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Rate of disease progression (ΔFS), measured as change in the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and body mass index (BMI), are predictors of survival in amyotrophic lateral sclerosis (ALS). Our aim in this study was to assess the utility of these clinical biomarkers along with neurophysiological measures, such as the split hand index (SI), in monitoring disease progression.Clinical trial data were collected from 107 patients recruited into the Tecfidera in ALS trial. The prognostic utility of clinical and neurophysiological measures, including ΔFS, BMI, SI, and neurophysiological index (NPI), were assessed cross-sectionally and longitudinally (40 weeks). The outcome measures of disease severity and progression included: (i) ALSFRS-R score; (ii) Medical Research Council (MRC) score; and (iii) forced vital capacity and sniff nasal inspiratory pressure.Fast-progressor ALS patients (ΔFS ≥1.1) exhibited significantly lower ALSFRS-R and total MRC scores at baseline. A baseline ΔFS score ≥1.1 was associated with a greater reduction in ALSFRS-R (P = .002) and MRC (P = .002) scores over 40 weeks. Baseline BMI25 was also associated with faster reduction of ALSFRS-R and MRC scores. SI and NPI were associated with disease severity at baseline, but not with subsequent rate of disease progression.Implementation of the assessed clinical and neurophysiological biomarkers may assist in patient management and stratification into clinical trials.

Immune-mediated neuropathies such as chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN) produce significant disability and often require maintenance treatment. There is a paucity of epidemiological data on these conditions in Australia.We undertook a prevalence study of CIDP and MMN in North Queensland and Tasmania, coinciding with a national census. Diagnoses were classified against the diagnostic criteria of the European Federation of Neurological Societies/Peripheral Nerve Society. Case ascertainment was undertaken via multiple methods, including survey of local neurologists across public and private clinics, search of neurophysiology, neurology and hospital databases, search of admitted hospital database collections using ICD codes and through immunoglobulin therapy prescription lists.The crude prevalence of CIDP was 5.00 per 100,000 (95% confidence interval [CI] 3.79-6.62) and the crude prevalence of MMN was 1.33 per 100,000 (95% CI 0.78-2.27). Prevalence was also investigated using National Blood Authority numbers of cases prescribed immunoglobulin therapy, indicating a CIDP prevalence of 5.72 per 100,000 (95% CI 4.41-7.43) and MMN prevalence of 1.94 per 100,000 (95% CI 1.24-3.03). There was no significant difference between these numbers and those calculated through access of patient records locally. There was no significant difference in prevalence between Tasmania and North Queensland for any category.This study updates the prevalence of CIDP and MMN in Australia. Understanding the distribution of CIDP and MMN patients and their need for treatment is essential for future resource planning and to enable monitoring and coordination of therapies such as immunoglobulin.

INTRODUCTION/AIMS Imbalance is a common feature of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Intravenous immunoglobulin (IVIg) exerts clinical benefit in CIDP, including improving balance, although objective markers of efficacy are lacking. Posturography is an established objective marker of balance; therefore, this study aimed to determine the utility of posturography as an objective marker of treatment efficacy in CIDP. METHODS Posturography was performed on 18 CIDP patients, established on IVIg infusions, and results were compared to age-matched healthy controls. CIDP patients were assessed just prior to IVIg infusion and at the mid-point of the cycle. Center of pressure (CoP) was measured and the total path traveled by CoP (Sway Path, SP) was calculated for five different conditions: feet placed in parallel 16 cm apart at the medial border with eyes open (16cmEO) and eyes closed (16cmEC); medial borders of the feet touching with eyes open (0cmEO) and eyes closed (0cmEC); and tandem stance. RESULTS The sway path (SP) was significantly increased in CIDP patients (mean SP 1191 ± 104 mm) when compared to healthy controls (mean SP 724 ± 26 mm, P

