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Volume 14.1 August 2026 emjreviews.com

Neurology

Review of the

EAN Congress 2026

Interviews:

Infographic:

Elena Moro and Kailash Bhatia discuss the future of EAN

Explore the current landscape of functional neurological disorder care

Contents Editorial Board 04

Congress Review

Welcome 07 Foreword 09

László Vécsei University of Szeged, Hungary

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of the European Academy of 10 Review Neurology (EAN) Congress 2026, 27th–30th June

Congress Features AI-Driven Clinical Decision 22 Advancing Support in Acute Stroke Nicholson J

Dementia with Lewy 25 Redefining Bodies: From Clinical Diagnosis to Targeted Therapies Thornber K

Poster Review in Understanding Disease 29 Advances Activity, Functional Outcomes, and Treatment Response in CIDP

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Find out more about our Neurology content

Interviews

Abstract Reviews 39

Risk of Epilepsy in People with Adult-Onset Hydrocephalus: Insights from the UK Biobank Buonocore J et al.

Treatment Interruption 42 Ocrelizumab in Clinically Stable Multiple Sclerosis: Prospective Evidence Supporting a Time-Limited Treatment Pause Konen FF et al.

and Early-Life Vulnerability in 45 Genetic Functional Neurological Disorder: A

Large-Scale Retrospective Cohort Study Ipavic E et al.

and Brain-First 49 Body-First Parkinson's Disease as a Route to Biological Trajectory-Aware Care Passaretti M

58 Peter J. Goadsby 63 Joanna Wardlaw 67 Angelo Antonini Infographic Functional Neurological Disorder:

70 Modern Diagnosis and Management Features the FTD Umbrella: 72 Beyond Time for a Biological Definition? Borrego-Écija S

with Aura: Does It Require 75 Migraine Different Treatment? Oldoni C and Karsan N

Congress Interviews

From Prediction to Prevention 80 SUDEP: Grundmann A

51 Elena Moro

Alpha-Synuclein 84 Incorporating Seed Amplification Assays in Parkinson’s Diagnosis

54 Kailash Bhatia

Plastini MJ and Concha-Marambio L

Urgent Need for a Parkinson’s 88 The Disease Patient Support Group in Latvia Abola P

Articles Cognitive Screening in 92 Rethinking Multiple Sclerosis: Detection and

Attribution for Patient-Centred Care Charvet L et al.

Consumption and Risk of 105 Alcohol Dementia and Cognitive Decline: From Evidence to Prevention Strategies Fares A

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Editorial Board Editor-in-Chief Prof László Vécsei University of Szeged, Hungary Head of the Neuroscience Research Group and President of the Doctoral Council, Department of Neurology, University of Szeged, Hungary. Professor Lászlo Vécsei has published over 600 peer-reviewed articles, primarily focusing on the pathomechanism of neurodegenerative disorders and multiple sclerosis.

Prof Ranko Raičević

Prof Nils Erik Gilhus

Military Medical Academy, Serbia

University of Bergen, Norway

Dr Natan Bornstein

Prof Hans-Peter Hartung

Shaare-Zedek Medical Center, Israel

University of Düsseldorf, Germany

Dr Rita Krishnamurthi

Prof Stefan Schwab

Auckland University of Technology, New Zealand

University of ErlangenNuremberg, Germany

Dr Nitin Butala

Dr Giuseppe Lanza Oasi Research InstituteIRCCS, Italy

Baptist Health, Florida, USA

Prof Antonio Federico University of Siena, Italy

Prof Amos Korczyn

Dr Marco Feligioni

Tel-Aviv University, Israel

Dr Ali Ahmed The Royal Wolverhampton NHS Trust, UK

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European Brain Research Institute ‘Rita Levi Montalcini’ Foundation, Italy

Aims and Scope EMJ Neurology is a free, open-access, peer-reviewed eJournal aiming to elevate the quality of neurology care globally by informing experts on the function and disease of the nervous system to help advance the development of this field. The journal is published annually, six weeks after the European Academy of Neurology (EAN) Congress, and features highlights from this congress, alongside interviews with experts in the field, reviews of abstracts presented at the congress, as well as in-depth features on congress sessions. Additionally, it covers advances within the clinical and pharmaceutical arenas by publishing sponsored content from congress symposia, which is of high educational value for healthcare professionals. This undergoes rigorous quality control checks by independent experts and the in-house editorial team. EMJ Neurology also publishes peer-reviewed research papers, review articles, and case reports in the field. In addition, the journal welcomes the submission of features and opinion pieces intended to create a discussion around key topics in the field and broaden readers’ professional interests. The journal is managed by a dedicated editorial team that adheres to a rigorous double-blind peer-review process, maintains high standards of copy editing, and ensures timely publication. EMJ Neurology endeavours to enhance knowledge, stimulate discussion, and contribute to a better understanding of disorders of the nervous system. Our focus is on research that is relevant to healthcare professionals in this field. We do not publish veterinary science papers or laboratory studies not linked to patient outcomes. We have a particular interest in topical studies that advance research and inform of coming trends affecting clinical practice in neurology.

Editorial Expertise EMJ is supported by various levels of expertise:

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Guidance from an Editorial Board consisting of leading authorities from a wide variety of disciplines. Invited contributors who are recognised authorities in their respective fields. Peer review, which is conducted by expert reviewers who are invited by the Editorial team and appointed based on their knowledge of a specific topic. An experienced team of editors and technical editors.

Peer Review On submission, all articles are assessed by the editorial team to determine their suitability for the journal and appropriateness for peer review. Editorial staff, following consultation with either a member of the Editorial Board or the author(s) if necessary, identify three appropriate reviewers, who are selected based on their specialist knowledge in the relevant area. All peer review is double blind. Following review, papers are either accepted without modification, returned to the author(s) to incorporate required changes, or rejected. Editorial staff have final discretion over any proposed amendments.

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We are always keen to hear from healthcare professionals wishing to discuss potential submissions, please email: editorial.assistant@emjreviews.com To submit a paper, use our online submission site: https://emj.kriyadocs.com/submissions/submit/emj/emj/login Submission details can be found through our website: www.emjreviews.com/contributors/authors Reprints All articles included in EMJ are available as reprints (minimum order 1,000). Please contact hello@emjreviews.com if you would like to order reprints. Distribution and Readership EMJ is distributed through controlled circulation to healthcare professionals in the relevant fields across Europe. Indexing and Availability EMJ is indexed on DOAJ, the Royal Society of Medicine, and Google Scholar®; selected articles are indexed in PubMed Central®. EMJ is available through the websites of our leading partners and collaborating societies. EMJ journals are all available via our website: www.emjreviews.com

Further details on coverage can be found here: www.emjreviews.com

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Submissions We welcome contributions from professionals, consultants, academics, and industry leaders on relevant and topical subjects. We seek papers with the most current, interesting, and relevant information in each therapeutic area and accept original research, review articles, case reports, and features.

Open Access This is an open-access journal in accordance with the Creative Commons Attribution-Non Commercial 4.0 (CC BY-NC 4.0) license. Congress Notice Staff members attend medical congresses as reporters when required. This Publication Launch Date: 2013 Frequency: Yearly Online ISSN: 2054-4529 All information obtained by EMJ and each of the contributions from various sources is as current and accurate as possible. However, due to human or mechanical errors, EMJ and the contributors cannot guarantee the accuracy, adequacy, or completeness of any information, and cannot be held responsible for any errors or omissions. EMJ is completely independent of the review event (EAN 2026) and the use of the organisations does not constitute endorsement or media partnership in any form whatsoever. The cover photo is of Geneva, Switzerland, the location of EAN 2026. Front cover and contents photograph: Front cover and contents photograph: Digitally enhanced image © BondGraphics / stock. adobe.com

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Stay at the Forefront of Modern Medicine High-level perspectives. Global experts. Essential updates. Join us for conversations with the minds shaping healthcare's future. Gain the distilled insights you need to lead in your field and make maximum impact.

Saranya Ravindran:

Jonathan Sackier:

Paediatric Emergency Medicine Registrar, Imperial College Healthcare NHS Trust

Non Executive Director & CMO, AiM Medical Robotics, Florida, USA

Catherine Glass: Associate NHS GP and Senior Appraiser, NHS England

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Welcome Dear Readers,

Editorial Director Andrea Charles

Welcome to the 2026 issue of EMJ Neurology. This issue features coverage from the 12th Congress of the European Academy of Neurology (EAN), alongside expert interviews, peer-reviewed research, and feature articles exploring key developments across the field. With articles examining the impact of alcohol consumption on dementia risk and the case for more patient-centred cognitive screening in multiple sclerosis, this issue showcases research that is shaping clinical thinking today.

Editor Sean Boyle Managing Editor Darcy Richards Associate Editor Helena Bradbury

Our feature articles spotlight expert commentary on incorporating α-synuclein seed amplification assays into Parkinson's disease diagnosis, the case for a biological definition of frontotemporal dementia, and progress towards preventing sudden unexpected death in epilepsy, among others.

Senior Copy Editor Noémie Fouarge Copy Editors Meghan Garcka, Lizzie Green, Sarah Jahncke

In addition, we present an infographic exploring the current landscape of functional neurological disorder care, where advances in classification, diagnosis, and treatment are improving recognition of a condition that remains widely misunderstood.

Editorial Leads Katrina Thornber, Aleksandra Zurowska Senior Editorial Co-ordinator Bertie Pearcey Editorial Co-ordinators Jess Nicholson, Alena Sofieva

As always, it was a delight to interview some of the field's leading neurologists and share their insights with our readers. Peter J. Goadsby shares his expert insight into migraine therapeutics, Joanna Wardlaw discusses advancements in small vessel disease and lacunar stroke, and Angelo Antonini provides an update on the Parkinson's disease landscape, including the 'gut-first versus brain-first' model. Be sure not to miss our exclusive interviews with the new EAN President, Kailash Bhatia, and Past President, Elena Moro. Our Congress coverage brings you key insights from this year's event in Geneva, Switzerland. It was a pleasure to attend in person and meet some of the people behind research that has real potential to change patients' lives. We look forward to next year's Congress in Gothenburg, Sweden.

Editorial Assistants Niamh Holmes, Josh Lister, Nonyelum Okonkwo, Roli Omamuli Creative Director Tim Uden

I would like to thank our Editorial Board, peer reviewers, authors, and interviewees for their continued support. I hope you find this issue insightful and informative for your clinical practice.

Design Manager Stacey White Senior Designers Tamara Kondolomo, Owen Silcox

Katrina Thornber Editorial Lead

Designers Shanjok Gurung, Fabio van Paris Junior Designers Fraser Hoey, Cameron Levett, Helena Spicer, Caleb Wylie

EMJ would like to thank these contributors • Dawood Fayaz Malik • Saira Saad

Marketing Director Stephanie Corbett Business Unit Lead Kelly Byrne

Chief Executive Officer Justin Levett

Editorial enquiries: editor@emjreviews.com Sales opportunities: salesadmin@emjreviews.com Permissions and copyright: accountsreceivable@emjreviews.com Reprints: info@emjreviews.com Media enquiries: marketing@emjreviews.com

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Foreword Dear Colleagues, It is with great pleasure that I introduce the 2026 edition of EMJ Neurology, drawing on insights from the 12th Congress of the European Academy of Neurology (EAN) in Geneva, Switzerland. This year's Congress theme, 'Brains, Bytes, & Beyond: Tech in Neurology', placed AI, computational approaches, and emerging technologies at the centre of the programme, and it is a theme that speaks to a broader shift now underway across our field. This shift is reflected across several contributions in this issue, from the growing role of α-synuclein seed amplification assays in refining Parkinson's disease diagnosis, to work examining how sudden unexpected death in epilepsy might move from prediction towards genuine prevention. Additionally, our contributors remind us that technological progress must be matched by conceptual clarity and by attention to the patient experience, whether that means reconsidering how we define frontotemporal dementia, rethinking cognitive screening in multiple sclerosis, or highlighting the everyday unmet needs of patients living with Parkinson's disease.

As computational tools become further embedded in neurological practice, the task ahead is to ensure that they strengthen, rather than replace, the clinical reasoning and patient-centred care at the heart of our specialty. Thank you to all contributors, reviewers, and our EMJ Neurology Editorial Board. We hope you find this edition informative and inspiring as we look forward to EAN 2027.

Technological progress must be matched by conceptual clarity and by attention to the patient experience

László Vécsei University of Szeged, Hungary

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Congress CongressReview Review GIANT ### 2024 2023 ● ●

EAN 2026 Insights From The Global Innovation and New Technology (GIANT) Health Event 2023

A total of 9,503 participants attended, comprising 7,590 onsite delegates and 1,913 joining virtually, representing 121 countries

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Congress Review Review of the European Academy of Neurology (EAN) Congress 2026 Location:

Geneva, Switzerland

Date:

27th–30th June 2026

Citation:

EMJ Neurol. 2026;14[1]:10-21. https://doi.org/10.33590/emjneurol/YH48S4OT

THE EUROPEAN Academy of Neurology (EAN) Congress 2026 opened in Geneva, Switzerland, with EAN President Elena Moro, Department of Psychiatry, Neurology and Neurological Rehabilitation, Grenoble University Hospital Center, France, welcoming participants to "my home, your home, the home of neurology." Geneva's long association with international dialogue suited the message, and Moro reminded the audience that neurology knows no borders. This year, the community came together in record numbers. A total of 9,503 participants attended, comprising 7,590 onsite delegates and 1,913 joining virtually, representing 121 countries. More than 370 speakers contributed to the scientific programme, underlining the breadth, diversity, and global relevance of the EAN community. During the Opening Session on Saturday 27th June, Moro presented the EAN's priorities for shaping the future of neurology across Europe, highlighting the Enhancing Neurology in Europe initiative and the associated Brussels Neurology Declaration, signed by presidents and delegates of national neurological societies. Through this, EAN is advancing a common agenda built around brain health for all, equal access to treatment and funding, improved prevention and care, a stronger neurological workforce, interventional neurology, research and innovation, and the responsible integration of new technologies and AI. Brain health was singled out as one of the strongest examples of cross-border CC BY-NC 4.0 Licence

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collaboration, with EAN's advocacy now extending from national settings to European and global policy platforms, including the European Parliament and the United Nations, alongside continued work with the WHO to support implementation of the Intersectoral Global Action Plan. Moro described how the Brain Health Mission has grown into an inclusive platform bringing together neurologists, strategic partners, patient organisations, and stakeholders beyond neurology, with initiatives ranging from school-based brain health activities to Public Brain Health Day in Geneva. The Presidential Symposium, held on Sunday 28th June, brought together the Congress' Named Lectures, presented to outstanding, active basic and clinical scientists. Frank Winkler, Department of Neurology, Heidelberg University Hospital, Germany, delivered the Brain Prize Lecture on neural influences on brain tumour growth and therapy resistance. Manju Kurian, University College London, UK, gave the Anita Harding Award Lecture on the translational arc for childhood movement disorders. Daniela Berg, University Hospital Tuebingen, Germany,

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presented the Moritz Romberg Award Lecture, reflecting on what research and patients can teach us about Parkinson's disease. John Rothwell, University College London, UK, delivered the Charles Édouard Brown-Séquard Award Lecture on noninvasive neuromodulation in neurology, and Riccardo Soffietti, University of Turin, Italy, closed the session with the Camillo Golgi Award Lecture on progress in gliomas, from histology to molecular biology and from surgery to precision therapies. The Congress was built around the overarching theme 'Brains, Bytes & Beyond: Tech in Neurology', which explored how computing is finding its way into neurological practice. Rapid advances in computing are transforming clinical medicine, and the outsourcing of core cognitive tasks from human agents to AI brings both opportunity and risk. The theme ran through a selection of invited lectures, a dedicated symposium on Innovations in Neurology, and two workshops examining AI applications across hospital and outpatient settings, with key sessions including 'AI in Hospital Neurology', 'Innovations in Neurology: From Brain Machine Interface to AI', and 'AI in Outpatient Neurology'. As the Congress came to a close, it also marked a change in leadership, with Kailash Bhatia, University College London, UK, formally taking office as EAN President and Moro moving into the role of Past President. EMJ had the pleasure of interviewing both Bhatia and Moro. Find their highlights and thoughts on what lies ahead for EAN within this issue of EMJ Neurology. Read on for key insights into this year's Congress, and don't miss our coverage of the EAN Congress 2027, which will be held in Gothenburg, Sweden, with the overarching theme 'Transforming Neurology: Embracing Every Brain'.

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Frailty Associated with Structural and Metabolic Brain Changes in Cognitively Unimpaired Adults NEW DATA presented at EAN 2026 has linked frailty in middle-aged adults with no cognitive impairment to measurable brain changes, including thinner cortex, smaller hippocampal volume, and lower brain glucose metabolism, with these patterns appearing regardless of amyloid status.1 Frailty is increasingly recognised as a multidimensional syndrome that raises dementia risk, yet how it affects the brain before cognitive symptoms emerge is not well understood. Understanding these early changes could help clarify whether frailty contributes to later cognitive decline through pathways distinct from Alzheimer's disease. This presentation examined structural and metabolic brain differences linked to frailty in middle-aged adults with no cognitive impairment, drawn from the ALFA+ cohort, all of whom had cerebrospinal fluid data on Alzheimer's disease biomarkers available. Frailty status was determined using a 35item Frailty Index. Linear regression models were then used to test how frailty scores related to several brain measures: predicted brain age, cortical thickness across the whole brain and in specific regions, overall brain volume, the extent of white matter hyperintensities, and glucose metabolism on PET imaging. All models were also rerun after accounting for cerebrospinal fluid amyloid-β 42/40 ratios, to establish whether any associations held independently of amyloid status. Of the 418 adults included in the analysis, 57 met the criteria for frailty.

Frailty scores correlated with an olderappearing brain on predicted brain-age measures, along with thinning in average, fronto-temporal, and Alzheimer'ssignature cortical regions, and a smaller hippocampus. Glucose uptake was also lower in frail participants across average, parietotemporal, and posterior cingulate regions, a pattern consistent with reduced neuronal activity in these areas. White matter hyperintensities, a marker of small vessel damage, were more extensive among frail participants, most notably in the fronto-parietal and basal ganglia regions. None of these relationships weakened once amyloid-β levels were accounted for. Taken together, the findings suggest that frailty is associated with brain atrophy, vascular injury, and reduced metabolic activity in regions typically affected by Alzheimer's disease and normal ageing, and that this pattern holds regardless of amyloid status. The authors framed frailty as a possible early marker of brain vulnerability that may appear before dementia becomes clinically apparent. As the data were observational, the findings show association rather than a confirmed causal or predictive role.

Frailty is associated with brain atrophy, vascular injury, and reduced metabolic activity

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RFC1 Repeat Expansions May Explain CANVAS Mechanism NEW RESEARCH, presented at EAN 2026, suggests that AAGGG repeat expansions in the RFC1 gene may contribute to the development of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) by reducing RFC1 expression, with a consequent impairment of the DNA damage response. The findings also indicate that these changes could increase the risk of clinically significant neuropathy following oxaliplatin treatment.2 CANVAS is a progressive neurological disorder characterised by impaired balance and coordination, sensory neuropathy, and vestibular dysfunction, and is increasingly recognised as one of the most common causes of ataxia and sensory neuropathy. Although previous studies failed to detect reduced RFC1 transcript or RCF1 protein levels, the recessive inheritance pattern of CANVAS and the identification of patients carrying compound heterozygous null variants have suggested that loss of RFC1 function may underlie the disease. Researchers therefore examined how AAGGG repeat expansions influence RFC1 expression and function. The team used reporter assays, human cerebellar tissue, patient-derived cell lines, induced pluripotent stem-cellderived neurones, and a Drosophila model to investigate the effects of the repeat expansion. They found that AAGGG expansions impaired transcription efficiency in a length-dependent manner, reduced RFC1 expression in the human cerebellum, and induced pluripotent stemcell-derived neurones. The expansions also impaired the DNA damage response. Patient-derived cell lines also showed

an increased apoptotic response after exposure to platinum compounds. CRISPR/Cas9-mediated removal of the AAGGG repeat restored RFC1 expression and the DNA damage response in patientderived cells, reversing key cellular changes observed in the disease model. In addition, neuronal-specific RFC1 knockdown in flies resulted in reduced survival, motor impairment, and increased DNA damage. The researchers also found that people carrying RFC1 repeat expansions who received oxaliplatin were at higher risk of developing clinically significant neuropathy than non-carriers. The findings support a cell- and tissuespecific reduction in RFC1 expression as a potential mechanism underlying CANVAS and provide a foundation for exploring strategies that restore RFC1 expression and DNA repair. Further research will be needed to determine how these findings translate into clinical practice, but they could support the development of therapies aimed at restoring RFC1 expression and help guide future studies into chemotherapy-induced neuropathy in people carrying RFC1 repeat expansions.

AAGGG expansions impaired transcription efficiency in a length-dependent manner

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Women with Parkinson's Disease Show Greater Alzheimer's Pathology Burden WOMEN with Parkinson's disease (PD) may be more likely than men to develop co-existing Alzheimer's disease (AD) pathology, according to research presented at EAN 2026.3

Women had more than double the odds of having a high amyloid plaque burden compared with men

AD and PD frequently occur together in older adults, but little is known about whether biological sex influences the development of Alzheimer's-related pathology in people with PD.

scores than male patients (6.5/15 versus 4.9/15; p=0.045) and greater Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuritic plaque density (1.7/3 versus 1.3/3; p=0.035).

In this study, researchers examined 230 autopsy-confirmed cases of PD enrolled in the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) and the Brain and Body Donation Program (BBDP). Participants underwent annual standardised clinical assessments conducted by neuropsychologists and specialist behavioural and movement disorder neurologists, followed by comprehensive neuropathological examinations after death.

Women were also more likely to have a high cortical plaque burden, defined as a total plaque score of at least 5 (56.8% versus 39.7%; p=0.015).

The investigators compared measures of AD pathology between male and female patients with PD, focusing particularly on amyloid plaque burden within the brain.

The authors concluded that female sex is associated with increased amyloid plaque pathology in Parkinson's disease, independent of ApoE ε4 status. These findings suggest a sex-specific vulnerability to Alzheimer's pathology among patients with PD and highlight the need for sex-informed approaches to the diagnosis and treatment of mixed neurodegenerative disease.

After adjusting for age at death and ApoE ε4 carrier status, female sex remained independently associated with greater amyloid pathology. Women had more than double the odds of having a high amyloid plaque burden compared with men (odds ratio: 2.18; 95% CI: 1.17–4.06; p=0.014).

Women with PD demonstrated significantly greater amyloid plaque pathology than men, regardless of whether they also met diagnostic criteria for AD. Female patients had higher mean cortical total plaque CC BY-NC 4.0 Licence

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Sleep-Heart Rhythm Coupling Linked to Cognitive Performance in Healthy Adults THE SYNCHRONISATION between brain activity during sleep and heart rhythm may provide a novel marker of cognitive health, according to research presented at EAN 2026.4

Both reduced slow-wave sleep activity and cardiac autonomic dysfunction have previously been associated with cognitive impairment. However, little is known about how interactions between these two physiological processes influence cognitive function. Researchers analysed data from 63 healthy volunteers who underwent cognitive testing and overnight sleep studies. A subset of 31 participants also received high-density EEG using 256 electrodes to map the cortical distribution of slow-wave–heart rhythm (SWHR) coupling during sleep. The team assessed several characteristics of SW-HR coupling, including temporal coherence, slow-wave amplitude, and globality, and examined their relationship with performance across multiple cognitive domains.

fronto-central brain regions. Stronger temporal and amplitude coupling was associated with better performance in several cognitive functions, including alertness, response inhibition, verbal memory, and visual memory. Increased slow-wave globality was also linked to improved cognitive outcomes, particularly visuospatial memory recall. No significant associations were observed for measures of density coupling. According to the authors, this is the first study to describe the cortical topography of SW-HR coupling and its relationship with cognition across multiple domains. The findings suggest that the interaction between sleep-related brain activity and autonomic function may represent a promising biomarker of brain health and cognitive performance.

The findings showed that SW-HR coupling was bidirectional and predominantly involved

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Apathy Predicts Cognitive Decline in Early Parkinson's Disease A STUDY presented at EAN 2026 investigated whether apathy and impulse-control behaviours (ICB) were associated with longitudinal cognitive decline, alterations in brain connectivity and structure, and genetic susceptibility in early Parkinson's disease (PD).5 PD is frequently accompanied by nonmotor symptoms, including motivational disturbances such as apathy and ICBs, which may influence long-term cognitive outcomes. While both are common in early PD, their relative contribution to cognitive decline and the biological mechanisms underpinning these associations remain unclear. In this study, a key finding was that baseline apathy predicted significantly faster cognitive decline over up to 15 years of follow-up, whereas ICBs showed little consistent association. Data were analysed from the Parkinson's Progression Markers Initiative (PPMI), including 1,502 participants with early PD at baseline. Participants underwent longitudinal cognitive assessment using latent global cognition and Montreal Cognitive Assessment (MoCA) scores. Resting-state functional MRI data were available for 310 participants, with structural imaging used to assess hippocampal volume and atrophy. The study also examined genetic susceptibility, including glucocerebrosidase (GBA) mutation status, while accounting for demographic factors, motor severity, depressive symptoms, and dopaminergic treatment. Apathy-containing phenotypes remained comparatively stable over time, whereas isolated ICBs were more transient. Higher baseline apathy independently predicted steeper decline in both latent global cognition and MoCA scores across followup, while ICB-related effects were weak and not robust after adjustment.

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Functional MRI identified an apathyassociated somato-motor–dorsalattention connectivity signature that was independent of disease severity and dopaminergic medication. Lower connectivity within this network predicted faster cognitive decline, mediated the relationship between apathy and cognitive deterioration in an age-dependent manner, and was associated with smaller hippocampal volume and more rapid subsequent atrophy. In contrast, ICB-related connectivity changes were attenuated after adjustment for levodopa-equivalent dose. Among participants with GBA-associated PD, apathy markedly increased vulnerability, with apathetic GBA carriers declining approximately five times faster than non-apathetic sporadic cases.

Baseline apathy predicted significantly faster cognitive decline over up to 15 years of follow-up These findings suggest that apathy is a stable clinical marker of future cognitive decline in early PD and may help identify individuals at increased risk for accelerated progression. Routine assessment of apathy could therefore support earlier risk stratification, monitoring, and targeted intervention in clinical practice, particularly in patients with GBA-associated PD. Limitations include the observational design, reliance on a single research cohort, and the smaller imaging subgroup, which may limit causal inference and generalisability.

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Seizure Improvement After Vorasidenib May Correlate with F-DOPA PET and D2HG SEIZURE improvement after vorasidenib in post-surgery patients with Grade 2 isocitrate dehydrogenase (IDH)-mutant glioma may be correlated with fluorodopa (F-DOPA) PET and D-2-hydroxyglutarate (D2HG) plasma levels, according to a new prospective study presented at EAN 2026.6 The utilisation of IDH inhibitors to improve seizure control is appealing because of the involvement of IDH mutations and D2HG in epileptogenesis. Researchers assessed patterns and timing of seizure response in patients with Grade 2 IDH-mutant glioma receiving vorasidenib after having surgery. The cohort comprised 56 patients, with seizures recorded at the end of each 28day cycle. MRI, [18F] F-DOPA PET, and D2HG plasma levels were performed at baseline and every three cycles. Twelve patients in the cohort had persistent seizures prior to vorasidenib, with a mean frequency of four per month. Nine of these 12 had measurable F-DOPA PET uptake. Over a median treatment duration of 11.6 months, six out of 12 patients achieved seizure freedom within one treatment

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cycle, while five out of 12 experienced gradual seizure improvement. One patient experienced an initial improvement but subsequently worsened by Cycle 4. Among patients with seizure reduction, eight out of nine showed reduced F-DOPA PET uptake by Cycle 3. Additionally, all 11 patients with durable seizure responses demonstrated reductions in plasma D2HG levels at Cycles 3 and 6 (mean change: −51% and −60%, respectively). MRI assessments showed stable disease in all patients according to response assessment in neuro-oncology criteria. These results contrasted with the patient who experienced seizure worsening over time. D2HG reduction was −53% at Cycle 3, but the patient demonstrated no further reduction or PET progression disease at Cycle 6. Researchers concluded that the findings from this study suggest that seizure improvement after vorasidenib may correlate with F-DOPA PET and D2HG plasma levels.

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Cervical Cord Atrophy in MS Exceeds Normal Ageing Effects UPPER cervical cord atrophy in patients with multiple sclerosis (MS) exceeds what would be expected from ageing alone, according to research presented at EAN 2026. This disease-specific effect is most pronounced in early adulthood and midlife, and is independent of sex or age at disease onset.7 Loss of spinal cord tissue is a recognised driver of disability in MS, and mean upper cervical cord cross-sectional area (MUCCA) is a validated way to track it in both newly diagnosed and long-standing disease. The relative contribution of disease-specific neurodegeneration, as distinct from ageing that would occur independently of diagnosis, has proven more difficult to quantify. To address this, the study built a reference curve for how MUCCA normally changes across life, then measured how far people with MS deviated from it.

Brain MRI and clinical records were drawn from 1,295 people with MS

peaking around the late 30s (p≤0.033), then declined from roughly age 50 years onwards (p≤0.008). Among people with MS, Z-scores worsened steadily from early adulthood through to the late 40s (p<0.001), with the pace of decline levelling off in older age groups. Neither the healthy group nor the MS group showed a meaningful difference by sex (p=0.256 and p=0.422, respectively). Those diagnosed in childhood had worse Z-scores than those diagnosed as adults or after 50 years of age (p<0.001), though once diagnosed, the pace of further decline was similar regardless of age of disease onset. Worse Z-scores also tracked with higher disability levels and other markers of brain damage on MRI (rho: −0.355–-0.372; all p<0.001).

Brain MRI and clinical records were drawn from 1,295 people with MS and 480 people without the condition, aged 18–70 years. MUCCA was measured at the C1 to C2/3 level and normalised for head size (nMUCCA). A regression model incorporating age, the square of age, sex, scanner type, and their interactions was fitted to the healthy group to define an expected nMUCCA trajectory across the lifespan; each person with MS was then scored against this curve to generate a Z-score quantifying how far their nMUCCA fell outside the age-typical range. The analysis also tested whether these Z-scores varied by sex or by whether the disease had started in childhood, adulthood, or after age 50 years.

The findings indicate that cervical cord atrophy in MS exceeds that attributable to ageing alone, an effect most pronounced in early and mid-adulthood, with the relative contribution of ageing increasing in later life. The authors attributed differences between onset groups mainly to how long people had lived with the disease rather than to the age of onset. Because nMUCCA tracked so closely with disability, they suggested it could serve as a marker of disease-driven damage distinct from ageing, though the cross-sectional design means the study shows a strong association rather than proof that it predicts future decline.

nMUCCA in the healthy group grew through the third and into the fourth decade of life, CC BY-NC 4.0 Licence

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Pupil Response May Help Predict Recovery of Consciousness After Acute Brain Injury A SPECIFIC feature of the pupil's response to light may help predict whether patients with acute brain injury will regain consciousness, according to research presented at EAN 2026.8 Predicting neurological recovery in patients who are critically ill remains a significant clinical challenge, particularly during the early stages of intensive care. While automated pupillometry is increasingly used to assess neurological function, its ability to predict longer-term recovery has not been fully established. In this prospective longitudinal study, researchers followed 250 patients with impaired consciousness after traumatic and non-traumatic brain injury admitted to the ICU. Patients underwent daily pupillometry alongside serial neurological assessments for up to 20 days. The investigators focused on the late lightoff response (LOR), which measures how quickly the pupil begins to dilate after a light stimulus is removed. Specifically, they assessed late LOR latency and examined whether it was associated with changes in patients' level of consciousness over the following week.

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Late LOR latency independently predicted improvement in neurological status 7 days later, even after accounting for baseline neurological function, time since injury, and sedation status. Notably, the predictive value of late LOR latency was most apparent in patients who were not sedated and appeared strongest among those with anoxic-ischaemic brain injury. By contrast, conventional pupillometry measures, including the Neurological Pupil Index and pupillary light reflex latency, did not predict subsequent improvements in consciousness despite often remaining within normal ranges early after injury. The authors concluded that late LOR latency captures subtle recovery-related changes in pupillary function that may precede clinically meaningful neurological improvement. If validated in future studies, this non-invasive measure could provide clinicians with an additional tool to identify patients with the potential for recovery following acute brain injury.

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References 1.

Toccaceli Blasi M et al. Frailty is associated with structural and metabolic brain changes in cognitively unimpaired adults. Abstract OPR-077. EAN Congress, 27-30 June, 2026.

Abstract EPO-0330. EAN Congress, 27-30 June, 2026. 4.

Curro R et al. CANVAS-associated AAGGG repeat expansions cause cellspecific reduction in RFC1 expression and impaired DNA damage response. Abstract OPR-031. EAN Congress, 27-30 June, 2026.

Driver-Dunckley E. Greater burden of Alzheimer's copathology in women with Parkinson's disease.

Filchenko I et al. Brain and heart cross-talk: cortical topography of slow-wave–heart rhythm coupling is associated with cognition. Abstract OPR-142. EAN Congress, 27-30 June, 2026. Attaallah B. Apathy marks brain network and genetic vulnerability to cognitive decline in Parkinson's disease. Abstract LB_02. EAN Congress, 27-30 June, 2026.

