ArticlesSensitivity and specificity of threshold tracking transcranial magnetic stimulation for diagnosis of amyotrophic lateral sclerosis: a prospective study
Introduction
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and invariably fatal neurodegenerative disorder of the upper motor neurons (UMNs) and lower motor neurons (LMNs).1 Diagnosis of the disease relies on identification of concurrent UMN and LMN dysfunction, with the level of diagnostic certainty dependent on the extent of UMN and LMN dysfunction.1, 2, 3 The clinically based ALS El Escorial criteria are deemed to be insensitive, particularly in early stages of the disease or for atypical phenotypes, potentially resulting in substantial diagnostic delays.4 Consequently, creation of adequate management strategies, including commencement of treatments such as riluzole, and recruitment into therapeutic trials, might be delayed, perhaps beyond the therapeutic time window.5
Despite rapidly evolving interest in ALS clinical trial methodology, the process of diagnosis remains complex. The first international workshop that aimed to reach a consensus on the definition of ALS diagnosis was held in El Escorial (Madrid, Spain) in 1990.6 Since then, many revisions and new approaches have appeared,2 including the most recent neurophysiologically based Awaji criteria.3 These criteria proposed that neurophysiological features of LMN dysfunction, as indicated by chronic neurogenic changes, fibrillation potentials or positive sharp waves, and fasciculations, were equivalent to clinical features of LMN dysfunction. Although the Awaji criteria had a higher sensitivity than the revised El Escorial criteria,7, 8, 9, 10, 11, 12, 13, 14 the diagnostic benefit seemed most prominent in patients with bulbar-onset disease.7 Additionally, the clinically probable laboratory-supported diagnostic category was abolished in the Awaji criteria, thereby necessitating identification of signs of UMN dysfunction in two regions to establish a diagnosis of ALS. In view of the difficulties with identification of UMN signs in ALS,15 the sensitivity of the Awaji criteria might be lower than that of the revised El Escorial criteria.11
The functional integrity of the UMN system in ALS can be objectively assessed by transcranial magnetic stimulation (TMS) techniques.16 Evidence from animal and human studies has established that TMS assesses UMN function, with neuronal activation mediated by specific ion channels and synaptic processes acting via different neurotransmitter systems.16, 17 One threshold tracking TMS technique18 that overcomes the motor-evoked potential (MEP) amplitude variability that is evident with conventional TMS techniques has established cortical hyperexcitability as a specific and early feature of ALS, differentiating the disease from mimic neuromuscular disorders.19 Importantly, cortical hyperexcitability has been postulated to progress to normal excitability or hypoexcitability during the course of the disease.16 Although diagnostic value of threshold tracking TMS was reported in one study,19 the testing was not done in accordance with the Standards for Reporting of Diagnostic Accuracy (STARD) and was limited to one centre. As such, generalisability of the results could not be definitively assessed.20 The aim of the present study was to establish diagnostic accuracy of the threshold tracking TMS technique in differentiation of ALS from mimic neuromuscular disorders. To avoid potential bias and ensure wide applicability of the findings, we recruited patients across three neuromuscular clinics in accordance with STARD criteria.
Section snippets
Study design and patients
In this prospective study, we recruited patients from three neuromuscular centres in Sydney, Australia. All patients underwent detailed clinical assessment and grading before enrolment, including electrodiagnostic investigations. We recruited patients prospectively and consecutively in keeping with the inclusion criteria. The study population consisted of patients with suspected ALS, although none of the patients had been diagnosed with the disease before recruitment. Inclusion criteria were as
Results
Between Jan 1, 2010, and March 1, 2014, we screened 333 patients (206 men and 127 women; mean age 57·6 years [SD 14·6]), 281 (84%) of whom met the inclusion criteria and were therefore enrolled (figure 1). 209 patients were eventually diagnosed with ALS. Of these, we classified 109 (52%) as Awaji definite or probable and 46 (22%) as Awaji possible. 54 (26%) patients did not meet Awaji criteria at initial assessment, although most progressed during follow-up, leading to reclassification into the
Discussion
Our findings show that threshold tracking TMS reliably distinguishes ALS from non-ALS mimic disorders. Reduction of averaged SICI seemed to be the most robust diagnostic biomarker and, when combined with motor cortex inexcitability, showed high sensitivity and specificity, with the number needed to test with TMS to diagnose one extra case of ALS being only 1·8. Importantly, diagnostic utility of threshold tracking TMS was similar between Awaji diagnostic categories and patients with
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