Sensitivity and specificity of threshold tracking transcranial magnetic stimulation for diagnosis of amyotrophic lateral sclerosis: a prospective study

Menon, Parvathi; Geevasinga, Nimeshan; Yiannikas, Con; Howells, James; Kiernan, Matthew C.; Vucic, Steve

doi:10.1016/s1474-4422(15)00014-9

Cited by 178 publications

(173 citation statements)

References 31 publications

Supporting

Mentioning

163

Contrasting

Unclassified

Order By: Relevance

“…Increases in MEP amplitude, representing cortical hyperexcitability, appear to be an early feature in ALS, and correlate with surrogate biomarkers of axonal degeneration such as the strength duration time constant [87,89,97]. Importantly, this increase in the MEP amplitude is not evident in mimic disorders, despite a comparable degree of lower motor neuron dysfunction [5,100], thereby reaffirming the importance of excitotoxicity in ALS pathogenesis [88,100,110].…”

Section: Alsmentioning

confidence: 84%

“…Underscoring this are findings of suboptimal sensitivity of the Awaji criteria in limb-onset ALS, attributed to clinical assessment of UMN dysfunction [161]. The thresholdtracking TMS technique has identified cortical dysfunction as a robust and early diagnostic biomarker of upper motor neuron dysfunction in ALS [5]. Importantly, reduced SICI (< 5.5 %) reliably differentiated ALS from mimicking disorders (Fig.…”

Section: Diagnostic Implicationsmentioning

confidence: 98%

“…3A), which together are indicative of cortical hyperexcitability [85][86][87][88][89]. Importantly, features of cortical hyperexcitability, as heralded by reduced SICI, occur in the early stages of ALS, precede the clinical and neurophysiological onset of lower motor neuron dysfunction, and correlate with biomarkers of peripheral neurodegeneration [5,87,90].…”

Section: Alsmentioning

confidence: 99%

“…Given, however, that SICI changes were not evident ALS-mimicking disorders, despite a comparable peripheral disease burden [5,100], would argue against such a notion. Of relevance, the partial normalization of SICI with riluzole [101], an antiglutaminergic agent which exerts modest therapeutic benefits in ALS, lend further credence to the notion for a pathogenic role of cortical hyperexcitability in ALS.…”

Section: Alsmentioning

confidence: 99%

“…In amyotrophic lateral sclerosis (ALS), TMS techniques have provided vital information on cortical dysfunction, which has been of pathophysiological and diagnostic significance, resulting in an earlier diagnosis and identification of novel therapeutic targets [5]. It should be highlighted, however, that most clinical studies no longer just use the Bdefinite^criteria for diagnosing ALS and this should be considered when discussing the TMS as an early diagnostic biomarker for ALS.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Transcranial Magnetic Stimulation for the Assessment of Neurodegenerative Disease

Vucic

Kiernan

2017

Neurotherapeutics

Self Cite

View full text Add to dashboard Cite

Transcranial magnetic stimulation (TMS) is a noninvasive technique that has provided important information about cortical function across an array of neurodegenerative disorders, including Alzheimer's disease, frontotemporal dementia, Parkinson's disease, and related extrapyramidal disorders. Application of TMS techniques in neurodegenerative diseases has provided important pathophysiological insights, leading to the development of pathogenic and diagnostic biomarkers that could be used in the clinical setting and therapeutic trials. Abnormalities of TMS outcome measures heralding cortical hyperexcitability, as evidenced by a reduction of short-interval intracortical inhibition and increased in motorevoked potential amplitude, have been consistently identified as early and intrinsic features of amyotrophic lateral sclerosis (ALS), preceding and correlating with the ensuing neurodegeneration. Cortical hyperexcitability appears to form the pathogenic basis of ALS, mediated by trans-synaptic glutamate-mediated excitotoxic mechanisms. As a consequence of these research findings, TMS has been developed as a potential diagnostic biomarker, capable of identifying upper motor neuronal pathology, at earlier stages of the disease process, and thereby aiding in ALS diagnosis. Of further relevance, marked TMS abnormalities have been reported in other neurodegenerative diseases, which have varied from findings in ALS. With time and greater utilization by clinicians, TMS outcome measures may prove to be of utility in future therapeutic trial settings across the neurodegenerative disease spectrum, including the monitoring of neuroprotective, stem-cell, and genetic-based strategies, thereby enabling assessment of biological effectiveness at early stages of drug development.

