3. Diagnostic utility of threshold tracking TMS in ALS: Comparative study to Awaji criteria

Abstract

The diagnosis of amyotrophic lateral sclerosis (ALS) relies on identification of a combination of upper (UMN) and lower motor neuron (LMN) clinical features. Such clinical criteria have resulted in significant diagnostic delays, perhaps beyond the therapeutic window period. In order to improve the sensitivity of diagnostic criteria, recently the Awaji criteria have been developed whereby neurophysiological evidence of LMN dysfunction was equated with clinical features of LMN dysfunction. While these criteria appeared to increase the diagnostic sensitivity for ALS, the involvement of UMNs was not objectively assessed by the Awaji criteria. Given that cortical hyperexcitability, as reflected by the threshold tracking transcranial magnetic stimulation (TTTMS) technique, was an early feature in ALS, the present study assessed the diagnostic utility of TTTMS, when compared to Awaji criteria, in establishing of an earlier diagnosis of ALS. Prospective cortical excitability studies were undertaken on a cohort of 65 patients classified as either “possible” or “probable/definite” ALS based on the Awaji criteria. Short-interval intracortical inhibition (SICI) was significantly reduced in ALS patients (1.57 ± 1.1%) when compared controls (10.6 ± 0.8%, P < 0.0001). Importantly, there was a comparable reduction of SICI in the ALS cohorts compared to controls (SICI POSSIBLE ; −1.88 ± 1.75, P < 0.0001, SICI PROBABLE/DEFINITE 2.77 ± 1.58, P < 0.0001). In addition, the cortical silent period duration was significantly reduced in the ALS patients compared to controls (CSP POSSIBLE 160.1 ± 12, P = 0.001, CSP PROBABLE/DEFINITE 177.8 ± 7, P = 0.0001) in ALS. Of further relevance, the diagnostic accuracy of the TTMS technique was 80% compared to 60% for the Awaji criteria in the present ALS cohort. Cortical hyperexcitability appears to be an early diagnostic biomarker for ALS. The TTTMS techniques may prove useful as a diagnostic aid for establishing an earlier diagnosis of ALS.