10 Review of the 11ᵗʰ Congress of the European Academy of Neurology (EAN), 21st–24th June 2025
Congress Features
20 The New McDonald Criteria: Faster and Improved Diagnosis of Multiple Sclerosis
Katrina Thornber
25 EAN 2025: What’s New in Neurology Guidelines?
Ada Enesco
Poster Review
28 Spotlight on Chronic Inflammatory Demyelinating Polyradiculoneuropathy: Improvements in Lower Limb Function with Efgartigimod and Insights into Treatment Satisfaction of Conventional CIDP Therapies
Abstract Reviews
35 Distinct Resting-State EEG Biomarkers Predict Amyloid Status and Conversion to Alzheimer’s Dementia in a Memory Centre
Cecchetti G et al.
38 The Epilepsy Deaths Register: Third-Party Reports of Sudden Unexpected Death in Epilepsy in Adults and Older Adolescents
Grundmann A et al.
40 Glymphatic Dysfunction in Clinical Phenotypes of Motor Neurone Disease
Bottale I et al.
42 Rapid Molecular Classification of Brain Tumours Through DNA Methylation Analysis with Nanopore Sequencing
Bondareva E et al.
44 Impact of Vascular Risk Factors on Motor Performance and Sensorimotor Network Integrity in Patients with Multiple Sclerosis
Albergoni M et al.
47 The Brain Functional Neural Organisation of Apathy and Depression in Amyotrophic Lateral Sclerosis: A Connectome-Based Study
Castelnovo V et al. Congress Interviews
Jana Midelfart-Hoff Interviews
56 Through A Patient’s Lens: Chronic Inflammatory Demyelinating Polyneuropathy Uncovered
Astri Arnesen 65 Lukas Rasulic 68 Christina Dalla
CANYON: The Largest Interventional Trial in Becker Muscular Dystrophy to Date
76 Lighting the Path: How Clinicians Can Encourage People with Multiple Sclerosis to Walk Their Own Road
Agne Straukiene Articles
79 Editor's Pick: Precision Medicine in Neurology: Advancing Care for Female Patients
Carvalho V et al.
95 Critical Management of Neurocysticercosis with Hydrocephalus and Paroxysmal Sympathetic Hyperactivity: A Case Report
Maule G et al.
102 The Intersection of Menopause and Epilepsy: A Review of Current Knowledge and Gaps
Voinescu PE et al.
114 Unveiling the Versatility of Neurosonology: Insights from Two Clinical Cases on Vertebrobasilar Pathology
Rabboni L et al.
Editorial Board
Editor-in-Chief
Prof László Vécsei
University of Szeged, Hungary
Contemporary 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 Raicevic
Military Medical Academy, Serbia
Dr Natan Bornstein
Shaare-Zedek Medical Center, Israel
Prof Giancarlo Comi
Scientific Institute San Raffaele, Italy
Dr Rita Krishnamurthi
Auckland University of Technology, New Zealand
Dr Giuseppe Lanza
University of Catania, Italy
Prof Nils Erik Gilhus University of Bergen, Norway
Prof Amos Korczyn
Tel-Aviv University, Israel
Prof Hans-Peter Hartung University of Düsseldorf, Germany
Prof Stefan Schwab University of ErlangenNuremberg, Germany
Dr Nitin Butala Baptist Health, Florida, USA
Prof Antonio Federico University of Siena, Italy
Prof Alberto Dubrovsky Favaloro University, Argentina
Dr Inna Lutsenko I.K. Akhunbaev Kyrgyz State Medical Academy, Kyrgyzstan
Dr Marco Feligioni
European Brain Research Institute ‘Rita Levi Montalcini’ Foundation, Italy
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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.
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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.
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Welcome
Dear Readers,
We are delighted to welcome you to the 2025 issue of EMJ Neurology, which showcases pivotal insights from the 11th Congress of the European Academy of Neurology (EAN), alongside topical features on the latest EAN guidelines for Parkinson’s disease and infectious encephalitis, and the revised McDonald criteria for multiple sclerosis diagnosis.
In this issue, you can also find multiple abstract reviews, highlighting cutting-edge research presented during the event, including the latest on sudden unexpected death in epilepsy, DNA methylation analysis for the molecular classification of brain tumours, predicting amyloid status and conversion to Alzheimer’s using resting state EEG biomarkers, and glymphatic dysfunction in motor neuron disease. We also present exclusive interviews with the EAN President, Secretary General, Treasurer, and Programme Committee Chair, as well as specialist interviews covering neurosurgery, Huntington’s disease, neuropsychiatric disorders, and neurophysiology.
We spotlight an expert commentary, which explores how clinicians can empower patients with multiple sclerosis through the integration of digital health tools, encouraging engagement with self-management, and increased clinician training in strategies for behavioural change and communication.
Amongst our peer-reviewed content, discover reviews summarising epilepsy during menopause and precision medicine for female neurological disease, as well as an interesting case report that discusses the complexities of neurocysticercosis management.
We would like to take this opportunity to thank our Editorial Board, the authors, peer reviewers, and interviewees for their valued contributions to this journal issue. We hope you can take away useful insights for your clinical practice.
Enjoy reading!
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Foreword
Dear Colleagues,
It is with great pleasure that I introduce the 2025 edition of EMJ Neurology. This year’s issue reflects the ever-evolving field of neurology, with insights from the 11th Congress of the European Academy of Neurology (EAN), alongside peer-reviewed research, expert interviews, and more.
This year’s Congress brought together leading minds in neurology from across the globe, fostering interdisciplinary collaboration and presenting the latest advances in clinical and basic science. The overarching theme of ‘Neurology within society’ shaped the Congress programme, with sessions highlighting how neurology influences decisions and developments in society, and vice versa. This year’s edition of EMJ Neurology further explores this theme, with articles that explore the intersection of menopause and epilepsy, the opportunities and challenges regarding precision medicine in females with neurological disorders, and how clinicians can empower patients with multiple sclerosis.
Alongside this, our curated collection of abstracts highlights exciting developments in the field, with topics ranging from EEG biomarkers in Alzheimer's disease to the brain functional neural organisation of apathy and depression in amyotrophic lateral sclerosis.
Complementing the Congress coverage, EMJ Neurology features conversations with several of today’s most influential neurologists. We are delighted to include interviews with EAN Secretary General Antonio Toscano, Treasurer Jana MidelfartHoff, and Programme Committee Chair Irena Rektorová. In addition, EMJ spoke to Astri Arnesen, Christina Dalla, and Lukas Rasulic on the latest advancements in Huntington's disease, psychedelic treatment in psychiatry, and functional neurosurgery, respectively.
This year’s Congress brought together leading minds in neurology from across the globe
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 2026 in Geneva, Switzerland.
László Vécsei
University of Szeged, Hungary
EAN 2025
With 45,000 members and 48 national neurological societies, EAN is definitely the home of neurology for many
Review of the 11ᵗʰ Congress of the European Academy of Neurology (EAN) Congress Review
THE SUMMER solstice this year was celebrated by many neurologists in the charming city of Helsinki, Finland, as they came together for the 11th Congress of the European Academy of Neurology (EAN). Specifically, 6,383 onsite and 1,983 virtual participants from 113 different countries spent the weekend learning, networking, and discussing new ideas.
With the early sunrises and the late sunsets, the atmosphere at this year’s congress was particularly warm, and felt appropriate for the overarching theme of ‘Neurology in Society’, as many locals spent the weekend enjoying Midsummer festivities. On the longest day of the year, Saturday 21st June 2025, EAN President Elena Moro welcomed attendees, and highlighted her 10-year journey with EAN. Moro then delved into the 4-year strategic plan that EAN began in 2024. This strategy, aimed at enhancing EAN’s mission to be the home of neurology, focuses on six areas: communication, advocacy, education, membership, research, and congress, which is the glue between all domains. With 45,000 members and 48 national neurological societies, EAN is definitely the home of neurology for many.
Moro then highlighted some of the incoming challenges for neurology in Europe. The shortage of neurology residents, the introduction of new expensive therapies, and the impact of climate change are among some of the key needs to be addressed. However, some challenges offer opportunities for innovation, with the ‘challenge’ of AI and the role of interventional neurology. Based on
these challenges, the EAN strategic plan addresses the top seven priorities for neurology within the next 10 years.
For this year’s congress, the theme of ‘Neurology within society’ explored how society impacts the progress, priorities, and relevance of neurology, and, conversely, how neurology influences decisions and developments in society. Sessions related to this theme were woven throughout the programme, including tailored workshops and symposia.
One ongoing EAN initiative that investigates the neurological impact on society is the Cost of Illness in Neurology in Europe (COIN-EU) project. Moro explained that this project assesses the burden of neurological diseases in Europe. She revealed that in Europe, the total annual cost of neurological disorders is 1,668,000,000,000 EUR, largely due to the cost of dementia (13.07%), sleep disorders (24.97%), and headache disorders (48.09%).1
Another initiative spotlighted during the Opening Session was the EAN Scientific and Coordinating Panel project, which Moro described as the ‘scientific backbone’ of
EAN. This project led to the development of the EAN Panel Yearbook, which highlights the most important advances in neurology, according to members of 23 scientific panels across various subspecialities of neurology.
Excitingly, Moro announced the launch of a new project: the EAN Neuro-DEI Digital Hub. This Hub will provide resources, insights, and collaborative efforts to advance diversity, equity, and inclusion in neurology. This includes content such as webinars and research papers on the sex and gender balance in clinical trials, the work of the Women’s Brain Project, and gender differences in common neurological disorders. On a similar note, Moro revealed another new initiative to celebrate women in neurology with the Anita Harding Award Lecture, held during the Presidential Symposium. This lecture aimed to spotlight progress in gender equality within neurology and encourage continued advancement for young female neurologists and neuroscientists.
The inspiring Opening Session ended with an opening lecture given by Sir John Hardy, Chair of the Molecular Biology of Neurological Disease, Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, London, UK, whose team was responsible for uncovering the first mutation directly implicated in Alzheimer's disease, leading to the highly influential 'amyloid-cascade' hypothesis. Hardy’s opening lecture, ‘Neurodegeneration. From genetics to pathogenesis to the beginning of mechanistic therapies’, spotlighted pioneering research in Alzheimer's and certainly set the tone for the exciting congress ahead.
Read on for key insights into this year’s congress, and don’t miss our coverage of EAN Congress 2026, which will be held in Geneva, Switzerland, with the overarching theme ‘Brains, Bytes & Beyond: Tech in Neurology’.
Nightmares Identified as Major Risk Factor for Early Death and Faster Ageing
FREQUENT nightmares are linked to accelerated biological ageing and a three-fold increase in the risk of premature death, according to new research presented at the EAN Congress 2025.2
Biological ageing explained 39% of the association between nightmares and premature mortality
In this study, data were analysed from 4,196 adults aged 26–74 years, drawn from four large population-based cohort studies in the USA. Nightmare frequency was self-reported at the start of the study, and participants were followed for up to 18 years. Premature death was defined as dying before the age of 75, and biological ageing was measured at baseline using a composite of three epigenetic clocks, which estimate the rate of molecular ageing in the body. During the follow-up period, 227 premature deaths were recorded. The analysis revealed a clear linear association between nightmare frequency and risk of early death (p<0.001). Adults who reported weekly nightmares had nearly three times the risk of dying prematurely compared to those who never experienced nightmares (adjusted hazard ratio: 2.73; p<0.001). Additionally, those with more frequent nightmares demonstrated significantly faster rates of biological ageing (p<0.001). Mediation analysis
also showed that accelerated biological ageing explained 39% of the association between nightmares and premature mortality, suggesting that the stress and sleep disruption caused by nightmares may directly impact cellular ageing.
Adults who reported weekly nightmares had nearly three times the risk of dying prematurely
These findings highlight nightmares as a significant risk factor for both accelerated ageing and early death in the general population. Addressing nightmares, whether through psychological therapies, sleep hygiene education, or treatment of underlying anxiety, could promote healthy ageing and reduce mortality risk.
Glucagon-Like Peptide-1 Receptor Agonists Show Promise in Reducing Migraine Burden
A NEW study offers hope for people living with chronic migraine, revealing that glucagon-like peptide-1 receptor agonists (GLP-1 RA) may significantly reduce the frequency and impact of migraine attacks. The findings, presented at the EAN Congress 2025, explore a novel approach targeting intracranial pressure regulation rather than traditional pain pathways.3
Researchers at the Headache Centre of the University of Naples Federico II, Italy, administered daily subcutaneous liraglutide (1.2 mg) to 26 patients with obesity and chronic migraine over a 12week period. Participants did not exhibit signs of idiopathic intracranial hypertension, ensuring the results reflected migrainespecific effects. Headache frequency and disability were tracked using patient diaries and Migraine Disability Assessment (MIDAS) scores, with weight change and tolerability monitored as secondary measures.
Over the course of treatment, patients experienced a marked reduction in headache days, falling from an average of 20 days per month to just under 9 days. This was accompanied by a significant drop in MIDAS scores, indicating improved daily functioning and reduced disruption from migraine. While patients showed a slight reduction in BMI, this was not statistically significant, and further analysis confirmed that headache improvements were unrelated to weight loss. Mild gastrointestinal side effects were reported in a minority of cases but did not necessitate discontinuing treatment.
These results suggest that GLP-1 RAs may ease migraines by modulating cerebrospinal fluid dynamics and reducing intracranial pressure, offering an entirely new treatment angle. As the effect appears independent of weight reduction, this supports the hypothesis that intracranial pressure, even within the upper normal range, may contribute to migraine pathophysiology.
Although this was a small pilot study, the clinical benefits were clear and the treatment was well-tolerated, pointing to the potential for GLP-1 RAs to play a future role in migraine management. Larger, controlled trials will be essential to validate these findings and determine long-term outcomes.
GLP-1 RAs may ease migraines by modulating cerebrospinal fluid dynamics and reducing intracranial pressure
Temporal Dynamics of Serum Neurofilament Light Chain Offer Insight for Multiple Sclerosis Monitoring
SERUM neurofilament light chain (sNfL), a blood biomarker reflecting neuroaxonal injury, has emerged as a promising tool for monitoring multiple sclerosis (MS) disease activity. While previous research has linked elevated sNfL levels with evidence of disease activity, its timing in relation to relapses and how it might best inform clinical decisions remains unclear. A new retrospective study presented at the EAN Congress 2025 provided detailed insights into the temporal behaviour of sNfL around relapses, with key findings highlighting that sNfL levels can remain elevated for up to 9 months following a relapse.4
The study analysed data from 162 people with MS, with an average age of 32.5 years and a median disease duration of just over 2 years. Participants had a median of seven serum samples collected across a median follow-up period of 10.4 years. sNfL concentrations were measured using Simoa HD-X technology (Quanterix, Billerica, Massachusetts, USA) and normalised using Z-scores to adjust for age and BMI. Gadolinium-enhanced MRI scans were used to detect radiological activity. Evidence of disease activity was defined as the occurrence of clinical relapses, confirmed disability progression (via Expanded Disability Status Scale [EDSS]), or radiological findings within 6 months of sample collection.
Statistical analysis revealed that sNfL Z-scores were significantly higher in patients who experienced disease activity within 1 year of sampling, but only when the samples were taken during clinical remission (p<0.001). Importantly, sNfL levels did not predict activity beyond this 1-year time frame. Further analysis around the timing of clinical relapses showed
that sNfL rose sharply at relapse onset (p<0.001), with levels remaining elevated for up to 9 months thereafter.
These findings underscore the relevance of sNfL as a short-term indicator of MS disease activity, particularly in identifying patients at risk during periods of apparent remission. However, the study also highlights limitations, including its retrospective nature, which may not fully reflect real-time clinical settings. For clinical practice, careful timing of sNfL measurement is essential. Elevated levels post-relapse may reflect recent activity rather than future risk, so interpretation must consider recent clinical history. Incorporating sNfL testing into routine MS management could support earlier interventions, but clinicians must remain aware of its temporal constraints.
sNfL Z-scores were significantly higher in patients who experienced disease activity within 1 year of sampling
Sleep Patterns Linked to Risk of Brain and Mental Health Conditions
A MAJOR study from the Bernese Sleep-Wake Registry has identified significant links between sleep traits and the development of chronic health conditions, suggesting that sleep monitoring could become an important tool in preventive healthcare.5
Researchers analysed data from 4,170 participants (63% male), using overnight polysomnography and measures of heart rate variability (HRV) to examine associations between sleep characteristics and 36 incident comorbidities. Participants were followed for a total of 13,217 person-years.
The study found that conventional sleep structure, or macroarchitecture, had limited associations with new health conditions. Sleepdisordered breathing was the exception, showing clear links to cardiovascular, endocrine, and metabolic diseases. In contrast, HRV, a measure of autonomic nervous system function, was strongly associated with multiple comorbidities.
Neurological conditions, including stroke, were linked to higher and more complex HRV patterns. On the other hand, psychiatric disorders, mainly depression, were associated with lower HRV, reduced complexity, and signs of diminished parasympathetic activity. Metabolic conditions were related to increased HRV, particularly with a dominant very lowfrequency component.
The study supports growing evidence that sleep plays a key role in healthy ageing. Looking to the future, the researchers will further explore the link between health outcomes and sleep microarchitecture.
Researchers analysed data from 4,170 participants (63% male), using overnight polysomnography and measures of heart rate variability
Insulin Resistance Predicts Faster Cognitive Decline in Alzheimer’s Disease
A RECENT study, presented at the EAN Congress 2025, investigated the role of insulin resistance as a marker for progression in Alzheimer's disease (AD).6
Researchers conducted a retrospective analysis over 10 years, examining 315 non-diabetic patients diagnosed with either AD or other neurodegenerative diseases (NDD) based on cerebrospinal fluid (CSF) biomarkers. Patients were stratified into three groups according to their triglyceride-glucose (TyG) index, a measure of insulin resistance: low, medium, and high. Baseline clinical features, CSF biomarkers, and disease progression were compared across these groups.
Among the 210 patients with AD, those with a high TyG index showed worse blood–brain barrier markers and a notable interaction with the apolipoprotein E (APOE) ε4ε4 genotype, although this was not observed in the NDD group. Despite similar baseline characteristics such as sex, education, APOE genotype, and CSF biomarkers, patients with AD and high insulin resistance also had more cardiovascular risk factors.
Importantly, in the subgroup of patients with mild cognitive impairment due to AD, a high TyG index was strongly associated with faster cognitive decline over 3 years. This association did not reach statistical significance for progression from mild cognitive impairment to dementia, though a similar trend was noted. No significant effect of insulin resistance on disease progression was found in the NDD group.
The findings suggest that insulin resistance may serve as a useful predictor of cognitive decline in early AD. Identifying patients with high insulin resistance could improve risk stratification and inform early intervention strategies aimed at slowing disease progression.
The findings suggest that insulin resistance may serve as a useful predictor of cognitive decline in early AD
AI Model Improves Accuracy in Polyneuropathy Diagnosis
ACCURATE diagnosis and management of polyneuropathies remains a significant challenge, especially for non-specialist neurologists. A recent study, presented at the EAN Congress 2025, explored the potential of the AI model GPT-4o (OpenAI, San Francisco, California, USA) to assist in diagnosing these complex conditions and guiding confirmatory testing.7
The research involved 100 confirmed polyneuropathy cases collected from tertiary care centres, with input from 26 neurologists across 19 centres in 10 countries, including both specialists and non-specialists.
Using a zero-shot chain-of-thought prompting method, GPT-4o generated a primary diagnosis, two differential diagnoses, and a recommended confirmatory test for each case. These outputs were compared to the neurologists’ own diagnoses and test choices, both before and after they reviewed GPT-4o’s suggestions. The study found that GPT-4o displayed strong consistency in its outputs and performed significantly better than non-specialists in accuracy of the leading diagnosis (65.5% versus 54.4%), though it was slightly less accurate than specialists (73.9%). When considering differential diagnoses, GPT-4o’s accuracy improved and again surpassed non-specialists but remained below the specialist level.
Interestingly, non-specialist neurologists improved their diagnostic accuracy after reviewing GPT-4o’s suggestions, indicating the model’s potential as a valuable decision support tool. Specialists showed a smaller, non-significant improvement. In terms of recommending appropriate diagnostic tests, GPT-4o matched the experts and notably outperformed non-specialists.
Despite promising results, GPT-4o made errors, such as over-relying on laboratory data or patient history, and sometimes overlooking important clinical details. Nevertheless, the study concludes that supervised integration of GPT-4o could help bridge the expertise gap in neurological care by supporting non-specialists and improving diagnostic accuracy in polyneuropathy.
References
1. European Academy of Neurology (EAN). The burden of neurological diseases. 2019. Available at: https:// www.ean.org/research/resources/theburden-of-neurological-diseases. Last accessed: 1 July 2025.
2. Otaiku A. Nightmares accelerate biological aging and predict premature mortality in humans. Abstract OPR-111. EAN Congress, 21-24 June, 2025.
3. Braca S et al. GLP-1R agonists for the treatment of migraine: a pilot prospective observational study. Abstract OPR-012. EAN Congress, 2124 June, 2025.
4. Martínez-Serrat M et al. Temporal dynamics of serum neurofilament light chain in MS: a retrospective study in a clinical routine setting. Abstract OPR079. EAN Congress, 21-24 June, 2025.
5. Filchenko I et al. Sleep and longevity: insights from sleep macroarchitecture and nocturnal heart rate variability. Abstract OPR-059. EAN Congress, 2124 June, 2025.
6. Gumina B et al. The triglycerideglucose index as predictor of cognitive decline in Alzheimer's spectrum disorders. Abstract OPR-066. EAN Congress, 21-24 June, 2025.
7. De Lorenzo A et al. Chat-GPT-4o in diagnosis and management of real-life polyneuropathy cases: comparative analysis with neurologists. Abstract OPR-023. EAN Congress, 21-24 June, 2025.
The New McDonald Criteria: Faster and Improved Diagnosis of Multiple Sclerosis
THE 2024 REVISED McDonald Criteria for multiple sclerosis (MS) diagnosis were explained in detail during a joint session between the European Academy of Neurology (EAN) and the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), chaired by Bruno Stankoff, Professor of Neurology at Université Pierre et Marie Curie (UPMC), Paris, France; and Celia Oreja-Guevara, Vice Chair of Neurology and Head of Multiple Sclerosis Center at the University Hospital San Carlos, Madrid, Spain. The session highlighted significant updates to these diagnostic criteria, as well as expert insights on their potential clinical applications.
THE 2024 REVISED CRITERIA
Xavier Montalban, Chair of the Department of Neurology-Neuroimmunology and Director of the Multiple Sclerosis Centre of Catalonia at Vall d'Hebron University Hospital in Barcelona, Spain, shed light on the history of MS diagnostics, revealing that the first diagnostic criteria for MS were established in 1954 and have been revised multiple times since. Notably, major updates occurred with the introduction of the McDonald Criteria in 2001, followed by further refinements in 2005, 2010, and 2017. Now, the most recent 2024 McDonald Criteria have been announced, with further changes in line with new research findings. In this session, experts delved deeper into the new revisions.
The first diagnostic criteria for MS were established in 1954 and have been revised multiple times since
The 2024 revised criteria, and all previous versions, were developed by the International Advisory Committee on Clinical Trials in Multiple Sclerosis (IACCTMS), and are sponsored by the National MS
Society (USA) and ECTRIMS. In total, 55 international experts with backgrounds spanning clinical management, radiology, methodology, epidemiology, and patient perspectives, from 16 different countries, contributed to the 2024 revised criteria.
Significant Updates
Historically, MS diagnostic criteria have been based on the following four pillars: the presence of symptoms suggestive of MS, demonstration of dissemination in time (DIT) and dissemination in space (DIS), exclusion of other diagnoses, and the idea that diagnosis can be based on clinical assessment alone. Montalban, however, emphasised that in light of new research, the 2024 revisions challenge these statements.
He highlighted some of the most significant revisions, including the reclassification of radiologically isolated syndrome (RIS) as MS under specific conditions, the removal of the requirement for demonstration of DIT, and the recognition of the optic nerve as a fifth topography for evidence of DIS. According to Montalban, the redefinition of RIS as MS in selected cases represents the most
international experts with backgrounds spanning clinical management, radiology, methodology, epidemiology, and patient perspectives, from 16 different countries, contributed to the 2024 revised criteria
consequential update, reflecting a shift toward a more biologically-based approach to MS diagnosis. Other noteworthy changes include updated DIS criteria, the introduction of the central vein sign (CVS) and paramagnetic rim lesions (PRL) as optional diagnostic tools, and the use of the same diagnostic criteria for primary progressive MS and relapsing MS.
DISSEMINATION IN TIME IS NOT NECESSARY FOR DIAGNOSIS
Montalban then focused on one significant change to the criteria: with advancements in MRI and cerebrospinal fluid (CSF) markers, DIT is no longer a necessary criterion for diagnosis, if there are lesions in four or five different topologies.
He honed in on the contradictory nature of using DIT as a diagnostic criterion whilst also wanting to treat patients early to improve long-term prognosis, as fulfilment of the DIT criterion requires observing new lesions or relapses over time, which can mean waiting months before a formal diagnosis. He stressed this point with the results of his research, which examined the impact of using different diagnostic criteria on prognosis.1 The results demonstrated that when using the earlier criteria, the probability of reaching an Expanded Disability Status Scale (EDSS) score of ≥3 by the age of 40 years was 0.86. In contrast, with the 2017 McDonald criteria, this probability decreased to 0.20, demonstrating the benefit of using a diagnostic criterion that prioritises earlier diagnosis.
In the 2017 McDonald Criteria, the presence of oligoclonal bands (OCB) in CSF was introduced as an alternative to DIT for individuals presenting with clinically isolated syndrome. This modification was heavily influenced by a pivotal study,2 which demonstrated that patients with clinically
isolated syndrome who had both DIS and positive CSF OCBs had a high hazard ratio for conversion to MS. Consequently, this combination was adopted in the revised criteria. The key takeaway from this study is that the most critical factor for diagnosing MS is the demonstration of DIS, specifically with lesions in typical anatomical locations. Moreover, the presence of OCBs further increases diagnostic confidence; however, DIT is not a necessary criterion.
IMPACT ON TREATMENT AND CLINICAL PRACTICE
In the next part of the session, Marcello Moccia, Department of Neuroscience, University of Naples Federico II, Italy, addressed the practical implications of these new criteria for treatment and clinical practice. Moccia emphasised an important point made by Montalban, that whilst the primary aim of diagnostic criteria is to make correct diagnoses, they are profoundly related to treatment and prognosis. This means that the criteria must enable early and precise diagnosis, which then informs timely initiation of diseasemodifying therapies, which is crucial for long-term prognosis.
Moccia then explained how new diagnostic tools, such as the CVS, PRL, optical coherence tomography, and kappa free light chains (kFLC), are being integrated into routine evaluations under the revised criteria, and the impact this can have on patient outcomes.
Kappa Free Light Chain Index
With the new 2024 criteria, individuals with suspected MS are evaluated for DIS based on the presence of lesions in up to five characteristic CNS regions: periventricular, cortical/juxtacortical, infratentorial, spinal cord, and the optic nerve.
If typical lesions are identified in at least two of these regions, an MS diagnosis can be established. However, if there is only one lesion in a single region, additional criteria must be met. Among these additional criteria, Moccia explained, is a newly refined
definition of CSF positivity. Traditionally, positive CSF has been defined by the presence of OCBs, specifically patterns 2 or 3. The revised criteria now include an alternative biomarker: a kFLC index >6.1. A key advantage of the kFLC index is that it is a fully automated, quantitative laboratory test, unlike OCB detection, which requires specialised technical expertise and subjective interpretation. Use of the KFLC index not only streamlines diagnosis but also enables prognostic assessment at the time of disease presentation, as kFLC measurements reflect increased immunoglobulin synthesis in MS. Globally, the ease of using the kFL index means it can be widely implemented, with the potential to improve diagnostic possibilities worldwide.
Central Vein Sign and Paramagnetic Rim Lesions
Other new markers introduced in the 2024 McDonald criteria include the CVS and PRLs, which require the use of iron-sensitive, susceptibility-based MRI sequences, such as T2-star or Fluid Attenuated Inversion Recovery (FLAIR). Both CVS and PRLs demonstrate very high specificity for MS, although their sensitivity is not very high; however, when present, these findings strongly indicate an MS diagnosis.
CVS is particularly valuable for distinguishing MS from other inflammatory and non-inflammatory central nervous system disorders, and it is unaffected by age or vascular comorbidities. Notably, CVS demonstrates even greater specificity than CSF OCBs, although it does not hold prognostic value. However, Moccia explained that it can help distinguish new MS lesions from other non-MS lesions during follow-up.
PRLs, on the other hand, can provide unique insights into the underlying pathophysiology of MS, as well as prognostic stratification. The detection of a single PRL is highly specific for MS, and, while PRLs are not a requisite for diagnosis, their presence strongly supports it. Moreover, PRLs are of particular interest because patients
A key advantage of the kFLC index is that it is a fully automated, quantitative laboratory test, unlike OCB detection
with these lesions are at higher risk of subsequent disease progression, independent of relapse frequency. Interestingly, Moccia revealed that sometimes PRLs can disappear, and when they do, this may be indicative of clinical improvements or stability; however, this remains a subject of ongoing research.
The inclusion of both CVS and PRLs in the revised criteria reflects the fact that, for the first time, we have moved beyond just counting MS lesions to now classifying lesions. This advance not only improves diagnostic confidence but also holds potential to refine prognostication, longterm management, and the development of precision medicine (particularly for therapies that target PRLs). From a technical perspective, the integration of susceptibility-weighted imaging protocols in routine MRI will facilitate the identification of these new markers, without significantly impacting diagnostic workflows.
CONCLUDING REMARKS
Moccia expressed confidence that the new 2024 McDonald Criteria will greatly enhance the accuracy and timeliness of MS diagnosis. Moving beyond the traditional requirements of DIT and DIS, the revised criteria introduce highly specific diagnostic tools that will aid earlier and more reliable diagnoses. He spotlighted one notable advancement, which is the inclusion of the optic nerve as a recognised region for lesion assessment, as this may enable the reclassification of cases previously considered RIS as definite MS.
Additionally, Moccia emphasised the shift toward a more mechanism-based approach to diagnosis. Whilst the increased complexity of the revised criteria presents new challenges, this complexity is justified by the goal of improving early recognition and reducing the risk of misdiagnosis. Furthermore, Moccia argued that to
counteract the increased complexity, we need to improve imaging protocols. Most importantly, by incorporating susceptibilityweighted imaging sequences and ensuring thorough assessment of the optic nerve through modalities such as visual evoked potentials, optical coherence tomography, or MRI. Additionally, routine CSF analysis should now include the kFLC index. He also
References
1. Tintore M et al. Effect of changes in MS diagnostic criteria over 25
argued for a cultural change. In the past, MS diagnosis relied on relatively straightforward criteria, but now, neurologists need to combine multiple diagnostic tools. Not every person suspected of having MS will require the full complement of assessments, but it is up to clinicians to tailor assessments for each individual with suspected MS.
years on time to treatment and prognosis in patients with clinically isolated syndrome. Neurology. 2021;97(17):e1641-52.
2. Arrambide G et al. The value of oligoclonal bands in the multiple sclerosis diagnostic criteria. Brain. 2018;141(4):1075-84.
AT THE 2025 European Academy of Neurology (EAN) Congress, held in Helsinki, Finland, a spotlight was placed on the evolving landscape of clinical practice guidelines. With a mission to standardise and elevate the quality of neurological care across Europe, EAN 2025 introduced updates and new guidance in key areas, including Parkinson’s disease and infectious encephalitis. The session also tackled a critical question: how can guideline adherence be improved to ensure real-world impact?
IMPROVING GUIDELINE IMPLEMENTATION
Katarina Rukavina, EAN Guideline Production Group Fellow, opened the session by outlining the EAN’s approach to developing and implementing clinical practice guidelines. Designed to improve patient outcomes and reduce variability in care, these guidelines establish high-quality, evidence-based standards across neurology.
