0.7:15.4 ± 1.2%, P 0.01) and during hyperpolarizing threshold electrotonus at 10–20 ms (T1DM −75.5 ± 0.8:−69.7 ± 0.8%, NC −78.4 ± 1:−72.7 ± 0.9%, P 0.01). Mathematical modelling demonstrated that these changes were due to reduced nodal Na + currents, nodal/paranodal K + conductances and Na + /K + pump dysfunction, consistent with axo-glial dysjunction as outlined in animal models of T1DM. Conclusions The study provided support for the occurrence of early changes in nodal and paranodal conductances in patients with T1DM. Significance These data indicate that axonal excitability techniques may detect early changes in diabetic patients, providing a window of opportunity for prophylactic intervention in T1DM.

Background: Abnormalities in membrane excitability and Na+ channel function are characteristic of amyotrophic lateral sclerosis (ALS). We aimed to examine the neuroprotective potential, safety and tolerability of the Na+ channel blocker and membrane stabiliser flecainide in ALS. Methods: A double-blind, placebo-controlled, randomised clinical trial of flecainide (200 mg/day) for 32-weeks with a 12-week lead-in phase was conducted in participants with probable or definite ALS recruited from multiple Australian centres (ANZCT Registry number ACTRN12608000338369). Patients were reviewed by a cardiologist to rule out cardiac contraindications. Participants were randomly assigned (1:1) to flecainide or placebo using stratified permuted blocks by a central pharmacy. The primary outcome measure was the slope of decline of the ALS Functional Rating Scale-revised (ALS FRS-r) during the treatment period. Findings: Between March 11, 2008 and July 1, 2010, 67 patients were screened, 54 of whom were randomly assigned to receive flecainide (26 patients) or placebo (28 patients). Four patients in the flecainide group and three patients in the placebo group withdrew from the study. One patient in the flecainide group died during the study, attributed to disease progression. Flecainide was generally well tolerated, with no serious adverse events reported in either group. There was no significant difference in the rate of decline in the primary outcome measure ALS-FRS-r between placebo and flecainide treated patients (Flecainide 0.65 [95% CI 0.49 to 0.98]; Placebo 0.81 [0.49 to 2.12] P = 0.50). However, the rate of decline of the neurophysiological index was significantly reduced in the flecainide group (Flecainide 0.06 [0.01 to 0.11]; Placebo 0.14 [0.09 to 0.19], P = 0.02). Placebo-treated patients demonstrated greater CMAP amplitude reduction during the course of the study in the subset of patients with a reduced baseline CMAP amplitude (Flecainide: −15 ± 12%; Placebo −59 ± 12%; P = 0.03). Flecainide-treated patients maintained stabilized peripheral axonal excitability over the study compared to placebo. Interpretation: This pilot study indicated that flecainide was safe and potentially biologically effective in ALS. There was evidence that flecainide stabilized peripheral axonal membrane function in ALS. While the study was not powered to detect evidence of benefit of flecainide on ALS-FRS-r decline, further studies may demonstrate clinical efficacy of flecainide in ALS.

It has been suggested that corticomotoneuronal drive to ankle dorsiflexors is greater than to ankle plantar flexor muscles, despite the finding that plantar flexors are no less active than TA during walking and standing. The present study was undertaken to determine whether there was differential involvement of distal lower limb muscles in amyotrophic lateral sclerosis (ALS), to elucidate pathophysiological mechanisms of selective muscle involvement. Prospective studies were undertaken in 52 ALS patients, including clinical assessment, disease staging (revised ALS functional rating scale), Medical Research Council sum score, and a scale of upper motor neurone (UMN) dysfunction. Motor unit number estimates (MUNE) and compound muscle action potentials (CMAP) from ankle dorsiflexors and plantar flexors were used to provide objective measures. A novel ‘split leg index’ was calculated as follows: SLI = CMAPDF ÷ CMAPPF. In ALS, there was significantly greater reduction of MUNE and CMAP amplitude recorded from plantar flexors when compared to dorsiflexors, suggesting preferential involvement of plantar flexor muscles, underpinning a ‘split leg’ appearance. The SLI correlated with clinical plantar flexor strength (R= −0.56, p

