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Matthew C. Kiernan - One of the best experts on this subject based on the ideXlab platform.

  • 036 Nerve Excitability and motor unit number estimation early biomarkers of Nerve involvement in hereditary amyloidosis attrv
    BMJ Neurology Open, 2021
    Co-Authors: Antonia S Carroll, Cindy S.-y. Lin, Steve Vucic, Susanna B Park, Neil G Simon, M M Reilly, Matthew C. Kiernan
    Abstract:

    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.

  • 8 predicting motor disorders from Nerve Excitability studies
    Clinical Neurophysiology, 2018
    Co-Authors: James Howells, Cindy S.-y. Lin, Matthew C. Kiernan, Nidhi Garg, Susanna B Park
    Abstract:

    Objective To investigate whether statistical models of Nerve Excitability study (NES) parameters are able to distinguish between motor disorders with overlapping clinical features. Methods 81 motor NES in median Nerve were undertaken in patients (55 males, mean age: 55.9 ± 13.1) with clinically diagnosed motor neuron disease (MND; N = 25), chronic inflammatory demyelinating polyneuropathy (CIDP; N = 32), multifocal motor neuropathy (MMN; N = 13) and Kennedy’s disease (KD; N = 11). Multinomial regression models were built using the Akaike information criterion (AIC) method to balance model complexity with goodness of fit and likelihood ratio tests to identify which NES output variables make the best predictive model. Results The final model was able to predict a patient’s diagnosis of MND (sensitivity 68%, specificity 87%), CIDP (sensitivity 77%, specificity 82%), MMN (sensitivity 88%, specificity 94%) and KD (sensitivity 41%, specificity 96%) incorporating the NES output variables of TEd undershoot, superExcitability (7 ms), subExcitability, stimulus threshold, latency and gender. Conclusions Motor NES profiles differ between motor disorders, enabling statistical modelling to separate different groups of patients with motor disorders. Significance Statistical modelling of NES data may aid clinicians in the differential diagnosis of motor disorders.

  • effects of hemodialysis on intraneural blood flow in end stage kidney disease
    Muscle & Nerve, 2018
    Co-Authors: Adeniyi Borire, Ria Arnold, Matthew C. Kiernan, Bruce A. Pussell, Natalie Kwai, Neil G Simon, Leo H Visser, Arun V. Krishnan
    Abstract:

    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<0.0001). Patients with detectable INBF had larger Nerves and more severe neuropathy (p<0.01). INBF parameters were significantly reduced after a session of dialysis (VSc: p<0.01; MPI: p<0.01). A significant relationship was found between interdialytic change in INBF and changes in Nerve Excitability. Discussion: Increased INBF is a potential marker for neuropathy severity in ESKD patients. This article is protected by copyright. All rights reserved.

  • Fampridine treatment and walking distance in multiple sclerosis: A randomised controlled trial.
    Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology, 2016
    Co-Authors: Hannah Pickering, Jenna Murray, Christine Cormack, Cindy S.-y. Lin, Matthew C. Kiernan, Andrew J. Martin, Arun V. Krishnan
    Abstract:

    Abstract 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.

  • Effect of fampridine on axonal Excitability in multiple sclerosis
    Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology, 2016
    Co-Authors: William Huynh, James Howells, Hannah Pickering, Jenna Murray, Christine Cormack, Cindy S.-y. Lin, Steve Vucic, Matthew C. Kiernan, Arun V. Krishnan
    Abstract:

    Abstract Objective 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. Methods Studies were performed at baseline and repeated 3months after institution of fampridine at standard dosing. Results 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%; p p p =0.02). Conclusion 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. Significance Modulation of fast K + conductances by fampridine may contribute to the improvement observed in MS symptoms including motor fatigue.

Hugh Bostock - One of the best experts on this subject based on the ideXlab platform.