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seizure control correlates with [18F]- DOPA PET response and D-2hydroxyglutarate plasma reduction. Abstract OPR-012. EAN Congress, 27-30 June, 2026. 7.

Jain K et al. Disentangling age-related and disease-specific upper cervical cord atrophy in multiple sclerosis. Abstract OPR-020. EAN Congress, 27-30 June, 2026.

Laigaard P et al. Pupillary light-off latency predicts 7-day improvement in consciousness in patients with acute disorders of consciousness. Abstract OPR-061. EAN Congress, 27-30 June, 2026.

Bruno F et al. IDH-mutant gliomas treated with vorasidenib: early

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Advancing AI-Driven Clinical Decision Support in Acute Stroke Author:

Jess Nicholson, EMJ, London, UK

Citation:

EMJ Neurol. 2026;14[1]:22-24. https://doi.org/10.33590/emjneurol/6114R8QK

REDEFINING the role of AI in acute stroke care, a presentation delivered during the session ‘AI in Hospital Neurology’ at the European Academy of Neurology (EAN) Congress 2026 examined how AI is evolving beyond automated image analysis to become a clinical decision-support tool. Susanna Wegener, Senior Physician, Department of Neurology, University Hospital Zurich, Switzerland, presented emerging research spanning prognostic prediction, treatment decisionmaking, and secondary stroke prevention. The presentation delivered a key message that successful AI implementation will rely not only on increasingly sophisticated algorithms, but also on clinically meaningful data, transparent predictions, and the trust of the clinicians using them.

PREDICTING FUNCTIONAL RECOVERY AFTER STROKE A central theme in the clinical uses of AI centres around whether it can meaningfully improve prognostic assessment following acute stroke. To explore this, Wegener presented a study comparing experienced stroke neurologists with convolutional neural network (CNN) models in predicting modified Rankin Scale (mRS) scores 3 months post-stroke.1 Experts were provided with clinical data, MRI imaging, or a combination of both. Using clinical information alone, neurologists achieved an accuracy of approximately 60%, with CNN models performing comparably. Adding MRI data improved prognostic accuracy for both clinicians and AI; however, the CNN model consistently outperformed expert neurologists overall, highlighting its potential to enhance, rather than replace, clinical decision-making. The findings were validated using CT angiography data from the MR CLEAN trial,2 the imaging modality more commonly used in routine clinical practice. The study compared prognostic performance between neurologists, neurologists assisted by the MR PREDICT score, and AI foundation 22

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models trained on CT data. As in the previous study, neurologists achieved an accuracy of approximately 60–65%, whereas the AI models consistently demonstrated superior performance. Although the MR Predict score improved prognostic accuracy among less experienced neurologists, it offered little additional benefit for highly experienced clinicians (Herzog et al., unpublished data, 2026).

The CNN model consistently outperformed expert neurologists overall, highlighting its potential to enhance, rather than replace, clinical decision-making Wegener noted that MR PREDICT scores rely on manual assessment of imaging variables, including the Alberta Stroke Program Early CT Score, collateral status, and occlusion location. Considerable variability exists among stroke specialists when assigning these measures, whereas AI models can automatically extract imaging features directly from CT scans, reducing subjectivity while improving the consistency of prognostic assessment.

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A key finding from this study showed that neurologists predicted more favourable functional outcomes than patients ultimately achieved, whereas neither the AI model nor the MR Predict score did. Clinicians overestimated the benefits of reperfusion therapies, while factors such as older age and male sex were weighted too negatively. These findings highlight the influence of cognitive biases on prognostic assessment and reinforce the potential for AI to provide more objective decision support when integrated alongside clinical expertise.

BUILDING BETTER AI MODELS Wegener argued that observed limitations in AI may reflect deficiencies in the outcome measures used to train current models. The mRS score provides a broad assessment of disability but does not distinguish stroke-related disability from unrelated events. Consequently, patients who die from unrelated stroke causes are still assigned the worst score. Developing more meaningful, objective endpoints, such as quantitative motor assessments, could enable AI models to better capture

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treatment effects and generate more clinically relevant predictions. As Wegener summarised, “it depends on what you feed in. What you get out is what you feed in,” underscoring that AI performance is fundamentally limited by the quality and relevance of the data used to train it. Recognising that model performance depends on the quality of input data, Wegener highlighted variables frequently overlooked by current prediction models. In the prospective STOP-Stroke study, clinicians recorded their predicted prognosis and the factors influencing their decisions (STOP-Stroke, unpublished data, Westphal). Preliminary data from 50 patients showed that before imaging, prognosis was driven primarily by National Institutes of Health Stroke Scale (NIHSS) score, age, and onset-to-door time. Imaging contributed less than expected as clinicians’ assessments continued to rely on clinical data. Before discharge, frailty, cognitive decline, and previous stroke emerged as additional key predictors. Together, these findings show consideration of factors that influence clinical decisions are integral to developing sophisticated AI models.

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EXPANDING AI BEYOND ACUTE CARE Beyond acute stroke management, Wegener highlighted AI’s potential to strengthen secondary stroke prevention by identifying patients with previously undetected atrial fibrillation. As many patients have imaging features suggestive of cardioembolic stroke despite no documented arrhythmia, prolonged cardiac monitoring is often required before anticoagulation can be prescribed. To address this challenge, Wegener discussed research using UK Biobank data, where machine learning models combined cardiac imaging with structural markers of atrial cardiomyopathy to identify individuals at risk of developing atrial fibrillation (Deseoe et al., in press, 2026). It was found that the ratio of left atrial to left ventricular volume outperformed atrial size alone, with these findings subsequently validated in stroke cohorts. Comparable predictive performance was achieved using foundation models trained on routine ECGs obtained during normal sinus rhythm, outperforming blood biomarkers and conventional clinical risk scores across multiple validation cohorts, including UK Biobank, Brazilian primary care, stroke cohorts, and Holter ECG datasets.

References 1.

Herzog L et al. Deep learning versus neurologists: functional outcome prediction in LVO stroke patients undergoing mechanical thrombectomy. Stroke. 2023;54(7):1830-9.

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Although prospective clinical trials are still required to establish whether these approaches improve patient outcomes, the findings suggest that AI can detect subtle signs of future atrial fibrillation using tests that are already routinely performed, enabling earlier identification of high-risk patients and more timely secondary stroke prevention.

FUTURE DIRECTIONS Looking ahead, the successful integration of AI into routine stroke care will depend on more than advances in algorithm performance. Developing clinically meaningful outcome measures, incorporating overlooked prognostic variables, and validating models across diverse populations will be essential. Supporting this effort, Wegener highlighted the European MAGIC Consortium, a multicentre initiative that brings together anonymised clinical and stroke imaging datasets from across Europe.3 By creating large, diverse datasets for AI development and validation, the consortium aims to improve model robustness and accelerate applications ranging from prognostic prediction to treatment selection and secondary stroke prevention. Prospective clinical trials will then be required to determine whether these technologies improve clinical decision-making and patient outcomes.

Berkhemer OA et al.; MR CLEAN Investigators. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372(1):11-20.

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Baazaoui H et al. The Multicentre Acute Ischemic Stroke imaGIng and Clinical data (MAGIC) repository: rationale and blueprint. Front Neuroinform. 2025;18:1508161.

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Redefining Dementia with Lewy Bodies: From Clinical Diagnosis to Targeted Therapies Author:

Katrina Thornber, EMJ, London, UK

Citation:

EMJ Neurol. 2026;14[1]:25-28. https://doi.org/10.33590/emjneurol/5CY897MD

DESPITE being the second most common degenerative dementia after Alzheimer’s disease, dementia with Lewy bodies (DLB) remains underrecognised, and disease-modifying treatments are not currently available. Experts at the European Academy of Neurology (EAN) Congress 2026 explored the evolving understanding of DLB, including advances in diagnosis, emerging biological definitions of disease, and the expanding therapeutic landscape. The session, held jointly with the European Section of the Movement Disorder Society, was chaired by Irena Rektorová, Masaryk University, Brno, Czechia; and Dag Aarsland, King's College London, UK.

REFINING THE DIAGNOSIS OF DEMENTIA WITH LEWY BODIES Opening the session, Evelien Lemstra, Amsterdam University Medical Centres, the Netherlands, highlighted the challenges associated with recognising DLB, a heterogeneous disorder with diverse clinical presentations. Although currently incurable, many symptoms can be treated, and early diagnosis remains essential to enable appropriate management. She emphasised that patients with DLB experience poorer outcomes compared with those with Alzheimer’s disease, including higher healthcare costs and increased likelihood of nursing home admission,1 raising the possibility that earlier recognition and intervention could improve future outcomes. Lemstra explained that DLB is characterised by α-synuclein pathology, although Alzheimer’s disease-related pathology is also concurrently present in a substantial proportion of patients. Unlike Alzheimer’s disease, where memory and language impairment are often prominent, DLB is typically associated with deficits in executive function, visuospatial abilities, and attention. CC BY-NC 4.0 Licence

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In 2017, the DLB Consortium published a refined diagnostic criterion, which distinguishes clearly between clinical features and diagnostic biomarkers.2 The clinical diagnostic framework is based on characteristic clinical features, with the ‘central feature’ being dementia.2 In addition, ‘core features’ include cognitive fluctuations, recurrent visual hallucinations, parkinsonism, and rapid eye movement sleep behaviour disorder (RBD). Cognitive fluctuations may involve marked variations in alertness and attention, with patients appearing relatively well at some times and markedly drowsy or confused at others. Visual hallucinations are often an early and distinctive feature of DLB, while parkinsonism may be absent at disease onset in many patients. Lemstra highlighted that many patients with DLB are unable to tolerate conventional antipsychotic treatments due to neuroleptic sensitivity. RBD, which involves abnormal behaviours during the dream phase of sleep, is also considered a characteristic feature of DLB. Additional ‘supportive features’ described in the diagnostic criteria include postural instability, syncope, autonomic dysfunction, and psychiatric symptoms.

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The diagnostic criteria also incorporate indicative biomarkers, including abnormalities on dopamine transporter imaging (DATScan; GE HealthCare, Chicago, Illinois, USA), myocardial scintigraphy using metaiodobenzylguanidine (MIBG), and polysomnography-confirmed RBD. Supportive biomarkers include relative preservation of medial temporal structures compared with Alzheimer’s disease, characteristic findings on fluorodeoxyglucose PET, including the cingulate island sign, and early electroencephalographic slowing. A key clinical challenge is distinguishing DLB from Parkinson’s disease dementia, given the clinical overlap between these disorders. The 1-year rule remains central to this distinction: when dementia occurs before or within 1 year of the onset of parkinsonism, the diagnosis is DLB, whereas Parkinson’s disease dementia refers to dementia developing after Parkinson’s disease is well-established.

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TOWARDS A BIOLOGICAL DEFINITION OF LEWY BODY DISEASE Lemstra explained that Lewy body disease encompasses many phenotypes, including DLB, Parkinson’s disease, Parkinson’s disease mild cognitive impairment, Parkinson’s disease dementia, prodromal Parkinson’s disease, mild cognitive impairment with Lewy bodies, prodromal DLB, and idiopathic RBD. As these phenotypes are mainly clinically defined, there is substantial overlap in symptomology, and Lemstra explained that this can be confusing for patients. Therefore, there has been a shift towards biologically defined disease. Rather than defining disease solely by clinical presentation, biological classifications aim to identify the underlying protein pathology, regardless of whether clinical symptoms are present. A major development enabling this transition has been the ability to detect α-synuclein pathology using real-time quaking-induced conversion, also known as a seeding amplification assay. This technique detects the aggregation properties of

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α-synuclein and has demonstrated high sensitivity and specificity for Lewy body diseases in selected cohorts.3 Although cerebrospinal fluid currently provides the strongest results, α-synuclein detection in skin samples and olfactory mucosa may provide less invasive diagnostic approaches in the future. In 2024, two proposed biological frameworks for Lewy body disease were published: the Neuronal Alpha-Synuclein Disease Integrated Staging System,4 and the SynNeurGe research diagnostic criteria.5 This first framework proposes that α-synuclein aggregation occurs first, followed by neurodegeneration, clinical symptoms, and functional impairment. The two main anchors for the staging system are α-synuclein pathology measured by real-time quaking-induced conversion and dopaminergic degeneration measured by DATScan. In comparison, SynNeurGe focuses on biological disease states rather than stages. It incorporates genetic status, α-synucleinopathy, neurodegeneration, and clinical symptoms to classify patients according to underlying biology. Importantly, neither of these frameworks is yet validated for clinical practice, and is instead used as research criteria to facilitate trial design. Important uncertainties remain, including whether pathological processes occur in a consistent sequence, how biomarker changes relate to clinical progression, and whether individuals with biological evidence of α-synuclein pathology but no symptoms should be considered patients or individuals at risk of future disease. Furthermore, Lemstra noted that Alzheimer’s co-pathology contributes to disease progression and survival in DLB,6 highlighting the importance of incorporating co-pathologies into future biological classification frameworks.

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CURRENT TREATMENTS AND THE SEARCH FOR DISEASEMODIFYING THERAPIES Aarsland highlighted the limited evidence base for managing DLB. Currently, the strongest evidence supports cholinesterase inhibitors, with rivastigmine and donepezil demonstrating beneficial effects in DLB. These treatments are generally well tolerated and remain the mainstay of therapy, although the supporting studies were conducted approximately 2 decades ago, highlighting the need for new approaches. Psychosis remains a major treatment challenge. Evidence for antipsychotic use specifically in DLB is limited, although quetiapine and clozapine appear least likely to worsen parkinsonism, according mostly to anecdotal evidence, Aarsland explained. Beyond symptomatic therapies, multiple disease-modifying strategies are under investigation. Given the central role of α-synuclein pathology in DLB, several approaches aim to reduce α-synuclein production, prevent aggregation, limit its spread, or enhance degradation. However, robust evidence for these strategies remains limited. Nevertheless, Aarsland highlighted several Phase II trials investigating different therapeutic approaches, including servimecine (CT1812), neflamapimod, and nilotinib, which have generated encouraging early findings. For example, servimecine was investigated in 130 patients with mild-to-moderate Lewy body disease over 6 months.7 The study met its primary endpoints of safety and tolerability, with encouraging numerical improvements across behavioural, functional, cognitive, and movement-related measures, although no effects were observed on plasma biomarkers. Another study highlighted by Aarsland was a Phase II trial of nilotinib involving 43 patients with DLB over 6 months.8 Although primarily designed to assess pharmacokinetics, the study reported improvements in several clinical and biomarker secondary measures, including

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a reduced number of falls, improved dopamine and Alzheimer’s-related biomarkers, and improved cognition compared with placebo.

α-synuclein seeding amplification assays could support patient stratification, while quantitative measures of α-synuclein signal may eventually provide outcome measures for disease-modifying therapies.

THE FUTURE OF DLB RESEARCH

Concluding the session, Aarsland emphasised that the field is moving towards biologically based disease classification, where patients may ultimately be characterised by their individual patterns of protein pathology rather than traditional clinical diagnoses. This could enable personalised combinations of therapies targeting specific pathological processes. Although DLB research remains behind that of Alzheimer’s disease and Parkinson’s disease, increasing trial activity and advances in biomarkers offer the prospect of more targeted treatments in the future.

Aarsland noted that there are currently around 40 active trials in Lewy body disease, with 11 including DLB populations. However, clinical trials remain challenging due to the lack of a universally accepted outcome measure. Symptoms vary considerably between patients, making it difficult to detect treatment effects. Initiatives such as the Core Outcome Set for DLB9 and the Lewy Body Dementia‐Domain Rating Scale (LBD‐DRS)10 aim to address these limitations. Biomarkers may also transform future trials.

References 1.

Mueller C et al. The prognosis of dementia with Lewy bodies. Lancet Neurol. 2017;16(5):390-8.

McKeith IG et al. Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB Consortium. Neurology. 2017;89(1):88-100.

Helbling C et al. α-Synuclein seed amplification assay methodology and performance in Parkinson’s disease, lewy body dementia, and multiple system atrophy: a meta-analysis. Clin Biochem. 2026;142:111093.

Simuni T et al. A biological definition of neuronal α-synuclein disease: towards an integrated staging system for research. Lancet Neurol. 2024;23(2):178-90.

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Höglinger GU et al. A biological classification of Parkinson's disease: the SynNeurGe research diagnostic criteria. Lancet Neurol. 2024;23(2):191-204.

van de Beek M et al. Association of the ATN research framework with clinical profile, cognitive decline, and mortality in patients with dementia with lewy bodies. Neurology. 2022;98(12):e1262-e72.

Galvin JE et al. Phase 2 study of zervimesine (CT1812) in participants with mild-to-moderate dementia with Lewy bodies (DLB). Alzheimers Dement. 2025;21(12):e71004.

Pagan F et al. Safety, cognitive, and behavioral outcomes in patients with dementia with lewy bodies treated with nilotinib. J Clin Med. 2025;14(12):4245.

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Kane JPM et al. A common outcome set for trials in dementia with Lewy bodies (DLB COS). Alzheimer's Dement. 2025;11:e70134.

10. Kane JPM et al.; The Lewy Body Dementia Domain Rating Scale Steering Group. The lewy body dementia domain rating scale: an update. Alzheimers Dement. 2025;21(Suppl 5):e102206.

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Poster Review

Advances in Understanding Disease Activity, Functional Outcomes, and Treatment Response in CIDP These poster presentations took place as part of the American Academy of Neurology (AAN) Annual Meeting, held between 18th–22nd April, 2026 in Chicago, Illinois, USA; the Canadian Neurological Sciences Federation (CNSF) Annual Congress, held between 25th–28th May, 2026 in Banff, Canada; the Peripheral Nerve Society (PNS) Annual Meeting, held between 13th–18th June, 2026 in Maastricht, the Netherlands; and the European Academy of Neurology (EAN) Congress, held between 27th–30th June, 2026 in Geneva, Switzerland Support:

The publication of this article was supported by argenx.

Speakers:

Jeffrey Allen,1 Hans Katzberg,2 Christian Eggers,3 Daniëlle Krijgsman,4 Roger Collet-Vidiella5 1. University of Minnesota, USA 2. Ottawa Hospital Research Institute, Canada 3. Kepler University Hospital, Linz, Austria 4. Center for Translational Immunology, University Medical Center Utrecht, the Netherlands 5. Neuromuscular Diseases Unit, Hospital de La Santa Creu I Sant Pau, Universitat Autònoma de Barcelona, Spain

Disclosure:

Allen reports consulting fees from Akcea Therapeutics, Alexion, Alnylam, Annexon Biosciences, argenx, CSL Behring, Grifols, Immunovant, ImmuPharma, Johnson & Johnson, and Takeda, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Alnylam, Annexon Biosciences, argenx, CSL Behring, and Takeda. Katzberg reports disclosures from Abcuro, Alexion, Alnylam, argenx, CSL Behring, Dianthus, Dyne, Merz, Octapharma, Roche, Takeda, and UCB. Eggers reports disclosures from argenx, Biogen, GlaxoSmithKline, and UCB. Krijgsman and Collet-Vidiella have declared no conflicts of interest.

Acknowledgements:

Writing assistance was provided by Helen Boreham, HB Medical (UK) Ltd, Wetherby, UK.

Disclaimer:

Prescribing information for healthcare professionals in the EU for Vyvgart ▼ (efgartigimod alfa) 20 mg/mL concentrate for solution for infusion and Vyvgart 1,000 mg solution for injection can be found here and for Vyvgart 1,000 mg solution for injection in the UK can be found here. ▼This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. Adverse events reporting information can be found at the end of this article.

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Keywords:

ADHERE, ADHERE+, chronic inflammatory demyelinating polyneuropathy (CIDP), efgartigimod, grip strength, IgG autoantibody, Inflammatory Neuropathy Cause and Treatment (INCAT) score, neurofilament light (NfL), post-hoc analysis, treatment naïve.

Citation:

EMJ Neurol. 2026;14[1]:29-37. https://doi.org/10.33590/emjneurol/34B7G51S

PHARM

ERSH

Meeting Summary Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare, severe, progressive, immune-mediated disease characterised by progressive or relapsing muscle weakness and sensory disturbance, which can lead to irreversible disability. The neonatal Fc receptor (FcRn) blocker efgartigimod is approved for the treatment of CIDP based on the pivotal ADHERE trial, in which it reduced relapse risk, improved disability scores, and was well tolerated in patients with CIDP. This article summarises data from several post-hoc analyses of the ADHERE trial presented as posters at leading neurology congresses in 2026. In the cohort of patients from the ADHERE trial who were treatment naïve and recently diagnosed with CIDP, efgartigimod showed evidence of clinical improvement (ECI) across multiple functional domains. Efgartigimod also demonstrated long-term improvements in grip strength and improved the key measure of arm and leg disability in patients with CIDP across the wider ADHERE population. Findings from molecular analysis showed a reduction in IgG autoantibody signatures in efgartigimod-treated patients in ADHERE, consistent with its mechanism of action, and identified neurofilament light (NfL) as a potentially useful biomarker for axonal damage in CIDP. Collectively, these analyses reflect the continued evolution of CIDP research, linking clinical outcomes with emerging biological insights to expand understanding of treatment response, disease activity, and patient heterogeneity.

Background CIDP is a chronic, progressive, immunemediated polyradiculoneuropathy characterised by demyelination, resulting in proximal and distal weakness and sensory disturbance.1,2 Axonal damage can develop over time, leading to irreversible disability in some patients.2-4 As the CIDP field continues to evolve, there is growing interest in integrating clinical outcomes with emerging insights into disease biology to better understand treatment response, disease biology, and patient heterogeneity.

of the only part of the IgG antibody that normally binds FcRn.5,6 The pivotal ADHERE study (NCT04281472) and its open-label extension ADHERE+ (NCT04280718) assessed the efficacy and safety of efgartigimod in CIDP (Figure 1).7-10 In this randomised, double-blinded, placebo-controlled trial, efgartigimod reduced relapse risk; led to clinically meaningful improvements in functional ability, daily activity, and grip strength versus placebo; and was well tolerated in participants with CIDP.7

Efgartigimod is a human IgG1 antibody Fc fragment that has been engineered for increased affinity to FcRn compared with endogenous IgG and is uniquely composed 30

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Figure 1: ADHERE and ADHERE+ study design.7-10

ADHERE screening, ≤4 weeks

ADHERE run-in period, ≤12 weeks

ADHERE Stage A, open-label phase, ≤12 weeks

Participants with an accurate diagnosis of CIDP identified for inclusion.

Prior CIDP treatments stopped and disease worsening assessed to confirm active disease.

All participants treated with efgartigimod PH20 SC; proportion of participants with improvement assessed.

ADHERE Stage B, randomised (1:1), placebo-controlled phase, ≤48 weeks Effect of efgartigimod PH20 SC versus placebo to prevent disease relapse assessed.

ADHERE+ open-label extension study, ≤2 years Long-term safety and efficacy of efgartigimod PH20 SC assessed.

CIDP: chronic inflammatory demyelinating polyneuropathy; PH20: recombinant human hyaluronidase; SC: subcutaneous.

Patients Who Are Treatment Naïve in ADHERE Patients who are treatment naïve are an underrepresented population in CIDP clinical trials, with limited evidence regarding early disease trajectories and first-line treatment response. Jeffrey Allen from University of Minnesota in the USA presented results at the American Academy of Neurology (AAN) 2026 Annual Meeting from a posthoc analysis of the open-label Stage A of the ADHERE trial in patients with a CIDP diagnosis <1 year who had never received prior CIDP treatment. This marks the first report from a large exploratory data set of efgartigimod in a patient population with CIDP who are treatment naïve.11 In total, 24 of the 322 patients in the ADHERE trial were treatment naïve. Mean age was 59.5 years, 66.7% were male, and the mean time since CIDP diagnosis was 2.4 months. All patients had unstable active disease at baseline, defined as abnormal examination with progressive or relapsing course.11 During Stage A of the ADHERE trial, 87.5% (n=21/24) of patients who were treatment naïve demonstrated confirmed ECI after ≤12 weeks treatment with open-label efgartigimod. The time to initial confirmed ECI was 39.5 days.11 Improvements meeting or exceeding the minimal clinically important difference (MCID) were reported with efgartigimod from Stage A baseline to Stage A last CC BY-NC 4.0 Licence

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assessment across a range of efficacy measures. Patients who were treatment naïve who received efgartigimod showed a mean (standard error) reduction of 1.0 (0.2) in Inflammatory Neuropathy Cause and Treatment (INCAT) score and a 10.7 (2.6) improvement in Inflammatory Rasch-Built Overall Disability Scale (I-RODS) centile metric score. Hand grip strength scores also improved by 15.3 (3.9) and 14.8 (3.4) kPa in the dominant and non-dominant hand, respectively.11

Key Takeaways

In this post-hoc analysis of the ADHERE trial, treatment with efgartigimod resulted in clinical improvements in patients who were treatment-naïve and recently diagnosed with CIDP, with nearly nine in 10 achieving confirmed ECI and a median time to response of ~40 days. Clinically meaningful improvements were observed across multiple functional domains, including disability, daily activities, and grip strength, with changes meeting or exceeding MCID thresholds. These findings add to the limited evidence base in treatment-naïve CIDP and provide insight into treatment response early in the disease course. Efgartigimod is approved in the USA irrespective of prior treatment status, whereas in Europe it is not currently indicated as a first-line treatment option.12

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Impact of Efgartigimod Treatment on Grip Strength Hans Katzberg from Ottawa Hospital Research Institute in Canada, presented results from a post-hoc analysis of the ADHERE/ADHERE+ study at the Canadian Neurological Sciences Federation (CNSF) 2026 Annual Congress, which evaluated the effect of efgartigimod treatment on grip strength.10 Reduced grip strength in CIDP impacts daily tasks such as holding objects, steering, and writing, thereby compromising patients’ quality of life and independence.1 Grip strength is also an objective, well-established, and convenient measure of muscle impairment.13 Reference values for grip strength (both hands) in healthy adults vary by age and sex; however, an increase of ≥8 kPa is considered an MCID.14-16 This post-hoc analysis assessed grip strength in Stage A responders from ADHERE run-in baseline through to Week 36 of the ADHERE+ open-label extension study, with a data cutoff of 16th February 2024. In total, 322 patients entered ADHERE Stage A, 221 were randomised and treated in ADHERE Stage B, and 228 rolled over and were treated in ADHERE+. The mean age of these 228 rolledover patients was 53.2 years, 62.3% were male, and grip strength in the dominant hand at ADHERE Stage A baseline was 39.0 kPa.10 Results showed an early clinical improvement in grip strength in patients treated with efgartigimod. Among those who received efgartigimod in ADHERE Stage A, the median time to first improvement was fastest for grip strength as compared to other clinical measures. Improvement in grip strength by ≥8 kPa occurred at 4.1 weeks, compared with 8.3 weeks for adjusted INCAT ≥1-point improvement and 6.4 weeks for I-RODS centile metric score ≥4-point improvement.10 During ADHERE Stage A, 66.5% (n=214/322) of patients reported ECI, defined as a ≥8 kPa improvement in either hand for mean grip strength, a ≥1-point improvement for adjusted INCAT, or a ≥4-point improvement for I-RODS centile metric score.15,16 Overall, 32

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80.4% (n=172/214) of efgartigimod responders achieved a ≥8 kPa improvement in either hand for mean grip strength. In Stage B, treatment with efgartigimod reduced the relative risk of grip strength deterioration by 71.5% compared with placebo, based on a 16 kPa relapse threshold from Stage B baseline in either hand (hazard ratio: 0.2850; 95% CI: 0.1517–0.5352; p<0.001).10 Notably, improvements in dominant hand grip strength with efgartigimod were sustained from ADHERE Stage A baseline to Week 36 of ADHERE+ and these improvements corresponded with time on treatment. A similar trend was noted for non-dominant grip strength scores (Figure 2).10 Looking at the cumulative magnitude of grip strength response, 69.8%, 50.3%, 38.9%, and 24.8% of patients achieved ≥8, ≥16, ≥24, and ≥32 kPa improvement, respectively, in grip strength in any hand compared with ADHERE run-in baseline by Week 36 of ADHERE+.10

Key Takeaways

Grip strength is an objective and patientrelevant measure of functional ability in CIDP, reflecting aspects of daily activity that are directly meaningful to patients. In this post-hoc analysis of ADHERE/ ADHERE+, improvements in grip strength were observed early and were sustained with continued efgartigimod treatment, with approximately 40–50% of patients achieving two-to-three times the MCID over extended follow-up. Together with the reduction in relapse risk observed in ADHERE, these findings support grip strength as a useful functional outcome for characterising treatment response in CIDP.1

INCAT Score Improvements with Efgartigimod The INCAT score is the standard measure of arm and leg disability in CIDP.15,17 The overall disability score is derived from the sum of the individual arm and leg disability scores. Scores range from 0=no disability to 10=maximum disability, with a decrease

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Figure 2: Dominant hand grip strength across ADHERE–ADHERE+ study in Stage A responders.10

An increase of ≥8 kPa in grip strength is considered a minimal clinically important difference.14,15 In ADHERE, participants receiving CIDP treatment entered a ≤12-week run-in during which CIDP treatments were withdrawn to identify participants with active disease. Mean (SE) dominant hand grip strength score at run-in baseline: 46.6 kPa (1.75; n=191/221; Stage B efgartigimod group: 44.4 kPa [2.39], n=97; Stage B placebo group: 48.9 kPa [2.57], n=94). Mean change in dominant hand grip strength from run-in baseline to Stage A baseline: –8.2 kPa (0.71; n=191/221; Stage B efgartigimod group: –8.1 kPa [0.99], n=97; Stage B placebo group: –8.2 kPa [1.02], n=94). CIDP: chronic inflammatory demyelinating polyneuropathy; PH20: recombinant human hyaluronidase; SC: subcutaneous; SE: standard error.

of ≥1 point considered to be an MCID.15,17 At the Peripheral Nerve Society (PNS) Annual Meeting 2026, Christian Eggers from Kepler University Hospital, Linz, Austria, presented a post-hoc analysis of patients who reported an improvement in their INCAT scores to normal or near-normal functional ability (i.e., INCAT score of 0 or 1) in the ADHERE/ ADHERE+ trial. Data cutoff for this interim analysis was 19th December 2025.18 At ADHERE Stage A baseline, the mean (SD) INCAT score in efgartigimod responders was 4.6 (1.7) and no patient had an INCAT score less than 2. Posthoc analysis showed an increase in the proportion of responders attaining an INCAT score of 0 or 1 over the course of the ADHERE/ADHERE+ study (Figure 3).18 Overall, 39.3% (n=77/196) of Stage A responders reached an INCAT score ≤1 at any point during ADHERE+.18 Of these, an INCAT score of 0 or 1 was maintained at CC BY-NC 4.0 Licence

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two or more consecutive visits in 80.5% (n=62/77), equivalent to a period of 12 weeks; and maintained for ≥3 consecutive visits (24 weeks) in 70.1% (n=54/77).18 Of note, efgartigimod-treated patients who reached an INCAT score of 0 or 1 also reported a higher mean improvement across all efficacy outcomes, including adjusted INCAT, I-RODS centile metric, and grip strength scores, compared with those who did not attain an INCAT score ≤1.18

Key Takeaways

This post-hoc analysis showed that nearly 40% of ADHERE Stage A responders treated with efgartigimod attained an INCAT score of 0 or 1 at any time during ADHERE+. Of these patients, 80.5% sustained an INCAT score of 0 or 1 for ≥3 months and 70.1% maintained it for ≥6 months. Patients who achieved an INCAT score of 0 or 1 on efgartigimod showed greater improvement

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Figure 3: Stage A responders with INCAT score of 0 or 1 in ADHERE/ADHERE+.18

39.3

Best assessment corresponds to the lowest measurement of INCAT score during ADHERE+, compared with that recorded at run-in or Stage A baseline. a

EFG: efgartigimod; INCAT: Inflammatory Neuropathy Cause and Treatment; PBO: placebo.

across all efficacy measures from Stage A baseline, with improvements remaining clinically meaningful regardless of threshold attainment. These findings suggest that normal to near-normal functional ability may be an achievable outcome for a subset of patients with CIDP and support consideration of low disability as a meaningful treatment goal in CIDP.18

IgG Autoantibody Signatures in the ADHERE Trial Evidence suggests an involvement of IgG responses in CIDP, yet pathogenic autoantibodies have not been consistently identified across the broader patient population.7,19-22 Autoantibodies to myelinassociated components, which may include glycolipids such as galactocerebroside and sulfatide, have been reported in ~40% patients with CIDP, indicating an incomplete understanding of antibodymediated mechanisms in CIDP.23-25 While the significance of anti-glycolipid antibodies in CIDP remains unclear, similar antibodies have been implicated in other immunemediated neuropathies, including Guillain-Barré syndrome.23,26

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At the PNS 2026 Annual Meeting, Daniëlle Krijgsman, from University Medical Center Utrecht in the Netherlands, presented a study of IgG autoantibody signatures from the ADHERE trial that aimed to improve understanding of disease-associated antibody profiles in CIDP.27 This study assessed the presence of IgG autoantibodies against glycolipids, including gangliosides, in patients with CIDP at baseline and the end of Stage A of ADHERE, using a glycoarray multiplex assay to assess glycolipid reactivity. This glycoarray included 16 single glycolipid/ phospholipid targets and 120 heteromeric complexes printed in duplicate. Fluorescently labelled anti-human IgG antibodies were used to quantify binding, which was measured in fluorescence intensity units.27 Although natural anti-glycolipid antibodies may contribute to pathogen defence and immune homeostasis, altered anti-glycolipid IgG reactivity was observed in CIDP. A numerically larger percentage of Stage A CIDP baseline samples (62%) from ADHERE showed at least one raised IgG-positive signal against any antigen as compared to healthy controls (55%). Distinct IgG antiglycolipid profiles were seen across CIDP subtypes, with asymmetric and atypical CIDP showing a different profile compared to typical CIDP.27