Objectives There is accumulating evidence of dysfunction of spinal circuits in the pathogenesis of amyotrophic lateral sclerosis (ALS). Methods The present study was undertaken to characterise the pathophysiological changes in segmental motoneuronal excitability in 28 ALS patients, using recruitment curves of the soleus H-reflex and M-wave, compared with clinical assessments of upper motor neuron (UMN) and lower motor neuron dysfunction. Results H-reflex recruitment curves established that H max / M max and slope ( H θ / M θ ) ratios predicted clinical UMN dysfunction ( p H θ / M θ were driven by reduced M θ . Assessment of H max / M max was similar in the ALS and control groups, and was affected by overlap of the H and M recruitment curves in ALS patients. Conclusion Changes in the slope ratio ( H θ / M θ ) in ALS suggested that alterations in peripheral motor nerve excitability following UMN damage may affect the recorded H-reflex. Increased collision of reflex discharges with antidromically-conducted motor impulses may be exacerbated in ALS due to preferential loss of large-caliber α-motoneurones, which may explain the similarities in H max / M max between groups. Significance Findings from the present study provide further insight into the pathophysiology of ALS, specifically the relative contributions of premotoneuronal and segmental motoneuronal dysfunction.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an inflammatory neuropathy, classically characterised by a slowly progressive onset and symmetrical, sensorimotor involvement. However, there are many phenotypic variants, suggesting that CIDP may not be a discrete disease entity but rather a spectrum of related conditions. While the abiding theory of CIDP pathogenesis is that cell-mediated and humoral mechanisms act together in an aberrant immune response to cause damage to peripheral nerves, the relative contributions of T cell and autoantibody responses remain largely undefined. In animal models of spontaneous inflammatory neuropathy, T cell responses to defined myelin antigens are responsible. In other human inflammatory neuropathies, there is evidence of antibody responses to Schwann cell, compact myelin or nodal antigens. In this review, the roles of the cellular and humoral immune systems in the pathogenesis of CIDP will be discussed. In time, it is anticipated that delineation of clinical phenotypes and the underlying disease mechanisms might help guide diagnostic and individualised treatment strategies for CIDP.

Autoantibodies to nodal/paranodal proteins have been reported in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). To determine the frequency of anti-paranodal antibodies in our cohort of CIDP patients and to validate the presence anti-nodal antibodies in MMN, sera were screened for IgG against human neurofascin 155, contactin-1, neurofascin 186 and gliomedin using ELISA. In CIDP patients, 7% were anti-NF155 IgG4 positive and 7% were anti-CNTN1 IgG4 positive. Positive results were confirmed using cell based assays and indirect immunofluorescence on teased nerve fibres. We did not detect IgG autoantibodies against these nodal/paranodal antigens in MMN patients.

Background Diabetic peripheral neuropathy is a common and debilitating complication of diabetes mellitus. Although strict glycaemic control may reduce the risk of developing diabetic peripheral neuropathy, the neurological benefits of different insulin regimens remain relatively unknown. Methods In the present study, 55 consecutive patients with type 1 diabetes mellitus underwent clinical neurological assessment. Subsequently, 41 non-neuropathic patients, 24 of whom were receiving multiple daily insulin injections (MDII) and 17 receiving continuous subcutaneous insulin infusion (CSII), underwent nerve excitability testing, a technique that assesses axonal ion channel function and membrane potential in human nerves. Treatment groups were matched for glycaemic control, body mass index, disease duration and gender. Neurophysiological parameters were compared between treatment groups and those taken from age and sex-matched normal controls. Results Prominent differences in axonal function were noted between MDII-treated and CSII-treated patients. Specifically, MDII patients manifested prominent abnormalities when compared with normal controls in threshold electrotonus (TE) parameters including depolarizing TE(10-20ms), undershoot and hyperpolarizing TE (90–100 ms) (P

Objective The aim of this study was to evaluate changes in sensory axonal excitability in the distal nerve in patients with cervical radiculopathy. Methods The patients were classified by the findings of cervical MRI into two subgroups: 22 patients with C6/7 root compression and 25 patients with cervical cord and root compression above/at C6/7. Patients were investigated using conventional nerve conduction studies (NCS) and nerve excitability testing. Sensory nerve excitability testing was undertaken with stimulation at the wrist and recording from digit II (dermatome C6/7). The results were compared with healthy controls. Both preoperative and postoperative tests were performed if the patient underwent surgery. Results Sensory axonal excitability was significantly different in both cohorts compared with healthy controls, including prolonged strength-duration time constant, reduced S2 accommodation, increased threshold electrotonus hyperpolarisation (TEh (90–100 ms)), and increased superexcitability. The changes in these excitability indices are compatible with axonal membrane hyperpolarisation. In five patients who underwent surgery, the postoperative sensory excitability was tested after 1 week, and showed significant changes in TE (TEh (90–100 ms) and TEh slope, p Conclusions The present study demonstrated distal nerve axonal hyperpolarisation in patients with cervical radiculopathy. These findings suggest that the hyperpolarised pattern might be due to Na + -K + ATPase overactivation induced by proximal ischaemia, or could reflect the remyelinating process. Distal sensory axons were hyperpolarised even though there were no changes in NCS, suggesting that nerve excitability testing may be more sensitive to clinical symptoms than NCS in patients with cervical radiculopathy.