  • axonal Excitability changes and acute symptoms of oxaliplatin treatment in vivo evidence for slowed sodium channel inactivation
    Clinical Neurophysiology, 2017
    Co-Authors: Rikke Heide, Hugh Bostock, Nanna B Finnerup, Lise Ventzel, Peter Grafe, Joseph Bergmans, Anders Fuglsangfrederiksen, Hatice Tankisi
    Abstract:

    OBJECTIVE: Neurotoxicity is the most frequent dose-limiting side effect of the anti-cancer agent oxaliplatin, but the mechanisms are not well understood. This study used Nerve Excitability testing to investigate the pathophysiology of the acute neurotoxicity. METHODS: Questionnaires, quantitative sensory tests, Nerve conduction studies and Nerve Excitability testing were undertaken in 12 patients with high-risk colorectal cancer treated with adjuvant oxaliplatin and in 16 sex- and age-matched healthy controls. Examinations were performed twice for patients: once within 3 days after oxaliplatin treatment (post-infusion examination) and once shortly before the following treatment (recovery examination). RESULTS: The most frequent post-infusion symptoms were tingling paresthesias and cold allodynia. The most prominent Nerve Excitability change was decreased superExcitability of motor axons which correlated with the average intensity of abnormal sensations (Spearman Rho = 0.80, p < .01). The motor Nerve Excitability changes were well modeled by a slowing of sodium channel inactivation, and were proportional to dose/m2 with a half-life of about 10d. CONCLUSIONS: Oxaliplatin induces reversible slowing of sodium channel inactivation in motor axons, and these changes are closely related to the reversible cold allodynia. However, further studies are required due to small sample size in this study. SIGNIFICANCE: Nerve Excitability data provide an index of sodium channel dysfunction: an objective biomarker of acute oxaliplatin neurotoxicity.

  • Altered motor Nerve Excitability in end-stage kidney disease
    2016
    Co-Authors: Richard K. S. Phoon, Bruce A. Pussell, John A. Charlesworth, Hugh Bostock
    Abstract:

    Although multiple toxins have been implicated in the development of uraemic neuropathy, no causative agent has been identified. In the present study, the Excitability properties of lower limbmotor Nerves in patients with end-stage kidney disease treated with haemodialysis were measured before, during and after a standard 5 h haemodialysis session, in an attempt to explore the pathophysiology of uraemic neuropathy. Compoundmuscle action potentials were recorded from tibialis anterior and extensor digitorum brevis, following stimulation of the common peroneal Nerve in 14 patients. Measures of Excitability were assessed in relation to changes in serum levels of potential neurotoxins, including potassium, calcium, urea, uric acid, parathyroid hormone and b-2-microglobulin. Before dialysis, measures of Nerve Excitability were significantly abnormal in the patient group for axons innervating tibialis anterior and extensor digitorum brevis, consistent with axonal depolarization: refractoriness was increased and superExcitability and depolarizing threshold electrotonus were reduced. Pre-dialysis Excitability abnormalities were strongly correlated with serum K+. Correlation was also noted between the severity of symptoms and Excitability abnormalities. Haemodialysis normalized the majority of Nerve Excitability parameters. In conclusion, lower limb motor axons in uraemic patients are depolarized before dialysis. The correlation between serum K+ and Excitability measures indicates that hyperkalaemia is primarily responsible for uraemic depolarization, and a likely contributing factor to th

  • Episodic ataxia type 1 without episodic ataxia: the diagnostic utility of Nerve Excitability studies in individuals with KCNA1 mutations
    Developmental medicine and child neurology, 2013
    Co-Authors: S. Veronica Tan, Elizabeth Wraige, Karine Lascelles, Hugh Bostock
    Abstract:

    Episodic ataxia type 1 (EA1) is caused by mutations in the KCNA1 gene encoding the fast potassium channel Kv1.1 and is characterized clinically by brief episodes of ataxia and continuous and spontaneous motor unit activity. Atypical presentations, in which the predominant manifestation is related to the peripheral nervous system, may lead to the diagnosis being missed or delayed, with the potential risk of individuals receiving inappropriate or unnecessary investigations and treatment. We present a case of a 15-year-old female with EA1 who had never had episodes of ataxia, and whose hand movements were initially thought to represent a tremor. Genetic screening for KCNA1 mutations was precipitated by the results of the Nerve Excitability studies (TROND protocol), which showed changes typical of reduced fast potassium channel conductance. This case highlights the utility of Nerve Excitability studies in identifying individuals with KCNA1 mutations.