Since adopting the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology in 2012, which enables a structured, transparent assessment of the certainty of evidence and strength of recommendations, the EAN has published 31 guidelines with contributions from over 400 taskforce members. Despite this progress, adherence remains inconsistent, ranging from 30–70% depending on the context.
To address this, guidelines must be developed with implementation in mind. Factors such as complexity, adaptability, and the clinical environment play a
significant role in uptake. Rukavina emphasised the importance of planning for implementation from the outset, including the use of established frameworks, the identification of barriers, and the involvement of key stakeholders. Successful implementation also depends on educating and engaging healthcare professionals, patients, and key opinion leaders.
UPDATES IN PARKINSON’S DISEASE
Katarzyna Smilowska, from the 5th Regional Hospital in Sosnowiec, Poland, presented newly developed guidelines for first-line monotherapy in early Parkinson’s disease (PD), one of the most pressing areas of need in neurology. PD is the second most common neurodegenerative disorder globally, with an expected prevalence of 25.2 million by 2050, which is an increase of 112% from 2021.1 This growing burden emphasises the need for individualised, evidence-based treatment strategies that account for patient-specific factors such as age, sex, daily functioning, and the risk of side effects.
Since adopting the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology in 2012, the EAN has published 31 guidelines with contributions from over 400 taskforce members
The last European guidelines for PD were published in 2006 by the European Federation of Neurological Societies (EFNS). The new recommendations are part of an ongoing collaboration between the EAN and the Movement Disorder Society - European Section (MDS-ES), developed using the GRADE methodology. This initiative has already resulted in guidelines on invasive treatment approaches for PD, and the current guidelines address earlystage management of PD with practical recommendations tailored for general neurologists and geriatricians.
Early PD was defined as either de novo PD (drug-naïve and untreated) or nonfluctuating PD. Critical outcomes included in the guideline assessment were healthrelated quality of life, severity of motor symptoms, and adverse effects such as dyskinesia and motor fluctuations. Additional important outcomes included activities of daily living, non-motor symptoms (e.g., hallucinations, delusions), carer quality of life, and treatment discontinuation due to side effects.
Key recommendations include initiating treatment in people with early PD using oral levodopa, dopamine agonists, or monoamine oxidase B (MAO-B) inhibitors over placebo. Among these, levodopa is preferred over dopamine agonists or MAO-B inhibitors as the initial treatment choice. The guidelines advise against starting combination
5-15 %
therapy at this early stage, and note that there is insufficient evidence to make a recommendation for or against the use of amantadine. Clinicians are also encouraged to provide patients and their caregivers with clear information about the potential side effects and safety profiles of the available treatments, including risks related to behavioural and cognitive disorders, excessive daytime sleepiness, sudden onset of sleep, and motor complications. Once the guideline has achieved consensus among taskforce members, it will be submitted for publication.
NEW GUIDELINES ON INFECTIOUS ENCEPHALITIS
Johann Sellner, Landesklinikum MistelbachGänserndorf, Austria, introduced the forthcoming joint EAN-European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines on the diagnosis and management of infectious encephalitis (IE) in adults. Expected to publish by the end of the year, these are the first IE guidelines to use the GRADE methodology.
IE remains a serious global health concern, and is most often caused by viral infections. Despite medical advances, case fatality rates still range from 5–15%, and up to two-thirds of survivors experience longterm complications such as cognitive impairment, epilepsy, or chronic
Despite medical advances, case fatality rates still range from 5–15%, and up to two-thirds of survivors experience long-term complications such as cognitive impairment, epilepsy, or chronic headaches
headaches.2,3 The last major European guideline on encephalitis was published in 2010 by the EFNS, and focused primarily on viral meningeal encephalitis. Since then, the clinical landscape has shifted significantly. New causative agents (e.g., bornavirus) have been identified, arboviruses such as West Nile virus and dengue virus have spread geographically, and there has been an increase in at-risk populations, including individuals who are immunosuppressed. Advances in diagnostics (e.g., nextgeneration sequencing, multiplex PCR) and new clinical data (such as the DexEnceph trial4 assessing dexamethasone for herpes simplex virus encephalitis) further justify an updated approach.
The new guideline, developed by a taskforce of 30 experts from nine European countries, includes 16 population, intervention, comparison, and outcomes (PICO) recommendations. Sellner highlighted five key PICO questions, two of which are supported by sufficient evidence for formal recommendations.
Key recommendations from the upcoming EAN-ESCMID guidelines emphasise that clinical features alone, such as abnormal behaviour, myoclonus, brainstem signs, and Parkinsonism or tremor, should not be solely relied upon to guide the management of suspected IE, as these symptoms may reflect other pathogens or autoimmune conditions. Instead, clinicians should conduct a thorough patient history, including immune status, recent travel, contact with infectious individuals, exposure to mosquitoes or ticks, and interaction with animals or potentially contaminated food, as this can offer critical diagnostic clues.
In terms of microbiological testing, the taskforce conditionally recommends against replacing pathogen-specific PCR
References
1. Su D et al. Projections for prevalence of Parkinson’s disease and its driving factors in 195 countries and territories to 2050: modelling study of Global Burden of Disease Study 2021. BMJ. 2025;388:e080952.
testing of cerebrospinal fluid with multiplex PCR panels, due to the latter’s lower sensitivity, particularly for herpes simplex virus-1 detection. Regarding treatment, intravenous acyclovir should be initiated as early as possible, ideally within 6 hours of hospital presentation, when encephalitis is suspected. However, the routine use of corticosteroids in herpes simplex virus encephalitis is not recommended, as current evidence does not support a beneficial impact on clinical outcomes.
Additional recommendations in the guideline address the use of CT before lumbar puncture; further investigations such as brain biopsy, neuroimaging, and electroencephalogram; the dosing and duration of acyclovir therapy; and the rehabilitation and follow-up care of patients recovering from IE.
CONCLUSION
The latest updates to EAN guidelines reflect the organisation’s commitment to ensuring evidence-based, practical, and implementable recommendations in neurology. By focusing on both emerging evidence and real-world application, the new guidance on PD and IE promises to better equip clinicians in addressing current and emerging challenges in neurology.
The latest updates to EAN guidelines reflect the organisation's commitment to ensuring evidence-based, practical, and implementable recommendations in neurology
2. Fillâtre P et al. Functional outcome after infectious encephalitis: a longitudinal multicentre prospective cohort study. Clin Microbiol Infect. 2025;31(3):459-65.
3. Landré S et al.; Steering committee and Investigators. Encephalitis in HIVnegative immunodeficient patients: a prospective multicentre study, France, 2016 to 2019. Euro Surveill. 2024;29(6):2300046.
4. University Hospital, Grenoble. Dexamethasone in herpes simplex virus encephalitis (DexEnceph). NCT03084783. https://clinicaltrials. gov/study/NCT03084783.
Spotlight on Chronic Inflammatory Demyelinating Polyradiculoneuropathy: Improvements in Lower Limb Function with Efgartigimod
and Insights into Treatment Satisfaction of Conventional
CIDP Therapies
A summary of selected data presented at the 11th Congress of the European Academy of Neurology (EAN), held in Helsinki, Finland, from the 21st–24th of June 2025.
Support: The publication of this article was supported by argenx.
Presenters: Simon Rinaldi,1 Sandra Paci2
1. Nuffield Department of Clinical Neurosciences, University of Oxford, UK
2. argenx BV, Ghent, Belgium
Disclosure: Rinaldi has received honoraria for lectures given at the request of Excemed, Fresenius, CSL Behring, UCB, argenx, the Beijing Association of Holistic and Integrated Medicine, and the Irish Institute of Clinical Neuroscience. Paci has declared no conflicts of interest.
Acknowledgements: Writing assistance was provided by Helen Boreham, HB Medical (UK) Ltd, Wetherby, UK.
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare immune-mediated disorder that affects sensory function and muscle strength. This article summarises selected data from poster and oral presentations on CIDP and the neonatal Fc receptor blocker, efgartigimod, at the European Academy of Neurology (EAN) Congress held in June 2025 in Helsinki, Finland.
In the pivotal ADHERE trial, subcutaneous (SC) efgartigimod PH20 demonstrated clinical efficacy in the treatment of patients with CIDP, reducing relapse risk and improving disability scores. Data from post hoc analysis of the ADHERE trial exploring the effect of efgartigimod on lower limb function were presented by Simon Rinaldi from the University of Oxford, UK. Results showed that selective reduction of IgG with efgartigimod PH20 SC treatment improved lower limb function in patients with CIDP. Notably, over 20% of patients (33/144) who required support to walk at run-
PHARMA PARTNERSHIP
in baseline (the moment when patients had to stop their prior treatment) could walk outdoors independently after efgartigimod treatment in the open-label stage of ADHERE (Stage A), and over a third (9/25) who were previously wheelchair-bound were able to walk outdoors with support.
Looking at CIDP through a broad lens, Sandra Paci from argenx in Ghent, Belgium, presented results from a real-world multinational survey that compared patients’ satisfaction with treatment across five European countries. Although some variability in treatment satisfaction was observed across the different countries, a clear association between disability level, fatigue, and satisfaction level was evident. The higher the level of disability and fatigue, the lower the probability of patients being satisfied with their treatment.
Introduction
CIDP is a severe, immune-mediated disease characterised by progressive or relapsing weakness in the proximal and/or distal muscles and sensory disturbances, leading to disability.1,2 IgG autoantibodies have been implicated as key mediators in the underlying pathophysiology of CIDP as part of a humoral-mediated immunobiological process.3,4
Efgartigimod is a human IgG1 antibody fragment that blocks the neonatal Fc receptor and results in targeted reduction of IgG levels, without affecting other immunoglobulins or reducing albumin.4-8 Coformulation of efgartigimod with recombinant human hyaluronidase (also known as PH20) allows for rapid administration of larger volumes as a single SC injection.8,9 Efgartigimod PH20 is currently approved in several countries, including the USA and Japan, for the treatment of adult patients with CIDP. As of 19th June 2025, the European Commission has also approved efgartigimod PH20 as a monotherapy for the treatment of adult patients with progressive or relapsing active CIDP after prior treatment with corticosteroids or immunoglobulins.8-10
Efgartigimod PH20 SC was evaluated clinically in the Phase II, double-blind, placebo-controlled ADHERE study, the largest randomised trial in CIDP to date.4 In this pivotal study, treatment with efgartigimod PH20 SC was associated with early onset of clinically meaningful improvements in disability scores and grip strength in patients with CIDP,
and significantly reduced the risk of relapse compared to placebo in those who responded to treatment.4
Effect of Efgartigimod PH20 SC on Lower Limb Function in Chronic Inflammatory Demyelinating Polyradiculoneuropathy in ADHERE
Post hoc analysis of the ADHERE study was carried out specifically to evaluate the effect of efgartigimod PH20 SC on lower limb function.11 The trial itself involved a run-in period (≤12 weeks; during which those on traditional CIDP therapy stopped their treatments to confirm active disease), followed by the open-label Stage A (≤12 weeks) in which all participants received 1,000 mg weekly efgartigimod PH20 SC.4 Responders were then randomised 1:1 to efgartigimod PH20 SC or placebo for ≤48 weeks in the double-blind Stage B.4 Thereafter, participants could continue to receive efgartigimod PH20 SC in the ADHERE+ open-label extension study which evaluated long-term safety and efficacy up to 2 years.
Outcomes assessed in the ADHERE trial included changes in adjusted Inflammatory Neuropathy Cause and Treatment (aINCAT) leg disability score, selected Inflammatory Rasch-built Overall Disability Scale (I-RODS) individual items, and Timed Up and Go (TUG) test. In total, 322 participants entered Stage A, of whom 221 with evidence of clinical improvement (responders) were randomised and treated in Stage B,
where 111 patients received efgartigimod PH20 SC and 110 received placebo.
Post hoc analysis showed that treatment with efgartigimod PH20 SC improved the time taken for patients to complete the TUG test by Stage A last assessment. In Stage A responders, TUG time was reduced by 3.6 seconds with efgartigimod PH20 SC treatment compared with run-in baseline. The TUG test completion time continued to improve in these participants, reaching a difference of 5.0 seconds at Week 36 of the ADHERE+ trial.11
Efgartigimod PH20 SC also improved lower limb function, as demonstrated by patients’ ability to perform selected I-RODS items such as walking up one flight of stairs, walking while avoiding obstacles, walking outdoors, and running. The proportion of participants who could easily perform these lower limb-dependent tasks increased during Stage A following efgartigimod PH20
SC treatment. (Figure 1A) Maintenance of, or further improvement in, efficacy was observed for patients randomised to efgartigimod PH20 SC during Stage B, while a loss of efficacy was observed in those who received placebo. (Figure 1B)11
Finally, some participants experienced substantial improvements in their INCAT leg disability scores with efgartigimod PH20 treatment. By Stage A last assessment, 23% of participants who had required support to walk outdoors (INCAT scores: 2–3) at run-in baseline were able to walk outdoors independently. (Figure 2A) Additionally, 36% of participants who were wheelchair bound with INCAT leg scores of ≥4 at runin baseline could walk outdoors with or without support after efgartigimod PH20 SC treatment in Stage A. (Figure 2B) However it should be noted that, as sample sizes in this analysis were small, further studies using real-world data are required to provide further validation of these findings.11
Run-In baseline
Stage A baseline
Stage A last assessment
Run-In baseline
Stage A baseline
Stage A last assessment
Run-In baseline
Stage A baseline
Stage A last assessment Run
The denominator for the percentage calculations in A) is based on all patients enrolled in Stage A with a run-in phase (N=286). The denominator for the percentage calculations in B) is based on all patients randomised in Stage B with a run-in phase (N=191).
Figure 1: Improvement in ability to perform selected Inflammatory Rasch-built Overall Disability Scale items with efgartigimod PH20 subcutaneous treatment.11
AFigure 2: Improvements in Inflammatory Neuropathy Cause and Treatment Leg Disability Score with efgartigimod PH20 subcutaneous treatment.11
Participants who improved from required support to walk outdoors (Leg Score: 2–3) to walking outdoors independently (Leg Score: 0–1)*
B
Participants who improved from wheelchair-bound (Leg Score: 4–5) to walking outdoors with/without support (Leg Score: 0–3)*
A) This is based on all patients enrolled in Stage A with a run-in phase and with an INCAT lower limb score of 2–3 at run-in baseline (N=145). B) This is based on all patients enrolled in Stage A with a run-in phase and with an INCAT lower limb score of 4–5 at run-in baseline (N=25).
*After having undergone mandated CIDP deterioration during the run-in period.
INCAT: Inflammatory Neuropathy Cause and Treatment.
In conclusion, these post hoc analyses show that selective reduction of IgG with efgartigimod PH20 SC treatment resulted in improved lower limb function in participants with CIDP.11
A Comparison of Treatment Satisfaction in CIDP across Five Countries: Results from a RealWorld Multinational Survey
Traditional treatments for CIDP include corticosteroids (CS), intravenous immunoglobulin (IVIG) and plasmapheresis (PLEX). These therapies are associated with a high treatment burden due to issues such as long-duration infusions and poor tolerability.12-14 Traditional treatment options for CIDP are also hampered by limited efficacy and lack of clinical response, meaning patients may experience residual neurological impairment and disability.12-14
Due to limited research in this area, little is currently known about the satisfaction of patients with CIDP with available
treatment options. To address these gaps in understanding, a real-world study with neurologists and patients with CIDP was carried out in Spain, France, Germany, and Italy. Key aims were to compare patients’ satisfaction with CIDP treatment among European countries, evaluate the association between treatment satisfaction and disability and fatigue, and assess the concordance between patient and neurologist satisfaction.15
Data were collected in the four European countries via cross-sectional physician and patient surveys carried out as part of Adelphi’s CIDP Disease Specific Programme™, which took place between September 2022–April 2023. Neurologists completed electronic record forms, including a question about their satisfaction with their patient’s treatment. Patients filled in a self-completion form, including questions about their overall treatment satisfaction. These patient and physician data sources were then linked, giving a total sample size of 199 patients. Overall, 57% of patients included in the analysis were male and mean age was 52.4 years. Since both
Significant association (p<0.0001): the higher the INCAT score, the lower the probability of the patient being satisfied
Current treatment refers to IVIG, CS, or PLEX.
% of patients that are satisfied with their treatment by fatigue level
Significant association (p=0.0001): the lower the FACIT score, the lower the probability of the patient being satisfied
CS: corticosteroids; FACIT: Functional Assessment of Chronic Illness Therapy; INCAT: Inflammatory Neuropathy Cause and Treatment; IVIG: intravenous immunoglobulin; PLEX: plasmapheresis.
forms had different wording for satisfaction, the two highest options were grouped and this was considered the proportion of patients or neurologists who were satisfied. Therefore, respondents giving one of the two highest ratings on the patient form (somewhat/very satisfied) or the neurologist form (satisfied/completely satisfied) were ranked as ‘satisfied’. Two measures related to disease severity were also assessed: disability, measured using the INCAT score; and fatigue measured by the Functional Assessment of Chronic Illness Therapy (FACIT) score.15
Country comparisons showed that the greatest satisfaction with CIDP treatment was in Germany, where 78% of patients reported being satisfied. Germany also had the highest proportion of patients with CIDP on treatment (94%) when compared to Italy (79%), Spain (75%), and France (63%). The lowest satisfaction was observed in France, where only 56% of patients reported being satisfied with their current CIDP treatment. However, it should
be noted that sample sizes per country were low, and there were differences in the distribution of disease severity.15
Results from this real-world multinational survey also showed a strong association between treatment satisfaction and both disability and fatigue. The higher the patients’ level of disability and fatigue, the lower the probability of their being satisfied with their CIDP treatment. (Figure 3) Overall, only a third of patients with severe disability were satisfied with their current treatment, as were less than 20% with severe fatigue.15
In terms of concordance between patient and physician satisfaction, in the majority of cases (82%), both patients and neurologists reported the same level of satisfaction with treatment. However, for 14% of patients, neurologists reported a higher level of treatment satisfaction than the patients themselves, while only a very small group of patients (4%) reported a higher satisfaction level than
Figure 3: Association between patient satisfaction with current treatments and disability/fatigue.15
their neurologist.15 This suggests that some healthcare professionals may be overestimating how satisfied patients are with their current CIDP treatment.
Overall, these real-world multinational survey results reveal a strong association between patients’ satisfaction with CIDP treatment and their level of disability and fatigue. The higher the disability and fatigue level, the lower the probability of being satisfied with treatment. Some variability in satisfaction levels with CIDP treatments was also evident among different European countries. Although patients and neurologists expressed the same treatment satisfaction level in most cases, when they did not, neurologists tended to report greater satisfaction than patients.15
Conclusion
In summary, these new data presented at EAN 2025 provide important insights into CIDP and its treatment. Results from the real-world survey reveal a clear link between patients’ treatment satisfaction and their levels of disability and fatigue. Notably, only a third of patients with severe disability and less than a fifth with severe fatigue were satisfied with their current treatment. There is an unmet need for CIDP treatment options that are convenient, fast-acting, and efficacious, and provide both patients and their healthcare professionals with a higher level of treatment satisfaction. Efgartigimod PH20 SC is a new therapeutic option for CIDP recently approved in Europe that was shown to improve lower limb function in treated patients in post hoc analysis of the pivotal ADHERE trial.
References
1. Rajabally YA. Chronic inflammatory demyelinating polyradiculoneuropathy: current therapeutic approaches and future outlooks. Immunotargets Ther. 2024;13:99-110.
2. 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.
3. Mathey EK et al. Chronic inflammatory demyelinating polyradiculoneuropathy: from pathology to phenotype. J Neurol Neurosurg Psychiatry. 2015;86(9):973-85.
4. Allen JA 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.
5. Ulrichts P et al. Neonatal Fc receptor antagonist efgartigimod safely and sustainably reduces IgGs in humans. J Clin Invest. 2018;128(10):4372-86.
6. Howard JF Jr et al. Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2021;20(7):526-36.
7. Broome CM et al. Efficacy and safety of the neonatal Fc receptor inhibitor efgartigimod in adults with primary immune thrombocytopenia (ADVANCE IV): a multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2023;402(10413):1648-59.
8. Howard JF Jr et al. Subcutaneous efgartigimod PH20 in generalized myasthenia gravis: a phase 3 randomized noninferiority study (ADAPT-SC) and interim analyses of a long-term open-label extension study (ADAPT-SC+). Neurotherapeutics. 2024;21(5):e00378.
9. Argenx. Vyvgart Hytrulo Prescribing information. 2024. Available at: https:// www.argenx.com/product/vyvgarthytrulo-prescribing-information.pdf. Last accessed: 25 June 2025.
10. European Medicines Agency (EMA). Vyvgart - opinion on variation to marketing authorisation. 2025.
Available at: https://www.ema.europa. eu/en/medicines/human/variation/ vyvgart. Last accessed: 25 June 2025.
11. Rinaldi S et al. Effect of efgartigimod PH20 SC on lower limb function in chronic inflammatory demyelinating polyradiculoneuropathy in ADHERE. Poster EPO-144. EAN Congress, 21-24 June, 2025.
12. Brun S et al. CIDP: Current treatments and identification of targets for future specific therapeutic intervention. Immuno. 2022;2(1):118-31.
13. Bus SRM et al. Clinical outcome of CIDP one year after start of treatment: a prospective cohort study. J Neurol. 2022;269(2):945-55.
14. Gorson KC. An update on the management of chronic inflammatory demyelinating polyneuropathy. Ther Adv Neurol Disord. 2012;5(6):359-73.
15. Paci S et al. A comparison of treatment satisfaction in CIDP across 5 Countries: results from a real-world multinational survey. Presented at EAN Congress, 21-24 June, 2025.
EAN 2025
Abstract Reviews
Drawing on key findings presented at the European Academy of Neurology (EAN) Congress 2025, the following abstract reviews spotlight the latest advancements in neurology. Authored by the presenters themselves, topics include EEG biomarkers for Alzheimer’s, glymphatic dysfunction in motor neurone disease, and vascular risk factors in multiple sclerosis.
Distinct Resting-State EEG Biomarkers Predict Amyloid Status and Conversion to Alzheimer’s Dementia in a Memory Centre
Authors: *Giordano Cecchetti,1-4 Silvia Basaia,3
Marco Cursi,2 Edoardo G. Spinelli,1,3,4 Elisa Canu,3
Francesca Caso,1 Roberto Santangelo,1,2 Giovanna Franca Fanelli,2 Giuseppe Magnani,1
Federica Agosta,1,3,4 Massimo Filippi1-5
1. Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
2. Neurophysiology Service, IRCCS San Raffaele Scientific Institute, Milan, Italy
3. Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
4. Vita-Salute San Raffaele University, Milan, Italy
5. Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
*Correspondence to cecchetti.giordano@hsr.it
Disclosure: Cecchetti has received honoraria for lectures from Neopharmed Gentili and Eli Lilly. Spinelli has received funding from the Next Generation EU programme, via the National Recovery and Resilience Plan (NRRP), under Investment PE8-Project Age-It. Agosta has received funding from the Next Generation EU programme, via the National Recovery and Resilience Plan (NRRP), under Investment PE8-Project Age-It; grants or contracts from the Italian Ministry of Health, the Italian Ministry of University and Research, Fondazione Italiana di Ricerca per la SLA (AriSLA), the European Research Council, the EU Joint Programme –Neurodegenerative Disease Research (JPND), and Foundation Research on Alzheimer Disease (France); and honoraria for lectures from Biogen Idec, Italfarmaco, Roche, Zambon, and Eli Lilly. Filippi has received funding from the Next Generation EU programme, via the National Recovery and Resilience Plan (NRRP), under Investment PE8-Project Age-It; grants or contracts from Biogen Idec, Merck-Serono, Novartis, Roche, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla; funding for consulting fees from Alexion, Almirall, Biogen, Merck, Novartis, Roche, and Sanofi; honoraria for speakers from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA; served on Advisory Boards for Alexion, Biogen, Bristol Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, and Takeda; served as Scientific Director for educational events for Biogen, Merck, Roche, Celgene, Bristol Myers Squibb, Eli Lilly, Novartis, and Sanofi-Genzyme; is Editor-in-Chief of the
Journal of Neurology; and is Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology. The other authors have declared no conflicts of interest.
Resting-state EEG (RS-EEG) has emerged as a non-invasive, low-cost tool for Alzheimer’s disease (AD) diagnosis and stratification. This study evaluated whether EEG-based biomarkers can predict amyloid status and clinical progression from mild cognitive impairment (MCI) to AD dementia in patients referred to a third-level memory clinic.1
METHODS
The authors retrospectively analysed 295 patients who were cognitively impaired and underwent a standardised diagnostic work-up, including neuropsychological assessment, cerebrospinal fluid (CSF) biomarker analysis, and 19-channel RSEEG recording (10–20 system, eyes closed; Table 1). Patients were classified as amyloidpositive (A+; n=184) or amyloid-negative (A-; n=111) based on CSF Aβ42/40 ratio. The MCI subgroup (n=106) was divided into MCI A+ (n=61) and MCI A- (n=45). A total of 39 individuals with MCI A+ were followed over 2 years, and 23 converted to AD dementia.
EEG preprocessing included bandpass filtering (1–45 Hz), independent component analysis-based artefact removal, and rereferencing to the average. Source-space analysis was performed using standardised low-resolution brain electromagnetic tomography, constrained to two networks of interest: the default mode network
Table 1: Demographic and clinical features of patients stratified according to their amyloid status and conversion status from mild cognitive impairment to dementia.
MCI_c 23
16
(43.08–
(52.23–
(55.04–
Values are averages and SDs (range). p values refer to T test models or the Chi-square test. Statistical significance was defined as p<0.05.
(DMN), typically affected in AD, and the salience network (SN), more often impaired in non-AD conditions. These networks were defined through a seed-based restingstate functional MRI analysis conducted in an independent cohort of healthy young adults, using canonical seeds placed in the posterior cingulate cortex (DMN) and anterior cingulate (SN). The resulting network maps were coregistered in Montreal Neurological Institute (MNI) space and parcellated into regions of interest. EEG source activity was then estimated voxel-wise and averaged across each region of interest to extract measures of current source density (CSD) and pairwise linear lagged connectivity (LLC), across δ (1–3.5 Hz), θ (4–7.5 Hz), α1 (8–10 Hz), α2 (10.5–12 Hz), and β (12–30 Hz) bands.
RESULTS
Patients who were A+ showed a general slowing of EEG cortical activity when compared to A- in both DMN and SN. Patients with MCI A+ showed significantly increased θ CSD and LLC in both networks, with peak differences in posterior DMN regions, consistent with early networklevel hyperconnectivity. Among subjects with MCI A+, converters exhibited reduced α1 CSD in the DMN and decreased α LLC across both DMN and SN. No significant changes emerged in the β band.
Support vector machine classifiers using significant EEG features were trained to predict amyloid status (at both whole group and MCI group levels) and MCI conversion.
Feature selection was guided by Shapley Additive Explanations, identifying occipital θ CSD and frontal α1 LLC as most predictive. The best-performing support vector machine models achieved around 60% balanced accuracy in all classifications, with robust results across 5-fold cross-validation.
CONCLUSION
This study underscores that AD causes early disruptions in cortical electrical activity, detectable through restingstate EEG. θ current source density and network connectivity emerged as early markers of amyloid-related pathology, while α connectivity remained relatively preserved in early stages and declined in patients progressing to dementia. These findings reflect a trajectory from early excitatory θ alterations to α disconnection, marking synaptic dysfunction and neurodegeneration.2-4 Machine learning models offer promising avenues for early detection and risk stratification.5 Notably, the DMN was more consistently impaired than the salience network, highlighting
its selective vulnerability in AD.2,3
RS-EEG may support scalable, noninvasive screening strategies in memory clinics, especially where access to amyloid PET or CSF biomarkers is limited. Future directions include longitudinal validation, integration with plasma biomarkers, and multimodal frameworks for non-invasive prediction of disease progression.
References
1. Cecchetti G et al. Distinct resting-state EEG biomarkers predict amyloid status and conversion to Alzheimer's dementia in a memory center. Abstract OPR-068. EAN Congress, 21-24 June, 2025.
2. Cecchetti G et al. Resting-state electroencephalographic biomarkers of Alzheimer's disease. Neuroimage Clin. 2021;31:102711.
3. Cecchetti G et al. EEG correlates in the 3 variants of primary progressive aphasia. Neurology. 2024;102(3):e207993.
4. Cassani R et al. Systematic review on restingstate EEG for Alzheimer's disease diagnosis and progression assessment. Dis Markers. 2018;2018:5174815.
5. Jeong J. EEG dynamics in patients with Alzheimer's disease. Clin Neurophysiol. 2004;115(7):1490-505.
The Epilepsy Deaths Register: Third-Party Reports of Sudden Unexpected Death in Epilepsy in Adults and Older Adolescents
Authors: *Alexander Grundmann,1,2 Jacob Brolly,1 Donald P Craig,1 Karen Osland,3 Jane Hanna,3 Elaine Hughes,4 Mike P. Kerr,5 Ben Donovan,3 Rhys H. Thomas1,2
1. Royal Victoria Infirmary, Newcastle-upon-Tyne, UK
2. Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, UK
3. SUDEP Action, Wantage, UK
4. Evelina London Children's Hospital, UK
5. Psychological Medicine and Clinical Neurosciences, Cardiff University, UK
*Correspondence to alexander.grundmann@nhs.net
Disclosure: Grundmann has received the European Academy of Neurology (EAN) Bursary as support for attending meetings/ travel for the EAN Congress 2025. Brolly has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from UCB Pharma. Craig has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Seer Medical. Osland was the Project Lead for the Epilepsy Deaths Register for the UK charity SUDEP Action until April 2020. Hanna was the Chief Executive for the UK charity SUDEP Action. Hughes has participated in multicentre commercial trials of fenfluramine for the treatment of epilepsy in Dravet syndrome; and is a member of the GW Pharmaceuticals-supported LGS Advisory Board. Kerr is Vice Chair of SUDEP Action, the charity that supports the Epilepsy Deaths Register. Donovan is the Project Lead for the Epilepsy Deaths Register for the UK charity SUDEP Action. Thomas has received grants or contracts from Angelini and UCB Pharma; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Angelini, Bial, Eisai, GW Pharma, Paladin, Neuraxpharm, Sanofi, Takeda, UCB Pharma, UNEEG, and Zogenix; and is the President of the ILAE British Branch.
Acknowledgements: The authors would like to thank all reporters for their contributions to the Epilepsy Deaths Register.
Keywords: Epidemiology, epilepsy, sudden unexpected death in epilepsy (SUDEP).
Sudden unexpected death in epilepsy (SUDEP) is the most significant complication of epilepsy, with an incidence of 1.2 per 1,000 patient-years.1 The major source for SUDEP case series has been medical case record review;2,3 however, most deaths occur at home, with family and friends as witnesses to the event or to the scene of death. The authors, therefore, aimed to describe SUDEP characteristics using reports of deaths from third parties and to explore this reporting as a sampling technique.4
MATERIALS AND METHODS
The authors collected characteristics of the deceased and narratives surrounding death via the SUDEP Action UK Epilepsy Deaths Register (EDR), a dual-purpose record for research and support to bereaved families. They included adults and older adolescents if they had a certified cause of death and a narrative consistent with definite or probable SUDEP. The authors extracted demographics, details of follow-up, events leading to death, and attitudes towards the condition and treatment during life from third-party reporters between 2013–2024.
RESULTS
The study identified 407 SUDEP cases. Ages ranged from 15–85 years, with the majority (76% of cases) occurring between the ages of 19–49 years; 59% were male. Most cases found were in the prone position (63%), and death most frequently occurred during sleep (69%). SUDEP was not recorded as the cause of death in 24.8% of cases, despite a consistent reporter account. An increased frequency of SUDEP was observed with longer epilepsy duration, with 41% diagnosed more than 10 years prior to death.
Table 1: Quotations from reporters regarding their feelings towards the communication of sudden unexpected death in epilepsy risk, both prior to and after the deceased’s death.
“We had no idea you could die from a seizure disorder. We had never heard of SUDEP.”
“I loved him so much, but I never knew he could just die in his sleep for no reason … Please inform people about it and save them my torment.”
“People need to know that even after years of no seizures that something catastrophic can still happen.”