Introduction: Patients with hereditary neuropathy with liability to pressure palsies (HNPP) manifest with episodes of focal paresis when exposed to mechanical stress, although the basis for vulnerability to conduction block remains relatively unexplained. Methods: Axonal excitability techniques were utilized to provide insights into pathophysiological mechanisms in 13 HNPP patients, stimulating median motor and sensory axons at the wrist. Results: In HNPP, distal latencies were prolonged, and motor and sensory amplitudes were reduced. Threshold was increased. Depolarizing and hyperpolarizing electrotonus was greater, and resting current–threshold slope was reduced. There were greater threshold changes in superexcitability, and refractoriness was decreased. Conclusions: Taken together, excitability testing in patients with HNPP established axonal hyperpolarization in both motor and sensory axons that may be attributable to changes in nerve architecture. In turn, the hyperpolarized resting membrane potential in HNPP may be a major predisposing factor for development of conduction block with mechanical stresses. Muscle Nerve 49: 858–865, 2014

Objective Potassium (K + ) has been implicated as a factor in the development of uraemic neuropathy. This study was undertaken to investigate whether hyperkalaemia plays a causal role in axonal dysfunction in end-stage kidney disease (ESKD). Methods Median motor nerve excitability studies were undertaken in four haemodialysis patients during a modified dialysis session. The serum K + level was "clamped" (fixed) for the first 3h of dialysis, whilst allowing all other solutes to be removed, this was followed by dialysis against low dialysate K + for a further 4h. Blood chemistry and nerve excitability studies were undertaken prior to, during and following dialysis. Results were compared to results from the same patients during routine dialysis sessions. Results All patients demonstrated significant nerve excitability abnormalities reflective of nerve membrane depolarization in pre-dialysis recordings ( p + remained elevated (5.0mmol/L) and nerve excitability remained highly abnormal, despite the significant clearance of other uraemic toxins. In contrast, studies undertaken during routine dialysis sessions demonstrated significant improvement in both serum K + and nerve function after 3h. Conclusions The current study has established a causal relationship between serum K + and axonal membrane depolarization in haemodialysis patients. Significance From a clinical perspective, strict K + control may help improve nerve function in ESKD.

IntroductionMutations in SCN1A encoding the Nav1.1 subunit of the neuronal sodium channel underlie the devastating epilepsy of Dravet’s syndrome.1 The mechanism by which Nav1.1 dysfunction causes seizures is not clear. In vitro and in silico channel evaluation can support mutation pathogenicity but cannot define the in vivo impact of channel dysfunction. Axonal excitability studies can show the pattern of single-channel dysfunction in disorders where the channel is peripherally expressed.2 This study was undertaken to determine whether axonal excitability studies could detect changes in Dravet’s patients related to the condition or due to medication effect.MethodsPatients with Dravet’s syndrome were recruited from clinics in Sydney and Melbourne and axonal excitability studies were performed. Excitability results were analysed in 3 age groups and compared to age-matched normal controls.ResultsTwenty six patients (ages 2–46) were studied. Findings were most pronounced in patients aged 20–46 (n=7) with 6.9% greater increase in threshold during hyperpolarization(p=0.1), 7.6% greater threshold decrease on depolarization(p=0.005) and, in the recovery cycle, 19.7% reduction in superexcitability(p=0.002) and 26% reduction in subexcitability(p=0.03). Axonal excitability studies resembled previously published changes seen in patients with sodium channel blockade caused by acute tetrodotoxin poisoning.3ConclusionsChanges in excitability of axonal membrane in Dravet’s syndrome are consistent with a decrease in sodium channel function. As the affected channel in Dravet’s syndrome is not peripherally expressed, the effect seen is likely due to the heavy anticonvulsant regime required to control epilepsy, combined with a progressive loss of sodium channel function that occurs with age.ReferencesMeisler MH, O’Brien JE, Sharkey LM. Sodium channel gene family: epilepsy mutations, gene interactions and modifier effects. J Physiol 2010;588:1841–1848.Tomlinson SE, Howells J, Burke D. In vivo assessment of neurological channelopathies: Application of peripheral nerve excitability studies. Neuropharmacology. 2018 Apr;132:98–107.Kiernan MC, Isbister GK, Lin CS, Burke D, Bostock H. Acute tetrodotoxin-induced neurotoxicity after ingestion of puffer fish. Ann Neurol 2005;57:339–48.

