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10. Effects of mexiletine on hyperexcitability in sporadic amyotrophic lateral sclerosis: Preliminary findings from a small phase II randomized controlled trial

Author

Weiss, Michael D, Macklin, Eric A, McIlduff, Courtney E, Vucic, Steve, Wainger, Brian J, Kiernan, Matthew C, Goutman, Stephen A, Goyal, Namita A, Rutkove, Seward B, Ladha, Shafeeq S, Chen, I‐Hweii Amy, Harms, Matthew B, Brannagan, Thomas H, Lacomis, David, Zivkovic, Sasha, Ma, Maxwell, Wang, Leo H, Simmons, Zachary, Rivner, Michael H, Shefner, Jeremy M, Cudkowicz, Merit E, Atassi, Nazem, and Group, for the Mexiletine‐2 ALS Study

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Brain Disorders, Rare Diseases, Neurodegenerative, Clinical Research, ALS, Neurosciences, Clinical Trials and Supportive Activities, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Neurological, Adult, Aged, Amyotrophic Lateral Sclerosis, Axons, Cortical Excitability, Double-Blind Method, Electrodiagnosis, Electromyography, Evoked Potentials, Motor, Female, Humans, Male, Median Nerve, Mexiletine, Middle Aged, Neural Conduction, Preliminary Data, Transcranial Magnetic Stimulation, Voltage-Gated Sodium Channel Blockers, amyotrophic lateral sclerosis, axonal excitability, outcome research, randomized controlled clinical trial, transcranial magnetic stimulation, Mexiletine-2 ALS Study Group, Medical and Health Sciences, Neurology & Neurosurgery, Biological sciences, Biomedical and clinical sciences
Abstract

BackgroundTo 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.MethodsTwenty ALS subjects were randomized to placebo and mexiletine 300 or 600 mg daily for 4 wk and assessed by transcranial magnetic stimulation and axonal excitability studies. The primary endpoint was change in resting motor threshold (RMT).ResultsRMT was unchanged with 4 wk of mexiletine (combined active therapies) as compared to placebo, which showed a significant increase (P = .039). Reductions of motor evoked potential (MEP) amplitude (P = .013) and accommodation half-time (P = .002), secondary outcome measures of cortical and axonal excitability, respectively, were also evident at 4 wk on mexiletine.ConclusionsThe 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.

Published
2021

12. A deep intronic variant in MME causes autosomal recessive Charcot–Marie–Tooth neuropathy through aberrant splicing

Author

Grosz, Bianca R., primary, Parmar, Jevin M., additional, Ellis, Melina, additional, Bryen, Samantha, additional, Simons, Cas, additional, Reis, Andre L. M., additional, Stevanovski, Igor, additional, Deveson, Ira W., additional, Nicholson, Garth, additional, Laing, Nigel, additional, Wallis, Mathew, additional, Ravenscroft, Gianina, additional, Kumar, Kishore R., additional, Vucic, Steve, additional, and Kennerson, Marina L., additional

Published
2024
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14. Clinical diagnostic utility of transcranial magnetic stimulation in neurological disorders. Updated report of an IFCN committee

Author

Vucic, Steve, Stanley Chen, Kai-Hsiang, Kiernan, Matthew C., Hallett, Mark, Benninger, David.H., Di Lazzaro, Vincenzo, Rossini, Paolo M, Benussi, Alberto, Berardelli, Alfredo, Currà, Antonio, Krieg, Sandro M, Lefaucheur, Jean-Pascal, Long Lo, Yew, Macdonell, Richard A, Massimini, Marcello, Rosanova, Mario, Picht, Thomas, Stinear, Cathy M, Paulus, Walter, Ugawa, Yoshikazu, Ziemann, Ulf, and Chen, Robert

Published
2023
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23. Distinct neuronal circuits mediate cortical hyperexcitability in amyotrophic lateral sclerosis.

