cover image European Journal of Neurology

European Journal of Neurology

2025 - Volume 32
Issue 7 | July 2025
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Article first published online:
27 Jun 2025 | DOI: 10.1111/ene.16357

ORIGINAL ARTICLE

Background

Atrial fibrillation (AF) increases the risk and severity of ischemic stroke, particularly in large vessel occlusion (LVO) cases. Atrial cardiomyopathy (AtCM) severity may explain why some AF patients suffer LVO while others develop distal cardioembolic strokes. This study aimed to investigate whether AtCM markers detected on acute brain‐cardiac CT are associated with LVO in AF patients presenting with ischemic stroke.

Methods

We analyzed 619 ischemic stroke patients admitted to Dijon University Hospital from November 2018 to March 2021. The cohort was divided based on the presence of LVO. Cardiac CT assessed left atrium volume (LAV), left atrial thrombus, and epicardial adipose tissue. Patients were grouped by LVO status.

Results

Of the 248 patients with acute stroke and AF, 138 (56%) had LVO. LVO patients had higher NIHSS scores (11 vs. 3,  < 0.001) and more frequent use of IV thrombolysis (27.7% vs. 12.3%,  = 0.030). Cardiac CT showed higher LAV in LVO patients (112.0 ± 43.0 cm vs. 100.1 ± 39.0 cm,  = 0.026). Multivariable analysis identified female sex (OR 1.98, 95% CI 1.12–3.50,  = 0.018) and LAV > 90 mL (OR 2.02, 95% CI 1.18–3.46,  = 0.010) as independent predictors of LVO.

Conclusions

Larger LAV and female sex independently predict LVO in AF patients, highlighting AtCM's role in stroke pathophysiology. Further research is needed to explore prevention strategies for high‐risk AF patients.

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Authors:
Soundous M'Rabet, Gauthier Duloquin, Pierre‐Antoine Garbuio, Angélique Bernard, Thibault Leclercq, Camil‐Cassien Bamdé, Pierre‐Olivier Comby, Frédéric Ricolfi, Yannick Béjot and Charles Guenancia
Article first published online:
07 Jul 2025 | DOI: 10.1111/ene.70079

ORIGINAL ARTICLE

Background

Cannabis is commonly used in persons with MS (pwMS) for symptom relief. Previous studies investigating the effects of cannabis on objective cognitive functioning in MS have yielded mixed results.

Aim

To examine associations of recreational cannabis use with objective cognitive performance in a large, consecutive clinical sample of pwMS.

Methods

In a cross‐sectional study, 847 pwMS provided information on cannabis consumption and were administered the Minimal Assessment of Cognitive Function in MS (MACFIMS) battery, assessing memory, executive function, language, and processing speed. Cognitive performance of cannabis users ( = 254) and nonusers ( = 593) was compared by means of a one‐way MANOVA. Multiple linear regressions then examined whether cannabis use independently predicted cognitive test results.

Results

A significant effect of cannabis use on cognitive performance was observed, (11, 692) = 1.955,  = 0.030, Wilks  = 0.970, with users performing significantly poorer than nonusers on the SDMT [(1, 703) = 6.099,  = 0.014]. Regression models, taking into account covariates (age, education, disease duration, anxiety, and fatigue) revealed that cannabis independently predicted performance on the SDMT, PASAT‐3, and PASAT‐2, all  < 0.001. Models explained 15.8%, 7.1%, and 8.7% of variance, respectively.

Conclusion

This cross‐sectional study provides evidence that cannabis use is associated with poorer processing speed and working memory in pwMS, thereby presenting a possible additional risk factor for cognitive impairment. This finding takes on added concern in light of cannabis use increasing with its legalization, and the worldwide increase of cannabis potency.

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Authors:
Anne Kever, Cecilia Meza and Anthony Feinstein
Article first published online:
05 Jul 2025 | DOI: 10.1111/ene.70142

ORIGINAL ARTICLE

Background

Music‐based neuromodulation has garnered interest as a potential therapeutic approach for drug‐resistant epilepsy. This study expands on prior research by examining the effects of different musical features on interictal epileptiform discharges (IEDs) within intracerebral EEG (iEEG).

Methods

Twenty‐five patients with drug‐resistant epilepsy undergoing presurgical iEEG evaluation participated in the study. Over 2 days, patients listened to various musical compositions characterized by distinct acoustic properties. EEG measurements were recorded before and after each listening session to evaluate IED changes.

Results

The study identified individualized patterns in IED reduction, with certain acoustic properties showing consistent effects across musical genres. Mozart's “Piano Concerto No. 27” K 595c globally reduced IEDs by 28% while listening to music ( = 0.0191) and 19% in the postmusic resting state ( = 0.0111); relaxation music increased IEDs by 55% ( = 0.0197). Based on the acoustic analysis of individuals, we identified compositions that significantly reduced IEDs, with reductions ranging from 32% to 44% ( = 0.0001). In contrast, compositions with differing acoustic properties did not result in significant changes in IEDs. These results suggest that specific acoustic properties, rather than genre, primarily influence IEDs.

Conclusions

The findings suggest that specific acoustic properties can influence brain activity in a reproducible manner at the individual level, modulating IEDs based on personalized testing and selection across a spectrum of musical genres. These results suggest the potential for music‐based neuromodulation as a personalized therapeutic approach in epilepsy management, emphasizing the importance of acoustic features over musical genre. Further research is needed to explore individual aspects of music‐based interventions.

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Authors:
Ondřej Strýček, Jiří Mekyska, Štěpán Miklánek, Michal Fusek, Klára Štillová, Martin Mazánek and Ivan Rektor
Article first published online:
05 Jul 2025 | DOI: 10.1111/ene.70151

ORIGINAL ARTICLE

Background

The outcome of levodopa/carbidopa intestinal gel (LCIG) in Parkinson's disease carriers of mutations (GBA‐PD) remains uncertain.

Objective

To evaluate the safety and efficacy of LCIG in a large PD cohort, focusing on variants.

Methods

This multicenter, retrospective, longitudinal “real‐world” study included consecutive patients with advanced PD treated with LCIG at 31 Italian centers; data were collected at baseline, 1‐, 5‐year, and last‐available follow‐up.

Results

Data from 512 PD patients (59% male, mean age and disease duration at LCIG initiation 67.0 ± 8.0 and 12.9 ± 5.0 years, respectively) were analyzed. genotyping was available for 306 patients (60%), of whom 40 (13%) had mutations or risk variants. Mean follow‐up on LCIG was 3.9 ± 2.9 years; 5‐year follow‐up data were available for 159 subjects. At baseline, GBA‐PD had a younger age, shorter PD duration, worse cognition, and more hallucinations than noncarriers. At 1‐ and 5‐year follow‐up, LCIG improved motor and non‐motor symptoms, OFF‐time, and dyskinesias in the entire population. In GBA‐PD, MDS‐UPDRS parts I, II, and III scores did not change, while part IV score improved significantly less than in noncarriers; cognition and orthostatic hypotension symptoms worsened more rapidly. Multivariate analysis of predictors for adverse events and LCIG discontinuation found no significant contribution from mutation status.

Conclusions

status does not increase the risk of adverse events or LCIG discontinuation. LCIG is a safe option for advanced GBA‐PD, even in patients with cognitive impairment at baseline. However, GBA‐PD experiences lower efficacy on motor disability and complications and faster cognitive decline than noncarriers.

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Authors:
Roberto Cilia, Fabiana Colucci, Emanuele Cereda, Antonio E. Elia, Valentina Leta, Silvia Barca, Maurizio Zibetti, Miryam Carecchio, Salvatore Bonvegna, Giovanna Calandra‐Buonaura, Rocco Cerroni, Rosa De Micco, Stefano Tamburin, Luca Magistrelli, Francesco Lena, Marcello M. Mascia, Marina Picillo, Giovanni Cossu, Massimo Marano, Alessandro Zampogna, Clelia Pellicano, Valentina Fioravanti, Andrea Pilotto, Roberta Zangaglia, Micol Avenali, Chiara Sorbera, Francesca Di Biasio, Federica Arienti, Alessandra Nicoletti, Caterina Bagella, Maria Chiara Malaguti, Alessandra Ranghetti, Elena Caputo, Dario Alimonti, Elena Torre, Gaia D. Oggioni, Catia Leuzzi, Luigi M. Romito, Nico Golfrè Andreasi, Grazia Devigili, Roberta Telese, Arianna Braccia, Gianfranco Gaudiano, Samanta Mazzetti, Federica Invernizzi, Barbara Garavaglia, Gabriele Imbalzano, Claudia Ledda, Pietro Antenucci, Andrea Gozzi, Giulia Bonato, Marco Percetti, Giulia Giannini, Luisa Sambati, Tommaso Schirinzi, Martina D'Anna, Domiziana Rinaldi, Francesco Cavallieri, Marco Liccari, Alberto Priori, Maria Sessa, Filippo Tamma, Margherita Canesi, Paolo Solla, Mario Zappia, Alessio Di Fonzo, Laura Avanzino, Angelo Quartarone, Enza Maria Valente, Claudio Pacchetti, Alessandro Padovani, Franco Valzania, Francesco E. Pontieri, Antonio Suppa, Maria Teresa Pellecchia, Nicola Modugno, Cristoforo Comi, Michele Tinazzi, Alessandro Tessitore, Alessandro Stefani, Pietro Cortelli, Ioannis U. Isaias, Angelo Antonini, Mariachiara Sensi, Leonardo Lopiano and Roberto Eleopra
Article first published online:
15 Jul 2025 | DOI: 10.1111/ene.70179

ORIGINAL ARTICLE

Background

GG homozygosity for the risk gene variant rs7665090 has been reported to enhance nuclear factor kappa B (NFκB) activity in T cells from multiple sclerosis (MS) patients. Here, we investigated the association between this polymorphism and the response to different disease‐modifying therapies in MS.