show abstract

Section: Alsmentioning

confidence: 84%

Section: Diagnostic Implicationsmentioning

confidence: 98%

Section: Alsmentioning

confidence: 99%

Section: Alsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Transcranial Magnetic Stimulation for the Assessment of Neurodegenerative Disease

Vucic

Kiernan

2017

Neurotherapeutics

Self Cite

View full text Add to dashboard Cite

show abstract

Cortical Hyperexcitability in Amyotrophic Lateral Sclerosis

Wainger

Cudkowicz

2015

JAMA Neurol

View full text Add to dashboard Cite

Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis

et al. 2021

Self Cite

View full text Add to dashboard Cite

IMPORTANCE Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor nervous system. Clinical studies have demonstrated cortical and spinal motor neuron hyperexcitability using transcranial magnetic stimulation and threshold tracking nerve conduction studies, respectively, although metrics of excitability have not been used as pharmacodynamic biomarkers in multi-site clinical trials. OBJECTIVE To ascertain whether ezogabine decreases cortical and spinal motor neuron excitability in ALS. DESIGN, SETTING, AND PARTICIPANTSThis double-blind, placebo-controlled phase 2 randomized clinical trial sought consent from eligible participants from November 3, 2015, to November 9, 2017, and was conducted at 12 US sites within the Northeast ALS Consortium. Participants were randomized in equal numbers to a higher or lower dose of ezogabine or to an identical matched placebo, and they completed in-person visits at screening, baseline, week 6, and week 8 for clinical assessment and neurophysiological measurements. INTERVENTIONS Participants were randomized to receive 600 mg/d or 900 mg/d of ezogabine or a matched placebo for 10 weeks. MAIN OUTCOMES AND MEASURESThe primary outcome was change in short-interval intracortical inhibition (SICI; SICI −1 was used in analysis to reflect stronger inhibition from an increase in amplitude) from pretreatment mean at screening and baseline to the full-dose treatment mean at weeks 6 and 8. The secondary outcomes included levels of cortical motor neuron excitability (including resting motor threshold) measured by transcranial magnetic stimulation and spinal motor neuron excitability (including strength-duration time constant) measured by threshold tracking nerve conduction studies.RESULTS A total of 65 participants were randomized to placebo (23), 600 mg/d of ezogabine (23), and 900 mg/d of ezogabine (19 participants); 45 were men (69.2%) and the mean (SD) age was 58.3 (8.8) years. The SICI −1 increased by 53% (mean ratio, 1.53; 95% CI, 1.12-2.09; P = .009) in the 900-mg/d ezogabine group vs placebo group. The SICI −1 did not change in the 600-mg/d ezogabine group vs placebo group (mean ratio, 1.15; 95% CI, 0.87-1.52; P = .31). The resting motor threshold increased in the 600-mg/d ezogabine group vs placebo group (mean ratio, 4.61; 95% CI, 0.21-9.01; P = .04) but not in the 900-mg/d ezogabine group vs placebo group (mean ratio, 1.95; 95% CI, −2.64 to 6.54; P = .40). Ezogabine caused a dose-dependent decrease in excitability by several other metrics, including strength-duration time constant in the 900-mg/d ezogabine group vs placebo group (mean ratio, 0.73; 95% CI, 0.60 to 0.87; P < .001).CONCLUSIONS AND RELEVANCE Ezogabine decreased cortical and spinal motor neuron excitability in participants with ALS, suggesting that such neurophysiological metrics may be used as pharmacodynamic biomarkers in multisite clinical trials.

show abstract

Sensitivity and specificity of threshold tracking transcranial magnetic stimulation for diagnosis of amyotrophic lateral sclerosis: a prospective study

Cited by 178 publications

References 31 publications

Transcranial Magnetic Stimulation for the Assessment of Neurodegenerative Disease

Transcranial Magnetic Stimulation for the Assessment of Neurodegenerative Disease

Cortical Hyperexcitability in Amyotrophic Lateral Sclerosis

Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis

Contact Info

Product

Resources

About