Depolarizing Threshold Electrotonus Research Articles

Prospective assessment of vincristine-induced peripheral neuropathy in paediatric acute lymphoblastic leukemia

ObjectiveVincristine is a mainstay treatment for paediatric cancers, particularly acute lymphoblastic leukemia (ALL), with common toxicity including vincristine-induced peripheral neuropathy (VIPN). The present study comprehensively assessed VIPN outcomes in patients receiving vincristine treatment for ALL. MethodsChildren diagnosed with ALL commencing vincristine treatment were prospectively evaluated (baseline, post-induction, pre-reinduction, post-reinduction, follow-up). VIPN was examined clinically using the Balis sensory/motor scale, neurophysiologically using axonal excitability techniques and quality-of-life using Pediatric Quality of Life Inventory. ResultsThirty-one patients were recruited to this study (age = 6.8 ± 4.4; 61.3% female). Incidence of motor VIPN (motor Balis grade > 0) symptoms were higher than sensory VIPN (sensory Balis grade > 0) at post-induction (92.0% vs 36.0%) and post-reinduction (81.8% vs 22.7%) vincristine treatment. Neurophysiological assessment also demonstrated greater change in motor axonal excitability parameters compared to sensory parameters including changes in depolarising threshold electrotonus (P < 0.0125), superexcitability and subexcitability parameters (all P < 0.0125). Follow-up assessment demonstrated persisting VIPN symptoms with reduced quality-of-life scores compared to baseline. ConclusionsClinical and neurophysiological evaluation of VIPN suggests vincristine produces a motor-prominent sensorimotor neuropathy in children which persisted at follow-up. SignificanceVIPN signs and symptoms develop early in the treatment course, in line with axonal excitability profiles. Early detection of significant nerve changes may support timely implementation of neuroprotection strategies.

Differences in nerve excitability properties across upper limb sensory and motor axons

ObjectiveThe excitability of motor and sensory axons of the main upper limb nerves were compared to characterise the differences between nerves and provide a guide for future studies in human diseases with median neuropathy at the wrist. MethodsAxonal excitability studies were undertaken on median and ulnar motor (APB and ADM) and sensory axons (D2 and D5) and the superficial radial axons (D1) using a threshold tracking technique. ResultsCompared to the median, ulnar motor axons had reduced early depolarising threshold electrotonus (TEd40(10–20 ms) p = 0.02) and superexcitability (p = 0.03). The ulnar sensory axons required a stronger stimulus (p = 0.02) and had a larger rheobase (p = 0.02) than median axons, but were otherwise comparable. The superficial radial axons were “fanned-in” compared to median, and to a lesser degree ulnar axons, with greater resting I/V slope. Mathematical modelling of the radial and median sensory axons suggested that a 15.1% reduction in conductances between nodal and internodal compartments accounted for 82% of this discrepancy. ConclusionsThe excitability parameters of motor and sensory axons are most comparable between median and ulnar nerves. SignificanceThe present study demonstrates the feasibility of, and provides normative data for, axonal excitability recordings of the radial and ulnar nerves. We suggest the use of ulnar recordings as an alternative to the median nerve in the setting of compressive neuropathy at the wrist.

Sensory and motor axonal excitability testing in early diabetic neuropathy

ObjectiveThe aim of the present study was to gain insight into the pathophysiology of diabetic polyneuropathy (DPN) and examine the diagnostic value of sensory and motor axonal excitability testing. MethodsOne hundred and eleven type 2 diabetics with and without DPN (disease duration: 6.36 ± 0.25 years) and 60 controls were included. All participants received a thorough clinical examination including Michigan Neuropathy Screening Instrument (MNSI) score, nerve conduction studies (NCS), and sensory and motor excitability tests. Patients were compared by the likelihood of neuropathy presence, ranging from no DPN (17), possible/probable DPN (46) to NCS-confirmed DPN (48). ResultsMotor excitability tests showed differences in rheobase and depolarizing threshold electrotonus measures between NCS-confirmed DPN group and controls but no changes in hyperpolarising threshold electrotonus or recovery cycle parameters. Sensory excitability showed even less changes despite pronounced sensory NCS abnormalities. There were only weak correlations between the above motor excitability parameters and clinical scores. ConclusionsChanges in excitability in the examined patient group were subtle, perhaps because of the relatively short disease duration. SignificanceLess pronounced excitability changes than NCS suggest that axonal excitability testing is not of diagnostic value for early DPN and does not provide information on the mechanisms.