  • in vivo loss of slow potassium channel activity in individuals with benign familial neonatal epilepsy in remission
    Brain, 2012
    Co-Authors: M.G. Hanna, Hugh Bostock, Susan E. Tomlinson, Matthew C. Kiernan, Bronwyn E Grinton, Dimitri M Kullmann, Ingrid E Scheffer, Samuel F Berkovic
    Abstract:

    Benign familial neonatal epilepsy is a neuronal channelopathy most commonly caused by mutations in KCNQ2 , which encodes the Kv7.2 subunit of the slow K+ channel. Kv7.2 is expressed in both central and peripheral nervous systems. Seizures occur in the neonatal period, often in clusters within the first few days of life, and usually remit by 12 months of age. The mechanism of involvement of Kv7.2 mutations in the process of seizure generation has not been established in vivo . In peripheral axons, Kv7.2 contributes to the nodal slow K+ current. The present study aimed to determine whether axonal Excitability studies could detect changes in peripheral Nerve function related to dysfunction or loss of slow potassium channel activity. Nerve Excitability studies were performed on eight adults with KCNQ2 mutations and a history of benign familial neonatal epilepsy, now in remission. Studies detected distinctive changes in peripheral Nerve, indicating a reduction in slow K+ current. Specifically, accommodation to long-lasting depolarizing currents was reduced in mutation carriers by 24% compared with normal controls, and the threshold undershoot after 100 ms depolarizing currents was reduced by 22%. Additional changes in Excitability included a reduction in the relative refractory period, an increase in superExcitability and a tendency towards reduced sub-Excitability. Modelling of the Nerve Excitability changes suggested that peripheral Nerve hyperExcitability may have been ameliorated by upregulation of other potassium channels. We conclude that subclinical dysfunction of Kv7.2 in peripheral axons can be reliably detected non-invasively in adulthood. Related alterations in neuronal Excitability may contribute to epilepsy associated with KCNQ2 mutations.

  • threshold dependent effects on peripheral Nerve in vivo Excitability properties in the rat
    Neuroscience Letters, 2010
    Co-Authors: Atsuko Mori, Hugh Bostock, Hiroyuki Nodera, Yoshiko Shibuta, Takahiro Okita, Ryuji Kaji
    Abstract:

    Various factors, including maturity, have been shown to influence peripheral Nerve Excitability measures, but little is known about differences in these properties between axons with different stimulation thresholds. Multiple Nerve Excitability tests were performed on the caudal motor axons of immature and mature female rats, recording from tail muscles at three target compound muscle action potential (CMAP) levels: 10%, 40% ("standard" level), and 60% of the maximum CMAP amplitude. Compared to lower target levels, axons at high target levels have the following characteristics: lower strength-duration time constant, less threshold reduction during depolarizing currents and greater threshold increase to hyperpolarizing currents, most notably to long hyperpolarizing currents in mature rats. Threshold-dependent effects on peripheral Nerve Excitability properties depend on the maturation stage, especially inward rectification (Ih), which becomes inversely related to threshold level. Performing Nerve Excitability tests at different target levels is useful in understanding the variation in membrane properties between different axons within a Nerve. Because of the threshold effects on Nerve Excitability and the possibility of increased variability between axons and altered electric recruitment order in disease conditions, Excitability parameters measured only at the "standard" target level should be interpreted with caution, especially the responses to hyperpolarizing currents.

Arun V. Krishnan - One of the best experts on this subject based on the ideXlab platform.