Diagnostic criteria for amyotrophic lateral sclerosis (ALS) are complex, incorporating multiple levels of certainty from possible through to definite, and are thereby prone to error. Specifically, interrater variability was previously established to be poor, thereby limiting utility as diagnostic enrollment criteria for clinical trials. In addition, the different levels of diagnostic certainty do not necessarily reflect disease progression, adding confusion to the diagnostic algorithm. Realizing these inherent limitations, the World Federation of Neurology, the International Federation of Clinical Neurophysiology, the International Alliance of ALS/MND Associations, the ALS Association (United States), and the Motor Neuron Disease Association convened a consensus meeting (Gold Coast, Australia, 2019) to consider the development of simpler criteria that better reflect clinical practice, and that could merge diagnostic categories into a single entity. The diagnostic accuracy of the novel Gold Coast criteria was subsequently interrogated through a large cross-sectional study, which established an increased sensitivity for ALS diagnosis when compared with previous criteria. Diagnostic accuracy was maintained irrespective of disease duration, functional status, or site of disease onset. Importantly, the Gold Coast criteria differentiated atypical phenotypes, such as primary lateral sclerosis, from the more typical ALS phenotype. It is proposed that the Gold Coast criteria should be incorporated into routine practice and clinical trial settings.

After initial investigation of patients presenting with symptoms suggestive of neuropathy, a clinical decision is made for a minority of patients to undergo further assessment with nerve biopsy. Many nerve biopsies do not demonstrate a definitive pathological diagnosis and there is considerable cost and morbidity associated with the procedure. This highlights the need for appropriate selection of patients, nerves and neuropathology techniques. Additionally, concomitant muscle and skin biopsies may improve the diagnostic yield in some cases. Several advances have been made in diagnostics in recent years, particularly in genomics. The indications for nerve biopsy have consequently changed over time. This review explores the current indications for nerve biopsies and some of the issues surrounding its use. Also included are comments on alternative diagnostic modalities that may help to supplant or reduce the use of nerve biopsy as a diagnostic test. These primarily include extraneural biopsy and neuroimaging techniques such as magnetic resonance neurography and nerve ultrasound. Finally, we propose an algorithm to assist in deciding when to perform nerve biopsies.

Objective To collect preliminary data on the effects of mexiletine on cortical and axonal hyperexcitability in sporadic amyotrophic lateral sclerosis (ALS) in a phase 2 double-blind randomized controlled trial. Methods Twenty ALS subjects were randomized to placebo and mexiletine 300 mg or 600 mg daily for 4 weeks and assessed by transcranial magnetic stimulation and axonal excitability studies. The primary endpoint was change in resting motor threshold (RMT). Results RMT was unchanged with 4 weeks of mexiletine (combined active therapies) as compared to placebo, which showed a significant increase (p=0.039). Reductions of motor evoked potential (MEP) amplitude (p=0.013) and accommodation half-time (p=0.002), secondary outcome measures of cortical and axonal excitability, respectively, were also evident at 4 weeks on mexiletine. Conclusions The relative stabilization of RMT in the treated subjects was unexpected and could be attributed to unaccounted sources of error or chance. However, a possible alternative cause is neuromodulation preventing an increase. The change in MEP amplitude and accommodation half-time supports the reduction of cortical and axonal hyperexcitability with mexiletine. This article is protected by copyright. All rights reserved.

Introduction Sensorimotor neuropathy associated with IgG4 antibodies to neurofascin-155 (NF155) was recently described. The clinical phenotype is typically associated with young onset, distal weakness, and in some cases, tremor. Methods From a consecutive cohort of 55 patients diagnosed with chronic inflammatory demyelinating polyneuropathy, screening for anti-NF155 antibodies was undertaken. Patients underwent clinical assessment, diagnostic neurophysiology, including peripheral axonal excitability studies and nerve ultrasound. Results Three of 55 chronic inflammatory demyelinating polyneuropathy patients (5%) tested positive for anti-NF155 IgG4. Patients presenting with more severe disease had higher antibody titers. Ultrasound demonstrated diffuse nerve enlargement. Axonal excitability studies were markedly abnormal, with subsequent mathematical modeling of the results supporting disruption of the paranodal seal. Discussion A broad spectrum of disease severity and treatment response may be observed in anti-NF155 neuropathy. Excitability studies support the pathogenic role of anti-NF155 IgG4 antibodies targeting the paranodal region. Muscle Nerve 57: 848-851, 2018.

