Multimodal diagnostic tools in amyotrophic lateral sclerosis: insights from an illustrative case series

Abstract

Background: ALS is a neurodegenerative disorder with a broad phenotypic spectrum. Diagnosis is challenging in non-classical presentations or early in the disease course. Beyond electromyography, complementary tests may provide evidence of lower motor neuron (LMN) and upper motor neuron (UMN) dysfunction and help exclude mimics. These include: brain MRI, peripheral nerve ultrasound, serum neurofilament, and transcranial magnetic stimulation (TMS). Objective: To illustrate the contribution of complementary investigations—brain MRI, TMS, neuromuscular ultrasound, and neurofilament—to the diagnostic workup of ALS using real-world cases. Methods: Retrospective descriptions of patients with suspected ALS at tertiary neuromuscular centers. Representative cases were selected to highlight diagnostic tools utility. Results: Case 1: A 68-year-old woman with progressive right spastic hemiparesis and normal ENMG. Brain MRI showed left precentral gyrus atrophy and a left motor band sign; T2/FLAIR revealed bilateral asymmetric corticospinal tract hyperintensity, left-predominant. These findings corroborated the UMN degeneration, in a Mill’s variant ALS. Case 2: An 80-year-old woman with a progressive, mainly spastic, dysarthria and dysphagia, with a normal ENMG. Cranial MRI demonstrated a bright tongue sign on T1-weighted sequences, indicating fatty substitution due to LMN denervation, indicating a bulbar-onset ALS. Case 3: A 35-year-old man with cervical-onset symptoms exhibited UMN and LMN signs in all limbs, left-sided worst. Brachial plexus ultrasound showed marked reduction in nerve cross-sectional area on the left due to LMN involvement. The patient progressed to a Classical ALS. Case 4: A 39-year-old woman with progressive right-hand weakness and atrophy, signs restricted to LMN dysfunction. EMG showed chronic and acute denervation in cervical anterior horn distribution. Serum neurofilament light chain: 130.9 pg/mL (reference: 9.6), supporting active neuroaxonal degeneration. The patient progressed to a Classical ALS. Case 5: A 49-year-old man with a 10-year history of right spastic hemiparesis and global pyramidal signs. EMG and brain/spine MRI were unremarkable. TMS showed increased motor threshold and reduced short-interval intracortical inhibition (SICI) on the right, consistent with corticospinal dysfunction and cortical hyperexcitability. Conclusion: Conclusion: In these selected cases, complementary investigations provided convergent evidence supporting ALS-related UMN and/or LMN degeneration. Integrating these modalities may increase diagnostic confidence and reduce time to diagnosis, especially in cases with subtle UMN signs. These findings reflect real-world clinical practice and support the growing role of complementary tools in the diagnostic workup of ALS.