IntroductionFibromyalgia (FM), a common chronic widespread pain syndrome with neurological symptoms affecting ∼10% of the population worldwide. Whereas small fibre neuropathy is a recognized part of FM, surprisingly little is known about large fibre neuropathy. The present study investigates the sensory and motor axonal properties using novel nerve excitability testing (NET) to seek a better understanding of the pathogenesis of this painful disorder.Methods25 FM patients were recruited from the Wan Fang Hospital in Taiwan who fulfilled the American College of Rheumatology diagnostic criteria.1 NCS, pain scores, blood tests and NET were performed in all patients and patients with factors that may confound the results of NET were excluded. Control data were obtained from age and gender-matched healthy controls (HC) who had no neurological deficits or known pain disorders.ResultsThe FM group showed an increase in superexcitability (pConclusionsAlterations in the sensory axonal parameters can be detected while NCS is normal, these findings are compatible with the concept that the sensory system is mainly involved in the pathogenesis of FM. Results implied probable hypofunction of the paranodal fast K+ channel in the sensory axons, known to be associated with the generation of pain.2 Our study highlights the advantage of NET over NCS, in the early detection of axonal dysfunction and may provide further understandings of future therapeutic treatment.ReferencesWolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Hauser W, Katz RS, Mease P, Russell AS, Russell IJ, Winfield JB. Fibromyalgia criteria and severity scales for clinical and epidemiological studies: a modification of the ACR Preliminary Diagnostic Criteria for Fibromyalgia. J Rheumatol 2011;38(6):1113–1122.Kuwabara S, Misawa S. Pharmacologic intervention in axonal excitability: in vivo assessment of nodal persistent sodium currents in human neuropathies. Curr Mol Pharmacol 2008;1(1):61–67.

Over the past 20 years, the most notable advance in understanding Guillain–Barre syndrome (GBS) has been the identification of an axonal variant. This advance arose chiefly through studies undertaken in East Asian countries and comprised two major aspects: first, the immunopathogenesis of axonal GBS related to anti-ganglioside antibodies and molecular mimicry of Campylobacter jejuni ; and second, the observation that distinct electrophysiological patterns of axonal GBS existed, reflecting reversible conduction failure (RCF). As a consequence, the pathophysiology of acute motor axonal neuropathy (AMAN) has perhaps become better understood than acute inflammatory demyelinating polyneuropathy. Despite these more recent advances, a critical issue remains largely unresolved: whether axonal GBS is more common in Asia than in Europe or North America. If it is more common in Asia, then causative factors must be more critically considered, including geographical differences, issues of genetic susceptibility, the role of antecedent infections and other potential triggering factors. It has become apparent that the optimal diagnosis of AMAN requires serial electrophysiological testing, to better delineate RCF, combined with assessment for the presence of anti-ganglioside antibodies. Recent collaborative approaches between Europe and Asia have suggested that both the electrophysiological pattern of AMAN and the seropositivity for anti-ganglioside antibodies develop similarly. Separately, however, current electrodiagnostic criteria for AMAN limited to a single assessment appear inadequate to identify the majority of cases. As such, diagnostic criteria will need to be revised to improve the diagnostic sensitivity for AMAN.

With a 3-fold increase in the number of cancer survivors noted since the 1970s, there are now over 28 million cancer survivors worldwide. Accordingly, there is a heightened awareness of long-term toxicities and the impact on quality of life following treatment in cancer survivors. This review will address the increasing importance and challenge of chemotherapy-induced neurotoxicity, with a focus on neuropathy associated with the treatment of breast cancer, colorectal cancer, testicular cancer, and hematological cancers. An overview of the diagnosis, symptomatology, and pathophysiology of chemotherapy-induced peripheral neuropathy will be provided, with a critical analysis of assessment strategies, neuroprotective approaches, and potential treatments. The review will concentrate on neuropathy associated with taxanes, platinum compounds, vinca alkaloids, thalidomide, and bortezomib, providing clinical information specific to these chemotherapies. CA Cancer J Clin 2013;63:419-437. ©2013 American Cancer Society, Inc.