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Analysis of IgG anti-glycolipid antibody count at baseline by prior CIDP treatment revealed that patients who had received treatment with Igs prior to entering ADHERE Stage A had the largest IgG antibody repertoire of the groups investigated. This suggests that prior treatment is a factor to consider in future anti-glycolipid IgG analyses in patients with CIDP.27

constrained by small sample sizes, heterogeneous patient populations, and limited longitudinal data.29-32 NfL itself is a structural protein indicative of ongoing axonal damage, but is not disease specific and varies naturally with age.29,30,33-35 In healthy individuals, mean serum NfL levels independent of age were reported to be <13–20 pg/mL, corresponding to NfL z-scores of ≤1.56.33,34

N-acetylgalactosamine-GD1a IgG seropositivity was found more frequently in Stage A responders than non-responders (33.5% versus 23.5%), whereas no predominant IgG specificity towards a single glycolipid was observed among efgartigimod non-responders.27

The ADHERE trial represents the largest and most comprehensive dataset to evaluate NfL in patients with CIDP to date.28 Serum NfL was measured at Stage A baseline in 214 patients and samples were collected throughout the study. The baseline demographic and patient characteristics of this biomarker set reflected that of the overall ADHERE population.28

Overall, 19 of the 20 anti-glycolipid IgGs detected in ≥30% of patients with CIDP at baseline showed a significant reduction in mean levels at the end of ADHERE Stage A, regardless of treatment response.27

Key Takeaways

This exploratory analysis identified a broad range of anti-glycolipid IgG reactivities in a large CIDP cohort from ADHERE, using an experimental glycoarray approach. Most anti-glycolipid IgG signals decreased by the end of Stage A, consistent with the IgG-lowering mechanism of efgartigimod. In addition, N-acetylgalactosamine-GD1a IgG seropositivity was more common among Stage A responders, suggesting that specific IgG signatures may warrant further investigation as markers of biological heterogeneity or treatment response in CIDP.27

NfL as a Potential Biomarker in CIDP Roger Collet-Vidiella from Hospital de la Santa Creu I Sant Pau in Barcelona, Spain, presented an analysis of the ADHERE trial at the European Academy of Neurology (EAN) 2026 Congress, which looked at NfL levels as a biomarker in CIDP.28 The role of NfL in CIDP is not fully established and prior studies have been CC BY-NC 4.0 Licence

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At Stage A baseline, the mean (SD) serum NfL level was 18.9 (22.6) pg/mL, corresponding to a mean NfL z-score of 0.64 (1.6). Serum NfL levels >20 pg/mL, corresponding to a z-score of ≥1.5, were reported in 24.3% of patients. Notably, NfL z-scores at Stage A baseline were significantly higher in patients with unstable active disease (CIDP Disease Activity Status [CDAS] 5) than in those with stable active disease (CDAS 2–4; p=0.03). Baseline NfL z-scores were similar across CIDP disease types, with no significant difference noted between typical and atypical CIDP (p=0.51).28 Serum NfL levels remained stable during ADHERE Stage A in responders treated with efgartigimod. In those with baseline levels within the healthy reference range (≤20 pg/mL), levels were stable during Stage A, while in those with elevated baseline levels (>20 pg/mL), NfL levels decreased by 18%. Baseline serum NfL z-scores did not differ between efgartigimod responder and non-responder groups.28 In patients with elevated baseline NfL who responded to efgartigimod in ADHERE Stage A, serum NfL levels declined during Stage A and further decreased during Stage B. This change was seen irrespective of subsequent treatment strategy in Stage B, i.e., occurred regardless of whether

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efgartigimod was continued or withdrawn. However, the interpretation of these findings is limited by the small sample sizes beyond Week 12.28

Key Takeaways

Approximately one-quarter of patients in the ADHERE trial had serum NfL levels above the healthy reference range at Stage A baseline, consistent with prior studies and potentially indicating ongoing axonal damage. Among efgartigimod responders with elevated baseline NfL, serum NfL levels declined during ADHERE Stage A and Stage B. Conversely, NfL levels remained stable with efgartigimod treatment among patients with baseline serum NfL within the healthy reference range. Overall, this study suggests that NfL levels may serve as a contextual biomarker when interpreted alongside clinical assessment in patients with CIDP. Further analyses are needed to determine whether NfL can inform prognosis or disease monitoring, particularly in cases with elevated baseline levels or dynamic changes over time.28

Conclusion Collectively, these recent ADHERE analyses reflect the continued evolution of CIDP research, linking clinical outcomes with emerging biological insights to expand understanding of treatment response, disease activity, and patient heterogeneity. Across analyses, efgartigimod was associated with early and sustained improvements in grip strength, supported attainment and maintenance of normal to near-normal functional ability in a subset of patients, and showed clinical improvement in treatment-naïve patients recently diagnosed with CIDP. In parallel, translational findings from ADHERE provide further support for a role of IgG-mediated immune activity in CIDP and highlight the potential value of contextual biomarkers such as antiglycolipid IgG signatures and NfL in characterising disease biology and disease activity. While these biomarker findings remain exploratory and require further validation, they contribute to an evolving view of CIDP management in which clinical outcomes, patient-relevant function, and biological context are considered together to support more individualised approaches to care.

Adverse events should be reported. Reporting forms and information can be found at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. Adverse events should also be reported to argenx on reportnow@argenx.com or by using the local medical information telephone number. You will find these in the package leaflet of the SmPC. Adverse event reporting details can also be found here.

References

Rajabally YA. Chronic inflammatory demyelinating polyradiculoneuropathy: current therapeutic approaches and future outlooks. Immunotargets Ther. 2024;13:99-110.

Querol L et al. Systematic literature review of burden of illness in chronic inflammatory demyelinating polyneuropathy (CIDP). J Neurol. 2021;268(10):3706-16.

Dimachkie M, Barohn R. Chronic inflammatory demyelinating polyneuropathy. Curr Treat Options Neurol. 2013;15(3):350-66.

Ulrichts P et al. Neonatal Fc receptor antagonist efgartigimod safely and sustainably reduces IgGs in humans. J Clin Invest. 2018;128(10):4372-86.

van Doorn IN et al. Challenges in the early diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy in adults: current perspectives. Ther Clin Risk Manag. 2024;20:111-26.

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Vaccaro C et al. Engineering the Fc region of immunoglobulin G to modulate in vivo antibody levels. Nat Biotechnol. 2005;23(10):1283-8.

Allen J et al. Safety, tolerability, and efficacy of subcutaneous efgartigimod in patients with chronic inflammatory demyelinating polyradiculoneuropathy (ADHERE): a multicentre, randomisedwithdrawal, double-blind, placebocontrolled, phase 2 trial. Lancet Neurol. 2024;23(10):1013-24.

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Eggers C et al. ADHERE+ trial interim analysis: long-term safety and efficacy of efgartigimod in chronic inflammatory demyelinating polyneuropathy (CIDP). Neuromuscular Disorders. 2025;53(Suppl):105858.

17. Hughes R et al. Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol. 2001;50(2):195-201.

27. Krijgsman D et al. IgG autoantibody signatures in chronic inflammatory demyelinating polyradiculoneuropathy: interpreting glycolipid reactivity from the ADHERE trial. Poster P442. PNS Annual Meeting, 13-16 June, 2026.

Allen J et al. Long-term safety and efficacy of efgartigimod PH20 in chronic inflammatory demyelinating polyradiculoneuropathy: ADHERE/ADHERE+ trial interim analysis. J Peripher Nerv Syst. 2026;31(3):e70140.

18. Eggers C et al. Impact of efgartigimod on inflammatory neuropathy cause and treatment scores: ADHERE/ADHERE+ post hoc analysis. Poster PP01.269. ICNMD Congress, 7-11 July, 2026.

28. Collet-Vidiella R et al. Neurofilament light chain as a biomarker in chronic inflammatory demyelinating polyradiculoneuropathy: insights from ADHERE. Poster P372. EAN Congress, 27-30 June, 2026.

10. Katzberg H et al. Treatment impact of efgartigimod PH20 SC on grip strength assessment in patients with CIDP: post hoc analysis of the ADHERE/ADHERE+ study. Poster 48. CNSF Congress, 25-28 May, 2026. 11. Allen J et al. Impact of subcutaneous efgartigimod PH20 on treatment-naïve participants with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in the ADHERE trial: post hoc analyses. Poster 9-002. AAN Annual Meeting, 18-22 April, 2026. 12. Argenx. VYVGART Summary of product characteristics. Available at: https://www.medicines.org.uk/emc/ product/101239/smpc. Last accessed: 11 June 2026. 13. Tsoumanis P et al. Evaluating grasp function in patients with chronic inflammatory demyelinating polyneuropathy using dynamometers: a comprehensive review. J Clin Med Res. 2025;17(3):136-44.

19. Querol L et al. Antibodies against peripheral nerve antigens in chronic inflammatory demyelinating polyradiculoneuropathy. Sci Rep. 2017;7(1):14411.

29. Hayashi T et al. Serum neurofilament light chain in chronic inflammatory demyelinating polyneuropathy. Brain Behav. 2021;11(5):e02084.

20. Mathey EK et al. Chronic inflammatory demyelinating polyradiculoneuropathy: from pathology to phenotype. J Neurol Neurosurg Psychiatry. 2015;86(9):973-85.

30. Luigetti M et al. Serum neurofilament and free light chain levels in patients undergoing treatment for chronic inflammatory demyelinating polyneuropathy. Int J Mol Sci. 2024;25(2):1254.

21. Yan WX et al. Passive transfer of demyelination by serum or IgG from chronic inflammatory demyelinating polyneuropathy patients. Ann Neurol. 2000;47(6):765-75.

31. Godelaine J et al. Prognostic value of neurofilament light chain in chronic inflammatory demyelinating polyneuropathy. Brain Commun. 2021;3(1):fcab018.

22. Manso C et al. Anti-neurofascin-155 IgG4 antibodies prevent paranodal complex formation in vivo. J Clin Invest. 2019;129(6):2222-36.

32. Llauradó A et al. Usefulness of serum neurofilament light chain in chronic inflammatory demyelinating polyradiculoneuropathy. J Neurol Sci. 2025;470:123397.

23. Querol L, Lleixà C. Novel immunological and therapeutic insights in Guillain-Barré syndrome and CIDP. Neurotherapeutics. 2021;18(4):2222-35.

14. Merkies IS et al. Assessing grip strength in healthy individuals and patients with immune-mediated polyneuropathies. Muscle Nerve. 2000;23(9):1393-401.

24. Collet R et al. Clinical and pathophysiological implications of autoantibodies in autoimmune neuropathies. Rev Neurol (Paris). 2023;179(8):831-43.

15. Van den Bergh PYK et al. European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint Task ForceSecond revision. Eur J Neurol. 2021;28(11):3556-83.

25. Kister A, Kister I. Overview of myelin, major myelin lipids, and myelinassociated proteins. Front Chem. 2023;10:1041961. 26. Rinaldi S et al. Antibodies to heteromeric glycolipid complexes in Guillain-Barré syndrome. PLoS ONE. 2013;8(12):e82337.

33. Beltran TA. Normative values for serum neurofilament light chain in US adults. J Clin Neurol. 2024;20(1):46-9. 34. Rodero-Romero A et al. Establishing normal serum values of neurofilament light chains and glial fibrillary acidic protein considering the effects of age and other demographic factors in healthy adults. Int J Mol Sci. 2024;25(14):7808. 35. Figdore DJ et al. Determination of pediatric and adult reference intervals for neurofilament light chain (NfL) in blood and a comparison to other recent studies. J Lab Precis Med. 2024;9:29.

16. Rajabally YA et al. Minimal clinically important differences in measuring treatment effects in CIDP: history, current use, limitations, and prospects. Muscle Nerve. 2025;72(5):1042-51.

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Abstract Reviews Drawing on cutting-edge research presented at the European Academy of Neurology (EAN) Congress 2026, these abstract reviews highlight key advances in neurology. The authors discuss the significance of their findings, the implications for clinical practice, and the future directions of their research.

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Abstract Review

Risk of Epilepsy in People with Adult-Onset Hydrocephalus: Insights from the UK Biobank Authors: Jolanda Buonocore,1,2 *Francesco Fortunato,1 Enrico Fratto,1,2 Ilaria Sammarra,1 Antonio Gambardella,1 Aldo Quattrone,2 Andrea Quattrone1,2

hydrocephalus is associated with an increased risk of incident epilepsy.4

1. Institute of Neurology, Department of Medical and Surgical Sciences, University 'Magna Graecia', Catanzaro, Italy 2. Neuroscience Research Centre, University 'Magna Graecia', Catanzaro, Italy *Correspondence to francescofortunato@unicz.it

Data were obtained from the UK Biobank, a large population-based cohort with approximately 15 years of follow-up.5 The study included 483,790 controls, 5,028 individuals with epilepsy, and 320 individuals with adult-onset hydrocephalus. Logistic regression demonstrated an association between hydrocephalus and epilepsy (OR: 9.6; 95% CI: 6.4–13.8; p<0.001). Among the 29 participants with both conditions, epilepsy preceded hydrocephalus in 44.8% of cases, occurred concurrently in 13.8%, and followed hydrocephalus in 41.4%, as shown in Figure 1. In sampled cohort analyses, adult-onset hydrocephalus was associated with an increased risk of incident epilepsy, with adjusted hazard ratios ranging from 14.62 (95% CI: 7.91–27.00; p<0.001) to 23.80 (95% CI: 12.87–44.03; p<0.001) across different models. The association remained consistent after adjustment for demographic, lifestyle, vascular, and genetic factors, as well as after excluding individuals with Alzheimer’s disease and other neurodegenerative disorders. No participants with both hydrocephalus and epilepsy had undergone shunt treatment.

Disclosure: Buonocore, Fratto, and Aldo Quattrone have received grants from the Italian Ministry of University and Research (MNESYS F63C22000640002–PE0000006). Fortunato has received honoraria from Lusofarmaco and Angelini Pharma; and meeting support from Lusofarmaco, Angelini Pharma, Jazz, Eisai, and UCB. Gambardella has received honoraria from Eisai, UCB Pharma, Angelini Pharma, Epygenix Therapeutics, and Rapport Therapeutics; meeting support from Eisai, UCB Pharma, and Angelini Pharma; and has participated on advisory boards for Eisai, UCB Pharma, and Angelini Pharma. Andrea Quattrone has received grants from the Italian Ministry of Health (PNRR-MCNT2-2023-12378387) and the Italian Society of neurology; and meeting support from Novartis (Data Monitoring Committee Member PSP trial) and Ferrer (Advisory Board PSP trial). Sammarra has declared no conflicts of interest. Acknowledgements: This research has been conducted using the UK Biobank Resource under Application Number 147093. Keywords: Adult-onset hydrocephalus, epilepsy, neurodegeneration, seizures, UK Biobank. Citation: EMJ Neurol. 2026;14[1]:39-41. https://doi.org/10.33590/emjneurol/1J754K0C

SUMMARY OF KEY FINDINGS Background

The relationship between adult-onset hydrocephalus and epilepsy remains poorly characterised. Although epilepsy has been reported in neurodegenerative disorders and in paediatric or shuntrelated hydrocephalus,1-3 evidence regarding its occurrence in idiopathic adult-onset hydrocephalus is scarce. This study investigated whether adult-onset CC BY-NC 4.0 Licence

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Conclusion

These findings suggest that adult-onset hydrocephalus is associated with an increased risk of epilepsy that is not fully explained by vascular risk factors, neurodegenerative comorbidities, or shunt-related complications. The results support consideration of epilepsy in individuals with adult-onset hydrocephalus, particularly when symptoms may be subtle or overlap with cognitive or motor manifestations of the condition. The large sample size, stringent selection criteria, and comprehensive adjustment for potential confounders strengthen the findings.

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Figure 1: Temporal relationship between adult-onset hydrocephalus and epilepsy diagnoses.

A) A

n=320

n=5,028

n=29

n=4

n=13

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B) B

Mean =3.7 yrs

Mean =−9.1 yrs Epilepsy<40 years

A) The classification of participants with both hydrocephalus and epilepsy (n=29) according to the relative timing of diagnoses: epilepsy preceding hydrocephalus (n=13), diagnosed in the same year (n=4), or following hydrocephalus (n=12). B) Scatter plot of age at hydrocephalus diagnosis versus age at epilepsy diagnosis for these participants. The horizontal red dashed line marks the exclusion threshold for epilepsy diagnosed at age ≤40 years, reflecting the study’s focus on late-onset cases. Mean age differences (Δ) between conditions are indicated for each group and cases with epilepsy onset before 40 years of age were not included.

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Abstract Review

WHAT CHALLENGE DOES THIS ADDRESS?

WHAT ARE THE NEXT STEPS FOR THE RESEARCH?

Evidence on the relationship between adult-onset hydrocephalus and epilepsy is limited, particularly in adults without secondary causes of hydrocephalus. This study addresses an important evidence gap by examining whether adult-onset hydrocephalus is associated with an increased risk of developing epilepsy over time.

Prospective studies are needed to confirm these findings and to investigate the biological mechanisms linking adultonset hydrocephalus and epilepsy. Future research incorporating detailed clinical phenotyping, electroencephalography, advanced neuroimaging, and fluid biomarkers may help clarify the nature of this association and its implications for clinical practice.

RELEVANCE TO EUROPEAN PRACTICE

References

These findings may be relevant to clinicians involved in the care of people with adult-onset hydrocephalus. Awareness of a possible association with epilepsy may inform clinical assessment, particularly when patients present with symptoms that could be consistent with seizures. The study also contributes to the evidence base on neurological comorbidities in older adults.

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Pellinen J et al. Improving epilepsy diagnosis across the lifespan: approaches and innovations. Lancet Neurol. 2024;23(5):511-21.

Kamondi A et al. Epilepsy and epileptiform activity in late-onset Alzheimer disease: clinical and pathophysiological advances, gaps and conundrums. Nat Rev Neurol. 2024;20(3):162-82.

Schubert-Bast S et al. Risk and risk factors for epilepsy in shunt-treated children with hydrocephalus. Eur J Paediatr Neurol. 2019;23(6):819-26.

Buonocore J et al. Risk of epilepsy in people with adult-onset hydrocephalus: insights from the UK Biobank. Abstract OPR-023. EAN Congress, 27-30 June, 2026.

Sudlow C et al. UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 2015;12(3):e1001779.

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Ocrelizumab Treatment Interruption in Clinically Stable Multiple Sclerosis: Prospective Evidence Supporting a Time-Limited Treatment Pause Authors: Franz Felix Konen,1 Franziska Axhausen,2 Stephanie Wolff,2 Pauline Mühlenbrock,2 Stefan Gingele,1 Konstantin Fritz Jendretzky,1 Sandra Nay,1 Lea Martha Grote-Levi,1 Philipp Schwenkenbecher,1 Sven G. Meuth,3 *Thomas Skripuletz,1 Steffen Pfeuffer2 1. Department of Neurology, Hannover Medical School, Germany 2. Department of Neurology, Justus Liebig University Giessen, Germany 3. Department of Neurology, University hospital Münster, Germany *Correspondence to skripuletz.thomas@mh-hannover.de Disclosure: Konen has received research grants from the Erwin-Röverö Foundation, Merck, Novartis, and Siemens; payment or honoraria from argenx, Alexion, Merck, Novartis, Takeda, Siemens, and UCB; support for attending meetings and/or travel from argenx, Alexion, Merck, Novartis, Takeda, and Siemens; and serves on an advisory board for Takeda and Merck. Grote-Levi has received support for attending meetings and/or travel from the European Academy of Neurology (EAN) for the 2025 Congress; and financial support from the PRACTIS Clinician Scientist Program, funded by Hannover Medical School and DFG (DFG ME 3696/3). Fritz Jendretzky has received support for attending meetings and/ or travel from Merck, argenx, Novartis, and Neuraxpharm. Schwenkenbecher serves on an advisory board for Servier Deutschland GmbH for neurooncology. Gingele has received grants from Alnylam and CSL Behring; consulting fees from AstraZeneca and Purpose Pharma; payment or honoraria from AstraZeneca, Alnylam, Pfizer, Alexion, Takeda, and CSL Behring; support for attending meetings and/or travel from CSL Behring; and has participated on advisory boards for AstraZeneca and Alnylam. Meuth has received grants from the DFG (German Research Foundation), Hempel Foundation for Science, Art and Welfare, BfR (German Federal Ministry of Food and Agriculture), Ministry of Culture and Science of the state of North-Rhine-Westphalia, DMSG (German Multiple Sclerosis Society), and Heinrich-Heine University Düsseldorf; honoraria for lecturing, and travel expenses for attending meetings, from Academy 2, argenx, Alexion, Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, BioNtech, BMS, Celgene, Datamed, Demecan, Desitin, Diamed, Diaplan, DIU Dresden, DPmed, Gen Medicine and Healthcare products, Genzyme, Hexal AG, IGES, Impulze

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GmbH, Janssen Cilag, KW Medipoint, MedDay Pharmaceuticals, Medudy, Merck Serono, MICE, Mylan, Neuraxpharm, Neuropoint, Novartis, Novo Nordisk, ONO Pharma, Oxford PharmaGenesis, QuintilesIMS, Roche, Sanofi-Aventis, Springer Medizin Verlag, STADA, Chugai Pharma, Teva, UCB, Viatris, Wings for Life International, and Xcend; and research funding from the German Ministry for Education and Research (BMBF), Bundesinstitut für Risikobewertung (BfR), Deutsche Forschungsgemeinschaft (DFG), Else Kröner Fresenius Foundation, Gemeinsamer Bundesausschuss (G-BA), German Academic Exchange Service, Hertie Foundation, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, German Foundation Neurology and Alexion, Almirall, Amicus Therapeutics Germany, Biogen, Diamed, DGM e.v., Fresenius Medical Care, Genzyme, Gesellschaft von Freunden und Förderern der Heinrich-Heine-Universität Düsseldorf e.V., HERZ Burgdorf, Merck Serono, Novartis, ONO Pharma, Roche, and Teva. Skripuletz has received honoraria for lectures, travel support for meeting attendance, and/or consultancy fees from Alexion, Alnylam, Amgen, argenx, Bayer, Biogen, Bristol Myers Squibb, Centogene, CSL Behring, Grifols, Hexal, Horizon, Janssen, Merck, Novartis, Pfizer, Purpose pharma, Roche, Sanofi, Siemens, SOBI, Teva, and Viatris. Nay has received payment or honoraria from argenx, Novartis, and Merck; and support for attending meetings and/or travel from Merck. Pfeuffer has received grants from Biogen, Merck Healthcare, and Novartis; payment or honoraria from argenx, Alexion, Biogen, Hexal, Merck Healthcare, Novartis, Roche, and Sanofi Aventis; support for attending meetings and/or travel from argenx, Alexion, Biogen, Merck Healthcare, Neuraxpharm, and Roche; and has participated on an advisory board for argenx, Alexion, Biogen, Hexal, Merck Healthcare, Novartis, Roche, and Sanofi Aventis. Wolff has received grants from Novartis; consulting fees from Roche; and payment or honoraria from Mylan and Novartis. Axhausen and Mühlenbrock have declared no conflicts of interest. Keywords: B cell depletion, disease reactivation, multiple sclerosis (MS), ocrelizumab, progression independent of relapse activity, treatment de-escalation, treatment discontinuation. Citation: EMJ Neurol. 2026;14[1]:42-44. https://doi.org/10.33590/emjneurol/4OA6ULV3

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SUMMARY OF KEY FINDINGS Background

Anti-cluster of differentiation (CD)20 therapies such as ocrelizumab constitute effective treatment options for relapsing multiple sclerosis (MS).1,2 While continuous B cell depletion effectively suppresses inflammatory disease activity, prolonged treatment may be associated with cumulative infection risk, hypogammaglobulinaemia, and increasing healthcare costs.1-3 Consequently, there is growing interest in determining whether treatment can be safely paused in carefully selected patients with stable disease.4 Konen et al.5 addressed this question in a prospective, multicentre, observational cohort study conducted at two German MS centres. Patients who received ocrelizumab for at least 12 months and remained free of inflammatory disease activity during the preceding year were eligible. Outcomes of patients who interrupted treatment were compared with those who continued therapy using 4:1 propensity score matching.5

Findings

Among 655 eligible patients, 290 were included in the matched analysis, comprising 58 patients who interrupted ocrelizumab treatment and 232 who continued therapy.5 Median follow-up after treatment interruption was 28.5 months.5 The primary outcomes were combined inflammatory activity (clinical relapse and/or new MRI lesions) and progression independent of relapse activity.5 Inflammatory disease activity remained largely suppressed during the first 2 years after treatment interruption.5 No statistically significant increase in combined inflammatory activity or disability progression was observed compared with patients who remained on continuous treatment.5 Receiver operating characteristic analyses further suggested that the anti-inflammatory benefit of ocrelizumab plateaued after approximately 29–30 months of therapy, whereas the CC BY-NC 4.0 Licence

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Abstract Review

likelihood of recurrent disease activity increased after approximately 30–32 months without treatment, indicating that protection gradually wanes during prolonged treatment interruption.5 At the time of treatment interruption, more than 90% of patients demonstrated complete peripheral B cell depletion. During the treatment-free period, CD19+ B cells gradually repopulated, with recovery beginning within the first year and continuing for up to 48 months.5 Serum IgG concentrations also increased progressively, suggesting partial recovery from treatmentassociated hypogammaglobulinaemia.5

Conclusion

These prospective data suggest that, in carefully selected patients with clinically stable MS, a planned interruption of ocrelizumab following approximately 30 months of treatment may represent a feasible short-term management strategy without an immediate increase in inflammatory disease activity.5 Importantly, these findings support treatment pausing rather than permanent discontinuation and emphasise the need for ongoing clinical and MRI monitoring, particularly beyond 2 years after treatment interruption.5

WHAT CHALLENGE DOES THIS ADDRESS? The optimal duration of anti-CD20 therapy remains uncertain, and clinicians increasingly face the challenge of balancing sustained disease control against the risks associated with long-term immunosuppression. This study addressed the unmet need for prospective evidence informing whether temporary interruption of ocrelizumab may reduce cumulative treatment burden while maintaining disease stability in selected patients.

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RELEVANCE TO EUROPEAN PRACTICE Across Europe, neurologists are increasingly considering personalised treatment strategies that minimise long-term safety risks without compromising efficacy. These findings provided important prospective evidence supporting individualised treatment pauses in clinically stable patients receiving ocrelizumab. Although treatment interruption should not yet be considered routine practice, the results may help inform shared decision-making regarding treatment duration, particularly in patients at increased risk of infections or hypogammaglobulinaemia. The study also reinforced the importance of structured clinical and MRI surveillance during treatment-free intervals.

WHAT ARE THE NEXT STEPS FOR THE RESEARCH?

help individualise the timing of treatment re-initiation. Ultimately, RCTs comparing continuous treatment with biomarkerguided treatment pauses will be required before treatment interruption can be incorporated into routine clinical practice.

References 1.

Hauser SL et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. 2017;376(3):221-34.

Montalban X et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med. 2017;376(3):209-20.

Cellerino M et al. Predictors of ocrelizumab effectiveness in patients with multiple sclerosis. Neurotherapeutics. 2021;18(4):2579-88.

Jouvenot G et al.; OFSEP Investigators. Highefficacy therapy discontinuation vs continuation in patients 50 years and older with nonactive MS. JAMA Neurol. 2024;81(5):490-8.

Konen FF et al. Discontinuation of ocrelizumab in multiple sclerosis: re-occurrence of disease activity. Abstract OPR-118. EAN Congress, 27-30 June, 2026.

Further prospective studies with larger patient populations and longer follow-up are needed to confirm these findings and better define which patients are most suitable for treatment interruption. Future research should also establish biomarkers including B cell kinetics and Ig recovery that may

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Abstract Review

Genetic and Early-Life Vulnerability in Functional Neurological Disorder: A Large-Scale Retrospective Cohort Study Authors: *Ester Ipavic,1,2 Thomas A. Pollak,3,4 Timothy R. Nicholson,3,4 Mark J. Edwards,3,4 Rok Berlot1,2 1. Faculty of Medicine, University of Ljubljana, Slovenia 2. Department of Neurology, University Medical Centre Ljubljana, Slovenia 3. Neuropsychiatry Research & Education Group, Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK 4. South London and Maudsley NHS Foundation Trust, UK *Correspondence to ester.ipavic@kclj.si Disclosure: Edwards has received grant funding from National Institute for Health and Care Research (NIHR); royalties from Oxford University Press for The Oxford Specialist Handbook of Parkinson’s Disease and Other Movement Disorders; honoraria for medical advice and educational events from Teva Pharmaceuticals; financial support for lectures from the International Parkinson and Movement Disorder Society and the FND Society (FNDS); payment for expert testimony for personal injury and clinical negligence cases (medical expert reporting); is a deputy editor of the European Journal of Neurology; a Medical Advisory Board member of FND Hope and the British Association of Performing Arts Medicine; and holds shares in Brain & Mind (Brain & Mind provides neuropsychiatric and neurological rehabilitation in the independent medical sector). Berlot has received grants from the Slovenian Research and Innovation Agency, supported as a member of the research programme Medical Physics (P1-0389). Nicholson has received grants from the UK National Institute for Health and Care Research (NIHR) and Medical Research Council (MRC), including for studies related to FND; royalties from CRC Press for The Pocket Prescriber textbook series; financial support for lectures from the FND Society (FNDS); payment for expert testimony for personal injury and clinical negligence cases (medical expert reporting, including in cases of FND); is co-chair of the patient liaison committee for FNDS; a Medical Advisory Board member of FND Hope UK; and a Medical Advisory Board member and trustee of FND Action. Pollak is a co-recipient of a grant from OpenAI; has received consultancy fees from Arialys Therapeutics; and payment for expert testimony for personal injury and clinical negligence cases (medical expert reporting, including in casesof FND). Ipavic has declared no conflicts of interest.

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Keywords: Biological vulnerability, earlylife vulnerability, functional motor disorder, functional neurological disorder (FND), functional seizures, TriNetX™ (TriNetX, LLC, Cambridge, Massachusetts, USA). Citation: EMJ Neurol. 2026;14[1]:45-48. https://doi.org/10.33590/emjneurol/RA77341D

SUMMARY OF KEY FINDINGS Background

Functional neurological disorder (FND) is a common and disabling condition with diverse presentations, such as motor (weakness, tremor, dystonia, gait), sensory, cognitive, and seizure-like symptoms, often in combination.1 It is understood as a disorder of brain network dysfunction, in which the brain generates overly strong predictions about body states that override incoming sensory and motor signals, and symptoms arise from this mismatch.2 Historically, FND has been conceptualised in terms of psychological stress or traumatic experiences, often arising in childhood.3 However, contemporary models situate it within a broader biopsychosocial framework, in which early-life biological influences are poorly characterised compared to psychosocial factors. Previously reported inherited and neurodevelopmental associations with FND include Ehlers–Danlos syndrome and hypermobility spectrum disorders,4 autism spectrum disorder,5 and ADHD.6 FND may be more likely to emerge in individuals with less reliable bodily signalling and regulatory systems, which may become apparent in the context of co-existing disease (e.g., FND emerging in Parkinson’s disease).7 Similarly, disturbances of motor, sensory, or integrative processing earlier in life could predispose to FND. The authors compared the prevalence of early-life biological vulnerability factors in FND against comparator cohorts, and examined whether distinct vulnerability profiles are associated with specific FND phenotypes.

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Figure 1: Early life biological vulnerability factors in FND versus migraine and depression (A) and early life biological vulnerability factors in functional motor disorder versus functional seizures (B).

Comparison with migraine

Comparison with depression

Inherited/congenital factors Ehlers–Danlos syndromes Hypermobility syndrome Hereditary motor and sensory neuropathy Primary disorders of muscles Congenital malformations and deformations of the musculoskeletal system Congenital malformations of the nervous system Congenital ear malformations causing impairment of hearing Congenital nystagmus Chromosomal abnormalities Perinatal factors Maternal and perinatal factors, affecting the newborn Disorders of newborn related to slow fetal growth and fetal malnutrition Disorders of newborn related to short gestation and low birth weight Disorders of newborn related to long gestation and high birth weight Respiratory distress of newborn Neurodevelopmental factors Intellectual disability Communication disorders Autism spectrum disorder ADHD Specific learning disorders Motor disorders OR More records in migraine

OR More records in FND

More records in depression

More records in FND

More records in functional seizures

More records in functional motor disorder

ORs (95% CI) are shown on a logarithmic scale. Filled dots indicate significance after Bonferroni correction (p<0.0025). FND: functional neurological disorder; OR: odds ratio.