Methods

The rs7665090 polymorphism was genotyped in 558 MS patients treated with injectable therapies [IFNβ ( = 213) and glatiramer acetate ( = 55)], oral therapies [dimethylfumarate ( = 97), teriflunomide ( = 41), and fingolimod ( = 37)], and natalizumab ( = 115). Treatment response was assessed after 1 year for injectable therapies using the Rio Score, which considers relapses, EDSS progression, and radiological activity on MRI. For oral therapies and natalizumab, response was evaluated after 2 years based on clinical and radiological disease activity. Univariable and multivariable logistic regression analyses were performed to assess treatment response for each therapy independently.

Results

GG homozygosity was associated with a favorable response outcome in patients treated with IFNβ in the multivariable analysis after adjusting for age and EDSS at treatment onset [OR 0.42 (0.18–0.94);  = 0.037]. This finding was restricted to MS patients carrying the GG risk genotype and seemed specific for IFNβ treatment, since the rs7665090 polymorphism did not influence the response to the other MS therapies.

Conclusion

The polymorphism rs7665090 is associated with a favorable response to IFNβ. This study illustrates how genotyping this polymorphism could serve as a useful biomarker in clinical practice to help identify MS patients who are likely to respond favorably to treatment, and encourages further replication in larger cohorts.

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Authors:
Andreu Vilaseca, Elena Urcelay, Sunny Malhotra, Mireia Castillo, Montserrat Aroca, Angela Vidal‐Jordana, Agustín Pappolla, René Carvajal, Georgina Arrambide, Adela González‐Jiménez, Irene Gómez‐Delgado, Alvaro Cobo‐Calvo, Neus Mongay‐Ochoa, Breogan Rodriguez‐Acevedo, Carmen Tur, Javier Villacieros‐Álvarez, Helena Ariño, Joaquín Castilló, Ana Zabalza, Luciana Midaglia, Delon La Puma, Jaume Sastre‐Garriga, Mar Tintoré, Jordi Río, Xavier Montalban and Manuel Comabella
Article first published online:
15 Jul 2025 | DOI: 10.1111/ene.70227

SHORT COMMUNICATION

Background

This study aimed to investigate the prevalence, characteristics, and determinants of peripheral neuropathy in a large cohort of patients affected by spinocerebellar ataxia type 27B (SCA27B), a late‐onset cerebellar ataxia caused by heterozygous GAA repeat expansions in the first intron of the gene.

Methods

A retrospective, multicenter study in which medical records of SCA27B patients diagnosed between January 2023 and July 2024 in 21 French ataxia/neurogenetic centers were reviewed. Those who had undergone electrodiagnostic study were included.

Results

Among 332 SCA27B patients, 170 had undergone an electrodiagnostic study and were included. Forty‐two (25%) were diagnosed with neuropathy: 16 with length‐dependent axonal sensorimotor neuropathy, 24 with length‐dependent axonal sensory neuropathy, one with sensory, and one with motor neuronopathy. Neuropathy was associated with male sex, older age at electrodiagnostic study, and risk factors for neuropathy but not with GAA expansion sizes. Patients with neuropathy had more severe disability at the last visit (median SARA score 12 vs. 8,  = 0.0024).

Conclusions

The prevalence of neuropathy in SCA27B patients was similar to that reported in the elderly general population. Neuropathies were predominantly non‐specific length‐dependent axonal neuropathies, primarily driven by aging and known risk factors rather than the underlying genetic abnormality.

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Authors:
Julian Theuriet, Lukas Paulet, Blandine Acket, Fabienne Ory‐Magne, Hocine Belbachir, Jean‐Baptiste Chanson, Françoise Bouhour, Chloé Laurencin, Caroline Froment Tilikete, Pierre Lardeux, Guillemette Clement, Armand Hocquel, Mathilde Renaud, Céline Bonnet, Cecilia Marelli, Sacha Weber, Camille Comet, Jean‐Philippe Azulay, Frédérique Fluchère, Giulia Coarelli, Anna Heinzmann, Claire Ewenczyk, Christophe Verny, Virginie Guillet‐Pichon, Lucie Guyant‐Marechal, Clément Desjardins, Audrey Riou, Bertrand Degos, Sandra Mercier, Cyril Goizet, Manon Degoutin, Chloé Angelini, Brice Laurens, Adrian Degardin, Nicolas Carrière, Gwenaël Le Guyader, Vincent Schneider, Gwendoline Dupont, Quentin Thomas, Maxime Merindol, Elsa Besse‐Pinot, Aurélie Méneret, Emmanuel Roze, Alexandra Durr, Stéphane Thobois, Mathieu Anheim, Thomas Wirth and Antoine Pegat
Article first published online:
27 Jun 2025 | DOI: 10.1111/ene.70247

ORIGINAL ARTICLE

Introduction

Lyme neuroborreliosis (NB), is caused by tick‐borne spirochetes in the sensu lato (sl) genospecies complex. Although the clinical manifestations of NB in adults and children are well documented, understanding neurobiological differences between these groups can improve diagnostic accuracy and treatment approaches. This study aimed to characterize and compare the clinical presentation and cerebrospinal fluid (CSF) findings of NB in children and adults at the time of hospital admission.

Methods

Retrospective analysis was performed of 3841 patients with an intrathecal sl antibody index test performed at the Department of Microbiology at Herlev Hospital (Capital region of Denmark) between January 2016 and January 2024. Adults and children were included based on the European criteria for NB and compared for symptoms, such as peripheral facial palsy, and CSF variables, such as white blood cell (WBC) counts.

Results

A total of 146 children and 267 adults were included. The annual incidence was 6.4 cases per 100 000 inhabitants. Median symptom duration before CSF analysis was 7 days for children and 21 days for adults. Facial palsy was the most common symptom in children (70%), whereas radicular pain predominated in adults (61%). CSF analysis showed significantly higher WBC counts in children vs. adults and significantly lower protein levels in children vs. adults, irrespective of symptom duration.

Conclusion

There are substantial differences in the clinical presentation and CSF findings of NB between adults and children. NB incidence was much higher than previously reported in Denmark, underscoring the need for improved clinical awareness and early diagnosis.

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Authors:
Al‐Hasan Hussein Dos, Nina Vindegaard Sørensen, Malini Vendela Sagar, Anne‐Mette Lebech, Anders Hougaard and Christian Stenør
Article first published online:
09 Jul 2025 | DOI: 10.1111/ene.70250

ORIGINAL ARTICLE

Introduction

This study investigated the phenomenology of tics in adults with primary tic disorders (Tourette syndrome, persistent motor or phonic tic disorders) and how these features are influenced by sex. It also examined the prevalence of comorbid psychiatric conditions and psychotropic medication use.

Methods

A cross‐sectional study was conducted on 227 adults with primary tic disorders from the Calgary and Paris Adult Tic Registry. Data collected included demographics, tic characteristics (using the Yale Global Tic Severity Scale), psychiatric comorbidities, and medication use. Statistical analyses were performed to compare data between sexes.

Results

The sex ratio was 1.8 males to 1 female. The most common motor tics were simple (eye blinking, simple head movements), and the most common phonic tic was throat clearing. There were no significant sex differences in tic phenomenology or severity. Generalized anxiety disorder (49.5%) and attention deficit hyperactivity disorder (ADHD) (35.8%) were the most common comorbidities. A lower proportion of women were diagnosed with ADHD, while a higher proportion were diagnosed with obsessive compulsive disorder.