“We all wish that we had known about the risk of SUDEP long ago.”
“I have talked to a few people with family members who suffer from epilepsy, and none of them have ever heard of SUDEP, so I feel very disturbed that they are not being told.”
“All the years of doctor's appointments… no one ever mentioned the risk of death/SUDEP. This leaves me so very, very angry.”
SUDEP: sudden unexpected death in epilepsy.
Anti-epileptic medication was prescribed in 91% of cases, with 24% reported as sometimes forgetting to take their medications. Sixteen percent of cases lived alone, and 16% of deaths were witnessed.
There was no significant association between seasonality or deprivation and cases of SUDEP, though increased deprivation was associated with home as the place of death (11.6% more) and with medication concerns (13.2% more). Fiftyone percent of reporters did not know that someone could die of epilepsy, and the impact of this can be seen in Table 1
CONCLUSION
Third-party death reports are an effective, underutilised tool to sample SUDEP deaths, which may currently be missed by conventional mortality records. Consistent with previous population studies, SUDEP in the EDR was seen more frequently in young adults, those
with longstanding epilepsy, during sleep, and most often found in a prone position.
Most of the SUDEP cases in the EDR had no medication concerns, did not live alone, and were under specialist follow-up, factors that are recognised as lowering risk. This heterogeneity across the spectrum of SUDEP deaths should prompt clinicians to openly discuss SUDEP risk with all people with epilepsy.
References
1. Sveinson O et al. Clinical risk factors in SUDEP: a nationwide population-based case-control study. Neurology. 2020;94(4):e419-29.
2. Tomson T et al. Influence of risk factor combinations on incidence rates of SUDEP. Neurology. 2025;104(5):e213372.
3. Opeskin K, Berkovic SF. Risk factors for sudden unexpected death in epilepsy: a controlled prospective study based on coroners cases. Seizure. 2003;12(7):456-64.
4. Grundmann et al. The Epilepsy Deaths Register: friend, family and care-giver reports of SUDEP in adults and older adolescents. Abstract OPR-068. EAN Congress, 21-24 June, 2025.
Glymphatic Dysfunction in Clinical Phenotypes of Motor Neurone Disease
Authors: Ilaria Bottale,1-3 Edoardo Gioele Spinelli,1-3 Silvia Basaia,1 Alma Ghirelli,1-3
1. Neuroimaging Research Unit, Division of Neuroscience IRCCS San Raffaele Scientific Institute, Milan, Italy
2. Vita-Salute San Raffaele University, Milan, Italy
3. Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
4. Neurophysiology Service, IRCCS San Raffaele Scientific Institute, Milan, Italy
5. Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
*Correspondence to filippi.massimo@hsr.it
Disclosure: Agosta has received research support for the present manuscript from the Italian Ministry of Health (IMH), Italian Ministry of University and Reseach (IMUR), Fondazione Italiana di Ricerca per la SLA (AriSLA), the European Research Council (ERC), the EU Joint Programme – Neurodegenerative Disease Research (JPND), and Foundation Research on Alzheimer Disease (France); and speaker honoraria from Biogen Idec, Roche, Eli Lilly, and GE Healthcare. Filippi serves as Editor-in-Chief of the Journal of Neurology, and Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology; has received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche, and Sanofi; research support from Biogen Idec, Merck-Serono, Novartis, Roche, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla; payment for scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol Myers Squibb, Eli Lilly, Novartis, and Sanofi-Genzyme; payment for speaking activities from Bayer, Biogen, Celgene, Chiesi Italia, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and Teva; and has participated in advisory boards for Alexion, Biogen, Bristol Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, and Takeda. The other authors have declared no conflicts of interest.
Acknowledgements: The authors would like to thank Professor Massimo Filippi, Professor Federica Agosta, Doctor Edoardo Gioele Spinelli, and the Neuroimaging Research Unit at San Raffaele Hospital in Milan for their support.
Keywords: Amyotrophic lateral sclerosis, diffusion tensor imaging analysis along the perivascular space (DTI-ALPS), glymphatic system, motor neurone diseases (MND), neuroimaging, proteinopathy, transactive response DNA binding protein 43 (TDP-43), white matter damage.
Converging evidence supports a key pathogenic role of the glymphatic system in the accumulation of pathological aggregates in several proteinopathies, including amyotrophic lateral sclerosis and other motor neurone diseases (MND). This study aimed to verify glymphatic function impairment utilising diffusion tensor imaging analysis along the perivascular space (DTI-ALPS), explore its clinical correlations in MND phenotypes, and evaluate the relationship between glymphatic dysfunction and white matter (WM) damage.1
METHODS
Fifty-seven patients with MND (41 with amyotrophic lateral sclerosis, seven with lower motor neuron presentations, and nine with upper motor neuron presentations) and 32 age- and sex-matched healthy controls underwent 3 Tesla brain MRI, including DTI sequences. The authors obtained DTI-ALPS index from each individual, evaluating its relationship with measures of motor and cognitive disability, site of symptom onset, cognitive status, genetic status, and fractional anisotropy of WM tracts. Comparisons between groups were evaluated using ANCOVA models, which were age- and sex-adjusted. Partial correlations with clinical and cognitive measures were also tested.
Figure 1: Group comparisons of diffusion tensor imaging analysis along the perivascular space index between healthy controls and amyotrophic lateral sclerosis with bulbar or spinal onset.
SUDEP: sudden unexpected death in epilepsy.
ALS spinal onset group
p=0.046
ALS bulbar onset group
RESULTS
Patients with MND exhibited significantly reduced DTI-ALPS index values compared to healthy controls (p<0.001). Patients with bulbar onset had lower DTI-ALPS values than those with spinal onset (p=0.046), as shown in Figure 1. Similar DTI-ALPS values were found across all MND phenotypes, with no effect of cognitive diagnosis or genetic status on these values. Significant correlations were identified between DTI-ALPS and disease duration (r=–0.30; p=0.03), and significantly lower values of DTI-ALPS were observed in patients presenting insomnia, compared to those without sleep disturbances (p=0.004). The authors assessed the relationship between DTI-ALPS index values and WM integrity, revealing significant positive correlations with fractional anisotropy in the anterior corona radiata (r=0.31; p=0.02) and the body of the corpus callosum (r=0.37; p=0.049).
CONCLUSION
This study confirms the presence of glymphatic dysfunction across MND phenotypes, with greater impairment observed in bulbar-onset cases, patients with longer disease duration, and those experiencing more pronounced sleep disturbances. These findings support a potential pathogenic role of glymphatic failure in the accumulation of transactive response DNA binding protein 43 (TDP43) proteinopathy in MNDs. Moreover, the observed positive correlations between DTI-ALPS indices and WM integrity suggest that glymphatic dysfunction may contribute to or reflect the extent of WM damage in these patients.
Reference
1. Bottale I et al. Glymphatic dysfunction in clinical phenotypes of motor neuron disease. Neurology. 2025;104(7 Suppl 1).
Rapid Molecular Classification of Brain Tumours Through DNA Methylation Analysis with Nanopore Sequencing
Authors: *Elena Bondareva,1,2 Sylvain Moser,1,2 Thomas Rötzer-Pejrimovsky,1-3 Romana Höftberger,1,2 Christine Haberler,1-3 Nicole Amberg1-3
1. Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Austria
2. Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, Austria
3. Comprehensive Cancer Center, Medical University of Vienna, Austria
*Correspondence to elena.bondareva.md@gmail.com
Disclosure: Bondareva has declared receipt of a nanopore bursary from Oxford Nanopore Technologies for participation in the 11th EAN Congress, held in Helsinki, Finland, between June 21st–24th 2025. The project was funded by Fellinger Krebsforschung.
Acknowledgements: The authors would like to thank P. Euskirchen and E. Perez from Charité–Universitätsmedizin Berlin, Germany, for support in applying the wet-lab protocol. Data analysis was performed using the NanoDx™ pipeline developed by P. Euskirchen (Charité Berlin, Institute of Neuropathology, Germany) and the Sturgeon pipeline developed by C. Vermeulen, M. Pagès-Gallego, and L. Kester et al. (Oncode Institute, Utrecht, the Netherlands). Parts of the figure were generated using BioRender.
Profiling of DNA methylation, a stable epigenetic marker of cell identity, has become a significant tool in precision cancer diagnostics, since DNA methylation reflects both somatically acquired changes and the cell-of-origin.1 Conventional diagnostics of brain tumours integrate histology, immunohistochemistry (IHC), and molecular classification with Infinium MethylationEPIC array (EPIC; Illumina, San Diego, California, USA) and gene panel sequencing.
However, these techniques require sample multiplexing for cost efficiency, leading to 2–4 weeks delay in obtaining integrative diagnosis, postponing tumour board and precision therapy initiation.2
METHODS
To shorten this time span, the authors analysed 45 native brain tumour samples using real-time nanopore sequencing. The goal was to implement a robust nanopore wet-lab workflow for clinical practice (Figure 1A), and evaluate accuracy of molecular classification in comparison with integrated neuropathological diagnosis.3 DNA was isolated, quantified, and sequenced on a MinION (Oxford Nanopore Technologies, UK) device. Data analysis was performed using the NanoDx™4 pipeline developed by Philipp Euskirchen (Charité Berlin, Institute of Neuropathology, Germany) and the Sturgeon5 pipeline developed by C. Vermeulen, M. PagèsGallego, L. Kester et al. (Oncode Institute, Utrecht, the Netherlands).
RESULTS
The authors found a tumour class prediction in 31 cases (71%) using the NanoDx classifier, and in 39 cases (89%) using the Sturgeon classifier. For NanoDx, the predicted molecular class was concordant with integrated neuropathological diagnosis in 29 cases (94% of classifiable cases), and in 29 cases for Sturgeon (74% of classifiable cases; Figure 1B).
CONCLUSION
The authors' analysis demonstrates that nanopore workflow shortens molecular classification of brain tumours, reducing diagnostic timing from 2–4 weeks to approximately 24 hours.
Figure 1: Diagnostic workflow and evaluation of the accuracy of molecular brain tumour classification with nanopore sequencing at the Division of Neuropathology and Neurochemistry, Medical University of Vienna, Austria.
A B
A) Conventional workflow (top) and novel nanopore sequencing-based diagnostic workflow (bottom) for neuropathological analysis of brain tumours.
B) Summary of the accuracy of tumour type prediction using nanopore sequencing (NanoDx and Sturgeon classifiers) compared to conventional integrated diagnosis.
Parts of the figure were generated using BioRender.
EPIC: Infinium MethylationEPIC array (Illumina, San Diego, California, USA); H&E: haematoxylin and eosin; IHC: immunohistochemistry; vs: versus.
This rapid profiling enables targeted IHC, facilitating an integrated tumour diagnosis potentially within 5 days, dramatically improving the timeline for precision therapy onset. Ongoing research aims to improve reliability by continuing to collect data and refine classifiers, implement targeted nanopore sequencing of specific genomic regions, like MGMT promoter, and assess the impact of faster integrated diagnosis on clinical outcomes.
References
1. Capper D et al. DNA methylation-based classification of central nervous system tumours. Nature. 2018;555(7697):469-74.
2. Patel A et al. Prospective, multicenter validation of a platform for rapid molecular profiling of central nervous system tumors. Nat Med. 2025;31(5):1567-77.
3. Bondareva E et al. Rapid molecular classification of brain tumors through DNA methylation analysis with nanopore sequencing. Abstract OPR-064. EAN Congress, 21-24 June, 2025.
4. Kuschel LP et al. Robust methylation-based classification of brain tumours using nanopore sequencing. Neuropathol Appl Neurobiol. 2023;49(1):e12856.
5. Vermeulen C et al. Ultra-fast deep-learned CNS tumour classification during surgery. Nature. 2023;622(7984):842-9.
Impact of Vascular Risk Factors on Motor Performance and Sensorimotor Network Integrity in Patients with Multiple Sclerosis
Authors: Matteo Albergoni,1 Paolo Preziosa,1,2 Gloria Ritrosos,1 Nicolò Tedone,1,2 Elisabetta Pagani,1 Loredana Storelli,1 Paola Valsasina,1 Massimo Filippi,1,2 *Maria A. Rocca1,2
1. IRCCS San Raffaele Scientific Institute, Milan, Italy
2. Vita-Salute San Raffaele University, Milan, Italy
*Correspondence to rocca.mara@hsr.it
Disclosure: Preziosa has received speaker honoraria from Roche, Biogen, Novartis, Merck, Bristol Myers Squibb, Genzyme, Horizon, and Sanofi; and research support from the Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla (FISM). Storelli has received grants and contracts from FISM within a fellowship programme; and speakers’ honoraria from Biogen. Filippi is the Editor-in-Chief for the Journal of Neurology, Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology; has received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche, and Sanofi; speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA; participation in Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, and Takeda; scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, Sanofi-Genzyme; and receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla. Rocca received consulting fees from Biogen, Bristol Myers Squibb, and Roche; speaker honoraria from Alexion, Biogen, Bristol Myers Squibb, Celgene, Horizon Therapeutics Italy, Merck Serono SpA, Mitsubishi-Tanabe Pharma, Neuraxpharm, Novartis, Roche, Sandoz, and Sanofi; receives research support from the MS Society of Canada, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla; and is the Associate Editor for Multiple Sclerosis and Related Disorders, and Associate Co-Editor for Europe and Africa for Multiple Sclerosis Journal. The other authors have declared no conflicts of interest.
Multiple sclerosis (MS) has been traditionally considered a chronic, immunemediated disease of the central nervous system (CNS).1 However, recent studies have highlighted the potential role of systemic factors, especially vascular comorbidities, in influencing disease progression.2,3 Vascular risk factors (VRF), including hypertension, diabetes, dyslipidaemia, obesity, alcohol intake, and smoking, have been associated with higher disease activity, greater lesion burden, faster brain atrophy, and earlier disability milestones in MS.4,5 While prior research has primarily examined the impact of VRFs on global MRI measures, their influence on specific CNS structural networks, such as the sensorimotor network (SMN), remains largely unexplored. Based on this background, the authors investigated the impact of VRFs on disability, motor performance, and the structural integrity of SMN regions in people with MS.6
METHODS
In this cross-sectional study, 268 patients with MS and 180 healthy controls (HC) were categorised based on VRF presence (HC-VRF[+]), MS-VRF[+]) or absence (HCVRF[-], MS-VRF[-]). Disability and motor performance were assessed using the Expanded Disability Status Scale (EDSS), the Timed 25-Foot Walk, and the NineHole Peg Test. Structural integrity of the SMN was evaluated using volumetric and diffusion-weighted MRI data. Specifically, the authors analysed cortical thickness of the primary motor and somatosensory cortices; normalised deep grey matter (GM) volume; volumes of the anterior (ACMA) and posterior (PCMA) cerebellar motor
Figure 1: Scatter plot showing the association between medial lemniscus fractional anisotropy and Expanded Disability Status Scale scores in patients with multiple sclerosis, with (red) and without (blue) vascular risk factors.
7.5
MS-VRF[-] MS-VRF[+]
EDSS score
Medial lemniscus FA
EDSS: Expanded Disability Status Scale; FA: fractional anisotropy; MS-VRF[-]: patients with multiple sclerosis without VRFs; MS-VRF[+]: patients with multiple sclerosis with VRFs; VRF: vascular risk factors.
areas; fractional anisotropy (FA), mean diffusivity (MD), and lesion volume (LV) of the middle (MCP) and superior (SCP) cerebellar peduncles, the medial lemniscus, and the corticospinal tract; as well as the mean upper cervical cord area (MUCCA). Group differences in clinical and MRI metrics and interactions between disease status and VRFs were explored. In patients with MS, associations between clinical and MRI data were analysed, focusing on VRF influence.
RESULTS
At least one VRF was present in 74 (41.1%) HC and 179 (66.8%) patients with MS. Smoking was the most common VRF among patients with MS, affecting 53.0%. Unfortunately, HC and MS groups were not age-matched (p value corrected for false discovery rate [pFDR]=0.003), with HCs being younger. Nevertheless, compared to their relatives and HC groups, patients with MS exhibited greater lesion burden, global and regional brain atrophy (including
deep GM and cerebellum), reduced cortical thickness, spinal cord atrophy, and widespread microstructural WM damage. MS-VRF[+] showed significantly more disability and a higher prevalence of progressive MS forms compared to MS-VRF[-] (pFDR≤0.004). A significant interaction between VRF and disease status was observed on walking capacity, manual dexterity, deep GM volume, ACMA volume, and medial lemniscus MD (pFDR≤0.039), suggesting an additive negative effect of VRFs on motor performance and the structural integrity of specific SMN regions. These findings are consistent with prior studies investigating individual VRFs’ impact on CNS structures.7-10 In patients with MS, higher EDSS scores were linked to damage across nearly all SMN regions (pFDR≤0.029). Notably, only for the medial lemniscus, the authors found a significant interaction effect between VRFs and FA of this tract in explaining disability (β:1.931, p=0.042; Figure 1). This result confirms the role of VRFs in worsening MS disability, and it is consistent with previous evidence
showing that central pontine lesions are more strongly associated with ageing and vascular comorbidities, while peripheral lesions are more MS-specific.11
CONCLUSION
VRFs appear to exacerbate disability and motor performance, and contribute to structural and microstructural damage of specific SMN regions among patients with MS. Targeting modifiable VRFs may represent a promising strategy to mitigate their impact on MS progression.
References
1. Filippi M et al. Multiple sclerosis. Nat Rev Dis Primers. 2018;4(1):43.
2. Marrie RA et al. Vascular comorbidity is associated with more rapid disability progression in multiple sclerosis. Neurology. 2010;74(13):1041-7.
3. Fitzgerald KC et al. Vascular comorbidity is associated with lower brain volumes and lower neuroperformance in a large multiple sclerosis cohort. Mult Scler. 2021;27(12):1914-23.
4. Salter A et al. Comorbidity and disease activity in multiple sclerosis. JAMA Neurol. 2024;81(11):1170-7.
5. Hempel S et al. A systematic review of modifiable risk factors in the progression of multiple sclerosis. Mult Scler. 2017;23(4):525-33.
6. Albergoni M et al. Impact of vascular risk factors on motor performance and sensorimotor network integrity in multiple sclerosis patients. Abstract OPR-040. EAN Congress, 21-24 June, 2025.
7. Brundel M et al. Brain imaging in type 2 diabetes. Eur Neuropsychopharmacol. 2014;24(12):1967-81.
8. Hanlon CA et al. Lower subcortical gray matter volume in both younger smokers and established smokers relative to non-smokers. Addict Biol. 2016;21(1):185-95.
9. de Leeuw FE et al. Hypertension and cerebral white matter lesions in a prospective cohort study. Brain. 2002;125(Pt 4):765-72.
10. Medawar E, Witte AV. Impact of obesity and diet on brain structure and function: a gut-brain-body crosstalk. Proc Nutr Soc. 2022;81(4):306-16.
11. Filippi M et al. The ageing central nervous system in multiple sclerosis: the imaging perspective. Brain. 2024;147(11):3665-80.
The Brain Functional Neural Organisation of Apathy and Depression in Amyotrophic Lateral Sclerosis: A Connectome-Based Study
Authors: Veronica Castelnovo,1,2 Elisa Canu,1,2
Silvia Basaia,1 Edoardo Gioele Spinelli,1-3
Fabiola Freri,1 Paride Schito,2 Tommaso Russo,2
Yuri Falzone,2 Federico Verde,4,5 Silvia Torre,4 Barbara Poletti,4,6 Lucio Tremolizzo,7 Ildebrando Appollonio,7 Nicola Ticozzi,4,5 Vincenzo Silani,4,5 Massimo Filippi,1-3,8,9 *Federica Agosta1-3
1. Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
2. Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
3. Vita-Salute San Raffaele University, Milan, Italy
4. Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy
5. Department of Pathophysiology and Transplantation, “Dino Ferrari” Center, Università degli Studi di Milano, Italy
6. Department of Oncology and HematoOncology, Università degli Studi di Milano, Italy
7. Neurology Unit, “San Gerardo” Hospital and University of Milano-Bicocca, Monza, Italy
8. Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
9. Neurophysiology Service, IRCCS San Raffaele Scientific Institute, Milan, Italy
*Correspondence to agosta.federica@hsr.it
Disclosure: Canu and Basaia have received research support for the present manuscript from the Italian Ministry of Health (IMH). Verde is an Associate Editor for the Journal of Alzheimer’s Disease. Poletti has received compensation from Liquidweb S.r.l.; and is an Associate Editor for Frontiers in Neuroscience. Silani has received compensation from AveXis (now acquired by Novartis), Cytokinetics, Italfarmaco, Liquidweb S.r.l., Novartis Pharma AG, Amylyx Pharmaceuticals, Biogen, and Zambon Biotech SA; support from IMH, AriSLA, and E-Rare Joint Transnational Call (JTC); and is on the Editorial Board for ALS/FTD, European Neurology, American Journal of Neurodegenerative Diseases (AJND), Frontiers in Neurology, and Exploration of Neuroprotective Therapy.
This study received support from the European Research Council (ERC; StG-2016_714388_NeuroTRACK) and Next Generation EU, in the context of the National Recovery and Resilience Plan, Investment PE8 - Project Age-It: “Ageing Well in an Ageing Society.” Agosta has received speaker
honoraria from Biogen Idec, Roche, Eli Lilly, and GE Healthcare; and research support from IMH, Italian Ministry of University and Research (IMUR), AriSLA, ERC, EU Joint ProgrammeNeurodegenerative Disease Research (JPND), and Foundation Research on AD (France). Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, IMH, IMUR, and Fondazione Italiana Sclerosi Multipla; compensation from Alexion, Almirall, Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi Takeda, and TEVA; payment for speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA; payment for scientific direction of events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, and Sanofi-Genzyme; serves on Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, and Takeda; is the Editor-in-Chief of the Journal of Neurology; and is an Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology. The other authors have declared no conflicts of interest.
Apathy and depression are the most prevalent neuropsychiatric symptoms in amyotrophic lateral sclerosis (ALS).1-3 Although insufficiently investigated, their distinction holds important clinical relevance for the accurate diagnosis of ALS with behavioural impairment,4 and for patients’ prognosis and management.2 In the present study, the authors aimed to assess both apathy and depressive symptoms in patients with ALS, and whether they have similar or different functional neural correlates.
METHODS
Using graph analysis and connectomics, global and lobar nodal properties, as well as regional functional brain connectivity, were assessed in patients with ALS without apathy/depression (ALSn; n=42), with apathy and without depression (ALSa; n=14), with depressive symptoms and without apathy (ALSd; n=20), and those with both apathy and depressive symptoms (ALSad; n=6), as well as 46 healthy controls. Correlations between brain functional properties, apathy, and depressive symptoms were performed in all patients.
RESULTS
Depressive symptoms were related with reduced path length within the bilateral basal ganglia (BG) network, while apathy was related with increased path length, decreased nodal strength, and local efficiency within the left BG network. Patients in the ALSa group showed altered functional nodal properties within the BG network compared to the ALSn and ALSd groups. Compared to healthy controls and all patients who were non-apathetic (ALSn and ALSd), all patients who were apathetic (ALSa and ALSad) exhibited altered functional nodal properties within parietal, occipital, and frontal networks. Patients who were non-apathetic showed
relatively preserved functional nodal properties in the BG network compared to those who were apathetic.
CONCLUSION
The author’s findings indicate differences in brain functional neural organisation associated with apathy and depression, underscoring the importance of distinguishing these symptoms in ALS and highlighting the need for targeted interventions.5
References
1. Abrahams S. Neuropsychological impairment in amyotrophic lateral sclerosis-frontotemporal spectrum disorder. Nat Rev Neurol. 2023;19(11):655-67.
2. Kutlubaev MA et al. Apathy in amyotrophic lateral sclerosis: systematic review and meta-analysis of frequency, correlates, and outcomes. Amyotroph Lateral Scler Frontotemporal Degener. 2023;24 (1-2):14-23.
3. Jellinger KA. Understanding depression with amyotrophic lateral sclerosis: a short assessment of facts and perceptions. J Neural Transm (Vienna) 2024;131(2):107-15.
5. Castelnovo V. The brain functional neural organization of apathy and depression in ALS: a connectome-based study. Oral Presentation OPR-006. EAN Congress, 21-24 June, 2025.
Congress Interviews
In these exclusive interviews, Irena Rektorová, European Academy of Neurology (EAN) Programme Committee Chair; Antonio Toscano, EAN Secretary General; and Jana Midelfart-Hoff, EAN Treasurer, discuss the EAN’s evolving priorities. They highlight the 2025 Congress theme “Neurology within society,” the importance of public awareness, cross-society collaboration, brain health, and how EAN’s leadership is fostering scientific advances, inclusivity, and educational outreach across Europe.
Irena Rektorová
Professor of Neurology and Head of the Movement Disorders Centre, Department of Neurology, St. Anne’s University Hospital; Coordinator of the Brain and Mind Research Programme, CEITEC, Masaryk University, Brno, Czechia; Chair of the Programme Committee, European Academy of Neurology (EAN)
Next year’s Congress has the overarching theme of 'Brains, Bytes & Beyond: Tech in Neurology'
Q1 The overarching theme for the European Academy of Neurology (EAN) Congress 2025 is "Neurology within society." What inspired the Programme Committee to select this theme?
The overarching theme was selected 2 years prior to the Congress, so I was not directly involved, as I was the chair of the Education Committee at that time. Instead, the team that decided on this topic did so in 2023. I have been involved in the Programme for next year’s Congress, which has the overarching theme of 'Brains, Bytes & Beyond: Tech in Neurology'. All the speakers have already been invited, and they've accepted the invitations. The reason for choosing the theme 2 years in advance is to ensure that we can get all the right speakers, and to allow enough time for the scientific panels to make proposals for the programme. The panel members should know what the overarching theme is and what is already planned, so that they do not overlap. Therefore,
we have the theme chosen for next year, and the full scientific and educational programme will be chosen by the Programme Committee members at the beginning of September from all the proposals.
Q2 In addition to AI, what innovations do you anticipate will be most prominent at EAN 2026?
We also have, for example, robots in neurology, such as for robotic surgery, as well as brain-machine interface. These are other topics that will be involved, but we will have workshops that are really focused on AI in various fields, such as in the outpatient clinic and in the hospital neurology department.
Q3 When developing the Programme for next year's Congress, what have been your main priorities?
We start from the proposals that we grade. This year, for the scientific part, we received around
180 proposals, from which we had to choose 11 symposia and 15 focused workshops. This is a hard choice, and a very hard job. We always want to make sure that we cover what we call the ‘big seven’ topics: stroke, movement disorders, dementia, neuromuscular and peripheral nerves, headache, multiple sclerosis, and epilepsy. We always want to have something in the programme on these topics. Then we try to be more creative and up to date. For example, this year it's neurorehabilitation during wars. This joint symposium targets the current situation and challenges regarding neurorehabilitation across Europe both inside and outside war zones. Experts in the fields discuss medical and patients’ perspectives, as well as the responsibilities of health policymakers.
Moreover, this year's Congress was enriched by two new session blocks. The first was breakthroughs in neurology over the last year, which focused on novel treatments presented by scientists and not pharma representatives. That went very well and was very well attended. The second new session type that we included was autogenic training, with both a lecture and real training.
The EAN President, Elena Moro, also introduced a new named lecture for the Presidential Symposium: the Anita Harding Award Lecture, to highlight the outstanding contributions of female neurologists/ neuroscientists. The 2025 awardee was Catherine Lubetzki, Pierre and Marie Curie University, Paris, France.
Then there is the educational part of the Congress, which is chosen beforehand by the teaching course subcommittee (which is part of the Education Committee), and this consists of various formats, such as teaching courses, interactive sessions, hands-on courses, and case-based workshops. The educational portion and the scientific portion each make up about half of the programme. We also schedule various special sessions with partner societies: TV shows, the Brain Challenge competition, Coffee with You, Public Brain Health Day, and much more.
Q4
There seems to be a strong presence of various societies at this year’s Congress. Is fostering broad participation from national and specialist societies a key priority for next year as well?
It definitely is. EAN has 48 national societies, and members of these societies are automatically Associate Members of EAN. They have, for example, free access to some parts of the EAN campus, they can participate as institutional members in the work of the scientific and coordinating panels, etc. Alternatively, if you want to become a Full Individual or Corresponding Member, or Resident and Research Member (RRFS), you have to pay the fee. There are some more things that become accessible, and there are more opportunities to work within the EAN task forces, committees, or panels. There are other membership possibilities, such as Fellows of Neurology, and especially Honorary Members, who deserve special recognition.
EAN further collaborates with many specialised societies, such as the European Headache Federation, the Movement Disorders Society – European section, the European Stroke Organisation, and the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). We suggest joint proposals for congress sessions from our various scientific and coordinating panels, as we cannot accommodate proposals from every single panel. These joint proposals can also be done with partner societies.
Q5 Your work has also looked at the positive impact of movement and dance on cognitive abilities. Can you tell us more about this?
That's our collaboration with the Faculty of Sports Studies at Masaryk University in Brno, Czechia. We included aged volunteers, as well as patients with mild cognitive impairment (MCI). It was done in small mixed groups. We know through experience that people with MCI cannot, for example, learn new languages or how to work with some apps, but they can learn new movements.
This dancing treatment did not include dancing in pairs because our study included more women than men. There was Hora dancing, as well as various other dances originating from Africa. In every single training session, the dance changed a little bit, so once the participants learned the sequences, it changed, with different music as well. The participants practised three times per week for half a year.
Altogether, 120 participants were randomised into two groups. It was a group of 60 people in the intermixed groups who trained, and 60 who went about life as usual. We scanned their brains, performed a very detailed cognitive examination, examined physical fitness, and examined mood. All of these were measured before and after the study. We had very interesting results. For example, even in these age groups, and including patients with MCI, there was enlargement of some cortices that are involved in learning novel movements. The cortical thickness of those areas increased. The connectivity, which we assessed with functional MRI, also increased between regions that are implicated in movement and cognitive functions, such as the fronto-parietal control network and the cerebellum. The increase in connections between these networks correlated with some cognitive outcomes, especially with enhanced attention.
Dance is a very joyful activity where you have to learn complex things, but the music, rhythm, and social contact that people get when they meet on a regular basis help. This complex, creative activity likely helps more than just running or cycling, although I don’t want to say that they’re not healthy.
EAN has 48 national societies, and members of these societies are automatically Associate Members of EAN
Director of Stroke Unit, Department of Clinical and Experimental Medicine, University of Messina, Italy; Secretary General, European Academy of Neurology (EAN)
Try and make people more aware of the impact of what they are eating and what they are doing
As the newly elected Secretary General, what are your top priorities for the European Academy of Neurology (EAN) in the coming years?
The EAN is looking to the future, and what we are mainly trying to promote is the Brain Health Mission. This is a very important campaign which aims to increase awareness of neurological disorders for the population, all institutions, and medical doctors, because neurological disorders are still a little bit obscure for some people. It's important to try to explain the pathophysiology of neurological disorders and how we could prevent them. Thus, one of the main pillars of this campaign is to try and make people more aware of the impact
of what they are eating and what they are doing. This is important from infancy or adolescence, especially avoiding certain activities or specific behaviours that can increase the risk of neurological disorders.
Additionally, there are a large number of neurological disorders that need to be better investigated. We know that one of the most important targets is to try to develop new drugs, especially for rare disorders. Within Europe, there are some areas that are more able and capable of this, whereas there are others that are less ready to start a campaign for new drugs. However, it is something that the EAN is strictly adhering to, because homogenising neurological knowledge across Europe is an important mission.
Q2
What new initiatives is the EAN pursuing to foster collaboration across national societies and neurological subspecialties?
There are several initiatives that are targeted to try and bridge the gap between the EAN and the national neurological societies. We have at least two forums with them per year to update and discuss what could be the best initiative to improve the neurological situation in every European country. As well as the national societies, which form a large group, there are several other entities that are linked to the EAN, including corresponding societies from Africa or Asia, task forces for specific topics, and, more specifically, all the EAN panels that are aimed to
Antonio Toscano
improve the knowledge and practice of different neurological subspecialties. This is an ongoing activity that lasts all year, with several contacts and possibilities to interact with expert colleagues interested in specific subspecialties such as headache, muscle disorders, movement disorders, cerebrovascular disorders, dementia, multiple sclerosis, and so on. This is a great opportunity to exchange ideas and experiences in the neurological fields with a continuous update.