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.

Introduction: We quantified intraneural blood flow (INBF) in 18 patients with end-stage kidney disease (ESKD) and examined its relationship with nerve size, neuropathy severity and nerve excitability parameters. Methods: Sonographic measurements of the median nerve were performed at the same site before and after haemodialysis. INBF was quantified by analysing power Doppler sonograms to obtain the vessel score (VSc) and maximum perfusion intensity(MPI). Corresponding median motor nerve excitability studies were performed. Neuropathy severity was assessed using total neuropathy score (TNS). Results: 39% of ESKD patients had detectable INBF compared to none in the control group (P

Introduction This study seeks to elucidate the optimal scan time to detect fasciculations by using ultrasound in the diagnosis of amyotrophic lateral sclerosis (ALS). Methods The intervals between fasciculations were recorded from tongue, abdominal, and limb muscles in ALS patients, incorporating assessment of the cumulative probability of 2 fasciculations occurring. Results From prospective studies of 228 muscles from 19 ALS patients, fasciculations were detectable in 68% of patients. The longest interfasciculation interval recorded was 81.4 s in the hand muscle. The cumulative probability of 2 fasciculations occurring was calculated as ≥0.9 in all muscles during a period of 60 s. Discussion A definition of 2 or more fasciculations occurring during a scan time of 60 s reliably allowed detection of fasciculations in ALS. Muscle Nerve, 2017

Introduction: Threshold tracking paired-pulse transcranial magnetic stimulation (TTTMS) examines cortical function and is useful for diagnosis of motor neuron disorders. Differences in cortical function have been identified between dominant and non-dominant limbs using constant stimulus methods, but they remain unclear, potentially due to methodological differences. In this study we aimed to clarify differences in cortical function between dominant and non-dominant limbs using TTTMS. Methods: Single-pulse TMS, TTTMS, and nerve conduction studies were performed in 25 healthy, right-handed participants by recording from the abductor pollicis brevis muscle. Results: There were no side-to-side differences observed in resting motor threshold, motor evoked potential (MEP) amplitude, MEP latency, central motor conduction time, cortical silent period, short-interval intracortical inhibition and facilitation, compound muscle action potential (CMAP) amplitude, CMAP latency, F-wave latency, or neurophysiological index. Conclusions: These findings suggest that, when using TTTMS, there are no differences in cortical function between dominant and non-dominant hemispheres. Muscle Nerve 55: 424–427, 2017

INTRODUCTION There is no specific treatment for neuropathy in chronic kidney disease (CKD). We compared nerve function across hemodialysis (HD) and peritoneal dialysis (PD). METHODS Subjects underwent neurological assessment and neurophysiological testing using nerve excitability studies. Pre- and postdialysis studies were undertaken in HD (n = 10) and PD (n = 10) patients and were compared with stage 4 CKD patients (n = 12) and healthy controls (n = 20). RESULTS There were prominent differences in nerve excitability between the groups (P

Introduction: Acute bulbar, neck, and limb weakness carries several potential differential diagnoses. Although a diagnosis can often be established clinically, investigations such as electrodiagnostic and antibody testing can provide support for the clinical diagnosis and may aid in understanding the pathogenesis. A 65-year-old woman presented with acute bulbar, neck, and rapidly progressive bilateral upper limb weakness. Methods: Clinical evaluation, electrophysiological, and serological studies were undertaken. Results: Neurophysiology demonstrated proximal conduction block. A clinical diagnosis of pharyngeal-cervical-brachial weakness, a localized variant of Guillain-Barre syndrome, was made. The patient received treatment with intravenous immunoglobulin and made a remarkable recovery over the next month. She was found to have serum monospecific anti-GT1a antibodies. Conclusions: We report a case of pharyngeal-cervical-brachial weakness with monospecific anti-GT1a antibodies and discuss the differential diagnosis of acute bulbar, neck, and limb weakness. Muscle Nerve, 2015

