EMG represents the most important diagnostic test in ALS as it can confirm the presence of muscle weakness due to anterior horn cell loss and it can reveal LMN involvement in clinically silent segments. As such, following the Awaji criteria, neurophysiological evidence of LMN dysfunction has now equivalent weight to clinical manifestations. Nevertheless, although EMG is almost always performed to confirm the clinical suspicion in ALS patients, there is relatively little information about its prognostic role. For these reasons, we investigated the correlation between neurophysiological signs of active and chronic denervation with clinical features, progression rate, and survival in a large cohort of ALS patients. We analysed the role of these EMG parameters as AD can be considered a marker of an ongoing muscle damage and CD an indicator of previously occurred muscle injury.

We found that patients with higher spinal AD and CD values showed significantly lower MRC scores and higher LMN scores. The association between these EMG parameters and clinical signs of LMN involvement suggests that AD and CD can be not only reliable biomarkers of muscle weakness [11] but also good predictors of the burden of clinical LMN signs. Furthermore, results obtained from correlations of AD and CD with ALSFRS-R underline the importance of these EMG findings as markers of functional disability in ALS individuals.

We observed a more rapid disease progression, as measured by the ΔFS, in those subjects with higher AD scores, while no such phenomenon could be observed for CD, suggesting that only active denervation signs are a good predictor of disease progression. In literature, previous similar investigations have been performed. For example, one report [12] studied the correlation of denervation signs (both active and chronic) in bulbar, cervical and lumbosacral regions with the progression from mild to severe ALS forms and with the deterioration of daily life activities (based on loss of speech function, loss of upper limb function, and loss of walking ability). This report, analysing a cohort of 363 patients, found that active denervation findings (defined as fibrillation potentials or positive sharp waves) in the cervical-upper limb area were prognostic factors for progression from mild to severe disability. In another study on 31 ALS patients, a higher occurrence of multiple discharges at baseline appeared to correlate with greater decline of the ALSFRS-R score, although this was not statistically significant [18]. In this cohort, ALS patients with multiple discharges at baseline showed deterioration in the fine motor function ALSFRS-R sub scores (items 4 and 5) between visits 10 weeks apart, while stability was observed in individuals without this EMG finding. Another report evaluated the relationship between high-density motor unit number estimation (MUNE) and ALSFRS-R in monitoring disease progression [19]. Patients classified as rapid progressors according to the decrement in MUNE at 4-month follow-up showed significantly lower ALSFRS-R scores at 8-month follow-up. In that study, MUNE proved to be more sensitive to motor neuron loss early in the disease course when compared to other clinical measures.

AD and CD were also directly correlated with MITOS and KSS, supporting the role of EMG parameters as markers of disease stage. Moreover, with regard to results obtained from survival analysis, we found an inverse correlation with AD, both in bulbar and spinal regions, indicating the importance of EMG as a prognostic instrument. Furthermore, our study underlined the major role of the presence of an ongoing active muscle damage (AD) in predicting survival if compared to the presence of previously remodelled motor units (CD). Indeed, notably, CD well correlates with ALS staging system scores and functional disability but is not associated with survival. Similarly, other previous studies analysed the role of EMG as a prognostic instrument.

A recent study of 92 patients calculated denervation values, considering for the score only sites that showed the contemporary presence of active and chronic denervation signs, for bulbar, cervical and lumbosacral regions. In this report higher general denervation scores (calculated summing the scores of the three body regions) and higher bulbar denervation scores were significantly associated with a reduced survival [11]. In another report of 103 patients, neurophysiological genioglossus involvement (defined by the contemporary presence of active and chronic denervation signs) at diagnosis was associated with reduced survival, a shorter time to moderate dysphagia and to severe dysarthria and it was a stronger prognostic factor than the presence of clinical bulbar lower motor neuron signs alone [12].

Our study has some limitations. Firstly, our cohort includes a relatively small number of patients at more advanced disease stages. Additionally, ours is a cross-sectional study and therefore longitudinal data on independent cohorts will be needed to assess evolution of EMG parameters over the course of the disease. The relatively low number of muscles studied does not allow to correlate specific EMG regional patterns with ALS phenotype and prognosis. We also did not routinely perform EMG of thoraco-abdominal muscles, and thus we cannot draw any association between neurophysiological parameters and respiratory function in our patients. Finally, the calculation of AD and CD scores was performed by a single neurophysiologist with experience in the field of motor neuron disease. As such, although the evaluator was blinded to clinical phenotype of ALS patients, it is not possible to determine the inter-rater reliability of AD and CD scores. Conversely, the EMG protocol adopted in our study is reproducible, being routinely used in a clinical setting at our ALS Clinic and generally well-tolerated by patients.

Our results confirm that EMG examination represents not only an essential diagnostic instrument, but also an important tool to better characterise phenotype, functional disability, disease progression and prognosis in ALS. Furthermore, we investigated the different role of AD, which in our work seems to be a reliable predictor of disease progression and survival, and CD, which conversely seems to better describe functional disability. Ours is the first study that describes all these correlations in a large cohort of patients, although longitudinal data on independent ALS populations will be needed to confirm these results.