Split hand and motor axonal hyperexcitability in spinal and bulbar muscular atrophy

ObjectiveThe ‘split hand’ sign refers to preferential wasting of the thenar and first dorsal interosseous muscles with relatively sparing of the hypothenar muscles in amyotrophic lateral sclerosis (ALS) and both...

Myelin protein zero gene dose dependent axonal ion-channel dysfunction in a family with Charcot-Marie-Tooth disease

ObjectiveThe myelin impairment in demyelinating Charcot-Marie-Tooth (CMT) disease leads to various degrees of axonal degeneration, the ultimate cause of disability. We aimed to assess the pathophysiological changes in axonal function related to the neuropathy severity in hypo-/demyelinating CMT patients associated with myelin protein zero gene (MPZ) deficiency. MethodsWe investigated four family members (two parents and two sons) harboring a frameshift mutation (c.306delA, p.Asp104ThrfsTer14) in the MPZ gene, predicted to result in a nonfunctional P0, by conventional conduction studies and multiple measures of motor axon excitability. In addition to the conventional excitability studies of the median nerve at the wrist, we tested the spinal accessory nerves. Control measures were obtained from 14 healthy volunteers. ResultsThe heterozygous parents (aged 56 and 63) had a mild CMT1B whereas their two homozygous sons (aged 31 and 39 years) had a severe Dejerine-Sottas disease phenotype. The spinal accessory nerve excitability could be measured in all patients. The sons showed reduced deviations during depolarizing threshold electrotonus and other depolarizing features which were not apparent in the accessory and median nerve studies of the parents. Mathematical modeling indicated impairment in voltage-gated sodium channels. This interpretation was supported by comparative modeling of excitability measurements in MPZ deficient mice. ConclusionOur data suggest that axonal depolarization in the context of abnormal voltage-gated sodium channels precedes axonal degeneration in severely hypo-/demyelinating CMT as previously reported in the mouse models. SignificanceMeasures of the accessory nerve excitability could provide pathophysiological markers of neurotoxicity in severe demyelinating neuropathies.

Peripheral nerve maturation and excitability properties from early childhood: Comparison of motor and sensory nerves

ObjectiveUnderstanding 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. MethodsThis 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. ResultsThe 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. ConclusionsMaturational trajectories of sensory and motor axons were broadly parallel in children and young adults, but sensory-motor differences were initiated early in maturation. SignificanceIdentifying 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.

Correlation between markers of peripheral nerve function and structure in type 1 diabetes.

Clinical and experimental studies in patients with type 1 and type 2 diabetes have demonstrated changes in ion channel function and nerve structure. In this study, we investigated the relationship between axonal dysfunction and morphological change in diabetic polyneuropathy by using neuromuscular ultrasound and nerve excitability techniques. We also explored possible differences in this relationship between type 1 and type 2 diabetes. Nerve ultrasound and corresponding motor excitability studies were undertaken in 110 diabetes patients (50 type 1; 60 type 2) and 60 age-matched controls (30 for each group). Neuropathy severity was assessed by using total neuropathy score. Median and tibial nerve cross-sectional areas were measured at nonentrapment sites by using high-resolution linear probe. Median and tibial nerve cross-sectional areas were significantly higher in diabetes patients compared with controls: type 1 (median=7.6±0.2mm2 vs 6.3±0.1mm2 ; tibial=14.5±0.7mm2 vs 10.8±0.3mm2 , P<.05) and type 2 (median=9.1±0.3mm2 vs 7.2±0.1mm2 ; tibial=18.5±1.0mm2 vs 12.8±0.5mm2 , P<.05). In the type 1 cohort, significant correlations were found between nerve cross-sectional area and excitability parameters including resting current-threshold slope (median: r=0.523, P<.0001; tibial: r=-0.571, P=.004) and depolarizing threshold electrotonus at 90 to 100ms (median: 0.424, P<.01; tibial: r=0.435, P=.030). In contrast, there was no relationship between excitability values and nerve cross-sectional area in the type 2 cohort. This study has identified correlation between markers of axonal membrane function and structural abnormalities in peripheral nerves of type 1 diabetes patients. The differential relationship in nerve function and structure between type 1 and type 2 diabetes provides clinical evidence that different pathophysiological mechanisms underlie the development of neuropathy in these patient groups.