Introduction Presentations to the neuromuscular clinic commonly involve hand muscle denervation, but few studies have evaluated hand muscle ultrasound. Methods Ultrasound studies of abductor pollicis brevis, first dorsal interosseous, and abductor digit minimi were prospectively performed in a cohort of 34 patients (77 muscles) with electromyography (EMG)-confirmed denervation, compared with 58 healthy control subjects. Results In control subjects, muscle thickness was highly reproducible [intraclass correlation coefficient (ICC) = 0.88–0.98], and echogenicity was moderately reproducible (ICC = 0.542–0.686). Age, gender, and body mass index influenced muscle thickness and echogenicity. Ultrasound changes in denervated muscles correlated with the severity of EMG abnormalities. A z-score cutoff of 0 identified denervated muscles with a sensitivity of 100% and 89% for echogenicity and muscle thickness, respectively. Conclusions Hand muscle ultrasound provides a noninvasive method to quantify muscle denervation and may be useful as a screening tool before EMG studies. Muscle Nerve 52: 221–230, 2015

Introduction: The distribution of clinical and neurophysiological abnormalities in patients with early amyotrophic lateral sclerosis (ALS) was investigated in an attempt to delineate patterns of disease spread. Methods: Clinical and electrodiagnostic data were collected from 150 ALS patients and analyzed based on the clinical region of onset. Results: Asymmetry of clinical and neurophysiological abnormalities was more marked in upper limb-onset than lower limb-onset disease. Significant rostral–caudal gradients of clinical weakness were identified in bulbar- and lower limb-onset disease. Neurophysiological evidence of the ALS “split-hand” pattern was evident irrespective of the region of disease onset. Limbs with and without evidence of clinical weakness demonstrated similar rates of abnormality on electromyography. Conclusions: These findings suggest a pattern of disease spread in ALS. This study may serve to guide ongoing development of disease quantitation biomarkers and the targeting of future neuroprotective strategies. Muscle Nerve 50: 894–899, 2014

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

Introduction Differences in cortical and axonal excitability may underlie preferential atrophy of abductor pollicis brevis (APB) and first dorsal interosseous (FDI) in amyotrophic lateral sclerosis, termed the split-hand. Consequently, this study aimed to determine whether differences in excitability follow a split-hand pattern across the intrinsic hand muscles. Methods Excitability studies were undertaken using threshold tracking techniques in 26 healthy controls with responses recorded over APB, FDI, and abductor digiti minimi. Results Short interval intracortical inhibition was significantly greater from the APB and FDI. In addition, motor evoked potential amplitude was greater, while cortical silent period was longer from APB and FDI. At a peripheral level, the strength-duration time constant was greater when recorded over APB. Conclusions This study establishes that differences in cortical excitability follow the split-hand pattern in healthy controls, a finding potentially explained by evolution of specialized activity of APB/FDI in complex hand tasks. Muscle Nerve 49: 836-844, 2014.

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.

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

Introduction: Although Kennedy disease (KD) is regarded as a pure lower motor neuron disorder, recent trans- cranial magnetic stimulation (TMS) studies have reported sub- clinical corticomotoneuronal dysfunction in KD. To clarify these findings, this study applied novel triple stimulation (TST) and threshold tracking TMS techniques to gain further insights into corticomotoneuronal function in KD. Methods: TMS studies were undertaken in 12 KD patients and 38 age-matched con- trols. Motor evoked potentials were recorded over the abductor pollicis brevis (threshold tracking TMS) and abductor digiti min- imi (TST). Results: The mean TSTtest:TSTcontrol amplitude (99 6 0.7%, normal >93%) and area (98.4 6 1.6%, normal >92%) ratios were normal in Kennedy disease. In addition, short-interval intracortical inhibition (SICI) was similar in KD and controls (KD: 8.1 6 1.3%; controls: 10.1 6 0.7%; P ¼ 0.11), as were the motor evoked potential amplitude, resting motor threshold, intracortical facilitation, and cortical silent period du- ration. Conclusions: Triple stimulation and threshold tracking TMS techniques have reiterated normal corticomotoneuronal function in KD. Muscle Nerve 44: 197-201, 2011

