Death represents the main hallmark of amyotrophic lateral sclerosis (ALS). Despite its importance in clinical care and phase III trials, many uncertainties remain on the cause of death due to the lack of post-mortem verifications. To provide a more robust approach to these causes, we performed a retrospective pathological study on a large cohort of patients. 100 ALS patients referred for a deterioration of their clinical condition and who died in the ALS clinic of Salpétrière had a complete macroscopic and microscopic post-mortem analysis. The clinical causes of death reported on medical records were compared to the results of autopsy. The concordance between clinical and pathological conclusions was insufficient (20%) to consider clinical assessment as a reliable marker of causes of death. At autopsy, broncho-pneumonia and pneumonia were the main causes of death. Heart failure, representing 10% of deaths, was two times more frequent in bulbar than in spinal ALS. Pulmonary embolism representing 6% of death was exclusively found in spinal onset patients and is related to lower limbs disability. An effort has to be made for a better understanding of the causes of deterioration of ALS patients. A more proactive attitude to treat respiratory infections could have a significant impact on survival.

There is an emerging need for biomarkers to better categorize clinical phenotypes and predict progression in amyotrophic lateral sclerosis. This study aimed to quantify cervical spinal gray matter atrophy in amyotrophic lateral sclerosis and investigate its association with clinical disability at baseline and after 1 year. Twenty-nine patients with amyotrophic lateral sclerosis and 22 healthy controls were scanned with 3T MR imaging. Standard functional scale was recorded at the time of MR imaging and after 1 year. MR imaging data were processed automatically to measure the spinal cord, gray matter, and white matter cross-sectional areas. A statistical analysis assessed the difference in cross-sectional areas between patients with amyotrophic lateral sclerosis and controls, correlations between spinal cord and gray matter atrophy to clinical disability at baseline and at 1 year, and prediction of clinical disability at 1 year. Gray matter atrophy was more sensitive to discriminate patients with amyotrophic lateral sclerosis from controls (P = .004) compared with spinal cord atrophy (P = .02). Gray matter and spinal cord cross-sectional areas showed good correlations with clinical scores at baseline (R = 0.56 for gray matter and R = 0.55 for spinal cord; P < .01). Prediction at 1 year with clinical scores (R2 = 0.54) was improved when including a combination of gray matter and white matter cross-sectional areas (R2 = 0.74). Although improvements over spinal cord cross-sectional areas were modest, this study suggests the potential use of gray matter cross-sectional areas as an MR imaging structural biomarker to monitor the evolution of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease leading to the loss of motor function and muscle strength. Nonpharmacologic neuromodulative therapeutic approaches such as active exercise may contribute to preserve motor functions in ALS, but this hypothesis remains debated. The present meta-analysis first aimed to evaluate the effect of active exercise on function and muscle strength preservation. Moreover, since the responsiveness to induced neuroplasticity of patients with ALS is being discussed, the second objective was to review the analogous effects of noninvasive brain stimulation (NIBS). Following PRISMA guidelines, we systematically reviewed PubMed, CENTRAL, NIH PMC, PEDro, ScienceDirect, and Web of Science databases from the period between January 10 and July 1, 2023. Criteria limited inclusion to randomized controlled trials comparing active exercise (aerobic or resistance) with usual care or NIBS with sham. The primary outcome was assessed based on functional assessment scores reported on validated clinical scales, and the secondary outcome analysis included muscle strength and neurophysiologic changes. Methodologic quality of the selected studies was assessed using the Physiotherapy Evidence-Based (PEDro) scale. Relative risk (RR) and heterogeneity (I²) were calculated with Revman software, and evidence quality was estimated by the GRADE quality scale. Thirteen studies were included. Analysis involved 393 patients among whom 164 underwent active exercise and 155 received usual care, 41 received NIBS and 33 underwent sham stimulations. The nature of active exercise was consistent across studies but varied in frequency. NIBS parameters were consistent for stimulation sites and session frequency. Function was significantly preserved in 5 of 9 studies on active exercise and 2 of 4 NIBS trials. Meta-analysis on functional scales indicated a moderate quality of evidence for the effectiveness of active exercises (RR = 0.61 [0.18, 1.04] with I² = 69%) compared with usual care and very low quality of evidence for NIBS (RR = -1.41 [-0.44, 3.26] with I² = 89%). Only 1 NIBS study revealed neuroplastic changes in the brain. Active exercise likely slows functional loss in ALS, but the effects of NIBS need further investigation to support their neuroprotective effectiveness. Moreover, both interventions require further neurophysiologic investigation to elucidate ALS neuroplasticity. This review has been registered in PROSPERO (CRD42023408121).