Q3 Are there any special collaborations or joint sessions at this year’s congress that you would like to highlight?
Yes, the EAN tries to favour collaboration among different scientific panels, because there are some common problems within all neurological disorders, and the collaboration between different panels on the same topic provides a broader view on the problems to be solved coming from a specific disorder. We are now also trying to favour collaboration between the EAN and other partner societies. This kind of interaction between scientific societies is relevant to trying to improve the general picture of these disorders.
Q4 For you personally, what has been your favourite session?
It's really difficult, but I think I’d say some of the interesting sessions about headache, cerebrovascular disorders, and neuromuscular disorders, especially in regard to gene therapy. And of course, we have to consider that AI use is now rapidly expanding and being used by every neurologist. Not all of us are aware of the possibilities and the risks of using
AI, so there were some sessions on this that were really interesting and important from an educational point of view.
Q5
With your extensive background in neurodegenerative and muscular disorders, which recent advances in these areas have been highlighted during this year’s congress?
For me, as the head of the stroke unit at my institution, there were some very interesting sessions on cerebrovascular disorders. I also have a keen interest and perform research in muscle disorders; so, on the one hand, for cerebrovascular disorders, I would like to outline that there were very relevant sessions, especially for stroke mimics, which is always a problem for neurologists. On the other hand, for muscle disorders, there was an important session covering the latest therapeutic news for myasthenia, muscle spinal atrophy, Duchenne muscular dystrophy, and Pompe Disease, which has been really well studied even more recently. There were also some promising trials for myotonic dystrophy. With all of this in mind, I suppose within 1–3 years we will definitely have new drugs.
Q6
What do you see as the key takeaways or messages from this year’s congress that you hope participants will bring back to their own practice or research?
I think the first one is to go back and remember the aim of the Brain Health Mission. It's very important to make the population aware about what they have to do and what they have to avoid, in order to not facilitate the onset of neurological disorders. This is, I think, a very important point.
Another point is regarding AI. This is something that has to be applied carefully, so that we don't think AI can solve all problems, but we apply it in a reasonable manner. Considering the more day-to-day problems, I would also outline its use for every kind of disorder. The important thing is to refer patients to the right centres, because we need an early diagnosis more and more. We now have several therapeutic tools to tackle different kinds of disorders, such as stroke, multiple sclerosis, neuromuscular disorders, Parkinson's disease, headache, and hopefully dementia in a few years; and what is really relevant, is to try to condense our efforts to make the diagnosis as soon as possible. When you have degenerated tissue, you cannot do much if you try to intercept at this point; if you are able to intercept the possible damage in these kinds of disorders earlier, you can treat them with more targeted therapy sooner, which could lead to better outcomes for patients.
It is well known that there is a group of European countries that are a little bit ahead compared to others, and although every country has its own excellence centre, some countries have 10. This is something that the EAN tries to homogenise, to improve the level of expertise in all countries. Alternatively, if this is not possible, there is a large opportunity to collaborate with different national societies and national neurological groups. This is something that is really important for the EAN, and one of the most important targets we want to reach.
Jana Midelfart-Hoff
Professor of Neurology, Head of Section and Assistant County Medical Officer, County Governor of Vestland, Bergen, Norway; Professor, VID Specialized University, Bergen, Norway; President, Norwegian Neurological Association; Treasurer, European Academy of Neurology (EAN)
Q1Having completed your first year as European Academy of Neurology (EAN) Treasurer, what have been the most rewarding and challenging aspects of the role so far?
The most rewarding aspect is definitely the people you meet on the board. There are so many enthusiastic and extremely competent colleagues. It has been a pleasure to work with them all as well as with the President. Under strong leadership, the administration is doing an excellent job. It is also very interesting to see the administration as a sort of miniEurope, with people coming from all over the continent, having different backgrounds and speaking different languages. I think this is also a great asset to the organisation.
As for the challenging aspects, these are mainly related to the current global landscape. We have the war going on in Ukraine, which of course also influences the EAN. We have to support our colleagues there in their truly tragic working conditions. We are also witnessing other conflicts and an increasingly unstable global situation. As a treasurer, I'm happy to say that the financial situation of the EAN is good. That said, I’m pleased to report that the EAN remains in a strong financial position. We have managed through the storms, but
We're also developing initiatives targeted towards young neurologists all over Europe
we must be very careful in how we invest our money so that we can reinvest it back into member activities.
Q2
What new strategies is EAN implementing to foster stronger scientific and social connections among European neurological societies?
We have a much closer collaboration with national neurological societies compared to previous years. It has been a continuous effort, though, by the last president. I, myself, was until recently the president of the Norwegian Neurological Association, which, of course, gives me background experience. I think that has been extremely useful, and that's what I can contribute to a very competent board. We are now hosting regular network meetings for national societies and taking a more proactive role in supporting them; for example, by writing letters and ensuring they feel integrated into the broader EAN network. We're also developing initiatives targeted towards young neurologists all over Europe, and we're beginning to extend our efforts to include mid-career neurologists as well. That's important because we need to recruit, but we also need to retain.
What I find very rewarding is working with the podcasts. At the moment, we have a splendid podcast that is more directed towards physicians and the neurology community. We are now launching two additional podcast series: one directed at the general public, and another supporting the EAN Brain Health Mission. The first pilot episode of the latter is
being released, and we plan to follow it with 12 episodes. Each will focus on a key topic, like diet or smoking, and feature expert guests from across Europe. We are going to speak in a language that is, I hope, easier to understand and more engaging for the public.
Q3
If you had to pick, which out of the 12 episodes do you think covers the most important topic for raising public awareness of neurological health?
It's hard to choose just one, but I am very enthusiastic about two episodes: physical activity and social activity. These two also intertwine because if we get people to be physically active, whether in dancing classes or a fitness studio, they will also, almost automatically, become socially engaged. There are other factors that are perhaps more obvious. For example, wearing a hearing aid significantly reduces the risk of dementia, as it’s linked to being socially active. If you can’t hear or see well, then you're less likely to participate in social activities. Thus, the episodes are loosely based on the targets of the Lancet Commission that they found as risk factors for dementia.
Q4
You are actively involved in the EAN Brain Health Mission and public education efforts. How is EAN working to enhance public understanding of brain health?
One important initiative is our podcast series, and then, of course, at this Congress, we also had the Public Health Day, which welcomed members of the local community in Helsinki, Finland. Attendees had the opportunity to hear from experts and representatives of patient organisations, who spoke about different neurological diseases
and aspects of brain health. The event was very well attended. We are going to repeat this initiative at our next Congress in Switzerland. What made it especially meaningful was the local engagement, Finnish healthcare professionals and patients spoke in their native language, with live translation provided. I believe these two initiatives are among the most important activities EAN is engaged in.
In addition, we are involved in the European Brain Health Council and participate in EUfunded projects. We have a highly skilled communications team working to promote brain health across various platforms. As board members, we are also encouraged, and do our best, to take part in events and initiatives that promote brain health. Thus, in addition to being an organisation dedicated to science and professional networking for European neurologists, the EAN has also evolved into a true champion of brain health.
Q5
Can you share details about any upcoming EAN initiatives or strategic priorities that you are particularly excited about, and how you see them shaping the future of European neurology in the coming years?
We have adopted a more proactive approach towards engaging the public through initiatives such as the EAN podcast and the public health meetings held at our congresses. I also really enjoy seeing how our highly competent colleagues are developing the EAN Campus as a tool for learning. I think that's very important, as it provides access to an incredible breadth of knowledge. Another area I find especially valuable is the growing
emphasis on physician wellbeing. I would particularly like to highlight the young neurologists who have taken an active role in this area. They have even created a podcast focused on physician wellbeing, involving not only neurologists but also psychiatrists. This interdisciplinary approach is crucial, as we need to think in multiple directions at once, advancing scientific knowledge, improving patient care, and ensuring that physicians can thrive in their roles. Ultimately, we need to ensure that our message reaches the public. Technology can enable tremendous progress, and our passion for science is strong, but none of it will matter if we don’t effectively communicate our message.
Interdisciplinary approach is crucial, as we need to think in multiple directions at once
Through A Patient’s Lens: Chronic Inflammatory Demyelinating
Polyneuropathy Uncovered
Interviewee:
Jean-Philippe Plançon1
1. European Patients Organization for Dysimmune & Inflammatory Neuropathies (EPODIN), Le Pouliguen, France
Support: The publication of this article was funded by argenx.
Disclosure: Plançon has declared no conflicts of interest.
Acknowledgements: Writing assistance was provided by Helen Boreham, HB Medical (UK) Ltd, Wetherby, UK.
Disclaimer: The views and opinions expressed in the article are those of the individual speaker and do not necessarily reflect those of argenx or EMJ. Data (references 1–6) will be made available by argenx upon request.
Keywords: Burden, care, chronic inflammatory demyelinating polyneuropathy (CIDP), journey, quality of life.
In this patient-focused interview, EMJ spoke to Jean-Philippe Plançon, a patient with chronic inflammatory demyelinating polyneuropathy (CIDP) and the current President of the European Patients Organization for Dysimmune & Inflammatory Neuropathies (EPODIN). Plançon has lived with CIDP for 25 years and, in his role as patient advocate, acts as a voice for patients with CIDP and other immune-mediated peripheral neuropathies at the European level.
INTRODUCTION
CIDP is a rare, progressive, immunemediated neurological disorder characterised by limb weakness. It can lead to functional disability or sensory deficits, with patients often reporting problems with mobility, balance, fatigue, and pain. As a result, CIDP is associated with a substantial clinical burden, impacting patients’ daily activities, work productivity, and healthrelated quality of life.1-5
JOURNEY TO DIAGNOSIS
Plançon described how he was first diagnosed with CIDP at 30 years old while working as a registered nurse in the ICU: “The initial symptom was that I lost the ability to use my left arm and I’m left-handed.” A lumbar puncture proved negative, and at that point in time “no further attempt was made to dig deep into the diagnosis, so life restarted more or less normally,” he explained.
PHARMA
PARTNERSHIP
However, several months later, Plançon began experiencing paraesthesia and was referred to a neurologist who suspected some type of peripheral neuropathy. “That was the entry for me into the disease, and [a] few months after I had the precise diagnosis of CIDP,” he explained. “However, even as a registered nurse, I didn’t understand. If a doctor says you have breast or prostate cancer, it’s terrible of course, but it generates some images in your head, whereas I had nothing to work with.”
Describing his emotional response to the diagnosis, Plançon confessed that: “The beginning of the disease was difficult. I struggled to accept I had CIDP, and felt angry sometimes. This is a process akin to losing someone you love. I loved the 30-year-old young man that I was, and I had to learn to lose this image.”
In terms of the diagnostic journey, Plançon described himself as “pretty lucky” to have received a relatively quick diagnosis. “It was evident from the fact that I couldn’t feel my fingers that it was something neurological, so it was a more typical presentation,” he explained. “If you consider the first acute symptoms to the diagnosis itself, it probably took 2 years.”
Real-world evidence shows that CIDP is often associated with an extended time to diagnosis, with over one-third of patients initially misdiagnosed.2 “Mine is not the worst story that I’ve heard,” Plançon confirmed. “For other patients, the diagnostic journey can be much longer, it can take 10 or even 15 years.”
IMPACTS ON DAILY LIFE AND WORK
“As a nurse, I needed my hands for very technical procedures in the ICU, so I decided to be proactive and change my work, becoming a healthcare manager and, after that, a teacher in a high school. The CIDP pushed me to change; I had to rethink my entire life,” Plançon explained.
He confirmed that, for many patients with CIDP, the diagnosis leads to a decrease in productivity, and this depends on
the severity and burden of the disease, availability/access to therapies, and the support and care provided by the health and social care system. “Sometimes you have to step back to be treated because you’re tired or because you’re too ill to work,” he noted. This impact on productivity is also reflected in real-world surveys, where CIDP has been shown to substantially affect patients’ employment, often hindering or completely preventing them from working.5 Many patients with CIDP are unemployed, retired, on long-term sick leave, or are working part time, with 53% citing CIDP as the key reason (Figure 1).2
Fortunately, Plançon responded positively to treatment with polyvalent immunoglobulin therapy, so his physical function has been more or less preserved. “I still have now some persistent symptoms, mainly weakness in my left hand, which can lead to difficulty doing usual daily things like writing, shaving, and doing up buttons,” he acknowledged. He also described some gait issues and impaired balance, and noted that “it’s always a little bit painful”. Plançon’s experience resonates with the wider CIDP community, where around half of all patients reported experiencing moderate-to-severe symptoms, despite many receiving treatment (Figure 2).2 As a consequence, 47% of patients rely on one or more mobility aids, most commonly canes or walking sticks.2
Plançon’s wife has been his main pillar of support in the 20 years since diagnosis, and he confirmed that CIDP can place a burden on both caregivers and wider family members. Real-world surveys have shown that over a quarter of patients with CIDP require assistance from a caregiver, and in many cases, this can have a reciprocal impact on the latter’s ability to work (Figure 3).2,4 Plançon explained that this impact on caregivers depends on the severity of the CIDP and the patient’s level of disability, as well as their overall ability to cope with the disease. He pointed out: “Someone in a wheelchair has to cope differently than someone like me on his own two feet and generally autonomous, so the burden is less.”
53% due to CIDP (n=75)
EMOTIONAL ASPECTS
In terms of the impact of CIDP on health and emotional well-being, Plançon said this was most pronounced at the beginning of the disease. “One of the very difficult things with the CIDP is you can’t predict the evolution of the disease. My wife was pregnant, I was 30, and I didn’t know what would happen to me nor my baby: if I was going to die, be in a wheelchair, [or] whether my baby was going to inherit the same disease. It was very complicated at that moment. In reality, to my knowledge CIDP has not been shown to have any impact on patient mortality, nor is it an inherited condition.”6
Surveys have shown that up to 24% of patients with CIDP are dealing with concomitant depression and anxiety, and that these psychological comorbidities are closely linked to symptom severity.2 Plançon added that how patients are affected psychologically by CIDP is very individualised. “Of course, there is a huge impact on your life,” Plançon acknowledged, “but it also depends on patient factors such as age, if they live alone, have family, or are in a lot of pain.”
After his diagnosis, Plançon described how, “psychologically speaking, I went from being
Working full time
Working part time
Retired
Unemployed
Long term sick leave
Homemaker
a young man who was very sporty to a person with a chronic disease. What I didn’t realise at first was the ‘C’ of CIDP. It took a long time to really understand that the chronic nature of the disease meant I would have to live with it my entire life.”
SUPPORT AND UNMET NEEDS
Continuing on this subject, Plançon said he had received very little ongoing support from healthcare professionals (HCP) during his CIDP journey, and attributed this mainly to short consultation times and infrequent visits. Now, for example, he only sees a neurologist once every year for routine tests and followup. “I don’t mean there is no support, I’m just not sure it’s the role of a neurologist to provide it,” he clarified. “My expectation is for a neurologist to be an expert in the disease. Of course, I expect them to understand my needs, but the main thing is to be able to refer patients to extra support in the form, for example, of psychologists and physiotherapists as required.”
Some analysis of medical and non-medical resources required by patients with CIDP showed that the mean number of HCP types involved in disease management was only 2.4. Patients most often saw a
Figure 1: Employment status (% of patients).
2: Top five symptoms (% of patients).3
Peripheral numbness
Peripheral tingling
Distal muscle weakness
Areflexia (loss of deep tendon reflexes)
Proximal muscle weakness
Figure 3: The caregiver burden in chronic inflammatory demyelinating polyneuropathy.3
...of patients required help from a caregiver (n=197) 25%
neurologist (81%), followed by a physical therapist (41%), and a family doctor/ general practitioner (38%).4 “The problem is we are talking here about a rare disease. This means there is little knowledge of the disease and few HCPs with professional expertise in CIDP,” Plançon noted.
Plançon stressed that there are “many unmet needs” within existing care pathways for CIDP. Particularly at the time of
Of whom... received help from a partner or spouse (n=49) 86%
4.1 (4.6)
Total mean (SD) hours of care/help received per day (n=40)
diagnosis, he emphasised the importance of ensuring patients fully understand the disease and its management, as unanswered questions can lead to anxiety. Ideally, additional support and education should be provided by a dedicated nurse or team, and follow-up should be with the same neurologist in order for “patients to build a relationship with their clinician.”
Figure
EDUCATING PATIENTS AND RAISING AWARENESS
Plançon stressed that the most important step for those newly diagnosed with CIDP is to engage with their local patient organisation, or other local patient groups, who can support them in understanding and accepting their diagnosis. “I’ve heard the same questions for 20 years: what will happen tomorrow? How is CIDP going to impact my daily life? Is there any treatment able to cure me?”
“These are complex questions with no clear answers,” he continued, “so the best way we can support patients is to outline the state of play in CIDP: this is what we know, and this is what we don’t know. This will avoid patients seeking information from inaccurate sources or looking for a ‘magic pill’ to treat the condition.”
Moving forward, Plançon highlighted the importance of increasing understanding and raising awareness of CIDP, because the
References
1. Paci S et al. CIDP patients’ health-related quality of life, daily activities and fatigue: results from a multinational real-world survey. Poster P494. PNS Annual Meeting, 17-20 May, 2025.
2. Paci S et al. Burden of illness and unmet need among patients with CIDP: results from a real-world survey. Abstract D003. RE(ACT) Congress, 5-7 March, 2025.
EU-EFG-25-00032 | July 2025
“invisible symptoms” mean the condition is often overlooked. “If we met tomorrow, you would just see a normal man,” he pointed out. The recent ‘Dare to Care’ webinar series developed by argenx (Amsterdam, the Netherlands) is one such measure, designed to help bring the patients’ perspective into focus and raise awareness among HCPs of the impact and everyday reality of living with CIDP.7 This platform brings together patients, caregivers, and experts to share experiences, explore real-world data, and foster meaningful discussions around CIDP.7
HOPES FOR THE FUTURE
Looking ahead, Plançon highlighted the need for more investment in fundamental CIDP research in the hope that this will lead to new treatment options for patients. He also emphasised the need to adopt a more integrative view of health in patients with CIDP. “It would be much more powerful if we were considered in a broader, integrative, and more holistic way,” Plançon concluded.
3. Paci S et al. CIDP patients’ journey to diagnosis: results from a real-world multinational survey. Poster EPR-096. EAN Congress, 21-24 June, 2025.
4. Paci S et al. Healthcare resource utilization and caregiver burden in CIDP: results from a real-world multinational survey. Poster EPR-095. EAN Congress, 21-24 June, 2025.
5. Paci S et al. The impact of CIDP on patients’ employment: results from a realworld multinational survey. Poster EPR092. EAN Congress, 21-24 June, 2025.
6. Querol L et al. Systematic literature review of burden of illness in chronic inflammatory demyelinating polyneuropathy (CIDP). J Neurol. 2020;268(10):3706-16.
7. argenx. Dare to Care webinar“Balancing Energy, Work & Productivity with Autoimmune Diseases.” Available at: https://argenx.com/events/dare-tocare Last accessed 26 Jun 2025.
Interviews
EMJ is honoured to feature three pioneering figures in neurology: Astri Arnesen, Lukas Rasulic, and Christina Dalla. Arnesen, President of the European Huntington Association (EHA), discusses international collaboration and patient engagement in Huntington’s care. A pioneer in the field, Rasulic explores new advances in peripheral nerve repair and multidisciplinary approaches to complex nerve injuries. Meanwhile, Dalla, an expert in neuropsychopharmacology and sex differences in neuropsychiatric disorders, shares her most impactful findings in depression and anxiety, alongside the emerging potential of psychedelic treatments in mental health.
Astri Arnesen
President and CEO, European Federation of Neurological Associations (EFNA); President, European Huntington Association (EHA)
How did your family’s experience with Huntington’s disease inspire your commitment to patient advocacy, and in what specific ways has this personal journey influenced your leadership and vision within both European Federation of Neurological Associations (EFNA) and European Huntington Association (EHA)?
At the
time,
Huntington’s was a rare disease, and it still is by definition, and we felt really alone and isolated
It all began when my mother was diagnosed with Huntington's disease. At the time, Huntington’s was a rare disease, and it still is by definition, and we felt really alone and isolated. Fortunately, just a few years earlier, the Norwegian Association for Huntington Disease had been established, and our doctor informed us about it. This was before the days of the internet, so we were put in touch directly with the association’s president, who kindly met with us. Through her, we also connected with other families affected by the disease. That experience was
a lifeline for us. Meeting others who were going through the same challenges made us realise we were not alone. We could exchange our concerns, questions, and feelings we had around this situation. For me, it was a helpful and supportive moment. From that point on, I became actively involved. Over time, I took on more responsibilities and eventually became the president of the Norwegian Association for Huntington Disease. My involvement then extended to the European space within the same organisation. It was really a personal experience of how helpful it was to have peer-to-peer engagement in the community. This personal journey has shaped my approach to advocacy.
Q2
Having been a patient advocate since the mid-1980s, you have witnessed significant progress in the field. What are the most persistent barriers patient advocacy groups
still face today in supporting individuals and families affected by neurological disorders?
There have definitely been positive changes over the years. The rise of the internet gives us more opportunities to reach people and share information. However, navigating that vast amount of information can still be overwhelming. Many individuals still struggle to find the right resources when they need them. A sense of isolation remains common, and not knowing where to turn for support is still something many people continue to experience. However, we are definitely seeing progress. Awareness is growing and stigma has lessened, but it is by no means erased. Thus, we are moving towards a better, improved situation: there are more experts out there and more opportunities to connect with others, but there are definitely still a lot of hurdles. The volume of information continues to be a barrier. That's why we are trying
to offer opportunities for people to connect and access what they need. The personal and individual needs will never disappear, so being able to arrange in-person events is still bringing a lot of value.
In terms of persistent hurdles, there are many. One of the biggest is the constraints on healthcare systems. The needs of people with Huntington's disease and other neurodegenerative diseases are often complex and go unmet. It's really difficult to have the healthcare system realise this. That's the first thing: to recognise where the needs are, and then to have the resources to support what’s needed.
Shame and stigma continue to be major issues within our community, not only because of Huntington's itself, but also because of its hereditary nature. Many people feel so much guilt in terms of bringing the disease onto future generations. There’s also the feeling that many people see
us as somehow partly to blame for having this disease in our families. That emotional burden can be the biggest hurdle of all.
Q3
EFNA’s recent 2025 General Assembly brought together member organisations from across Europe. What were the key initiatives of this meeting?
Each year, we bring EFNA members together from the 22 disease-specific patient organisations under our umbrella, including those focused on conditions like Huntington's, Parkinson’s, multiple sclerosis, dystonia, ataxia, pain, and headache. It’s empowering to see so many groups come together. I always leave the meeting feeling energised by the progress being made across these diverse areas. While the change is going slowly, we are moving in the right direction, and that’s really encouraging. And then for us as a group, we can see where we can harness the best synergies in
what we do, and the topics that really unite our voices to be clear and stand together in advocacy, in terms of getting neurology on the healthcare agenda. There’s no doubt that neurological disorders have been vastly under-prioritised, which is difficult to understand given the prevalence, complexity, and severity of these diseases. One of our key messages is that the decision-makers must recognise the urgent need to give neurological disease groups the higher priority they warrant. Another key focus is research. Very few of our diseases have disease-modifying therapies available. Although we are moving towards that, we really need to continue encouraging, supporting, and doing whatever we can to make that research happen.
Q4
And what was the highlight of the meeting for you?
The day after the General Assembly, we had a workshop on health literacy. Last summer, EFNA conducted a survey with nearly 5,000 respondents, and it highlighted several important things. One key finding was that people struggle to feel believed or understood by their doctor. They also found it difficult to clearly explain the symptoms they were experiencing and to describe what was happening in their bodies. This is important because it contributes to delays in receiving an accurate diagnosis. For instance, it can take years for people to be properly diagnosed. Increasing health literacy could help address this, not just for patients and their families but also for doctors or clinicians. Clinicians also need to be able to communicate more efficiently. At the workshop in Brussels, Belgium, this came through really clearly. Clinicians are conveying a lot
of information, but patients can struggle to absorb it, especially due to the medical terminology used. Once you've been diagnosed, you have enough to process just from that alone, and you may not even hear the rest of the information being shared.
Q5
Looking ahead to the October session, what do you hope to achieve by integrating clinicians’ perspectives through collaboration with the European Academy of Neurology (EAN)?
The EAN is an important collaborative partner for us. As the big union representing neurologists, we really welcome that partnership on this health literacy project. At this year’s session in Brussels, the attendees were patient advocates and a few presenters from industry and others, but next time there will also be clinicians to provide their input and for us to have that discussion. I very much look forward to it. I know that Elena Moro, as the President of the EAN, has talked about the importance of health literacy. However, there are also aspects where clinicians themselves can benefit, by improving their communication skills and having a better dialogue with their patients.
Q6
The EHA recently launched Huntington Academy (HA), an e-learning platform dedicated to Huntington’s disease. What gaps in education or support does this platform aim to address?
Over the years, in different working groups I have been involved in, we have been discussing the idea of creating an online resource for family carers. Carers take on a lot of responsibility and duties, often feeling very isolated as they try
to navigate their role with little support. This need for accessible, targeted education has long been recognised within the community. The idea for EHA eventually took shape during discussions on another project, where we worked with partners in Belgium, Spain, and other countries. Some of these partners were familiar with the Erasmus+ programme and identified it as a potential funding opportunity. That's how the project began; we made this application to Erasmus+ and were thrilled to receive the grant, as it enabled us to allocate some resources. The project grew, and it would not have been possible, at the scale we have been able to deliver, without the generous contributions from our four partners. We are very proud of what we’ve achieved. It is a unique initiative, built on interviews with healthcare professionals, providers, and family carers. We drew from their experiences and their advice to others, and built this e-learning platform. This content includes nine modules, covering both basic information about Huntington's disease and specific areas about psychological support, oral care, and physiotherapy. Each module is designed to offer practical, accessible guidance. When we presented the platform to members of the HA organisations, their response was overwhelming, and this is a dream come true.
Q7
EFNA’s mission emphasises influencing policy, communicating with members, and building strategic alliances. Can you share examples of successful partnerships or advocacy efforts?
There are many, but I think I should mention the European Brain Council (EBC), where EFNA is a very active member.
Through this umbrella federation, EFNA collaborates closely with the clinical societies and other stakeholders to advocate for the prioritisation of neurology and brain health, as well as to promote research in these areas.
EFNA also runs an interest group in the EU parliament. In collaboration with members of the European parliament, we host two annual meetings, a tradition that has continued for around 10 years. Each meeting focuses on a topic relevant to current global or EU-level developments, providing an opportunity to influence policy and raise awareness among the decision-makers about the needs of those living with neurological disorders. This is a key initiative we’re proud to lead. I would also argue that our collaboration with the EAN and their brain health mission is particularly important, as it gives us more opportunities to reach the public with an unified message on crucial topics that need better understanding. One of the roles that the EHA is taking on is to act as a bridge between the research community and the general public. People often don't understand the scientific terminology, so we translate it into simple, accessible language. We aim to make scientific information more digestible, using accessible or even child-friendly terms where appropriate. We see this as an important role, and one we are proud to take on.
Q8 Looking ahead, what are your priorities for advancing this mission in the coming years?
There are several key priorities. First, we’re preparing for the upcoming European partnership on brain health, which will launch its programming in January 2026. This initiative aims to consolidate
various EU calls related to brain health under one umbrella. We’re optimistic about the synergies it can create across different fields and stakeholders, and we would definitely like to see succeed. A goal will be to improve the implementation of patient involvement in research, ensuring that patient organisations are seen as partners. Up to now, patient groups and patient representatives are often asked to provide input, but we are rarely compensated for this contribution. I'm not speaking for myself personally, but on behalf of all patient organisations. We cannot function sustainably without proper funding. We therefore need support to exist as a network, to coordinate efforts, to stay informed, and to provide relevant input. If the brain health partnership recognises this need and integrates patient organisations as eligible partners for project funding, it will mark real progress in embedding patient voices at the core of EU health research. I would also like to mention the new health technology assessment regulations that have been introduced at the EU level and are now starting to be implemented. Until now, everything has happened at the local, regional, or national level, but with this regulation, the aim is to conduct assessments at the European level, much like the system in place for the European Medicine Agency (EMA). Through EFNA, I'm actively involved in the health technology assessment stakeholder forum, which could serve as a tool, or programme, to increase patient involvement in these procedures. Hopefully, it can help build the infrastructure that allows us to consistently provide input to these different procedures and evaluations. We also hope this regulation helps
shorten the timeline from drug approval to actual patient access, and address the inequalities in access across Europe. If all countries within the EU can comply with this joint evaluation assessment, and streamline their own national processing, that would be an amazing progression to see over the next 10 years.
Each module is designed to offer practical, accessible guidance
Lukas Rasulic
Neurosurgeon, Full Professor at the Faculty of Medicine, University of Belgrade, Serbia; Head of the Department of Peripheral Nerve Surgery, Functional Neurosurgery and Pain Management Surgery, Clinic for Neurosurgery, University Clinical Centre of Serbia, Belgrade, Serbia; Secretary, European Association of Neurosurgical Societies (EANS)
As Head of the Department of Peripheral Nerve Surgery and a leading expert in this field, what do you consider the most significant recent advances in peripheral nerve repair and reconstruction, and how are these changing patient outcomes?
Recent advances in peripheral nerve repair and reconstruction are significantly enhancing patient outcomes. Key developments include the transition from simple nerve repair to promoting functional regeneration through a better understanding of the molecular environment necessary for nerve growth. Bioengineered nerve grafts, such as synthetic conduits and decellularised allografts, enable tailored repairs while reducing the morbidity associated with traditional autografts.
Regenerative approaches, utilising mesenchymal stem cells and Schwann-like cells within scaffolds, combined with localised growth factor delivery, are facilitating faster and more robust axonal regeneration. Furthermore, the incorporation of electrical stimulation, both intraoperatively and via implantable devices, has been shown to enhance reinnervation.
neuromas and aiding prosthetic integration.
These innovations collectively reduce recovery times and restore important sensory and motor functions, transforming the prognosis for patients who previously faced permanent disability. Ultimately, the convergence of bioengineering, neurobiology, and digital technology is redefining outcomes across various nerve injuries, enhancing both precision and recovery.
Q2
Your research and clinical work span both peripheral nerve surgery and functional neurosurgery. How do you integrate these specialties in complex cases, and what are the main challenges and opportunities at their intersection?
The integration of peripheral nerve surgery and functional neurosurgery is increasingly vital for managing complex cases, particularly involving neuropathic pain and motor deficits. These fields overlap when addressing issues like chronic pain or trauma recovery, where it is essential to both repair nerves and modulate how the brain interprets nerve signals.
Collaborative, multispecialty care is crucial in managing complex nerve injuries
Technological advancements like high-resolution imaging, tractography-enhanced MRI, and fluorescence-guided mapping have improved surgical precision in dissection and nerve localisation. Techniques such as targeted muscle reinnervation and regenerative peripheral nerve interfaces are now standard, particularly for preventing
Key challenges include determining the optimal timing for interventions, as nerve regeneration is time-sensitive, while neuromodulation often requires extended planning. Successful integration necessitates multidisciplinary collaboration and careful patient selection.
However, significant opportunities arise from this convergence. Techniques like nerve transfers and neuromodulation, including spinal cord or cortical stimulation, enable enhanced motor control and pain management. Moreover, innovations like brain-computer interfaces and bidirectional neuroprosthetics are closing the feedback loop between intent and movement, allowing for a more integrated and personalised approach to restoring function. This holistic strategy not only aims to reconstruct anatomy, but also to meaningfully improve functional restoration in terms of definitive patient outcomes.
Q3
How do you see the role of collaborative care, particularly integrating vascular, orthopaedic, and plastic surgery, evolving in the management of complex nerve injuries? What models or protocols have proven most effective in your experience?