Paclitaxel is used in the adjuvant treatment of breast cancer. It induces disabling and potentially long-lasting sensory neuropathy. This study systematically and prospectively investigated sensory function, using clinical grading scales, quantitative sensory testing, and neurophysiological and nerve excitability studies in 28 patients with early-stage breast cancer. After administration of 529 ± 41 mg/m(2) paclitaxel, 71% of patients developed neuropathic symptoms by 6 weeks of treatment. Early and progressive increases in stimulus threshold (P < 0.05) and reduction in sensory amplitudes from 47.0 ± 3.3 μV to 42.4 ± 3.4 μV (P < 0.05) occurred by 4 weeks, with a further reduction by final treatment (33.7 ± 3.0 μV, P < 0.001). The majority of patients (63%) did not experience recovery of neuropathic symptoms at follow-up. Axonal disruption did not relate to membrane conductance dysfunction. We found that paclitaxel produces early sensory dysfunction and leads to persistent neuropathy. Importantly, significant axonal dysfunction within the first month of treatment predated symptom onset, suggesting a window for neuroprotective therapies.

The causal relationship between electrical injury and development of amyotrophic lateral sclerosis (ALS) remains controversial. We describe the case of a 25-year-old man who developed ALS after a severe electrical injury. Cerebral magnetic resonance imaging (MRI) demonstrated hyperintensities involving the corticospinal tract. Functional testing with transcranial magnetic stimulation established that the motor cortex was relatively inexcitable. In addition, there were features of denervation on electromyography and muscle biopsy that supported concomitant lower motor neuron findings and the diagnosis of ALS.

Tick paralysis (TP) is an uncommon disorder caused by a neurotoxin secreted by engorged female ticks. The cause of TP remains unclear, although alterations in axonal ion channel function and neuromuscular transmission have been proposed. In the present case, nerve excitability techniques, which provide information regarding axonal ion channel function, were used to elucidate the mechanism underlying weakness in a 45-year-old man who presented with weakness following a tick bite in the lateral aspect of the left axilla. Standard clinical nerve conduction studies were undertaken during the acute phase of symptoms and following clinical recovery. Nerve excitability studies were performed to investigate possible changes in ion channel properties distal to the site of conduction failure. Nerve conduction studies and electromyography suggested the possibility of a lesion involving the lower trunk of the left brachial plexus. Nerve excitability studies distal to the site of the tick bite demonstrated an abrupt increase in refractoriness, a marker of recovery from inactivation of Na+ channels. There was normalization of both nerve conduction and nerve excitability parameters associated with clinical recovery. The alteration in refractoriness is similar to that noted in disorders involving the terminal portion of the motor nerve. The changes raise the possibility that TP may cause weakness through impairment of distal neural transmission. Muscle Nerve, 2009

Neuropathy is a common complication of end-stage kidney disease (ESKD), typically presenting as a distal symmetrical process with greater lower-limb than upper-limb involvement. The condition is of insidious onset, progressing over months. and has been estimated to be present in 60%-100% of patients on dialysis. Neuropathy generally only develops at glomerular filtration rates of less than 12 ml/min. The most frequent clinical features reflect large-fiber involvement, with paresthesias, reduction in deep tendon reflexes, impaired vibration sense, muscle wasting, and weakness. Nerve conduction studies demonstrate findings consistent with a generalized neuropathy of the axonal type. Patients may also develop autonomic features, with postural hypotension, impaired sweating, diarrhea, constipation, or impotence. The development of uremic neuropathy has been related previously to the retention of neurotoxic molecules in the middle molecular range, although this hypothesis lacked formal proof. Studies utilizing novel axonal excitability techniques have recently shed further light on the pathophysiology of this condition. Nerves of uremic patients have been shown to exist in a chronically depolarized state prior to dialysis, with subsequent improvement and normalization of resting membrane potential after dialysis. The degree of depolarization correlates with serum K(+), suggesting that chronic hyperkalemic depolarization plays an important role in the development of nerve dysfunction in ESKD. These recent findings suggest that maintenance of serum K(+) within normal limits between periods of dialysis, rather than simple avoidance of hyperkalemia, is likely to reduce the incidence and severity of uremic neuropathy.