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Findings

Using TriNetX™ (TriNetX, LLC, Cambridge, Massachusetts, USA), a large electronic health records database, the authors assessed rates of genetic, congenital, perinatal, and neurodevelopmental diagnoses, selected to capture a range of early-life conditions, including those that may affect the integrity of the sensory and motor systems. Comparisons were performed between 188,868 individuals with FND and sociodemographically matched migraine and depression cohorts. The prevalence of these factors was also compared between matched cohorts of 42,015 individuals with motor FND and functional seizures. Compared with migraine and depression, FND was associated with increased odds of heritable connective tissue disorders, heritable neuromuscular disorders, and congenital malformations, including those of the musculoskeletal system and sensory organs (odds ratio [OR]: 1.7–3.0). Apart from ADHD, which was more prevalent in the depression cohort, neurodevelopmental disorders were consistently more prevalent in FND (OR: 1.9– 5.4), alongside increased rates of perinatal adversity related to short gestation, low birth weight, and newborn respiratory distress (OR: 1.8–2.6; Figure 1A). In the comparison of different clinical phenotypes, motor FND showed stronger associations with connective tissue, neuromuscular, and musculoskeletal conditions, whereas functional seizures were more strongly associated with chromosomal abnormalities and neurodevelopmental disorders (Figure 1B).

Conclusion

FND showed higher rates of early-life biological vulnerability factors than control cohorts with migraine and depression. These factors spanned several domains, indexing a broad early-life and developmental susceptibility. Distinct associations were observed for functional motor and seizure presentations. The authors’ findings support the current move from dichotomous ‘psychogenic–organic’ to more nuanced and biologically informed vulnerability–resilience models of FND accounting for the full range and varying combinations of potential biopsychosocial aetiologies.

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WHAT CHALLENGE DOES THIS ADDRESS? FND research has traditionally focused on psychological stress and trauma as key predisposing factors. While these remain important, this framing may inadvertently reinforce stigma and the outdated psychogenic–organic dichotomy. To move towards a genuinely biopsychosocial model, a better understanding of the biological underpinnings is needed. The authors’ findings represent a step in that direction, suggesting that early-life biological vulnerability factors are more prevalent in FND than in matched control conditions.

RELEVANCE TO EUROPEAN PRACTICE FND remains under-recognised and under-resourced, with stigma a persistent barrier to care. Evidence of early-life biological vulnerability may support a more comprehensive assessment and strengthen the case for appropriately resourced, multidisciplinary care.

WHAT ARE THE NEXT STEPS FOR THE RESEARCH? Replication in prospectively recruited FND cohorts is needed, given the limitations of electronic health records. Future studies could assess whether early-life biological vulnerability factors act synergistically, how these profiles influence symptom trajectories and outcomes, and why similar vulnerabilities lead to different clinical presentations.

References 1.

Ipavic E et al. Genetic and early-life vulnerability in functional neurological disorder: a large-scale retrospective cohort study. Eur J Neurol. 2026;33(1):15-16.

Hallett M et al. Functional neurological disorder: new subtypes and shared mechanisms. Lancet Neurol. 2022;21(6):537-50.

Yong K et al.; Edinburgh Paediatric FND Study Group. Functional neurological disorder in children and young people: incidence, clinical features, and prognosis. Dev Med Child Neurol. 2023;65(9):1238-46.

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Fernandez A et al. Functional neurological signs in hypermobile Ehlers–Danlos syndrome and hypermobile spectrum disorders with suspected neuropathic pain. Brain Behav. 2024;14(2):e3441.

Smythe L et al. Co-occurring functional neurological disorder and autism: an exploratory study of comorbidities in a retrospective cohort study using TriNetX. J Neurol. 2025;272(10):653.

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Tamilson B et al. Perinatal, neurodevelopmental and childhood health factors in patients with functional neurological disorder: a retrospective case-record study in a tertiary neuropsychiatry cohort. BMJ Neurol Open. 2026;8(1):e001515.

Pareés I et al. Functional (psychogenic) symptoms in Parkinson’s disease. Mov Disord. 2013;28(12):1622-7.

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Body-First and Brain-First Parkinson's Disease as a Route to Biological Trajectory-Aware Care

SUMMARY OF KEY FINDINGS

together with a higher risk of conversion to PD and to PD dementia. The phenotypes were stable over time and reproducible using unsupervised deep learning. Imaging supported divergent spreading: body-first cases showed more caudal locus coeruleus involvement and symmetrical striatal and glymphatic alterations (bottom-up, consistent with Braak staging), whereas brain-first cases showed rostral locus coeruleus changes and asymmetric alterations (top-down). Genetic analysis identified phenotype-specific variants, including TRIM40 and IP6K2, associated with worse motor and cognitive outcomes in prodromal cases.

Background

Conclusion

Author: *Massimiliano Passaretti1 1. Karolinska Institutet, Stockholm, Sweden *Correspondence to massimiliano.passaretti@ki.se Disclosure: The author has declared no conflicts of interest. Keywords: Body-first, brain-first, Parkinson's disease (PD), personalised medicine, prodromal biomarkers, trajectory-aware staging. Citation: EMJ Neurol. 2026;14[1]:49-50. https://doi.org/10.33590/emjneurol/Y4458845

Parkinson's disease (PD) is clinically heterogeneous, and its pathology begins years before motor symptoms appear. The Synuclein Origin and Connectome (SOC) model proposes two phenotypes: ‘bodyfirst’ PD, in which α-synuclein pathology starts in the peripheral autonomic nervous system and spreads symmetrically from the bottom up, and ‘brain-first’ PD, which begins in the central nervous system and spreads asymmetrically from the top down. Until now, these phenotypes had not been tested longitudinally across both prodromal and clinical stages, nor linked to their underlying imaging and genetic mechanisms.

Methods

The author analysed 910 prodromal and 1,120 clinical PD cases from the Parkinson's Progression Marker Initiative (PPMI), with longitudinal clinical, imaging, and genetic data spanning 12 years.1

Results

Body-first cases showed greater motor dysfunction, anxiety, and depression at baseline, and faster longitudinal motor decline and attention loss than brain-first cases, in both prodromal and clinical stages, CC BY-NC 4.0 Licence

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Body-first and brain-first PD are distinct biological entities with specific clinical, imaging, and genetic profiles that are identifiable from the prodromal stage. Recognising them supports earlier, trajectory-aware prognosis and more targeted therapeutic strategies.

WHAT CHALLENGE DOES THIS ADDRESS? PD is still staged, treated, and enrolled on trials as a single disorder, yet patients with apparently similar motor diagnoses follow strikingly different courses. Existing subtyping approaches (tremordominant versus non-tremor, or cognitive classifications) are clinically unstable and cannot be applied before motor onset. This leaves an unmet need: a biologically grounded way to identify, from the earliest stages, which patients face faster decline, greater cognitive risk, and a more aggressive multisystem course, the very patients in whom accurate prognosis and early intervention matter most. By anchoring phenotypes to the presumed site and pattern of α-synuclein spread, and showing that they are stable and detectable already in the prodromal phase,

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this work addresses the gap between PD's recognised heterogeneity and the tools available to act on it.

capacity evolve. In short, it reframes PD heterogeneity as structured and clinically usable, rather than random noise.

RELEVANCE TO EUROPEAN PRACTICE

WHAT ARE THE NEXT STEPS FOR THE RESEARCH?

The practical message is that a given level of motor impairment today does not translate into the same disease burden tomorrow: its prognostic weight depends on the individual disease trajectory. Identifying individual disease features with widely available clinical questionnaires, such as rapid eye movement sleep behaviour disorder screening and autonomic assessment, would let us move from a ‘one-box’ model of PD towards trajectoryaware staging, placing patients not only on a severity axis but on the correct rail. This matters most in prodromal and early disease, where recognising a poorer-prognosis course could concentrate monitoring and support a comprehensive, holistic strategy aimed at pre-empting the many non-motor complications of complex PD, in particular falls, psychiatric and cognitive decline, and urinary tract infections.

The classification currently relies on clinical scales that carry subjective bias, so more objective confirmation (metaiodobenzylguanidine scintigraphy, α-synuclein seeding assays, and fluid biomarkers) is needed, alongside larger and more representative cohorts than PPMI to ensure generalisability. Future genomewide studies should extend the phenotypespecific genetic signals (TRIM40, IP6K2, RIT2, CTSB) and clarify genotype– phenotype relationships, ideally integrating the genome with the exposome (early-life environmental and occupational exposures). The broader goal is a mechanism-aware staging framework that combines initiation phenotype, a dynamic index of motor compensation, and multisystem biomarkers. Such a framework could sharpen clinicaltrial enrolment around shared biological pathways and match interventions to the impaired pathway; for example, gut-barrier and microbiota strategies in body-first cases, or lysosomal-targeted drugs such as ambroxol in GBA carriers. Confirming these phenotypes as reliable, actionable markers is the key question that remains.

Moreover, this approach can begin to reshape clinical research: by improving the granularity of trial inclusion criteria and, once distinct underlying aetiologies can be demonstrated, by targeting specific mechanisms and directing future disease-modifying therapies to those who stand to benefit most. Phenotype could likewise inform decisions on advanced therapies, such as focused ultrasound, deep brain stimulation, or levodopa infusion, as pathology and compensatory

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Reference 1.

Passaretti M et al. Clinical progression and genetic pathways in body-first and brain-first Parkinson's disease. Abstract OPR-098. EAN Congress, 27-30 June, 2026.

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Congress Interview

Congress Interviews EMJ had the pleasure of speaking with Elena Moro, European Academy of Neurology (EAN) President (2024–2026), and incoming President Kailash Bhatia, reflecting on a meeting shaped by advances in AI and computational neurology, alongside continued collaboration across the field. They discuss EAN initiatives spanning national and international partnerships, including the Brain Health Mission and the Diversity, Equity, and Inclusion in Neurology panel that Moro helped established. Bhatia also shares his perspective on advances in movement disorders, and his vision for the future of neurology under his presidency. Featuring: Elena Moro and Kailash Bhatia

Citation:

EMJ Neurol. 2026;14[1]:51-53. https://doi.org/10.33590/emjneurol/LG6S7K73

Q1 Elena Moro Professor of Neurology, Grenoble Alpes University; Division of Neurology, CHU of Grenoble, France; Past President (2024–2026), European Academy of Neurology (EAN)

43 national neurological societies signed the Brussels Neurology Declaration in Europe

As the European Academy of Neurology (EAN) President, one of your key priorities has been brain health, spanning public engagement, education, and advocacy initiatives. What do you think has been the most meaningful shift in how brain health is understood or discussed today compared with when you began your presidency? During my presidency, together with my Board, I built upon the work carried out by my two predecessors, Claudio Bassetti, University of Bern, Switzerland, and Paul Boon, Ghent University, Belgium. I believe that during these last 2 years, the initiatives undertaken by the EAN at a national level with the national neurological societies, and at an international level with the Brain Health Mission, the European Brain Council (EBC), the European Psychiatric Association (EPA), the WHO, and other partner societies, have helped improve

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understanding of the concept of brain health and have led to several practical initiatives in prevention, advocacy, research, and education. As an example of this EAN work, last March, 43 national neurological societies signed the Brussels Neurology Declaration in Europe, a collaborative engagement to address, within the next 10 years, the seven most relevant priorities that neurology is facing in Europe. In this common strategic plan, brain health is the first priority on which the 45,000 neurologist members of the EAN will focus.

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The Strategic Research Agenda was developed in response to the mismatch between the enormous burden of neurological disease and the resources devoted to understanding it. The agenda identified headache and pain, Alzheimer's disease, epilepsy, and sleep-wake disorders as particularly high priorities. Why have some of these conditions remained comparatively under-recognised despite their substantial impact on patients and health systems?

Partnership), although still not enough. To further advance research, Europe also needs to encourage the adoption of new technologies by reducing the huge and discouraging administrative burden, and support data sharing among researchers, which remains nearly impossible, even within individual countries.

The answer is very complex. First, many neurological disorders, especially neurodegenerative ones, have pathogenetic mechanisms that are still not fully understood, and this is the main reason why it is difficult to find effective treatment or cures for them. Moreover, a considerable amount of financial support for education, research, and care should be constantly invested, and this is not the case in several European countries. However, thanks to the brain health campaign, Europe has recently increased funding for research in neurology (the Brain Health

Under your presidency, EAN established the Environmental Influences in Neurology Task Force. Climate change is often discussed in respiratory or cardiovascular health, but much less in neurology. What do you think neurologists still underestimate about the relationship between the environment and neurological disease? Indeed, neurologists have only recently paid attention to the environmental influences on several neurological disorders. One of the main reasons has been the difficulty in measuring the real contribution of pollution, climate change, pesticides, microplastics, and ultra-processed food to the pathogenesis of brain and

nervous system disorders. Today, this is easier to study thanks to technological and epidemiological advances. Therefore, several studies have recently unveiled the potentially significant impact that the environment has on the pathogenesis and management of several neurological disorders.

As co-chair of the EAN Gender and Diversity Issues in Neurology Task Force, you have highlighted that conditions such as stroke and Parkinson's disease can differ significantly across sex and gender. How well is neurology currently accounting for those differences in research and clinical practice, and where do the biggest gaps remain? Indeed, several years ago, I established the Gender and Diversity Task Force in neurological disorders (which has now evolved into the EAN Coordinating Panel for Diversity, Equity, and Inclusion in Neurology) because I realised that neurologists are often not aware that symptoms, disease severity, response to treatment, access to care, and overall management can

Women with Parkinson’s disease develop dyskinesia much more frequently and more severely

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greatly differ in women compared to men. This lack of knowledge can have a relevant impact on the way we manage and treat people living with neurological disorders. As neurologists, we need to personalise the care of our patients if we want to be effective. To give a practical example, women with Parkinson’s disease develop dyskinesia much more frequently and more severely than men with Parkinson’s disease. Knowing this, neurologists should use lower doses of levodopa or propose alternative treatments.

This year's Congress theme is ‘Brains, Bytes & Beyond: Tech in Neurology’. While some areas of neurology have embraced digital technologies, biomarkers, and AI, others have progressed more slowly. Which parts of the field are at greatest risk of being left behind by this technological transformation and why? Theoretically, rare neurological disorders can be at risk of benefiting less from technological

transformation, since new technologies need big data and financial investments. On the other hand, rare neurological disorders need technology to improve understanding and treatment. Looking at recent progress, I believe that all subdisciplines in neurology will ultimately benefit equally.

As you prepare to hand over the presidency to Kailash Bhatia, University College London, UK, which achievement are you most proud of, and which unfinished priority do you most hope the next leadership team will continue to advance?

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further strengthened the EAN’s relationship with the EBC, EPA, and British Medical Association (BMA). We have also established a neuroethics group to better address many new ethical issues in clinical practice and research, and we have initiated a project to develop neuro-public health for neurologists. I am confident that the new EAN leadership will continue to further develop these important initiatives.

Besides the work I initiated in the field of gender and diversity in neurology, I am particularly proud of the work carried out together with the national neurological societies, which has culminated in the Enhancing Neurology in Europe project and the Brussels Neurology Declaration in Europe. This project will be finalised under the new EAN Board. I am also proud to have

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EMJ Neurol. 2026;14[1]54-57. https://doi.org/10.33590/emjneurol/8W25MF9R

Citation:

With more than 2 decades in the movement disorders field, what advance has most changed the lives of patients, and what problem has proved far harder to solve than you expected?

Kailash Bhatia Professor of Clinical Neurology, Department of Clinical and Movement Neuroscience, Institute of Neurology, University College London, UK; President, European Academy of Neurology (EAN)

You implant the leads in a patient, then you turn on the stimulator, and within a second and a half, the tremor disappears

In my view, the biggest advance that has changed lives is functional neurosurgery; for example, deep brain stimulation surgery and, more recently, focused ultrasound, and seeing this almost magic-like amelioration of tremor and bradykinesia. You implant the leads in a patient, then you turn on the stimulator, and within a second and a half, the tremor disappears. It is like magic. To me, if you are talking about what has changed the lives of people, that is the most important advancement. That sort of surgery has really made a big difference, particularly in people with advanced Parkinson’s disease, where drug treatments were leading to fluctuations and dyskinesias, where some doses work and some do not, where the tremor comes back, and so on. Then they undergo deep brain stimulation surgery and there is an immediate response to the tremor; their dyskinesias and fluctuations improve. There is also another development: focused ultrasound. This is non-invasive whereby using sound waves a thermolytic lesion is made. Lo and behold, the patient who is awake lying in a scanner, you can start to see the tremor disappear. That is like magic. I am being careful in answering this question because you asked me what has changed the lives of people, and certainly

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functional neurosurgery would be one the biggest advances. If you ask what has proved harder to solve, it is stopping the disease, modifying the disease, or preventing its spread. In this context, let me give the example of Parkinson’s disease, one of the most important movement disorder conditions. One major advance has been genetics, which then led us to a better understanding of the pathophysiology. For example, we were all very excited when we learned more about α-synuclein in the brain and thought that if we were able to do something about it, block it somehow with antibodies and so on, we were hopeful that we would have great results in disease modification. However, disease modification has been the problem. We thought that new approaches, using antibodies and similar strategies, would be very successful, but they have not been so far. The knowledge has not yet translated into therapy. So, are we addressing the pathophysiological mechanism in the wrong way? Is it simply a question of choosing the right people to include in trials? There are many questions still to be answered.

This year's Congress theme is ‘Brains, Bytes & Beyond’. In an era driven by genetics, large datasets, and now AI, what insights do we risk overlooking if we spend less time with individual patients, and how do we prevent this? Actually, I think there are two ways to look at this. The conventional concern is that AI is going to replace doctors, that

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doctors will not spend much time with patients, and that a bot will be answering their questions. I actually think that if AI is used properly, and this is what we hope will happen, then AI modelling, which can handle large datasets, can help us in a different way. One way to envisage this is that you have a symptom or a problem and begin addressing it before you see the doctor through an AI model. People are already talking about registering the types of movements we make. So, if you have a tremor, for example, there may be ways to examine you digitally even before you go and see a doctor. Imagine being at home on your computer. An AI model analyses your movements and is able to say, “We are dealing with a tremor. There are these additional features. It is very likely that this could be Parkinson’s disease.” Or perhaps we have a hyperkinetic movement disorder. The AI model may suggest that this is chorea. It may detect slow eye movements and suggest that this could be somebody with Huntington’s disease. Before you

even meet your doctor, the AI model may already have made some predictions about what this person may have. You may even receive a request to send a genetic sample if that is relevant. By the time you actually go to meet the doctor, they already have all of this information. In fact, the doctor can then spend more time with you rather than less. So, this fear that patients will be met by a bot and that no human will be there is not going to happen. AI can actually give us more time because the preparatory work will already have been done. I think that is the way I would want AI to be used, and the way I think it will help us, rather than replacing us or reducing the time we have with our patients. Now you have a person who has already been assessed as being very likely to have Parkinson’s disease, and you can spend more time explaining what to expect, what is going to happen, and so on. At the moment, the opposite happens. We spend a lot of time arriving at the diagnosis and then have very little time left to explain

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what to expect. This could make a big difference in the amount of time you can spend actually talking to the patient about the disorder, what to expect, and so on, because you are spending less time reaching preliminary conclusions.

Having trained in India, worked in Europe, and later served as the European Academy of Neurology (EAN) liaison to the Indian Academy of Neurology (IAN), can you point to a partnership between neurological communities in different regions that has genuinely improved research, education, or patient care, and what made it work? I think there are two things to say in this regard. One is that disease does not have boundaries. We saw that during COVID-19, for example. On the other hand, there are certain things that are specific or particularly relevant to certain countries. If you think of the Zika virus, for example, or, more recently, the Ebola virus, there are infections and other conditions that are more common in certain regions. What we

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So, this fear that patients will be met by a bot and that no human will be there is not going to happen. AI can actually give us more time because the preparatory work will already have been done

have to do is learn from each other. If you take India as an example, there are excellent clinicians there who can bring to the table their experience with conditions that we do not routinely encounter. They may have experience with disorders that we only see occasionally in Europe, and they can educate us. Likewise, in some of the more developed countries, there may be more advanced therapies, drug development programmes, and similar advances that can be transferred in the other direction. So, I think the key is simply this: learn from each other.

At this year's Congress, you co-chaired sessions on European brain health and the implementation of the WHO Intersectoral Global Action Plan on epilepsy and other neurological disorders (iGAP). In practical terms, what does successful implementation look like, and where are we currently falling short? The first thing to say is that the EAN is totally committed to the brain health mission and, in that context, to the WHO iGAP. We have been supporting the WHO in its iGAP plan, particularly in the lessserved areas of Europe. The issue with the brain health mission, in my view, is that we need to start early, and it depends on education and awareness, both in the public and, even more importantly, among the lay neurologists. At the moment, we have many organisations telling us how important the brain health mission is. However, until we get the lay neurologist invested in this 56

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as a stakeholder, nothing is going to happen. Here in Europe, we have already started at the school level. There have been programmes in Austria and Switzerland, for example, where we tell children how important the brain is. We give them a little brain to play with and say, “This is your brain. You have a brain like that, and you've got to look after it, because only you can look after it.” We then explain how to look after your brain: make sure you do not fall and sustain trauma, make sure you sleep well, eat a good diet, exercise, and so on. The reason we are doing that is because we want to bring in prevention. Good sleep, exercise, avoiding head injuries, a good diet (such as a Mediterranean diet), and social interaction are all important. In fact, I am putting together a little paper called ‘Sow the Seeds Now’. ‘SEEDS’ stands for Sleep, Exercise, Environment, Diet, and Social interaction. For example, there are very good data emerging about pollution and pesticides, with links suggesting that pesticides may contribute to neurodegenerative diseases such as Parkinson's disease. There was a recent paper that generated considerable press interest, suggesting that if you live within 3 miles of a golf course, your chances of developing Parkinson's disease increase by several fold. In Parkinson's disease, in addition to regular treatment, one of the things shown to be particularly beneficial is exercise. By exercise, we mean something as simple as walking briskly for 30 minutes,

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three times a week. If people could incorporate that into their lives, it would be very helpful. Avoiding a head injury is also important. You have seen examples such as boxers, including Muhammad Ali, developing a type of Parkinsonism, so avoiding head injury matters. We have talked about diet and sleep. Social interaction is also important. Parkinson's disease is largely a disease of ageing, and as we age, many of us become isolated. Social interaction therefore decreases. There are many studies showing this association. A large study was recently published by a Chinese group using a British sample. They divided participants into three groups: those with very little social interaction, who were more or less isolated; those with a moderate amount of social interaction; and those with a high level of social interaction involving family and friends. The group with a high level of social interaction had a much lower risk of developing Parkinson's disease compared with those who had little or no social interaction. So, we need to sow these seeds. We need to start early. We have to think about brain health not as something we address only after disorders develop and then say, “My goodness, we do not have good treatments.” We need to think about prevention. We have an example of this from the past. Cardiovascular medicine reduced stroke and heart attacks by a huge amount using a similar approach: exercise, looking after diabetes,

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controlling cholesterol, and so on. This has been very successful. We have to do the same. How do we do that? This is where it comes down to education. All the various organisations have to get involved because this is a global issue, not just a European one. Stakeholders such as the EAN, WHO, World Federation of Neurology (WFN), and others are already working on this, but we have to be even more energetic in promoting education for prevention. That should be the goal.

On Sunday, you introduced the Moritz Romberg Lecture ‘What research and patients may teach us: Parkinson's disease, a history and perspective of learning’ delivered by Daniela Berg (University Hospital Schleswig-Holstein, Kiel, Germany). In your own career, what is the most important thing a patient has taught you that the literature did not? I think the most important thing is to listen to your patient. We all have very large workloads, and we are very busy. Not really listening to your patients is something that can happen quite often. When I say, “Don't just hear, listen,” that is very important, because every patient is different. We have our descriptions: “You have Parkinson's disease, and these are the drugs you need to take.” But one person’s circumstances may be very different to somebody else’s circumstances. You need to listen to your patients to understand what their individual needs might be, what support they have, and the many other factors that affect their lives. What I have learned, not from the literature, because none of the books tell you this, is that you have to listen to your patient. You have to make decisions that are as tailor-made as possible for that individual, rather than simply saying, “Here you are. You have

Parkinson's disease. Take this prescription and go home.”

As you take on the EAN presidency, what do you most want your tenure to be remembered for, and what is the single biggest challenge facing European neurology that you most want to address? As I mentioned earlier, we have already committed ourselves to the brain health mission, and that is our major focus. As the incoming president, I will continue with that work because we are heavily invested in it, and it is one of the most important aspects of neurology at the moment. The other area I would like to concentrate on is inequity. Although we think of Europe as one entity, it is very clear that there are substantial differences between countries. For example, there are countries in Europe where advanced therapies for Parkinson's disease, which we take for granted in some of the more affluent countries, are not available. One example is pump therapies. Earlier, I mentioned deep brain stimulation for people who experience fluctuations. Another option is levodopa infusion delivered by a pump. These treatments are expensive, they require specialist support and training, and they are not available in many countries because of cost. As further advances emerge, this problem of inequity is only going to increase. Although it is not related to movement disorders, you may have heard about spinal muscular atrophy in children, where highly effective treatments are available but are extremely expensive. You may also have heard about drugs being introduced for Alzheimer's disease that offer modest improvements. Not all countries have adopted these

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treatments; even in the UK, I do not think we have them. Increasingly, this situation will extend across many neurological disorders. Autoimmune conditions may require expensive immune therapies and immune testing. Genetic testing is increasingly required for many disorders. There is not a level playing field. What I hope to do is first understand the extent of the problem. We need to identify what is available and what is not available across different countries, perhaps using common conditions such as Parkinson's disease as examples. Then we need to determine how access can be improved. That is the inequity issue. The final priority, of course, is prevention, and in that regard, the brain health mission. My view is that, until we make the lay neurologist a stakeholder, progress will be limited. At the moment, many neurologists are overwhelmed because the number of neurologists is limited and the clinical burden is high. When brain health initiatives are mentioned, they may think, “This is another thing being added to my workload. What do I gain from it?” If they can be helped to understand that they have an important role in this, and that they are already stakeholders, whether they realise it or not, then things can change. Education needs to be provided to neurologists and to primary healthcare professionals because they are the people who can implement preventive measures. We can advocate as much as we like, but the people working in the field, dealing directly with patients and the wider population, need education and support. That is what we hope to achieve through programmes designed to provide that education.

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Interviews EMJ had the pleasure of speaking with Peter J. Goadsby, Joanna Wardlaw, and Angelo Antonini about the latest advances in neurology, spanning migraine therapeutics, small vessel disease and lacunar stroke, and the evolving landscape of Parkinson's disease. They discussed how emerging models of disease pathophysiology, including the 'gut-first versus brain-first' theory of Parkinson's, alongside advances in diagnosis and treatment, are reshaping clinical understanding and improving outcomes for patients. Featuring: Peter J. Goadsby, Joanna Wardlaw, and Angelo Antonini

EMJ Neurol. 2026;14[1]:58-62 https://doi.org/10.33590/emjneurol/O77EP99H

Citation:

When you began your work, the vascular theory of migraine was still dominant. What specific observations most clearly convinced you that vascular change was epiphenomenal rather than causal?

Peter J. Goadsby Dean of Biomedical Sciences; Senior Associate to the President, King Abdullah University of Science and Technology, Saudi Arabia; Professor Emeritus, University of California Los Angeles, USA; Honorary Consultant Neurologist, King’s College Hospital and Great Ormond Street Hospital, London, UK

I think migraine is fundamentally a disorder of sensory modulation

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When I first heard people talk about migraine, there were two things that struck me as odd about the vascular theory. The first was that, at the time, there was a concept that migraine was caused by some sort of circulating serotonin-releasing factor producing vasodilation. That struck me as an odd thing to suggest because anything that circulated would go to both sides of the head, whereas migraine is predominantly one-sided, so that didn’t make any sense to me. The other thing was that, at the time, James W. Lance’s group at the University of New South Wales, Australia, was interested in the symptoms that occur before pain, the so-called premonitory symptoms, such as concentration impairment and fatigue. August 2026

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It was simply impossible for me to think about blood vessels causing people to be fatigued. Maybe that was just because I didn’t know enough at the time, but it didn’t seem to make any sense to me. So, because the existing explanations didn’t make sense, it made me think that there was likely to be a neural explanation, a central nervous system explanation, instead.

Your work led to the discovery that migraine involves the release of the neuropeptide calcitonin gene-related peptide (CGRP) from trigeminal sensory nerves, and ultimately the development of gepants, CGRP receptor antagonists. The success of gepants is extraordinary, but many patients either partially respond or do not respond at all. What does non-response teach us about migraine heterogeneity? CGRP pathway blockers come in two forms. There are gepants, and there are also the CGRP

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monoclonal antibodies that bind either to CGRP itself or to the receptor. The work that I did identifying CGRP was conducted with Lars Edvinsson at Lund University, Sweden. Only about half of migraine sufferers who are treated will have a useful response, and about 40% will have a spectacular response. So, what that tells you is that there are other aspects of the pathway, other transmitters, that must be involved. That’s frustrating for the people who don’t respond, of course, but I see it as an opportunity. To me, it says there’s more to do, and, invariably, the researchers’ clarion call is that more research is needed.

One of the most fascinating aspects of gepants is their dual acute and preventive role. What does that duality reveal about migraine pathophysiology? First, it establishes that the notion that there’s a strict demarcation between preventive treatments and acute treatments must be wrong.

If you look at the literature, it’s not the first example of this, but it’s certainly the clearest example. It suggests that the limitation on an acute drug not becoming preventive, or a preventive drug not being used acutely, is largely due to either pharmacokinetics or pharmacodynamics. Preventive drugs, generally speaking, are not absorbed very quickly. If you take drugs like topiramate or propranolol, they’re absorbed relatively slowly, so they’re impractical simply from a pharmacokinetic point of view. You can’t get them on board fast enough. And then, there are unexpected consequences. Triptans are great acute treatments, and they would probably be good as preventives, except for the blood vessel constriction aspect. In a proportion of people, they increase blood pressure, and their ability to induce headaches, so-called medication overuse headache, which isn’t universal but happens in a substantial proportion of patients, means that taking them every day carries so

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many downside risks that you wouldn’t think about using them as preventive treatments. The overarching point for me is that if you attack the right mechanism, or block the right mechanism, then it really becomes a question of pharmacokinetics, absorption, and side effects as to whether you’ll be able to use the medicine in both an acute and a preventive fashion. I suspect that’s going to be the general rule as we get more specific drugs, that you’ll be able to develop drugs that can do either. A really good example is eptinezumab, a monoclonal antibody given intravenously that works quite well acutely. Its intravenous administration is as effective as a gepant given orally. So that’s a clear-cut example of a preventive treatment working acutely. Then, of course, you have all the gepant data for a class that started as acute treatments and also works preventively.

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I think the other important thing is that it makes early medicine development a lot easier, because you no longer have to think about models and systems in terms of whether they’re preventive or acute; it’s simply not a relevant concept. What you’re trying to do preclinically in the laboratory is understand the drivers in the biology and then target them. If you come up with a medicine that has a long half-life, and there are more people who need it as a preventive medicine, then you may go down that road. If you come up with a medicine that’s incredibly quickly absorbed and has a short half-life, then you may go down the acute treatment road. At that point, development starts to be driven by those considerations and not by the mechanism itself. Europeans will be familiar with flunarizine, which they tend to think of purely as a preventive medicine, but there’s actually a randomised, placebo-controlled trial showing that it can be an effective acute treatment when given intravenously. Now, no one really does that; it was never developed that way, and it’s not especially practical intravenously, but it does show you that the principle is there, and that the underlying principle is probably correct.

CGRP-targeted therapies represent one of the clearest examples of translational neuroscience succeeding in medicine. Do you worry that increasingly restrictive treatment pathways risk delaying biologically appropriate therapy until migraine has already become entrenched? In an ideal world, you’d give every person in front of you the treatment that’s ideal for them. But we don’t actually know what’s ideal for everyone sitting in front of us. Are there people who would 60

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be better off getting onto these newer medicines earlier? Sure. Is that practical from a cost point of view? No.

quarter of people every 20 years. In 100 years, you’ve more or less got the problem figured out. That’s actually not too bad.

Do I look at the long game? Yes. If I look at the gepant tablets, they’ll eventually come off patent, and someone will make a cheap generic version. Triptans were like that 25 years ago. Back then, doctors would tell patients that triptans were expensive, whereas now no one says that anymore because they’ve all gone generic.

In the history of humanity, migraine is a very old problem; descriptions go back to around 4,000 BC. So, to think that we might get most of it sorted within 100 years is pretty good going.

So, in the short term, yes, cost restrictions are a downside, but in the medium term, I accept the consequences of medicines being expensive initially, because I think it facilitates the development process. Ultimately, with tablets, you leave something behind. Look at propranolol; there was a time when propranolol was expensive. Now, it’s generic, cheap as pennies and widely useful.

There are hieroglyphic depictions of people holding or applying things to their heads, which some people interpret as representations of headache disorders. More interestingly, there are translations of medical writings from Mesopotamia dating back 3000 years.

The fact that the WHO now lists sumatriptan as an essential medicine for every country because it’s become cheap enough is remarkable. If you’d said something like that 30 years ago, people would not have believed, “These medicines are too expensive,” and so on. Thirty years later, the money that was sloshing around, so to speak, has left a legacy: a cheap, effective medicine such as sumatriptan that WHO believes the developing world should be able to use. That really is a legacy, one generation leaving something behind for the next. I think the same thing will happen with gepants and the tablet medicines that follow. So yes, currently it’s a downside, but in the longer term, if we keep developing new medicines, you only have to come up with something really spectacular for a August 2026

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Just out of interest, how do we know migraine was being described in 2,000 BC?