Collaborative, multispecialty care is crucial in managing complex nerve injuries, especially those from high-energy trauma that
involve nerve, vascular, skeletal, and soft tissue damage. At the Department of Peripheral Nerve Surgery, Functional Neurosurgery and Pain Management of the Neurosurgery Clinic, University Clinical Center of Serbia, Belgrade, Serbia, we have established multidisciplinary teams that include vascular, orthopaedic, plastic, and peripheral nerve surgeons almost 35 years ago, enabling optimal intervention timing and coordination.
This structured approach often follows staged protocols that prioritise vascular repair, fracture stabilisation, soft tissue coverage, and nerve reconstruction, when possible, in one surgical stage, within a critical regeneration window. Joint case conferences and shared electronic platforms facilitate communication and streamline care, promoting a unified focus on functional recovery.
Effective collaboration, such as simultaneous nerve grafting during flap reconstruction and immediate nerve assessments during
vascular repairs, significantly enhances outcomes while reducing complications. These protocols transform fragmented care into integrated pathways, ensuring comprehensive treatment and empowering each specialty in the healing process.
Q4 As the European Association of Neurosurgical Societies’ (EANS) Secretary, you have been recognised for your significant efforts to enhance international collaboration. Can you share an example of a recent initiative or programme within EANS that aims to strengthen knowledge exchange among European neurosurgeons?
A current contemporary initiative from EANS is the Emerging Technologies and Innovations in Neurosurgery (ETIN) Task Force, which promotes collaboration among neurosurgeons, engineers, and technologists to advance robotics, AI, augmented reality, and neuro-navigation.
EANS Task Forces, Sections, and Committees host webinars, roundtables, and collaborative forums that facilitate the exchange of ideas and techniques. It also supports pilot projects and shared research, ensuring neurosurgeons actively shape the future of surgical tools. EANS Annual Meetings and Congresses sublimate professional and scientific achievements through a modern interactive platform to deliver highest quality transmission of knowledge and experience to each individual member and participant, keeping and continuously elevating the high spirit of European neurosurgery.
EANS has enhanced its educational ecosystem through the EANS Academy e-learning platform, the Young Neurosurgeons’ Meeting, and transatlantic exchange programmes with AANS. These initiatives foster continuous, structured knowledge exchange, reinforcing a collaborative culture and setting high practice standards in modern neurosurgery providing best treatment options for each individual patient through
individually tailored treatment planning, following detailed patient consent.
Q5Looking ahead, what emerging technologies or techniques do you believe will most transform peripheral nerve surgery and global neurosurgical care over the next decade?
Emerging technologies will profoundly transform peripheral nerve surgery and global neurosurgical care over the next decade. Key advancements include brain-machine interfaces and bidirectional neuroprosthetics, which will enable patients with amputations or spinal injuries to regain movement and sensation.
Tissue-engineered nerve grafts, such as 3D-printed conduits containing Schwann cells and growth factors, will most likely replace traditional autografts and facilitate personalised reconstruction. AI-assisted surgical planning and augmented reality navigation will enhance precision, particularly in resourcelimited settings.
Gene and cell therapies will extend the intervention window for chronic injuries, while low-cost simulation platforms and telementored surgery will democratise access to training and care globally. These innovations will work synergistically to shift focus from structural repair to functional restoration.
To realise this potential, the neurosurgical community must combine advanced research with practical implementation and foster collaborative models to ensure equitable access to these advancements, regardless of geography or socioeconomic status.
Emerging technologies will profoundly transform peripheral nerve surgery and global neurosurgical care over the next decade
Christina Dalla
Professor of Pharmacology, Medical School, National and Kapodistrian University of Athens, Greece; President, Hellenic Brain Council; President, Mediterranean Neuroscience Society; Communication Committee Chair, Federation of European Neuroscience Societies (FENS)
Q1Your work largely focuses on sex differences in neuropsychiatric disorders, particularly in depression and anxiety. What are the most impactful or surprising findings that your work has uncovered?
This line of research is very promising, potentially for early intervention in depression, and particularly for women in menopause or perimenopause
We have been working on that for many years, since my PhD thesis, which was over 25 years ago. During my postdoctoral studies at Rutgers University, New Brunswick, New Jersey, USA, I also focused on sex differences, mostly in learning and neurogenesis. When I started my own lab, we continued exploring similar questions. One major area of focus has been identifying sex differences in baseline behaviours in male and female rats; although we sometimes also work with mice, we primarily use rats. A crucial early step was validating behavioural paradigms in females, which had often been overlooked. For example, in open field tests, female rats tend to be more active than males. We’ve also observed sex differences in learning behaviours, and in tests like the forced swim test. However, while these sex differences appear at baseline, they often disappear after administering antidepressants. In a way, these drugs equalise the behavioural responses between sexes. This suggests that, even if males and females start from different baselines or have different underlying neurochemical or neurobiological mechanisms, such as variations in serotonin levels, the drug could still have the same effect in some cases. This is very interesting.
For example, we have found that the corticosterone levels are
different in females and males. We know that corticosterone tends to be higher in females, yet the deregulation of the hypothalamic–pituitary–adrenal (HPA) axis appears to play a more significant role in male depression. This is important for translational work, because many animal models of depression rely on stress and HPA axis dysregulation. I often see grant proposals that assume these mechanisms apply across sexes, but we have shown that this isn’t always the case. Understanding these differences is key before testing new drugs.
Another key point is the oestrous cycle, particularly when studying behaviours like those measured in the forced swim test. While the cycle does not change baseline behaviours in the forced swim test, it can vary the antidepressant response. That’s why it’s important to include both males and females, and to account for different phases of the oestrous cycle when possible. A drug could be effective only in males, or only in females during a particular phase of the cycle. It's better to include different phases of the cycle or different developmental stages, like puberty or post-menopause. Of course, this approach is more time-consuming and more expensive, but it's important, at least, to be aware of it and to take it into consideration.
A finding from our lab came from a former PhD student, now a psychiatrist, who identified the nucleus reuniens in the thalamus as a key player in the stress response. This brain region connects the prefrontal cortex and hippocampus. When we disrupted these regions
in rats, they did not have a stress response, even under chronic mild stress; they were resilient to stressors. We later confirmed that this circuit plays a similarly crucial role in females. Our data, from behavioural studies, electrophysiology, and neuroplasticity indices, highlighted that the integrity of the prefrontal cortex–hippocampus circuit is essential for a normal stress response. That’s one of the most important findings from our lab, and it's why we’re now focusing most of our research on this circuit.
Historically, there was a belief that females were more biologically variable due to hormonal changes, which led to their exclusion from many studies. However, more recent meta-analyses show that males can be just as variable, due to differences in testosterone levels. This assumption was likely driven by bias and convenience, and many studies treated females as smaller versions of males or ignored sex altogether. In older studies from the 1970s and 1980s,
sometimes only females were used, and sometimes the sex of the animal wasn’t reported at all. In autoimmune disease research, females were used more often because autoimmune disorders, like multiple sclerosis, are more prevalent in females, and it’s easier to induce autoimmune disorders in them. Conversely, cardiovascular studies were mostly conducted in males, while learning studies sometimes used females because they performed better in certain tasks like classical conditioning. Our lab was among the first, 25 years ago, to start validating behavioural effects for animal models of psychiatric disorders in females, and conducting side-byside comparisons of males and females.
Q2Your recent research has highlighted the G protein-coupled oestrogen receptor 1 (GPER1) membrane oestrogen receptor as a rapid-acting target in psychopharmacology. Can you tell us more about this research, and explain the significance of GPER1
in the context of neuropsychiatric disorders?
Yes, this is an ongoing study. We’ve already had many results, and we are planning more experiments and grant applications to further explore its potential, as the findings so far have been very promising. GPER1 is a membrane-bound oestrogen receptor that differs from the classical oestrogen receptors, which are steroidal and located in the cytoplasm. Instead, GPER1 functions more like G-proteincoupled receptor (GPCR), enabling it to produce rapid, and nongenomic effects. We already have findings showing that activating GPER1 can have rapid antidepressant effects, mainly in females. We have also studied its potential as a chronic treatment, with results indicating that its long-term effects are comparable to selective serotonin reuptake inhibitors in depression models.
However, we believe it can also produce rapid effects. For example, we have done
experiments involving local infusion into the hippocampus in both males and females, and we observed that the effect is mainly seen in females. Specifically, local infusion of a GPER1 agonist produced a rapid anxiolytic and antidepressant effect in females. We are planning further experiments using genetic tools to investigate what happens when we overexpress the receptor and then activate it with an agonist, and we are also considering knockdown studies to reduce the receptor’s expression. We believe this line of research is very promising, potentially for early intervention in depression, and particularly for women in menopause or perimenopause, when oestrogen levels start to decrease.
Of course, we know that oestrogens are not only produced in the ovaries and other glands, but are also locally synthesised in the brain, including in males. It is interesting to explore what happens when we manipulate these local effects as well. This could also have potential relevance for postpartum depression, since neuroestrogens are locally synthesised and act in the brain.
Q3
Beyond neuropsychiatric disorders, does this treatment have potential for other neurological disorders?
Yes, it does. In fact, it has been extensively studied in relation to cognition, and so it could be promising for dementia or Alzheimer's disease. Alzheimer's disease is more frequent in women than men, like depression and anxiety, so it could be particularly relevant for Alzheimer's. It has also been studied for Parkinson's disease, multiple sclerosis, and stroke, because neurosteroids,
especially neuroestrogens, are also involved, and they can act like neuromodulators locally in the synapse. Thus, it could be promising for many different disorders that we may not even be aware of yet.
Q4
As a member of the European College of Neuropsychopharmacology (ECNP) Psychedelics Network, what are your upcoming research plans involving psychedelics, and what questions are you hoping to address?
This network is a very active and collaborative group. It brings together many of Europe’s leading experts, as well as connections to industry and patient groups, and I find it exciting to be part of such a dynamic community. For me, it was a natural progression to research psychedelics. I know it's very much a current trend, and everybody wants to work on psychedelics, but my PhD thesis was on serotonin, depression, and sex differences. Of course, for me, it was the logical next step. So far, we have only done work with ketamine, which is not a classical psychedelic. It’s a dissociative drug, and we have mostly used ketamine as a positive control in our studies. By the end of this year, we plan to begin studies on classical psychedelics, primarily with psilocybin, and we hope to explore dimethyltryptamine and 55-methoxy-N,Ndimethyltryptamine in the future.
We participate at a Marie Curie doctoral network, a European initiative primarily supporting PhD students. Some of our collaborators are also members of the ECNP Psychedelics Network. The focus will mostly be preclinical, investigating sex differences in animal models of depression. One key question
What we do know is that the psychedelic experience itself appears to be crucial
is whether the effects of psychedelics vary across the different phases of the oestrous cycle, which is relevant given that these are acute treatments. Understanding the optimal timing of administration may be essential for therapeutic outcomes.
We are also interested in analysing data from human studies to explore sex differences in response; for instance, differences between premenopausal or postmenopausal women, menstrual cycle phases, or the influence of hormonal contraceptives, which many women use. These factors remain largely unexamined, even though these drugs are already entering Phase III clinical trials and may soon be licensed, whereas in some countries they are already used for psychiatric indications. Understanding how to administer these treatments in women, and whether differential effects exist, is a key priority.
We also participate at a COST Action network, which supports broader European networking, advocacy, education, and dissemination efforts, and facilitates future grant applications. We are considering applying for Horizon Europe grants in the autumn or next year. At the university hospital, we’re fortunate to have a dedicated facility for human psychedelic studies, where psychiatrists are trained in investigational psychedelic use, and it's exciting that we are starting this work. All clinical use will take place in controlled medical settings, similar to how ketamine is administered, which is currently only in hospital settings in Greece. I'm also a member of the committees at the national drug organisation in Greece that assess and authorise the use of these drugs. In our case, this will
have to be within hospitals, under strictly controlled conditions. People are excited because they see a potential new treatment that acts effectively and quickly, unlike traditional antidepressants, which often take more than a month to show results and don’t work for everyone.
Q5 Is it possible for psychedelic treatment to be effective without any form of cognitive-behavioural therapy or psychotherapy, or are both always necessary for a positive outcome?
That’s a very good question, and one that remains open. There’s currently some debate among researchers on this topic. Many believe that the therapeutic effect of psychedelics depends on combining the drug with a very specific psychotherapeutic approach (not necessarily cognitive behavioural therapy), which they view as necessary. Others argue that psychotherapy may not always be necessary. At this stage, it’s still under
investigation. What we do know is that the psychedelic experience itself appears to be crucial. This became clearer as studies moved away from the idea that microdosing might be sufficient. Most now support the notion that a full psychedelic experience is needed to achieve therapeutic outcomes. As for the psychotherapy component, having a therapist present not only enhances safety, but also likely improves the overall therapeutic benefit.
Q6 Do you anticipate any sex differences in the effects of psychedelics?
I would expect different responses, because psychedelics act on serotonin receptors, particularly serotonin 2A (5HT2A) receptors, which have sex-based differences, and are also influenced by hormonal changes, such as fluctuations in oestrogen and progesterone. These hormonal variations could lead to different effects between sexes. It’s unclear whether these
differences will be clinically meaningful, but it's important to investigate. For example, some women experience physiological or emotional changes before menstruation, which could affect how they respond to psychedelics. It may be advisable to avoid administration during this phase. On the other hand, high oestrogen levels might interact with the drug, which could have implications for both safety and efficacy. Hormonal contraceptive use and menopausal status could also influence responses. We may need to consider dose adjustments or tailored approaches depending on these factors. Moreover, since neuroplasticity is known to fluctuate throughout the menstrual cycle, and psychedelics influence neuroplasticity, we might observe different effects depending on the cycle phase.
Q7In your leadership roles with the Greek Association of Academic Women, the University of Athens Gender Equality Committee, and the ALBA Network, you are deeply involved in promoting diversity and equity in brain sciences. From your perspective, what progress has the field made towards greater inclusion, and what challenges remain?
I'm also involved in the gender equality initiatives, both at my university, where I serve on the Gender Equality Committee, and within the Mediterranean Neuroscience Society, where I am currently the President. I will soon transition to the role of Past President, having served for several years. Across these organisations, many of the same issues need to be addressed. In general, I think that there has been some progress, especially in Europe. There is progress and many efforts, including the
ALBA Network, which is part of the Federation of European Neuroscience Societies (FENS). However, there is a lot of work to be done.
First of all, we need to change the mentality in some countries, as we still see many issues related to discrimination, not only against women, but also concerning sexual orientation, transgender individuals, and others. So, there is a lot to be done. In Greece, we have many women in research and neuroscience, and many students in medical schools as well. There are now a lot of women pursuing PhD studies, and even at the professor level, we have a significant number of women in academia. However, we still lack women in leadership positions. Sometimes, this is referred to as the glass ceiling effect, where women can only progress up to a certain point. At my school, we have never had a woman serve as Dean, or even Vice Dean. Thus, there is still much work to be done across different countries, and each country has its own specific issues. However, we're trying, and there are many initiatives currently underway.
First and only approved precision Fc-Fragment therapy in gMG. VYVGART shows significant and improvement in daily activities.
Fc, fragment crystallisable region; FcRn, neonatal Fc receptor; gMG, generalised myasthenia gravis; PFS, pre-filled syringe.
3. Cavalcante P, et al. Front Immunol. 2024;15:1404191. 4. Howard JF, 5. Bril V, et al. Poster Presented at the (AAN) Annual Meeting; April 13–18, 2024; Denver, Colorado.
EU-VYV-25-00069 | Date of preparation: July 2025
VYVGART 1000 mg solution for subcutaneous injection, in pre-filled syringe (efgartigimod alfa)
Abbreviated SmPC
Please refer to the Summary of Product Characteristics before prescribing.
Indication: As add-on to standard therapy for the treatment of adult patients with generalised Myasthenia Gravis (gMG) who are antiacetylcholine receptor (AChR) antibody positive.
Presentation: Solution for injection. Each pre-filled syringe contains 1 000 mg of efgartigimod alfa in 5 mL (200 mg/mL).
Posology and administration: Treatment must be initiated and supervised by a physician experienced in the management of patients with neuromuscular disorders. The first treatment cycle and first administration of the second treatment cycle must be administered either by or under the supervision of a healthcare professional. Subsequent treatment should be administered by a healthcare professional or may be administered at home, if a healthcare professional determines that it is appropriate, by a patient or caregiver after adequate training in the subcutaneous injection technique. Patients or caregivers should be instructed to inject Vyvgart according to the directions provided in the package leaflet. For comprehensive instructions for the administration of the medicinal product, please refer to the Instructions for Use in the package leaflet. Posology: The recommended dose is 1 000 mg to be administered subcutaneously in cycles of once weekly injections for 4 weeks. Subsequent treatment cycles should be administered according to clinical evaluation. The frequency of treatment cycles may vary by patient. The safety of initiating subsequent cycles sooner than 7 weeks before the start of the previous treatment cycle has not been established. For patients currently receiving efgartigimod alfa intravenously, the solution for subcutaneous injection may be used as an alternative. It is recommended to switch between formulations at the start of a new treatment cycle. No safety and efficacy data in patients switching formulations during the same cycle is available.Administration: Only administer via subcutaneous injection. After removing the pre-filled syringe from the refrigerator, wait for at least 30 minutes before injecting to allow the solution to reach room temperature. A safety needle, which is not included in the carton, should be connected to the pre-filled syringe. Use aseptic technique when handling the prefilled syringe and during administration. Do not shake the pre-filled syringe. During administration of the first treatment cycle and first administration of the second treatment cycle of efgartigimod alfa, appropriate treatment for injection and hypersensitivity-related reactions should be readily available. The recommended injection sites (abdomen) should be rotated, and injections should never be given into moles, scars, or areas where the skin is tender, bruised, red or hard. The medicinal product should be injected for approximately 20 to 30 seconds. The injection may be slowed if the patient experiences discomfort. Missed dose: If a scheduled injection is not possible, treatment may be administered up to 3 days before or after the scheduled time point. Thereafter, the original dosing schedule should be resumed until the treatment cycle is completed. If a dose needs to be delayed for more than 3 days, the dose should not be administered to ensure consecutive doses are given with an interval of at least 3 days. Elderly: No dose adjustment is required in patients aged 65 years and older. Renal impairment: Limited safety and efficacy data in patients with mild renal impairment is available, no dose adjustment is required for patients with mild renal impairment. There is very limited safety and efficacy data in patients with moderate or severe renal impairment. Hepatic impairment: No data in patients with hepatic impairment are available. No dose adjustment is required in patients with hepatic impairment. Paediatrics: The safety and efficacy of efgartigimod alfa in a paediatric population has not been established. Contraindications: Hypersensitivity to efgartigimod alfa or to any of the excipients Recombinant human
hyaluronidase (rHuPH20); L-arginine hydrochloride, L-histidine; L-histidine hydrochloride monohydrate; L-methionine; Polysorbate 80 (E433), Sodium chloride; Sucrose; Water for injections. Warnings and precautions: Traceability: The product name and batch number of the administered product should be clearly recorded. Myasthenia Gravis Foundation of America (MGFA) Class V patients: Treatment in MGFA Class V patients (i.e., myasthenic crisis), defined as intubation with or without mechanical ventilation except in the setting of routine postoperative care has not been studied. The sequence of therapy initiation between established therapies for MG crisis and efgartigimod alfa, and their potential interactions, should be considered. Infections: As efgartigimod alfa causes transient reduction in IgG levels the risk of infections may increase. The most common infections observed in clinical trials of efgartigimod alfa were upper respiratory tract infections and urinary tract infections. Patients should be monitored for clinical signs and symptoms of infections during treatment. In patients with an active infection, the benefit risk of maintaining or withholding treatment with efgartigimod alfa should be considered until the infection has resolved. If serious infections occur, delaying treatment with efgartigimod alfa should be considered until the infection has resolved. Injection reactions and hypersensitivity reactions: injection reactions such as rash or pruritus may occur. Cases of anaphylactic reaction have been reported with efgartigimod alfa intravenous in the post-marketing setting. The first treatment cycle and first administration of the second treatment cycle must be administered under the supervision of a healthcare professional. Patients should be monitored for 30 minutes after administration for clinical signs and symptoms of injection reactions. Should a reaction occur and based on the severity of the reaction, appropriate supportive measures should be initiated. Subsequent injections may be cautiously administered, based on clinical evaluation. If an anaphylactic reaction is suspected, administration of Vyvgart should be immediately discontinued and appropriate medical treatment initiated. Patients should be informed of the signs and symptoms of hypersensitivity and anaphylactic reactions and advised to contact their healthcare professional immediately should they occur. Immunisations: All vaccines should be administered according to immunisation guidelines. The safety of immunisation with live or live attenuated vaccines and the response to immunisation with these vaccines during therapy during treatment with efgartigimod alfa are unknown. For patients that are being treated with efgartigimod alfa, vaccination with live or live attenuated vaccines is generally not recommended. If vaccination with live or live attenuated vaccines is required, these vaccines should be administered at least 4 weeks before treatment and at least 2 weeks after the last dose of efgartigimod alfa. Other vaccines may be administered as needed at any time during treatment with efgartigimod alfa. Immunogenicity: In the active controlled study ARGX-113-2001, preexisting antibodies that bind to efgartigimod alfa were detected in 12/110 (11%) patients with gMG. Anti efgartigimod alfa antibodies were detected in 19/55 (35%) patients treated with efgartigimod alfa subcutaneous compared to 11/55 (20%) patients treated with the intravenous formulation. Neutralising antibodies were detected in 2 (4%) patients treated with efgartigimod alfa subcutaneous and 2 (4%) patients treated with efgartigimod alfa intravenous. The impact of antibodies to efgartigimod alfa on clinical efficacy or safety, pharmacokinetics and pharmacodynamic cannot be assessed given the low incidence of neutralizing antibodies. Immunosuppressant and anticholinesterase therapies: When nonsteroidal immunosuppressants, corticosteroids and anticholinesterase therapies are decreased or discontinued, patients should be monitored closely for signs of disease exacerbation. Sodium content: This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially ‘sodium free’. Polysorbates: This medicinal product contains 2.1 mg of polysorbate 80 in each syringe which is equivalent to 0.4 mg/mL. Polysorbates
may cause allergic reactions. Interactions: Efgartigimod alfa may decrease concentrations of compounds that bind to the human neonatal Fc Receptor (FcRn), i.e., immunoglobulin products, monoclonal antibodies, or antibody derivatives containing the human Fc domain of the IgG subclass. Postponement of initiation of treatment with these products to 2 weeks after the last dose of any given treatment cycle of efgartigimod alfa is recommended. Close monitoring of the intended efficacy response of such products is recommended. Plasma exchange, immunoadsorption, and plasmapheresis may reduce circulating levels of efgartigimod alfa. Fertility, pregnancy and lactation: Use efgartigimod alfa in pregnancy or lactating women only if the benefit outweighs the risk. Therapeutic monoclonal antibodies are known to be actively transported across the placenta (after 30 weeks of gestation) by binding to the FcRn. Efgartigimod alfa may be transmitted from the mother to the developing foetus. As efgartigimod alfa is expected to reduce maternal antibody levels, and is also expected to inhibit the transfer of maternal antibodies to the foetus, reduction in passive protection to the newborn is anticipated. Consider the risks and benefits of administering live / live-attenuated vaccines to infants exposed to efgartigimod alfa in utero. No information is available regarding the presence of efgartigimod alfa in human milk, the effects on the breastfed child or the effects on milk production. No data are available on the effect of efgartigimod alfa on fertility in humans. Animal studies showed no impact of efgartigimod alfa on male or female fertility parameters. Effects on ability to drive and use machines: No or negligible influence on the ability to drive or use machines. Undesirable effects: The most frequently observed adverse reactions were injection site reactions (33%), upper respiratory tract infections (10.7%) and urinary tract infections (9.5%). The overall safety profile of Vyvgart subcutaneous was consistent with the known safety profile of the intravenous formulation. Very common (≥ 1/10): injection site reactions, upper respiratory tract infections. Common (≥1/100 to <1/10): Urinary tract infection, bronchitis, nausea, myalgia, procedural headache*. Not known Anaphylactic reaction. Please refer to the Summary of Product Characteristics for additional information on selected adverse reactions before prescribing. *Intravenous administration only Overdose: There are no known specific signs and symptoms of overdose with efgartigimod alfa. In the event of overdose, adverse events are not expected to differ from those observed at the recommended dose. Patients should be monitored for adverse reactions, and appropriate symptomatic and supportive treatment initiated. There is no specific antidote for overdose with efgartigimod alfa. Storage: Store in a refrigerator (2oC to 8oC). Do not freeze. Store in original packaging to protect from light. Package quantities: 5 mL solution in a single use pre-filled syringe (type I glass) with a rubber stopper and a rubber tip cap.. Pack size: 1 pre filled syringe; 4 pre filled syringes. Not all pack sizes may be marketed. Marketing authorisation number: EU/1/22/1674/003-4 Marketing Authorisation Holder: argenx BV, Industriepark- Zwijnaarde 7, 9052 Gent, Belgium Full prescribing information, (SmPC) is available from: https://www.ema.europa.eu/en/documents/productinformation/vyvgart-epar-product-information_en.pdf
Date of preparation: Mar 2025 Job code: EU-VYV-25-00053
Adverse event reporting Adverse events should be reported via the national reporting system listed in Appendix V. Adverse events with this product should also be reported to reportnow@argenx.com
This medicinal product is subject to additional monitoring.
CANYON: THE LARGEST INTERVENTIONAL TRIAL IN
Sevasemten is an investigational agent that is currently not approved for use by any regulatory authority in any territory. Citation: EMJ Neurol. 2025;13[1]:74-75. https://doi.org/10.33590/emjneurol/LIDP8091
BACKGROUND
Becker muscular dystrophy is a rare, progressive, debilitating neuromuscular disease with no currently approved therapies.1
In muscular dystrophies, excessive contraction-induced damage of muscle fibers can occur, with fast muscle fibres being most susceptible to injury.2,3
Fiber breakdown leads to the release of muscle proteins (such as creatine kinase and fast skeletal muscle troponin I) into the circulation, where they can be measured as disease-related biomarkers.4
Sevasemten is an investigational, novel, oral, fast skeletal myosin inhibitor designed to protect muscle against contraction-induced injury while preserving function.5
BECKER NATURAL HISTORY
• Individuals with Becker experience progressive muscle degeneration and weakness, leading to eventual loss of muscle function.1
• The NSAA is a clinically meaningful measure utilised in natural history studies of muscular dystrophy to longitudinally assess global function.6-9
• Multiple natural history studies in individuals with Becker demonstrate a consistent and irreversible decline in NSAA average score of 0.9 to 1.7 points annually.6-9
Consistent rate of functional decline
THE CANYON TRIAL10
• The CANYON trial (NCT05291091) is a Phase II, double-blind, placebo-controlled study of sevasemten.
• CANYON assessed safety, pharmacokinetics, biomarkers of muscle damage (CK), and functional measures, in adults and adolescents with Becker (with data currently available for the adult dataset only).
ADULT PRIMARY EFFICACY ENDPOINT
Change from baseline in CK averaged across Months 6, 9 and 12
Years of observation
EFFICACY RESULTS10
Primary Endpoint:
Study design
sevasemten
Ambulatory males aged dystrophin mutation and an on corticosteroids, with a Adults
sevasemten
* p=0.02
The CANYON trial met its primary endpoint, with a 28% average decrease in CK in sevasemten-treated patients vs placebo (p=0.02).
References
1. Magot A et al. J Neurol. 2023;270(10):4763-81
2. Moens P et al. J Muscle Res. Cell Motil. 1993;14(4):446-51.
3. Webster C et al. Cell. 1988; 52(4):503-13.
** p<0.001
IN BECKER MUSCULAR DYSTROPHY TO DATE
territory. The publication of this Infographic was funded by Edgewise Therapeutics.
SAFETY10
• There was a notable imbalance between adult participants in the sevasemten and placebo groups at baseline, with the sevasemten group having more advanced disease based on all functional measures and MRI.
INCLUSION CRITERIA
12 to 50 years with a an Becker phenotype, not a NSAA between 5-32
design - 12 months
sevasemten 10 mg PO daily
Placebo
mg or 12.5 mg PO daily
Placebo
PATIENTS ENROLLED
Adults: 40
Adolescents: 29
6 9 12
Assessment (NSAA); change from baseline at month 12 (such as TNNI2), timed function tests, MRI
Baseline NSAA Score Change from Baseline at 12 months
Sevasemten-treated patients showed stabilisation of NSAA, while the placebo group declined in line with natural history.
10. McDonald C et al. Poster #O78. MDA Clinical and Scientific Conference, 16–19 March, 2025. 11. ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT05291091. Last accessed: 21 May 2025. 12. ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT06066580. Last accessed: 21 May 2025.
• Sevasemten was well tolerated in the CANYON study, with no new safety concerns observed.
• Headache and dizziness were the most commonly reported adverse events.
Discontinuation due to TEAE
KEY MESSAGES
CANYON is the largest interventional trial in Becker to date and the first to achieve its primary endpoint, reduction in circulating levels of creatine kinase.
Sevasemten-treated patients showed trends toward stabilisation of NSAA at 12 months compared to placebo, a key secondary endpoint.
Sevasemten was well-tolerated, with no new safety concerns identified.
Research with sevasemten in Becker is ongoing with the GRAND CANYON trial11 and MESA, an open-label extension study.12
Lighting the Path: How Clinicians Can Encourage People with Multiple Sclerosis to Walk Their Own Road
Author: *Agne Straukiene1
1. Department of Neurology, Torbay Hospital, UK *Correspondence to agne.straukiene@nhs.net
Disclosure: The author has declared no conflicts of interest.
Acknowledgements: AI was used to enhance language clarity and flow, for formatting and editing assistance, and to identify literature that supported the article’s clinical points.
Received: 27.06.25
Accepted: 07.07.25
Keywords: Chronic care, digital tools, mobile health, multiple sclerosis (MS), patient empowerment, self-management, shared decision-making.
Multiple sclerosis (MS) is a complex, lifelong neurological condition that presents with unpredictable symptoms, progressive disability, and fluctuating psychosocial challenges. Managing MS effectively requires more than medical treatment; it demands that people living with the disease develop skills to manage its impact on daily life. Increasingly, research highlights that, when individuals with MS are equipped to self-manage, they experience improved clinical outcomes, enhanced psychological wellbeing, and greater autonomy in healthcare decisionmaking.1 However, empowering patients is not a passive process. It is an active, structured task for healthcare professionals.
RECOGNISING SELFMANAGEMENT AS A CORE COMPONENT OF MULTIPLE SCLEROSIS CARE
The concept of self-management in chronic illness is not new, but its application in
neurological conditions like MS is still evolving. Studies have consistently demonstrated that patients who engage in self-management strategies, such as symptom tracking, fatigue pacing, and health literacy, show better quality of life and disease coping mechanisms.1-3 Clinicians must therefore treat self-management as a cornerstone of good care, not an optional add-on.
Yet, encouraging a person with MS to self-manage involves more than issuing instructions. It requires a partnership model that blends clinical expertise with a patient’s lived experience. This means shifting from the traditional ‘expert-patient’ hierarchy to a collaborative framework where shared decision-making is central.
INTEGRATING DIGITAL HEALTH TO ENHANCE PATIENT ENGAGEMENT
Digital tools, particularly mobile health platforms, present exciting new opportunities to scale self-management support. A growing number of applications allow patients to log symptoms, monitor
relapses, manage medication schedules, and access tailored educational content on MS.4 These platforms are not merely convenient; they can fundamentally change how care is delivered.
For example, some apps facilitate realtime symptom monitoring, enabling earlier clinical intervention. Others offer cognitive behavioural therapy-informed modules or fatigue management courses. Importantly, mobile health solutions can reduce the information gap between appointments, helping patients feel more in control of their condition even outside of the clinical setting.5,6
However, digital literacy, data security, and app quality remain key concerns. Clinicians must guide patients towards evidencebased tools, co-develop usage plans, and actively incorporate patient-reported data into care discussions.
THE ROLE OF THE CLINICIAN: FROM GATEKEEPER TO FACILITATOR
While technology can extend care, it cannot replace the human connection between clinicians and patients. Healthcare professionals, including neurologists, MS nurses, and allied health teams, must become facilitators of self-management. This includes providing clear explanations of disease mechanisms, helping patients navigate uncertainty, and offering tools for fatigue, mobility, and pain management.