  • effect of exenatide on peripheral Nerve Excitability in type 2 diabetes
    Clinical Neurophysiology, 2021
    Co-Authors: Tushar Issar, Ria Arnold, Natalie Kwai, Ann M Poynten, Kerrylee Milner, Arun V. Krishnan
    Abstract:

    Abstract Objective To assess the effect of exenatide (a GLP-1 receptor agonist), dipeptidyl peptidase-IV (DPP-IV) inhibitors, and sodium-glucose co-transporter 2 (SGLT-2) inhibitors on measures of peripheral Nerve Excitability in patients with type 2 diabetes. Methods Patients receiving either exenatide (n = 32), a DPP-IV inhibitor (n = 31), or a SGLT-2 inhibitor (n = 27) underwent motor Nerve Excitability assessments. Groups were similar in age, sex, HbA1c, diabetes duration, lipids, and neuropathy severity. An additional 10 subjects were assessed prospectively over 3 months while oral anti-hyperglycaemic therapy was kept constant. A cohort of healthy controls (n = 32) were recruited for comparison. Results Patients receiving a DPP-IV or SGLT-2 inhibitor demonstrated abnormalities in peak threshold reduction, S2 accommodation, superExcitability, and subExcitability. In contrast, patients treated with exenatide were observed to have normal Nerve Excitability. In the prospective arm, exenatide therapy was associated with an improvement in Nerve function as patients demonstrated corrections in S2 accommodation, superExcitability, and subExcitability at follow-up. These changes were independent of the reductions in HbA1c following exenatide treatment. Conclusions Exenatide was associated with an improvement in measures of Nerve Excitability in patients with type 2 diabetes. Significance Exenatide may improve peripheral Nerve function in type 2 diabetes.

  • effects of hemodialysis on intraneural blood flow in end stage kidney disease
    Muscle & Nerve, 2018
    Co-Authors: Adeniyi Borire, Ria Arnold, Matthew C. Kiernan, Bruce A. Pussell, Natalie Kwai, Neil G Simon, Leo H Visser, Arun V. Krishnan
    Abstract:

    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<0.0001). Patients with detectable INBF had larger Nerves and more severe neuropathy (p<0.01). INBF parameters were significantly reduced after a session of dialysis (VSc: p<0.01; MPI: p<0.01). A significant relationship was found between interdialytic change in INBF and changes in Nerve Excitability. Discussion: Increased INBF is a potential marker for neuropathy severity in ESKD patients. This article is protected by copyright. All rights reserved.

  • Fampridine treatment and walking distance in multiple sclerosis: A randomised controlled trial.
    Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology, 2016
    Co-Authors: Hannah Pickering, Jenna Murray, Christine Cormack, Cindy S.-y. Lin, Matthew C. Kiernan, Andrew J. Martin, Arun V. Krishnan
    Abstract:

    Abstract 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.

  • Effect of fampridine on axonal Excitability in multiple sclerosis
    Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology, 2016
    Co-Authors: William Huynh, James Howells, Hannah Pickering, Jenna Murray, Christine Cormack, Cindy S.-y. Lin, Steve Vucic, Matthew C. Kiernan, Arun V. Krishnan
    Abstract:

    Abstract Objective 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. Methods Studies were performed at baseline and repeated 3months after institution of fampridine at standard dosing. Results 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%; p p p =0.02). Conclusion 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. Significance Modulation of fast K + conductances by fampridine may contribute to the improvement observed in MS symptoms including motor fatigue.

  • 14 haemodialysis alters Nerve morphology in chronic kidney disease
    Clinical Neurophysiology, 2016
    Co-Authors: Adeniyi Borire, Ria Arnold, Arun V. Krishnan
    Abstract:

    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.

Susan E. Tomlinson - One of the best experts on this subject based on the ideXlab platform.