When you read those texts, you can clearly see themes that resemble migraine. If someone is described as having pain or discomfort in the head, avoiding light, and vomiting, particularly if the patient is a woman, there’s a good chance they’re describing migraine. Scholars who study those ancient languages have pulled together these descriptions and published them in collections and books, and when you go through them, you can recognise clinical patterns that are remarkably familiar today.

Aura remains one of the most neurologically intriguing phenomena in medicine. What aspect of aura physiology do you think is still most poorly understood? I think how it starts is still poorly understood. I can trigger an aura in the laboratory by poking a needle into the brain during recordings, but clearly that’s not

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what’s happening in people in realworld situations. So how does it happen de novo? To understand the beginning of something is to understand how to stop it. We understand quite a lot about the process itself, but I don’t think we yet understand what triggers it at the very outset, and that seems to me crucial if we’re going to understand how to prevent it. Do you have any theories? I think the predisposition is there all the time, but it’s normally being suppressed, and the suppression systems are cycling up and down. I suspect it’s more than one suppression system. Let’s say you have the inherited tendency. The reason I say that is because we’ve seen, with functional imaging, that you can trigger an attack of migraine experimentally. If you look at people with the inherited tendency who are triggered into a migraine without aura, and then specifically look at those who have a history of aura, they don’t necessarily develop aura during the experiment. But if you look at the blood flow in that group after giving them, say, a nitroglycerin trigger, you can detect reduced occipital cortex blood flow. It’s not at a level that’s producing symptoms, but you can measure it. I think there’s a biological signature there all the time. They always have the biology, or at least the predisposition, and then something pushes the system past a threshold that kicks the process off. I suspect that threshold is controlled by multiple systems in the brain, because most things in the brain have redundancy built into them.

My guess is that there are several cycling regulatory signals, perhaps five different systems, and they all have to reach their nadir at roughly the same time. That alignment may take time, and it’s probably influenced by other circumstances as well. So, I think it’s a combination of having the predisposition and then developing synchronous dysfunction in the systems that normally keep the biology in check. Now, whether that synchronisation is random or whether something actively causes it, I don’t know. At the moment, it’s essentially an untestable hypothesis.

Do you think migraine with aura and migraine without aura are fundamentally the same disorder expressed differently, or biologically distinct entities that we continue to group together for clinical convenience? I think it depends on how high up you want to look at it from. You know, everyone on Earth looks the same if you’re far enough away. When I look at migraine with and without aura, it still strikes me as migraine. I think aura is a particular physiology that can be involved in migraine, but I’m not sure that aura is quintessentially what migraine is about. I probably have a slightly disruptive view about that. I think migraine is fundamentally a disorder of sensory modulation, a problem with controlling incoming information, a heightened sensitivity to sensory input: photophobia, allodynia, vertigo, and so forth. Aura seems a little separate from that process because, as we currently understand it, the best model for aura is cortical spreading depression, or cortical spreading depolarisation, and that is

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not fundamentally a sensory dysmodulatory process, although the disinhibitory aspects would also explain aura. So, are they fundamentally the same? I think people with migraines probably do share the same underlying problem. I don’t think the biology of aura itself is fundamentally the same, although its facilitation may be. Both seem to involve a failure to properly contain abnormal activity, if I can put it that way. The nervous system really likes to keep things in check. The body is like that generally, all physiology is. If your heart rate goes up because of sympathetic activation, the vagus nerve tries to bring it back down again. That’s homeostasis. The drive toward homeostasis is very strong and very well developed in humans. I suspect that, at its core, migraine involves dysfunction of systems that would otherwise maintain homeostatic control. That’s the fundamental thing that migraine with aura and migraine without aura share. So, in the bigger picture, I would definitely be more of a lumper than a splitter when it comes to migraine with aura versus migraine without aura. Certainly, from a preventive standpoint, both forms seem to respond to the same preventive treatments. I don’t think we’ve really answered whether that’s equally true for acute treatments. We certainly haven’t addressed it fully with the gepants because we don’t yet have an injectable formulation to study that question properly. The jury is still a little bit out there, but, overall, my answer would be yes.

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Research has shown that frequent use of codeine-containing medicines for migraine can contribute to medication-overuse headache and dependence risk. Why do opioid-containing agents such as codeine remain so entrenched in migraine care despite the evidence against them? The dependence risk is fundamentally an opioid issue. Whether you have migraine or not, if you repeatedly expose someone to opioids, there’s a risk of dependence. Medication-overuse headache is a different and more interesting phenomenon, because it can be produced by triptans, which don’t have abuse or dependence potential, and it can also be produced by opioids like codeine, which do have dependence potential. So, I don’t think dependence itself is the key issue in medication-overuse headache because they’re actually quite distinct phenomena. One of the things the medicines associated with medicationoveruse headache have in common is that their receptors are found in brainstem sensorymodulating regions. For example, in the periaqueductal gray you’ll find both triptan receptors and opioid receptors.

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Another common feature is that these medicines are all agonists; they activate the receptor. So, you can imagine repeated activation continually driving those systems. By contrast, antagonists such as the CGRP blockers prevent activation but don’t themselves turn the receptor on. If you repeatedly activate a system, you’re going to induce downstream changes in second messenger pathways and broader network function. I think that, at some level, is probably the biological basis of what’s going on. So why do opioids remain entrenched in migraine care? Partly because they’re old, familiar drugs that people are used to using for pain. If you think migraine is fundamentally just a head pain problem, then the logic becomes: first use paracetamol, then a nonsteroidal anti-inflammatory, and, if that doesn’t work, scale up to codeine. There’s a familiarity factor, but also a tendency to lump migraine together with other pain conditions, which I think is a mistake because migraine is certainly much more than just pain. Then, there's the safety. People really don't die taking 30 or 60 mgs of codeine, and you don’t necessarily need a sophisticated diagnosis to prescribe it; you can simply say “head pain.”

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Finally, what are the most important translational gaps that remain in migraine medicine today, and which of your current research directions are aimed at closing them? One of the things we’re quite interested in at the moment is understanding vertigo in migraine, and particularly this condition called vestibular migraine, where vertigo is a prominent component. We want to understand why about half the people we see have some degree of vertigo associated with their attacks. Very often, vertigo is not the main feature, but for people with vestibular migraine, it’s a really big deal. In the same way, for some people with migraine, light sensitivity is a big deal, and they come to the clinic wearing sunglasses. But for others, light is not such a major issue. We don’t really understand why. At the moment, we’re particularly interested in understanding how vertigo and migraine fit together, how they affect each other, and how best to treat that aspect of the disorder. Very little systematic work has been done to look at that physiology, and that’s one of the translational gaps we’re trying to address.

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Citation:

EMJ Neurol. 2026;14[1]:63-66. https://doi.org/10.33590/emjneurol/15G060FF

Earlier in your career, small vessel disease was often regarded as an unavoidable consequence of ageing. What evidence first made you question that assumption?

Joanna Wardlaw Chair of Applied Neuroimaging, Head of Neuroimaging Sciences, and Co-Director of Edinburgh Imaging, University of Edinburgh; Director, Row Fogo Centre for Research into Ageing and the Brain, University of Edinburgh; Foundation Chair, UK Dementia Research Institute Centre at the University of Edinburgh, UK

Maintaining vascular health is likely to be very important because healthy blood vessels support these clearance and exchange processes

There were several things, but a main one was that the visible features that we see on brain imaging were so variable. You could have people in their 50s who had quite a lot of small vessel disease features, and people in their 70s, 80s, 90s who had hardly any. And if it was so inevitable and primarily due to ageing, then you would have expected a slightly more consistent pattern. I would say it is still the case that many people just dismiss it as: “Oh, it’s your age.” So, I am not sure that things have changed that much.

Small vessel disease and lacunar stroke were historically interpreted through atherosclerosis models, whereas your work has emphasised endothelial dysfunction and diffuse microvascular injury. How settled is that shift now, and what evidence most strongly displaced the traditional view? This is partly because a large proportion of ischaemic strokes are indeed due to atheroma or an embolus, and by association it was assumed that lacunar ischaemic stroke must be the same. There have been many studies showing that patients with lacunar stroke do have atheroma, but that does not necessarily mean that the two are directly connected. I first started questioning this some time ago, when we looked at people who had had a lacunar ischaemic stroke or who had white

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matter disease, which is a feature of small vessel disease, we could find no relationship between the location of the atheromatous stenosis (of any degree) in the underlying arteries, and the side of the brain affected by the lacunar stroke or that the white matter disease was worse on the side with the atheroma. Recently, we found that the patients who had atheroma were much less likely to have a lacunar ischaemic stroke and much more likely to have cortical ischaemic stroke. There were patients with lacunar stroke who did have some atheroma, but there was no relationship between the side of the atheroma and the side of the lacunar stroke. Interestingly, we did find a relationship between widening of the large arteries that supply the brain and lacunar stroke and small vessel disease. What tends to happen at the moment is that lacunar ischaemic strokes get treated just like any other type of ischaemic stroke in terms of secondary prevention. But actually, having done some large-scale metaanalyses, for the European Stroke Guidelines for example, we really struggled to find good evidence that antiplatelet drugs really help prevent recurrent lacunar ischaemic stroke. We certainly found no evidence that they were helpful for people who had white matter disease but had not yet had a stroke. We actually found quite a lot of evidence to suggest that antiplatelet drugs could be hazardous in these people because they cause bleeding without any benefit of reducing ischaemic strokes, so it is slightly complicated.

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Before STRIVE, definitions of small vessel disease varied widely across centres. How did standardising MRI descriptors change not just comparability, but the way we interpret what these lesions actually represent biologically?

Perivascular spaces were long dismissed as incidental MRI findings, yet they are increasingly linked to brain fluid clearance pathways. How central is impaired clearance to small vessel disease, and how close are we to measuring it clinically?

Before STRIVE, there were a lot of assumptions about the various different types of lesions seen on brain scans. People assumed that these were all different, and that they all had a different aetiology or causative mechanism. I think what STRIVE helped to do was, first of all, simplify the language used to describe the lesions so that people were on the same page. We did an update in 2019 and identified some more features that can reasonably be considered part of the small vessel disease spectrum, and I think that would not have been so straightforward without STRIVE initially pulling the main features together. It has also helped to translate high-end imaging research into clinical practice, and improve standardisation of radiological reporting, and the way that information gets translated into clinic letters to GPs or to patients. So, I think it has had knock-on effects on clinical practice. But while it has helped on a number of fronts, I think there is still a long way to go. Recognising that small vessel disease is not just a consequence of ageing, and not just about vascular risk factors or atheroma, is still something we are working through.

Neurology

We have shown that enlargement or increased visibility of perivascular spaces is likely an early stage in small vessel disease. And like some other small vessel disease features, perivascular spaces can also reverse, at least early on. In terms of brain fluid clearance, there has been rising interest, particularly in Alzheimer’s disease research, because the damaging protein accumulation may be linked with failure of clearance mechanisms. It then became apparent that perivascular spaces are probably part of that overall fluid clearance pathway. In the last 10 years, other groups and we have developed methods to try and track fluid movement through the brain in people using brain MRI techniques. The brain sits in a fluid environment inside the skull, and it was always assumed this was mainly for buoyancy and protection, but actually, that fluid circulation system is now recognised to play an important role in continuously clearing waste. We are now seeing emerging patterns in some brain diseases that are consistent with slowed clearance, where debris and proteins may not be clearing as efficiently as they should. This is a very complex process, and we are only just beginning to unpick it, but there appear to be relationships with small vessel disease progression, as well as inflammation and other processes. Small vessels are likely important also because their

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pulsation with each heartbeat and other vascular dynamics help drive fluid movement through the brain. So, the brain fluid and waste clearance system is an engineering challenge in a sense: maintaining high blood flow, exchange of oxygen and glucose, and clearance of waste to support healthy brain cell activity, all within a closed box (the skull).

Do you think there could one day be therapies targeting clearance? Potentially. For example, some general anaesthetic agents may be less disruptive to clearance processes. Many Alzheimer’s therapies are already aimed at increasing clearance of amyloid and tau proteins. Maintaining vascular health is likely to be very important because healthy blood vessels support these clearance and exchange processes. Drugs that improve the function of the lining of small vessels, the endothelium, may therefore also help maintain or improve clearance, and potentially slow or reverse progression of small vessel disease and other neurodegenerative pathologies.

Much of small vessel disease is clinically silent until a stroke, or cognitive or physical decline emerges. When abnormalities are found incidentally, what should guide clinical communication and management? This is a common problem, and we are trying to increase the information about current management, for example through the European Stroke Organisation Guidelines. There is a range of things that can be triggering, but currently it is mostly about controlling vascular risk factors

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such as blood pressure, diabetes, not smoking, cholesterol, adopting a healthy lifestyle including diet, exercise and good sleep habits, and maintaining a reasonable body weight. Diet, in particular not adding salt to your diet, as well as the usual dietary advice encouraging a Mediterranean-orientated diet, with not too much saturated fat or meat, is essential. Everything should be eaten in moderation, but certainly with plenty of green leafy vegetables. Vegetables like beetroot, spinach, kale, chard, and celery all contain compounds which actually actively help blood vessels maintain their function by supporting the formation of nitric oxide (NO), which is a really key molecule that helps control blood vessel function so as to maintain optimum blood flow. One of the reasons why some of the newer diabetic drugs may help reduce the risk of heart attacks and strokes in addition to controlling diabetes is because they help reduce BMI (hence are now also popular for weight loss) and help improve blood vessel health. If someone has a scan and it does show evidence of small vessel disease, then it is worth asking whether the amount is ‘appropriate for age’. Small vessel disease does increase with age; however, there is a lot of inherent variation with no absolute rights and wrongs. It is an opportunity to check for vascular risk factors that could be treated (especially blood pressure) or lifestyle elements that could be modified (especially smoking cessation and more exercise). If someone has a particularly striking degree of small vessel disease, particularly at a youngish age, then there are a number of rare genetic causes

which are being recognised that can run in families and which are worth considering if this might be the case.

LACI-2 (LACunar Intervention Trial 2) tested repurposed agents such as isosorbide mononitrate and cilostazol as the first potential specific treatments for lacunar stroke, with LACI-3 scaling this approach. What makes repurposing attractive in small vessel disease specifically, and what would a positive result change in routine practice? The advantage of repurposing established drugs from their existing use to a new area is that their safety is usually already well understood, unexpected adverse effects are unlikely, and the drugs are generic, so they are less expensive and potentially very affordable for most healthcare systems. It happens that there are a number of repurposed drugs, or drugs already in use for other conditions including cardiovascular disease, which have modes of action that theoretically might help improve the health of the small blood vessels in the brain, and this might help prevent the long-term effects of small vessel disease. Isosorbide mononitrate has been widely used for many decades to help control angina and ischaemic heart disease. It is a bit like glyceryl trinitrate (GTN) that people take as an oral spray or tablet under the tongue if they are having an angina attack, except that isosorbide mononitrate is given as a regular dose. It increases the amount of NO that helps restore small blood vessel function and tone, and a number of other things, such as reducing blood vessel inflammation.

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Cilostazol is considered an antiplatelet drug, but actually it has a number of other effects. It helps improve endothelial function, it helps stop the breakdown of NO so that the NO lasts longer, and it has secondary effects which help the small blood vessels to interact better with other cells in the brain to maintain their health too. We could not decide which one of these two drugs to test, so we thought we would test both in the LACI-2 trial. The LACI-2 results suggested that one or both drugs, particularly when used together, may reduce recurrent lacunar ischaemic stroke, reduce dependency, reduce cognitive decline, and improve quality of life. So now, we are testing if this is true in the LACunar Intervention Trial 3 (LACI-3), which is Phase III, larger, and including more centres, aiming for about 1,300 patients. If either or both drugs show the benefit seen in LACI-2, we have already discussed this with the UK drug regulator, who gave us advice on the conduct of LACI-3 to ensure that if the results are positive, then the licence for the drugs could be extended so the drugs can be prescribed to patients with lacunar ischaemic stroke.

Dementia research has been heavily weighted toward amyloid biology. How well does current research investment reflect disease burden and modifiability in ageing brains? There have been surveys looking at numbers of trials in different types of dementia, and the vast majority of funding is going into Alzheimer’s disease, with a very small number of trials looking at vascular causes. Nonetheless, there is a large amount of evidence showing that good lifestyle and blood pressure

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management, etc are associated with a lower risk of cognitive decline or dementia. There is also some evidence from clinical trials supporting better lifestyle, blood pressure, and vascular risk factor control, which may not necessarily prevent cognitive decline entirely, but they help slow it. If you are at risk of cognitive decline or in early stages, you should have your blood pressure managed anyway, regardless of dementia risk. Dementia clinics are in an ideal position to implement vascular risk reduction according to standard vascular disease prevention principles. But everybody is so focused on amyloid and tau that vascular contributions often get ignored. Vascular disease is not the only one; Lewy body dementia and other types of dementia are also somewhat under-recognised, but vascular is particularly important because we know so much about how to manage it already from stroke medicine. The brain is nothing without its blood supply. But even in the Alzheimer’s field, many people still do not really appreciate the relevance of small vessel disease such as white matter lesions or visible perivascular spaces. They may accept that perivascular spaces are involved in waste clearance, but still see these features as epiphenomena.

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Meanwhile, there is optimism around antibody therapies for Alzheimer’s disease, which is understandable. But in the end, I think we will have a combination approach to prevention and treatment of cognitive decline and dementia, a bit like stroke prevention where there is treatment to reduce blood lipids, treatment to reduce blood pressure, and treatment to stop platelets sticking together and clots forming. Given the multifactorial components of dementia, it is unlikely there will be a single magic bullet.

If you had to choose one unresolved question that would most change diagnosis or treatment, what would it be? I think we have important signals of benefit around the drugs we are testing in the LACI trials. I would like to see those drugs tested in vascular cognitive impairment, or even cognitive impairment more broadly. We have a small singlecentre trial starting imminently in people attending memory clinics with a mainly vascular cause of cognitive decline. There could be mixed vascular and some Alzheimer’s pathology since this scenario is very common; we are not excluding Alzheimer’s pathology, just ensuring there is a main vascular component.

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It is a small start, but ideally, we need a larger trial. One of the things that holds everything up is that obtaining the approvals, the regulatory environment, even for repurposed drugs, is very complex and timeconsuming. The whole process from writing the protocol to finally getting the green light to recruit and treat participants can take many, many months, and that is after the years that it can take to get the funding to pay for the trial. And if I had one additional suggestion, it would be for people to look more closely at brain lesion patterns on imaging, because different patterns of disease and types of lesion can reflect different underlying causes, and this will inform prevention and treatment in the long run. We are moving from ‘this is small vessel disease’ to more specific inferences: e.g., vascular risk factor- or lifetime vulnerability -related disease, cerebral amyloid angiopathy, apolipoprotein E-related patterns, or rarer genetic forms. That next level of stratification would be very helpful.

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Citation:

Angelo Antonini Full Professor of Neurology; Head of the Parkinson and Movement Disorders Unit, University Hospital of Padua, Italy

Parkinson’s is not merely a localised brain disease; it is a complex, systemic multi-organ syndrome

EMJ Neurol. 2026;14[1]:67-69. https://doi.org/10.33590/emjneurol/244OCN6K

For decades, we treated Parkinson’s as if it were strictly an isolated issue in the substantia nigra. But if you actually sit in the clinic and listen to patients, you quickly realise the problem is located in multiple organs.

The ‘gut-first versus brain-first’ model holds up well in clinical practice, as it gives us a biological explanation for the vast heterogeneity we see in our patients.

For most of its history, Parkinson's has been framed as a disease of dopamine loss in the brain, and treatment has followed that logic. You've increasingly argued that we need to look beyond the brain. What first convinced you that Parkinson's is a systemic disease?

Long before a patient ever develops a tremor or stiffness, they routinely share stories of years spent dealing with constipation, sleep disturbances (like rapid eye movement sleep behaviour disorder), smell problems, and autonomic issues like orthostatic hypotension. Furthermore, when we look at pathology, we find misfolded α-synuclein aggregates distributed throughout the peripheral nervous system: in the skin, the colon, and the vagus nerve. By the time motor symptoms appear, up to 50–70% of dopaminergic neurones in the brain are already gone. Realising this made it clear to me that Parkinson’s is not merely a localised brain disease; it is a complex, systemic multi-organ syndrome. Treating it purely as a dopamine deficit in the brain is like trying to fix an entire electrical grid by replacing just one lightbulb.

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Your group has shown that misfolded α-synuclein can be found in the duodenum of patients, even early in the disease. How well does the gut-first versus brain-first picture actually hold up when you see patients, and what would it take for peripheral tissue to become a genuine diagnostic tool?

Gut-first: these are the patients who present with early autonomic failure and sleep disorders years before motor symptoms surface. In these individuals, the pathology clearly starts in the enteric nervous system and ascends via the vagus nerve to the brainstem. Brain-first: conversely, other patients present with classic asymmetrical motor symptoms first, with very little early autonomic disruption. Our work identifying α-synuclein pathology and enteric gliosis in the duodenum of early-stage patients explicitly confirms this peripheral involvement. To turn peripheral tissue biopsies into a routine, everyday diagnostic tool, we need two things: standardisation and sensitivity. Techniques like seed amplification assays have revolutionised our ability to detect tiny amounts of misfolded proteins. If we can fully standardise skin biopsies or simple mucosal swabs so that any standard clinical pathology lab can replicate them reliably, we can transition peripheral tissue from a

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research curiosity into a definitive diagnostic cornerstone.

You've drawn a comparison with cancer: that we should be trying to catch Parkinson's early, before significant neuronal loss. With skin biopsies and blood-based markers now emerging, are we close to diagnosing the disease before symptoms appear?

Advanced Parkinson's care still revolves largely around motor control, yet you've shown that non-motor symptoms drive much of the disability and loss of quality of life. Why have they remained so neglected, and what would it take to move them to the centre of treatment?

The cancer analogy is vital, because it challenges our current therapeutic passivity. In oncology, you don’t wait for a tumour to metastasise and cause organ failure before you begin treatment. You screen, you find it at Stage 0 or 1, and you intervene. In Parkinson's, we have historically waited for the neurological equivalent of Stage 4, widespread neuronal death, before writing our first prescription.

They have been neglected because they are largely invisible and difficult to quantify. A tremor is obvious; you can see it across the room, and you can measure it easily on a clinical scale. But you cannot easily ‘see’ a patient's cognitive slowdown, their crippling anxiety, their pain, or the fact that they have not slept through the night in years. Furthermore, motor symptoms respond well to early dopaminergic drugs, which created a historic bias toward focusing on what we could fix with a simple pill.

Technologically, we are incredibly close to a pre-symptomatic diagnosis. The emergence of skin biopsies and blood-based biomarkers (such as checking for α-synuclein in neural extracellular vesicles or tracking neurofilament light chain) means we can now see the molecular signature of Parkinson’s in the body years before the first tremor appears.

Moving non-motor symptoms to the centre requires a total paradigm shift in how we evaluate treatment success. Redefine ‘outcomes’: clinical trials must stop treating motor scores as the sole outcome. If a drug improves walking speed but worsens hallucinations or orthostatic hypotension, it is not a win for the patient.

However, a diagnostic tool is only as useful as the actions it unlocks. Being able to predict who will get Parkinson's is a monumental scientific victory, but it creates an ethical and clinical dilemma if we do not have the disease-modifying therapies ready to deploy. The detection science is nearly there; now our therapeutics must catch up. The first Phase III studies with the monoclonal antibody prasinezumab are ongoing and hopefully will provide the first disease-modifying molecule for clinical use.

Holistic management: we must actively use comprehensive tracking tools in daily practice.

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Interestingly, advanced continuous drug delivery systems have shown us that when you stabilise the dopaminergic system continuously, many non-motor fluctuations improve as well. This proves that treating the whole person holistically helps across both motor and non-motor spectrums.

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With deep brain stimulation, intestinal levodopa gel, apomorphine, and now subcutaneous infusions all available, how do you decide which patient needs which therapy when there are almost no head-to-head trials to lean on? In the absence of massive headto-head clinical trials, we have to look past the generic diagnosis and map the therapy to the patient’s distinct clinical phenotype, cognitive status, and lifestyle. To simplify this transition, I advocate for clear, simple, proactive screening protocols like the Making Informed Decisions to Aid Timely Management of Parkinson's Disease (MANAGEPD) tool or the 5-to-1 rule: if a patient is taking oral levodopa five or more times a day, or has 2 hours of daily ‘off-time’, or 1 hour troublesome dyskinesia, it is time to stop tweaking oral medications and look at advanced options. The selection then becomes highly individualised: Deep brain stimulation: ideal for younger, cognitively sharp patients whose main challenges are severe tremors or motor fluctuations, and who are comfortable with neurosurgery. Levodopa-carbidopa intestinal gel: highly effective for delivering absolute stability, but it requires a permanent percutaneous endoscopic gastrojejunostomy tube. This is excellent for patients who have reliable caregiver support and need robust, consistent delivery. Continuous subcutaneous infusions: the newer subcutaneous levodopa/foslevodopa infusions represent a spectacular middle ground.

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They offer the benefits of continuous dopaminergic stimulation without requiring invasive abdominal or brain surgery. This is a game changer for patients transitioning into the advanced stage who want to maintain autonomy without undergoing major procedures.

Looking ahead, what remains the most important unanswered question in Parkinson's for you? We use the term ‘Parkinson’s disease’ as if it is a single monolithic entity, but it isn't.

It is an umbrella term for a collection of different biological pathways that happen to share a final common path of motor symptoms. A patient with a GBA mutation behaves differently from someone with a LRRK2 mutation, who behaves differently from a patient who is ‘gut-first’, presenting with early dementia.

medicine for Parkinson's, one where we can identify the biological subtype of the individual and match it immediately to a targeted therapy before a significant number of brain cells are lost.

Until we can precisely map a patient's exact biological endophenotype, our clinical trials for disease-modifying therapies continue to struggle. The challenge is how to create a flawless system of precision

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Functional Neurological Disorder: Moder EMJNeurol. Neurol.2026. 2026;14[1]:70-71. https://doi.org/10.33590/emjneurol/EC428W38 EMJ https://doi.org/10.33590/emjneurol/EC428W38

FND has undergone a significant conceptual shift in the past decade, from a diagnosis of exclusion to one made on positive clinical signs, but clinical practice is lagging behind.

The Paradigm Shift

Once judged as purely psychological, a 'conversion disorder', FND is now understood as a disorder of brain function.1 FND is defined as 'a clinical syndrome with genuinely experienced neurological symptoms which are distressing and impairing, and show dysfunction of the nervous system'.1

Hysteria

Conversion disorder

FND

T F

Diagnosis: Positive 'Rule In' Criteria

Diagnosis must be positive, based on the presence of physical signs, including but not limited to the following:4

What We Know: The

Psychological factors, including adv can increase the risk of FND alongsid neurodiversity and coexisting neurolo Hoover's sign: functional limb weakness5 Hip extension is weak on direct testing, but returns to normal when the opposite hip is flexed against resistance

Tremor entrainment5 When the patient taps a set rhythm with the unaffected hand, the tremor matches that rhythm, stops, or can't be sustained

Functional/dissociative seizures5,6 Sensations and states of consciousness; dissociative attacks with no ictal EEG correlate

Cognitive6 Memory difficulties that are worse during formal bedside testing than casual conversation

Other diagnostic considerations, including marked symptom fluctuation and the exclusion of alternative diagnoses, remain important when making the diagnosis.

fMRI shows altered functional connectivity.1,2 FND is understood as a disorder of brain networks spanning emotion/salience processing, attention, motor control, sense of agency, predictive coding, and interoception.2

Motor control shifts from automatic processing, causing, for example, a je 'robotic' movement.3

There is increased connectivity betw amygdala and SMA, and executive-co show reduced regulation over motor systems.3

In a 2024 survey of 580 patients, only one in 10 felt that their diagnosis was clearly explained.3

References: 1. 2. 3. 4.

Dworetzky BA, Baslet G. Neurotherapeutics. 2025;22(4):e00612. 5. Espay AJ et al. JAMA Neurol. 2018;75(9):1132-41. Finkelstein S et al. J Neurol Neurosurg Psychiatry . 2025;96:383-95:e334767. 6. Lehn A et al. BMJ Neurol Open. 2025;7(1):e000970. Phillips W. BMJ Neurol Open. 2025;7(2):e001309. 7. BY-NC Keatley 4.0 ES etLicence al. J Neuropsychiatry Clin Neurosci. 2026;DOI:10.1176/app Neurology ● August 2026 ● Copyright © 2026 EMJ ● CC American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders: DSM-5™ (2013) 8. Tolchin B et al. Neurology. 2026;106(1):e214466. 5th edition, Washington, D.C.: American Psychiatric Association Publishing.

rn Diagnosis and Management

Subtypes:1

Burden:

Seizures: functional/ dissociative seizures (formerly 'psychogenic non-epileptic seizures')

Cognitive: brain fog, memory difficulties

Motor: weakness or paralysis, dystonia, tics, tremor, jerks, gait disorder

Speech and swallowing: slurred speech, stutter, difficulty swallowing

Incidence:

10–22 1–18 /100,000 adults

/100,000 children1,2

Prevalence:

80–140

/100,0001,2

Dizziness: persistent postural-perceptual dizziness

Visual: functional blindness

Morbidity and mortality:

The DSM criteria currently cover only sensory and motor subtypes; cognitive FND and PPPD have separate, though related, criteria.3

Evidence-Based Treatment: A Multidisciplinary Approach

e FND Brain

The current evidence primarily favours the use of psychological and rehabilitative therapies for the treatment of FND, most commonly being physiotherapy for motor FND and psychotherapy for seizures.

verse life events, de factors such as ogical conditions.

A multidisciplinary approach for more complex cases could include:6

to 'explicit' erky,

• Physiotherapy: facilitating/retraining normal movement • Occupational therapy: supports self-management with interventions for energy conservation, graded activity resumption, sensory modulation, and vocational rehabilitation • Speech pathologists: for those with speech, voice, language, cognitive-communication, and swallowing disorders • Psychologists: Therapies such as CBT address functional symptoms, coexisting psychological conditions, and perpetuating factors relating to arousal, avoidance, fear of symptoms, emotional expression and awareness, and interpersonal conflicts

74%

patients

74% of patients who received multidisciplinary, symptom-based rehabilitation showed clinically meaningful improvement.7

ween the ontrol regions

pi.neuropsych.20250222.

The 2025 AAN functional seizures guideline, the first from AAN to focus on FND, states that psychological interventions may be effective in functional seizures.8 The guideline also recommends that antiseizure medications should not be prescribed for functional seizures without co-occurring epilepsy.

Abbreviations: AAN: American Academy of Neurology; CBT: cognitive behavioural therapy; fMRI: functional MRI; FND: functional neurological disorder; PPPD: persistent postural-perceptual dizziness; PTSD: post-traumatic 71 stress disorder; SMA: supplementary motor area.

Feature

Beyond the Frontotemporal Dementia Umbrella: Time for a Biological Definition? Author:

*Sergi Borrego-Écija1,2 1. Alzheimer's and Other Cognitive Disorders Unit, Neurology Service, Hospital Clíınic de Barcelona, Spain 2. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Spain *Correspondence to borrego@clinic.cat

Disclosure:

The author has declared no conflicts of interest.

Received:

01.07.26

Accepted:

15.07.26

Keywords:

Behavioural neurology, frontotemporal dementia (FTD), frontotemporal lobar degeneration.

Citation:

EMJ Neurol. 2026;14[1]:72-74. https://doi.org/10.33590/emjneurol/4KNU3VG0

INTRODUCTION: THE MYTH OF A SINGLE FTD The reader will permit the author to introduce this letter with a digression: to mark the release of a Hollywood film based on Homer’s ‘The Odyssey’, I recently undertook a rereading of the epic poem. I also revisited the long-standing debate surrounding Homer himself and found that, despite centuries of scholarship and enduring uncertainty, two assertions are still commonly repeated: on one hand, many experts argue that Homer was not a single person, but rather the product of a long oral tradition involving generations of storytellers. On the other hand, he is frequently described as having been blind. Taken together, these two notions appear contradictory, yet both continue to coexist in the popular and academic imagination. A similar phenomenon can be observed in frontotemporal dementia (FTD). Over the last two decades, genetic, pathological, and molecular research has provided overwhelming evidence that FTD is not a single disease entity. The deposition of distinct proteins in the brain, including tau, transactive response DNA binding protein of 43 kDa (TDP-43), and group of FUS, 72

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EWS, and TAF15 (FET) proteins, and the observation that diverse genetic mutations acting through different pathogenic mechanisms can lead to comparable clinical syndromes strongly support this conclusion.1 Nevertheless, a huge amount of the current literature (including papers authored by the present writer) continue to draw conclusions about FTD as if it were a single disease. The following are a few examples extracted from manuscripts from this work’s author (selected in order to not offend other authors): “the inexistent correlation with Mini-Mental State Examination (MMSE) scores in patients with FTD could be due to the fact that MMSE is not a sensitive cognitive measure in these patients”2 or “the scale was not able to discriminate Alzheimer’s disease from FTD.”3 These sentences consider FTD as a single entity when it is now evident that it is not. These conclusions might be valid for some forms of FTD but not for others. Another example: in recent years, it has been repeatedly stated that FTD and amyotrophic lateral sclerosis are part of the same continuum. While this is undoubtedly true for some forms of FTD, it is not true for all of them; patients with tauopathies, for example, do not develop amyotrophic lateral sclerosis as part of the natural

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history of their disease. In this context, continuing to group fundamentally different biological entities under a single label risks becoming the equivalent of comparing apples and oranges.