Neurotoxicity is a significant clinical side effect of immunosuppressive treatment used in prophylaxis for rejection in solid organ transplants. This study aimed to provide insights into the mechanisms underlying neurotoxicity in patients receiving immunosuppressive treatment following renal transplantation. Clinical and neurophysiological assessments were undertaken in 38 patients receiving immunosuppression following renal transplantation, 19 receiving calcineurin inhibitor (CNI) therapy and 19 receiving a calcineurin-free (CNI-free) regimen. Groups were matched for age, gender, time since transplant and renal function and compared to normal controls (n = 20). The CNI group demonstrated marked differences in nerve excitability parameters, suggestive of nerve membrane depolarization (p < 0.05). Importantly, there were no differences between the two CNIs (cyclosporine A or tacrolimus). In contrast, CNI-free patients showed no differences to normal controls. The CNI-treated patients had a higher prevalence of clinical neuropathy and higher neuropathy severity scores. Longitudinal studies were undertaken in a cohort of subjects within 12 months of transplantation (n = 10). These studies demonstrated persistence of abnormalities in patients maintained on CNI-treatment and improvement noted in those who were switched to a CNI-free regimen. The results of this study have significant implications for selection, or continuation, of immunosuppressive therapy in renal transplant recipients, especially those with pre-existing neurological disability.

Limited evidence to date has demonstrated changes in excitability that develops over the contralateral motor cortex after a cerebellar infarct. As such, the present study investigated changes in excitability over the contra- (contraM1) and ipsilateral motor cortices (ipsiM1), in patients with acute cerebellar infarct, to determine whether the changes may have functional relevance. Paired-pulse transcranial magnetic stimulation, combined with detailed clinical assessment, was undertaken in ten patients presenting with acute unilateral cerebellar infarct. Studies were undertaken within 1 week of ictus and followed longitudinally at 3-, 6-, and 12-month periods. Comparisons were made with 15 age-matched controls. Immediately following a stroke, short-interval intracortical inhibition (SICI) was significantly reduced over the contraM1 in all patients (P = 0.01), while reduced over the ipsiM1 in those with severe functional impairment (P = 0.01). Moreover, ipsiM1 SICI correlated with impairment (r = 0.69, P = 0.03), such that less SICI was observed in those patients with most impairment. Cortical excitability changes persisted over the follow-up period in the context of clinical improvement. Following an acute cerebellar infarct, excitability abnormalities develop over both motor cortices, more prominently in patients with severe functional impairment. The cortical changes, particularly over the ipsilateral motor cortex, may represent a functionally relevant plastic process that may guide future therapeutic strategies to better facilitate recovery.

Introduction: Maladaptive plasticity involving the unaffected hemisphere (UH) in stroke patients may contribute to post-stroke deficits, including spasticity. We investigated the central and peripheral effects of botulinum toxin in post-stroke spasticity to determine whether there is modulation of cortical processes in the UH. Methods: Transcranial magnetic stimulation and peripheral nerve excitability studies were undertaken in 5 stroke patients with upper limb spasticity before (T1) and 6 weeks after (T2) botulinum injection. Results: Transcranial magnetic stimulation demonstrated inexcitable motor cortices of the affected hemisphere at T1 and T2, and short-interval intracortical inhibition (SICI) in the UH was significantly reduced at T1. At T2, SICI in the UH increased significantly compared with T1, normalizing to controls, and was found to be associated with clinical improvements in spasticity. Peripheral excitability parameters were unchanged after injection. Conclusion: Cortical excitability changes were demonstrated in UH, suggesting that the clinical benefits of botulinum toxin relate to modulation of abnormal central reorganization (maladaptive plasticity) in post-stroke spasticity.