T38. Altered axonal excitability in spinal and bulbar muscular atrophy

Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease characterized with prominent fasciculations. Fasciculations suggest motor nerve hyperexcitability and potentially result in a burden to motor neuron. Axonal excitability and nerve conduction studies were performed in 31 patients with SBMA and 140 with amyotrophic lateral sclerosis (ALS). These results were compared with those of 16 healthy males (HM). In SBMA, correlations between neurophysiological studies and clinical profiles were examined. Patient backgrounds in SBMA were as follows; mean age; 58 years, mean disease duration; 152 months, mean ALS functional rating scale (ALSFRS-R); 41, mean CAG repeat expansion; 46, mean compound muscle action potential (CMAP) amplitude on abductor pollicis brevis muscle was 6.0 mV. Compared with HM, SBMA patients had longer strength-duration time constant (SDTC), greater threshold change in depolarizing threshold electrotonus (TEd) and greater supernormality (all p < 0.05). ALS patients had similar findings and smaller late subexcitability (all p < 0.05). In SBMA, TEd (90–100 ms) was related to ALSFRS-R (R = 0.42, p < 0.05), and CAG repeat was related to CMAP amplitude (R = −0.52, p < 0.05) and superexcitability (R = −0.46, p < 0.05). Patients were divided into two groups according to CMAP amplitude (over and under 5 mV). Compared with HM, SBMA patients with over 5 mV had greater TEd (10–20 ms) and greater superexcitability (all p < 0.05). SBMA patients with under 5 mV had longer SDTC, greater TEd and greater superexcitability (all p < 0.05). ALS patients with over 5 mV had greater TEd (90–100 ms) and greater superexcitability (all p < 0.05). ALS patients with under 5 mV had longer SDTC, greater TEd, greater superexcitability and smaller subexcitability (all p < 0.05). A previous study investigated axonal excitabilities in 7 patients with SBMA and revealed increased sodium currents. Our findings suggest that SBMA patients have increased sodium and decreased fast potassium currents. Similar findings and decreased slow potassium currents were found in ALS. This difference may suggest that ALS patients have more hyperexcitable motor nerve. Moreover, our findings suggest that decreased fast potassium currents are related to CAG repeat expansion in SBMA. It is already reported that SBMA patients have disruption of axonal transport. CAG repeat expansion may bring about axonal hyperexcitability and result in a burden to motor neuron.