Conclusion

The male predominance of tic disorders is less marked in adulthood compared to childhood. Tic phenomenology and severity do not significantly differ between sexes. These findings provide valuable insights into the clinical presentation of tic disorders in adults. Future research will explore severity of comorbid mental health conditions, how these influence tic severity, treatment outcomes and quality of life.

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Authors:
Christelle Nilles, Yulia Worbe, Andreas Hartmann, Davide Martino, Julian Fletcher, Naoual Serari, Catherine Deans, Isabella Davenport, Emmanuel Roze and Tamara Pringsheim
Article first published online:
23 Jul 2025 | DOI: 10.1111/ene.70252

ORIGINAL ARTICLE

Background

The Addenbrooke's Cognitive Examination‐III (ACE‐III) is a common cognitive screening measure. We provide performance deciles, descriptive performance bands and indices of reliable change between repeat assessments using the ACE‐III in a large cohort of dementia participants and healthy controls.

Methods

Baseline data from 727 participants diagnosed with a dementia syndrome and 157 healthy controls were used to calculate performance deciles and descriptive bands. A subset of 393 participants diagnosed with a dementia syndrome completed two annual assessments. These data were used to calculate 95% confidence intervals of characteristic yearly change in each dementia syndrome. Data from a subset of 74 healthy participants who completed two assessments were used to calculate reliable change indices.

Results

Baseline performance was grouped into five descriptive performance bands across the entire spectrum of scores: Very Mild, Mild, Moderate, Severe and Very Severe. Deciles and performance bands are provided for all dementia participants combined, for each syndrome where  > 50, and for healthy controls, stratified by group, sex and years of education. A decline of −7 to −9 points yearly was characteristic for the dementia population, and this varied between syndromes. Reliable change calculations indicate that a 5‐point decline from within the ‘normal’ range (88–100) is the minimum clinically important decline on the ACE‐III.

Conclusions

This study presents a suite of reference data on the ACE‐III in a range of dementia syndromes, providing important insight and support to clinicians who work with people living with cognitive impairments.

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Authors:
James Carrick, Sau Chi Cheung, David Foxe and Olivier Piguet
Article first published online:
30 Jun 2025 | DOI: 10.1111/ene.70257

ORIGINAL ARTICLE

Background

Kleine‐Levin Syndrome (KLS) is a neurological disorder of unknown pathophysiology. It is characterized by relapsing–remitting episodes of hypersomnia, with cognitive symptoms and behavioral disturbances. The diagnosis relies on clinical criteria, which require further standardization. Our main objective was to better phenotype and systematically quantify the severity and impact of cognitive and behavioral symptoms, hypersomnolence and dysautonomia in a well‐characterized population of KLS patients.

Methods

Forty‐three consecutive KLS patients diagnosed in a National Reference Center for Rare Hypersomnias underwent a standardized clinical and polysomnographic evaluation and completed validated questionnaires with their relatives. The Behavioral Dysexecutive Syndrome Inventory (BDSI) assessed their behavior during most episodes. The Idiopathic‐Hypersomnia Severity Scale (IHSS) assessed different hypersomnolence components (inertia, sleepiness, prolonged sleep), and the Scale for Outcomes in Parkinson's Disease‐Autonomic (SCOPA‐AUT) assessed dysautonomia. The latter two scales were completed twice to differentiate symptoms during and between episodes.

Results

During symptomatic periods, behavioral changes were observed in all BDSI domains, more than half of patients showing reduced activities and apathy, anticipation–organization–initiation difficulties, disinterest, irritability–aggression, perseveration–stereotypies, and sexual or eating disorders. IHSS scores were severe and higher during episodes (42.6 ± 5.8 vs. 15.6 ± 9.8,  < 0.0001), and each item higher. The SCOPA‐AUT scores were higher during episodes (12.1 ± 8.5 vs. 8.5 ± 8.2,  = 0.0001), particularly in the cardiovascular, pupillomotor, and thermoregulation domains.

Conclusions

Our findings suggest the relevance of the BDSI for the evaluation of dysexecutive behavioral symptoms in KLS. The IHSS would be useful for phenotyping hypersomnolence and the SCOPA‐AUT for assessing dysautonomia during episodes. Future studies could combine the BDSI with imaging and other biomarkers to explore the neuroanatomical correlates of this enigmatic disorder.

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Authors:
Lucie Barateau, Joseph Diab, Ophélie Thobois, Sofiene Chenini, Séverine Béziat, Isabelle Jaussent and Yves Dauvilliers
Article first published online:
27 Jun 2025 | DOI: 10.1111/ene.70259

ORIGINAL ARTICLE

Background

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that impairs both upper and lower motor neurons. Mutations in the neurofilament heavy () gene are associated with a higher risk for ALS. This study aimed to evaluate the brain metabolism in patients with ALS and gene mutations (NEFH‐ALS) and assess its correlation with emotional and cognitive changes.

Methods

This prospective study enrolled 119 patients with ALS and 128 age‐ and gender‐matched health controls. Study assessments included demographic data collection, questionnaires for motor function, cognition, and depression, and brain F‐18 FDG PET/CT (18F‐fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT)) scan. Correlation between brain metabolism and clinical questionnaire scores was performed. Chain‐mediation model analysis for the NEFH‐ALS group was conducted. Cox regression and Kaplan–Meier survival analysis were also performed.

Results

There were 26 NEFH‐ALS patients. Patients with NEFH‐ALS showed brain glucose hypometabolism in the cortex‐striatum/limbic system‐brainstem circuit when compared with healthy controls ( < 0.05). Decreased brain glucose metabolism was correlated with impairments of motor function ( = 0.477,  = 0.014, FDR corrected  = 0.014), cognitive scores ( = 0.549,  = 0.004, FDR corrected  = 0.009), and depression ( = −0.523,  = 0.009, FDR corrected  = 0.009). This study showed that brain glucose hypometabolism could lead to impairment of motor function, which was mediated by cognition and depression. Survival analysis showed that brain glucose metabolism was an independent prognostic factor for patients with ALS.

Conclusions

Reduced brain glucose metabolism in the cortex‐striatum/limbic system‐brainstem circuit may potentially serve as an independent prognostic factor for patients with ALS and NEFH mutation.

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Authors:
Xinyu Song, Xueying Wang, Fan Hu, Pan Liu, Ziqin Liu, Jiping Yi, Renxu Xu, Wenfeng Cao, Yuanchao Zhang, Junling Wang, Alessandro Grecucci, Xiaoping Yi and Bihong T. Chen
Article first published online:
03 Jul 2025 | DOI: 10.1111/ene.70261

SHORT COMMUNICATION

Background

Despite effective therapeutic control of relapses, many patients with multiple sclerosis (MS) experience, from the earliest phases of disease, disability accrual, which mostly occurs as progression independent of relapse activity (PIRA). In this observational study, we aimed at evaluating the genetic contribution to PIRA, using polygenic risk scores (PRS) in a cohort of 1162 Italian patients.

Methods

PRS were derived from the largest multi‐centric genome‐wide association study on MS severity, conducted on more than 20,000 patients. The scores were computed at 5 ‐value thresholds after a clumping procedure. Association with the rate of PIRA events was tested by fitting negative binomial regression models.

Results

Analyses revealed a trend for association of PRS with the rate of PIRA events, which were significant in the subset of patients with age at onset ≤ 50 years (Rate Ratio = 1.148, 95% CI: 1.01 to 1.304,  = 0.0328). An interaction effect was identified between PRS and AAO, indicating a significant mild antagonistic effect (RR = 0.98, 95% CI: 0.96 to 1.0,  = 0.033).

Conclusions

Our results suggest an influence of severity‐related genetic load on the rate of PIRA events, especially in subjects with disease onset before the age of 50 years, characterized by a less prominent effect of aging processes on disability accumulation. This finding supports previous observations from other studies of an age‐dependent influence of genetic risk scores on complex traits.

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Authors:
Ferdinando Clarelli, Melissa Sorosina, Antonino Giordano, Elisabetta Mascia, Giulia Visentin, Matteo Missaglia, Lucia Moiola, Maria A. Rocca, Massimo Filippi and Federica Esposito
Article first published online:
30 Jun 2025 | DOI: 10.1111/ene.70264

ORIGINAL ARTICLE

Background

Functional recovery from ischemic stroke (IS), the main cause of adult disability worldwide, is influenced by many factors, and a portion of interindividual variability remains unexplained.

Methods

Observational study in a tertiary stroke centre of patients with IS analyzed using shotgun metagenomic sequencing (January 2020–March 2022). Functional outcomes were assessed according to modified Rankin Scale (mRS) scores 3‐months post‐IS, considering 0–2 favorable and 3–6 unfavorable. The causal relationship between several bacteria and post‐IS outcomes was explored via two‐sample Mendelian randomization (MR) analyses using Genome‐Wide Association Analysis (GWAS) summary statistics.