Riluzole, a benzothiazole derivative, has been shown to be effective in prolonging survival in amyotrophic lateral sclerosis. The mechanisms by which riluzole exerts neuroprotective effects in amyotrophic lateral sclerosis remains to be fully elucidated, although inhibition of glutamatergic transmission and modulation of Na+ channel function have been proposed. In an attempt to determine the mechanisms by which riluzole exerts neuroprotective effects, in particular to dissect the relative contributions of inhibition of glutamatergic transmission and Na+ channel modulation, the present study utilized a combination of cortical and peripheral axonal excitability approaches to monitor changes in excitability and function in patients with amyotrophic lateral sclerosis. Cortical assessment was undertaken by utilising the threshold tracking transcranial magnetic stimulation (TMS) technique and combined with peripheral axonal excitability studies in 25 patients with amyotrophic lateral sclerosis. Studies were performed at baseline and repeated when patients were receiving riluzole 100 mg/day. At the time of second testing all patients were tolerating the medication well. Motor evoked potential and compound muscle action potential responses were recorded over the abductor pollicis brevis muscle. At baseline, features of cortical hyperexcitability were evident in patients with amyotrophic lateral sclerosis, indicated by marked reduction in short interval intracortical inhibition ( P < 0.001) and cortical silent period duration ( P < 0.001), as well as an increase in the motor evoked potential amplitude ( P < 0.01). Riluzole therapy partially normalized cortical excitability by significantly increasing short interval intracortical inhibition (short interval intracortical inhibitionbaseline 0.5 ± 1.8%; short interval intracortical inhibitionON riluzole 7.9 ± 1.7%, P < 0.01). In contrast, riluzole did not exert any modulating effect on cortical silent period duration ( P = 0.45) or motor evoked potential amplitude ( P = 0.31). In terms of peripheral nerve function, axonal excitability studies established that, relative to control subjects, patients with amyotrophic lateral sclerosis had significant increases in depolarizing threshold electrotonus [amyotrophic lateral sclerosisbaseline TEd (90–100 ms) 49.1 ± 1.8%; controlsTEd (90–100 ms) 45.2 ± 0.6%, P < 0.01] and superexcitability (amyotrophic lateral sclerosisbaseline 30.1 ± 2.3%; control subjects 23.4 ± 1.0%, P < 0.01) at baseline. Following institution of riluzole therapy there was a significant reduction in superexcitability (amyotrophic lateral sclerosisbaseline 30.1 ± 2.3%; amyotrophic lateral sclerosisON riluzole 27.3 ± 2.3%, P < 0.05) and refractoriness at 2 ms (amyotrophic lateral sclerosisbaseline 98.7 ± 10.7%; amyotrophic lateral sclerosisON riluzole 67.8 ± 9.3%, P < 0.001). In conclusion, the present study has established that riluzole exerts effects on both central and peripheral nerve function, interpreted as partial normalization of cortical hyperexcitability and reduction of transient Na+conductances. Taken together, these findings suggest that the neuroprotective effects of riluzole in amyotrophic lateral sclerosis are complex, with evidence of independent effects across both compartments of the nervous system. * Abbreviations : ALS : amyotrophic lateral sclerosis ALSFRS-R : Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised SICI : short interval intracortical inhibition

OBJECTIVE Pharmacological agents for diabetic peripheral neuropathy (DN) target a number of mechanisms, including sodium channel function and γ-aminobutyric acid–minergic processes. At present, prescription is undertaken on a trial-and-error basis, leading to prolonged medication trials and greater healthcare costs. Nerve-excitability techniques are a novel method of assessing axonal ion channel function in the clinical setting. The aim of this study was to determine the effects of axonal ion channel dysfunction on neuropathy-specific quality-of-life (QoL) measures in DN. RESEARCH DESIGN AND METHODS Fifty-four patients with type 2 diabetes mellitus underwent comprehensive neurologic assessment, nerve-conduction studies, and nerve-excitability assessment. Neuropathy severity was assessed using the Total Neuropathy Score. Neuropathy-specific QoL was assessed using a DN-specific QoL questionnaire (Neuropathy-Specific Quality of Life Questionnaire [NeuroQoL]). Glycosylated hemoglobin and BMI were recorded in all patients. RESULTS NeuroQoL scores indicated significant QoL impairment (mean 9.08 ± 5.93). Strength-duration time constant (SDTC), an excitability parameter reflecting sodium channel function, was strongly correlated with QoL scores (r = 0.545; P < 0.005). SDTC was prolonged in 48.6% of patients who experienced neuropathic symptoms. A significant correlation was also noted between SDTC and neuropathy severity (r = 0.29; P < 0.05). This relationship was strengthened when looking specifically at patients with clinically graded neuropathy (r = 0.366; P < 0.05). CONCLUSIONS The current study has demonstrated an association between markers of sodium channel function and QoL in DN. The study demonstrates that excitability techniques may identify patients in whom altered sodium channel function may be the dominant abnormality. The findings suggest that excitability techniques may have a role in clinical decision making regarding neuropathic treatment prescription.