Evidence suggests that patients involved in treatment decisions report higher satisfaction, better adherence, and improved health outcomes.7 Shared decision-making is not simply about offering choices; it’s about structuring the consultation to ensure that patients understand their options, values, and preferences.
Clinicians must also take into account the psychological toll of MS. Anxiety, depression, and cognitive changes can affect a patient’s capacity to engage in self-management. As such, self-management support must be holistic, addressing both the physical and emotional dimensions of care.
TRAINING AND SYSTEM-LEVEL CHANGE: ENABLERS OF PATIENT PARTNERSHIP AND AUTONOMY
Effective patient empowerment depends on how well healthcare professionals are trained in communication and behavioural change strategies. Studies show that clinicians may feel underprepared to deliver structured self-management support and require adequate training to improve confidence and effectiveness.8 Integrating this training into medical education and continuing professional development is therefore essential.
Healthcare systems must also evolve to support this model of care. Allocating time during appointments, using structured patient-reported outcome measures, and enabling multi-professional collaboration are all critical. Policies and reimbursement models that recognise the value of self-management could catalyse broader adoption.
LOOKING AHEAD: BUILDING A CULTURE OF PARTNERSHIP
The future of MS care lies not only in advanced therapies, but also in building a culture where people with MS are equal partners in their care and help to create joint communication tools.9 Empowering patients to self-manage is not about shifting responsibility; it’s about offering the tools, trust, and time to enable independence.
Clinicians must commit to embedding self-management support into everyday practice, harnessing digital innovations while maintaining human connection. By doing so, they can transform MS care from a reactive model to a proactive, personcentred partnership.
References
1. Kidd T et al. A systematic review of the effectiveness of self-management interventions in people with multiple sclerosis at improving depression, anxiety and quality of life. PLoS One. 2017;12(10):e0185931.
2. Taylor SJC et al. A rapid synthesis of the evidence on interventions supporting self-management for people with long-term conditions (PRISMS – practical systematic review of self-management support for long-term conditions. Health Soc Care Deliv Res. 2014;DOI:10.3310/ hsdr02530.
3. Shawli ASJ et al. Fatigue and self-management among multiple sclerosis patients. Am J Nurs Res. 2019;7(4):550-60.
4. Salimzadeh Z et al. Mobile applications for multiple sclerosis: a focus on self-management. Acta Inform Med. 2019;27(1):12-8.
5. Ytterberg C et al. A qualitative study of cognitive behavioural therapy in multiple sclerosis: experiences of psychotherapists. Int J Qual Stud Health Well-being. 2017;12(1):1325673.
6. Whitehead L, Seaton P. The effectiveness of self-management mobile phone and tablet apps in long-term condition management: a systematic review. J Med Internet Res. 2016:18(5):e97.
7. Keenan A et al. Shared decisionmaking in the treatment of multiple sclerosis: results of a cross-sectional, real-world survey in Europe and the United States. Patient Prefer Adherence. 2024;18:137-49.
8. Mata ÁNS et al. Training in communication skills for selfefficacy of health professionals: a systematic review. Hum Resour Health. 2021;19(1):30.
9. Oreja‐Guevara C et al. Joint healthcare professional and patient development of communication tools to improve the standard of MS care. Adv Ther. 2019;36(11):3238-52.
Precision Medicine in Neurology: Advancing Care for Female Patients
Editor's Pick
Precision medicine in neurology is increasingly recognising the significant influence of sex and gender on disease manifestation, progression, and treatment response. Understanding how biological sex and gender-related factors contribute to neurological conditions is crucial for developing personalised and effective therapies. This review focuses on advancing care for female patients, as well as sex-based differences and their impact on neurological disorders.
László Vécsei
University of Szeged, Hungary
Authors: Vanessa Carvalho,1-3 Katarina Rukavina,4 Barbara Mostacci,5 Addie M. Peretz,6 Michele Romoli,7 Mar Tintoré,8 9 Mafalda Soares,10 11 Maria Teresa Ferretti,12 Gennarina Arabia,13 Marianne DeVisser,14 Elena Moro,15 *Esther Bui16 17
1. Serviço de Neurologia, Departamento de Neurociências, Hospital de Santa Maria, Unidade Local de Saúde de Santa Maria, Lisbon, Portugal
2. Centro de Estudos Egas Moniz, Faculdade de Medicina da Universidade de Lisboa, Portugal
3. Instituto Gulbenkian de Medicina Molecular, Lisbon, Portugal
4. Movement Disorders Hospital Beelitz, Germany
5. Programma Epilessia, IRCCS Istituto delle Scienze Neurologiche di Bologna, Italy
6. Department of Neurology & Neurological Sciences, Stanford University, Palo Alto, California, USA
7. Department of Neurosciences, Comprehensive Stroke Center, Bufalini Hospital, Cesena, Italy
8. Multiple Sclerosis Centre of Catalonia (Cemcat), Department of Neurology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Spain
9. Universitat de Vic-Universitat Central de Catalunya (UVic-UCC), Spain
10. Neurology Department, Hospital de S. José, Unidade Local de Saúde São José, Lisbon, Portugal
11. Centro Clínico Académico de Lisboa, Portugal
12. Center for Alzheimer Research, Karolinska Institute, Stockholm, Sweden
13. Department of Medical and Surgical Sciences, Institute of Neurology, Magna Græcia University, Catanzaro, Italy
14. Department of Neurology, Amsterdam Neuroscience, Amsterdam University Medical Centre, University of Amsterdam, the Netherlands
15. Grenoble Alpes University, Division of Neurology, CHU of Grenoble, Grenoble Institute of Neuroscience, INSERM U 1216, France
16. Division of Neurology, Department of Medicine, University of Toronto, Canada
17. Krembil Brain Institute, University Health Network, Toronto, Canada
*Correspondence to Esther.Bui@uhn.ca
Disclosure:
Tintoré has received compensation for consulting services and speaker honoraria from Almirall, Bayer Schering Pharma (now known as Bayer AG), Biogen-Idec, Genzyme, Immunic Therapeutics, Janssen, Merck-Serono, Novartis, Roche, Sanofi-Aventis, Viela Bio (now a part of Horizon Therapeutics), and Teva Pharmaceuticals; is on the Data Safety Monitoring Board for Parexel and UCB Biopharma; and was previously on the Relapse Adjudication Committee for IMCYSE SA. Ferretti has received compensation for consulting services and speaker honoraria from Angelini, Prodeco, EPH Health, Roche, and Biogen. Mostacci has received personal fees for consultancy, advisory boards, and speaker honoraria from LivaNova, Angelini, Eisai, Lusofarmaco, and Kanso; and non-financial support (travel expenses) from LivaNova, Eisai, and Angelini. Moro has received a France Parkinson grant, with payment to the institution. The other authors have declared no conflicts of interest.
Acknowledgements: Carvalho and Rukavina are co-first authors.
Growing evidence suggests that biological sex influences disease risk, clinical presentation, treatment response, and prognosis across neurological conditions. Despite this increasing awareness of important sex differences, neurological research and clinical care remain insufficiently tailored to females.
In this review, the authors highlight the importance of integrating sex-specific considerations into precision medicine for neurological disorders. Focusing on five high-prevalence and high-burden neurological conditions (epilepsy, migraine, stroke, multiple sclerosis, and neurodegenerative diseases), this review identifies critical knowledge gaps and actionable opportunities for advancing care for females. Such gaps and opportunities include: 1) improved pregnancy and lactation data in epilepsy; 2) hormonal influences across the menstrual cycle, pregnancy, and menopause in migraine; 3) sex-based disparities in symptom recognition, treatment access, and rehabilitation for stroke patients; 4) the influence of sex hormones on disease onset, progression, and prognosis in multiple sclerosis; and 5) sex differences in pathophysiology and clinical trajectories in neurodegenerative diseases.
This review proposes a roadmap for integrating sex-based considerations into three key domains: clinical care, research, and neurology training. Prioritising and advancing these initiatives is essential for improving neurological care and represents a critical step towards equitable precision medicine.
Key Points
1. Sex-specific biological factors influence neurological disorders throughout life, impacting clinical presentation, response to treatment, and prognosis, yet they remain underexplored in neurology. As clinicians move towards tailored approaches to patient care with precision medicine, integrating sex-specific considerations will be essential.
2. Sex-specific considerations for female patients include pregnancy-related safety data for anti-seizure medications, hormone-related influences on migraine disease severity, sex disparities in stroke care, sex-specific disease course in multiple sclerosis, and sex-based differences in incidence and presentation of neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease.
3. Addressing female-specific needs, especially during key life stages of pregnancy and menopause, ensures equitable representation in clinical trials, guidelines, and training programmes, and improves precision medicine in neurological care.
BACKGROUND
Historically, sex-related differences have been underexplored in neurology. It is important to highlight the distinction between sex and gender as, though different, they have previously been used interchangeably. Sex refers to biological and physiological attributes, such as chromosomal composition, hormonal profiles, and phenotypic traits that distinguish males, females, and intersex individuals. In contrast, gender relates to the socially and culturally constructed roles, behaviours, identities, and expectations associated with being a man, woman, or non-binary person. Sex and gender are independently important variables of both health and disease, interacting throughout an individual’s life course, and it is important for them to be differentiated in both research and the real-world setting.1 This review will focus on sex-based differences and their impact on neurological disorders.
Neuroscience research has been predominantly male-focused, a trend rooted in longstanding biases within scientific and cultural frameworks.2,3 This imbalance has significant implications for the quality and effectiveness of healthcare. In cardiology, the imbalance has been well documented. In the early 1990s, studies identified that female patients were less likely to be referred to diagnostic or interventional procedures when presenting with myocardial infarction, unstable angina, or chest pain, compared to male counterparts. In a cohort
of patients hospitalised due to coronary heart disease in two different hospitals, 27.5% and 28.7% of males underwent angiography compared to only 16.1% and 17.7% of females, respectively.4 Similarly, with coronary revascularisation, 15.5% and 14.1% of males received treatment compared to only 7.4% and 6.5%, of females, respectively.4 This bias remains persistent, with a recent study showing that females presenting with chest pain are 20% less likely than males to have a troponin test performed, 36% less likely to be admitted to a specialised unit, and 35% more likely to die in the emergency department.5 Furthermore, although the prevalence of ischaemic heart disease tends to be higher in males within specific age groups, as females tend to live longer, in absolute numbers, ischaemic heart disease affects more female than male patients.6,7 Furthermore, symptoms more commonly seen in females, such as pain in the back, jaw, or neck,6 are still often described and taught as ‘atypical’ ischaemic cardiac symptoms.8,9
In neurology, there is now increasing attention paid to the impact of sex differences on the epidemiology, access to care, diagnosis, response to treatment, and prognosis of several neurological disorders.10 For female patients, unique, sex-specific biological considerations shape brain development and vulnerability to neurological disorders throughout life. While hormonal shifts play a role, factors like brain structure, immune function, and genetics also contribute to why neurological disorders
affect females and males differently. In adolescence, steroid sex hormones modulate brain and behaviour to organise neural circuits for adult social and reproductive behaviours. Several brain MRI studies show sexual dimorphisms across puberty, such as the increase in amygdala volume in males only and increases in hippocampus volume in females only.11 In addition, important differences in mental health conditions emerge in adolescence, such as the prevalence of depression in females while a greater prevalence of conduct and addiction disorders are observed in males.12 During pregnancy, there is evidence of a remarkable period of hormonally driven neuroplasticity with a linear decrease of grey matter and total brain volume, with a partial rebound in the postpartum period,13 tied to the rise in progesterone and 17β-oestradiol. Besides the biological effects of pregnancy in the brain, this important window in life is linked to the increased likelihood of vascular
disorders and a decreased likelihood of relapses in several autoimmune disorders, such as multiple sclerosis (MS), which have a higher risk of relapse postpartum, while in others, such as myasthenia gravis, 30–40% of patients have disease exacerbation.14,15 Finally, menopause, comprising up to 40% of a female’s lifespan, introduces cognitive and neurological shifts not explained solely by the decline of oestrogen. For example, postmenopausal females are at a higher risk for Alzheimer’s disease (AD), a condition that affects two-to-three times more females than males.16 Genetic risk factors like APOE-ε4 may impact females more strongly, possibly due to interactions of brain metabolism with ageing.16 Important life stages such as pregnancy and menopause represent key windows of opportunity to understand more precisely the impact of sex-specific biological factors on neurological illness, as summarised in Figure 1
Perimenopause, Menopause, and Postmenopause
Cycle Pregnancy
Figure 1: General considerations for female patients.
Significant gaps due to sex bias in research remain. In response to these historical biases, international policies have evolved to mandate the inclusion of sex-based considerations in research. For example, under the Horizon 2020 research framework, the European Commission emphasised the systematic integration of the sex and gender dimension in research and innovation. This directive has been further reinforced by Horizon Europe (2021–2027), which requires grant applicants to include sex and gender considerations in research design, methodologies, and analysis, with the goal of improving scientific quality and societal relevance.17 These policy shifts reflect a growing consensus that sex-disaggregated data and gender-sensitive methodologies are essential to robust, equitable, and precision-based science.
In this review, experts in their respective fields discuss five major groups of neurological disorders to highlight key gaps in neurological care and opportunities to prioritise and advance precision medicine informed by sex-based considerations, as summarised in Table 1
These five groups (epilepsy, migraine, stroke, MS, and neurodegenerative diseases) were selected based on their high prevalence and the critical influence of sex-related factors on their pathophysiology, clinical presentation, and management, and are highlighted in Figure 2.
EPILEPSY
Existing Gaps
Of the 70 million people with epilepsy worldwide, at least 15 million are females of childbearing potential (FOCB). Assuming, from epidemiological estimates, that 0.5% of births are to females with epilepsy (FWE), about 650,000 children are born to this population.18 Pregnancy represents multiple, often competing priorities between maternal and fetal health. As seizure control is critical during pregnancy, anti-seizure medications (ASM) should in most circumstances
be continued, despite increased risk of major congenital malformations (MCM) and neurodevelopmental disorders.19,20 For example, the unadjusted prevalence of MCMs among lower risk ASMs such as lamotrigine, levetiracetam, and oxcarbazepine ranges from 3.1–3.5%, and can reach as high as 9.7% with valproic acid exposure. This is elevated compared to the 2.4–2.9% rate seen among children of people without epilepsy.21,22 While research on epilepsy and pregnancy has progressed, key gaps remain. Pregnancy data on many newer ASMs remain limited or inconclusive.20-25 For all ASMs, there continues to be a much-needed ability to understand the genetic and epigenetic mechanisms behind their teratogenic potential and impact on long-term neurodevelopment, and to identify subtle cognitive or behavioural effects that may emerge later in life.25-30 Due to restrictions on topiramate and valproate use in FOCB, stemming from their well-documented risks during pregnancy,20,24,25,30,31-39 more data are needed to identify safer and more effective alternatives (including dose-related risks and polytherapy options), as well as the subset of patients who are at the greatest risk for medically refractory seizures, especially with non-valproate treatments.40-44
Regarding prenatal care, at least 0.4 mg of folic acid supplementation remains recommended to mitigate ASM-related MCMs and neurodevelopmental risks, yet the optimal and safe folic acid dosage remains unclear.23,45-48 In postpartum care, while breastfeeding is generally encouraged with emerging lactation safety data for older ASMs, these safety data are still scarce for newer ASMs.18,23
As newer ASMs are increasingly used, awareness of interactions with sex steroid hormones is needed, not only to ensure the safety and effectiveness of exogenous sex steroid hormones from contraceptives, menopause replacement therapy, or assisted reproduction therapies, but also to ensure adequate seizure control in pregnancy. Furthermore, hormonal therapies for catamenial (associated with menstruation) epilepsy and seizure threshold changes during menopause are underexplored.49
General Considerations
Epilepsy
Migraine
Stroke
MS
Neurodegenerative diseases
Existing Gaps
• Male predominance in most clinical trials
• Sex-related characteristics and differences often omitted or insufficiently documented
• Safety of newer ASMs in pregnancy, breastfeeding, and long-term impact on children of FWE
• Impact of hormone therapies on epilepsy and ASMs
• Impact of sex hormones on migraine is understudied
• Use of hormonal modulation in females who have migraine with aura remains controversial
• Migraine is a risk factor for adverse pregnancy outcomes
Issues beyond reproduction are even more overlooked. Clinical trials rarely analyse sex-specific efficacy and safety of ASMs, as well as both endogenous and exogenous sex steroid hormonal influences in the menopause continuum, resulting in persistent suboptimal care for females across the lifespan. To date, there remains limited evidence to guide the management of females in perimenopause and menopause.50,51
Opportunities for Advancement
To optimise pregnancy outcomes in FOCB, research must prioritise global participation in large-scale ASM pregnancy registries. These should include neurodevelopmental follow-up of offspring through infancy, childhood, and adolescence. Expanding population-based registries beyond Northern Europe, where current population data mostly come from,20,45,46,52-55 is also essential to capture more representative
Table 1: Summary of key gaps and opportunities in neurology.
Epilepsy
• Seizure control in pregnancy
• Teratogenicity of medications
• Long-term developmental outcomes of children exposed to medications in utero
Migraine
• A risk factor for adverse pregnancy outcomes
• Worsening with menses and perimenopause
• Impact and safety of menopause hormone therapy
Stroke
• Sex-specific stroke risks
• Atypical stroke presentation
• Inequitable access to acute stroke therapy
• Higher post-stroke disability and mortality
Multiple Sclerosis
• Disproportionately affects females
• Milder and relapsing remitting disease course
• Safety of medications in pregnancy
• Postpartum disease exacerbation
Neurodegenerative Disease
• Sex differences in memory performance
• Hormone related motor fluctuations in Parkinson’s disease
• Surgical menopause associated with increased risk of Parkinson’s disease and Alzheimer’s disease
data. To this extent, even the early identification of potential teratogenic risks from newer ASMs through case reports and small case series is crucial.
Preclinical and pharmacogenomic studies, as well as investigations into environmental influences, may clarify teratogenic mechanisms and consequently promote personalised therapy for girls and FOCB. Further clinical studies are needed to expand the identification predictors of response to non-valproate treatments, particularly in genetic generalised epilepsies, to improve individualised
treatment strategies and accurately assess risk–benefit profiles.
Bioethical research involving clinicians, ethicists, and patients is critical to support truly personalised counselling. Such frameworks must consider not only biological risk, but also the individual’s values, context, and societal factors. Ethical tools should also guide decision-making in clinical and policy settings.
Additional priorities include multicentre studies on ASM excretion in breast milk, neonatal blood concentrations,
Figure 2: Precision-based medicine in neurology for female patients.
and long-term developmental effects. Pharmacokinetic studies must assess interactions between any new ASM and oestrogens and progestins. Multicentric prospective studies are also needed on characterising catamenial epilepsy, including trials on progestin therapy, and on seizure patterns and ASM metabolism during and after menopause. Future ASM trials must systematically assess sexbased differences in drug response and adverse effects.
MIGRAINE
Existing Gaps
Migraine is predominantly a disorder impacting females, although males with migraine are often overlooked and underrepresented in clinical trials.56 According to the Global Burden of Disease (GBD) database study, migraine is the leading cause of disability-adjusted life years among FOCB,57 with nearly one in every four individuals experiencing migraine. Studies have shown that migraine attacks occurring perimenstrually tend to be more disabling, longer lasting, associated with more bothersome symptoms, and are more refractory to treatment compared with migraine at other times of the menstrual cycle.58
During pregnancy, migraine is a risk factor for adverse pregnancy outcomes. In a prospective study of 10,038 females who were nulliparous, a self-reported history of migraine was associated with 26% higher odds of adverse pregnancy outcomes. This effect is mediated predominantly by hypertensive disorders of pregnancy such as pre-eclampsia and preterm birth.59 Currently, according to the United States Preventive Services Task Force (USPSTF), migraine is not considered a risk factor that would prompt the consideration of low-dose aspirin for pre-eclampsia prevention.60
Following reproductive years, during the menopausal transition, migraine tends to worsen. In addition to experiencing more frequent and severe migraine attacks during perimenopause, females with migraine also
experience increased vasomotor symptoms, mood disturbances, and sleep disruption.61
Despite the distinct influence of hormonal epochs on migraine and the impact of migraine on the risk of vascular events, treatment options for migraine are not specific to the dynamic physiologic changes exacerbating migraine. These milestones are often neglected in clinical practice. For FOCB, clinicians do not routinely inquire about reproductive plans or contraceptive use, leaving patients at risk for conceiving while on potentially teratogenic medications. While pregnant, patients experiencing migraine are often left without appropriate and safe migraine treatment options, in part, reflecting the paucity of robust clinical studies on the safety of migraine treatments in pregnancy. Perimenopausal symptoms, which significantly contribute to migraine, are often overlooked by clinicians. In addition, the risk of medications, in particular calcitonin gene-related peptide antagonists, to bone health and vascular health has not yet been well explored.62,63 This class of medications may adversely impact both organ systems, which are more vulnerable within the menopause continuum. Furthermore, data on sexrelated differences in efficacy have been raised, with these drugs being less effective in the acute treatment of male patients.64
Opportunities for Advancement
Further understanding the influence of hormones on migraine pathophysiology represents a critical opportunity towards precision-based migraine treatment. The potential impact on migraine of various forms of hormonal manipulation (through hormonal contraception or hormone therapy) in the menopause continuum is understudied and deserves attention to help identify formulations with more favourable outcomes for migraine and more favourable safety profiles. To date, multiple societies, including the European Headache Federation (EHF) and the WHO, recommend against the use of combined hormonal contraceptives for females who have migraine with aura.65 Yet, the International Headache Society (IHS) suggests that
low dose oestrogen can be considered for females who have migraine with visual aura on a case-by-case basis.66,67 With many females either taking or desiring hormonal contraception with oestrogen, and the renewed interest in menopause hormone therapy, a more in-depth appreciation for sex-specific risk of stroke at distinct doses and formulations of oestrogen represents a critical opportunity to better inform safe and evidence-based care of females with migraine.
STROKE
Existing Gaps
Despite advances in stroke research, precision medicine remains inadequately tailored to females, resulting in significant disparities in prevention, diagnosis, treatment, and outcomes. Similar to cardiac disease, females often present with stroke symptoms that are considered atypical, such as fatigue or mental status changes, leading to misdiagnosis and delayed treatment.16 Consequently, they are less likely to receive timely interventions like thrombolysis, or be admitted in high-intensity care units, despite evidence suggesting that they may benefit more from such treatments.16,68,69
The underrepresentation of females in clinical trials further exacerbates these issues. Studies reveal that females are enrolled at lower rates than male counterparts, particularly in trials focusing on stroke treatment, intracerebral haemorrhage, and rehabilitation.69 This lack of representation limits the applicability of research findings to female patients and hinders the development of sex-specific treatment protocols.
Moreover, sex-specific risk factors, such as pregnancy-related complications, hormonal therapies, and migraine, are often underrecognised in stroke risk assessments and inadequately targeted with prevention strategies.70 Additionally, females are more likely to experience worse recovery poststroke, influenced by factors like older age at onset, higher prevalence of comorbidities, and social determinants of health.68,70
Recovery outcomes also differ by sex. Females are generally older at the time of stroke onset, with an average age of 72.9 years compared to 68.6 years for males. This age difference contributes to higher post-stroke disability and mortality rates among females.16,68,71-73 For instance, within 3–6 months post-stroke, 15% of females are unable to eat independently compared to 9% of males, 37% of females require assistance with dressing versus 20% of males, and 32% of females need help transferring from bed to chair compared to 13% of males.16,68,71-73 These disparities underscore the need for sex-specific approaches in stroke prevention, treatment, and rehabilitation to improve outcomes.
Opportunities for Advancement
Despite progress in stroke care, significant opportunities remain to enhance outcomes for females across the continuum of cardiovascular prevention, hyperacute treatment, and rehabilitation. A precision medicine approach must acknowledge sexspecific risk factors, including lower access rates to rapid diagnostic pathways, lower socioeconomic status,74 higher prevalence of atrial fibrillation as a stroke aetiology in female patients, adverse pregnancy outcomes, and hormonal transitions like menopause, all of which disproportionately affect stroke risk in females.
In the realm of primary and secondary prevention, sex disparities in medication adherence are critical. Chen et al.75 reported that females had significantly higher nonadherence to cholesterol-lowering (prevalence ratio: 1.80; 95% CI: 1.14–2.84) and antiplatelet therapies (prevalence ratio: 1.53; 95% CI: 1.003–2.34) at 90 days poststroke.75 This gap may stem from differences in health beliefs, caregiver responsibilities, and socioeconomic barriers. Tailored interventions, including patient education and culturally competent care models, are vital to improve adherence and reduce recurrent stroke risk.
Hyperacute stroke management presents another opportunity. Although females tend to present with more severe strokes, when matched for baseline risk factors, the
outcomes after endovascular thrombectomy do not significantly differ by sex (odds ratio for good functional outcome: 0.89; 95% CI: 0.66–1.2; symptomatic intracranial haemorrhage odds ratio: 1.00; 95% CI: 0.44–2.26).76 Nevertheless, females are still less likely to receive endovascular thrombectomy,69,77 and delays due to atypical symptom presentation and lower prehospital recognition contribute to worse outcomes.78 Targeted education for both clinicians and the public on sex-specific stroke symptoms could help bridge this gap.
Rehabilitation strategies must also evolve. Females experience higher rates of poststroke disability, depression, and reduced access to outpatient therapy.68 Integrating mental health services and caregiver support into rehabilitation planning could mitigate these disparities. Furthermore, rehabilitation trials must increase female enrolment and disaggregate data by sex to inform best practices.78
Optimising stroke care for females requires a sex-considered framework spanning risk identification, equitable acute intervention, and individualised recovery plans. Institutional policies and clinical research must reflect these imperatives to close the persistent outcome gap.
MULTIPLE SCLEROSIS
Existing gaps
Multiple sclerosis (MS) disproportionately affects females, with a female to male ratio of 2–3:1. This sex disparity has been rising in recent years, but the precise factors driving this increasing incidence remain unclear. Understanding these factors is crucial, as both genetic and environmental influences likely contribute to this trend.79
Although it is well-established that MS progresses differently between males and females, the influence of sex hormones on prognosis is underexplored.80 A recent large-scale survey on women’s health issues for individuals with MS identified menopause, pregnancy, and
hormonal treatments as priority research areas, underscoring the need for further exploration into how these factors affect MS progression.81
While the impact of MS on ovarian reserve remains poorly understood, significant research is emerging on pregnancy and breastfeeding. However, much remains unknown regarding the safety of diseasemodifying therapies, highlighting a need for treatments that can offer protective effects during these stages of a female’s life.82 Further research is also required to investigate how menopause interacts with MS, particularly in terms of symptom management and disability worsening.83,84
Finally, regional differences in grey matter atrophy suggest sex-specific mechanisms in disease progression, emphasising the need for more targeted research on brain volume dynamics in MS.85,86 Understanding these sex differences in brain atrophy is crucial, and linking this research with other areas of neurology could provide broader insights into neurodegenerative diseases.
Opportunities for Advancement
MS is more prevalent in females, but more disabling in males. Moreover, while females are more commonly affected by a relapsingremitting course, males tend to experience progressive forms more frequently. Exploring the biological mechanisms behind these sex differences presents a significant opportunity to uncover disease pathogenesis.87,88 Indeed, females living with MS might pose as a model for understanding neurological autoimmune diseases, as MS onset typically occurs in young females and persists throughout their entire lifespan. This may also present a unique opportunity to understand disease progression in the context of hormonal fluctuations across different life stages, from adolescence to menopause.89
The difference in disease progression across sexes in MS warrants further investigation into mechanisms like the glymphatic system, which appears to be impaired in progressive forms. This system could be crucial in understanding
neurodegeneration in females with MS, and may offer a new therapeutic target for disease progression.90
Exploring neuroprotective treatments, particularly those that leverage oestrogen’s known effects on neuroprotection and remyelination, presents an exciting avenue for research. Trials exploring oestriol’s effects on cognitive function and its combination with disease-modifying therapies have demonstrated promise, though further studies are needed to confirm long-term benefits.91,92 Similarly, the investigation of selective oestrogen receptor modulators offers hope for treatments that can protect and repair the myelin sheath in females with MS.93
Together, these opportunities highlight the need for continued exploration into sexspecific therapeutic strategies, considering hormonal influences and females’ unique biology. With a deeper understanding of these mechanisms, treatment outcomes for females with MS can be improved, ultimately advancing precision neurology.
NEURODEGENERATION
Existing Gaps
AD and other neurodegenerative diseases (Parkinson’s disease [PD] being the fastest growing one) are the largest contributors to neurological health loss.94 In both AD and PD, females have traditionally been underrepresented in clinical trials.95,96 However, although concerning knowledge gaps persist, the evidence on sex-related differences in the pathophysiology, natural history, and management of neurodegenerative diseases is emerging.97
For example, in a recent meta-analysis of six studies with a total of 1,376 participants with AD (55% female), female sex was associated with faster tau accumulation localised to inferior temporal (β=−0.14; 95% CI: −0.22–-0.06; p=0.009), temporal fusiform (β=−0.13; 95%CI: −0.23–-0.04; p=0.02), and lateral occipital regions (β=−0.15; 95%CI: −0.24–0.06; p=0.009) compared with male sex,
possibly suggesting a heightened risk of cognitive decline in females compared to males.98 At the same time, healthy females outperform males in neurocognitive tests. Sex differences in memory performance, particularly verbal, begin in childhood, and grow larger in effect size just postpuberty.99 Although these differences decrease with menopause, a certain degree of female advantage remains in the healthy ageing brain through midlife and old age, possibly leading to the underdiagnosis of AD-related mild cognitive impairment and dementia among females.98,100
Substantial sex-based differences also exist in PD. While the incidence of PD is, in general, higher in males compared to females, it increases significantly in females who underwent hysterectomy and bilateral oophorectomy before menopause.101 Females with PD are at increased risk of developing highly disabling motor complications, including motor fluctuations, dyskinesias, and non-motor fluctuations (especially depression/anxiety, sleep/fatigue, and dysautonomia domains), compared to male patients. However, females remain disproportionally underrepresented in referrals for device-aided therapies compared to the general PD population.102-105 Furthermore, although catamenial fluctuations in PD are a phenomenon that has been described since the 1980s,106,107 little is known regarding the impact of both exogenous and endogenous hormones in disease management and progression. On the other hand, male patients with PD have a higher risk of cognitive impairment in comparison to female patients.108
Although PD is predominantly affecting elderly individuals, it can also, particularly in its monogenic forms, affect FOCB. Data regarding the safety of drugs used in the management of PD in pregnancy are still scarce,109 and multicentred registries are lacking.110
Opportunities for Advancement
As data emerges to implicate the role of neuroactive sex steroid hormones, such as 17β-oestradiol, and their endogenous fluctuations in learning and memory,
clinicians need to account for these differences in neuropsychological testing when assessing cognitive impairment.100 Consequently, sex-specific timing considerations need to be included into indications for anti-Aβ and anti-tau treatments in a more personalised approach for females with AD.98
In PD, α-synuclein seed amplification assays are a novel tool enabling the biochemical diagnosis of the disease. They also allow for detecting individuals who are already at prodromal stages of PD.111 Females who underwent hysterectomy and bilateral oophorectomy before menopause, and are thus at heightened risk of developing AD and PD alike, should be followed up, assessed with seed amplification assays early, and be included in RCTs of diseasemodifying molecules. Concerning treatment for symptomatic PD, there are no available guidelines for the treatment of pregnant patients with PD or specifically addressing the higher risk to develop dyskinesia and specific impulse compulsive behaviour. Sex should be considered when selecting device-aided therapies for people with PD.104 Importantly, the reasons for inappropriately less frequent referrals of females for device-aided therapies need to be unearthed and strategically tackled. Moreover, non-motor symptoms are differently affecting male and female patients with PD.109
MAPPING A WAY FORWARD: PRECISION-MEDICINE FOR HALF THE POPULATION
Specifically addressing existing gaps and opportunities by integrating sex-based considerations in neurology across clinical care, research, and neurology training will ultimately advance precision medicine for all.112 While this review has focused on sex-specific or biological considerations in females affected by neurological conditions, gender considerations are rarely isolated from sex considerations.