LOOKING BENEATH THE FTD UMBRELLA The reason why we continue to make such generalisations is obvious: our ability to distinguish these diseases during life remains limited. Current diagnostic frameworks still rely primarily on clinical syndromes rather than underlying biology. However, the emergence of diseasemodifying therapies is exposing the limitations of this approach. A syndromebased classification that was entirely appropriate a decade ago may no longer be sufficient in the era of precision therapeutics. Even the major clinical syndromes included under the FTD umbrella, the behavioural variant of FTD and semantic variant primary progressive aphasia, and non-fluent/agrammatic primary progressive aphasia, have repeatedly been shown to be associated, albeit with varying degrees of overlap, with different underlying neuropathological processes. As therapeutic strategies increasingly target specific proteins or molecular mechanisms, the need to identify these biological substrates in vivo becomes paramount. Clinical trials directed against tau pathology, for example, require participants with taurelated disease, not simply patients fulfilling clinical criteria for FTD. The continued use of FTD as a biologically nonspecific category may therefore become an obstacle to therapeutic development. A similar paradigm shift has already taken place in Alzheimer’s disease, where biological definitions based on biomarkers have progressively complemented and, in some contexts, surpassed purely clinical definitions. FTD research is now approaching a comparable turning point. Although molecular classification remains imperfect and many patients cannot yet be assigned with confidence to a specific pathology during life, the scientific evidence accumulated over recent years is sufficient CC BY-NC 4.0 Licence

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to begin building biologically informed diagnostic frameworks. The current diagnostic criteria for FTD syndromes, established in 2011, have proven enormously valuable for the syndromic diagnosis of thousands of patients worldwide.4,5 However, their capacity to predict the underlying molecular pathology remains limited, particularly in behavioural variant of FTD. Advances in the treatment of neurodegenerative disorders now call for a new generation of diagnostic criteria aimed not merely at identifying syndromes, but at estimating the biological disease process driving them. Future efforts should focus on the development of diagnostic criteria for specific molecular subtypes, such as 3-repeat tauopathies, 4-repeat tauopathies, TDP-43 subtype A, B, and C proteinopathies, among others. These criteria should adopt a multimodal approach, integrating clinical features, genetics, neuroimaging, and fluid biomarkers. Importantly, this effort does not start from a position of ignorance. The scientific community has already accumulated substantial knowledge regarding clinicopathological associations. For example, the presence of progressive supranuclear palsy-like features may increase the likelihood of an underlying 4-repeat tauopathy, whereas isolated and asymmetric anterior temporal lobe atrophy may suggest TDP-43 Type C pathology. While no single feature is likely to provide sufficient diagnostic certainty, combining multiple sources of evidence could enable the development of biologically informed diagnostic frameworks capable of predicting the underlying disease process during life. The discovery and validation of fluid or neuroimaging biomarkers will undoubtedly accelerate this transition. A significant amount of research is currently being conducted with the aim of identifying biomarkers that will enable clinicians to differentiate between tau, TDP-43, and FET forms of FTD. In the last few years, some biomarkers have shown promising results.6-8 In parallel, large collaborative initiatives such as the Horizon Europe-funded PREDICTFTD consortium are expected to play a key role in validating existing biomarkers and discovering new ones.9

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CONCLUSION The question is no longer whether FTD represents a single disease or a collection of distinct disorders; the evidence has largely answered that question already. The challenge now is to translate this knowledge into diagnostic criteria, research strategies, and therapeutic trials that reflect the biological heterogeneity of the disease. As the field moves towards precision medicine, reliance on syndromic definitions alone is becoming increasingly insufficient.

References

Rascovsky K et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011;134(Pt 9): 2456-77.

Pérez-Millan A et al. Cortical thickness modeling and variability in Alzheimer’s disease and frontotemporal dementia. J Neurol. 2024;271(3):1428-38.

Gorno-Tempini ML et al. Classification of primary progressive aphasia and its variants. Neurology. 2011;76(11): 1006-14.

Falgàs N et al. Diagnostic accuracy of MRI visual rating scales in the diagnosis of early onset cognitive impairment. J Alzheimers Dis. 2020;73(4):1575-83.

Fontana E et al. Detection of TDP-43 seeding activity in the olfactory mucosa from patients with frontotemporal dementia. Alzheimers Dement. 2024;20(2):1156-65.

Rademakers R et al. Advances in understanding the molecular basis of frontotemporal dementia. Nat Rev Neurol. 2012;8(8):423-34.

The future of FTD research and treatment will depend on our ability to identify the molecular pathology underlying each clinical presentation and to develop biologically informed frameworks for diagnosis and patient selection. Just as the figure of Homer conceals a more complex reality than traditionally assumed, the term FTD encompasses a range of distinct diseases that must be recognised and studied individually if truly targeted therapies are to become a reality.

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Honey MIJ et al. An acetylated tau-174 CSF biomarker discriminates between TDP-43 and tau pathology in patients with frontotemporal lobar degeneration. Nat Med. 2026;DOI:10.1038/s41591026-04341-6.

Chatterjee M et al. Plasma extracellular vesicle tau and TDP-43 as diagnostic biomarkers in FTD and ALS. Nat Med. 2024;30(6):1771-83.

PREDICTFTD. Accelerating the validation of predictive liquid biomarkers for frontotemporal dementia diagnosis and subclassification. Available at: https://www.predictftd.eu/. Last accessed: 15 July 2026.

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Does Migraine with Aura Require Different Treatment Strategies Compared to Migraine Without Aura? Authors:

Carolina Oldoni,1 *Nazia Karsan2 1. Postgraduate Program in Medical Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil 2. Headache Group, Wolfson SPaRC, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, UK *Correspondence to nazia.karsan@kcl.ac.uk

Disclosure:

The authors have declared no conflicts of interest.

Received:

29.06.26

Accepted:

28.07.26

Keywords:

Aura, cortical spreading depression, migraine, treatment.

Citation:

EMJ Neurol. 2026;14[1]:75-79. https://doi.org/10.33590/emjneurol/Y9V8LE12

INTRODUCTION Migraine has two main forms: migraine with aura (MwA) and migraine without aura (MwoA).1 The former is less common and only affects around 30% of patients with migraine.2 Even in those who experience aura, these symptoms tend not to accompany every attack.3 Rarer still are the genetic forms of MwA, such as familial hemiplegic migraine, which can pose a specific diagnostic and therapeutic challenge, as aura tends to be particularly disabling and prolonged in those affected.4 International migraine treatment guidelines do not establish significant distinctions between the preventive and acute treatment of MwA and MwoA, adopting a generally unified therapeutic approach.5 This uniformity of practice, whilst pragmatic, is also consistent with growing evidence, largely mechanistic, for a dissociation between the aura and the headache phases of the migraine attack;6 therefore, treatments that are targeted at headache, or headache prevention, should, at least in theory, be considered consistently efficacious across MwA and MwoA. Treatment or prevention of problematic aura symptoms in the minority CC BY-NC 4.0 Licence

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of patients in whom these are present poses a separate challenge, and to date no RCTs have been published that specifically evaluate aura-targeted treatments in this patient subset. A summary of the comparisons between MwA and MwoA is shown in Table 1.

BIOLOGICAL MECHANISMS Biologically, cortical spreading depression (CSD) is deemed a likely electrophysiological substrate of the migraine aura.7 In animal models, CSD can activate the trigeminovascular system and meningeal nociceptors.8 Human neuroimaging studies have shown changes in cerebral blood flow and blood-oxygenlevel dependent signal during aura, supporting CSD as a plausible substrate, which may then link cortical events to subsequent trigeminovascular activation.7,9 However, CSD and trigeminal nociception are not obligatorily coupled; aura can occur without subsequent headache, and headache without a preceding aura.8 This temporal dissociation, the fact that the majority of patients with migraine have MwoA, and the fact that those who experience aura typically have more

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Table 1: Summary of comparisons between MwA and MwoA.

Feature

MwA

MwoA

Epidemiology

Less common; affects ~30% of people with migraine. Genetic forms (e.g., familial hemiplegic migraine) are rarer still and can be particularly disabling.

The more common presentation, accounting for the majority of migraine. Patients with aura will typically still report more attacks without accompanying aura, than those with.

Pathophysiology

CSD is the likely electrophysiological substrate of aura and seems to have a predilection for the occipital cortex. An occipital cortical ‘trait’ is seen on imaging in an imaging study, even when aura is not symptomatically present.

Headache still arises via trigeminovascular activation. Whether asymptomatic (‘silent’) CSD occurs in those with MwoA, or in attacks without aura in MwA, is debated; CSD and headache are not obligatorily coupled in either subtype, and do not need temporal correlation.

Vascular risk

Established independent risk factor for ischaemic stroke, especially in young women (approximately doubled RR). Risk is synergistically increased by smoking and CHC use; current guidelines recommend against CHC use in this group.

Most studies show no significantly increased stroke risk, after confounders are adjusted for. If an increased risk is present, it is much smaller than for MwA and may reflect associated vascular risk factors rather than the migraine biology itself.

Treatment (current approach)

Acute/preventive headache treatment is largely the same as MwoA (triptans, gepants, traditional oral migraine preventives, CGRP mAbs). Aura-specific considerations: caution with triptans in prolonged/complex aura; magnesium, memantine, flunarizine, or sTMS sometimes used for problematic aura, though evidence is limited (uncontrolled or single-trial data).

Standard acute and preventive migraine treatment (triptans, gepants, traditional oral migraine preventives, CGRP mAbs), targeted at the headache phase.

CGRP mAbs: calcitonin gene-related peptide monoclonal antibodies; CHC: combined hormonal contraceptive; CSD: cortical spreading depression; MwA: migraine with aura; MwoA: migraine without aura; RR: relative risk; sTMS: single-pulse transcranial magnetic stimulation.

attacks without aura than with, help explain why MwA and MwoA share broadly similar treatment strategies, since the headache itself appears to arise through trigeminovascular activation, whether or not an aura is symptomatically present. The precise mechanistic and temporal relationships between CSD and headache generation in humans, while increasingly supported by imaging evidence, are not yet fully resolved. A summary of possible links between the processes is shown in Figure 1.

TREATMENT Some agents that act on CSD may, on mechanistic grounds, offer greater benefit in MwA, although this idea rests on pathophysiological plausibility rather than direct clinical evidence, and it remains debated whether CSD occurs 76

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in an asymptomatic form in silent cortex in patients who never experience aura,10 or indeed in those with MwA who also have attacks without accompanying aura. Imaging studies suggest an aura ‘trait’ within the occipital cortex in patients with MwA regardless of whether aura is symptomatically present, pointing to a genetic vulnerability of this brain area in this patient group.11 Single-pulse transcranial magnetic stimulation (sTMS) inhibits CSD in animals,12 and, in a randomised sham-controlled trial, was an effective option for the acute treatment of MwA via neuromodulation of the occipital cortex.13 Magnesium may be beneficial in MwA, possibly through N-methyl-D-aspartate (NMDA) antagonism, both in the acute phase, including termination of prolonged aura,14 and in migraine prevention.15

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Figure 1: The possible links between CSD, aura, CGRP release, and migraine headache.

Cortical spreading depression

Trigeminovascular activation and CGRP release

Aura

Headache

Migraine pain

Aura symptoms

Image made using BioRender.com. CGRP: calcitonin gene-related peptide; CSD: cortical spreading depression.

However, intravenous magnesium can paradoxically and anecdotally worsen headache in some patients (although there is no strong published evidence that magnesium directly worsens migraine in a reproducible subset of patients), and evidence for an aura-specific benefit is limited to small case series and openlabel data rather than controlled trials. Gastrointestinal side effects can complicate treatment. Among NMDA receptor antagonists, memantine has also been reported, in uncontrolled data, to reduce aura,16 and is used in some settings for migraine prevention.17 In the authors’ experience, they are more likely to offer flunarizine18 or memantine in patients with problematic aura. sTMS is not widely available in most clinical settings. The safety of triptans in MwA remains debated. In the authors’ practice, they avoid them in patients with prolonged or complex aura (such as hemiplegic or brainstem aura), but are less cautious when typical aura is present and lasts less than an hour. In clinical practice, there are therefore common themes in managing MwA and MwoA, although a few special considerations exist in MwA. These include the modestly increased stroke risk in MwA, especially in young women who are smokers and/or using oestrogen-containing contraceptives. Co-existing vascular CC BY-NC 4.0 Licence

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comorbidities like hypertension may contribute to this risk in those affected. New or prolonged aura, aura without headache, and associated atypical neurological features (an abrupt onset with the deficit maximal symptom intensity from the onset, predominantly negative symptoms, associated fever, altered mental status, or focal neurological deficit) are among some of the red flags when evaluating a patient with headache, and should prompt investigation for alternative causes such as ischaemic stroke or transient ischaemic attack. In observational and meta-analytic data, MwA is an established independent risk factor for ischaemic stroke, reflecting shared vascular pathophysiology and some overlapping risk factors between aura and stroke.19 A central hypothesis is that CSD induces focal oligaemia that can progress to infarction in neural tissue with a genetic or metabolic predisposition. The aura phase also appears to release inflammatory cytokines. These trigger endothelial activation, oxidative stress, and a systemic prothrombotic state.19 In women with MwA, observational data indicate that combined hormonal contraceptives increase stroke risk synergistically, particularly in smokers.20 Current guidelines from major medical societies therefore contraindicate or recommend against their use in this population.21 Whilst recent large-scale observational studies suggest

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that modern low-dose formulations of combined hormonal contraceptives may carry lower absolute stroke risk than previously estimated,22 these findings remain insufficient to change current recommendations. Shared decisionmaking that carefully weighs individual cardiovascular risk factors, age-related absolute risk, and alternative contraceptive options remains essential when counselling women with MwA about contraception. Smoking is a major modifiable contributor to ischaemic stroke risk in this group, and its cessation should be actively encouraged as a priority in reducing that risk.

CONCLUSION

NOVEL THERAPIES The newest drugs in clinical practice for migraine are the calcitonin gene-related peptide (CGRP)-targeted treatments, which comprise the preventive CGRP monoclonal antibodies (mAbs) and the acute and preventive small-molecule CGRP receptor antagonists (gepants). Although CGRP mAbs effectively reduce migraine frequency, their large molecular size limits penetration across the blood–brain barrier, so their primary site of action has been thought to be predominantly peripheral. However, preliminary data suggest that some cerebrospinal fluid penetration occurs.23 Accordingly, preclinical evidence indicates that mAbs probably do not prevent the initiation of CSD itself, but may modulate it by attenuating the subsequent trigeminovascular sensitisation.24 In animal models, gepants may also modulate CSD without blocking its initiation,25 although they may penetrate the blood–brain barrier at higher concentrations than mAbs.26 Gepants have a more favourable vascular profile than triptans and mAbs, owing to their lack of vasoconstrictive properties, short half-lives, and reversible receptor antagonism. Unlike triptans, they do not typically raise blood pressure. The acute treatment of the headache is similarly unaffected by aura status: triptans taken during the aura, before pain onset, neither prevent nor delay the subsequent headache,27 confirming that the aura offers no window for earlier abortive treatment in studies to date. Further studies evaluating 78

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gepants administered during aura may follow, as recent evidence suggests efficacy when taken during the migraine prodrome for preventing subsequent headache.28 For patients with complex or prolonged aura, the non-vasoconstrictive profile of gepants makes them a reasonable alternative to triptans; here the relevant consideration is vascular rather than temporal. Future research should clarify how these novel therapies influence CSD, and therefore aura, so that treatment can be directed at neuronal mechanisms rather than chosen on vascular grounds alone.

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Despite the mechanistic and clinical features that set MwA apart, its treatment remains, for now, largely indistinguishable from that of MwoA. This shared approach is pragmatic and has a mechanistic rationale: the headache appears to arise through trigeminovascular activation regardless of migraine subtype, and the newer, mechanism-specific treatments were tested in trials that combined MwA and MwoA, and were not powered to detect differences between them. The aura itself is the exception, with no evidencebased targeted treatment of its own. Historically, we have relied on non-specific agents developed for other indications for migraine treatment, and side effects and poor tolerability have caused patient and physician frustration and delayed adequate control. CGRP-targeted therapies have started to change the landscape for both acute and preventive migraine treatment, but their value in MwA compared with MwoA remains currently undefined, as does their relationship to CSD, a process that appears distinct from, and perhaps parallel to, trigeminovascular activation. Progress towards treatments tailored to MwA will depend on several advances in the current era: clarifying how CGRP-targeted therapies act on CSD, and whether this brings any subtype-specific benefit; and developing treatments aimed at the aura itself, by testing their effect on both the aura and any headache that follows. Designing trials that stratify patients by phenotype rather than combining all heterogeneous patients

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together, with endpoints and biomarkers able to separate aura from pain mechanisms, will likely contribute to our understanding of any fundamental biological differences between MwA and MwoA going forwards. Until these questions are answered, treatment at the moment cannot be usefully personalised to migraine phenotype broadly in the absence of aura-specific

References 1.

Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013;33(9):629-808.

Rasmussen BK, Olesen J. Migraine with aura and migraine without aura: an epidemiological study. Cephalalgia. 1992;12(4):221-8.

Charles A. The pathophysiology of migraine: implications for clinical management. Lancet Neurol. 2018;17(2):174-82.

Thomsen LL et al. A population‐based study of familial hemiplegic migraine suggests revised diagnostic criteria. Brain. 2002;125(6):1379-91.

Vgontzas A, Burch R. Episodic migraine with and without aura: key differences and implications for pathophysiology, management, and assessing risks. Curr Pain Headache Rep. 2018;22(12):78.

Moskowitz MA. Rethinking migraine with aura: why cortical spreading depolarization (depression), not aura, causes headaches. Cephalalgia. 2025;45(9):03331024251370629. Hadjikhani N et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci U S A. 2001;98(8):4687-92. Zhang X et al. Activation of meningeal nociceptors by cortical spreading depression: implications for migraine with aura. J Neurosci. 2010;30(26):8807-14. Lauritzen M et al. Clinical relevance of cortical spreading depression in neurological disorders: migraine, malignant stroke, subarachnoid and intracranial hemorrhage, and traumatic brain injury. J Cereb Blood Flow Metab. 2011;31(1):17-35.

10. Hansen JM et al. Distinctive anatomical and physiological features of migraine aura revealed by 18 years of recording. Brain. 2013;136(Pt 12):3589-95.

treatment evidence. Hopefully, in the future, advances in human neuroimaging, biological and treatment-related biomarkers, and further understanding of the role of CGRP and other neuropeptides like pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) in aura, will allow us to better manage the currently underserved MwA patient group.

11. Karsan N et al. Regional cerebral perfusion during the premonitory phase of triggered migraine: a double-blind randomized placebocontrolled functional imaging study using pseudo-continuous arterial spin labelling. Headache. 2023; 63(6):771-87. 12. Andreou AP et al. Transcranial magnetic stimulation and potential cortical and trigeminothalamic mechanisms in migraine. Brain. 2016;139(Pt 7):2002-14. 13. Lipton RB et al. Single-pulse transcranial magnetic stimulation for acute treatment of migraine with aura: a randomised, double-blind, parallelgroup, sham-controlled trial. Lancet Neurol. 2010;9(4):373-80. 14. Rozen TD. Aborting a prolonged migrainous aura with intravenous prochlorperazine and magnesium sulfate. Headache. 2003;43(8):901-3. 15. Peikert A et al. Prophylaxis of migraine with oral magnesium: results from a prospective, multi-center, placebo-controlled and double-blind randomized study. Cephalalgia. 1996;16(4):257-63. 16. Charles A. Memantine for prevention of migraine: a retrospective study of 60 cases. J Headache and Pain. 2007;8(4):248-50. 17. Li G et al. Role of memantine in adult migraine: a systematic review and network meta-analysis to compare memantine with existing migraine preventive medications. Front Pharmacol. 2024;15:1496621. 18. Karsan N et al. Flunarizine in migrainerelated headache prevention: results from 200 patients treated in the UK. Eur J Neurol. 2018;25(6):811-7. 19. Borończyk M et al. Migraine and stroke: correlation, coexistence, dependence - a modern perspective. J Headache and Pain. 2025;26(1):39.

(EHF) and the European Society of Contraception and Reproductive Health (ESC). J Headache Pain. 2017;18(1):108. 21. Bushnell C et al. 2024 guideline for the primary prevention of stroke: a guideline from the American Heart Association/American Stroke Association. Stroke. 2024;55(12):e344-424. 22. Ihara K et al. Estrogen exposure from modern contraceptives and vascular risk in women with migraine: a nationwide electronic medical record database study. Cephalalgia. 2025;45(12):03331024251404924. 23. Rorabaugh J et al. Measurement and modeling of peripherally administered anti-CGRP monoclonal antibody in CSF and brain of healthy volunteers (S22.006). Neurology. 2024;102:3622. 24. Melo-Carrillo A et al. Fremanezumab and its isotype slow propagation rate and shorten cortical recovery period but do not prevent occurrence of cortical spreading depression in rats with compromised blood-brain barrier. Pain. 2020;161(5):1037-43. 25. Close LN et al. Cortical spreading depression as a site of origin for migraine: role of CGRP. Cephalalgia. 2019;39(3):428-34. 26. Pistolesi A et al. Biodistribution of atogepant and rimegepant in mouse peripheral and central structures of relevance to migraine pathogenesis. Cephalalgia. 2025;45(11): 03331024251378713. 27. Bates D et al. Subcutaneous sumatriptan during the migraine aura. Neurology. 1994;44(9):1587-92. 28. Dodick DW et al. Ubrogepant for the treatment of migraine attacks during the prodrome: a phase 3, multicentre, randomised, double-blind, placebocontrolled, crossover trial in the USA. Lancet. 2023;402(10419):2307-16.

20. Sacco S et al. Hormonal contraceptives and risk of ischemic stroke in women with migraine: a consensus statement from the European Headache Federation

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SUDEP: From Prediction to Prevention Author:

*Alexander Grundmann1,2 1. Translational and Clinical Research Institute, Newcastle University, UK 2. Newcastle-upon-Tyne NHS Foundation Trust, UK *Correspondence to alexander.grundmann@nhs.net

Disclosure:

The author has declared no conflicts of interest.

Received:

06.07.26

Accepted:

21.07.26

Keywords:

Epilepsy mortality, prediction, prevention, sudden unexpected death in epilepsy (SUDEP).

Citation:

EMJ Neurol. 2026;14[1]:80-83. https://doi.org/10.33590/emjneurol/S3X7U7GL

INTRODUCTION Sudden unexpected death in epilepsy (SUDEP) remains the leading directly epilepsy-related cause of death. It is predominantly nocturnal and unwitnessed, and most of those who die are found prone in bed.1,2 Overall annual incidence is approximately 1.2 per 1,000 patient-years in people with epilepsy, rising to 2.6–4.8 per 1,000 in drug-resistant cohorts,3 and it occurs throughout the lifespan, most frequently in the third and fourth decades. A single generalised tonic– clonic seizure (GTCS) can prove fatal in an otherwise well young adult. The only prevention measure with randomised support is indirect. A metaanalysis of placebo-controlled trials found that adjunctive antiseizure medication, through reducing seizures, lowered the incidence of seizure-related mortality roughly sevenfold, though these trials were not designed to measure SUDEP.4 Reducing seizures is therefore the only measure that we can state with confidence prevents SUDEP, albeit at the population rather than the individual level. No intervention has yet been tested in a trial designed to prevent SUDEP, and we cannot say whether recommended measures have lowered its incidence.5 Prevention has two components:

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identifying those at risk and acting to reduce that risk, and interrupting the fatal process once it begins. As this commentary argues, each is challenging for different reasons.

HOW THE TARGET HAS CHANGED The understanding of what makes a seizure fatal has shifted over time. Early attention focused on seizure-induced cardiac arrhythmia, then on postictal brainstem failure, impaired arousal, blunted responses to rising carbon dioxide, and depressed respiratory drive. Video-EEG recordings of patients who died in monitoring units captured a stereotyped terminal cascade: hyperventilation, then central apnoea, bradycardia, and asystole.1 In the last decade, emphasis has settled on an integrated failure of brain, heart, and respiration.6 SUDEP is not a single mechanism but a family of them: positional asphyxia, failure of respiratory drive and arousal, cardiac arrhythmia, and autonomic dysfunction.6 An intervention works only if it matches the mechanism: repositioning for asphyxia, stimulation and rescue for failure of arousal, and a cardiac-directed approach for arrhythmia. No single strategy can protect everyone.

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PREDICTION AND INTERRUPTION These two problems are difficult for different reasons. Prediction, identifying who will die and when, is limited by the rarity of SUDEP, its mechanistic heterogeneity, and biomarkers whose group-level associations have so far translated poorly to the individual. Postictal generalised EEG suppression (PGES) illustrates this gap: associated with SUDEP across cohorts,7 it is nonetheless inconsistent within the same person from seizure to seizure, and is unreliable as a predictor for individuals.8 Interruption, arresting the cascade once it has begun, faces different obstacles: a window of minutes, usually in someone unobserved; an effective action that differs by mechanism and may not be identifiable at the time; and an event that cannot ethically be left unattended to randomise a rescue. Sudden arrhythmic death shows that interruption can be operationalised once the mechanism is defined and an effective rescue device exists. Cardiac arrhythmia is common in epilepsy, and patients do receive pacemakers;9 chronic epilepsy itself can remodel the heart, adding a further arrhythmic substrate.10 Even so, the chain to lives saved in people with epilepsy is unproven: pacing prevents syncope but has not been shown to prevent SUDEP, and ictal asystole is usually self-limiting.11 The cardiac field is nonetheless decades ahead with a deployable rescue for a defined mechanism. For the respiratory and positional mechanisms behind most SUDEP, we are earlier still: whether the cascade can be interrupted at all, by what, and within what window, is largely unknown. One rodent model has given us hope for feasibility: transient diaphragmatic pacing reduced postictal mortality, though it did not always restore breathing (likely reflecting coexistent laryngospasm).12

WHAT WE CAN DO NOW Two recent prospective studies used videoEEG to test peri-ictal biomarkers against subsequent SUDEP. In the REPO₂MSE study (1,074 adults with drug-resistant CC BY-NC 4.0 Licence

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focal epilepsy), the pre-specified endpoint of oxygen desaturation below 80% did not separate those who died from controls, and the number of antiseizure medications was not associated with risk.13 A larger cohort found peri-ictal central apnoea associated with SUDEP (a link that weakened after adjustment), while living alone and frequent convulsions persisted as known risks.14 Both cohorts came from monitoring units, with few deaths and wide uncertainty, and the association with apnoea was not significant with exclusion of possible and near-SUDEP cases. A caution is needed here: a biomarker that correlates with death is not necessarily a target that saves lives when modified. In the Cardiac Arrhythmia Suppression Trial, drugs that suppressed the surrogate (ventricular ectopy) increased mortality.15 Prevention requires evidence that changing a marker changes the outcome, which for SUDEP currently holds for no peri-ictal variable. With that caveat, four measures can be appraised. Seizure prevention acts furthest upstream; supervision and detection serve prediction, or enable a further rescue; and only repositioning would interrupt the cascade directly (this remains untested).

Medication Adherence and Seizure Prevention

Non-adherence is a recognised modifiable risk factor, and subtherapeutic drug levels are common at post-mortem, though confounded by redistribution. Recent prospective data found no association between the number of antiseizure medications and SUDEP.13 Adherence matters not because a drug level is protective but because it maintains seizure control. It is also among the few SUDEP relevant factors measurable in life, through drug levels, refill records, or possession ratio. Supporting seizure control, including timely medication changes and specialist or surgical referral where seizures remain refractory, is deliverable prevention.

Nocturnal Supervision and Detection

Nocturnal supervision carries a protective signal, though evidence is observational and

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guidelines endorse it only weakly. Sharing a bedroom or using a listening device is associated with reduced risk, apparently independent of seizure control, yet the most recent systematic review judged the certainty very low and found no adequate evidence for detection devices.5 Supervision is, moreover, least deliverable to those at highest risk: younger adults with refractory convulsions, often living alone. Wearable devices detect convulsions with high sensitivity; however, it is unknown whether these alarms improve outcomes.16 Detection, though, is not prevention. A device that senses a seizure must also summon someone who can reach the patient and intervene in a way that interrupts the SUDEP process. The first step is established; the second is not. Conversely, firm evidence that supervision reduced mortality would itself show the cascade can be interrupted.

Body Position

About 73% of SUDEP cases are found prone, with the proportion being higher in younger decedents.2,17 These data come from observations after death, invariably without knowing the position before the terminal seizure. The implied mechanism is logical but unproven: positional airway obstruction and reduced ventilatory drive prevents recovery and the resultant hypoxia impairs self-rescue, as in sudden infant death syndrome; this pattern was seen in 11 of 13 patients with positional data in MORTEMUS.1 Advising against prone sleeping addresses only part of the problem, since in monitored cases prone position arose nearly as often from the convulsion itself as from sleeping posture.1 Prevention must instead focus on postictal repositioning.

Postictal Repositioning

Here the evidence is weakest. No study has causally tested whether turning a patient from prone to lateral after a seizure prevents SUDEP. The supporting data are indirect and almost entirely from video-EEG: early peri-ictal intervention (repositioning, airway clearance, oxygen, stimulation) shortens respiratory dysfunction and PGES, and postictal immobility tracks the depth of respiratory compromise.18 No one 82

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has quantified prospectively how often repositioning occurs, how fast, and whether speed matters. Video-EEG suits that first step, relating repositioning latency to the duration of apnoea, desaturation, and PGES. A definitive trial would move into the community, where most SUDEP occurs, and could not be designed until data showed which surrogate to target.

Communication

Underlying all of these is engagement. The risks described here are modifiable (even if their impact on SUDEP is unestablished), but only by the person with epilepsy. Taking medication reliably, reporting seizures accurately, adjusting sleeping arrangements, and heeding nocturnal events are acts the patient must choose to undertake, none of which follows from a clinic letter alone. Informed discussion is therefore not an adjunct to prevention but how every measure above is delivered. And because risk runs across the whole epilepsy population, that conversation should be routine, not only for those labelled high-risk.

WHAT WE MUST STILL ESTABLISH We understand how people die of SUDEP far better than how to prevent it. Several answerable questions block the path from plausible to proven. Which seizures are fatal, and which, of hundreds, are survived? In an individual, which mechanism will prove lethal, positional, respiratory, or cardiac, and can it be identified in advance? Does earlier repositioning shorten the at-risk window? Can trials be designed not to identify risk but to reduce it? The epilepsy monitoring unit can begin to answer several of these. It records physiology and is where the phenotypes of the operative mechanism can be defined. Yet, while apnoea and EEG suppression are increasingly captured, the two variables most needed for the positional mechanism are often missing: body position, timestamped through the event, and the latency and nature of repositioning. The video holds both, but neither is routinely coded in a form usable for research. Coding

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them to a common standard, alongside the parameters that established cohorts already capture, would give every recorded convulsion a minimum peri-ictal dataset. SUDEP is too rare in monitored patients for mortality to be a feasible endpoint, but the unit can answer the question on which any prevention trial depends: whether the cascade is interruptible, and within what window. The one randomised attempt to improve postictal recovery, naloxone administration during monitored seizures, did not improve oxygenation, a measure of how early this work remains.19

References 1.

Ryvlin P et al. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. Lancet Neurol. 2013;12(10):966-77.

Grundmann A et al. The epilepsy deaths register: third-party reports of SUDEP in adults and older adolescents. Seizure. 2025;132:20-9.

Harden C et al. Practice guideline summary: sudden unexpecteddeath in epilepsy incidence rates and risk factors. Neurology. 2017;88(17): 1674-80.

Ryvlin P et al. Risk of sudden unexpected death in epilepsy in patients given adjunctive antiepileptic treatment for refractory seizures: a meta-analysis of placebo-controlled randomised trials. Lancet Neurol. 2011;10(11):961-8. Maguire MJ et al. Treatments for the prevention of sudden unexpected death in epilepsy (SUDEP). Cochrane Database Syst Rev. 2020;4:CD011792. Devinsky O et al. Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention. Lancet Neurol. 2016;15(10):1075-88.

While SUDEP risk can be stratified across groups, it cannot yet be predicted in the individual. Novel respiratory, sleep, electroclinical, and anatomical markers are improving mechanistic understanding, though most require external validation and assessment of clinical utility. Despite this, prevention should not await a perfect predictive model. The current priorities are clear and can be delivered now: reduction of convulsive seizures, timely management of drug resistance, and honest and proportionate communication around appropriate nocturnal supervision and seizure first aid.

Lhatoo SD et al. An electroclinical case-control study of sudden unexpected death in epilepsy. Ann Neurol. 2010;68(6):787-96.

Lamberts RJ et al. Postictal generalized EEG suppression: an inconsistent finding in people with multiple seizures. Neurology. 2013;81(14):1252-6.

Rugg-Gunn FJ et al. Cardiac arrhythmias in focal epilepsy: a prospective long-term study. Lancet. 2004;364(9452):2212-9.

10. Verrier RL et al. The epileptic heart: concept and clinical evidence. Epilepsy Behav. 2020;105:106946. 11. Tényi D et al. Ictal asystole: a systematic review. Epilepsia. 2017;58(3):356-62. 12. Purnell BS et al. Diaphragmatic pacing for the prevention of sudden unexpected death in epilepsy. Brain Commun. 2022;4(5):fcac232. 13. Ryvlin P et al. Seizure-related biomarkers of sudden unexpected death in epilepsy (SUDEP) in drugresistant focal epilepsy (REPO2MSE): a prospective, multicentre case–control study. Lancet Neurol. 2026;25(1): 50-60.