Background The present study was undertaken to determine whether there were changes evident in axonal membrane function prior to the onset of neuropathy in patients with type 1 and type 2 diabetes. Methods From a cohort of 110 consecutive referrals, nerve excitability was investigated in 40 diabetic patients without clinical evidence of neuropathy (20 type 1 diabetic patients and 20 type 2 diabetic patients). Groups were matched for gender, disease duration and HbA1c. Studies were also undertaken in two control groups, younger controls and older controls, matched for age and gender with the diabetic cohorts. Results Subjects with type 1 diabetes demonstrated significant nerve excitability abnormalities when compared with younger normal controls. Specifically, type 1 subjects showed a significant reduction at multiple time points in both depolarising and hyperpolarising threshold electrotonus. Additionally, the relative refractory period was prolonged (type 1, 3.19 ms; younger normal controls, 3.0 ms; p

Axonal excitability techniques were developed to assess axonal resting membrane potential and ion channel function in vivo, and thereby provide greater molecular understanding of the activity of voltage gated ion channels and ion pumps underlying nerve and membrane function. Axonal excitability studies provide complimentary information to conventional nerve conduction studies, using submaximal stimuli to examine the properties underlying the excitability of the axon. Such techniques have been developed both as a research technique to examine disease pathophysiology and as a clinical investigation technique. This chapter provides an overview of axonal excitability techniques, addressing the role of key ion channels and pumps in membrane function and highlighting examples of clinical case studies, where such techniques have been utilized, including motor neuronopathies, tracking progression of chemotherapy-induced peripheral neuropathy, and assessing treatment response in chronic inflammatory demyelinating polyneuropathy.

This study investigated sensory and motor nerve excitability properties to elucidate the development of diabetic neuropathy. A total of 109 type 2 diabetes patients were recruited, and 106 were analyzed. According to neuropathy severity, patients were categorized into G0, G1, and G2+3 groups using the total neuropathy score-reduced (TNSr). Patients in the G0 group were asymptomatic and had a TNSr score of 0. Sensory and motor nerve excitability data from diabetic patients were compared with data from 33 healthy controls. Clinical assessment, nerve conduction studies, and sensory and motor nerve excitability testing data were analyzed to determine axonal dysfunction in diabetic neuropathy. In the G0 group, sensory excitability testing revealed increased stimulus for the 50% sensory nerve action potential (P

Introduction Patients diagnosed with amyotrophic lateral sclerosis (ALS) generally have a limited medical history and a normal body mass index, raising the possibility of a premorbid ALS phenotype. Methods The prevalence of cardiometabolic factors was analyzed in 58 ALS patients via comprehensive cardiovascular assessments and compared with Australian population norms. Results ALS patients had good cardiac fitness and no reported cardiovascular events. Average blood pressure, heart rate, PR interval, and corrected QT interval were in the normal range. There were significantly fewer obese women in the ALS cohort (13.6%, P

Objective To elucidate longitudinal changes in axonal function in amyotrophic lateral sclerosis (ALS) patients, and to relate such changes with motor unit loss and functional impairment. Methods 37 ALS patients (age, 53.7±1.7years; 22 males) were studied using axonal excitability techniques at baseline and 12weeks follow-up. Results Longitudinal measurements across excitability parameters suggested increasing K + channel dysfunction, with further increases in depolarising threshold electrotonus (90–100ms, baseline, 46.8±1.0%; follow-up, 48.7±0.8%; P =0.02) and superexcitability (baseline, −24.0±1.2%; 12weeks, −26.0±1.2%; P =0.04). Patients with preserved compound muscle action potential (CMAP) amplitude at follow-up developed more severe changes in axonal excitability than those in whom CMAP decreased from baseline, suggesting that the most pronounced disease effects were on motor axons immediately prior to axonal loss in ALS patients. Fine motor decline was associated with more severe changes in axonal excitability, suggesting that functional impairment was related to axonal dysfunction. Conclusions Longitudinal changes in axonal excitability in ALS patients suggest increasing K + channel dysfunction in motor axons. Significance Axonal excitability studies enable investigation of longitudinal changes in axonal ion channel dysfunction, and thereby the processes that potentially contribute to axonal degeneration in ALS.

