title: Sensitivity and specificity of threshold tracking transcranial magnetic stimulation for diagnosis of amyotrophic lateral sclerosis: a prospective study.
abstract: BACKGROUND
  Diagnosis of amyotrophic lateral sclerosis (ALS) remains problematic, with substantial diagnostic delays. We assessed the sensitivity and specificity of a threshold tracking transcranial magnetic stimulation (TMS) technique, which might allow early detection of upper motor neuron dysfunction, for the diagnosis of the disorder.
  
  
  METHODS
  We did a prospective study of patients referred to three neuromuscular centres in Sydney, Australia, in accordance with the Standards for Reporting of Diagnostic Accuracy. Participants had definite, probable, or possible ALS, as defined by the Awaji criteria; or pure motor disorder with clinical features of upper and lower motor neuron dysfunction in at least one body region, progressing over a 6 month follow-up period; or muscle wasting and weakness for at least 6 months. All patients underwent threshold tracking TMS at recruitment (index test), with application of the reference standard, the Awaji criteria, to differentiate patients with ALS from those with non-ALS disorders. The investigators who did the index test were masked to the results of the reference test and all other investigations. The primary outcome measures were the sensitivity and specificity of TMS in differentiating ALS from non-ALS disorders; these measures were derived from receiver operator curve analysis.
  
  
  RESULTS
  Between Jan 1, 2010, and March 1, 2014, we screened 333 patients; 281 met our inclusion criteria. We eventually diagnosed 209 patients with ALS and 68 with non-ALS disorders; the diagnosis of four patients was inconclusive. The threshold tracking TMS technique differentiated ALS from non-ALS disorders with a sensitivity of 73·21% (95% CI 66·66-79·08) and specificity of 80·88% (69·53-89·40) at an early stage in the disease. All patients tolerated the study well, and we did not record any adverse events from performance of the index test.
  
  
  CONCLUSIONS
  The threshold tracking TMS technique reliably distinguishes ALS from non-ALS disorders and, if these findings are replicated in larger studies, could represent a useful diagnostic investigation when combined with the Awaji criteria to prove upper motor neuron dysfunction at early stages of ALS.
  
  
  BACKGROUND
  Motor Neuron Disease Research Institute of Australia, National Health and Medical Research Council of Australia, and Pfizer.
authors.affiliation: Derek Craig Motor Neuron Disease Research Centre, Western Clinical School, University of Sydney, NSW, Australia.
authors.forename: Parvathi
authors.initials: P
authors.lastname: Menon
authors.affiliation: Derek Craig Motor Neuron Disease Research Centre, Western Clinical School, University of Sydney, NSW, Australia.
authors.forename: Nimeshan
authors.initials: N
authors.lastname: Geevasinga
authors.affiliation: Westmead Hospital, Westmead, Royal North Shore Hospital, University of Sydney, NSW, Australia.
authors.forename: Con
authors.initials: C
authors.lastname: Yiannikas
authors.affiliation: Brain and Mind Research Institute, Royal Prince Alfred Hospital, University of Sydney, NSW, Australia.
authors.forename: James
authors.initials: J
authors.lastname: Howells
authors.affiliation: Brain and Mind Research Institute, Royal Prince Alfred Hospital, University of Sydney, NSW, Australia.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Kiernan
authors.affiliation: Derek Craig Motor Neuron Disease Research Centre, Western Clinical School, University of Sydney, NSW, Australia; Department of Neurology, University of Sydney, NSW, Australia. Electronic address: steve.vucic@sydney.edu.au.
authors.forename: Steve
authors.initials: S
authors.lastname: Vucic
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis*; D002540:Cerebral Cortex / Q000503:physiopathology*; D005260:Female; D017408:Guidelines as Topic / Q000592:standards; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012372:ROC Curve; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D016037:Single-Blind Method; D050781:Transcranial Magnetic Stimulation / Q000592:standards*