Results

Comparing 128 patients with favorable and unfavorable post‐IS functional outcomes, β‐diversity analysis showed a separation in microbial structure, and α‐diversity measures revealed greater bacterial richness in the favorable outcomes group. Taxonomic profiling of the samples showed that a greater abundance of pathogenic bacteria (e.g., , , ) was associated with an unfavorable outcome. Functional profiling of the samples revealed differences in the ethylbenzene degradation pathway and in 16S rRNA (uracil1498‐N3)‐methyltransferase. MR confirmed increased pyruvate levels to be causally associated with post‐IS favorable outcomes ( = −0.50, 95% CI: −0.91, −0.10).

Conclusions

Our study points to gut microbiota differences in patients with unfavorable versus favorable 3‐month post‐IS outcomes. Patients with unfavorable outcomes presented gut microbiota dysbiosis and alterations in multiple metabolic pathways.

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Authors:
Miquel Lledós, Luís Prats‐Sánchez, Elena Muiño, Natalia Cullell, Laia Llucià‐Carol, Jara Cárcel‐Márquez, Cristina Gallego‐Fabrega, Jesús M. Martín‐Campos, Rebeca Marín, Ana Aguilera‐Simón, Marina Guasch‐Jiménez, Garbiñe Ezcurra‐Díaz, Pol Camps‐Renom, María del Mar Freijo, Joan Martí‐Fàbregas and Israel Fernández‐Cadenas
Article first published online:
21 Jul 2025 | DOI: 10.1111/ene.70265

SHORT COMMUNICATION

Background

Rasmussen's encephalitis (RE) is a rare, chronic, neurological disorder characterized by progressive focal epilepsy and hemispheric atrophy. Late‐onset RE poses diagnostic challenges due to atypical clinical features and nonspecific early MRI findings.

Methods

This case series underscores the value of [18F]FDG PET in detecting unihemispheric hypometabolism and crossed cerebellar diaschisis at diagnosis, before MRI changes appear.

Results

During follow‐up, PET identified active disease through hypermetabolic foci or pseudo‐normalized metabolism, indicative of subclinical seizures, while stable hypometabolism signaled quiescence.

Conclusion

Combining PET with MRI enhances diagnostic accuracy and guides treatment decisions in managing RE.

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Authors:
Laura Rozenblum, Lydia Chougar, Franck Bielle, Bertrand Mathon, Vincent Navarro, Sophie Dupont and Aurélie Kas
Article first published online:
27 Jun 2025 | DOI: 10.1111/ene.70266

ORIGINAL ARTICLE

Introduction

Inflammatory polyradiculoneuropathy (IPN) has been associated with intracranial hypertension (IH) in various case reports, suggesting a potential link between the two conditions. However, the prevalence of IH in patients with IPN has not been addressed by prospective studies.

Methods

In this cross‐sectional prospective study, we prospectively screened consecutive patients with chronic IPN for the presence of clinical and paraclinical signs of IH (fundoscopy, perimetry, optical coherence tomography, ultrasonography) between August 31, 2021, and December 31, 2023.

Results

Of 27 patients included (median age: 61.0 years [IQR 22.0]; 30.8% female; median time since diagnosis: 49.5 months [IQR 42.0]), ten patients (37.0%) with IPN had sonographic evidence of IH (IPN + IH), with 40% reporting symptoms of IH. Compared to patients without signs of IH, IPN + IH were younger (40.5 years [24.0] vs. 63.0 years [10.0]) and had higher CSF total protein (67.7 mg/dL [57.6] vs. 56.1 mg/dL [26.7]). However, IPN + IH did not have higher BMI (24.1 [5.2] vs. 26.0 [3.8]) or female predominance (33.3% vs. 29.4%).

Discussion

Signs of IH seem to be a common feature in IPN, indicating a likely association. The demographic and clinical profile of IPN + IH patients differs from that of idiopathic IH, suggesting that IH in IPN is likely secondary and may be linked to elevated CSF protein. Given that the majority of patients were asymptomatic and that the specificity of IH symptoms remains low, routine screening for subclinical IH signs may be warranted in this population.

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Authors:
Stefan Macher, Nik Krajnc, Jakob Rath, Wolfgang Marik, Martin Michl, Christoph Stapf, Nina Mueller, Klaus Novak, Christian Woeber, Sina Zaic, Gudrun Zulehner, Fritz Zimprich, Berthold Pemp and Gabriel Bsteh
Article first published online:
27 Jun 2025 | DOI: 10.1111/ene.70267

ORIGINAL ARTICLE

Background

The aim of this international retrospective study was to assess 4‐year change using the Hammersmith Functional Motor Scale Expanded (HFMSE) in individuals with type II and III spinal muscular atrophy (SMA) treated with nusinersen and to establish predictors of HFMSE changes.

Methods

Individuals with type II or III SMA, and at least 4 years of nusinersen‐only treatment were included. All were assessed using the HFMSE. Age at baseline, sex, motor function, copy number, and age of onset were also retrospectively collected. Linear mixed effect models were used to calculate yearly changes and trajectory predictors.

Results

We included 73 individuals with SMA type II (mean age 8.58 years, SD 7.91, IQR 3.04–10.70) and 111 type III (mean age 7.91 years, SD 17.83, IQR 8.15–34.42). Over 4 years, mean changes were + 4.18 (95% CI: 2.85–5.50) for SMA II and + 1.08 (95% CI: 0.12–2.04) for SMA III. Age (SMA II: −0.34\[−0.51 to −0.17]; SMA III: −0.13\[−0.20 to −0.06],  < 0.001) and baseline HFMSE (SMA II: 1.02\[0.70–1.34]; SMA III: 0.79\[0.71–0.87],  < 0.001) were the strongest predictors of progression, with younger age and higher baseline scores associated with better outcomes. Functional status was only predictive for type III (6.96\[4.26–9.66]).

Conclusion

Our results confirm that, given a follow up of 4 years, there is a persistent impact of nusinersen on clinical progression that is better observed in younger patients with higher HFMSE scores at baseline, especially during the first 2 years of treatment.

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Authors:
Giorgia Coratti, Francesca Bovis, Marika Pane, Amy Pasternak, Emilio Albamonte, Irene Mizzoni, Allan M. Glanzman, Simone Morando, Jacqueline Montes, Ilaria Cavallina, Sally Dunaway Young, Tina Duong, Enrica Rolle, Matthew Civitello, Roberto De Sanctis, Chiara Bravetti, Federica Ricci, Giulio Gadaleta, Tiziana Mongini, Maria Sframeli, Maria Carmela Pera, Sonia Messina, Adele D'Amico, Michela Catteruccia, Noemi Brolatti, Michio Hirano, Zarazuela Zolkipli‐Cunningham, Basil T. Darras, Enrico Bertini, Claudio Bruno, John Day, Valeria A. Sansone, Richard S. Finkel, Eugenio Mercuri, Rafael. S. Rodriguez‐Torres, Nicola Forcina, Giulia Norcia, Giulia Stanca, Sara Carnicella, Lavinia Fanelli, Antonella Longo, Michela Nani, Laura Antonaci, Giacomo De Luca and Roberto Materia
Article first published online:
27 Jun 2025 | DOI: 10.1111/ene.70268

ORIGINAL ARTICLE

Background

Autoimmune nodopathy exhibits suboptimal responses to conventional immunotherapies. This study investigates the efficacy and safety of efgartigimod, a neonatal Fc receptor blocker, in this condition.

Methods

A prospective single‐center study enrolled four antibody‐confirmed autoimmune nodopathy patients receiving weekly efgartigimod (10 mg/kg) over 4 weeks. Disease progression was assessed using validated neurological scales (INCAT, ISS, I‐RODS, and MRC) at baseline (Week 0), weekly during treatment (Weeks 1–4), and 4‐week post‐treatment follow‐up (Week 8).

Results

Four patients (3 females, aged 17–72) responded to efgartigimod within 2 weeks, showing varied improvement based on antibody subtype. Patient 1 (anti‐NF186 IgG3+) achieved full remission by Week 2 (INCAT 3 → 0). Patient 2 (anti‐NF155 IgG4+) improved progressively (MRC 112 → 119; I‐RODS 36 → 40). Patient 3 (anti‐NF155 IgG1/IgG4+) quickly stabilized gait in the first week and gradually recovered (INCAT 5 → 2). Patient 4 (anti‐CNTN1 IgG1/IgG2/IgG3/IgG4+) reduced tremors rapidly and improved sensorimotor function (ISS 8 → 6; I‐RODS 12 → 14) despite a treatment interruption due to a fracture. Antigen‐specific efficacy varied: NF186 neuropathy resolved completely, while IgG4‐dominant paranodal cases (NF155/CNTN1) partially recovered, prompting sequential B‐cell‐targeted strategies. No severe adverse events occurred.