T44. Abnormalities of motor axonal properties in amyotrophic lateral sclerosis

Introduction To date, changes of axonal sodium and potassium currents have been reported in amyotrophic lateral sclerosis (ALS) (Bostock et al., 1995; Kanai et al., 2006), and the association to prognosis and characteristic symptoms such as fasciculations has been discussed. To confirm the previously reported changes, multiple axonal excitability properties were measured in patients with ALS, and compared with age-matched controls. Methods A total of 55 patients with sporadic ALS, who visited to Juntendo University Hospital from 2013 to 2017, were included in the study. Multiple excitability measurements were performed in the median nerve at the wrist using a computerized program (QTRAC with multiple excitability protocol, Institute of Neurology, London, UK). Results The age range of the patients was from 30 to 82 years old (median 62.7 years old), and there were 31 male and 24 female. As clinical phenotypes, 13 patients were bulber onset type, 31 were upper limbs onset type, 9 were lower limbs onset type, and 2 were multiple onset type. In ALS, there were extremely greater changes in depolarizing threshold electrotonus (P Conclusion This study suggested increased persistent sodium currents and reduced potassium currents in motor axons, as well as previous studies. Both of these changes lead to axonal hyperexcitability, and may contribute to the generation of fasciculations. Because neuronal hyperexcitibility is one of hypotheses of cause of neuronal death in ALS, these changes may also contribute motor neuronal death in ALS.

O122 Nerve excitability at different target levels in multifocal motor neuropathy

Objectives To determine if different types of motor axons in multifocal motor neuropathy (MMN) are affected differently. Methods In 17 MMN patients we performed excitability tests of the median nerve motor axons at three target levels (20%, 40%, and 60% of the maximum CMAP). Motor responses were recorded from the thenar muscle. Nerve conduction findings included motor conduction block, demyelinative slowing, or normal values in the forearm region of the median nerve. Mann-Whitney test was used for statistical analysis between groups. Results Excitability parameters between 20% and 40% target levels did not demonstrate any difference. Depolarizing threshold electrotonus peak (TEdpeak) and S2 accommodation differed significantly between 40% and 60% target levels. Largest differences were observed between 20% and 60% target levels: fanning out of threshold electrotonus ( p = 0.008) was more pronounced at 60% target level, resting ( p = 0.029) and minimal ( p = 0.017) current-voltage slopes were steeper at 20% target level, TEd peak ( p = 0.007) and S2 accommodation ( p = 0.024) were greater at 20% target level. Discussion Discrepancies in the excitability parameters among axons with different thresholds may highlight selective nerve abnormalities in MMN, which renders them more vulnerable to develop axon damage along the course of MMN. Conclusions Current technique showed that motor excitability-abnormalities in MMN differ between axons with different thresholds. Significance Excitability tests applied at different target levels may reveal specific ion-channel disfunction in different types of motor axons in MMN.

Altered axonal excitability properties in facial palsy.

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

3-2-01. Decreased motor axonal potassium currents in peripheral nerve hyperexcitability syndrome with negativity for anti-VGKC antibody and positivity for anti-CRMP5 antibody

Peripheral nerve hyperexcitability (PNH) syndromes are caused by spontaneous discharges originating from motor axons. Antibodies against voltage-gated potassium channels (VGKC) are detected in some patients with PNH syndrome, but the cause in the remaining patients has not yet been clarified. The index patient was a 46-year-old female with recurred thymoma and myasthenia gravis. Six month after the start of chemotherapy, she developed myokymia, fasciculations and muscle cramps in both her lower limbs. A nerve conduction studies revealed mild axonal polyneuropathy and a motor F-wave examination showed marked after-discharges. Needle electromyography showed fasciculation potentials and myokymic discharges. From these results, the patient was diagnosed with PNH syndrome. Nerve excitability study showed extremely greater supernormality in the recovery cycle and greater changes in depolarizing threshold electrotonus than control, suggesting decreased slow potassium currents in the motor axons. Serological tests revealed the absence of anti-VGKC antibody and the presence of anti-collapsin response mediator protein 5 (CRMP5) antibody. A recent study reported that CRMP5 plays an important role in axon–Schwann cell cooperation during development and nerve regeneration. The coexistence of nerve regeneration and anti-CRMP5 antibody may cause abnormal axon–Schwann cell interaction, which would result in slow potassium channel dysfunction and associated symptoms such as myokymia.