  • In vivo assessment of neurological channelopathies: Application of peripheral Nerve Excitability studies.
    Neuropharmacology, 2017
    Co-Authors: Susan E. Tomlinson, James Howells, David Burke
    Abstract:

    With the rapid evolution of understanding of neurological channelopathies comes a need for sensitive tools to evaluate patients in clinical practice. Neurological channelopathies with a single-gene basis can manifest as seizures, headache, ataxia, vertigo, confusion, weakness and neuropathic pain and it is likely that other genetic factors contribute to the phenotype of many of these disorders. Ion channel dysfunction can result in abnormal cell membrane Excitability but utilisation of advanced neurophysiology techniques has lagged behind developments in clinical, genetic and imaging evaluation of channelopathies. However, momentum in the application of in vivo axonal Excitability testing sees these tests emerging as valuable tools, with the capacity to provide sensitive and specific insights into the mechanism of disease. While single-channel function cannot be directly measured in vivo, evaluation of subjects with single-gene channelopathies has provided insights into the effects of mutation-related alterations of membrane Excitability, as well as compensatory adaptive changes. By showing how ion channel dysfunction can affect axonal Excitability in vivo, studies of the Excitability of peripheral Nerve axons complement in vitro analysis of single channel activity. The interpretation of results is enhanced by mathematical modelling of axonal function and insights provided by in vitro work. This article is part of the Special Issue entitled 'Channelopathies.'

  • in vivo loss of slow potassium channel activity in individuals with benign familial neonatal epilepsy in remission
    Brain, 2012
    Co-Authors: M.G. Hanna, Hugh Bostock, Susan E. Tomlinson, Matthew C. Kiernan, Bronwyn E Grinton, Dimitri M Kullmann, Ingrid E Scheffer, Samuel F Berkovic
    Abstract:

    Benign familial neonatal epilepsy is a neuronal channelopathy most commonly caused by mutations in KCNQ2 , which encodes the Kv7.2 subunit of the slow K+ channel. Kv7.2 is expressed in both central and peripheral nervous systems. Seizures occur in the neonatal period, often in clusters within the first few days of life, and usually remit by 12 months of age. The mechanism of involvement of Kv7.2 mutations in the process of seizure generation has not been established in vivo . In peripheral axons, Kv7.2 contributes to the nodal slow K+ current. The present study aimed to determine whether axonal Excitability studies could detect changes in peripheral Nerve function related to dysfunction or loss of slow potassium channel activity. Nerve Excitability studies were performed on eight adults with KCNQ2 mutations and a history of benign familial neonatal epilepsy, now in remission. Studies detected distinctive changes in peripheral Nerve, indicating a reduction in slow K+ current. Specifically, accommodation to long-lasting depolarizing currents was reduced in mutation carriers by 24% compared with normal controls, and the threshold undershoot after 100 ms depolarizing currents was reduced by 22%. Additional changes in Excitability included a reduction in the relative refractory period, an increase in superExcitability and a tendency towards reduced sub-Excitability. Modelling of the Nerve Excitability changes suggested that peripheral Nerve hyperExcitability may have been ameliorated by upregulation of other potassium channels. We conclude that subclinical dysfunction of Kv7.2 in peripheral axons can be reliably detected non-invasively in adulthood. Related alterations in neuronal Excitability may contribute to epilepsy associated with KCNQ2 mutations.

  • in vivo assessment of hcn channel current i h in human motor axons
    Muscle & Nerve, 2009
    Co-Authors: David Burke, Susan E. Tomlinson, Martin Koltzenburg, Hugh Bostock
    Abstract:

