Enhancing Respiratory Assessment and Monitoring to Extend Survival in Amyotrophic Lateral Sclerosis.

Respiratory failure is the first cause of death in amyotrophic lateral sclerosis (ALS) and currently ventilatory support is the only available treatment for it. Respiratory monitoring is essential to start non-invasive ventilation (NIV) timely, enhancing quality of life and extending survival in ALS. Different pulmonary function tests (PFTs) are available for respiratory function monitoring, each one with specific strengths and limits. However, there is no consensus about the correct type of monitoring, so as the cut-off values that should be used to indicate NIV prescription. Based on this, we aimed at evaluating the sensitivity of different widely used PFTs, such as forced vital capacity (FVC), slow vital capacity (SVC), sniff nasal inspiratory pressure (SNIP) and peal cough flow (PCF), in monitoring respiratory function. For this aim we performed a longitudinal observational multi-centre study that assessed patterns of decline of different PFTs during disease course, based on various clinical and demographic characteristics, with specific focus on sex and type of onset. We demonstrated how pattern of decline is different between sexes and types of onset, with PCF and SNIP having a faster decline in females with bulbar onset, thus being particularly indicated for respiratory monitoring in this category of patients. We then explored the role of other less used tools in ALS, such as maximal voluntary ventilation (MVV) and serum chloride levels, as potential markers of respiratory failure and survival in ALS. For this aim, we studied the correlations of MVV and serum chloride levels with other respiratory measures and clinical variables in a large retrospective cohort of ALS patients included in the PARALS registry. We showed how both MVV and serum chloride levels at diagnosis can detect early respiratory impairment in ALS, being good predictors of survival and time to NIV initiation. Particularly, a reduction of MVV score at diagnosis could be an earlier marker of respiratory failure in ALS in comparison with FVC, being associated with a reduced endurance and increased fatigability. Additionally, since ALS is a clinical heterogeneous disease, based on both respiratory and clinical features, we aimed at identifying prognostic clusters of patients with different survivals and benefits from NIV. By performing a consensus cluster analysis, we identified five distinct clusters of patients, that could be useful in both clinical practice to stratify risk guiding decision making processes, and in clinical trials to identify prognostic categories of patients with different expected benefits from treatment. Finally, in the last part of our project we studied the prevalence of ventilatory support usage in the last years, including both NIV and tracheostomy, in a large retrospective study including ALS patients from PARALS registry, diagnosed from 2008 to 2015. We confirmed a positive trend in ventilatory support usage, in line with current guidelines indications. We also identified the clinical and demographic determinants influencing NIV prescription and survival after NIV initiation, helping clinicians in the decision of ventilatory support prescription, based on the expected benefit from it.