As such, the authors' review does not explore the interconnectivity of sociodemographic factors influencing
sex-considered health measures. In fact, gendered aspects such as a woman’s employment and education status, as well as her marital and caregiver status, can contribute to observed gender disparities in clinical trial participation, which prompts a call for gender-informed study recruitment methods.113 Gender-specific considerations, such as disproportionate caregiving, paid work constraints, and cultural norms, are likely to play a part in women’s ability and willingness to enrol in clinical trials. Although out of the scope of this review, gendered aspects of bias should also be addressed to increase parity on research, such as flexible or remote visit options and stipends for childcare, transportation, or lost wages.114
Furthermore, important male-specific patterns (such as higher rates of cluster headache and higher risk of primary progressive MS in male compared to female patients) are acknowledged but remain outside the scope of this review.
Clinical Care
In clinical care, there is an urgent need to develop neurology clinical practice guidelines that incorporate femalespecific health issues across the lifespan. It is notable that, while sex-specific considerations extend beyond reproduction, reproductive health-related research constitutes the majority of existing sexconsidered neurological research.10 Femalespecific considerations must be integrated into diagnostic criteria, as numerous neurological disorders present differently in females compared to males, leading to risks of misdiagnoses and inappropriate treatment. In females with neurological disorders, the interactions between neuroactive sex steroid hormones and their endogenous fluctuations throughout reproductive life and the menopause continuum need to be emphasised. Precision-based medicine for females with neurological disorders requires sex-specific data and guidelines during different hormonal life stages. Applying a comprehensive precision medicine approach, neurological history taking needs to consider symptoms across the
menstrual cycle and discuss potential interactions between oral contraceptives or menopause hormone therapy and neurological symptoms. Knowledge on the safety of medications during family planning, pregnancy, and breastfeeding is essential. This includes addressing the teratogenic risks, the potential impact on fertility, and maternal and fetal safety. In cases where medications are contraindicated in pregnancy or during hormonal transitions, neurologists must be familiar with safe and effective alternatives, including nonpharmacological strategies. Females with neurological disorders must be included in shared decision-making together with their neurologists on reproductive choices, contraceptives, or menopause hormone therapy use during different hormonal life stages. Input from endocrinology, obstetrics/gynaecology, and psychiatry in multidisciplinary care models can help neurologists navigate the complex overlay between neurological symptoms and hormonal health.
Research
In research, to ensure findings are sexspecific, fixed quotas (for example, in accordance with the epidemiological representation of sexes) for the inclusion of females in clinical trials are urgently needed across all areas of neurology. This could be achieved through funding agencies and regulatory bodies requiring sex-considered research designs and incentivising studies that investigate neurological conditions, specifically in females. Furthermore, sexdisaggregated data need to be analysed in clinical trials, and hormonal status (e.g., premenopausal, perimenopausal, postmenopausal, hormonal therapy use, and pregnancy) should be systematically documented and incorporated into trial design and interpretation. Research must systematically consider the impact and potential interactions of hormonal changes across the lifespan on neurological symptoms, as well as on the effectiveness and tolerability of neurological medications. Furthermore, prospective registries are urgently needed to document the safety of neurological medications in the context of family planning, pregnancy,
and breastfeeding. Technology should be leveraged to advance sex-specific research; for instance, AI could be used to reanalyse older datasets for sex-based differences, while electronic medical records offer new opportunities to systematically integrate sex considerations into clinical research design.
Neurology Training
In education, there is the opportunity to disseminate clinical guidelines and research to health practitioners, as well as train the next generation of experts informed on sex- and gender-specific considerations. The European Academy of Neurology (EAN)’s Diversity, Equity and Inclusion coordinating panel reviewed all the education programmes in Europe on sex and gender education and identified a scarcity of sex and gender specific topics in medical curricula.17 From undergraduate medical training to postgraduate neurology training and continuing medical education, topics related to sex-specific influences on neurological presentation, disease trajectory, response to therapy, and longterm outcomes must be systematically integrated alongside multidisciplinary efforts with endocrinology, obstetrics, gynaecology, and psychiatry. Medical education must emphasise the importance of sex-specific diagnostic criteria and the impact of sex steroid hormones on neurological conditions. In the USA and Canada, a dedicated Women’s Neurology curriculum has been developed and is endorsed by the American Academy of Neurology (AAN), marking an important step towards formalising sexand gender-based neurological education. Similar initiatives beyond the North Americas are urgently needed.
In advancing sex-specific considerations, there is an exciting chance to open new pathways for a more precise understanding of neurological illness. Neurology has an important opportunity to prioritise a more expansive and inclusive understanding of sex-specific differences, and in doing so, everyone stands to gain from implementation of precision medicine at a fundamental level.
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Critical Management of Neurocysticercosis with Hydrocephalus and Paroxysmal Sympathetic Hyperactivity: A Case Report
Authors: *Geran Maule,1,2 Ahmad Alomari,1,2 Mohammad Khraisat,1,2 Andrea Chalker,2 Gabriella Orellana,1,2 Gohar Majeed2
1. University of Central Florida, Orlando, Florida, USA
2. HCA Florida North Florida Hospital, Gainesville, Florida, USA
*Correspondence to geran.maule@ucf.edu
Disclosure: This work was supported by HCA Healthcare and/or an HCA Healthcare affiliated entity. The views expressed in this publication represent those of the author(s) and do not necessarily represent the official views of HCA Healthcare or any of its affiliated entities. The authors have declared no conflicts of interest.
Introduction: Neurocysticercosis, a parasitic infection caused by Taenia solium larvae, is a prevalent health challenge in regions with poor sanitation and among individuals migrating from endemic areas. This case report discusses the complexities of neurocysticercosis management.
Main symptoms and clinical findings: A 23-year-old male with neurocysticercosis-related hydrocephalus and paroxysmal sympathetic hyperactivity (PSH), presented with altered mental status, headaches, and neurological deterioration. MRI findings revealed numerous cystic lesions and characteristic findings indicative of neurocysticercosis, with subsequent CT imaging identifying progressive hydrocephalus.
Main diagnoses, therapeutic interventions, and outcomes: Neurocysticercosis with hydrocephalus and PSH was diagnosed. This necessitated the placement of a ventriculoperitoneal shunt and external ventricular drain. Despite initial improvement with antiparasitic and corticosteroid therapy, the patient’s clinical course was complicated by seizures and autonomic dysregulation. PSH was suspected due to episodes of tachycardia and diaphoresis, requiring intensified anticonvulsant therapy and sedative management with propofol. Treatment adjustments included dual antiparasitic therapy (albendazole and praziquantel) and rigorous intracranial pressure management.
Conclusion: This case highlights the complexities of neurocysticercosis management, particularly when complicated by hydrocephalus and PSH, emphasising the need for early recognition and dynamic treatment modifications. As neurocysticercosis increasingly affects non-endemic regions, healthcare systems must be equipped to recognise and treat its severe manifestations, with broader public health efforts focusing on prevention in endemic areas and among migrant populations.
Key Points
1. This case report explores the intensive care management of a young patient with neurocysticercosis, complicated by low-pressure hydrocephalus and paroxysmal sympathetic hyperactivity.
2. The case highlights the delicate balance of cerebrospinal fluid diversion, timing of antiparasitic therapy, and autonomic stabilisation in a critically ill patient with central nervous system infection.
3. This emphasises the need for greater clinician awareness of low-pressure hydrocephalus and paroxysmal sympathetic hyperactivity, two under-recognised but serious complications that require timely, nuanced, and multidisciplinary care to improve outcomes.
INTRODUCTION
Neurocysticercosis, a parasitic brain infection caused by the larvae of Taenia solium that leads to cysts in the central nervous system, is a significant public health issue in regions with poor sanitation and in populations migrating from endemic areas. Humans become infected by ingesting T. solium eggs, which develop into oncospheres capable of migrating to various organs, with a predilection for the central nervous system.1 The clinical manifestations of neurocysticercosis vary widely depending on cyst location, burden, developmental stage (active, transitional, or calcified), and host immune response, encompassing a spectrum from asymptomatic infection to severe neurological complications.1,2 While seizures and epilepsy are the most common presentations, other manifestations, such as hydrocephalus and focal neurological deficits, further complicate timely diagnosis and management.1,3,4
A large-scale study identified generalised seizures as the most prevalent symptom (62.5%), followed by headache (37.5%), focal seizures (20.8%), and localising neurological signs (16.6%), with radiological findings most commonly showing parenchymal lesions (81%) and single lesions in over half of the cases (53.5%).5 Interestingly, dietary habits played a notable role, as 39% of patients were vegetarians, and only 17.6% reported pork consumption.5
Hydrocephalus is a well-recognised complication of neurocysticercosis, resulting from either direct obstruction by cysts or an inflammatory response causing
cerebrospinal fluid (CSF) flow obstruction.5 It is present at the onset of the disease in 16–51% of patients.5 Notably, hydrocephalus associated with neurocysticercosis may exhibit distinct characteristics, such as lowpressure hydrocephalus (LPH), which poses challenges in both clinical and radiological diagnosis, due to its atypical pressure profiles and imaging findings.5,6 Current guidelines recommend surgical removal for hydrocephalus caused by viable cysts, while ventriculoperitoneal (VP) shunts and close monitoring for complications are better suited for degenerating cysts, which evoke widespread inflammation.5
Paroxysmal sympathetic hyperactivity (PSH) is a poorly understood condition characterised by episodic tachycardia, hypertension, hyperthermia, and diaphoresis following acute brain injury. PSH may exacerbate neurological deterioration and complicate ICU management if not recognised and addressed in a timely manner.7,8 This case illustrates the multifaceted challenges in diagnosing and managing the rare combination of neurocysticercosis with concurrent LPH and PSH.
CASE PRESENTATION
Patient Information
A 23-year-old Hispanic male, recently immigrated from Mexico, presented with altered mental status, headaches, nausea, and vomiting. His past medical, family, and psychosocial history were unremarkable, with no known genetic conditions or prior
neurological issues. There was no family history of seizures, neurodegenerative diseases, or autoimmune conditions.
Clinical Findings
On admission, he exhibited confusion and intermittent agitation. Neurological examination revealed impaired cognition and bilateral upper extremity hyperreflexia. He had no prior history of neurological deficits or psychiatric illness.
Diagnostic Assessment
Initial MRI revealed numerous round, symmetrically distributed lesions throughout both cerebral hemispheres, highly suggestive of neurocysticercosis (Figure 1). These lesions had a central area resembling CSF, surrounded by a sharply defined rim with adjacent white matter oedema. The characteristic 'dual rim sign' on post-contrast images, along with mild haemosiderin deposition in a lesion near the left lateral ventricle, supported the
diagnosis. Additional filling defects and fluid levels in the lateral ventricles suggested cellular debris or cystic material, consistent with neurocysticercosis-related abscesses.
CSF analysis showed a neutrophilic pleocytosis (white blood cells: 100 cells/ µL; 87–98% neutrophils), elevated protein (up to 121 mg/dL), and normal-to-high glucose (47–79 mg/dL), with negative Gram stain and negative PCR for Herpesviruses and Toxoplasma gondii. HIV testing was non-reactive. T. solium IgG by ELISA was performed and the result was negative (4.0). This does not rule out neurocysticercosis, particularly in the setting of parenchymal or ventricular disease, where serological sensitivity may be limited.
Therapeutic Intervention
The patient was started on dexamethasone and albendazole as per infectious disease and neurosurgery recommendations. Due to hydrocephalus, a right parietal
Axial MRI images demonstrating multiple cystic lesions consistent with neurocysticercosis. The top row consists of T2-weighted and fluid-attenuated inversion recovery sequences, showing hyperintense cystic lesions with surrounding oedema. The bottom row displays T1-weighted post-contrast images, highlighting ring-enhancing lesions with perifocal oedema, indicative of an active neurocysticercosis infection.
A
E F G H B
Figure 1: MRI of neurocysticercosis lesions.
VP shunt with a low-pressure valve was placed (Figure 2). Shortly after, worsening symptoms and ventricular dilation necessitated revision. Albendazole was initiated only after the VP shunt and steroid therapy to prevent exacerbation of cerebral oedema. Continuous monitoring of beatto-beat blood pressure and heart rate was performed using an arterial line, providing real-time, accurate measurements. The arterial line also facilitated serial sodium lab draws to maintain serum sodium between 140–150 mEq/L, in addition to routine labs.
His condition initially improved over the following three days, with increased alertness, spontaneous eye opening, and appropriate motor responses. He was subsequently downgraded from the ICU. However, on postoperative Day 7, he experienced an acute neurological deterioration marked by right-beating nystagmus and a rapid decline to a Glasgow Coma Scale score of 3. He was intubated for airway protection, and a CT scan revealed significant left lateral ventricle dilation, new left-to-right subfalcine
herniation, and worsening hydrocephalus. Emergent left-sided external ventricular drain (EVD) placement was performed. Despite the presence of a functioning VP shunt, worsening hydrocephalus and herniation suggested shunt malfunction. A bedside shunt tap revealed minimal return and delayed refill, prompting urgent placement of an EVD for direct intracranial pressure (ICP) control.
Following intubation, the patient displayed seizure-like activity, including opsoclonus and head jerking, managed with IV lorazepam. PSH was suspected based on concurrent tachycardia (110–130 beats per minute) and diaphoresis. Levetiracetam 1,500 mg and lacosamide 100 mg were initiated twice daily. EEG findings showed generalised alpha activity with theta and delta slowing, consistent with dynamic encephalopathy and cortical irritability, but without seizure activity.
Throughout his hospitalisation, he remained critically ill with progressive cerebral oedema, likely due to the inflammatory response to dying parasites. Albendazole
CT of the brain status post-right parietal approach ventriculoperitoneal shunt placement, with improved dilation of the ventricles compared to prior imaging.
Figure 2: Head CT post ventriculoperitoneal shunt.
therapy was escalated with praziquantel due to clinical worsening. Sodium goals were adjusted to 145–155 mEq/L, managed with 3% sodium chloride boluses and sodium chloride tablets. His EVD was set at -5 mmHg for ICP management.
Follow-up and Outcomes
The most recent brain CT showed stable ventriculomegaly; unchanged, small-volume left-sided ventricular haemorrhage; and persistent multiple cerebral abscesses. The patient remained intubated and sedated on propofol, receiving aggressive antiparasitic, anticonvulsant, and supportive care. He had shown some neurological improvement, including withdrawal to pain, eye opening to voice, and ability to follow simple commands. Following extensive discussion with the ICU and neurosurgical teams regarding prognosis and goals of care, the patient’s family elected for transfer to Mexico for continued supportive treatment. He remained intubated at the time of transfer and subsequently passed away.
TIMELINE OF KEY CLINICAL EVENTS
Please refer to Table 1 for details on the timeline of clinical events from initial presentation to subsequent transfer to a facility in Mexico.
DISCUSSION
This case of neurocysticercosis, with the severe complications of LPH and PSH, highlights the immense clinical and diagnostic challenges inherent to managing this complex parasitic infection. Neurocysticercosis, caused by the larval form of T. solium, remains a significant burden in endemic areas and among migrant populations from these regions.2
Neurocysticercosis-Related Hydrocephalus
Hydrocephalus is a frequent and severe complication of neurocysticercosis, often
resulting from cyst obstruction of CSF pathways or inflammatory reactions around cysts, leading to oedema and obstruction of CSF flow.1,3 Hydrocephalus in neurocysticercosis arises from mechanical obstruction and inflammation.5 Cysts obstruct CSF flow at key ventricular sites, causing acute symptoms like headache, or chronic issues such as gait abnormalities. Degenerating cysts trigger intense inflammation, leading to arachnoiditis, impaired CSF absorption, and fibrosis, compounding the obstruction and increasing morbidity.5
Neurocysticercosis-induced hydrocephalus can sometimes take the unusual form of LPH, where patients show clear signs of ventriculomegaly, but their CSF pressure readings appear deceptively normal, or even low.4-6 This can make diagnosis tricky, as LPH does not fit the typical pattern most clinicians expect in hydrocephalus cases.5 Because of this, recognising and treating LPH requires a different approach. As standard methods often fall short, innovative strategies, such as gently pressing on the valve intermittently to encourage drainage, or keeping the patient in a semi-reclined position, can make a big difference. In this case, the use of a low-pressure valve in the VP shunt and ensuring the patient remained in a semi-reclined position were integral to managing symptoms effectively and stabilising the patient’s condition. These methods have helped improve symptoms and lead to good recoveries, even when other treatments have failed.4,6 Acting quickly is key, as delays in addressing LPH can lead to long-term cognitive or neurological issues, making early recognition all the more critical.4,5
Paroxysmal Sympathetic Hyperactivity in Neurocysticercosis: A Compounding Factor
PSH, a condition characterised by episodic autonomic dysregulation (e.g., tachycardia, hypertension, and hyperthermia), is a recognised complication in patients with acute brain injuries, but is poorly understood in the context of neurocysticercosis and has been rarely reported in the literature.7,9,10 While PSH mechanisms remain under investigation,
they are believed to involve disrupted autonomic regulation from hypothalamic or midbrain injury, potentially exacerbated by inflammatory processes.8,9
The suspicion of PSH led to modifications in the patient’s anticonvulsant regimen, with increased dosing of levetiracetam and lacosamide, and the initiation of sedative management using propofol. Although beta-blockers are a treatment option for managing symptomatic tachycardia and hypertension associated with PSH, they were not administered due to concerns about potential haemodynamic instability and the risk of exacerbating the patient’s bradycardia and hypotension. Instead, the focus was on optimising anticonvulsant therapy and sedation to control the PSH symptoms effectively, which allowed for better management of his complex condition.
Given that PSH can exacerbate neurological deterioration, rapid intervention was necessary to mitigate further brain injury and to stabilise autonomic fluctuations. This case reinforces the importance of early recognition of PSH symptoms, as failure to address them can lead to a cascade of detrimental effects, further compromising an already tenuous prognosis.10
Therapeutic Adjustments and Management Strategies
Initial antiparasitic therapy with albendazole was combined with corticosteroids to reduce inflammation secondary to parasite die-off, a critical step in minimising the inflammatory response associated with cyst lysis.3 Imaging studies, such as CT and MRI, provided detailed insights into the stage of the disease, revealing inflammatory changes around degenerating cysts and aiding in tailoring treatment.11 However, due to the patient’s continued clinical deterioration, praziquantel was added to the regimen, a decision supported by literature advocating dual therapy in severe or refractory cases.11 The significant cerebral oedema observed, likely triggered by an inflammatory response, necessitated intensive ICP management with hypertonic saline. Targeted sodium goals were employed, emphasising the importance of balancing effective ICP
reduction with minimising risks such as hyperchloraemia and osmotic demyelination syndrome.12 These interventions highlight the necessity of combining neuroimaging advances, pharmacologic strategies, and ICP management protocols for optimising outcomes in severe neurocysticercosis cases.
This case serves as a stark reminder of the grim prognosis associated with advanced neurocysticercosis with concomitant hydrocephalus and PSH. Although the patient showed some responsiveness (e.g., withdrawal to pain and eye opening to voice), the high risk of permanent neurological impairment remained. In endemic areas and migrant populations, health education, improved sanitation, and screening for parasitic infections are vital to reducing the incidence of neurocysticercosis and its life-threatening complications.13 Physicians must recognise the importance of identifying neurocysticercosis as a global health issue, with implications for healthcare systems in non-endemic countries due to increasing migration and travel. The diverse presentation of neurocysticercosis, including LPH and PSH, demands that clinicians in non-endemic areas remain vigilant and well-informed to diagnose and manage this condition effectively.
References
1. White AC Jr, Garcia HH. Clinical manifestations associated with neurocysticercosis: a systematic review. Clin Infect Dis. 2011;52(7):911-7.
2. Garcia HH, Del Brutto OH. Clinical symptoms, diagnosis, and treatment of neurocysticercosis. Lancet Neurol. 2014;13(12):1202-15.
3. White AC Jr et al. Diagnosis and treatment of neurocysticercosis: 2017 clinical practice guidelines by the IDSA and ASTMH. Clin Infect Dis. 2018;66(8):e49-75.
4. Hamamoto Filho PT et al. Hydrocephalus in neurocysticercosis: challenges for clinical practice and basic research perspectives. World Neurosurg. 2019;126:264-71.
CONCLUSION
Discussed herein is the rarity and clinical complexity of managing severe neurocysticercosis when complicated by LPH and PSH. LPH itself is an uncommon variant of hydrocephalus that defies the typical diagnostic patterns of elevated CSF pressure, making it especially challenging to identify and manage in regions where neurocysticercosis is rarely encountered. Similarly, PSH is seldom reported in the context of neurocysticercosis, adding another layer of diagnostic and therapeutic difficulty. These complications are more likely to be overlooked in non-endemic areas of the USA, where clinicians may have limited experience with the nuanced presentations of neurocysticercosis.
INFORMED CONSENT
The patient’s father (legal representative) provided informed consent for the publication of this case report, including the use of imaging and clinical details while ensuring confidentiality.
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8. Thomas A, Greenwald BD. Paroxysmal sympathetic hyperactivity and clinical considerations for patients with acquired brain injuries: a narrative review. Am J Phys Med Rehabil. 2019;98(1):65-72.
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The Intersection of Menopause and Epilepsy: A Review of Current Knowledge and Gaps
Authors: Paula E. Voinescu,1-3 Kelsey M. Smith,4 Thazin Latt,5 Modhi Alkhaldi,6 Preeti Puntambekar,7 Katherine Zarroli,8 Emily Pegg,9,10 Barbara Decker,11 Anumeha S. Sheth,12 Kelly R. Conner,13,14 Gloria Ortiz-Guerrero,4 Isha Snehal,4 Leah Blank,15 Rebecca Bromley,10 Jennifer Cavitt,16 Suparna R. Krishnaiengar,8 Temenuzhka Mihaylova,17 Debra Moore-Hill,18 Anna Norton,10 *Esther Bui,19,20 Lata Vadlamudi21,22
1. Department of Neurology, Division of Epilepsy, Brigham and Women’s Hospital, Boston, Massachusetts, USA
2. Department of Medicine, Division of Women's Health, Brigham and Women's Hospital, Boston, Massachusetts, USA
3. Harvard Medical School, Boston, Massachusetts, USA
4. Department of Neurology, Division of Epilepsy, Mayo Clinic, Rochester, Minnesota, USA
5. AdventHealth Medical Group, Orlando, Florida, USA
6. Department of Neurology, College of Medicine, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia
7. Department of Neurology, Westchester Medical Center Health Network, New York Medical College, Valhalla, USA
8. Department of Neurology, University of Florida College of Medicine-Jacksonville, Florida, USA
9. Manchester Centre for Clinical Neurosciences (MCCN), Salford Royal Hospital, UK
10. Division of Neuroscience, The University of Manchester, UK
11. Department of Neurology, Mary Washington Healthcare, Fredericksburg, Virginia, USA
12. Ayer Neuroscience Institute Comprehensive Epilepsy Center, Hartford HealthCare, Connecticut, USA
13. Department of Physician Assistant Studies, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
14. Department of Neurology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
15. Icahn School of Medicine at Mount Sinai, New York, USA
16. Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Ohio, USA
17. University of Michigan, Ann Arbor, USA
18. Wellstar MCG Health, Augusta, Georgia, USA
19. Division of Neurology, Department of Medicine, University of Toronto, Canada
20. Krembil Brain Institute, University Health Network, University of Toronto, Canada
21. The University of Queensland, UQ Centre for Clinical Research, Herston, Australia
22. Department of Neurology, Royal Brisbane & Women's Hospital, Australia
*Correspondence to Esther.Bui@uhn.ca
Disclosure:
Voinescu has received grants from the Epilepsy Foundation of New England Blue Sky Award and 2023 Casey Toolin McAuliffe Memorial IGNITE Award; PhD opponent honoraria from the University of Bergen, Norway; and speaker honoraria from the Philippines League Against Epilepsy. Smith has received research support from UCB Pharma. Bromley has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from UCB Pharma. Conner has received payment or honoraria for speakers’ bureaus from SK Life Science, Inc.; and honoraria for lectures, presentations, speakers’
bureaus, manuscript writing, or educational events from UCB Pharma. Conner has received payment or honoraria for speakers’ bureaus from SK Life Science, Inc.; and honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from the Penry APP Mini Fellowship in Epilepsy. Blank has received salary support from the National Institute on Aging; and grant support from the National Institiute on Aging (K23AG080163). Norton’s PhD project is affiliated with the Division of Neuroscience, The University of Manchester, UK; and she has received co-funding from the Epilepsy Research Institute UK and The University of Manchester. Vadlamudi has received the Metro North Clinician Research Fellowship and Queensland Health Clinical Research Fellowship; speaker honoraria and/or consultancy fees from Eisai and UCB Pharma; and is an investigator on a collaborative research project with UCB Pharma, not influencing the current piece of work. Bui and Vadlamudi have contributed equally to this work. The other authors have declared no conflicts of interest.
Acknowledgements: The authors would like to thank all members of the Epilepsy in the Childbearing Ages Through Menopause (ECAM) Consortium - Menopause Committee for the insightful discussions that contributed to the development of this article. ECAM Menopause Committee members that are not named authors include: Julie Roth, Brown University, Providence, Rhode Island, USA; Lynn Lu, University of North Carolina, Chapel Hill, USA; Jyoti Pillai, Tower Health/Reading Hospital, West Reading, Pennsylvania, USA; Vessela Giger, Central Michigan University, Mount Pleasant, USA; Barbara Mostacci, MD, IRCCS Istituto delle Scienze Neurologiche di Bologna, Italy; Emanuele Cerulli Irelli, Sapienza University, Rome, Italy; Genna Waldman, University of Pennsylvania, Philadelphia, USA; Jamie Maguire, Tufts University School of Medicine, Boston, Massachusetts, USA; Hellen E. Scharfman, New York University, USA; and Nishtha Gupta, University of Vermont, Burlington, USA.
While hormonal changes have been recognised to influence seizure control and have been studied in association with menstrual cycles and pregnancy, there is a paucity of data on the menopause transition in epilepsy. Given the known effects of sex steroid hormones on neuronal excitability, their endogenous fluctuations during perimenopause, as well as menopause hormone treatments, may alter seizure control. Epilepsy may also be associated with premature ovarian insufficiency and early menopause. This is especially important for epilepsy-related comorbidities, for which menopause can constitute a second hit, such as osteoporosis. Additional considerations for females with epilepsy across the menopause continuum include changes in antiseizure medication clearance and potential interactions with menopausal hormone therapy or other concomitant medications. This comprehensive review summarises the currently available literature on epilepsy and menopause, highlights gaps in knowledge, and underscores the need for research efforts, particularly longitudinal studies investigating the menopause transition.
Key Points
1. Given the known influence that endogenous sex hormone fluctuations and exogenous hormone therapies can have on seizure susceptibility and antiseizure medication clearance, there are many important clinical considerations regarding the menopause transition for females with epilepsy.
2. The article summarises the currently available literature on epilepsy and menopause, including the influence of epilepsy on the timing of menopause and associated comorbidities; considerations about how the menopause transition may influence seizure frequency and antiseizure medication clearance; and the use of menopausal hormone therapy.
3. The relationship between menopause and epilepsy is complex. The currently available literature is sparse, and there is a lack of evidence-based practice guidelines for managing epilepsy through the menopause transition. Further studies, including longitudinal studies that follow females with epilepsy from their reproductive years through the menopausal continuum, are necessary to better understand the relationship between epilepsy and menopause.
INTRODUCTION
Epilepsy is a serious and common neurological condition, characterised by recurring, unprovoked seizures, affecting approximately 25 million females worldwide.1 Historically, the term ‘women’ has been used to encompass both sex- and genderspecific issues in epilepsy. In this paper, the term ‘female’ will be used where appropriate to highlight sex-specific considerations in epilepsy. Sex-specific research studies of people with epilepsy have focused primarily on care during the reproductive years, while few studies have addressed hormonal influences beyond reproductive stages, such as perimenopause, menopause, and post-menopause, collectively known as the menopause continuum. Sex steroid hormones (SSH) exert unequivocal effects on neuronal excitability. Oestrogen increases excitation through its effects on glutamate receptors. In contrast, progesterone neuroactive metabolites, such as allopregnanolone, are positive modulators of γ-aminobutyric acid (GABA) receptors, thereby potentiating inhibition. However, activation of progesterone receptors may increase excitation through effects on α-amino-3hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, reflecting the complex molecular actions of progesterone.2 The ability to identify individuals with heightened sensitivity to hormonal fluctuations and personalise treatment is limited. These challenges are especially pronounced during perimenopause and menopause.3
Fluctuations in SSH, such as oestrogen and progesterone, during perimenopause and menopause may affect both neuronal excitability and antiseizure medication (ASM) clearance, which can additionally impact the frequency and severity of seizures. This is further influenced by individual variability in hormonal fluctuations, sensitivity to SSH changes, and age-related alterations in ASM metabolism and clearance.
This article will review epilepsy in the context of SSH changes during perimenopause and menopause; the complex relationship between ASMs, SSHs, and bone health; and key gaps and opportunities for future research to personalise care for individuals during perimenopause and menopause.
METHODS
An extensive search was done using the search terms ‘epilepsy’ and ‘menopause’ to gather articles from 2006–2023 on PubMed, Ovid, and the Cochrane Library for analysis. Key articles published prior to 2006 that pertained to this subject were also included within the scope of this approach. The authors selected predominantly original research articles with relevant information on the metabolic pathways of ASMs and pharmacokinetic changes in pregnancy/ postpartum, with occasional relevant reviews included. The initial selection was further supplemented with studies identified by co-authors to be relevant for inclusion.
The article was reviewed and edited by expert clinicians and scientists from the Epilepsy in the Childbearing Age Through Menopause (ECAM) Consortium - Menopause Committee. ECAM is an international consortium of clinicians and scientists with the mission to advance optimal care for patients with gestational potential and epilepsy across their lifespan, by fostering interdisciplinary research and clinical collaborations across participating institutions.
SEX STEROID HORMONES AND EPILEPSY
Females with epilepsy present unique challenges due to the cyclical fluctuation of SSH concentrations and their metabolites throughout the lifespan. Such hormone shifts can impact seizure susceptibility in a complex manner, as highlighted in the authors’ recent article on the biosynthesis, regulation, and mechanisms of action of such hormones and their impact on epilepsy.4
Sex Steroid Hormones During Transition to Menopause
The pattern of SSH fluctuations is divided into three biological stages: (1) premenstrual/pre-menarche years; (2) menstrual/reproductive years; and (3) menopausal years, with two main transition periods: adolescence and perimenopause. Perimenopause is a key transitional period involving increased anovulatory cycles with fewer cyclic progesterone elevations and unpredictable oestrogen surges that can last up to 10 years.
Although SSHs fluctuate during the perimenopause years, the extent and pattern of these fluctuations remain poorly understood. In 2001, a multidisciplinary group of experts convened a Stages of Reproductive Aging Workshop (STRAW), establishing the STRAW criteria, a consensus-derived staging system that defines reproductive, perimenopausal, and menopausal transition, as well as postmenopausal stages, and which has been updated in subsequent years.5 The
STRAW criteria were derived from cohort studies of midlife females with chronic illness and endocrine disorders, examining changes in menstrual, endocrine, and ovarian markers. These markers included anti-Müllerian hormone, inhibin-B, folliclestimulating hormone, and antral follicle count, and they established stages for the menopausal transition and postmenopausal phase. The STRAW criteria enable a standardised terminology for these important life stages. The authors’ review will highlight epilepsy in the context of these reproductive life stages, as summarised in Figure 1.