    The "Trond" protocol of Nerve Excitability tests has been used widely to assess axonal function in peripheral Nerve. In this study, the routine Trond protocol was expanded to refine assessment of cAMP-dependent, hyperpolarization-activated current (I(h)) activity. I(h) activity is generated by hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channels in response to hyperpolarization. It limits activity-dependent hyperpolarization, contributes to neuronal automaticity, and is implicated in chronic pain states. Published data regarding I(h) activity in motor Nerve are scant. We used additional strong, prolonged hyperpolarizing conditioning stimuli in the threshold electrotonus component of the Trond protocol to demonstrate the time-course of activation of I(h) in motor axons. Fifteen healthy volunteers were tested on four occasions during 1 week. I(h) action was revealed in the threshold electrotonus by the limiting and often reversal, after about 100 ms, of the threshold increase caused by strong hyperpolarizing currents. Statistical analysis by repeated-measures analysis of variance enabled confidence limits to be established for variation between subjects and within subjects. The results demonstrate that, of all the Excitability parameters, those dependent on I(h) were the most characteristic of an individual, because variance between subjects was more than four times the variance within subjects. This study demonstrates a reliable method for in vivo assessment of I(h,) and also serves to document the normal variability in Nerve Excitability properties within subjects.

Cindy S.-y. Lin - One of the best experts on this subject based on the ideXlab platform.

  • 036 Nerve Excitability and motor unit number estimation early biomarkers of Nerve involvement in hereditary amyloidosis attrv
    BMJ Neurology Open, 2021
    Co-Authors: Antonia S Carroll, Cindy S.-y. Lin, Steve Vucic, Susanna B Park, Neil G Simon, M M Reilly, Matthew C. Kiernan
    Abstract:

    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.

  • 8 predicting motor disorders from Nerve Excitability studies
    Clinical Neurophysiology, 2018
    Co-Authors: James Howells, Cindy S.-y. Lin, Matthew C. Kiernan, Nidhi Garg, Susanna B Park
    Abstract:

    Objective To investigate whether statistical models of Nerve Excitability study (NES) parameters are able to distinguish between motor disorders with overlapping clinical features. Methods 81 motor NES in median Nerve were undertaken in patients (55 males, mean age: 55.9 ± 13.1) with clinically diagnosed motor neuron disease (MND; N = 25), chronic inflammatory demyelinating polyneuropathy (CIDP; N = 32), multifocal motor neuropathy (MMN; N = 13) and Kennedy’s disease (KD; N = 11). Multinomial regression models were built using the Akaike information criterion (AIC) method to balance model complexity with goodness of fit and likelihood ratio tests to identify which NES output variables make the best predictive model. Results The final model was able to predict a patient’s diagnosis of MND (sensitivity 68%, specificity 87%), CIDP (sensitivity 77%, specificity 82%), MMN (sensitivity 88%, specificity 94%) and KD (sensitivity 41%, specificity 96%) incorporating the NES output variables of TEd undershoot, superExcitability (7 ms), subExcitability, stimulus threshold, latency and gender. Conclusions Motor NES profiles differ between motor disorders, enabling statistical modelling to separate different groups of patients with motor disorders. Significance Statistical modelling of NES data may aid clinicians in the differential diagnosis of motor disorders.

  • Fampridine treatment and walking distance in multiple sclerosis: A randomised controlled trial.
    Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology, 2016
    Co-Authors: Hannah Pickering, Jenna Murray, Christine Cormack, Cindy S.-y. Lin, Matthew C. Kiernan, Andrew J. Martin, Arun V. Krishnan
    Abstract:

    Abstract 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.

  • Effect of fampridine on axonal Excitability in multiple sclerosis
    Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology, 2016
    Co-Authors: William Huynh, James Howells, Hannah Pickering, Jenna Murray, Christine Cormack, Cindy S.-y. Lin, Steve Vucic, Matthew C. Kiernan, Arun V. Krishnan
    Abstract:

    Abstract Objective 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. Methods Studies were performed at baseline and repeated 3months after institution of fampridine at standard dosing. Results 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%; p p p =0.02). Conclusion 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. Significance Modulation of fast K + conductances by fampridine may contribute to the improvement observed in MS symptoms including motor fatigue.

  • 7. Effects of fampridine PR on axonal function in multiple sclerosis
    Clinical Neurophysiology, 2014
    Co-Authors: Hannah Pickering, Jenna Murray, Cindy S.-y. Lin, Matthew C. Kiernan, Arun V. Krishnan
    Abstract:

    Objective 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. Methods 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. Results 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 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). Conclusions 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.