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14. Ochoa-Urrea M et al. Risk markers for sudden unexpected death in epilepsy: an observational, prospective, multicentre cohort study. Lancet. 2025;406(10511):1497-507. 15. Echt DS et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991;324(12):781-8. 16. Beniczky S et al. Automated seizure detection using wearable devices: a clinical practice guideline of the International League Against Epilepsy and the International Federation of Clinical Neurophysiology. Epilepsia. 2021;62(3):632-46. 17. Liebenthal JA et al. Association of prone position with sudden unexpected death in epilepsy. Neurology. 2015;84(7):703-9. 18. Seyal M et al. Impact of periictal interventions on respiratory dysfunction, postictal EEG suppression, and postictal immobility. Epilepsia. 2013;54(2):377-82. 19. Rheims S et al. Efficacy of naloxone in reducing hypoxemia and duration of immobility following focal to bilateral tonic-clonic seizures. Epilepsia Open. 2025;10(3):880-93.

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From Biological Detection to Clinical Decision-Making: Incorporating α-Synuclein Seed Amplification Assays in Parkinson’s Diagnosis Authors:

Melanie J. Plastini,1 *Luis Concha-Marambio1 1. Amprion Inc., San Diego, California, USA *Correspondence to luis@ampriondx.com

Disclosure:

Concha-Marambio is an employee of Amprion Inc; holds stock options; and is a named inventor of patents related to the α-synuclein seed amplification assay, which have been assigned to Amprion Inc. Plastini is a full-time employee of Amprion Inc; and holds stock options.

Received:

02.07.26

Accepted:

17.07.26

Keywords:

α-synuclein (αSyn), biomarkers, biological diagnosis, clinical implementation, Parkinson’s disease (PD), precision medicine, seed amplification assay (SAA), synucleinopathy.

Citation:

EMJ Neurol. 2026;14[1]84-87. https://doi.org/10.33590/emjneurol/3QK65W9Z

INTRODUCTION Parkinson’s disease (PD) remains largely a clinical diagnosis based on characteristic motor features and supportive clinical criteria. However, clinicopathological studies report diagnostic accuracies of 70–85%, with even lower accuracy in early disease and atypical parkinsonism. Critical to the development and implementation of precision diseasemodifying therapies is the availability of biomarkers that reflect underlying biology rather than clinical phenotype. Detection of misfolded α-synuclein (αSyn) in the cerebrospinal fluid (CSF) by seed amplification assay (SAA) is recognised as a promising diagnostic tool for neurodegenerative disorders. Studies have demonstrated high sensitivity and specificity for detecting underlying synuclein pathology, including validation in more than 600 neuropathologically confirmed cases, with similar performance in clinically diagnosed PD.1 Accumulating evidence suggests that αSyn-SAA has 84

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the potential to reshape the diagnosis of synucleinopathies by improving diagnostic confidence in selected clinical contexts. However, widespread clinical implementation requires a deeper understanding of how biomarker results should be interpreted across diverse patient populations.

BIOLOGICAL DIAGNOSIS AND CURRENT RESEARCH FRAMEWORKS Unlike traditional biomarkers that capture downstream consequences of disease, αSyn-SAA amplifies and detects misfolded αSyn aggregates, the primary component of Lewy bodies and Lewy neurites that are a pathological feature of PD and related synucleinopathies. Multicenter studies have reported sensitivity exceeding 85–90% for clinically diagnosed PD, with high specificity among healthy controls and other neurodegenerative diseases.1 Particularly impactful were the initial findings in the Parkinson’s Progression

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Markers Initiative (PPMI) cohort,1 which demonstrated αSyn-SAA positivity in 87.7% of PD participants and 86% of prodromal participants prior to evidence of dopaminergic deficit, suggesting that αSyn pathology, detectable by αSynSAA, may precede neurodegeneration detectable by conventional imaging. Recent advances in αSyn-SAA technology have demonstrated the ability to distinguish multiple system atrophy (MSA) from PD and other synucleinopathies, representing an important clinical advance given the rapid progression and poorer prognosis associated with MSA.2 These findings have resulted in enthusiasm for moving toward a biologically defined framework for PD,3,4 similar to the biomarkerbased framework adopted in Alzheimer’s disease (AD). Recent research criteria increasingly incorporate αSyn-SAA as evidence of underlying synucleinopathy. However, translating a biomarker from research settings into clinical care requires more than diagnostic accuracy alone. While emerging SAAs have demonstrated clear clinical utility in distinguishing MSA from other synucleinopathies, the broader challenge of clinical implementation lies not in whether a biomarker can detect active disease, but in establishing clinical use guidelines and how these assays can best inform patient care across a range of presentations.

REAL-WORLD COHORTS, DIVERSE POPULATIONS, AND ACCESSIBILITY Most studies have focused on wellcharacterised research cohorts enriched for PD and related synucleinopathies. However, in routine neurology clinics, patients often present with overlapping symptoms, vascular disease, medication effects, or uncertain diagnoses. Moreover, increasing evidence suggests that synuclein pathology frequently coexists with other neurodegenerative diseases, including AD.5 As clinical adoption of αSyn-SAA expands, performance across broader patient populations, including individuals with nonspecific symptoms, atypical parkinsonism, and community-based CC BY-NC 4.0 Licence

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cohorts, will further define the real-world utility of αSyn-SAA and refine evidencebased clinical use guidelines. Although current testing relies on CSF, continued advances in blood and skin-based assays may further improve accessibility. Beyond the need for CSF, technical aspects of the assay require strong laboratory skills and close attention to detail. To ensure reproducible and reliable results, αSyn-SAA should be performed by trained professionals operating under an established quality management system using rigorously qualified SAA-competent materials sourced through standardised quality control processes. As for any in vitro diagnostic test, compliance with relevant regulatory standards is required for the use of αSyn-SAA as part of medical decision-making. In the USA, the test is currently offered to clinicians as a laboratory developed test, in compliance with Clinical Laboratory Improvement Amendments (CLIA) regulations, through a centralised commercial laboratory. In Europe, implementation must comply with the EU In Vitro Diagnostic Regulation (IVDR). This is also likely to occur initially through centralised reference laboratories operating under standardised workflows. In addition to scientific and regulatory considerations, clinical implementation is influenced by intellectual property and licensing frameworks. Many of the methodological advances that enable robust, analytical, and clinical validation are proprietary, meaning that commercial implementation may require access to licensed technologies in addition to regulatory approval. As assay methodologies and access become increasingly standardised, broader adoption across healthcare systems is anticipated.

NEGATIVE TEST RESULT IN SYMPTOMATIC INDIVIDUALS Although αSyn-SAA demonstrates high specificity for PD, not all individuals with parkinsonism test positive. A negative result may reflect a non-synucleinopathy disorder, technical and biological variability, or lower positivity in specific genetic subtypes such as LRRK2-associated PD. A recent analysis of αSyn-SAA-negative

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participants in the PPMI cohort found that 14.3% underwent diagnostic revision during follow-up, highlighting that a negative test can represent biological heterogeneity and disorders that mimic PD rather than a false negative.6 Importantly, more advanced SAA technologies can distinguish Type 1 synuclein seeds associated with PD and dementia with Lewy bodies from Type 2 synuclein seeds associated with MSA.2 Earlier-generation assays were unable to detect Type 2 seeds and may have yielded negative results in symptomatic individuals. The new accuracy of this distinction has prompted recommendations for assay-specific result interpretation and clinical management. αSyn-SAA results should therefore be interpreted within the broader clinical context, alongside clinical examination and other available imaging and biomarker data. Defining the implications of biomarker-negative parkinsonism remains an important area for future research.

POSITIVE TEST RESULT IN INDIVIDUALS WITH NONSPECIFIC SYMPTOMS Symptoms such as chronic constipation, mild cognitive impairment, or subtle motor complaints are common in the ageing population and are not specific to synucleinopathy. If such an individual tests positive for αSyn-SAA, does this indicate prodromal PD, incidental Lewy body disease, or merely increased future risk? This issue mirrors challenges previously encountered in AD, where amyloid positivity alone does not necessarily equate to symptomatic disease. Studies of prodromal populations suggest that αSyn-SAA positivity can precede motor symptom onset by years.7,8 Isolated rapid eye movement sleep behaviour disorder, in particular, has been associated with prodromal PD. The rate of phenoconversion in these cases is still being researched; however, in a 2025 PPMI analysis of 96 participants with prodromal PD, defined by RBD and/or hyposmia with mild dopamine-transporter imaging deficits, 23 phenoconverted over follow-up of up to 9.2 years: 21 to PD and two to dementia with Lewy bodies.8 αSyn-SAA-positive 86

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participants were significantly more likely to phenoconvert, and faster amplification was associated with greater risk. However, the assay did not independently predict the timing of conversion for an individual. These findings support αSyn-SAA as a means of detecting underlying pathology and elevated phenoconversion risk and may support enrichment for prevention trials. As testing becomes more widely available, clinicians will increasingly encounter biomarker-positive individuals who do not meet diagnostic criteria for PD or other synucleinopathies. Establishing evidencebased approaches for counselling, monitoring, and treatment management in these cases will be imperative, while underscoring the need to interpret positivity alongside clinical features, imaging, genetics, and other biomarkers.

POSITIVE TEST RESULT IN ASYMPTOMATIC INDIVIDUALS Studies have shown that participants who test positive and are asymptomatic, cognitively unimpaired, and with no known underlying neurological disorders can progress to a clinical synucleinopathy over 10 years and report more synucleinopathyrelated non-motor symptoms.9,10 This raises the possibility of identifying at-risk individuals before irreversible neurodegeneration occurs, an essential step toward preventive therapies. The detection of αSyn pathology in asymptomatic individuals may ultimately lead to the ability to diagnose and treat prior to the onset of clinical symptoms, as well as track disease progression and phenoconversion over time. However, without effective diseasemodifying therapies, the ethical and psychological implications of disclosing biomarker positivity also warrant careful consideration. Longitudinal studies are still needed to determine conversion rates, timelines, and modifiers of disease progression among asymptomatic SAApositive individuals.

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FUTURE APPLICATIONS AND THE PATH FORWARD αSyn-SAA represents a major advance in the field of neurodegenerative disorder biomarkers, particularly in the biological detection of neuronal synucleinopathy. Importantly, a positive αSyn-SAA should not be interpreted as synonymous with a biological diagnosis of PD, but rather as evidence of underlying α-synuclein pathology to improve diagnostic confidence in selected clinical contexts. Consistent with emerging biological frameworks, additional biomarkers reflecting nigrostriatal dysfunction, together with

References 1.

Siderowf A et al. Assessment of heterogeneity among participants in the Parkinson's Progression Markers Initiative cohort using α-synuclein seed amplification: a cross-sectional study. Lancet Neurol. 2023;22(5):407-17. Ma Y et al. Sensitivity and specificity of a seed amplification assay for diagnosis of multiple system atrophy: a multicentre cohort study. Lancet Neurol. 2024;23(12):1225-37. Höglinger GU et al. A biological classification of Parkinson's disease: the SynNeurGe research diagnostic criteria. Lancet Neurol. 2024;23(2):191-204. Simuni T et al. A biological definition of neuronal α-synuclein disease:

clinical evaluation, remain necessary to fully characterise disease stage and phenotype. Nevertheless, widespread clinical implementation requires a deeper understanding of biomarker interpretation across the disease continuum. As the field makes advances and new iterations of frameworks for biologically defined neurodegenerative diseases, αSyn-SAA is poised to become an important component of the diagnostic toolkit. Yet, like all biomarkers, its greatest value is when integrated with clinical phenotype, imaging, and complementary biomarkers to guide patient care.

towards an integrated staging system for research. Lancet Neurol. 2024;23(2):178-90. 5.

Tosun D et al. Association of CSF α-synuclein seed amplification assay positivity with disease progression and cognitive decline: a longitudinal Alzheimer's Disease Neuroimaging Initiative study. Alzheimers Dement. 2024;20(12):8444-60.

Brooker SM et al. Clinical and imaging characteristics of Parkinson's disease with negative alpha-synuclein seed amplification assay. Mov Disord. 2026;41(5):1114-27.

Concha-Marambio L et al. Accurate detection of α-synuclein seeds in cerebrospinal fluid from isolated rapid eye movement sleep behavior

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disorder and patients with Parkinson's disease in the DeNovo Parkinson (DeNoPa) cohort. Mov Disord. 2023;38(4):567-78. 8.

Coughlin DG et al. α-Synuclein seed amplification assay amplification parameters and the risk of progression in prodromal Parkinson disease. Neurology. 2025;104(5):e210279.

Palmqvist S et al. Cognitive effects of Lewy body pathology in clinically unimpaired individuals. Nat Med. 2023;29(8):1971-8.

10. Winer JR et al. Effects of α-synuclein pathology on synaptic dysfunction and clinical outcomes in normal aging. Alzheimers Dement. 2026;22(5):e71455.

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The Urgent Need for a Parkinson’s Disease Patient Support Group in Latvia Author:

*Paula Abola1 1. Faculty of Business and Management Studies, European International University, Paris, France *Correspondence to paula.abola@uj.edu

Disclosure:

The author has declared no conflicts of interest.

Received:

12.06.25

Accepted:

07.05.26

Keywords:

Healthcare access, Latvia, Parkinson’s disease (PD), patient support groups (PSG), quality of life.

Citation:

EMJ Neurol. 2026;14[1]:88-91. https://doi.org/10.33590/emjneurol/9FOGHF20

INTRODUCTION Across Europe, people living with Parkinson’s disease (PD) increasingly benefit from strong patient advocacy organisations and community-based support groups. These initiatives provide education, psychosocial support, and advocacy, while acting as a bridge between patients, caregivers, and healthcare systems.1,2 It is important to distinguish between patient organisations (PO) and patient support groups (PSG). POs typically operate at a systems level, focusing on advocacy, policy influence, and large-scale awareness initiatives. In contrast, PSGs are centred on the individual illness experience, providing direct peer support, practical guidance, and psychosocial connection throughout the disease journey. While both structures are complementary, PSGs address immediate day-to-day needs that are often unmet within formal healthcare systems.3 In Latvia, however, there is currently no national PSG or formalised network for those with PD. This absence leaves patients and caregivers without a central hub for reliable information, peer connection, or advocacy. Estimates suggest that several thousand individuals are living with PD in 88

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Latvia, consistent with prevalence patterns across Europe, yet structured support services remain limited.4 The creation of such a group in Latvia is not just desirable but urgently needed. This feature discusses why PD patient support structures matter, the current gaps in Latvia, the potential benefits for patients and healthcare providers, and the practical steps that could make this initiative a reality.

WHY PSGs MATTER PD is a complex neurodegenerative disorder with both motor and non-motor symptoms. Beyond tremor, rigidity, and bradykinesia, many individuals experience fatigue, sleep disturbances, anxiety, and cognitive challenges.5,6 These symptoms often extend beyond what neurologists can fully address in brief clinical visits, highlighting the value of community-based support. POs across Europe play a pivotal role in filling this gap. They provide educational resources tailored to patient and caregiver needs; offer psychosocial support, reducing feelings of isolation and stigma; advocate for equitable access to treatment and services at the national and EU level;

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and serve as a platform for peer-to-peer knowledge exchange, allowing patients to learn from others’ lived experiences. More specifically, PSGs provide safe, structured environments where individuals can share personal experiences, develop coping strategies, and receive emotional support from peers facing similar challenges. This peer-based model has been shown to reduce isolation and improve psychological resilience.3 Evidence suggests that participation in support groups improves patient empowerment, disease knowledge, coping strategies, and even adherence to treatment.7 For example, European initiatives have demonstrated that patient-centred engagement enhances patients’ ability to participate in care decisions and improves communication with healthcare providers.8 Moreover, such groups act as a structured way for policymakers and clinicians to hear directly from those affected.

THE CURRENT SITUATION IN LATVIA Despite the benefits seen elsewhere, Latvia lacks a national PD patient support organisation. From informal conversations with patients, it is clear that many feel isolated and uncertain about how to navigate their disease outside of clinical encounters. For example, patients frequently report feeling that clinical consultations focus primarily on symptom management, while broader concerns, such as coping with fatigue, maintaining social participation, or managing uncertainty about disease progression, remain insufficiently addressed. Challenges are particularly acute in rural regions. Patients often face long travel distances to see neurologists, limited local resources, and few opportunities to connect with others who share their experiences. Some informal peer networks exist in small circles, but there is no coordinated national structure, educational platform, or collective voice.

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The absence of such a group also places Latvia at a disadvantage compared with other European countries. Organisations like Parkinson’s Europe and the Parkinson’s Foundation list dozens of member associations across the continent.1,2 In fact, the majority of European countries have at least one national PD support group, highlighting Latvia as a notable gap in the regional support landscape.

LESSONS FROM OTHER CONTEXTS The impact of support groups in other countries demonstrates what Latvia could gain. For instance, surveys across Europe have shown that patient advocacy improves quality of life, enhances patient involvement in care, and strengthens collaboration with healthcare providers.5 In addition, recent research conducted in Latvia itself highlights how clinical symptoms, such as fatigue and cognitive impairment, profoundly affect quality of life for patients with PD.6 Yet, without a support infrastructure, these issues are rarely addressed outside clinical management. Establishing a support group would provide a mechanism to address exactly these unmet needs. Importantly, PSGs also contribute to biomedical research. They facilitate patient recruitment for studies, support the dissemination of research findings in accessible formats, and help ensure that research priorities reflect patient needs and lived experiences. Engaged patient communities have been shown to strengthen the relevance and impact of clinical and translational research in PD.7

PRACTICAL STEPS TOWARDS BUILDING A LATVIAN PD SUPPORT GROUP Creating a PO does not require large-scale infrastructure or funding. Successful models elsewhere suggest a phased, communitydriven approach:

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1. Establish a core team: A small group of patients, caregivers, neurologists, and allied health professionals could serve as the founding committee. 2. Develop a central contact point: This could begin as a website or social media platform offering curated educational resources in Latvian and links to reliable international materials. 3. Organise pilot meetings: Monthly virtual or in-person meetings could provide a forum for sharing experiences and inviting guest speakers. 4. Seek collaboration: Partnerships with Parkinson’s Europe and regional POs would enable knowledge transfer and potential funding opportunities. 5. Scale gradually: Over time, the initiative could grow into a national advocacy body, representing Latvian patients at European levels and engaging policymakers in dialogue. Table 1 outlines a simple staged roadmap.

A clear call to action is therefore warranted: national stakeholders, including the Ministry of Health, neurological societies, and patient advocacy bodies, should prioritise the establishment and support of a PD PSG as part of a broader strategy for chronic disease management.

FUTURE PROSPECTS AND REMAINING QUESTIONS Looking ahead, the question is not whether Latvia needs a PD support group, but how to make it happen. The barriers, such as limited resources, lack of awareness, and geographic dispersion, are real but not impossible to overcome. Key unanswered questions include: •

Who will take the lead in initiating this effort?

•

How can patients in rural regions be meaningfully included?

•

IMPLICATIONS FOR HEALTHCARE AND POLICY

What role can digital platforms play in overcoming geographic barriers?

•

The establishment of a PD support group in Latvia would not only benefit patients and caregivers, but also healthcare providers and policymakers. Neurologists and allied health professionals would gain a channel to better understand patient experiences, while policymakers would receive direct feedback from those affected by PD.

How can sustainable funding be secured without overburdening patients?

Addressing these questions requires collaboration across patients, clinicians, non-governmental organisations, and policymakers. Even small first steps, such as creating an educational website or hosting a regular patient meeting, would represent meaningful progress.

This gradual scaling approach is particularly important, as it allows PSGs to evolve organically into broader POs, thereby linking individual-level support with system-level advocacy.

From a health system perspective, PSGs may also contribute to improved selfmanagement, reduced healthcare utilisation for preventable complications, and more efficient use of specialist services. At a societal level, such an initiative would help reduce stigma, promote early 90

diagnosis, and encourage more proactive disease management. Importantly, Latvia’s integration into European PD networks would amplify the patient voice in shaping research and policy agendas.7

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CONCLUSION Latvia’s patients with PD and caregivers currently lack a structured support system. Lessons from across Europe show that PSGs enhance empowerment, improve quality of life, and provide a collective voice in

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Table 1: A staged roadmap for establishing a Latvian Parkinson’s disease support group.

Stage

Key actions

Outcomes

Initial

Identify core team, establish online presence

Contact hub, visibility

Pilot

Host monthly patient meetings (virtual/in-person)

Peer connection, feedback

Growth

Expand membership, formalise legal structure

National representation

Integration

Partner with European networks, engage policymakers

Advocacy, inclusion in EU initiatives

healthcare decision-making. Establishing such a group in Latvia would not require major resources but would deliver significant

benefits for patients, families, and the healthcare system. The time to act is now.

References 1.

Parkinson’s Europe. Our members. 2026. Available at: https://parkinsonseurope. org/who-we-are/our-members/. Last accessed: 7 February 2026.

Abola P et al. Regional features in the treatment of Parkinson’s disease in the Baltic States compared to Germany. BMC Health Serv Res. 2026;26(1):873.

Parkinson’s Foundation. Resources & support. 2026. Available at: https:// www.parkinson.org/resources-support. Last accessed: 7 February 2026.

Bloem BR, Stocchi F. Move for change part III: a European survey evaluating the impact of the EPDA charter for people with Parkinson's disease. Eur J Neurol. 2015;22(1):133-41.

Minibajeva O et al. Clinical symptoms influencing Parkinson’s patients’ quality of life in Latvia: a single-center cohort study. Medicina (Kaunas). 2023;59(5):935.

Soilemezi D et al. Understanding support systems for Parkinson's disease management in community settings: a cross-national qualitative study. Health Expect. 2023;26(2):670-82.

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Boon P et al. A strategic neurological research agenda for Europe: towards clinically relevant and patient-centred neurological research priorities. Eur J Neurol. 2024;31(3):e16171.

Domingos J et al. People with early onset Parkinson’s disease: empowered to improve care. J Parkinsons Dis. 2023;13(4):633-6.

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Rethinking Cognitive Screening in Multiple Sclerosis: Detection and Attribution for Patient-Centred Care Authors:

*Leigh Charvet,1 Kasey Brink Saeed,1 Giuseppina Pilloni1 1. Departments of Psychiatry and Neurology, NYU Grossman School of Medicine, New York, USA *Correspondence to leigh.charvet@nyulangone.org

Disclosure:

The authors have declared no conflicts of interest.

Received:

23.06.26

Accepted:

22.07.26

Keywords:

Cognitive impairment, cognitive screening, disease progression, multiple sclerosis (MS), neuropsychology, patient-centred care, psychometrics, Symbol Digit Modalities Test (SDMT).

Citation:

EMJ Neurol. 2026;14[1]:92-104. https://doi.org/10.33590/emjneurol/34B7G51S

Abstract Cognitive screening in multiple sclerosis (MS) serves two important clinical purposes: identifying individuals who may require more comprehensive evaluation and monitoring cognitive change over time. Cognitive performance is associated with employment, daily functioning, and quality of life, and a definable subgroup of individuals with MS experiences clinically meaningful impairment. However, brief screening scores are increasingly interpreted as indicators of MS disease activity or progression despite limited evidence that routine surveillance improves patient outcomes or reliably distinguishes neurological change from practice effects, motor impairment, fatigue, mood, medication burden, and other influences. Historical prevalence estimates may also overstate individual risk when normal base rates of low scores and variable impairment criteria are not considered. Digital platforms may improve accessibility and measurement frequency but do not resolve these attributional and psychometric limitations. This narrative review examines the validated uses and limitations of cognitive screening in MS and argues for an interpretation that is contextual, psychometrically grounded, and linked to actionable clinical decisions. Cognitive screening should identify concerns requiring further evaluation, not independently determine their cause, permanence, or relationship to disease progression.

Key Points 1. Routine cognitive screening is increasingly used in multiple sclerosis (MS) despite limited evidence that repeated surveillance improves outcomes or reliably detects disease progression in individuals. While clinically valuable, overinterpretation of nonspecific findings may reinforce expectations of decline and lead patients to misattribute everyday cognitive lapses to MS progression. 2. This review summarises the strengths and limitations of cognitive screening in MS, including the nonspecific nature of subjective complaints, state-dependent cognitive performance, psychometric requirements for individual interpretation, historical prevalence estimates, and the promise and limitations of emerging monitoring approaches.

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3. Cognitive complaints and low screening scores are common and influenced by multiple factors. Screening can identify patients who warrant fuller evaluation, but findings should not be attributed to MS disease activity without considering fatigue, sleep disturbances, affective symptoms, pain, medication burden, substance use, and other potentially modifiable contributors. Formal neuropsychological evaluation should be used when results will inform diagnosis, rehabilitation, accommodations, disability determination, or treatment decisions. Explicit reassurance is appropriate when fears exceed objective evidence.

INTRODUCTION Few health concerns carry greater psychological weight than the possibility of cognitive decline. Surveys consistently identify loss of memory and thinking abilities as among the most feared health outcomes, reflecting the uniquely personal threat that cognitive impairment poses to identity, independence, and one’s sense of self.1,2 This concern is particularly salient for people diagnosed with multiple sclerosis (MS), a lifelong neurological disorder without a cure. Most commonly diagnosed in young adulthood and increasingly recognised in paediatric populations, diagnosis is lifealtering and introduces profound uncertainty regarding future progression and functional decline.3,4 Cognitive dysfunction has long been recognised as a clinically meaningful manifestation of MS and remains a major source of disability and reduced quality of life for many affected individuals.5,6 The prospect of cognitive decline emerges during formative stages of education, career development, relationship building, family formation, parenting, and identity development, when cognitive abilities are central to independence, achievement, and future planning, compounding the psychological and social impact of diagnosis. Over the past three decades, substantial effort has been devoted to recognising and characterising historically underrecognised symptoms of MS, often referred to as “invisible” symptoms. Increased clinical attention to cognitive dysfunction represented an important advance in MS care, given its established associations with employment, daily functioning, and health-related quality of life.6-8 Consensus recommendations increasingly encourage routine cognitive screening as part of CC BY-NC 4.0 Licence

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standard MS care to identify individuals who may benefit from more comprehensive evaluation.8-10 Importantly, these recommendations position screening as a trigger for additional assessment rather than a standalone diagnostic or disease-activity biomarker.10 Greater emphasis has also been placed on longitudinal monitoring, with changes in cognitive performance proposed as early indicators of disease progression that may inform treatment decisions.9,11 In practice, monitoring often relies on the Symbol Digit Modalities Test (SDMT), a brief and clinically practical measure commonly interpreted as an index of information-processing speed. However, SDMT performance also depends on attention, visual scanning, working memory, associative learning, response selection, and motor speed. It therefore provides a limited window into cognition and cannot independently determine the cause of reduced performance.10,12 Evidence remains limited regarding whether routine surveillance identifies clinically meaningful disease activity that would otherwise be missed or improves patient outcomes.8,13-15 At the same time, repeated monitoring may influence how patients understand their prognosis, particularly when low scores or modest fluctuations are attributed to disease progression without adequate consideration of measurement variability and alternative contributors. This review examines the validated clinical uses and interpretive limitations of cognitive screening results as indicators of MS-related impairment or progression.

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SUBJECTIVE COGNITIVE COMPLAINTS ARE COMMON AND NONSPECIFIC Cognitive difficulty is among the most commonly reported symptoms in MS, alongside fatigue and depression.16 In a recent cohort, 76.8% of individuals with MS reported subjective cognitive difficulties, whereas only 15.2% met criteria for objective cognitive impairment.17 While MS can result in objective cognitive impairment, subjective complaints more commonly involve inefficiency in sustained information processing: patients becoming overwhelmed when multitasking, struggling to keep pace in complex conversations, or experiencing mental fatigue that accumulates across the day rather than discrete memory failure. Cognitive complaints are also common in the general population and across a wide range of medical and psychiatric conditions (Figure 1), limiting their specificity as indicators of MS-related neurological dysfunction.18-28 Population estimates range from approximately 25–53%, with complaints particularly frequent during depression, chronic pain, fatigue-related disorders, menopause, and other periods of physiological or psychological stress.18-29 These complaints represent one of the primary drivers of cognitive screening in MS, reflecting neurologists’ understandable desire to evaluate and respond to patient concerns. In the context of an MS diagnosis, cognitive symptoms that might otherwise be attributed to stress, fatigue, or other situational factors become reframed as evidence of disease activity or progression. In MS, subjective cognitive complaints demonstrate only weak correspondence with objective neuropsychological performance and reflect affective, fatigue-related, pain-related, and broader psychological distress more strongly than cognitive impairment itself.17,22,30,31 This pattern was recently demonstrated by Van Laethem et al.19 in a cohort of 205 individuals with early MS, finding only a weak association between subjective and 94

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objective cognitive performance (ρ=0.21).19 In the final model, subjective cognitive performance was independently and negatively associated with pain (β=–1.52; p<0.001), dizziness (β=–0.97; p=0.01), fatigue (β=–0.27; p=0.001), and depressive symptoms (β=–0.22; p<0.001), with the model explaining 53% of the variance. While objective processing speed was in fact associated with walking impairment and thalamic volume, subjective cognitive performance was not significantly associated with volumetric MRI measures.19 Conversely, individuals with more substantial impairment may underreport difficulties because metacognitive insight itself can decline alongside cognitive dysfunction.32 Collectively, these findings demonstrate a marked discrepancy between subjective cognitive concerns and objectively measured impairment in MS. Cognitive complaints remain clinically meaningful as indicators of symptom burden, distress, and reduced quality of life, but neither subjective complaints nor objective findings independently establish MS as the cause. The central clinical question is not simply determining whether cognitive symptoms are present but understanding what they reflect.

COGNITIVE PERFORMANCE SHOULD NOT BE TREATED AS A DISEASE-ACTIVITY BIOMARKER Even when objective testing is performed, the interpretation problem remains. Cognitive performance differs fundamentally from most biomarkers and clinical measures used in neurological care. In MS, cognitive dysfunction most commonly involves slowed processing speed and attention inefficiency, rather than the progressive amnestic syndromes characteristic of Alzheimer’s disease and other neurodegenerative disorders. As a result, recall-weighted screening tools such as the Montreal Cognitive Assessment (MoCA) may be poorly aligned with the cognitive phenotype most relevant to MS. Cognitive changes in MS are often diffuse, variable, and only modestly associated with conventional disease markers, including lesion burden

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Figure 1: Subjective cognitive complaints across general and clinical populations, including common MS comorbidities.18-28

Cognitive complaints are a common feature of chronic illness and psychological distress and are not specific to MS or indicative of underlying neurological dysfunction. MS is highlighted in purple for comparison. Estimates are approximate and derived from multiple sources. CI: cognitive impairment; MCI: mild cognitive impairment; MDD: major depressive disorder; MS: multiple sclerosis.

and physical disability.33,34 Mechanisms such as network disruption and diaschisis are increasingly recognised as contributors beyond focal lesion location alone.35 Importantly, reduced processing efficiency is often experienced subjectively as memory difficulty, conversational slowing, distractibility, or word-finding problems despite the absence of primary amnestic impairment.36-39 Patients often describe this as “memory loss” even when the underlying difficulty reflects attentional efficiency and processing speed.7,40 Unlike measures such as MRI lesion burden, retinal thinning, or walking speed, cognitive performance is highly sensitive to context and state-dependent influences.33 Attention, processing speed, and memory efficiency reflect a combined influence of CC BY-NC 4.0 Licence

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neurological, psychological, physiological, and environmental contributors, making attribution to MS disease activity alone inherently uncertain. This challenge is particularly relevant when interpretation relies on brief cognitive screening rather than comprehensive neuropsychological evaluation, which can better account for non-neurological factors and performance variability. Clinical testing may further amplify these state-dependent influences. Patients may be anxious about imaging results, disability progression, employment, or treatment decisions while anticipating evaluation of their cognitive functioning.41 Processing speed and efficiency measures are inherently state-dependent and fluid, making them particularly sensitive to transient influences. Experimental

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evidence consistently demonstrates that acute stress degrades attentional control, working memory, and processing speed through prefrontal disruption and autonomic arousal.42,43 These are the same cognitive operations most commonly assessed in MS screening. A low score obtained during a stressful clinic visit may reflect transient state-dependent influences as much as stable neurological dysfunction. Together, these factors distinguish cognitive performance from conventional biomarkers. Cognitive tests measure behaviour rather than pathology directly. Low performance may indicate cognitive inefficiency, but does not establish its cause, determine its permanence, or necessarily demonstrate disease progression. Recent longitudinal studies from the Swedish Multiple Sclerosis Registry further illustrate these interpretive challenges, demonstrating that changes in cognitive screening performance may be substantially influenced by practice effects and other nonspecific factors.11 As a result, cognitive screening scores should be interpreted as contextual clinical observations rather than objective markers of underlying disease activity.