3-2-11. Peripheral nerve excitability changing in spinocerebellar ataxia type 6 (SCA6)

Abstract Motor nerve excitability testing in the median nerve with QtracS program (©Professor H. Bostock, UCL) was compared between 15 spinocerebellar ataxia type 6 (SCA6) patients and 22 age-matched healthy controls. Motor nerve excitability testing in tail nerve of 2 male mice was compared between before and after intraperitoneal injection of ω -agatoxin-IVA. Compared with normal controls, SCA6 showed statistically significant decrease of depolarizing threshold electrotonus (p ω -agatoxin-IVA. The present study indicates that motor nerves of SCA6 increase slow potassium currents derived from dysfunction of mutant protein, P/Q type voltage gated calcium channels.

Axonal Dysfunction Precedes Motor Neuronal Death in Amyotrophic Lateral Sclerosis.

Wide-spread fasciculations are a characteristic feature in amyotrophic lateral sclerosis (ALS), suggesting motor axonal hyperexcitability. Previous excitability studies have shown increased nodal persistent sodium conductances and decreased potassium currents in motor axons of ALS patients, both of the changes inducing hyperexcitability. Altered axonal excitability potentially contributes to motor neuron death in ALS, but the relationship of the extent of motor neuronal death and abnormal excitability has not been fully elucidated. We performed multiple nerve excitability measurements in the median nerve at the wrist of 140 ALS patients and analyzed the relationship of compound muscle action potential (CMAP) amplitude (index of motor neuronal loss) and excitability indices, such as strength-duration time constant, threshold electrotonus, recovery cycle and current-threshold relationships. Compared to age-matched normal controls (n = 44), ALS patients (n = 140) had longer strength-duration time constant (SDTC: a measure of nodal persistent sodium current; p < 0.05), greater threshold changes in depolarizing threshold electrotonus (p < 0.05) and depolarizing current threshold relationship (i.e. less accommodation; (p < 0.05), greater superexcitability (a measure of fast potassium current; p < 0.05) and reduced late subexcitability (a measure of slow potassium current; p < 0.05), suggesting increased persistent sodium currents and decreased potassium currents. The reduced potassium currents were found even in the patient subgroups with normal CMAP (> 5mV). Regression analyses showed that SDTC (R = -0.22) and depolarizing threshold electrotonus (R = -0.22) increased with CMAP decline. These findings suggest that motor nerve hyperexcitability occurs in the early stage of the disease, and precedes motor neuronal loss in ALS. Modulation of altered ion channel function could be a treatment option for ALS.

14. Haemodialysis alters nerve morphology in chronic kidney disease

Introduction Peripheral neuropathy is highly prevalent in chronic kidney disease (CKD), occurring in 90–100% of patients receiving dialysis. Previous neurophysiological studies using nerve excitability techniques have demonstrated changes in axonal function following a single session of dialysis. The present study was undertaken to examine whether there were morphological changes that may accompany these alterations in nerve function. Methods 15 CKD patients on thrice-weekly high-flux haemodialysis were recruited and studies were conducted before and after a single session of haemodialysis. Serial measurements of median nerve cross-sectional area (CSA), echogenicity and intraneural blood flow were also performed at a non-entrapment site (distal forearm) using high resolution ultrasonography (10–18 MHz probe). Intraneural blood flow was measured by obtaining 5 twenty-second clips of Power Doppler sonograms. Intraneural blood flow and echogenicity data were semi-quantitatively analyzed using a specialized and well-validated software to obtain the median nerve perfusion intensity (PI) and the percentage of hypoechoic area (pHA) respectively. Corresponding nerve excitability studies were undertaken on median motor axons. Results Overall, there was a significant decrease in CSA and PI post-dialysis (p 0.05). A reduction in CSA occurred in 90% of patients (9.05 ± 0.89 mm2 vs 8.51 ± 0.98 mm2), while 80% and 75% had a decrease in PI (0.79 ± 0.47 cm/s vs 0.47 ± 0.24 cm/s) and pHA (56.0 ± 1.0% vs 55.0 ± 1.6) respectively. Furthermore, the change in morphological measures was significantly correlated with excitability indices of membrane potential (PI and depolarising threshold electrotonus r = 0.67 p 0.05). Conclusion This study demonstrates morphological changes in peripheral nerves following a single session of dialysis. These changes correlate with the extent of change in measures of axonal function and may contribute to the development of axonal injury in CKD.