Conclusions

Efgartigimod provided rapid functional recovery in autoimmune nodopathy. Differential responses by IgG subclass and antigenic targets highlight the necessity for biomarker‐guided strategies.

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Authors:
Hongfei Tai, Songtao Niu, Hua Pan, Fan Jian, Zhenxian Hu, Na Chen, Ying Wang and Zaiqiang Zhang
Article first published online:
10 Jul 2025 | DOI: 10.1111/ene.70269

ORIGINAL ARTICLE

Background

Despite successful recanalization following endovascular thrombectomy (EVT) for acute ischemic stroke (AIS) with large‐vessel occlusion (LVO), many patients fail to achieve excellent functional outcomes. Post‐EVT intra‐arterial thrombolysis (IAT) has emerged as a potential adjunctive strategy to improve microvascular reperfusion and clinical recovery.

Methods

We conducted a systematic review and meta‐analysis of randomized‐controlled clinical trials (RCTs) comparing IAT plus best medical therapy (BMT) versus BMT alone in LVO‐AIS patients with successful recanalization post‐EVT. The primary efficacy outcome was 3‐month excellent functional outcome [modified Rankin Scale (mRS)‐score: 0–1]. Secondary efficacy outcomes included good functional outcome (mRS‐score: 0–2) and reduced disability (mRS‐score shift analysis) at 3 months. The primary safety outcome was symptomatic intracranial hemorrhage (sICH); secondary safety outcomes included any‐ICH and 3‐month all‐cause mortality. Subgroup and network meta‐analyses were performed evaluating the effects of different thrombolytic agents.

Results

Seven RCTs were included, comprising 1083 patients treated with IAT and 1048 patients treated with BMT alone. IAT was associated with higher likelihood of excellent functional outcome (RR: 1.23; 95% CI: 1.11–1.36;  = 0%) and reduced disability at 3 months (common‐OR: 1.10; 95% CI: 1.03–1.18;  = 0%) compared with BMT alone. Similar rates of 3‐month good functional outcome, 3‐month mortality, sICH and any‐ICH were observed. Although no significant subgroup differences emerged, in the network meta‐analysis alteplase ranked highest in efficacy [surface under the cumulative rank curve (SUCRA): 90%], followed by tenecteplase (61%) and urokinase (40%) in achieving 3‐month excellent functional outcome.

Conclusions

IAT improves excellent functional outcomes without compromising safety in LVO‐AIS patients with successful recanalization after EVT.

Trial Registration

The prespecified protocol of the present systematic review and meta‐analysis has been registered in the International Prospective Register of Ongoing Systematic Reviews PROSPERO (registration ID: CRD420251035903)

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Authors:
Lina Palaiodimou, Nikolaos M. Papageorgiou, Guillaume Turc, Benjamin Gory, Aikaterini Theodorou, Eleni Bakola, George Magoufis, Stavros Spiliopoulos, Michail Mantatzis, Nitin Goyal, Marios Themistocleous, Amrou Sarraj, Aristeidis H. Katsanos, Urs Fischer, Andrei V. Alexandrov and Georgios Tsivgoulis
Article first published online:
07 Jul 2025 | DOI: 10.1111/ene.70270

CORRECTION

Correction to “Predictors of Recovering Full Consciousness: Results From a Prospective Multisite Italian Study”

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Article first published online:
22 Jul 2025 | DOI: 10.1111/ene.70271

ORIGINAL ARTICLE

Background

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons. Transcranial sonography (TCS) is a valuable tool for assessing deep brain structures. This study aimed to analyze TCS findings in both sporadic (sALS) and familial ALS (fALS) patients and compare them to healthy controls (HC).

Methods

This cross‐sectional study included 278 patients with sALS and 31 patients with genetically confirmed fALS, and 93 age‐ and gender‐ matched HC. TCS was used to assess substantia nigra (SN) and brainstem raphe (BR) echogenicity and third ventricle diameter (TVD). Functional disability was evaluated using the ALS Functional Rating Scale‐Revised.

Results

BR hypoechogenicity was more frequent in fALS (41.9%) and sALS (37.4%) patients, compared to HC (10.8%) ( < 0.001). Right SN hyperechogenicity was observed in 28.1% of sALS, 16.1% of fALS, and 8.6% of HC ( = 0.004). Left SN hyperechogenicity was found in 33.5% of sALS, 29.0% of fALS, and 4.3% of HC ( = 0.004). SN hyperechogenicity findings on either side were highest in sALS (48.4%) compared to fALS (31.0%) and HC (13.3%) ( < 0.001), with a borderline difference between fALS and sALS ( = 0.08). BR hypoechogenicity and SN hyperechogenicity were more common in male patients. Increased TVD correlated with older age, later disease onset, bulbar onset, and lower MMSE scores.

Conclusions

TCS is an easily applicable and sensitive diagnostic tool that offers novel insights into several brainstem structures and identify significant differences in their echogenicity between ALS patients and healthy controls, while pointing out similar but not identical patterns of echogenicity in both ALS forms.

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Authors:
Ivo Bozovic, Emir Licina, Bogdan Bjelica, Ognjen Milicevic, Aleksa Palibrk, Ivana Basta, Stojan Peric, Aleksandra Pavlovic, Zorica Stevic and Milija Mijajlovic
Article first published online:
13 Jul 2025 | DOI: 10.1111/ene.70272

OBITUARY

Lessons From Professor Jan van Gijn

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Authors:
Elena R. Lebedeva and Charles Warlow
Article first published online:
01 Jul 2025 | DOI: 10.1111/ene.70274

ORIGINAL ARTICLE

Background

Cerebral cavernous malformations (CCMs) contribute to focal drug‐resistant epilepsy (fDRE), with surgical outcomes varying due to an incomplete understanding of the interplay between CCM‐impacted regions and areas exhibiting ictal or interictal epileptogenicity. This study quantified the epileptogenicity of brain structures sampled by stereo‐electroencephalography (SEEG) electrodes in patients with fDRE and supratentorial CCMs, focusing on the irritative zone (IZN) and epileptogenic‐zone network (EZN). It also established a framework for describing EZN organization relative to CCM‐affected regions.

Methods

Retrospective multicentric cohort study involving fDRE patients with supratentorial CCMs, explored using SEEG, recruited from five French tertiary epilepsy centers. SEEG‐sampled brain regions were classified as lesional, perilesional, or non‐lesion‐associated according to their anatomic relationship with the CCMs and using the Virtual Epileptic Patient brain atlas parcellation. IZN quantification was performed using spike rates per minute. EZN was evaluated using the Epileptogenicity Index or Permutation Entropy Index according to the seizure‐onset pattern. Data were analyzed using both descriptive and inferential statistics.

Results

The study included 22 patients, 10 of whom underwent post‐SEEG epilepsy surgery. IZN biomarkers differed significantly between lesional, perilesional, and non‐lesion‐associated areas, whereas EZN biomarkers did not. EZN included lesional areas in 50% of cases, with complex multi‐lobar networks identified in most patients. Postsurgical seizure freedom was achieved in 70% of SEEG‐explored patients.

Conclusions

Our findings highlight the complex relationship between CCMs and the EZN, supporting SEEG in the presurgical work‐up of selected patients with CCMs and fDRE. A network‐based surgical approach may improve outcomes by tailoring resections to the EZN.

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Authors:
Ionuț‐Flavius Bratu, Lucie de Clerck, Hélène Catenoix, Luc Valton, Jérôme Aupy, Anca Nica, Sylvain Rheims, Sandrine Aubert‐Conil, Jeanne Benoit, Julia Makhalova, Ophélie Galli, Samuel Medina Villalon and Fabrice Bartolomei
Article first published online:
01 Jul 2025 | DOI: 10.1111/ene.70276

ORIGINAL ARTICLE

Background

Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is an autosomal dominant systemic disease, with an overall poor prognosis. Markers of disease onset are urgently required to optimize the timing of treatment initiation. Nerve conduction studies (NCS) are an objective, reproducible, and non‐invasive tool for following large nerve fiber involvement. Our objective was to determine whether the presence of intracutaneous amyloid deposition (ICAD) was associated with a higher risk of developing the disease, defined as a decline observed on nerve conduction studies, in a population of carriers not meeting the criteria for overt disease.