ATTRIBUTION BIAS AND THE COMPLEXITY OF COGNITIVE SYMPTOMS The presence of an MS diagnosis creates a powerful attribution bias for both patients and clinicians. Common symptoms such as fatigue, cognitive difficulty, pain, mood changes, and sensory complaints are often interpreted as manifestations of MS disease activity despite numerous alternative medical, psychological, and lifestyle-related explanations.44 These symptoms are common across many medical and psychiatric conditions and are not specific to MS,23-26,45 yet there is a tendency to attribute both cognitive symptoms and low cognitive scores directly to disease pathology when multiple alternative contributors coexist. Difficulties with attention, memory, processing speed, word-finding, and cognitive fatigue occur across numerous medical, 96

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psychiatric, developmental, hormonal, and environmental conditions, and are common features of everyday cognition, particularly during periods of stress, sleep disruption, illness, pain, emotional distress, and hormonal transition (Figure 2). The menopausal transition represents an important contributor to subjective cognitive complaints.46 Most women experiencing subjective complaints during the menopausal transition perform within normal limits on objective cognitive testing, underscoring the dissociation between reported difficulty and measurable dysfunction.20 This is particularly relevant in MS, where women are disproportionately affected, and transitions to secondary progressive disease commonly emerge during midlife, making attribution of cognitive symptoms to MS pathology especially challenging. Fatigue, sleep disturbance, mood symptoms, pain, and medication burden can each independently reduce processing efficiency.23,45-50 This is particularly relevant in MS, where polypharmacy is common and centrally acting medications used for fatigue, pain, spasticity, mood, and sleep, including gabapentin, baclofen, benzodiazepines, anticholinergic agents, antidepressants, and cannabis, may produce cognitive effects that are difficult to distinguish from MS-related change.50-55

THE SDMT, BRIEF INTERNATIONAL COGNITIVE ASSESSMENT FOR MS, AND WHAT LOW SCORES ACTUALLY MEAN Cognitive involvement in MS exists along a continuum, and findings classified as ‘cognitive impairment’ in prevalence studies often reflect subtle slowing on screening measures rather than severe cognitive dysfunction, loss of independence, or progressive neurocognitive decline. The SDMT (oral administration) has become the dominant cognitive screening measure in MS because of its brevity, practicality, and sensitivity to neurological dysfunction.56 However, the clinical conclusions drawn

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Figure 2: Determinants of cognitive test performance in multiple sclerosis.

MS disease burden Practice effects

Fatigue

Developmental and educational history

Sleep dysfunction

Cognitive test performance

Testing environment

Mood and anxiety

Visual function

Pain

Motor function

Polypharmacy Stress

Cognitive test performance reflects the combined influence of neurological, psychological, physiological, and environmental factors. Screening scores should therefore be interpreted within clinical context and not viewed as direct biomarkers of MS disease activity. MS: multiple sclerosis.

from SDMT performance often exceed what the measure itself can determine. Although commonly described as a measure of information processing speed, SDMT performance reflects the combined influence of processing efficiency, visual scanning, motor speed, speech output, and overall neurological functioning.11,57,58 CC BY-NC 4.0 Licence

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Further, the magnitude of change required to establish reliable decline on the SDMT is often greater than clinicians and patients assume, limiting interpretation of small score fluctuations,59 and it has shown limited sensitivity for tracking progression over time (even in the context of documented disease activity or motor progression).11,58

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As an example, the authors recently examined oral SDMT performance in two independent MS cohorts. Cognitive processing speed measures accounted for only 28% of SDMT variance, indicating that nearly three-quarters of SDMT variance reflected influences beyond cognitive processing speed alone.60 Manual dexterity measures (e.g., Nine Hole Peg Test)61 independently predicted oral SDMT performance, and individuals with severe versus moderate motor impairment had more than double the risk of cognitive impairment classification (40% versus 17%) on the SDMT despite equivalent processing speed on other measures.62 These findings indicate that SDMT performance cannot be interpreted as a pure measure of cognitive processing speed, particularly in the presence of motor impairment. Because motor slowing is common in MS and often worsens with disease duration, serial decline on the oral SDMT and other timed, motor-dependent measures may be confounded by motor progression and should not be interpreted as evidence of cognitive deterioration in isolation. Recent longitudinal registry data illustrate both the potential value and the interpretive difficulty of serial SDMT assessment. Early improvements following initiation of high-efficacy DMTs were substantially attenuated after accounting for repeated testing, indicating a material contribution from practice effects, while durable differences between treatment groups remained limited. These findings do not negate the potential clinical relevance of cognitive change but demonstrate the need to separate treatment effects from retest effects and other sources of variability.11 The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) broadens screening by combining SDMT with measures of verbal and visuospatial learning.63-65 This provides greater cognitive coverage than the SDMT alone, but the memory measures primarily assess learning and encoding efficiency rather than storage and consolidation deficits characteristic of Alzheimer’s disease and related neurodegenerative disorders.66

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Performance remains influenced by numerous state-dependent and nonneurological factors (Figure 2).67,68 BICAMS can therefore identify a broader pattern of reduced performance but cannot independently determine whether low scores reflect MS pathology, transient state-dependent influences, or other contributing factors.

THE PSYCHOMETRIC REQUIREMENTS FOR VALID COGNITIVE INTERPRETATION Interpretation of cognitive screening results requires more than a score. Valid clinical interpretation depends on three psychometric foundations: appropriate normative comparison, consideration of base rates, and reliable methods for determining whether observed change exceeds expected variability. Normative comparisons must account for age, education, sex, language background, and cultural context. A score appearing impaired relative to a young, highly educated sample may be entirely unremarkable for a 60-year-old individual with 12 years of education whose first language is not English. Yet normative samples for many MS cognitive measures remain incompletely stratified, and few adequately account for bilingualism, cultural differences, or educational systems outside North America and Western Europe. Base rates are equally important. Low cognitive scores occur commonly in healthy individuals.69-72 For example, among neurologically healthy older adults, 73% obtain at least one borderline score on neuropsychological testing, and approximately 20% obtain two or more scores within formally impaired ranges despite the absence of neurological disease.70,71 Without accounting for these expected low scores, cognitive impairment may be overidentified through normal statistical variation alone. This problem increases with the number of tests administered, the frequency of testing, and the sensitivity of the measures used.

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Interpretation of longitudinal change presents an additional challenge. Score differences are not clinically meaningful simply because they occur. Change must exceed thresholds that distinguish true change from measurement variability, and these thresholds vary according to age, baseline performance, retest interval, and psychometric characteristics of the measure itself. Commonly cited SDMT change thresholds59 provide useful reference points but do not substitute for individual-level reliable change methodology, and equivalent standards remain unavailable for many newer cognitive measures. These considerations fundamentally determine the validity of clinical interpretation. Without appropriate norms, base-rate correction, and reliable change methodology, cognitive screening risks mistaking measurement noise and normal variability for clinically meaningful dysfunction. More frequent testing does not resolve this limitation; to the contrary, it imposes another interpretive challenge by introducing learning effects. In the absence of robust psychometric infrastructure, increasingly sensitive measures and digital monitoring platforms may detect more fluctuation, increasing uncertainty without clarifying disease status. The result is a greater risk of normal variability being misinterpreted as evidence of cognitive decline or disease progression. Common clinical assumptions and the psychometric limitations of cognitive screening are summarised in Supplementary Table 1. Definitions of cognitive impairment also vary across research and clinical settings. Studies use different cutoffs, commonly ranging from 1.0–1.5 SD below normative means, and differ in the number of low scores required for classification. Hancock and colleagues found that a −1.0 SD threshold classified 17% of healthy participants as impaired on two measures within a domain, compared with 1% using a −1.5 SD threshold.73 Emerging cognitivephenotyping approaches may improve specificity by replacing binary impaired/ intact classifications with domain-based profiles that better reflect the heterogeneity of cognitive involvement in MS.73,74 CC BY-NC 4.0 Licence

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COGNITIVE IMPAIRMENT PREVALENCE AND DISEASE PROGRESSION: WHAT DO CURRENT DATA ACTUALLY SHOW? Estimates suggesting that 50–70% of individuals with MS develop cognitive impairment have become deeply embedded in both professional and patient understanding of the disease.7,8 Although derived largely from earlier cohort studies with variable definitions, differing neuropsychological thresholds, and batteries of varying length, these figures shaped decades of clinical communication and reinforced the perception that cognitive decline is an expected feature of MS.6 A major limitation of many early prevalence estimates was the limited consideration of base rates of low scores among neurologically healthy individuals. Definitions of cognitive impairment also varied substantially across studies, with classifications based on different test batteries, thresholds, and the numbers of low scores required for impairment designation.75 Without appropriate correction, individuals obtaining one or more low scores across a battery of tests could be classified as cognitively impaired despite performance patterns that occur commonly in healthy populations. As a result, historical prevalence estimates may reflect a combination of genuine MSrelated cognitive dysfunction, base-rate statistical low scores expected in healthy individuals, and the cumulative influence of fatigue, stress, medication burden, and testing conditions. The principal factors contributing to overestimation of cognitive impairment prevalence are summarised in Supplementary Table 2. More recent work suggests substantially lower prevalence rates. In a metaanalysis of 50 studies, including nearly 6,000 individuals with relapsing-remitting MS (RRMS), Wu et al.75 estimated cognitive impairment prevalence at approximately 32.5% using more stringent neuropsychological criteria. Importantly, the included studies span treatment eras from 1990 through 2023, and therefore

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largely predated the widespread use of contemporary high-efficacy diseasemodifying therapies. As earlier diagnosis and more aggressive treatment strategies become standard, it is plausible that contemporary cognitive risk may be lower still, although this remains to be established in modern treatment-era cohorts. Cognitive inefficiency identified during testing is not synonymous with severe functional impairment or inevitable decline. Many individuals with mild weaknesses remain employed, independent, and fully engaged in complex daily roles. At the same time, a definable subgroup develops genuine, MS-attributable cognitive impairment with substantial functional consequences and requires careful recognition and support. The distinction is therefore not between impairment and no impairment, but between statistically low performance, clinically meaningful dysfunction, and progressive decline. Communicating historical estimates of 50–70% without these distinctions may lead patients to overestimate their individual risk and interpret ordinary cognitive lapses as evidence of deterioration.

COGNITIVE CHANGE IN PROGRESSIVE MS: VARIABILITY, TRAJECTORY, AND THE LIMITS OF SCREENING AS A DISEASE MARKER Patients with progressive MS often fear a steady, irreversible trajectory of cognitive decline, with concerns about cognition intertwined with fears of dementia, dependency, and loss of identity. Yet longitudinal evidence suggests that cognitive change in progressive MS is considerably more variable and nonlinear than either patients or clinicians commonly assume. Risk factors for cognitive inefficiency in MS increase with age, disease duration, structural disease burden, and progressive disease subtype.9 Some studies have reported cognitive impairment rates approaching 80% in secondary progressive MS,76 but these estimates inherit many of the same definitional, psychometric, and 100

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base-rate limitations discussed above. Reported rates vary substantially according to the measures used, thresholds selected, patient characteristics, and duration of follow-up. When cognitive change does occur, slowed processing speed and verbal learning are among the most affected domains. However, interpretation remains challenging. Reduced performance on timed cognitive measures may reflect changes in cognition, motor speed, visual efficiency, fatigue, medication effects,67 or combinations of these factors. The SDMT and similar processing speed measures cannot reliably distinguish among these mechanisms. Consequently, motor progression may produce apparent worsening on the oral SDMT and other timed, motor-dependent measures without equivalent deterioration in underlying cognitive processing. Longitudinal staging frameworks illustrate these limitations. Wójcik et al.77 categorised more than 1,000 individuals with MS, including 900 with relapsing-remitting MS and 173 with secondary progressive MS, into stages of cognitive dysfunction using an event-based model based on patterns of performance across the SDMT, memory, attention, and executive function measures.77 Importantly, the proposed stages do not represent fixed or irreversible states. The authors noted that 7.3% of participants reverted to an earlier stage during follow-up, highlighting the potential influence of recovery, variability, and practice effects on longitudinal classification.77 Longitudinal data similarly challenge assumptions of inevitable decline. In a 36-month prospective study of patients with RRMS, 20 of 33 individuals classified as cognitively impaired at baseline showed improvement or impairment in fewer cognitive domains at follow-up.78 Over an 11-year follow-up of 148 patients with RRMS, 51.4% remained cognitively stable.79 Such findings challenge assumptions of inevitable or linear decline and highlight the substantial variability that characterises cognitive trajectories in MS. For patients, being told they have entered ‘Stage 1 cognitive dysfunction’ is unlikely to be interpreted as a psychometric classification;

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it is more likely experienced as evidence of cognitive decline. Current screening measures provide limited support for inferring disease progression at the individual level when used alone. Treatment escalation should therefore not rest on brief screening scores in isolation, but on evidence that observed change exceeds expected variability, is clinically meaningful, and is consistent with the broader neurological picture.

CLINICAL IMPLICATIONS AND RECOMMENDATIONS When patients present with cognitive concerns, the initial response should include systematic review of potentially modifiable contributors, including sleep dysfunction, fatigue, mood, pain, stress, medication burden, substance use, and hormonal transition, alongside neurological assessment.17 Subjective complaints remain clinically meaningful regardless of their relationship to objective cognitive performance, serving as important indicators of symptom burden, distress, and reduced quality of life. Routine cognitive screening has an important role when interpreted cautiously and within the appropriate clinical context. However, screening scores should not be viewed as biomarkers of disease activity, used in isolation to infer disease progression, or assumed to represent irreversible neurological decline. Cognitive dysfunction can substantially affect employment, academic performance, medication management, driving, financial decision-making, and overall independence, regardless of its underlying cause. Screening is most valuable when findings lead to effective and accessible next steps. Low scores may appropriately prompt comprehensive neuropsychological evaluation when there are functional concerns at work, school, or home, although access is often constrained by cost, availability, and wait times. Neuropsychological evaluation does not CC BY-NC 4.0 Licence

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directly alter the underlying cognitive trajectory, but can clarify cognitive strengths and weaknesses, support differential diagnosis, guide accommodations and compensatory strategies, and inform rehabilitation or disability decisions.80 Some of the most actionable approaches are not specific to MS. Reviewing medication burden and cannabis use, treating mood disorders, optimising sleep, addressing fatigue, promoting physical activity, and managing cardiovascular and metabolic risk may yield meaningful cognitive and functional benefit. Identifying cognitive inefficiency without addressing these modifiable contributors risks increasing concern while diverting attention from interventions most likely to improve cognitive health and daily functioning.81-84 A patient-centred framework recognises that cognitive performance reflects the interaction of neurological disease burden with numerous nonspecific, fluctuating, and potentially modifiable influences. Cognitive symptoms deserve careful evaluation, but patients also deserve accurate information about what cognitive screening can and cannot determine. Communication should acknowledge uncertainty, avoid overinterpretation of isolated findings, and preserve agency rather than reinforce expectations of inevitable decline. The goal of cognitive assessment should not be surveillance for its own sake, but improving function, quality of life, and clinical decision-making in ways that meaningfully benefit patients (Table 1).

CONCLUSION Awareness of cognitive dysfunction in MS has improved clinical care and validated an important dimension of the disease experience. A genuine MS-attributable cognitive phenotype exists, and some individuals experience clinically meaningful cognitive decline that affects employment, independence, and quality of life. Cognitive screening can help identify patients who warrant further evaluation.

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Table 1: Practical principles for cognitive screening and communication in MS.

Principle

Clinical guidance

Contextualise cognitive scores

A single low result does not independently establish clinically meaningful cognitive impairment.

Address modifiable contributors first

Fatigue, sleep, mood, pain, medications, hormonal transition, and testing conditions all influence performance independently of disease burden.

Review polypharmacy carefully

Gabapentin, baclofen, benzodiazepines, anticholinergics, sedating antidepressants, and cannabis can produce cognitive effects indistinguishable from MS-related change.

Consider the testing environment

Screening during stressful clinic visits may underestimate everyday performance.

Avoid implying inevitability

Cognitive trajectories are heterogeneous and nonlinear. Historical prevalence estimates do not imply inevitable decline at the individual level.

Distinguish distress from impairment

Subjective complaints deserve validation even when objective testing is normal or equivocal.

Use formal evaluation purposefully

Neuropsychological assessment is most valuable for clarifying functional concerns, guiding rehabilitation, supporting accommodations, or informing disability determination.

Reassurance is therapeutic

When cognitive fears exceed objective evidence, explicit reassurance is itself a clinical intervention.

MS: multiple sclerosis.

The next step is more precise interpretation. Subjective complaints, low scores, and longitudinal changes must be evaluated using appropriate norms, base rates, reliable-change methods, functional context, and consideration of potentially modifiable contributors. Brief screening measures should inform, rather than independently determine, conclusions about disease activity, progression, or treatment escalation.

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As MS care advances, cognitive assessment should become more purposeful, contextualised, and actionable. The central question is not only whether performance has changed, but whether the change is reliable, what it reflects, and how the information can improve the patient’s function and quality of life. Cognitive screening does not merely detect illness experience; how its findings are interpreted and communicated may also shape it.

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Alcohol Consumption and Risk of Dementia and Cognitive Decline: From Evidence to Prevention Strategies Author:

*Auda Fares1 1. Marien-Hospital Wesel, Germany *Correspondence to audafares@yahoo.com

Disclosure:

The author has declared no conflicts of interest.

Received:

11.04.26

Accepted:

20.07.26

Keywords:

Alcohol, Alzheimer’s, cognition, dementia, prevention.

Citation:

EMJ Neurol. 2026;14[1]:105-112. https://doi.org/10.33590/emjneurol/CE9368V5

Abstract Alcohol use disorders serve as a significant and modifiable risk factor for the development of dementia, underscoring the urgent need for proactive clinical and public health interventions. Emerging research suggests that the relationship between alcohol consumption and cognitive health is nuanced, with studies indicating that the lowest risk for cognitive dysfunction and dementia is associated with low-level intake, specifically around 30 g and 15 g of alcohol per day, respectively. To effectively mitigate the long-term impact of alcohol-related cognitive decline, healthcare systems must prioritise the integration of routine screening for heavy drinking into standard medical care, ensuring timely access to intervention and treatment. Beyond individual clinical efforts, the implementation of broader population-level alcohol policies remains a vital strategy to reduce excessive consumption and ultimately lower the societal burden of alcohol-related dementia.

Key Points 1. While heavy drinking is a major, modifiable risk factor for neurodegeneration and cognitive decline, the debate continues regarding whether low-to-moderate consumption offers neuroprotective benefits or carries inherent risks. 2. Healthcare systems must implement routine screening for heavy drinking and integrate targeted behavioural interventions to protect older adults from cognitive impairment, falls, and overall health decline. 3. Reducing or eliminating alcohol intake significantly lowers dementia risk, improves physical and mental wellbeing, and reduces the substantial economic burden on healthcare systems.

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INTRODUCTION As the global prevalence of dementia is projected to rise from 57.4 million in 2019 to 152.8 million by 2050, addressing modifiable risk factors like alcohol consumption has become critical for geriatric care.1 While heavy drinking is a clear neurodegenerative risk, the impact of light-to-moderate intake on the ageing brain remains debated, necessitating a nuanced approach to preserve cognitive reserve.2 Given the current limitations of disease-modifying treatments, this paper synthesises emerging evidence to provide practical, age-appropriate strategies that promote informed consumption habits and support long-term cognitive health in older adults.

MATERIALS AND METHODS This narrative review investigates evidence-based strategies to mitigate cognitive decline and prevent dementia in alcohol-consuming populations through a systematic search of Medline, the Cochrane Library, and Google Scholar. Utilising key terms such as “Dementia,” “Alcohol,” “Alzheimer Disease,” “Cognition,” and “Prevention,” the study prioritised literature that elucidates mechanistic pathways of neurodegeneration, identifies modifiable risk factors, and evaluates effective pharmacological or lifestyle interventions. By synthesising clinical data on vascular health and neurological deterioration, the review categorises findings into pathophysiology, lifestyle modifications, and therapeutic efficacy. Although the analysis provides a cohesive framework for risk reduction, the authors acknowledge that study heterogeneity, varying follow-up durations, and inconsistent definitions of cognitive impairment limit the generalisability of current findings and underscore the necessity for standardised future research.

EPIDEMIOLOGICAL EVIDENCE

centred on whether low-to-moderate intake offers neuroprotection or carries inherent risk. While some meta-analyses suggest a J-shaped curve, identifying a “sweet spot” for cognitive preservation,3 recent high-capacity studies and genetic analyses increasingly challenge this, pointing towards a linear association between intake and dementia risk.4,5 Much of the discrepancy in the literature is attributed to methodological biases, such as the “sick quitter” effect, where individuals with declining health cease drinking and confounding comorbidities.4,6 Regardless of the debate regarding moderate consumption, there is a strong consensus that excessive intake is a major neurotoxic agent and a significant driver of systemic pathologies, such as cardiovascular disease and hypertension, which independently exacerbate cognitive impairment.4,6,7 Ultimately, given that alcohol acts as a modifiable risk factor, reducing high-volume consumption remains a critical public health strategy for mitigating a substantial portion of global dementia incidence.4

POTENTIAL MECHANISMS Protective Effects at Low-to-Moderate Consumption

Emerging preclinical research suggests that low-to-moderate ethanol exposure may offer neuroprotective benefits, particularly by mitigating amyloid-β (Aβ)induced synaptic damage in Alzheimer’s disease models.8,9 Furthermore, moderate preconditioning has been observed to suppress neuroinflammatory proteins associated with cognitive impairment.10,11 While these findings indicate that limited ethanol intake might modulate protective cellular pathways, the underlying mechanisms remain unclear. It is critical to note that these results are derived from experimental laboratory settings and require rigorous clinical validation before any therapeutic implications for human health can be established.

The relationship between alcohol consumption and cognitive decline remains a subject of intense epidemiological debate, 106

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Detrimental Effects of Excessive Alcohol Consumption

The neuroprotective effects of alcohol are dramatically overshadowed by the detrimental consequences of excessive consumption. Chronic and heavy alcohol use significantly impacts brain health through several mechanisms:

Increased Aβ accumulation and tau phosphorylation

While low concentrations may offer protection, excessive alcohol consumption has been linked to increased Aβ accumulation and tau phosphorylation, key pathological features of Alzheimer’s disease and other neurodegenerative disorders.12 This leads to neuronal dysfunction and, ultimately, cell death.

Thiamine deficiency and glutamate excitotoxicity

Chronic alcoholism frequently results in thiamine deficiency.13 This deficiency disrupts energy metabolism in neurones, leading to an excessive release of glutamate, an excitatory neurotransmitter. Glutamate overstimulation causes excitotoxicity, a process leading to neuronal damage and death. This effect may act synergistically with the direct neurotoxic effects of alcohol itself.

Hyperhomocysteinaemia

Chronic alcohol intake is associated with hyperhomocysteinaemia, elevated levels of homocysteine, an amino acid implicated in increased risk of cognitive impairment, hippocampal atrophy, and mood disorders.14,15

Indirect effects and associated risk factors

Heavy alcohol use increases vulnerability to various brain-damaging factors, including falls, head injuries, and hepatic encephalopathy.16 Moreover, it contributes to vascular risk factors such as high blood pressure, stroke, atrial fibrillation, and heart failure, all of which can compromise brain health. The association with other risk factors (tobacco smoking, depression, social isolation, poor treatment adherence, and malnutrition) further elevates the risk of dementia and other neurodegenerative outcomes. CC BY-NC 4.0 Licence

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Implications of Addressing Alcohol Consumption in the Elderly

Addressing alcohol use in the elderly has significant implications for individuals, their families, and the broader healthcare system. These implications encompass:

Improved health outcomes

Reducing or eliminating alcohol consumption significantly enhances both physical and mental wellbeing by lowering the risks of liver disease, cardiovascular issues, cancer, and cognitive decline while simultaneously improving sleep and mood.17 To successfully achieve these health improvements, individuals can utilise psychological interventions such as motivational interviewing, which clarifies personal reasons for change, and expectancy challenges, which dismantle misconceptions regarding alcohol’s social benefits.18 By integrating an awareness of these health advantages with targeted behavioural strategies, individuals can effectively overcome obstacles and sustain long-term sobriety.

Reduced risk of falls and injuries

Reducing alcohol consumption is a critical strategy for preventing falls and injuries in older adults, as alcohol significantly impairs balance and coordination.19 This danger is heightened by the common practice of combining alcohol with psychotropic medications, necessitating vigilant monitoring by primary healthcare providers.20 Consequently, screening for alcohol use during fall-related clinical assessments is essential, though further research is required to better understand the synergistic risks that alcohol poses when interacting with pharmaceutical treatments in the geriatric population.

Enhanced cognitive function

Reducing alcohol consumption is a critical step in mitigating the risk of cognitive decline and dementia, particularly for heavy drinkers who have shown the potential for significant cognitive recovery after long-term abstinence.19 While previous research suggested potential protective effects of moderate drinking,21,22 current scientific consensus increasingly warns that there may be no entirely safe level of

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alcohol consumption for brain health.6 This is especially vital given the physiological vulnerabilities that often cause women to experience more rapid cognitive deterioration than men.19 Nevertheless, clinical evidence indicates that maintaining abstinence for at least 6 months can effectively stabilise and improve cognitive function across all genders, underscoring that it is rarely too late to pursue recovery and preserve neurological health.19

use, individuals can effectively protect their neurological integrity and improve their functional independence in later years.29

Reduced healthcare costs

Underreporting alcohol use among older adults is a significant challenge, often driven by profound feelings of stigma, shame, or fear of external judgement.30 This barrier is compounded by a lack of standardised metrics for measuring stigma, making it difficult to fully grasp the scale of the issue.31 To improve detection and intervention, healthcare providers must adopt proactive, anti-stigma strategies, such as normalising alcohol discussions during routine screenings and utilising nonjudgemental language.32,33 By fostering a supportive, autonomous environment that prioritises patient comfort, clinicians can bridge the gap in reporting and offer more effective, person-centred care.32,33

Alcohol-related health problems are a significant burden on healthcare systems. By addressing alcohol use in the elderly, we can potentially reduce the number of hospital admissions, emergency room visits, and long-term care needs, resulting in substantial cost savings.23

Improved quality of life

Reducing alcohol consumption significantly enhances overall quality of life by fostering stronger relationships, increased social engagement, and improved emotional wellbeing.17 While clinical interventions have traditionally focused on those with alcohol dependence,24,25 emerging research indicates that even moderate drinkers experience measurable mental health gains through reduced intake.26 Although some cross-sectional studies have suggested a link between moderate use and wellbeing, the scientific consensus increasingly favours the holistic advantages of minimising or eliminating alcohol consumption.27,28 Consequently, choosing to limit alcohol intake serves as a pathway to achieving a more stable and vibrant lifestyle.

Mitigation of dementia risk

Reducing alcohol consumption is a vital strategy for mitigating dementia risk and preserving long-term cognitive function. Mounting evidence indicates that excessive alcohol intake is an avoidable health burden, often leading to a diminished quality of life and premature mortality. Encouragingly, recent randomised controlled studies demonstrate that modifying these habits regardless of an individual’s prior history can yield significant, immediate, and lasting benefits for brain health and overall longevity.29 By actively managing alcohol 108

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Current Scope and Limitations

Efforts to address alcohol consumption in older adults often encounter specific obstacles that can limit the efficacy of support programmes.

Underreporting and stigma

Age-related physiological changes

Older adults are increasingly vulnerable to alcohol-related harm due to age-related physiological shifts, including reduced liver function and decreased total body water, which heighten sensitivity to alcohol even at modest intake levels.17 Despite lower overall consumption rates compared to younger demographics, this population faces a disproportionately high and rising incidence of alcohol-related health complications.34 Consequently, rigorous monitoring of alcohol use in older adults is essential to generate the evidence-based data necessary for informing public health policy, prioritising clinical interventions, and ensuring the efficient allocation of resources to address this critical health concern.34

Comorbidity and polypharmacy

Older adults frequently face a complex interplay between multiple chronic conditions and polypharmacy, rendering them particularly susceptible to adverse alcohol–drug interactions, such as

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heightened sedation, impaired drug metabolism, and unstable blood pressure.35 These interactions not only complicate clinical assessments but also elevate the risk of severe outcomes, including falls, fractures, and the exacerbation of preexisting health issues like depression and cardiovascular disease.35 To mitigate these risks, a collaborative, dual-pronged approach is essential: clinicians must employ rigorous screening of alcohol consumption and cognitive health, while simultaneously empowering patients through transparent education regarding the dangers of mixing substances.35 By fostering this open dialogue, healthcare providers can help prevent therapeutic failure and toxic overdoses, ultimately ensuring that patients are equipped to safeguard their long-term functional wellbeing through informed decision-making.35

visits and culturally competent support, is essential to ensuring equitable and effective treatment for the ageing population.41

One-size-fits-all approach

Current alcohol consumption guidelines and interventions often fail to consider the individual variability of older adults, neglecting their unique risk profiles and medical histories.

Expert Consensus on Future Strategic Priorities

To overcome these challenges and improve the management of alcohol use in the elderly, the following future directions and recommendations are proposed:

Enhanced screening and assessment •

Universal screening in primary care: implement routine alcohol screening for all older adults during primary care visits using validated tools like the CAGE Adapted to Include Drugs (CAGE-AID) Questionnaire or Michigan Alcohol Screening Test - Geriatric Version (MAST-G)42

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Focus on incidental findings: train healthcare professionals to recognise incidental medical findings that may indicate problem drinking, such as elevated liver enzymes or unexplained falls

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Consider cognitive function: incorporate cognitive screening into alcohol assessments to identify individuals with cognitive impairment who may be more vulnerable to the effects of alcohol

Lack of awareness and training

To effectively address alcohol use in the elderly, healthcare systems must overcome the barrier of inadequate professional training and awareness.36,37 Because current gaps in clinical education often result in missed opportunities for intervention, there is an urgent need for frequent, pragmatic training that empowers interdisciplinary teams to identify and manage substance use within complex medication regimens.37 By fostering a culture of individual accountability and proactive reporting, clinicians can enhance early detection and better safeguard older adults against the severe physical and cognitive risks of unsafe alcohol consumption.38

Limited access to treatment

Older adults encounter significant barriers to alcohol treatment, including physical mobility issues, limited financial resources, and a lack of age-appropriate programming.39 In rural regions, these challenges are intensified by a total absence of specialised, culturally sensitive services, leaving seniors with complex health and cognitive needs unsupported.40 To address these systemic gaps, healthcare providers should prioritise the integration of telehealth and home-based care models. Implementing these flexible delivery methods, alongside consistent home CC BY-NC 4.0 Licence

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Personalised interventions •

Tailored advice: provide personalised advice on alcohol consumption based on individual risk profiles, medical conditions, and medication interactions

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Motivational interviewing: utilise motivational interviewing techniques to engage older adults in behaviour change and promote self-efficacy

•

Cognitive behavioural therapy: offer cognitive behavioural therapy

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interventions to address underlying psychological issues that may contribute to alcohol use43 •

Medication-assisted treatment: consider medication-assisted treatment for individuals with severe alcohol dependence, while carefully monitoring for potential side effects and interactions with other medications44

Enhanced primary care role •

Education and training: provide comprehensive education and training to primary care providers on the unique risks of alcohol use in older adults and evidence-based intervention strategies45

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Brief interventions: equip primary care providers with the skills to deliver brief interventions to address alcohol use during routine office visits

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Collaboration with specialists: foster collaboration between primary care providers and addiction specialists to ensure access to specialised treatment for complex cases

Collaborative care models •

Multidisciplinary teams: develop multidisciplinary teams that include physicians, nurses, pharmacists, social workers, and mental health professionals to provide comprehensive care to older adults with alcohol use problems

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Family involvement: involve family members or carers in the treatment process, with the patient’s consent, to provide support and encouragement

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Community-based resources: connect older adults with communitybased resources, such as support groups, senior centres, and transportation services

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Targeted outreach: conduct targeted outreach to high-risk subgroups, such as veterans, individuals with mental health disorders, and those living in isolation

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Educational materials: develop and disseminate educational materials tailored to the needs of older adults, including brochures, websites, and videos

Policy recommendations •

Funding for research: increase funding for research on alcohol use in the elderly, including studies on the epidemiology, risk factors, and effective interventions

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Coverage for treatment: expand insurance coverage for alcohol treatment services, including counselling, medication-assisted treatment, and residential rehabilitation

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Regulation of alcohol advertising: regulate alcohol advertising to protect vulnerable populations, such as older adults, from misleading or harmful messages

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Age-appropriate guidelines: develop age-appropriate alcohol consumption guidelines that consider the unique physiological and social factors that influence alcohol use in older adults

Future research •

Longitudinal studies: conduct longitudinal studies to examine the long-term effects of alcohol use on cognitive function, physical health, and quality of life in older adults

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Interaction with dementia: investigate the complex interaction between alcohol consumption and dementia, differentiating between different types of dementia and varying levels of alcohol use (ideally involving cohort studies with detailed alcohol consumption patterns and neuroimaging data)

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Effectiveness of interventions: evaluate the effectiveness of different interventions for addressing alcohol use in the elderly, including behavioural

Education and awareness •

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Public health campaigns: launch public health campaigns to raise awareness about the risks of alcohol use in older adults and promote healthy ageing behaviours

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therapies, medication-assisted treatment, and integrated care models •

Cultural and social factors: explore the cultural and social factors that influence alcohol use in older adults from diverse backgrounds

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CONCLUSION To address the rising burden of alcoholrelated dementia, it is imperative to shift from passive awareness to proactive, personalised clinical screening for the ageing population. By integrating tailored interventions with robust community support, healthcare systems can effectively manage one of the few modifiable risk factors for cognitive decline. Bridging the gap between epidemiological research and geriatric practice is essential to safeguarding the cognitive health of the global elderly demographic.

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40. Asante D et al. Understanding unmet care needs of rural older adults with

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