7. Pathophysiological basis of motor neuronal hyperexcitability in amyotrophic lateral sclerosis

Objective Motor neuronal hyperexcitability potentially contributes to motor neuron death in amyotrophic lateral sclerosis (ALS). We aimed to reveal pathomechanisms of motor neuron hyperexcitability in ALS. Methods Threshold tracking transcranial magnetic stimulation and multiple excitability measurements were performed in 130 healthy controls (HC), 83 sporadic ALS (sALS) patients, 11 patients with superoxide dismutase-1 (SOD-1) mutations, 16 C9orf72 hexanucleotide repeat expansions and 2 FUS mutations. Results Compared to HC, in peripheral nerve excitability sALS had greater strength-duration time constant (p 0.05), depolarizing threshold electrotonus (p 0.0001) and superexcitability (p 0.05) and smaller late subexcitability (p 0.05). In cortical excitability, sALS had reduced short interval intracortical inhibition (p 0.0001). These indices were not significantly different in SOD-1 and C9orf72, compared to sALS. Conclusion These findings suggest both sALS and familial ALS have increased sodium currents, decreased potassium currents, rendering to peripheral nerve hyperexcitability. In addition, all ALS patients demonstrated decreased intracortical inhibition. Significance Motor neuronal hyperexcitability may be a common feature in both sALS and familial ALS associated with different pathological bases.

Axonal ion channel dysfunction in c9orf72 familial amyotrophic lateral sclerosis.

Abnormalities of axonal excitability characterized by upregulation of persistent sodium (Na+) conductances and reduced potassium (K+) currents have been reported in sporadic amyotrophic lateral sclerosis (SALS) phenotypes and linked to the development of clinical features such as fasciculations and neurodegeneration. To investigate whether abnormalities of axonal ion channel function, particularly upregulation of persistent Na+ conductances and reduced K+ currents, form the pathophysiological basis of chromosome 9 open reading frame 72 (c9orf72) familial amyotrophic lateral sclerosis (FALS). This was a prospective study. Clinical and functional assessment, along with motor-nerve excitability studies, were undertaken in 10 clinically affected patients with c9orf72 FALS, 9 asymptomatic c9orf72 mutation carriers, and 21 patients with SALS from 3 hospitals and 2 outpatient clinics. Axonal excitability variables were measured in patients with c9orf72 ALS and results compared with matched patients with SALS and healthy control participants. Strength-duration time constant (τSD) was significantly increased in the patients with c9orf72 FALS and those with SALS (mean [SD], c9orf72 FALS: 0.50 [0.02] milliseconds; SALS: 0.52 [0.02] milliseconds; P < .01) when compared with control participants (mean [SD], 0.44 [0.01] milliseconds). In contrast, there were no significant changes of τSD in asymptomatic c9orf72 mutation carriers (P = .42). An accompanying increase in depolarizing threshold electrotonus at 90 to 100 milliseconds (TEd 90-100 milliseconds) was also evident in the c9orf72 FALS (P < .05) and SALS (P < .01) cohorts. Mathematical modeling suggested that an increase in persistent Na+ conductances, along with reduced K+ currents, best explained the changes in axonal excitability. Importantly, these abnormalities in axonal excitability correlated with the motor amplitude (τSD: R = -0.38, P < .05 and TEd 90-100 milliseconds: R = -0.44, P < .01), muscle weakness (TEd 90-100 milliseconds: R = -0.32, P < .05), and the ALS Functional Rating Scale (TEd 90-100 milliseconds: R = -0.34, P < .05). Findings from the present study establish that upregulation of persistent Na+ conductances and reduced K+ currents were evident in both c9orf72 FALS and SALS cohorts, and these changes in axonal excitability were associated with motor neuron degeneration.

