Objective: Despite its clinical heterogeneity, amyotrophic lateral sclerosis is unified by early and prominent alterations in cortical excitability, increasingly recognized as contributors to disease progression. This study assessed whether the ratio between motor evoked potential (MEP) amplitude, reflecting upper motor neuron integrity, and compound muscle action potential (CMAP) amplitude, indexing lower motor neuron function, could provide an accessible marker of corticospinal excitability to stratify patients by phenotype, stage, and survival. Methods: In this multicenter retrospective study, 743 amyotrophic lateral sclerosis patients from 16 tertiary centers in Italy were analyzed. The MEP:CMAP ratio, recorded from upper limb muscles, was categorized as hyperexcitable, normal, or hypoexcitable. Phenotypes included progressive muscular atrophy (or lower motor neuron), flail arm/leg, classic, bulbar, patient with predominant upper motor neuron signs (or pyramidal), and primary lateral sclerosis. Disease stage was assessed using King's staging. Survival was analyzed using Kaplan–Meier curves and Cox regression models. Results: The MEP:CMAP ratio differed significantly across phenotypes ( p < 0.0001), with hyperexcitability predominating in lower motor neuron, flail, classic, and bulbar forms, and hypoexcitability in pyramidal and primary lateral sclerosis. Hypoexcitability increased in advanced King's stages ( p < 0.0001). Hyperexcitable patients had shorter survival ( p = 0.004), including when tested within 1 year of onset ( p = 0.006). Cox regression identified the MEP:CMAP ratio as an independent survival predictor (HR 1.84, 95% CI 1.12–3.03, p = 0.016). Interpretation: This real‐world study supports the clinical value of the MEP:CMAP ratio as a scalable biomarker of cortical excitability in amyotrophic lateral sclerosis, with prognostic relevance across phenotypes and disease stages. ANN NEUROL 2025;98:801–813

Neuromuscular diseases (NMDs) include a heterogeneous group of progressive chronic conditions that frequently lead to substantial physical disability and loss of autonomy. Although motor and functional impairments of NMDs are well documented, the psychological burden remains underexplored. This narrative review synthesizes current literature regarding four psychological domains in individuals with NMDs: (i) anxiety, (ii) depression, (iii) coping strategies, and (iv) quality of life. Evidence indicates that anxiety and depressive symptoms are highly prevalent in the spectrum of NMDs, influenced by factors such as disease severity, onset age, and perceived social support. Maladaptive coping strategies, including avoidance and denial, are associated with poorer mental health outcomes and reduced involvement in rehabilitation. In contrast, adaptive strategies, such as acceptance and problem-focused coping, may help buffer psychological distress. Quality of life is consistently reported to be lower in people with NMDs compared to the general population, with psychosocial factors such as social support playing a role. Despite these findings, psychological care remains inconsistently integrated in NMD management.

The timely introduction of non-invasive ventilation (NIV) is extremely relevant in the multidisciplinary management of patients affected by amyotrophic lateral sclerosis (ALS) and is based on the proper identification of red flags for early diaphragmatic exhaustion. Polygraphic sleep recording may provide insightful information on the ongoing respiratory impairment; in particular, atypical breathing patterns need to be recognized, as the application of current guidelines for sleep-related hypoxemia or sleep apnea may be insufficient for detecting early signs of diaphragmatic fatigue. We report the case of a 51-year-old man affected by ALS who was asymptomatic for breathing impairment, but whose nocturnal polysomnographic recording, despite not significant for obstructive sleep apnea nor for conventional hypoventilatory patterns, strongly suggested initial respiratory failure, as lately confirmed by the pulmonary follow-up. We discuss the advantages of including sleep recording in the clinical work-up of patients affected by ALS.

Charcot–Marie–Tooth disease (CMT) rarely presents with painful symptoms, which mainly occur in association with myelin protein zero (MPZ) gene mutations. We aimed to further characterize the features of painful neuropathic phenotypes in MPZ-related CMT. We report on a 58-year-old woman with a longstanding history of intermittent migrant pain and dysesthesias. Examination showed minimal clinical signs of neuropathy along with mild changes upon electroneurographic examination, consistent with an intermediate pattern, and small-fiber loss upon skin biopsy. Genetic testing identified the heterozygous variant p.Trp101Ter in MPZ. We identified another 20 CMT patients in the literature who presented with neuropathic pain as a main feature in association with MPZ mutations, mostly in the extracellular MPZ domain; the majority of these patients showed late onset (14/20), with motor-nerve-conduction velocities predominantly in the intermediate range (12/20). It is hypothesized that some MPZ mutations could manifest with, or predispose to, neuropathic pain. However, the mechanisms linking MPZ mutations and pain-generating nerve changes are unclear, as are the possible role of modifier factors. This peculiar CMT presentation may be diagnostically misleading, as it is suggestive of an acquired pain syndrome rather than of an inherited neuropathy.

Facioscapulohumeral muscular dystrophy (FSHD) is a progressive inherited myopathy characterized by muscle weakness, fatty infiltration, and consequent reduction in functional capacity. In this context, physical exercise (PE) has been proposed as a non-pharmacological strategy aimed at preserving physical efficiency. However, its prescription in FSHD has historically been approached with caution due to concerns regarding overwork weakness and potential exacerbation of muscle damage. As a result, clinical management has often remained conservative, with limited and non-standardized PE recommendations. Nevertheless, physical inactivity may further contribute to deconditioning, loss of autonomy, and deterioration in quality of life, highlighting a clear tension between perceived risk and potential benefit. In this framework, identifying safe and effective PE strategies represents a central unmet need in FSHD care. Possibly due to disease rarity and historical concerns, the available literature on PE in FSHD remains fragmented, limiting the strength of definitive conclusions. A structured synthesis of existing evidence may help clarify feasible and potentially effective exercise modalities, as well as guide the development of optimized intervention strategies. This review critically examines the current evidence on PE in FSHD, with specific reference to aerobic, anaerobic, and combined training interventions. The potential synergistic role of concomitant nutritional strategies is also considered. The critical analysis highlights exercise modalities that appear more consistently safe and potentially beneficial, while underscoring substantial methodological limitations across studies. Finally, emerging concepts in exercise tailoring are discussed, with the aim of addressing the clinical variability of FSHD and informing future prospective, controlled investigations.