Todd A. Hardy

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.

Neurology(R) Neuroimmunology & Neuroinflammation • July 22, 2025

Avani Yeola, Samuel Houston, Anupriya Aggarwal, Rashmi Gamage, Vicki Maltby, Marzena Fabis Pedrini, Linh Le Kavanagh, Vera Merheb, Kristy Nguyen, Fiona X Lee, Susan Walters, Marinda Taha, Annmaree O'connell, Vilija Jokubaitis, Angie Roldan, Mastura Monif, Helmut Butzkueven, Sandeep Sampangi, Louise Rath, Katherine Fazzolari, Todd Hardy, Heidi Beadnall, Michael Barnett, Allan Kermode, Christopher Dwyer, Tomas Kalincik, Simon Broadley, Stuart Turville, Stephen Reddel, Sudarshini Ramanathan, Jeannette Lechner Scott, Anneke Van Der Walt, Fabienne Brilot

Objective: Although disease-modifying therapies (DMTs) may suppress coronavirus disease 2019 (COVID-19) vaccine responses in people with multiple sclerosis (pwMS), limited data are available on the cumulative effect of additional boosters. Maturation of Spike immunoglobulin G (IgG) to target a greater diversity of SARS-CoV-2 variants, especially past the BA.1 variant, has not been reported. In addition, the prediction of variant-specific protection, given that Spike antibody testing is not performed routinely, remains a challenge. We, therefore, evaluated whether additional vaccine doses improved the breadth of cross-variant recognition to target emerging SARS-CoV-2 variants. Machine learning-based models were designed to predict variant-specific protection status. Methods: In a prospective observational cohort (n = 442), Spike IgG titers and live virus neutralization against D614, BA.1, BA.2, BA.5, XBB.1.1, XBB.1.5, and EG.5.1 variants were determined in 1,011 serum samples (0-12 months after 2-4 doses). Predictive protection models were developed by K-fold cross-validation on training and test data sets (random split 70:30). Results: After primary vaccination, pwMS on immunosuppressive disease-modifying therapy (IMM-DMT) had 10-fold and 7.2-fold lower D614 Spike IgG titers than pwMS on low-efficacy (LE)-DMT and cladribine (p < 0.01). After 4 doses, pwMS on IMM-DMT had significantly lower Spike IgG titers, compared with pwMS on low-efficacy disease-modifying therapy, for D614 (p < 0.05), as well as BA.1, BA.2, BA.5, XBB.1, XBB.1.5, and EG.5.1(p < 0.01). The breadth of Spike IgG to recognize variants other than the cognate antigen increased after 4 doses of all DMTs. Although pwMS on IMM-DMT displayed reduced cross-variant recognition, a fourth dose resulted in a 2-4-fold increase in protection against newer variants and a reduction in two-thirds of pwMS without protective Spike IgG (p < 0.0001). Tixagevimab and cilgavimab did not induce additional cross-variant protection. Variant-specific predictive models of vaccine protection were influenced by treatment, time since primary vaccination, and age, with high sensitivity (99.4%, 95% CI 96.8-99.99) and specificity (72.0%, 95% CI 50.6-87.9) for XBB.1.5/EG.5.1 variants. Conclusions: Despite not eliciting adequate antibody response in pwMS on IMM-DMT, COVID-19 boosters improve the breadth of the humoral response against SARS-CoV-2 emerging variants. Vaccine protection can be predicted by statistical modeling.

Neurology(R) Neuroimmunology & Neuroinflammation • June 19, 2025

Nabil Seery, Robb Wesselingh, Paul Beech, Laurie Mclaughlin, Tiffany Rushen, Amy Halliday, Liora Horst, Sarah Griffith, Mirasol Forcadela, Tracie Tan, Christina Kazzi, Cassie Nesbitt, James Broadley, Katherine Buzzard, Andrew Duncan, Wendyl D'souza, Yang Tran, Anneke Van Der Walt, Genevieve Skinner, Bruce Taylor, Andrew Swayne, Amy Brodtmann, David Gillis, Ernest Butler, Tomas Kalincik, Udaya Seneviratne, Richard Macdonell, Stefan Blum, Sudarshini Ramanathan, Charles Malpas, Stephen Reddel, Todd Hardy, Terence O'brien, Paul Sanfilippo, Helmut Butzkueven, Mastura Monif