Author

Pavey, Nathan, Hannaford, Andrew, van den Bos, Mehdi, Kiernan, Matthew C, Menon, Parvathi, and Vucic, Steve

Subjects
AMYOTROPHIC lateral sclerosis, TRANSCRANIAL magnetic stimulation, INTERSTIMULUS interval, MOTOR cortex
Abstract

Cortical hyperexcitability is an important pathophysiological mechanism in amyotrophic lateral sclerosis (ALS), reflecting a complex interaction of inhibitory and facilitatory interneuronal processes that evolves in the degenerating brain. The advances in physiological techniques have made it possible to interrogate progressive changes in the motor cortex. Specifically, the direction of transcranial magnetic stimulation (TMS) stimulus within the primary motor cortex can be utilized to influence descending corticospinal volleys and to thereby provide information about distinct interneuronal circuits. Cortical motor function and cognition was assessed in 29 ALS patients with results compared to healthy volunteers. Cortical dysfunction was assessed using threshold-tracking TMS to explore alterations in short interval intracortical inhibition (SICI), short interval intracortical facilitation (SICF), the index of excitation and stimulus response curves using a figure-of-eight coil with the coil oriented relative to the primary motor cortex in a posterior-anterior, lateral-medial and anterior-posterior direction. Mean SICI, between interstimulus interval of 1–7 ms, was significantly reduced in ALS patients compared to healthy controls when assessed with the coil oriented in posterior-anterior (P = 0.044) and lateral-medial (P = 0.005) but not the anterior-posterior (P = 0.08) directions. A significant correlation between mean SICI oriented in a posterior-anterior direction and the total Edinburgh Cognitive and Behavioural ALS Screen score (Rho = 0.389, P = 0.037) was evident. In addition, the mean SICF, between interstimulus interval 1–5 ms, was significantly increased in ALS patients when recorded with TMS coil oriented in posterior-anterior (P = 0.035) and lateral-medial (P < 0.001) directions. In contrast, SICF recorded with TMS coil oriented in the anterior-posterior direction was comparable between ALS and controls (P = 0.482). The index of excitation was significantly increased in ALS patients when recorded with the TMS coil oriented in posterior-anterior (P = 0.041) and lateral-medial (P = 0.003) directions. In ALS patients, a significant increase in the stimulus response curve gradient was evident compared to controls when recorded with TMS coil oriented in posterior-anterior (P < 0.001), lateral-medial (P < 0.001) and anterior-posterior (P = 0.002) directions. The present study has established that dysfunction of distinct interneuronal circuits mediates the development of cortical hyperexcitability in ALS. Specifically, complex interplay between inhibitory circuits and facilitatory interneuronal populations, that are preferentially activated by stimulation in posterior-to-anterior or lateral-to-medial directions, promotes cortical hyperexcitability in ALS. Mechanisms that underlie dysfunction of these specific cortical neuronal circuits will enhance understanding of the pathophysiological processes in ALS, with the potential to uncover focussed therapeutic targets. [ABSTRACT FROM AUTHOR]

Published
2024
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24. Reduction in short interval intracortical inhibition from the early stage reflects the pathophysiology in amyotrophic lateral sclerosis: A meta‐analysis study.

Author

Higashihara, Mana, Pavey, Nathan, Menon, Parvathi, van den Bos, Mehdi, Shibuya, Kazumoto, Kuwabara, Satoshi, Kiernan, Matthew C., Koinuma, Masayoshi, and Vucic, Steve

Subjects
AMYOTROPHIC lateral sclerosis, TRANSCRANIAL magnetic stimulation, EVOKED potentials (Electrophysiology), INTERSTIMULUS interval, PATHOLOGICAL physiology, RILUZOLE
Abstract

Background and purpose: Cortical hyperexcitability has been identified as a diagnostic and pathogenic biomarker of amyotrophic lateral sclerosis (ALS). Cortical excitability is assessed by transcranial magnetic stimulation (TMS), a non‐invasive neurophysiological technique. The TMS biomarkers exhibiting highest sensitivity for cortical hyperexcitability in ALS remain to be elucidated. A meta‐analysis was performed to determine the TMS biomarkers exhibiting the highest sensitivity for cortical hyperexcitability in ALS. Methods: A systematic literature review was conducted of all relevant studies published in the English language by searching PubMed, MEDLINE, Embase and Scopus electronic databases from 1 January 2006 to 28 February 2023. Inclusion criteria included studies reporting the utility of threshold tracking TMS (serial ascending method) in ALS and controls. Results: In total, more than 2500 participants, incorporating 1530 ALS patients and 1102 controls (healthy, 907; neuromuscular, 195) were assessed with threshold tracking TMS across 25 studies. Significant reduction of mean short interval intracortical inhibition (interstimulus interval 1–7 ms) exhibited the highest standardized mean difference with moderate heterogeneity (−0.994, 95% confidence interval −1.12 to −0.873, p < 0.001; Q = 38.61, p < 0.05; I2 = 40%). The reduction of cortical silent period duration along with an increase in motor evoked potential amplitude and intracortical facilitation also exhibited significant, albeit smaller, standardized mean differences. Conclusion: This large meta‐analysis study disclosed that mean short interval intracortical inhibition reduction exhibited the highest sensitivity for cortical hyperexcitability in ALS. Combined findings from this meta‐analysis suggest that research strategies aimed at understanding the cause of inhibitory interneuronal circuit dysfunction could enhance understanding of ALS pathogenesis. [ABSTRACT FROM AUTHOR]