Methods

We included 98 presumed asymptomatic pathogenic variant carriers with normal baseline NCS results and available follow‐up testing results. Baseline evaluation included a neurological examination, short‐term heart rate variability (HRV), electrochemical sweat conductance (ESC), intraepidermal nerve fiber density (IENFD), assessment of the presence of intracutaneous amyloid deposits (ICAD), and cardiac parameters. Follow‐up neurological and cardiological evaluations were performed. NCS deterioration was defined as a 20% decrease in sensory nerve action potential (SNAP) in the lower limbs.

Results

During a median follow‐up of 5 years, 11/98 (11%) carriers presented a NCS deterioration. Presence of ICAD at baseline was significantly associated with NCS decline.

Conclusion

The presence of ICAD at baseline is associated with a subsequent NCS deterioration in presumed asymptomatic pathogenic variant carriers. Skin biopsy for the analysis of amyloidosis deposit and small fiber density should be recommended in the evaluation of carriers and lead to discuss treatment initiation when abnormal, even in asymptomatic carriers.

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Authors:
Nina Schulz, Diane Beauvais, Cécile Cauquil, Céline Labeyrie, Iulia Iliescu, Bruno Francou, Clovis Adam, Andoni Echaniz‐Laguna, Luca Leonardi, Vincent Algalarrondo, David Adams and Guillemette Beaudonnet
Article first published online:
14 Jul 2025 | DOI: 10.1111/ene.70277

ORIGINAL ARTICLE

Background and Purpose

Unlike acute unilateral vestibulopathy or vestibular neuritis (AUVP/VN), of which the diagnosis is made based on well‐established neurotologic findings, the diagnosis of idiopathic acute unilateral audiovestibulopathy (iAUAV, also known as labyrinthitis) still requires further elucidation.

Methods

We retrospectively reviewed the medical records of patients with first‐onset acute audiovestibulopathy (AAVS) in a referral‐based university hospital in South Korea between March 2018 and September 2024. The results of video‐oculography, video head‐impulse, and other neurotologic evaluations were included for analysis. In addition, an MRI dedicated to the inner ear was conducted. The findings were compared with 80 patients with AUVP/VN.

Results

A total of 73 patients with iAUAV (age range = 20–85 years, mean age ± SD = 60 ± 18 years, 33 male) were included in the analyses. 26% and 12% of patients showed ipsilesional nystagmus and predominant downbeat nystagmus, respectively. The vestibulo‐ocular reflex (VOR) gain was decreased in horizontal (HC,  = 41), posterior (PC,  = 23), and anterior canals (AC,  = 9), showing more frequent involvement of PC compared to those with AUVP/VN ( = 0.002). Positive MRI results were found in 28 patients with iAUAV (28/68, 41%), showing high signal intensities over the vestibule ( = 27), cochlea ( = 25), HC ( = 21), PC ( = 21), and AC ( = 7) on MRIs.

Conclusions

Patients with iAUAV can show various neurotologic findings that deviate from typical AUVP/VN. Recognition of these findings can aid in a deeper understanding of the pathophysiology of iAUAV, which is distinct from AUVP/VN, and differentiation from other etiologies of AAVS that can have a debilitating prognosis.

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Authors:
Keun‐Tae Kim, Arim Park, Sun‐Uk Lee, Euyhyun Park, Byungjun Kim and Ji‐Soo Kim
Article first published online:
09 Jul 2025 | DOI: 10.1111/ene.70278

ORIGINAL ARTICLE

Objective

To identify the Electroencephalogram (EEG) microstate characteristics that can distinguish between patients with first unprovoked seizure (FUS) and newly diagnosed epilepsy (NDE), providing insight into predicting the progress of FUS to NDE, and to find the predictive biomarkers for the responsiveness to initial antiseizure medication (ASM) therapy.

Methods

Fifty‐six NDE patients in a drug naïve state, 26 FUS patients, and 31 healthy controls (HCs) were compared on microstates features of 21‐channel resting‐state EEG without artifact. Four classic EEG microstates (A, B, C and D) were derived. The global explained variance (GEV), mean duration (MD), time coverage (TC), and frequency of occurrence (FO) of each microstate were calculated.

Results

NDE and FUS patients exhibited decreased MD, TC, and FO in microstate C compared to the HCs. The FUS patients showed decreased MD, TC, and FO in microstate A compared to the NDE patients. Non‐seizure free (NSF) patients showed longer MD, higher TC, and FO in microstate B compared to the seizure free (SF) patients.

Significance

EEG microstate serves as electrophysiological markers that can distinguish between patients with FUS and NDE. Additionally, EEG microstate parameters can also serve as the predictive biomarkers for the responsiveness to initial ASM therapy.

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Authors:
Kailing Huang, Deng Chen, Linyu Tian, Xintong Wu, Jinmei Li, Ling Liu, Jian Guo, Wendan Tao, Hongxi Chen, Yingying Zhang, Xiang Huang, Yuming Li, Qiuxing Lin, Peiwen Liu, Danyang Cao, Wenhao Li, Dong Zhou and Dongmei An
Article first published online:
01 Jul 2025 | DOI: 10.1111/ene.70279

LETTER TO THE EDITOR

Reply to Comments on the Article “Machine Learning Predicts Risk of Falls in Parkinson's Disease Patients in a Multicenter Observational Study”

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Authors:
Maria Chiara Malaguti, Chiara Longo, Monica Moroni, Flavio Ragni, Stefano Bovo, Marco Chierici, Lorenzo Gios, Laura Avanzino, Roberta Marchese, Francesca Di Biasio, Matteo Pardini, Denise Cerne, Paola Mandich, Manuela Marenco, Antonio Uccelli, Bruno Giometto, Giuseppe Jurman, Venet Osmani and NeuroArt P3 Network
Article first published online:
04 Jul 2025 | DOI: 10.1111/ene.70281

ORIGINAL ARTICLE

Objectives

This study aims to assess the efficacy of de‐escalating from natalizumab (NTZ) to cladribine (CLAD), dimethyl fumarate (DMF), fingolimod (FTY), ponesimod (PONE), siponimod (SIPO) and teriflunomide (TERI).

Material and Methods

We analyzed data from 388 patients in the Austrian MS Treatment Registry who initiated NTZ treatment and remained on therapy for at least 3 months before switching to one of the moderately effective therapies within 1 year. Patients were required to remain on the de‐escalation therapy for at least 3 months.

Results

Over a mean treatment duration of 42 months, the estimated ARR (annualized relapse rate) was 0.22 for highly effective therapy and 0.36 for de‐escalation therapies over 61 months ( = 0.009). EDSS scores increased significantly from 2.8 to 3.1 during de‐escalation ( < 0.001). Relapse probability during the treatment gap varied by interval: 14 patients (5.2%) in the < 3 months group, 14 patients (15.7%) in the 3–6 months group, and 13 patients (39.4%) in the 6–12 months group ( < 0.001). Male sex, lower baseline ARR (prior to the initiation of hDMT) and during transition, older age, shorter disease duration, and lower EDSS scores at both baseline and post‐transition were significantly associated with a reduced risk of relapse and longer time to first relapse following de‐escalation.

Conclusions

Our findings reveal an increased risk of relapses and EDSS worsening following de‐escalation from NTZ. Additionally, relapse probability and EDSS progression were influenced by ARR during transition and EDSS scores at the end of the transition period.

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Authors:
Michael Guger, Christian Enzinger, Bettina Heschl, Franziska Di Pauli, Christane Gradl, Stefan Kalcher, Erich Kvas and Thomas Berger
Article first published online:
04 Jul 2025 | DOI: 10.1111/ene.70282

REVIEW ARTICLE

Aims

The present systematic review and meta‐analysis study aimed to investigate the putative relationship between pre‐diabetes and neuropathy.

Methods

Original studies that assessed the association of pre‐diabetes patients with neuropathy disorders in humans without setting and country were selected. The methodological quality of the included articles was evaluated using NHLBI quality assessment tools for observational studies. The meta‐analysis was conducted using the relevant effect sizes to compare outcomes and the random‐effects restricted model. An value > 50% and a  < 0.05 indicated substantial heterogeneity. Galbraith plot is demonstrated for heterogeneity. Egger's and Begg's test was used to evaluate publication bias. A non‐parametric trim‐and‐fill analysis of publication bias was used to assess the number of missing studies.

Results

According to the standardized mean difference (SMD) of included articles, there was a statistically significant association between pre‐diabetes and the occurrence of peripheral neuropathy in the increasing neuropathy assessment metrics (e.g., Impaired unilateral vibration perception, Neuropathic pain, Sensory nerve dysfunction) 0.23[0.14; 0.33] and in decreasing neuropathy assessment metrics (e.g., corneal nerve fiber density, corneal nerve fiber length, warm threshold, cold threshold) −1.04[−1.05; −0.57].