While substantial alterations in myelination and axonal growth have been described during maturation, their interactions with the configuration and activity of axonal membrane ion channels to achieve impulse conduction have not been fully elucidated. The present study utilized axonal excitability techniques to compare the changes in nerve function across healthy infants, children, adolescents and adults. Multiple excitability indices (stimulus-response curve, strength-duration time constant, threshold electrotonus, current-threshold relationship and recovery cycle) combined with conventional neurophysiological measures were investigated in 57 subjects (22 males, 35 females; age range 0.46-24 years), stimulating the median motor nerve at the wrist. Maturational changes in conduction velocity were paralleled by significant alterations in multiple excitability parameters, similarly reaching steady values in adolescence. Maturation was accompanied by reductions in threshold (P < 0.005) and rheobase (P = 0.001); depolarizing and hyperpolarizing electrotonus progressively reduced (P < 0.001), or 'fanned-in'; resting current-threshold slope increased (P < 0.0001); accommodation to depolarizing currents prolonged (P < 0.0001); while greater threshold changes in refractoriness (P = 0.001) and subexcitability (P < 0.01) emerged. Taken together, the present findings suggest that passive membrane conductances and the activity of K(+) conductances decrease with formation of the axo-glial junction and myelination. In turn, these functional alterations serve to enhance the efficiency and speed of impulse conduction concurrent with the acquisition of motor skills during childhood, and provide unique insight into the evolution of postnatal human peripheral nerve function. Significantly, these findings bring the dynamics of axonal development to the clinical domain and serve to further illuminate pathophysiological mechanisms that occur during development.

Background. With the advent of novel brain stimulation techniques aimed at improving functional outcome, understanding poststroke plasticity becomes critical for the appropriate selection of patients and optimal timing to introduce neuromodulatory interventions. Objective. To better define the temporal evolution of central and peripheral neuroplastic changes in the first 3 months after stroke and their clinical implications. Methods. Transcranial magnetic stimulation, peripheral nerve excitability, and clinical assessments were undertaken longitudinally in 31 acute stroke patients, comprising a total of 384 clinical studies. Results. During the hyperacute phase (

To evaluate the development of diabetic neuropathy, the current study examined changes in peripheral axonal function. Nerve excitability techniques were undertaken in 108 type 2 diabetic patients with nerve conduction studies (NCS), HbA1c levels, and total neuropathy score (TNS). Patients were categorized into two cohorts: patients with diabetes without neuropathy (DWN group [n = 56]) and patients with diabetes with neuropathy (DN group [n = 52]) and further into severity grade 0 (TNS 0–1 [n = 35]), grade 1 (TNS 2–8 [n = 42]), and grade 2/3 (TNS 9–24 [n = 31]). Results revealed that the DWN group had a significantly increased threshold, prolonged latency, and changes in excitability parameters compared with age-matched control subjects. Patients with neuropathy demonstrated significant alteration in recovery cycle parameters and depolarizing threshold electrotonus. Within the DWN cohort, there were significant correlations between HbA1c level and latency and subexcitability, whereas the estimated glomerular filtration rate correlated with superexcitability in patients with neuropathy. Furthermore, excitability parameters became progressively more abnormal with increasing clinical severity. These results suggest a spectrum of excitability abnormalities in patients with diabetes and that early axonal dysfunction may be detected prior to the development of neuropathy. As progressive changes in excitability parameters correlated to neuropathy severity, excitability testing may provide a biomarker of the early development and severity of diabetic neuropathy, providing insights into the pathophysiological mechanisms producing axonal dysfunction.

Introduction: In this study we investigated the changes in axonal excitability and the generation of neurological symptoms in response to focal nerve compression (FNC) of the median nerve in carpal tunnel syndrome (CTS). Methods: Sen- sory excitability recordings were undertaken in 11 CTS patients with FNC being applied at the wrist using a custom-designed electrode. Results: During FNC, refractoriness increased signifi- cantly (62.4 6 3.4%; P < 0.001), associated with a rapid reduc- tion in superexcitability (16.9 6 2.8%; P < 0.001) and sensory nerve action potential amplitude (SNAP) (32.4 6 3.9%; P < 0.001), consistent with axonal depolarization. Associated with these changes, paresthesiae steadily increased throughout FNC, as did numbness. Reductions in SNAP amplitude and superexcitability developed more rapidly for CTS patients during FNC compared with controls, and these changes were associ- ated with more marked symptoms. Conclusions: Axonal responses to compression are impaired in CTS. This may sug- gest a greater reliance on axonal membrane Na þ /K þ -ATPase function. Muscle Nerve 44: 402-409, 2011