Published
2024
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25. Serum neurofilament light chain in hereditary transthyretin amyloidosis: validation in real-life practice.

Author

Carroll, Antonia S., Razvi, Yousuf, O'Donnell, Luke, Veleva, Elena, Heslegrave, Amanda, Zetterberg, Henrik, Vucic, Steve, Kiernan, Matthew C., Rossor, Alexander M., Gillmore, Julian D., and Reilly, Mary M.

Subjects
TRANSTHYRETIN, CYTOPLASMIC filaments, AMYLOIDOSIS, GENE conversion, ASYMPTOMATIC patients
Abstract

Neurofilament light chain (NfL) has emerged as a sensitive biomarker in hereditary transthyretin amyloid polyneuropathy (ATTRv-PN). We hypothesise that NfL can identify conversion of gene carriers to symptomatic disease, and guide treatment approaches. Serum NfL concentration was measured longitudinally (2015–2022) in 59 presymptomatic and symptomatic ATTR variant carriers. Correlations between NfL and demographics, biochemistry and staging scores were performed as well as longitudinal changes pre- and post-treatment, and in asymptomatic and symptomatic cohorts. Receiver-operating analyses were performed to determine cut-off values. NfL levels correlated with examination scores (CMTNS, NIS and MRC; all p <.01) and increased with disease severity (PND and FAP; all p <.05). NfL was higher in symptomatic and sensorimotor converters, than asymptomatic or sensory converters irrespective of time (all p <.001). Symptomatic or sensorimotor converters were discriminated from asymptomatic patients by NfL concentrations >64.5 pg/ml (sensitivity= 91.9%, specificity = 88.5%), whereas asymptomatic patients could only be discriminated from sensory or sensorimotor converters or symptomatic individuals by a NfL concentration >88.9 pg/ml (sensitivity = 62.9%, specificity = 96.2%) However, an NfL increment of 17% over 6 months could discriminate asymptomatic from sensory or sensorimotor converters (sensitivity = 88.9%, specificity = 80.0%). NfL reduced with treatment by 36%/year and correlated with TTR suppression (r = 0.64, p =.008). This data validates the use of serum NfL to identify conversion to symptomatic disease in ATTRv-PN. NfL levels can guide assessment of disease progression and response to therapies. [ABSTRACT FROM AUTHOR]

Published
2024
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34. Measurement of axonal excitability: Consensus guidelines

Author

Kiernan, Matthew C., Bostock, Hugh, Park, Susanna B., Kaji, Ryuji, Krarup, Christian, Krishnan, Arun V., Kuwabara, Satoshi, Lin, Cindy Shin-Yi, Misawa, Sonoko, Moldovan, Mihai, Sung, Jiaying, Vucic, Steve, Wainger, Brian J., Waxman, Stephen, and Burke, David

Published
2020
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39. The clinical profile of NMOSD in Australia and New Zealand