Increased supernormality in patients with multiplet discharges: Evidence for a common pathophysiological mechanism behind multiplets and fasciculations

ObjectiveTo determine whether there is a relation between electrically evoked multiplet discharges (MDs) and motor axonal excitability properties. We hypothesized that electrically evoked MDs share their underlying pathophysiological mechanism with fasciculations. MethodsHigh-density surface EMG and motor nerve excitability recordings of the thenar muscles were performed in 22 patients with motor neuron disease (MND) in their differential diagnosis and who were referred for EMG examination. ResultsSupernormality (hyperexcitable phase following the refractory period) was significantly increased in patients with MDs (n=10) compared to patients without MDs (n=12) (25.5% vs 17.0%; p=0.02). Depolarizing threshold electrotonus differed significantly between both groups as well (TEdpeak, 76.6% vs 66.6%, p<0.01; TEd90-100ms, 51.7% vs 44.3%, p<0.01) ConclusionsOur findings imply that the same pathophysiological excitability changes are involved in generating MDs and fasciculations. Yet, MDs may be quantified more easily, and may be more specific for abnormal distal excitability than fasciculations, because fasciculations may originate along the motor axon as well as in the neuron cell body. SignificanceMDs are potentially useful as objective measure of increased distal axonal excitability at individual motor unit level and might complement clinical studies in MND.

P850: Electrophysiological pattern in GLUT1 deficiency syndrome (A275T mutation)

s of Poster Presentations / Clinical Neurophysiology 125, Supplement 1 (2014) S1–S339 S269 Figure 2. The relationship between muscle strength and transcranial stimulation motor evoked potential. Conclusions: There is the positive relation between the MEP amplitude and the muscle strength. So, the fixed quantity evaluation method using the statistical technique makes TCS-MEP reliable. And TCS-MEP may enhance us to remove tumors in central nervous system and at the same time preserve motor functions. Moreover this relation between MEP and muscle strength is useful for understanding the motor control system. P850 Electrophysiological pattern in GLUT1 deficiency syndrome (A275T mutation) C. Giliberto1, V. Sofia1, R. Barone2, R. Guerrini3, M. Zappia1 1University of Catania, Department G.F. Ingrassia, Section of Neurosciences, Catania, Italy; 2University of Catania, Pediatric Neurology, Department of Pediatrics, Catania, Italy; 3University of Florence, Pediatric Neurology, Unit and Laboratories, Children’s Hospital A. Meyer, Florence, Italy Question: Glucose transporter type 1 deficiency syndrome (GLUT1DS) is characterized by impaired glucose transport across the blood-brain barrier due to SLC2A1-gene mutation. GLUT1DS infancy onset shows epileptic encephalopathy, ataxia and microcephaly although paroxysmal exerciseinduced dyskinesia and epilepsy may also be observed. Exercise and recovery-induced modifications of GLUT4 and GLUT1 expression in human muscle have been reported.We describe clinical and electromyographyc correlates of a GLUT1DS patient with adult-onset of exercise-induced dystonia. Patients and methods: A 19 year old male with mild mental retardation presented with a two-year history of episodic stiffness in his calves and feet and painless flexion of the toes followed by leg weakness triggered by exertion and starvation and alleviated by rest and eating. His father had experienced exercise-induced leg dystonia at younger age. A heterozygous missense of mutation (c.823G>A; p.A275T) of SLC2A1 gene was found in the proband and his father.The proband underwent an electromyographyc study after voluntary contraction (5 minutes) to investigate muscle membrane excitability with the evaluation of compound muscle action potential (CMAP) amplitude. Results: The test disclosed significant decrement of CMAP amplitude up to −42% (n.v.≤−20%) after 40 minutes from exercise with respect to the pre-exercise CMAP amplitude (baseline). The same test repeated after carbohydrate-rich food intake showed a significant improvement of CMAP from baseline (−26%). Conclusions: The electrophysiological study after exercise showed a reduction of CMAP amplitude in this patient with GLUT1DS (A275T mutation). Our data suggest a possible involvement of muscle membrane excitability in GLUT1DS. P851 Tracking the spatiotemporal profile of cortical and peripheral motor axon hyperexcitability in amyotrophic lateral sclerosis E. Bakola1, P. Kokotis1, R. Carr2, M. Schmelz2, M. Rentzos1, T. Zambelis1, N. Karandreas1 1University of Athens, Medical School, Department of Neurology, Athens, Greece; 2University of Heidelberg, Mannheim Medical School, Department of Anesthesiology, Mannheim, Germany Question: Recent studies using magnetic and electrical excitability tracking tools have confirmed early hyperexcitability in ALS. This study sets out to use excitability testing to examine directly the spatiotemporal profile of cortical and peripheral hyperexcitability in ALS patients simultaneously, to associate these parameters to the clinical course of the disease and to compare them with healthy controls. Methods: Nineteen patients with first-diagnosed definite ALS (group A), four patients with advanced disease (group B) and ten control healthy volunteers (group C) were included in the study. Multiple axonal excitability properties (threshold electrotonus, strength-duration time constant, recovery cycle, current-threshold relationship) and TMS investigations including measurement of resting motor threshold (RMT) and motor evoked potential (MEP) were measured. Results: In group A there were greater changes in depolarizing threshold electrotonus (TD) compared with group B (t-test p<0.03). No differences in recovery cycle, strength-duration time constant, current-threshold relationship were noted between the three groups. Regarding the cortical excitability parameters, there was a significant decrease in the slope of MEP amplitude to TMS intensity in group B with the advanced disease in comparison to controls (Mann-Whitney U test p<0.05). ANCOVA showed strong correlation between TD and slope of cortical excitability (p<0.01) after correcting for the status of the disease (groups A,B,C). Conclusions: These are preliminary results of an ongoing study trying to understand the changes in axonal and cortical excitability in first-diagnosed and advanced disease in order to provide insight into the pathophysiological basis of the disease and furthermore provide useful information for the best treatment approach in the future.

