Standardized Definition of Progression Independent of Relapse Activity (PIRA) in Relapsing-Remitting Multiple Sclerosis.JAMA neurology • April 14, 2025
Jannis Müller, Sifat Sharmin, Johannes Lorscheider, Serkan Ozakbas, Rana Karabudak, Dana Horakova, Bianca Weinstock Guttman, Vahid Shaygannejad, Masoud Etemadifar, Raed Alroughani, Francesco Patti, Sara Eichau, Alexandre Prat, Alessandra Lugaresi, Valentina Tomassini, Allan Kermode, Maria Amato, Recai Turkoglu, Ayse Altintas, Katherine Buzzard, Aysun Soysal, Anneke Van Der Walt, Helmut Butzkueven, Yolanda Blanco, Oliver Gerlach, Samia Khoury, Michael Barnett, Nevin John, Jeannette Lechner Scott, Matteo Foschi, Andrea Surcinelli, Vincent Van Pesch, Julie Prevost, Maria Sa, Davide Maimone, Marie D'hooghe, Stella Hughes, Suzanne Hodgkinson, Chris Mcguigan, Elisabetta Cartechini, Bruce Taylor, Daniele Spitaleri, Mark Slee, Pamela Mccombe, Bassem Yamout, Pascal Benkert, Jens Kuhle, Ludwig Kappos, Izanne Roos, Tomas Kalincik, Marc Girard, Pierre Duquette, Marzena Fabis Pedrini, William Carroll, Olga Skibina, Riadh Gouider, Saloua Mrabet, Cristina Ramo Tello, Claudio Solaro, Mario Habek, Bart Van Wijmeersch, Radek Ampapa, Richard Macdonell, Celia Oreja Guevara, Koen De Gans, Guy Laureys, Jiwon Oh, Justin Garber, Orla Gray, Eduardo Agüera Morales, Jose Sanchez Menoyo, Tamara Castillo Triviño, Nikolaos Grigoriadis, Thor Petersen, Todd Hardy, Steve Vucic, Stephen Reddel, Sudarshini Ramanathan, Abdullah Al Asmi, Mihaela Simu, Seyed Baghbanian, Dieter Poehlau, Talal Al Harbi, Juan Rojas, Norma Deri, Patrice Lalive, Melissa Cambron, Tunde Csepany, Neil Shuey, Barbara Willekens, Cameron Shaw, Danny Decoo, Jennifer Massey, Özgür Yaldizli, Tobias Derfuss, Cristina Granziera
Progression independent of relapse activity (PIRA) is a significant contributor to long-term disability accumulation in relapsing-remitting multiple sclerosis (MS). Prior studies have used varying PIRA definitions, hampering the comparability of study results. To compare various definitions of PIRA. This cohort study involved a retrospective analysis of prospectively collected data from the MSBase registry from July 2004 to July 2023. The participants were patients with MS from 186 centers across 43 countries who had clinically definite relapsing-remitting MS, a complete minimal dataset, and 3 or more documented Expanded Disability Status Scale (EDSS) assessments. Three-hundred sixty definitions of PIRA as combinations of the following criteria: baseline disability (fixed baseline with re-baselining after PIRA, or plus re-baselining after relapses, or plus re-baselining after improvements), minimum confirmation period (6, 12, or 24 months), confirmation magnitude (EDSS score at/above worsening score or at/above threshold compared with baseline), freedom from relapse at EDSS score worsening (90 days prior, 90 days prior and 30 days after, 180 days prior and after, since previous EDSS assessment, or since baseline), and freedom from relapse at confirmation (30 days prior, 90 days prior, 30 days before and after, or between worsening and confirmation). For each definition, we quantified PIRA incidence and persistence (ie, absence of a 3-month confirmed EDSS improvement over ≥5 years). Among 87 239 patients with MS, 33 303 patients fulfilled the inclusion criteria; 24 152 (72.5%) were female and 9151 (27.5%) were male. At the first visits, the mean (SD) age was 36.4 (10.9) years; 28 052 patients (84.2%) had relapsing-remitting MS, and the median (IQR) EDSS score was 2.0 (1.0-3.0). Participants had a mean (SD) 15.1 (11.9) visits over 8.9 (5.2) years. PIRA incidence ranged from 0.141 to 0.658 events per decade and persistence from 0.753 to 0.919, depending on the definition. In particular, the baseline and confirmation period influenced PIRA detection. The following definition yielded balanced incidence and persistence: a significant disability worsening compared with a baseline (reset after each PIRA event, relapse, and EDSS score improvement), in absence of relapses since the last EDSS assessment, confirmed with EDSS scores (not preceded by relapses within 30 days) that remained above the worsening threshold for at least 12 months. Incidence and persistence of PIRA are determined by the definition used. The proposed standardized definition aims to enhance comparability among studies.
Clinical Utility of Far-Field Potentials in Amyotrophic Lateral Sclerosis.Muscle & Nerve • April 24, 2025
Aicee Calma, Nathan Pavey, Claudia Silva, Yukiko Tsuji, Mehdi A Van Den Bos, Michelle Farrar, Parvathi Menon, Steve Vucic
Objective: Far field potentials (FFP) have been proposed as a reliable neurophysiological prognostic biomarker in amyotrophic lateral sclerosis (ALS). This study evaluates the diagnostic utility of ulnar nerve FFP in ALS.
Methods: Comprehensive peripheral neurophysiological assessments were conducted in 62 ALS and 43 ALS-mimicking disorder participants. The ulnar nerve was stimulated at the wrist, recording motor responses over the abductor digit minimi (ADM) muscle. Conventional compound muscle action potentials (CMAP), FFP, and near field potential amplitudes were recorded, alongside the split-hand index, neurophysiological index, motor unit number estimation (MScanFit-MUNE), and motor unit index (MUNIX). Diagnostic utility was evaluated using receiver operating characteristic (ROC) analysis.