Author

Bukhari, Wajih, Clarke, Laura, O’Gorman, Cullen, Khalilidehkordi, Elham, Arnett, Simon, Prain, Kerri M., Woodhall, Mark, Silvestrini, Roger, Bundell, Christine S., Ramanathan, Sudarshini, Abernethy, David, Bhuta, Sandeep, Blum, Stefan, Boggild, Mike, Boundy, Karyn, Brew, Bruce J., Brownlee, Wallace, Butzkueven, Helmut, Carroll, William M., Chen, Celia, Coulthard, Alan, Dale, Russell C., Das, Chandi, Dear, Keith, Fabis-Pedrini, Marzena J., Fulcher, David, Gillis, David, Hawke, Simon, Heard, Robert, Henderson, Andrew P. D., Heshmat, Saman, Hodgkinson, Suzanne, Jimenez-Sanchez, Sofia, Kilpatrick, Trevor J., King, John, Kneebone, Chris, Kornberg, Andrew J., Lechner-Scott, Jeannette, Lin, Ming-Wei, Lynch, Christopher, Macdonnell, Richard A. L., Mason, Deborah F., McCombe, Pamela A., Pereira, Jennifer, Pollard, John D., Reddel, Stephen W., Shaw, Cameron, Spies, Judith, Stankovich, James, Sutton, Ian, Vucic, Steve, Walsh, Michael, Wong, Richard C., Yiu, Eppie M., Barnett, Michael H., Kermode, Allan G., Marriott, Mark P., Parratt, John, Slee, Mark, Taylor, Bruce V., Willoughby, Ernest, Wilson, Robert J., Brilot, Fabienne, Vincent, Angela, Waters, Patrick, and Broadley, Simon A.

Published
2020
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41. Incidence of pregnancy and disease-modifying therapy exposure trends in women with multiple sclerosis: A contemporary cohort study

Author

Nguyen, Ai-Lan, Havrdova, Eva Kubala, Horakova, Dana, Izquierdo, Guillermo, Kalincik, Tomas, van der Walt, Anneke, Terzi, Murat, Alroughani, Raed, Duquette, Pierre, Girard, Marc, Prat, Alexandre, Boz, Cavit, Sola, Patrizia, Ferraro, Diana, Lugaresi, Alessandra, Lechner-Scott, Jeannette, Barnett, Michael, Grand'Maison, Francois, Grammond, Pierre, Ramo-Tello, Cristina, Turkoglu, Recai, McCombe, Pamela, Pucci, Eugenio, Trojano, Maria, Granella, Franco, Spitaleri, Daniele, Van Pesch, Vincent, Soysal, Aysun, Oreja-Guevara, Celia, Verheul, Freek, Vucic, Steve, Hodgkinson, Suzanne, Slee, Mark, Ampapa, Radek, Prevost, Julie, Menoyo, Jose Luis Sanchez, Skibina, Olga, Solaro, Claudio, Olascoaga, Javier, Shaw, Cameron, Madsen, Klaus Gregaard, Naidoo, Kerisha, Hyde, Robert, Butzkueven, Helmut, and Jokubaitis, Vilija

Published
2019
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50. Effect of Disease Modifying Therapy on Disability in Relapsing-Remitting Multiple Sclerosis Over 15 Years

Author

Kalincik, Tomas, Diouf, Ibrahima, Sharmin, Sifat, Malpas, Charles, Spelman, Tim, Horakova, Dana, Havrdova, Eva Kubala, Trojano, Maria, Izquierdo, Guillermo, Lugaresi, Alessandra, Prat, Alexandre, Girard, Marc, Duquette, Pierre, Grammond, Pierre, Jokubaitis, Vilija, van der Walt, Anneke, GrandʼMaison, Francois, Sola, Patrizia, Ferraro, Diana, Shaygannejad, Vahid, Alroughani, Raed, Hupperts, Raymond, Terzi, Murat, Boz, Cavit, Lechner-Scott, Jeannette, Pucci, Eugenio, Van Pesch, Vincent, Granella, Franco, Bergamaschi, Roberto, Spitaleri, Daniele, Slee, Mark, Vucic, Steve, Ampapa, Radek, McCombe, Pamela, Ramo-Tello, Cristina, Prevost, Julie, Olascoaga, Javier, Cristiano, Edgardo, Barnett, Michael, Saladino, Maria Laura, Sanchez-Menoyo, Jose Luis, Hodgkinson, Suzanne, Rozsa, Csilla, Hughes, Stella, Moore, Fraser, Shaw, Cameron, Butler, Ernest, Skibina, Olga, Gray, Orla, Kermode, Allan, Csepany, Tunde, Singhal, Bhim, Shuey, Neil, Piroska, Imre, Taylor, Bruce, Simo, Magdolna, Sirbu, Carmen-Adella, Sas, Attila, and Butzkueven, Helmut

Published
2020
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