Threshold electrotonus involves tracking the changes in axonal excitability produced by subthreshold polarizing currents and is the only technique that allows insight into the function of internodal conductances in human subjects in vivo. There is often an abrupt transient reversal of the threshold change as excitability increases in response to conditioning depolarizing currents (S1 phase). In recordings from motor axons, it has been recently demonstrated that this notch or inflection is due to activation of low-threshold axons. We report that a notch is frequently seen in sensory recordings (in 33 of 50 healthy subjects) using the standard threshold electrotonus protocol. When large, the notch can distort subsequent phases of threshold electrotonus and could complicate quantitative measurements and modeling studies.

To investigate peripheral nerve function and its potential contribution to symptoms of weakness in myotonic dystrophy type 1 (MD), nerve excitability was assessed in 12 MD patients. Compound muscle action potentials (CMAPs) were recorded at rest from abductor pollicis brevis (APB) following stimulation of the median nerve. Stimulus-response behavior, threshold electrotonus, a current-threshold relationship, and recovery cycles were successfully recorded in each patient. Compared with controls, there was significant reduction in CMAP amplitude in MD patients. This was accompanied by reduction in depolarizing threshold electrotonus and an increase in refractoriness and in the duration of the relative refractory period. To determine whether alteration in axonal resting membrane potential was a factor underlying these changes, axonal excitability was assessed following maximal contraction of APB for 60 seconds. Following contraction, there was reduction in CMAP amplitude for a submaximal stimulus (by 51.5+/-11.8%) and an increase in super-excitability (of 22.2+/-12.0%), consistent with activity-dependent hyperpolarization, with a greater increase in threshold for MD patients compared to controls (MD group, 22.3+/-5.1%; controls, 11.7+/-2.1%; P

In this study, nerve excitability protocols were adapted for lower-limb recordings in 25 healthy subjects to enable comparison of excitability parameters between proximal and distal recording sites of the same nerve and between different nerves. Excitability parameters (stimulus–response curves, strength–duration properties, threshold electrotonus, a current–threshold relationship, and the recovery cycle) were recorded from tibialis anterior, extensor digitorum brevis, and abductor hallucis. Excitability recordings were technically possible from each site, and normative values were established for lower-limb nerves. In this process, inter- and intranerve differences in excitability properties were demonstrated: stimulus intensity and rheobase were reduced in recordings from proximal sites; the relative refractory period and late subexcitability were increased; superexcitability was reduced; and a relative “fanning-in” occurred for threshold electrotonus curves recorded from proximal sites. Such a length-dependent gradient in nerve excitability may underlie the greater tendency for ectopic activity to arise from the proximal segments of motor axons and may contribute to the length-dependent involvement of motor axons in the development of peripheral neuropathy. Muscle Nerve 29: 645–655, 2004

Introduction: The mechanisms of lead neuropathy remain unexplained. A 48-year-old painter presented after undertaking a 3-week project of paint removal without the use of a protective mask. Two weeks later, he developed fasciculations, weakness, and muscle wasting. Nerve conduction studies demonstrated a motor neuropathy. A high serum lead level was identified, leading to a diagnosis of acute lead neuropathy. Methods: To investigate the pathophysiology, nerve excitability studies were undertaken acutely and in convalescence. Studies were undertaken at baseline and after the induction of limb ischemia. Results: Prominent abnormalities of excitability were noted, including a rightward shift of stimulus–response curves, reduction in depolarizing threshold electrotonus, and increased refractoriness. These changes became more severe with limb ischemia, and there was abolition of the superexcitable period and increased refractoriness. Conclusions: We identified prominent changes in nerve excitability in lead neuropathy. The results suggest that there is impairment of axonal energy-dependent processes in lead neuropathy. Muscle Nerve, 2012

Excitability properties were recorded from 14 volunteers following stimulation of the recurrent motor branch of the median nerve in the palm. Distal stimulation resulted in significantly lower strength-duration time constant and lower threshold during prolonged hyperpolarization than did wrist stimulation in the same subjects. These differences may be geometric in origin or alternatively may arise from functional changes distally, particularly reduced expression of persistent Na(+) conductances and more hyperpolarization-activated current. Excitability studies using palm stimulation provide information closer to the neuromuscular junction, where membrane properties are preferentially affected in a variety of clinical conditions.

