WASHINGTON, DC—A novel threshold tracking transcranial magnetic stimulation (TMS) technique reliably distinguishes between amyotrophic lateral sclerosis (ALS) and non-ALS disorders, according to research presented at the 67th Annual Meeting of the American Academy of Neurology. The technique may help neurologists identify upper motor neuron dysfunction at early stages of ALS, said Nimeshan Geevasinga, MBBS, a neurologist, neurophysiologist, and Clinical Lecturer at the University of Sydney. The study was published in the May issue of Lancet Neurology.
Nimeshan Geevasinga, MBBS
The diagnosis of ALS requires upper and lower motor neuron findings. While neurophysiologic features of lower motor neuron dysfunction are equivalent to clinical features, according to the Awaji criteria, the assessment of upper motor neuron dysfunction is based on clinical observation. “There are some difficulties in trying to get a definitive or probable diagnosis” of ALS if neurologists are unable to find upper motor neuron signs, said Dr. Geevasinga. Some patients with the underlying disease process never receive an Awaji probable or Awaji definite diagnosis.
The threshold tracking TMS technique potentially could assess upper motor neuron dysfunction. It uses a paired pulse to measure short-interval intracortical inhibition (SICI), a marker of cortical hyperexcitability, which research has identified as an early feature of ALS.
Awaji Criteria Used as Reference
To assess the sensitivity and specificity of the threshold tracking TMS technique, Dr. Geevasinga and his research colleagues conducted a prospective multicenter study in Sydney according to Standards for the Reporting of Diagnostic Accuracy Studies criteria. Researchers screened 333 patients (206 males, mean age 57.6) between January 1, 2010, and March 1, 2014, and 281 patients met the inclusion criteria. Researchers applied the Awaji criteria to differentiate participants with definite, probable, or possible ALS from those with neuromuscular disorders mimicking ALS. All participants underwent the threshold tracking TMS index test, and the researchers who conducted this test were masked to patients’ diagnoses.
Researchers diagnosed ALS in 209 patients and non-ALS disorders in 68 patients. The diagnosis was inconclusive for four patients. The threshold tracking TMS technique differentiated ALS from non-ALS disorders with a sensitivity of 73% and a specificity of 81%. Researchers assessed sensitivity and specificity using a cutoff of 5.5%. “When we looked at the early onset ALS patients who are categorized as Awaji possible, the findings were almost identical to those of patients who were Awaji probable or definite. So, this test is just as good early on in the disease process as it is later on,” said Dr. Geevasinga.
Detecting Cortical Hyperexcitability
The researchers found that SICI was the best diagnostic parameter of the markers of cortical hyperexcitability that they had studied, including motor evoked potential amplitude and cortical silent period, with an area under the curve of 0.8, Dr. Geevasinga said. “If you are getting patients who are scoring a 0 SICI, almost certainly these patients are going to have ALS,” he added. “There are very few other neuromuscular disorders that are going to cause that degree of cortical hyperexcitability.”
Diagnosing ALS sooner may help researchers find effective therapies, said Dr. Geevasinga. “By utilizing biomarkers of motor neuron dysfunction such as the TMS test, we can potentially recruit patients into clinical trials at an earlier stage,” he concluded.
—Jake Remaly