cover image European Journal of Neurology

European Journal of Neurology

2026 - Volume 33
Issue 9 | September 2026
Previous Issue

ISSUE INFORMATION

Issue Information

Read full article
Free access for EAN members – please log in.
Authors:
Article first published online:
26 Aug 2026 | DOI: 10.1111/ene.70641

INVITED REVIEW

Introduction and Aims

The European Academy of Neurology (EAN) joined the Horizon Europe EBRAINS 2.0 research consortium to co‐develop recommendations for prospective acquisition and integration of clinical and research core multi‐scale human datasets for connectome analysis in stroke, Parkinson's disease (PD), and glioma (GBM).

Methods

Using an online Delphi survey method, expert consensus was sought on 28 statements for each of the following protocols in stroke, PD and GBM: clinical core/research brain MRI, minimum/extended clinical outcomes, minimum/extended cognition assessments, case report forms (CRF). The level of agreement for each statement was predefined as ≥ 80%. 536 experts from four EAN Scientific Panels (SP) (SP Neuro‐oncology [ = 70], SP Movement Disorders [ = 206], SP Neuroimaging [ = 112], SP Stroke [ = 148]) were invited to participate in this Delphi process.

Results

Two Delphi voting rounds were conducted to reach the predefined level of agreement (≥ 80%; range: 80.49%–100%) for all items to establish consensus on protocol recommendations for stroke, PD and GBM. Cumulative response rate from SP experts was 25% ( = 135 from 30 European countries) for the first, and 32% ( = 173 from 35 European countries) for the second Delphi voting round.

Discussion

These consented protocols provide a pragmatic framework for harmonizing multi‐scale data acquisition for connectome analyses in stroke, PD, and GBM. Further, these protocols allow future modular extensions for other datasets, e.g., neurophysiological data or non‐imaging biomarkers, and serve as a role model for brain network analyses in other neurological disorders.

Read full article
Free access for EAN members – please log in.
Authors:
Thomas Berger, Lorenzo Pini, Alessandro Salvalaggio, Simone Cauzzo, Christine Klein, Maria Lolich, Alberto Picca, Dauren Ramankulov, Maria A. Rocca, Roberta Rudà, Alessandro Sodero, Alessandro Tessitore, Thomas Truelsen, Roland Wiest, Gereon R. Fink, Elena Moro, Philippe Ryvlin and Maurizio Corbetta
Article first published online:
09 Sep 2026 | DOI: 10.1111/ene.70708

ORIGINAL ARTICLE

Background

Hereditary variant transthyretin amyloidosis (ATTRv) is caused by > 140 pathogenic gene variants. The heterogeneous presentation of ATTRv clinical phenotypes complicates diagnosis and staging of patients. Tools that improve early detection of ATTRv symptoms and signs and identify risk of transition to clinically detectable disease are needed.

Methods

A retrospective, multicenter study at amyloid centers in France, Spain, Portugal, and the United Kingdom (December 2023–December 2024) assessed asymptomatic carriers (ACs) and ACs who transitioned to symptomatic disease within the previous 2 years (newly symptomatic carriers [NSCs]). A new 23‐question asymptomatic carrier neurologic assessment (ACNA) was developed to screen for the potential transition to clinically detectable ATTRv‐polyneuropathy (PN). Question topics spanned sensory, autonomic, and systemic signs and symptoms. Fisher's exact tests were conducted to evaluate the association between each individual question and disease status (i.e., NSC vs. AC). Logistic regression models with a Firth correction were used to estimate odds ratios and corresponding 95% confidence intervals.

Results

The study included 217 carriers (AC,  = 128; NSC,  = 89) with 18 unique transthyretin variants; 166 (76.5%) had p.Val50Met. Of 23 ACNA questions, 17 were significantly associated with transition to symptomatic disease for all patients. The pattern of neurologic signs and symptoms found to be associated with p.Val50Met and other common variants reflected what is known about variant‐specific symptomatology. Confounding factors included age, medical center of treatment, and variant type.

Conclusion

The ACNA questionnaire may be a clinically valuable tool to screen ACs for risk of transition to symptomatic ATTRv‐PN but requires validation.

Read full article
Free access for EAN members – please log in.
Authors:
Isabel Conceição, Juan González‐Moreno, Andoni Echaniz‐Laguna, Kuangnan Xiong, Adam Castaño, Jonathan C. Fox, Julian D. Gillmore, Pablo Garcia‐Pavia and Mary M. Reilly
Article first published online:
07 Sep 2026 | DOI: 10.1111/ene.70729

ORIGINAL ARTICLE

Background

In Parkinson's disease (PD), sleep‐related oscillatory dynamics between basal ganglia and cortical nodes may inform sleep dysfunction. The subthalamic nucleus (STN) is highly interconnected with human sleep circuitry and is a current target of interest for sleep neuromodulation.