7. Effects of fampridine PR on axonal function in multiple sclerosis

Fampridine PR (prolonged-release 4-aminopyridine tablets) is a treatment for walking disability in multiple sclerosis (MS). While 4-aminopyridine is known to block kV 1.1 potassium channels in vitro, the mechanisms underlying its beneficial effects in the clinical setting have not been investigated. The aim of the present study was to investigate the effects of fampridine on axonal function in an MS cohort. Studies were conducted on 13 MS patients and 29 aged-matched controls. Studies were conducted at baseline and 6 weeks following the commencement of fampridine PR 10 mg b.d. Axonal function was assessed using nerve excitability techniques, which provide information on axonal ion channel function and membrane potential. Neurophysiological parameters were correlated with clinical measures of functional ability, namely hand grip dynamometry, 9-hole peg test, timed 25 foot walk and through questionnaires assessing aspects of upper and lower limb function. There were prominent alterations in nerve excitability parameters noted in baseline recordings in MS patients compared to age-matched controls. Specifically there were reductions in depolarizing threshold electrotonus at 40–60 ms and 90–100 ms ( p = 0.007 and p < 0.001 respectively). These changes were accompanied by reduced superexcitability ( p = 0.002). Following fampridine treatment these abnormalities became less prominent, with mean values approaching the normal range. Significant correlations were also noted between changes in nerve excitability parameters following fampridine treatment and measures of functional performance. Of note, changes in hyperpolarizing threshold electrotonus at the 90–100 ms correlated with changes in hand grip strength ( r = −0.615) and in subjective assessments of lower limb function using the ABILOCO questionnaire ( r = 0.587). The study has demonstrated baseline alterations in nerve excitability parameters in MS patients, which improve following fampridine PR treatment. Furthermore, the study has demonstrated that there are significant correlations between changes in excitability and measures of functional performance and that these are detectable in measures of both upper and lower limb function.