Conclusion

Policymakers should give special attention to preventive strategies and effective lifestyle interventions for these patients to reduce the risk of neuropathy and its consequences.

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Authors:
Roya Riahi, Setayesh Seindareh, Ashraf Aminorroaya, Majid Ghasemi, Jafar Mehvari and Mohammad Reza Maracy
Article first published online:
08 Jul 2025 | DOI: 10.1111/ene.70283

ORIGINAL ARTICLE

Objective

This study investigates whether cerebral amyloid angiopathy (CAA) patients with Alzheimer's disease (AD)‐like CSF profile exhibit radiological features characteristic of AD, specifically reduced hippocampal and amygdala volumes.

Methods

From a database of 162 probable CAA cases (Boston 2.0 criteria) at the Fondazione IRCCS Istituto Neurologico Carlo Besta, 44 patients underwent CSF analysis (Aβ42, Aβ40, and p‐Tau181) and brain MRI with volumetric T1 sequences. Participants with CSF levels of Aβ42 < 640 pg/mL and ‐Tau181 > 56.5 pg/mL were classified as CAA/AD+; otherwise, as CAA/AD−. Hippocampal and amygdala volumes were assessed using volBrain software, and statistical analyses included t‐tests and Mann–Whitney tests.

Results

CAA/AD+ patients ( = 22) were older than CAA/AD− (median age: 73 vs. 67 years,  = 0.006). No significant differences were observed in total hippocampal or amygdala volumes. However, Cornu Ammonis 2–3 (CA2–CA3) hippocampal subfield volume and its ratio to total intracranial volume were significantly lower in CAA/AD+ patients (0.29 vs. 0.35,  = 0.015; 0.02 vs. 0.03,  = 0.011).

Discussion

We found that CA2–CA3 atrophy, potentially linked to tau pathology, was a distinctive feature in our CAA/AD+ cohort. While total hippocampal and amygdala volumes did not differentiate these groups, CA2‐CA3 volume may serve as a radiological marker for identifying biological overlaps between CAA and AD. Future studies should validate these findings and explore their implications for neurodegenerative diseases.

Trial Registration

Identifier: NCT04204642

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Authors:
Benedetta Storti, Mario Stanziano, Giulia Marinoni, Alice Mazzè, Alessandro Francia, Esteban Zacarias, Camilla Strazzabosco, Carolina De Toma, Nicola Rifino, Giorgio Boncoraglio, Giuseppe Di Fede, Giuliana Pollaci, Laura Gatti, Isabella Canavero and Anna Bersano
Article first published online:
08 Jul 2025 | DOI: 10.1111/ene.70284

CASE REPORT

Introduction

Myasthenia gravis (MG) is an autoimmune disorder characterised by autoantibodies against the acetylcholine receptor (AChR‐Ab). Morvan syndrome (MoS) is a rarer autoimmune disease with neuromyotonia, dysautonomia and encephalopathy, associated with antibodies targeting contactin‐associated protein‐like 2 (CASPR2) and may coexist with MG, particularly in patients with thymoma.

Case Report

A 57‐year‐old man with AChR‐Ab MG was treated with pyridostigmine and prednisone for one year and then presented with a severe exacerbation. The symptoms were not controlled despite intravenous immunoglobulins and plasmapheresis. Chest CT revealed a thymoma. Zilucoplan (a C5 complement inhibitor) was started, with rapid improvement. Efgartigimod (a neonatal Fc receptor (FcRn) antagonist) was added to stabilise residual symptoms prior to thymectomy. Three weeks after the third and final efgartigimod cycle, the patient had no symptoms of MG but began to develop profuse sweating, then generalised hypertonia, fasciculations, myoclonus and dysautonomia, consistent with MoS, which were confirmed by the presence of anti‐CASPR2 antibodies. Symptoms improved markedly after resumption of efgartigimod.

Conclusion

This case provides the first evidence of the efficacy of efgartigimod in the treatment of MoS and suggests that FcRn inhibition may be beneficial in IgG4‐mediated disorders beyond MG. It also highlights the importance of considering coexisting autoimmune conditions in thymoma, particularly when new symptoms occur under selective immune modulation. Finally, it emphasises the need to understand immunopathological mechanisms when choosing immunomodulatory treatment.

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Authors:
Vincent Fabry, Celso Rual, Chloé Bost, Blandine Acket, Julien Maquet and Pascal Cintas
Article first published online:
09 Jul 2025 | DOI: 10.1111/ene.70285

ORIGINAL ARTICLE

Introduction

Cognitive impairment is common in secondary progressive multiple sclerosis (SPMS), with executive dysfunction disproportionately so. The frontal assessment battery (FAB) is a bedside test assessing executive function. This study explores the distribution of FAB scores in a large SPMS cohort and their associations with disability.

Methods

Data were analysed from 294 participants in a cognitive substudy of the MS‐STAT2 trial (NCT03387670). Associations between baseline FAB scores, ambulation status (Expanded Disability Status Scale [EDSS] < 6.0 vs. ≥ 6.0) and other disability measures were assessed using generalised linear models, adjusting for age, education, gender and disease duration. FAB performance was also compared against other cognitive tests (SDMT, CVLT‐II, BVMT‐R).

Results

23.8% of participants scored the FAB maximum of 18; 29.9% scored below the clinical threshold of 16. FAB scores showed moderate correlations with SDMT ( = 0.46), CVLT‐II ( = 0.36) and BVMT‐R ( = 0.43), and participants scoring < 16 were significantly more likely to be impaired across these cognitive domains ( < 0.001). Lower baseline FAB scores were significantly associated with higher EDSS, slower T25FW and reduced manual dexterity (9HPT) (all < 0.005) at baseline and longitudinally, with performance comparable to other validated cognitive tests.

Conclusions

We present a large cohort of FAB scores in the SPMS population. Lower FAB scores are associated with both concurrent and future disability and may offer a scalable tool for identifying individuals at greater risk of progression and a robust trial outcome measure.

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Authors:
Charles Wade, Anisha Doshi, Sean Apap Mangion, Tom Williams, Alessia Bianchi, Floriana De Angelis, Sarah Wright, Nevin John, Alberto Calvi, Marie Braisher, James Blackstone, Jennifer Nicholas and Jeremy Chataway
Article first published online:
09 Jul 2025 | DOI: 10.1111/ene.70286

ORIGINAL ARTICLE

Background and Purpose

Inter‐individual variability in levodopa responsiveness complicates personalized treatment of Parkinson's disease (PD). Previous studies have suggested that magnetic resonance imaging (MRI)‐based indices of the perivascular space (PVS) and choroid plexus (CP) volume may be related to levodopa responsiveness. This study integrated multiple MRI indices, including CP volume, free water (FW) fraction, PVS volume fraction (PVSVF), and diffusion tensor imaging along the PVS (DTI‐ALPS), to investigate their associations with levodopa responsiveness.

Methods

This retrospective study included 100 participants with PD (median age, 63.5 years; 53% females) who underwent 3T MRI between March 2023 and December 2024 and were grouped into good ( = 54) and poor ( = 46) responders based on the results of an acute levodopa challenge test. CP volume, FW fraction, PVSVF, and DTI‐ALPS index were calculated. The Mann–Whitney test and binary logistic regression were used for analysis.

Results

Participants in the poor responder group had a higher CP volume ( = 0.048) and FW fraction ( < 0.01) than those in the good responder group. Higher CP volume (odds ratio [OR], 0.986;  = 0.038) and FW fraction (odds ratio [OR], 0.883;  < 0.01) were significantly associated with poor levodopa responsiveness, while higher PVS volume fraction, higher PVSVF‐BG, higher PVSVF‐WM, and lower DTI‐ALPS were not.

Conclusion

Higher CP volume and FW fraction were independently associated with poor levodopa responsiveness. CP volume and FW fraction measurements may be valuable imaging biomarkers for predicting levodopa responsiveness.

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Authors:
Zekai Chen, Sibo Huang, Yuefei Liang, Die Cai, Xi Zhou, Wenjie He and Jun Xia
Article first published online:
11 Jul 2025 | DOI: 10.1111/ene.70290

ORIGINAL ARTICLE

Objective

To investigate the relation between intrathecal antibody production, as reflected by kappa free light chain (KFLC) metrics, and multiple sclerosis (MS) prognosis‐related markers and study its modulation following MS treatment.

Methods

This study comprised matched plasma and cerebrospinal fluid (CSF) samples from a total of 130 persons with MS (pwMS), 99 of whom were untreated at baseline. Paired samples from 73 pwMS (18 on dimethyl fumarate (DMF), 10 on fingolimod, 6 on natalizumab, 25 on rituximab (RTX) and 14 after autologous hematopoietic stem cell transplantation (HSCT)) were used to analyze treatment effects on KFLC metrics. KFLC was measured by nephelometry while clinical and paraclinical data were collected from the patient charts. HLA typing was performed with SNP genotyping.