The Menopause Transition
The effect of epilepsy on the timing of reproductive cycling cessation Epilepsy may affect reproductive health, and while data on fertility is equivocal,6,7 several lines of evidence support a higher rate of premature ovarian insufficiency and early menopause in females with epilepsy. In one study, females with epilepsy (N=50; 41 with focal and nine with generalised epilepsy), interviewed about symptoms and assessed with endocrine markers, had a significantly higher rate of non-surgical premature perimenopause and menopause compared with control females without epilepsy (14% versus 3.7%; p<0.042). The mean age of estimated premature ovarian insufficiency in the epilepsy cohort was 39.6 years (range: 37–42 years), with no clear correlation with epilepsy duration, severity, or ASM type. Interestingly, the only clinical factor that correlated with premature ovarian insufficiency was a history of catamenial seizure exacerbation (pattern aligned with the cyclic hormonal fluctuation during the menstrual–ovarian cycle; p<0.02).8
Yet another study, which surveyed a cohort of females with epilepsy aged ≥45 years, raised concern that a higher seizure burden was associated with the earlier cessation of reproductive cycling (p=0.014). No correlation with ASMs was observed, consistent with the previous study. This study concluded that seizures may disrupt hypothalamic and pituitary function or alter neurally mediated trophic effects on the ovary.9
Principalcriteria: Menstrualcycle
Antiseizure medication considerations
Cyclical, predictable fluctuations in the circulating oestrogen and progesterone concentrations as dictated by the hypothalamic–pituitary–ovarian axis
Catamenial epilepsy affects ~50% with menstrual exacerbation seen in ~70%
Possible interactions between ASMs and hormonal contraceptives. Many ASM concentrations decrease due to clearance changes during pregnancy Fertility treatments may affect some ASM concentrations
Progesterone declines due to more frequent anovulatory cycles; oestrogen fluctuates unpredictably and with transient concentrations above reproductive levels
Menopause Continuum
Consistently low levels of estrogen and progesterone due to cessation of ovarian hormone production
Possible risk of increased seizure frequency/severity, especially for those with prior catamenial seizure exacerbation
Lamotrigine concentrations may be altered by endogenous SSHs fluctuations and MHT. Other ASM concentrations may be affected, but no study to date to assess this
Adapted from Harlow SD et al.4 used under CC BY-NC 4.0.
Possible improvement in seizure frequency/severity
Lamotrigine concentrations may rise due to low endogenous SSH concentrations. Other ASM concentrations may be affected, but no study to date to assess this
The course of epilepsy during perimenopause and menopause
Assuming a simplified view that progesterone, through the metabolite allopregnanolone, is predominantly an anticonvulsant, while oestrogen, through the metabolites oestradiol and oestrone, is a proconvulsant, the expected outcome is that perimenopausal females experience unpredictable periods of heightened seizure intensity and frequency.4 It is conceivable that seizure worsening is more likely to happen in early perimenopause, with higher amplitude oestrogen surges, and less so in late perimenopause, when the concentrations settle towards lower values. Indeed, females with catamenial epilepsy, thought to be more sensitive to hormonal fluctuations, were shown to have a higher risk of seizure worsening during perimenopause, followed by an improvement in seizure frequency and severity at the completion of menopause.9-11
Around half of females with epilepsy have a catamenial pattern,12,13 while about two-thirds of all females have seizure worsening during perimenopause.10 A crosssectional study using mailed questionnaires completed by 42 respondents evaluated the course of epilepsy from reproductive years through perimenopause and menopause, and concluded that the high percentage of females in the perimenopausal group who took synthetic hormone replacement therapy were significantly associated with an increase in seizures (p=0 001).10 This group went on to investigate the effect of menopausal hormone therapy on seizures at this stage in life.14
In contrast, a cross-sectional study employing a structured interview of 61 participants in the menopause continuum (46 postmenopausal and 15 perimenopausal)15 found mixed results regarding seizure frequency at
Figure 1: Stages of reproductive ageing and clinical considerations for females with epilepsy.
menopause. Among the 49 participants with epilepsy onset before menopause, 40.8% reported seizure worsening, 26.5% reported improvement, and 32.6% reported no definitive change at menopause. Interestingly, 12 (20%) of the 61 females from the study reported that seizures first began during or after menopause, with eight having no proven cause for their epilepsy.
Additional SSHs of importance through the menopause continuum, though less commonly considered, are testosterone and its metabolites, androstanediol and oestradiol.16 During menopause, testosterone serum concentration changes as well, affecting sexual function, mood, bone health,17 and possibly neuronal excitability and seizure control.
With the limited available data, females with epilepsy may have an increased risk for seizure worsening at perimenopause and possibly a lower risk in the postmenopausal period. In the absence of definitive staging of the menopause continuum and therapeutic strategies to address this problem, there are currently no guidelines available for creating a personalised treatment plan during this vulnerable period.
Menopausal Hormonal Therapy
Current MHT employs combined oestrogenprogestin therapy for people with an intact uterus (who need a progestin to prevent oestrogen-related endometrial hyperplasia) and oestrogens alone for females who have undergone hysterectomy.18 The use of MHT at menopause decreased significantly after the initial findings of the Women’s Health Initiative (WHI) published in 2002,19 which reported an increased risk for invasive breast cancer. After conducting an evidence-based analysis of the subsequent literature in the following two decades, the 2022 North American Menopause Society position statement acknowledged that the risks of hormone therapy differ depending on type, dose, duration of use, route of administration, timing of initiation, and whether a progestin is used.20 Their consensus recommendations emphasise the importance of MHT as the most effective treatment for vasomotor and genitourinary
symptoms, and it has been shown to prevent bone loss and fracture. For females aged younger than 60 years or those within 10 years of menopause onset, with no contraindications, the benefit–risk ratio is favourable for the treatment of menopauserelated signs and symptoms, as well as prevention of bone loss.
The effect of menopausal hormone therapy in people with epilepsy
Given evidence that people with epilepsy may be at risk of early menopausal onset8,9 and have multifactorial risks for osteoporosis,22 consideration of MHT is important. An additional concern for people with epilepsy is the influence of exogenous SSH administration on seizure control.
One randomised, placebo-controlled, double-blind clinical trial investigated the effect of conjugated equine oestrogens/ medroxyprogesterone acetate (0.625 mg of conjugated equine oestrogens (CEE/ MPA) plus 2.5 mg of medroxyprogesterone acetate) compared with placebo on seizure frequency in postmenopausal females with epilepsy.22 The study was halted before the enrolment target, after publication of the WHI study results in July 2002.19 Despite the low numbers (n=21), the study demonstrated a significant conjugated equine oestrogens/ medroxyprogesterone acetate doserelated increase in seizure frequency in postmenopausal females with epilepsy, as well as altered ASM levels in two patients.
Another interview-based cross-sectional study yielded conflicting findings: 31/61 (51%) of menopausal patients had used MHT (MHT-specific details were not provided and likely various preparations were used), 22 (71%) experienced no changes in seizure frequency, five (16%) showed improvement, and four (13%) reported worsening.15
A recent systematic review summarised what is known about the impact of MHT on seizure frequency, noting only three human studies and limited evidence available.22 Despite the limited evidence, at perimenopause, some experts may use forms of MHT to suppress hormonal fluctuations and help with seizure control when other therapies fail. This approach has a biological rationale due to the
shared biology with catamenial epilepsy. As more MHT options emerge, with guidelines supporting their use in the general population, there is a pressing need for more research due to the unique implications of MHT on seizure control.
SEX STEROID HORMONES AND ANTI-SEIZURE MEDICATIONS
ASMs provide the foundation for the medical treatment of epilepsy. When selecting an ASM, there are multiple primary factors that are considered, including the type of epilepsy (generalised or focal), childbearing potential, comorbidities, and concurrent medications. Current practice often overlooks the impact of changes in SSHs, which could have a significant effect on medication metabolism and possibly efficacy, depending on the patient’s biological stage.
Pharmacokinetic Changes During Transition to Menopause
There is a bidirectional interaction between ASM and SSHs. ASMs that induce hepatic enzymes (such as cytochrome P450 3A4 [CYP3A4]) and increase sex hormonebinding globulin (SHBG) accelerate SSHs metabolism and lower their circulating concentrations, which may be relevant when considering MHT options. Conversely, there is solid evidence from pregnancy studies that SSHs affect the clearance of many ASMs.23-25
There are several additional broader considerations for older people with epilepsy, such as heightened sensitivity to neurocognitive adverse effects, ASM interactions and reduced metabolism, deleterious effects on bone health, and cholesterol homeostasis.27-28 People with epilepsy reported better quality of life on monotherapy compared to polytherapy.29 It may be beneficial to transition to monotherapy to improve quality of life; however, such changes must be carefully balanced with the need to maintain stable seizure frequencies.
The effect of ageing on glomerular filtration rate (GFR) is well known with a gradual decrease occurring over time, which is not
specific to patients with epilepsy. Although glomerular filtration is directly proportional to body weight, there may also be weightindependent sex differences in GFR.30 Importantly, females with an earlier onset of menopause have a higher incidence of decreased GFR than females with a longer reproductive period.31 Therefore, ASMs that are predominantly renally-leared, for example, levetiracetam, lacosamide, and zonisamide, may theoretically accumulate to higher serum concentrations in postmenopausal years when compared to reproductive years.
Lamotrigine and Sex Steroid Hormones
Lamotrigine has a bidirectional interaction with SSHs. Oestrogen can reduce serum lamotrigine concentrations, and lamotrigine can decrease sex hormone concentrations, in particular progesterone,32 though the effect is modest.
Prior work on hormonal contraception and lamotrigine interactions,33,34 as well as pregnancy-related changes in lamotrigine clearance35,36 demonstrated that UGT-glucuronidases, which metabolise lamotrigine, are influenced by oestrogen concentrations. Glucuronidation is highest at the end of pregnancy, and it is likely to be significantly decreased at menopause due to low oestrogen concentrations. Indeed, one study with samples from 507 females and 302 males taking lamotrigine found that clearance as a function of bioavailability increased after age 18 years, peaked at 36 years, and gradually declined with advancing age.37 Another study of dose/concentration ratios for 752 males and 1,115 females on lamotrigine showed a decline in females aged 51–55 years, when dose/concentration ratios became significantly lower among females than among males in this age group (p<0.05).38
The interaction between lamotrigine and oestrogen is especially important when considering the use of MHT at menopause. Exogenous oestrogen may lead to an increased lamotrigine clearance, resulting in low lamotrigine concentrations, which may exacerbate seizures. The previously mentioned CEE/MPA trial in epilepsy found
that patients taking lamotrigine in the treatment arm not only had an increase in seizure frequency, but also a decrease in lamotrigine concentrations by 25–30%.14 Findings were reinforced by a retrospective study that analysed 79 users of lamotrigine and MHT, and found that oestradiol/ oestriol-based MHTs reduced lamotrigine serum concentration-to-dose ratios.39 The magnitude of this interaction is variable and has been attributed to interindividual differences in the hepatic glucuronidases involved in lamotrigine metabolism.35,40
Despite the above data, lamotrigine serum concentrations are not routinely monitored during perimenopause, when they are likely to fluctuate. Similarly, when patients attain postmenopausal status, if on the same dose, they most likely have higher serum concentrations than during reproductive years and may benefit from a dose reduction to prevent risk of toxicity.
Enzyme-Inducing Anti-Seizure
Medications
and Sex Steroid Hormones
Strong (e.g., phenobarbital, primidone, phenytoin, carbamazepine, oxcarbazepine, cenobamate) and weaker hepatic enzyme CYP3A4 inducers (e.g., topiramate, perampanel, clobazam) increase the metabolism of SSHs, resulting in lower concentrations. Some ASMs (e.g., carbamazepine, oxcarbazepine) also induce SHBG, which results in reduced SSH concentrations.41 Therefore, regimens including any of these ASMs may be expected to require adjustments in the dosage of hormone therapy.
BONE HEALTH AND OTHER COMORBIDITIES AT MENOPAUSE
Bone Health During the Menopause Continuum
Oestrogen regulates bone remodelling by inhibiting osteoclasts and is essential for bone health.42 Menopause is known to be the most important risk factor for bone loss in females. The lack of ovarian-derived oestrogen after menopause accelerates bone mineral density loss compared to
males and significantly increases the risk of fractures. Osteoporosis is defined as a bone mineral density 2.5 standard deviations below gender matched controls (T-score < –2.5), and osteopenia is defined as a T-score between –1 and –2.5. Approximately 30% of postmenopausal females in the USA have osteoporosis, and 54% have osteopenia.43
Epilepsy is associated with a significant increased risk of osteoporosis and has been shown to be associated with a twoto six-times increased risk of fractures.44 The underlying pathophysiology of this increased risk is not completely understood, and multiple mechanisms are likely involved. The increased risk of fracture is present even when excluding seizurerelated fractures.44 ASMs have been found to contribute to the increased risk of metabolic bone disease in people with epilepsy.45 Enzyme-inducing ASMs lead to reduced concentrations of vitamin D and can also reduce the concentrations of oestrogen and testosterone by increasing SHBG concentrations, mechanisms that contribute to bone loss.44 Non-enzyme inducing ASMs, such as valproate, have been found to impact bone health as well. In a cross-sectional study of premenopausal females, carbamazepine, phenytoin, and valproate were associated with significantly lower concentrations of calcium compared to lamotrigine.46 This study also found that phenytoin was associated with higher concentrations of bone-specific alkaline phosphatase and reduced concentrations of insulin growth factor-1 (IGF-1) compared to carbamazepine, valproate, and lamotrigine. Epilepsy itself has been found to negatively influence bone health. A study of biochemical markers of bone metabolism of children with self-limited epilepsy with centrotemporal spikes, which included an untreated group, concluded that epilepsy alone can affect many aspects of bone metabolism.45 Smoking and alcohol consumption, and a sedentary lifestyle are also more common among people with epilepsy, which can contribute to an increased risk of osteoporosis.
The combined risks associated with oestrogen deficiency after menopause, as well as earlier menopause associated
with epilepsy leading to longer oestrogen deficiency, and the negative effects of epilepsy and ASMs on bone health all contribute to the risk of osteoporosis and fractures in postmenopausal females with epilepsy. In a study of 26 postmenopausal females with epilepsy, 62% had osteoporosis compared to 27% in a matched control group.47 It is crucial for clinicians to recognise that postmenopausal females with epilepsy are especially vulnerable to developing osteoporosis, as hip fractures are associated with a 1-year mortality rate of around 20%.43 However, evidence-based guidelines about the ideal screening and prevention strategies are lacking. Lifestyle factors that support bone health, such as adequate nutrition, weight-bearing exercise, and avoidance of smoking and alcohol, should be encouraged. Vitamin D and calcium supplementation should be encouraged, especially for those with an inadequate dietary intake and those at higher risk for osteoporosis.48 Routine screening of 25-hydroxyvitamin D should be considered once or twice per year, especially in those taking enzyme-inducing ASMs.49 Screening dual-energy X-ray absorptiometry scans should be considered in patients with epilepsy at elevated risk, including postmenopausal females.48 If osteoporosis is identified, then a referral to an endocrinologist or bone specialist should be considered for further management.
Other Comorbidities During Transition to Menopause
Sleep disturbances, a common symptom of perimenopause and menopause, may further exacerbate seizure risk. Vasomotor symptoms, such as night sweats and hot flushes, combined with chronic insomnia, contribute to sleep deprivation, a welldocumented seizure trigger. Gómez-Santos et al.50 reported that menopausal females exhibit a loss of circadian robustness and worsening sleep quality compared to premenopausal females, which could negatively impact control.50 Interestingly, gabapentin has been shown to reduce vasomotor symptoms in menopausal females. There is evidence that gabapentin improves sleep quality and reduces hot flushes, which could potentially improve seizure control in females with epilepsy during menopause.51,52
These findings highlight the dual benefits of gabapentin for managing both seizures and menopausal symptoms.
The decline in oestrogen levels during menopause can exacerbate metabolic changes and increase the risk of insulin resistance, Type 2 diabetes, dyslipidaemia, and coronary artery atherosclerosis.53,54 This can disproportionately affect females with epilepsy who are at risk for earlier menopause. An earlier age of menopause also affects cardiovascular mortality.55 A recent cohort study found that epilepsy was associated with a higher risk of diabetes and adverse post-diabetes outcomes, such as infections and septicaemia.56 The clustering of comorbidities in menopause should prompt more effective risk factor management in females with epilepsy. ASMs such as valproate can be associated with metabolic disturbances, weight gain, and insulin resistance, in addition to elevating androgen levels, leading to hyperandrogenism and associated metabolic issues.57 Balancing and targeting other comorbidities during the transition to menopause in females with epilepsy can improve overall quality of life in this population.
DISCUSSION
While hormonal shifts during menstrual cycles and pregnancy offer insight into how the menopause continuum may affect seizure control in females with epilepsy, specific data on this topic are scant. No longitudinal studies have followed individuals with epilepsy through the menopausal continuum, resulting in significant knowledge gaps and a lack of evidence-based practice guidelines for managing epilepsy through the menopausal continuum.
When considering the influence of perimenopause and menopause on seizure control, current data are limited to small studies, primarily reliant on questionnaires. While anecdotal evidence suggests that seizure control may worsen during perimenopause secondary to unpredictable hormonal fluctuations, and improve with lower oestrogen concentrations in
postmenopause, longitudinal studies are necessary to accurately determine this relationship. Furthermore, the contribution from endogenous hormonal fluctuations and medication clearance changes should be further examined. These studies would require following females with epilepsy from their reproductive years through the menopause continuum. Ideally, they would track seizure control; menstrual cycle patterns; follicular-stimulating hormone, anti-Müllerian hormone, and oestrogen concentrations; and ASM concentrations. With advancing technology and the ability to quantitatively track seizure frequency, such as the Responsive Neurostimulation System (RNS®; NeuroPace, Mountain View, California, USA), there may be future opportunities to objectively track seizures through the menopause transition. Longitudinal studies would also provide further data about the risks of early menopause in females with epilepsy, as current data from small studies suggest there is an elevated risk, potentially impacting seizure control. Systematically integrating data collection on a patient’s reproductive state may also further inform whether menopause (and not age alone) could be an important factor for surgical outcomes, especially as epilepsy surgery can be efficacious and safe in older populations (age: ≥50 years).58
Another important aspect of management that requires further study over the menopause continuum is the change in ASM metabolism and its impact on clinical care. For example, evidence supports that critical changes in metabolism occur with ageing for lamotrigine. With reduced clearance in postmenopausal years, lamotrigine concentrations may rise and lead to an increased risk of toxicity. The influence of hormonal changes at menopause on other ASMs also requires further study. Therapeutic drug monitoring has been instrumental during pregnancy in understanding clearance changes and optimising clinical care; a comparable approach may be beneficial during the menopausal continuum, with strategic adjustments for individual timelines.
MHT is the main treatment for bothersome menopause symptoms, such as vasomotor
symptoms. Moreover, MHT may have longterm health benefits for people with early menopause. However, the one clinical trial studying MHT in epilepsy demonstrated worsened seizure frequency in a dosedependent manner.14 Since this trial, the knowledge and use of MHT have greatly evolved, with a better understanding of the safety, efficacy, and ideal doses and routes of administration. Many MHTs have not been studied in females with epilepsy. Equally important, the effects of menopause symptoms and the consequences of leaving them untreated on seizure control remain unknown. Randomised, placebo-controlled trials are needed to evaluate the safety and efficacy of various MHTs, with attention to both seizure control and menopause symptom management.
Evidence demonstrates that postmenopausal females with epilepsy face an elevated risk of osteoporosis and fractures. Epilepsy itself, ASMs, and low oestrogen levels after menopause are established contributors to bone density loss. Despite these known risk factors, optimal screening protocols, including timing and frequency of bone mineral density assessments, and follow-up strategies for patients without baseline osteoporosis have yet to be defined. Although lifestyle interventions to preserve bone health are advocated, evidence-based approaches to mitigate fracture risk in this population with epilepsy are lacking.
Although not discussed in detail here, several medical conditions beyond osteoporosis, many of which are already comorbid with epilepsy, may experience a ‘second hit’ due to physiological changes at menopause, potentially accelerating their progression in people with epilepsy compared to those without. Particularly important for both quality of life and mortality are sleep disorders, cognitive decline, and cardiovascular disease.
In conclusion, perimenopause and menopause represent a crucial and significant transition in every female’s life. Evolving research on perimenopause and menopause may be applied to the postmenopause stage, with potential
opportunities for preventative models of care. Several important considerations arise for people with epilepsy in this transitional state, including the influence of hormonal changes on seizure control, alterations to ASM metabolism, the effects of MHTs on epilepsy, and bone health. There are
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Unveiling the Versatility of Neurosonology: Insights from Two Clinical Cases on Vertebrobasilar Pathology
Authors: Laura Rabboni,1 *Vincenzo Inchingolo,2 Teresa Popolizio,3 Lucia Florio,2 Giuseppe d’Orsi,2 Maura Pugliatti1
1. Clinical Neurology Unit, Neurosciences and Rehabilitation Department, University of Ferrara, Italy
2. Neurology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
3. Radiology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
*Correspondence to v.inchingolo@gmail.com
Disclosure: The authors have declared no conflicts of interest.
A variety of imaging modalities, including magnetic resonance angiography, computed tomographic angiography, digital subtraction angiography, and ultrasound, can be employed to identify haemodynamic changes in patients with cerebrovascular disorders. This article underscores the diagnostic utility of neurosonological assessment of cerebral vessels through two illustrative clinical cases involving pathologies of the vertebrobasilar circulation.
Key Points
1. This article demonstrates the value of neurosonology as a non-invasive, bedside diagnostic tool through two distinct vertebrobasilar cases, one ischaemic stroke with complex haemodynamic compensation and one malformative arteriovenous fistula with reversed flow patterns, highlighting how neurosonological insights complement neuroradiological imaging and guide diagnosis, treatment planning, and follow-up.
2. Neurosonology enables the dynamic, real-time evaluation of cerebral circulation, even in anatomically challenging regions such as the vertebrobasilar system. It facilitates the detection of reversed flow, collateral pathways, and velocity changes, thereby supporting risk stratification, treatment decisions, and follow-up in patients with posterior circulation disorders.
3. The accuracy and clinical utility of neurosonological assessments critically depend on the operator’s expertise, underscoring the importance of dedicated educational programmes and continuous skill development.
INTRODUCTION
Neurosonology is a versatile, non-invasive diagnostic modality for evaluating cerebral circulatory disorders.1 It provides realtime haemodynamic and morphological information, enabling the identification of occlusions, stenoses, and other vascular abnormalities. In addition to diagnostic applications, neurosonology allows for longitudinal monitoring and contributes prognostically to clinical decisionmaking.2 Although its morphological detail and panoramic view may be more limited compared with neuroradiological techniques,3,4 neurosonology offers distinct advantages: it is more accessible, noninvasive, easily repeatable, and can be performed without moving the patient, particularly in the stroke unit. Moreover, unlike computed tomographic angiography (CTA), it does not involve exposure to ionising radiation, and unlike magnetic resonance angiography, it can be used in patients with metallic implants or poor compliance. As such, neurosonology serves as a valuable complement to neuroradiological investigations.5,6 This article presents two clinical cases in which the combined use of neurosonology and radiological imaging facilitated a comprehensive understanding of two distinct vertebrobasilar pathologies, one ischaemic, and the other malformative.
METHODS
Neurosonological assessment was performed according to established protocols, employing extracranial and transcranial colour-coded duplex sonography for haemodynamic evaluation of the vertebrobasilar system.7 Severe intracranial vertebral artery (VA) stenosis was defined according to the criteria proposed by Danyel et al.,8 which identify a peak systolic velocity (PSV) of ≥120 cm/s in the V4 segment, together with poststenotic flow alterations and/or collateral circulation, as indicative of high-grade stenosis (70–99%).
Whenever possible, neurosonological findings included the reporting of
quantitative parameters for each evaluated vessel, specifically PSV, end-diastolic velocity (EDV), resistance index (RI), and, where appropriate, pulsatility index (PI). The RI was calculated as (PSV–EDV)/PSV, while PI was calculated as (PSV–EDV)/mean flow velocity.
FIRST CASE
A 57-year-old man presented with a 3-week history of subjective dizziness, nausea, and postural instability, with a tendency to fall to the left and difficulty walking (post-National Institutes of Health Stroke Scale [NIHSS] score of 5). The patient had a history of arterial hypertension and uncontrolled diabetes. An emergency brain CT scan showed signs of subacute left cerebellar and occipital ischaemia. As there were no indications for revascularisation treatment, the emergency study was not completed with a CTA. In the stroke unit, a comprehensive neurosonological examination of the cerebrovascular arteries revealed the following findings.
On the left side:
• Patency of the VA in the extracranial segment, with a marked increase in RI (PSV: 30 cm/s; EDV: 4 cm/s; RI: 0.86; Figure 1A).
• No detectable flow signal in the V3 segment, with reversed flow in the V4 segment, continuous with the ipsilateral posterior inferior cerebellar artery (PICA; PSV: 36 cm/s; EDV: 16 cm/s; PI: 0.88; Figure 1B).
On the right side:
• Severe stenosis in the V4 segment (PSV: 410 cm/s; EDV: 218 cm/s; PI: 0.68; Figure 1C).
• Patency of the basilar artery (BA) with a normal velocity profile (PSV: 48 cm/s; EDV: 22 cm/s; PI: 0.85; Figure 1D).
C) TCCD of the right V4 segment showing severe stenosis.
D) TCCD of the BA revealing normal flow velocity profile and direction.
Subsequent CTA confirmed severe stenosis in the right V4 segment, normal visualisation of the left VA from its origin to the distal V2 segment, missing V3 segment, and reappearance in the V4 segment before terminating in the PICA (Figure 2). The case was discussed with interventional radiology and, given the patient’s asymptomatic status and adequate haemodynamic compensation, the best medical treatment was chosen. This included dual antiplatelet therapy (aspirin 100 mg daily and clopidogrel 75 mg daily) and atorvastatin 80 mg daily for 3 months, followed by clopidogrel 75 mg daily and atorvastatin 40 mg daily.
The patient continues to undergo neurosonological follow-up. Angiographic intervention with potential stent placement remains a secondary option in the event of clinical deterioration. In this clinical setting, serial neurosonological evaluation remains an indispensable tool for haemodynamic surveillance, achieved by 1) quantifying the post stenotic peak systolic velocity in the right V4 segment, a surrogate of satisfactory inflow to the left posterior inferior cerebellar artery through the inverted ipsilateral vertebral artery and, by extension, to the basilar trunk; and 2) ascertaining the direction of flow within the basilar artery, which, when orthograde, confirms adequate perfusion from the stenotic V4
Figure 1: Neurosonological findings in Case 1 (ischaemic vertebrobasilar disease).
A) Extracranial duplex ultrasound of the left VA showing preserved patency with a marked increase in resistance index.
B) TCCD of the left V4 segment demonstrating reversed flow towards the PICA, with absent flow signal in the V3 segment.
CTA confirming severe stenosis of the right V4 segment. The left VA is visualised from its origin to the distal V2 segment, with absence of opacification in V3 and reappearance in V4 ending in the PICA, consistent with segmental occlusion and distal re-entry.
basilar
vertebral artery, but when retrograde it indicates the recruitment of carotid–posterior communicating collateral pathways. Noninvasive monitoring not only provides essential insights into haemodynamics, but also supports therapeutic decisionmaking regarding the timing of potential endovascular intervention.
SECOND CASE
An 11-year-old girl presented with a palpable, pulsatile swelling in the right suboccipital region. A previously performed magnetic resonance angiography revealed malformed vessels in the right lateral cervical region, involving the jugular bulb and the extracranial segment of the
ipsilateral VA, with venous structures pertaining to the external jugular vein and the vertebral vein in a pattern suggestive of an arteriovenous fistula or malformation.
The neurosonological examination revealed:
• Enlarged right extracranial VA (7.1 mm diameter) with high flow velocities and reduced RI (PSV: 190 cm/s; EDV: 90 cm/s; RI: 0.60; Figure 3A).
• The right V3 segment, consisting of abnormal, convoluted arterial vessels with high flow velocities (PSV: 460 cm/s; EDV: 300 cm/s) and a PI below normal (0.2; Figure 3B), receiving inflow not only from the right V2 segment, but also from the
Figure 2: Computed tomographic angiography findings in Case 1.
A) Extracranial duplex ultrasound of the right VA demonstrating vascular enlargement (7.1 mm diameter), increased PSV and EDV, and reduced resistance index (RI: 0.60).
B) TCCD of the right V3 segment showing abnormal, tortuous arteries with very high flow velocities (PSV: 460 cm/s, EDV: 300 cm/s) and a low pulsatility index (PI: 0.2). Reversed flow from the ipsilateral V4 segment indicates a steal phenomenon.
C) Colour Doppler imaging of arterialised venous drainage into the internal jugular vein and ipsilateral vertebral venous plexus.
ipsilateral V4 segment, which exhibited reversed flow, indicating a vascular steal phenomenon directed towards V3 instead of towards the BA.
• Venous efferent vessels with arterialised flow draining into the internal jugular vein and the ipsilateral vertebral venous plexus (Figure 3C).
Neurosonology was particularly advantageous for establishing the diagnosis of arteriovenous fistula, clarifying the haemodynamic context, and guiding multidisciplinary discussion
on the therapeutic approach. The modality provided complementary information to neuroradiological studies, enabling the assessment of dynamic vascular flow patterns not visible on static imaging. The utility of ultrasound in the assessment and management of cerebral arteriovenous malformations, particularly its ability to evaluate real-time haemodynamics and provide insights into shunt flow, has been well-documented in the literature.9,10 The patient is scheduled for endovascular treatment and remains under clinical and neurosonological follow-up.
Figure 3: Neurosonological findings in Case 2 (arteriovenous fistula).
DISCUSSION
Neurosonology demonstrates remarkable versatility in the assessment of posterior cerebral circulation disorders, as illustrated by the present cases. Its dynamic, realtime evaluation enables not only the identification of stenoses and abnormal flow direction, but also offers insights into collateral circulation, haemodynamic compensation, and the temporal evolution of vascular pathologies. Unlike static radiological modalities, neurosonology allows clinicians to monitor changes over time and observe cerebral haemodynamics in response to physiological or clinical conditions directly at the patient’s bedside. Despite these advantages, certain limitations remain inherent to neurosonological techniques. The reliability of intracranial assessment is still challenged by the absence of universally accepted velocity cut-off values for stenosis grading, particularly within intracranial arteries. The criteria proposed by Baumgartner,11 based on conventional angiography, have long provided a binary classification of stenoses as <50% or >50%. More recently, Danyel et al.8 have advanced the field by introducing thresholds derived from CTA comparison, allowing a clinically relevant distinction between <50%, 50–69%, and severe (70–99%) stenoses, an approach that reflects the risk stratification routinely adopted in stroke care. Furthermore, technical factors such as the inadequacy of the temporal bone acoustic window, especially in elderly and female patients, can limit the feasibility of intracranial insonation. However, evaluation of the VA V4 segment via the suboccipital window generally remains reliable, except in cases with unfavourable neck anatomy.
These considerations underline the importance of integrating neurosonology with neuroradiological imaging. While
neurosonology cannot replace advanced radiological techniques, it should be regarded as an essential, complementary diagnostic tool that enriches the overall assessment. The dynamic nature of neurosonology, which provides immediate, repeatable, and physiologically meaningful data, proves invaluable, both for the initial work-up and the longitudinal monitoring of patients with ischaemic and malformative disorders of the posterior cerebral circulation. Thus, neurosonology enables a deeper understanding of the pathophysiology and supports more timely and informed clinical decision-making in real-world practice. It is important to acknowledge that the effectiveness of neurosonology heavily relies on operator skill and comprehensive training, emphasising the need for specialised education and continuous professional development to ensure accurate and reliable assessments.
CONCLUSION
These two cases highlight the remarkable versatility of neurosonology in the investigation of vertebrobasilar disorders with differing pathophysiological backgrounds. By documenting distinctive flow alterations and haemodynamic patterns in vivo, neurosonology proved essential for a nuanced interpretation of posterior circulation pathology. Beyond its established diagnostic value, these observations underscore its role in elucidating complex vascular dynamics and supporting tailored, patientcentred management in both ischaemic and malformative conditions of the vertebrobasilar system. Moreover, due to the operator-dependent nature of neurosonology, ongoing specialised training and continuous education are essential to develop and maintain the skills necessary for optimal diagnostic accuracy.
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