Results: In ALS, FFP amplitude was significantly lower (5.07 ± 0.36 mV) compared to ALS mimics (8.25 ± 0.40 mV, p < 0.001). FFP amplitude exhibited a moderate-to-strong correlation with neurophysiological biomarkers, including CMAP amplitude (ρ = 0.77, p < 0.001), split-hand index (ρ = 0.53, p < 0.001), neurophysiological index (ρ = 0.52, p < 0.001), MUNIX (ρ = 0.69, p < 0.001), and MScanFit-MUNE (ρ = 0.66, p < 0.001). Weak-to-moderate correlations were also observed with clinical measures of disease progression, including upper limb muscle strength, ALS functional rating score-revised (ALSFRS-R) and the rate of decline in the ALSFRS-R fine motor subscore. ROC analysis demonstrated that FFP amplitude reliably distinguished ALS from mimicking disorders (AUC = 0.80, 95% CI: 0.71-0.89), with consistent diagnostic accuracy across ALS phenotypes.
Conclusions: The diagnostic capability of FFP amplitude was comparable to established neurophysiological biomarkers utilized in ALS. It is a promising prognostic and diagnostic biomarker for ALS. Its simplicity and reproducibility complement traditional neurophysiological measures, offering potential for clinical application in ALS diagnosis and monitoring.
Longitudinal assessment of cortical motor function in amyotrophic lateral sclerosis.Scientific Reports • January 13, 2025
Dhayalen Krishnan, Dayna-lee Talbot, Jasmine Ashhurst, Susanna Park, Steve Vucic, Hannah Timmins, Matthew Kiernan
Background Short interval intracortical inhibition (SICI) remains the most sensitive parameter to assess motor cortical function in amyotrophic lateral sclerosis (ALS). While an initial value of SICI has been utilised to support a diagnosis of ALS, less is known about progression of change. Methods Motor cortex function was prospectively assessed in ALS patients, through serial threshold tracking transcranial magnetic stimulation (TMS) assessment over more than 12 months. Motor cortical potentials were recorded from the abductor pollicis brevis (APB). Demographic information and clinical variables were analysed. Results A cohort of 52 ALS patients (69.2% limb-onset disease; 47.2% right-side) were assigned to undergo longitudinal assessment of cortical motor function. Mean ALSFRS-R score at baseline was 39.5 ± 1.0 denoting relatively milder clinical deficits at study commencement. Cortical motor dysfunction was evident at baseline, with reduction in averaged SICI (p = 0.004) when compared to healthy controls. In terms of disease trajectory, ALS patients experienced a significant decline in averaged SICI overtime. When compared to initial assessment, averaged SICI was significantly reduced after 12 months (p = 0.004). There was no significant main effect of site of onset on averaged SICI (p = 0.78). The progressive change in averaged SICI was more robust in the dominant hemisphere, with the proportion of ALS patients who demonstrated a clinically abnormal averaged SICI value (< 5.5%) increasing by 50%, compared to 15.4% for the non-dominant hemisphere. Conclusion ALS patients demonstrate progressive cortical motor abnormalities, evident through longitudinal assessment. While SICI represents a diagnostic biomarker, the rate of decline in the present series is consistent with disease progression, suggesting a potential role to monitor the efficacy of therapeutic intervention.
The effect of cold-water mouth swilling on thermal perceptions and heat-related symptoms for people with multiple sclerosis exercising in a hot environment.European Journal Of Applied Physiology • January 08, 2025
Georgia Chaseling, Katrina Blackett, Steve Vucic, Michael Barnett, Scott Davis, Ollie Jay, Nicole Vargas
Objective: Cold-water ingestion improves exercise capacity in the heat for people with multiple sclerosis (MS). Whether cold-water ingestion also mitigates heat-related MS symptoms is unknown. Ingesting fluid is also limiting for people with MS with impaired bladder function. Therefore, we tested the hypothesis that swilling or ingesting cold-water (7°C) compared to ingesting thermoneutral water (37°C) would mitigate the onset of perceived MS heat-related symptoms and thermal sensation in heat-sensitive people with MS during exercise in the heat.
Methods: On three occasions, 13 heat-sensitive participants with MS (41 ± 12 y; 67 ± 12 kg; 1.7 ± 0.1 m; 33.3 ± 9.4 ml·kg-1·min-1) cycled at 40% VO2max at 35 ± 1°C; 30 ± 2% RH until volitional exhaustion (maximum of 60 min). Every 15 min, participants ingested (7IN) or swilled (7SW) 7°C, or ingested 37°C (37IN) water. Thermal sensation, heat-related MS symptoms, rectal (Tre), and mean skin (Tsk) temperature were recorded throughout.
Results: Thermal sensation was cooler in the 7SW (P < 0.01) and 7IN (P = 0.04) compared to the 37IN trial, but heat-related symptoms (P = 0.57), fatigue (P = 0.90), ΔTre (37IN: 0.74 ± 0.37°C; 7IN: 0.65 ± 0.38°C; 7SW: 0.67 ± 0.34°C; P = 0.38) and ΔTsk (37IN: 1.61 ± 0.82°C; 7IN: 1.67 ± 0.78°C; 7SW: 1.64 ± 0.69°C; P = 0.91), were not different between trials. Nine participants completed 60 min of exercise in the 37IN trial whereas 10 participants completed 60 min of exercise in the 7IN and 7SW trials.
Conclusions: Swilling and ingesting 7°C water induces a cooler thermal sensation in heat-sensitive people with MS exercising in the heat but does not mitigate heat-related MS symptoms. The capacity to complete 60 min of exercise with cold-water ingestion and swilling were comparable.