Results

The KFLC local concentration (KFLC loc) and index was higher in HLA‐DRB1*15:01 carriers and correlated with the number of CSF mononuclear cells, IgG index, and CSF levels of CXCL13 and neurofilament light chain, the latter particularly during remission ( = 0.27,  = 0.045). With regard to treatment effects, we found that treatment with DMF, RTX, and HSCT resulted in a decrease of CSF‐KFLC levels and/or KFLC loc and index. Interestingly, the rate of decrease in KFLC index correlated with time since first treatment ( = −0.41,  = 0.045).

Conclusion

These findings support an involvement of intrathecal antibodies in non‐relapsing MS pathology and inform on the effect of current treatments. The slow rate of decrease in KFLC index following B cell depletion stresses the need for early treatment start.

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Authors:
Frida Duell, Klara Asplund Högelin, Benjamin Vlad, Stephan Neidhart, Mohsen Khademi, Ilijas Jelcic, Magnus Hansson and Faiez Al Nimer
Article first published online:
11 Jul 2025 | DOI: 10.1111/ene.70291

ORIGINAL ARTICLE

Background

Frailty, defined as an age‐related syndrome of multidimensional physiological decline, may serve as a valuable marker to identify brain‐injured patients who are less likely to benefit from aggressive treatment, thus avoiding unnecessary interventions. Here we aimed to evaluate the predictive value of the Clinical Frailty Scale (CFS) score for functional outcome.

Methods

This retrospective study included 1008 patients admitted to the neurological intensive care unit (ICU), with ischemic and hemorrhagic stroke (subarachnoid hemorrhage, SAH and intracerebral hemorrhage, ICH), and traumatic brain injury (TBI). Outcome was evaluated with the modified Rankin Scale (mRS) at ICU discharge. Correlations and univariate analyses identified factors linked to higher CFS levels, while multivariable logistic regression evaluated CFS's potential to predict poor outcome (mRS ≥ 4).

Results

Patients were admitted with ischemic stroke ( = 256, 25%), hemorrhagic stroke ( = 516, 51%) or TBI ( = 236, 23%) and the mean age was 66 years (IQR, 54–77). All disease severity grades were included, with a median GCS of 14 (9–15) at admission. The median premorbid CFS was 2 (1–3) with 9.2% of patients classified as frail (CFS ≥ 5). In multivariable analysis, CFS ≥ 5 was independently associated with poor outcome (adjOR [95% CI] 2.83 [1.50–5.33],  = 0.001). In a subgroup of patients aged ≥ 65 years ( = 532, 53%), a CFS‐score of ≥ 5 was associated with poor outcome (adjOR [95% CI] 2.51 [1.24–5.09],  = 0.011), whereas age itself was not associated with poor outcome ( = 0.095).

Conclusions

Frailty as measured by the CFS remained a significant predictor of outcome, whereas age alone was not associated with poor outcome in patients aged ≥ 65 years.

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Authors:
Anna Berek, Philipp Kindl, Alois J. Schiefecker, Klaus Altmann, Lauma Putnina, Raimund Helbok, Bettina Pfausler, Ronny Beer and Verena Rass
Article first published online:
14 Jul 2025 | DOI: 10.1111/ene.70292

CASE REPORT

Background and Aims

IgG4‐related disease (IgG4‐RD) is a rare disease considered an acquired systemic autoimmune condition. Myotonic dystrophy type 2 (DM2) is a rare dominantly inherited multisystem disorder, with a high prevalence of associated autoimmune diseases, but IgG4‐RD has not been described in this context.

Methods

A case series of three patients with concurrent IgG4‐RD and DM2.

Results

All three patients, from a cohort of 47 patients with DM2 (prevalence = 6%), were male, aged 61–80 years and exhibited at least pancreatic involvement. Elevated IgG4 levels were observed in blood, and two patients had lymphoplasmacytic infiltrates rich in IgG4+ plasma cells and CD4+ T cells, with fibrosis present in biopsies. In two cases, DM2 was diagnosed after IgG4‐RD. All patients presented with a myopathic phenotype in the lower limbs, with myotonic discharges at myography.

Interpretation

The prevalence of IgG4‐RD in the cohort of DM2 herein is more than 1000 times higher than expected. As both diseases display common organ involvement, especially the pancreas, IgG4‐RD screening should be considered in DM2 patients with diabetes or/and atypical associated phenotypes. Additionally, genetic testing for DM2 should be considered in IgG4‐RD patients with elevated creatine kinase levels, myopathic phenotype, cardiac disorders and/or cataracts. The present report also suggests that IgG4‐RD may have a genetic predisposition, potentially elucidating an aspect of the disease's pathophysiology.

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Authors:
Antoine Pegat, Juliette Svahn, Mathieu Gerfaud‐Valentin, Cecile‐Audrey Durel, Stéphane Durupt and Emilien Bernard
Article first published online:
09 Jul 2025 | DOI: 10.1111/ene.70293

LETTER TO THE EDITOR

Reply to: “Before Coming to the Conclusion That Inclusion Body Myositis Is a Risk Factor for a Heart Attack, All Influencing Factors Must Be Taken Into Account”

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Authors:
Elie Naddaf
Article first published online:
17 Jul 2025 | DOI: 10.1111/ene.70295

LETTER TO THE EDITOR

Letter to the Editor: “Long‐Term Persistent Headache After SARS‐CoV‐2 Infection: A Follow‐Up Population‐Based Study”

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Authors:
Jianghao Yu, Lu Xu, Tingting Zhou and Jinwei Li
Article first published online:
18 Jul 2025 | DOI: 10.1111/ene.70296

LETTER TO THE EDITOR

Before Coming to the Conclusion That Inclusion Body Myositis Is a Risk Factor for a Heart Attack, All Influencing Factors Must Be Taken Into Account

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Authors:
Josef Finsterer and Sinda Zarrouk
Article first published online:
17 Jul 2025 | DOI: 10.1111/ene.70297

ORIGINAL ARTICLE

Background

The stress hyperglycemia ratio (SHR) has been linked to adverse outcomes in various conditions, yet its association with Parkinson's disease (PD) remains unclear. This study investigates the relationship between SHR and PD risk across sex and glucose metabolism statuses using data from the UK Biobank.

Methods

In this prospective cohort study, 406,271 participants without baseline PD from the UK Biobank were included. SHR was calculated as [FPG (mmol/L)]/[1.59 × HbA1c (%)−2.59] and divided into tertiles. Incident PD cases were identified via linked medical records. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), with analyses stratified by sex and diabetes status (nondiabetic, prediabetic, diabetic).

Results

Over a median follow‐up of 9 years, 2837 PD cases were identified. In men, elevated SHR was associated with increased PD risk, with the highest tertile (T3) showing a significantly higher risk compared with the lowest (T1) (HR: 1.20, 95% CI: 1.06–1.37). This association was strongest in nondiabetic men (T3 vs. T1: HR: 1.25, 95% CI: 1.08–1.45). No significant associations were observed in women or in prediabetic or diabetic men, either across tertiles or as a continuous variable.

Conclusion

Elevated SHR is independently linked to an increased PD risk in men, particularly those without diabetes, but not in women or other glucose metabolism groups. These findings suggest a sex‐specific role of acute metabolic stress in PD pathogenesis and emphasize the need to consider glucose metabolism status in PD risk assessment.

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Authors:
Haiyan Zhou, Yuzhi Mi, Xiaoyu Zhang, Wen Sun and Wenfang Xu
Article first published online:
16 Jul 2025 | DOI: 10.1111/ene.70299

LETTER TO THE EDITOR

Author Response: “A Transfer Strategy Utilizing a Helicopter and a Ground Ambulance Together Does Not Prolong Door‐In‐Door‐Out Times in Thrombectomy Patients: A Retrospective Analysis”

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Authors:
Pauli Vuorinen, Joonas Kiili, Markku Grönroos, Ilkka Virkkunen, Heini Huhtala, Piritta Setälä and Sanna Hoppu
Article first published online:
23 Jul 2025 | DOI: 10.1111/ene.70303

LETTER TO THE EDITOR

“Letter to the Editor: A Transfer Strategy Utilizing a Helicopter and a Ground Ambulance Together Does Not Prolong Door‐In‐Door‐Out Times in Thrombectomy Patients: A Retrospective Analysis”

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Authors:
Noor Un Nisa, Umar Aziz and Shah Jahan
Article first published online:
23 Jul 2025 | DOI: 10.1111/ene.70306