Objective: Few studies have evaluated acute immunotherapy and relapse prevention strategies in patients with anti-leucine-rich glioma-inactivated 1 (LGI1) antibody (Ab)-mediated encephalitis. The objective of this study was to analyze the outcomes of acute and long-term immunotherapy strategies in this population. Methods: We undertook a multicenter cohort study of 55 patients with anti-LGI1 Ab-mediated encephalitis, either recruited prospectively or identified retrospectively from 10 Australian hospitals as part of the Australian Autoimmune Encephalitis Consortium. Clinical data were collected, including treatment durations of all relevant immunotherapies. Clinical outcomes that we examined included (1) time to first clinical relapse, (2) improvement on modified Rankin Scale (mRS), and (3) favorable binary composite clinical-functional outcome at 12 months. A favorable outcome was defined as fulfilling all three of mRS less than 3, a score of 1 or less in the memory dysfunction component of the Clinical Assessment Scale in Autoimmune Encephalitis, and absence of drug-resistant epilepsy. Results: Rituximab, adjusted for concomitant use of other immunotherapies, was associated with increased time to first relapse (hazard ratio 0.10; 95% CI 0.001-0.85; p = 0.03). Intravenous pulsed methylprednisolone was associated with an improvement in mRS (OR 4.48; 95% CI 1.03-21.3; p = 0.048) and a favorable composite clinical-functional outcome (OR 4.96; 95% CI 1.07-27.2; p = 0.049) at 12 months. Conclusions: Rituximab may be effective at preventing relapses in patients with anti-LGI1 Ab-mediated encephalitis. Acute methylprednisolone treatment may be associated with favorable outcomes at 12 months. Methods: This study provides Class IV evidence that for patients with anti-LGI1 Ab-mediated encephalitis, rituximab prevents relapses and acute methylprednisolone is associated with favorable outcomes at 12 months.

Neurology(R) Neuroimmunology & Neuroinflammation • May 30, 2025

Nabil Seery, Robb Wesselingh, Paul Beech, Laurie Mclaughlin, Tiffany Rushen, Amy Halliday, Liora Ter Horst, Sarah Griffith, Mirasol Forcadela, Tracie Tan, Christina Kazzi, Cassie Nesbitt, James Broadley, Katherine Buzzard, Andrew Duncan, Wendyl D'souza, Yang Tran, Anneke Van Der Walt, Genevieve Skinner, Bruce Taylor, Andrew Swayne, Amy Brodtmann, David Gillis, Ernest Butler, Tomas Kalincik, Udaya Seneviratne, Richard Macdonell, Stefan Blum, Sudarshini Ramanathan, Charles Malpas, Stephen Reddel, Todd Hardy, Terence O'brien, Paul Sanfilippo, Helmut Butzkueven, Mastura Monif

Objective: Rituximab is an anti-CD20 monoclonal antibody used in patients with anti-NMDAR antibody (Ab)-mediated encephalitis as both an acute escalation therapy and a longer term relapse risk-reduction treatment. The potential long-term benefit of a single course administered during the acute disease phase on future relapse risk is uncertain. Moreover, the optimal dosing duration to reduce relapse risk is unknown. The aim of this study was to evaluate the effect of a single course of rituximab on relapse incidence. We also studied the duration of effect of a course of rituximab in adult patients with anti-NMDAR Ab-mediated encephalitis. Methods: We recruited 67 patients with anti-NMDAR Ab-mediated encephalitis from 10 Australian hospitals. Rituximab exposure was quantified as a time-varying covariate in Cox proportional hazard models. Results: A single course of rituximab was associated with longer time to first relapse (hazard ratio [HR] 0.11, 95% CI 0.02-0.70, p = 0.02). For patients in whom redosing is considered, rituximab was associated with longer time to first relapse at 6 months after the last infusion, after adjusting for concurrent immunotherapies and the presence of ovarian teratoma at disease onset (HR 0.05, 95% CI 0.00-0.48, p = 0.005). The treatment effect did not persist out to 12 months after a given course (HR 0.60, 95% CI 0.15-2.44, p = 0.47). Conclusions: A single course of rituximab reduces the risk of relapse of anti-NMDAR antibody-mediated encephalitis. In select patients for whom redosing of rituximab is considered, administration at 6 months delays relapses. Methods: This study provides Class IV evidence that rituximab delays relapses in patients with anti-NMDAR antibody-mediated encephalitis.

Multiple Sclerosis (Houndmills, Basingstoke, England) • April 12, 2025

Sandra Elias, Todd Hardy, Aijaz Khan, Jessica Redgrave, Nigel Hoggard, Stuart Coley, Richard Dyde, Ronan O'malley, Zeid Yasiry, David Paling

Baló's concentric sclerosis (BCS) is regarded as a rare variant of multiple sclerosis (MS), characterised by multi-layered ring-like lesions in cerebral white matter. Despite pathological overlap with MS, the effect of treatment with MS disease-modifying therapies remains unclear. The only extant case report of alemtuzumab in BCS described a lack of clinical response in a patient who had previously not responded to corticosteroids, plasmapheresis and cyclophosphamide. The authors speculated that alemtuzumab may have been effective if started earlier in the disease process. We present the outcomes of a patient with BCS who responded clinically and radiologically to alemtuzumab over a 6-year follow-up.