A recently described method for recording multiple excitability parameters of human motor nerves has been adapted to the study of sensory nerves. The protocol measures stimulus-response behavior using two stimulus durations (from which the distribution of strength-duration time constants is estimated), threshold electrotonus to 100 ms polarizing currents, a current-threshold relationship (indicating inward and outward rectification), and the recovery of excitability following supramaximal activation. The method was tested on 50 healthy volunteers, stimulating the median nerve at the wrist and recording the antidromic compound sensory nerve action potential (SNAP) from digit 2. The excitability measurements were similar, where comparisons were possible, with published sensory nerve data, and confirmed differences from motor nerves, particularly in strength-duration behavior and recovery cycle, likely to reflect functional differences between sensory and motor nerves. Although slower than for motor nerves, the sensory nerve recordings were sufficiently quick (16 to 18 min) to allow them to be included in routine clinical studies. We propose that this method, which provides quite different and complementary information about nerve function to conventional conduction studies, provides a useful new approach for exploring the pathophysiology of sensory neuropathies.

From measurements of nerve excitability and the changes in excitability produced by nerve impulses and conditioning currents, it is possible to infer information about the membrane potential and biophysical properties of peripheral axons. Such information cannot be obtained from conventional nerve conduction studies. This article describes a new method that enables several such measurements to be made on a motor nerve quickly and reproducibly, with minimal operator intervention. The protocol measures stimulus-response behavior using two stimulus durations (from which the distribution of strength-duration time constants can be estimated), threshold electrotonus to 100-ms polarizing currents, a current-threshold relationship (indicating inward and outward rectification), and the recovery of excitability following supramaximal activation. The method was tested on 30 healthy volunteers, stimulating the median nerve at the wrist and recording from the abductor pollicis brevis. The results were comparable with previously published normal data, but the recordings took less than 10 min. The convenience and brevity of the new method make it appropriate for routine clinical use.

Although the acute clinical effects of ciguatera poisoning, due to ingestion of ciguatoxin, are mediated by activation of transient Na+ channels, the mechanisms underlying ciguatera sensitization remain undefined. Axonal excitability studies were performed by stimulating the median motor and sensory nerves in two patients with ciguatera sensitization. Excitability parameters were all within normal limits, thereby arguing against dysfunction of axonal membrane ion channels in large-diameter fibers in ciguatera sensitization.

Compared with control subjects, patients with amyotrophic lateral sclerosis (ALS) have been reported to experience less or no paresthesias during and after release of ischemic compression of the upper arm for 10 min. This is reminiscent of the resistance to ischemia of diabetic patients, in whom sensory and motor axons undergo less ischemic depolarization and less postischemic hyperpolarization than in control subjects. The present study compared the changes in axonal excitability produced by ischemia for 10 min in 21 patients with ALS and 14 age-matched control subjects. Fewer patients reported intraischemic or postischemic paresthesias and the intensity of paresthesias was less, but this was significant only for postischemic paresthesias. There were quantitatively similar changes in refractoriness, supernormality, and strength-duration time constant during ischemic compression, but the increase in excitability of motor axons was less during the second half of ischemia in the patients. After release of ischemia the postischemic hyperpolarization was greater in the ALS patients, the opposite of what occurs in diabetes. These changes could reflect reduced intraneural K+ accumulation due to loss of motor axons or an alteration in nerve metabolism or membrane properties. Either way, the present study has failed to confirm previous reports of “ischemic resistance” in ALS, and indicates that the changes in axonal properties in ALS are not analogous to those in diabetes mellitus. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21: 1692–1700, 1998