Methods

To investigate correlated cortical–subcortical activity, we recorded simultaneous PSG and STN local field potentials (LFP) in 19 patients undergoing deep brain stimulation (DBS) for PD. We evaluated the correlation in spectral power between STN‐LFP and EEG during polysomnogram (PSG)‐defined stages of sleep. In addition, we analyzed aperiodic 1/f spectral parameters (exponent and offset), which have been identified as markers of arousal across sleep stages. Finally, we trained classifiers on aperiodic features to test whether 1/f structure alone could recover PSG‐defined sleep stages from EEG and STN‐LFP.

Results

Results revealed a significant interaction between recording modality and sleep stage. During wakefulness and REM sleep, STN‐LFP exhibited a significantly steeper spectral slope compared to scalp EEG. However, this dissociation diminished with sleep depth; slopes appeared more similar during N2 and reversed during N3, where EEG became steeper than LFP. Across subjects, the aperiodic component showed robust state dependence and modality differences with STN‐LFP maintaining higher exponents overall. STN‐LFP aperiodic features alone classified sleep stages above chance and outperformed scalp EEG, approaching the combined‐modality ceiling.

Conclusion

These findings highlight distinct subcortical electrophysiological signatures in sleep‐dependent regulation of neural arousal across brain networks in PD. These insights offer potential biomarkers for both invasive and non‐invasive forms of closed‐loop neuromodulation strategies targeting sleep dysfunction.

Trial Registration

identifier: NCT04620551

Read full article
Free access for EAN members – please log in.
Authors:
Lisa Hirt, Ruby Martini, Siqun Tang, Michael Summers, Lesile West, Clete Kushida, Stephen V. Gliske, Dulce Maroni, Younghoon Nho, Casey H. Halpern, Aviva Abosch and John A. Thompson
Article first published online:
26 Aug 2026 | DOI: 10.1111/ene.70733

ORIGINAL ARTICLE

Background

Migraine's economic burden is mostly due to reduced work productivity, which is underestimated by commonly used patient‐reported outcome measures (PROMs). In this prospective, multicentric, real‐world study, we used the HEADWORK questionnaire (HWq), a disease‐specific work‐related PROM, to assess the impact of anti‐calcitonin gene receptor peptide (anti‐CGRP) monoclonal antibodies (mAbs) on work‐related limitations.

Methods

Migraine patients eligible for treatment with anti‐CGRP mAbs were enrolled from three headache centers: IRCCS C.Besta, Mondino Foundation and Policlinico Campus Bio‐Medico. Migraine days per month (MMDs), monthly acute medications (MAMs), and HWq were collected every 3 months up to 12 months of follow‐up. A GLM design was used to address change in HWq scales' score (primary endpoint), MAMs and MMDs; we also tested whether change in HWq differed across responders' group and defined minimum clinically important difference (MCID) for HWq.

Results

Out of 175 patients (130 females, mean age 48.9 ± 8.8) 152 completed the study. Among them: 37 (24.3%) were non‐responders, 69 (45.4%) were responders, and 46 (30.3%) were super‐responders. A reduction in all endpoints was observed since the first 3 months of treatment and maintained up to 12‐month follow‐up. Time*group interaction showed a superior effect, both in HWq scales and MAMs, with super‐responders achieving the best outcome.

Conclusions

A significant reduction in MMDs and MAMs and an improvement in both HWq scales in patients under mAbs treatment was found from the 3‐month follow‐up onwards. The positive impact on work‐related disability should be taken into consideration in planning cost‐effectiveness evaluations and drug policy strategy.

Read full article
Free access for EAN members – please log in.
Authors:
Danilo Antonio Montisano, Gloria Vaghi, Claudia Altamura, Alessandra Parisi, Roberto De Icco, Marilena Marcosano, Alessia Marcassoli, Erika Guastafierro, Michele Corrado, Domenico D'Amico, Grazia Sances, Fabrizio Vernieri, Cristina Tassorelli, Alberto Raggi and Licia Grazzi
Article first published online:
30 Aug 2026 | DOI: 10.1111/ene.70738

INVITED REVIEW

Background

About 80% of people with epilepsy live in low‐and‐middle‐income countries (LMICs) where the treatment gap is high. Limited access to neurologists, diagnostic tools, and antiseizure medications, combined with persistent stigma, contribute to poor outcomes, including premature mortality. Artificial intelligence (AI) offers potential to address these gaps through scalable, low‐cost solutions for diagnosis, investigation, management, and monitoring.

Methods

This review examines three recent and complementary AI applications in epilepsy care for LMICs: a smartphone‐based diagnostic tool for convulsive epilepsy developed using population‐based data from five sub‐Saharan African countries; an automated EEG interpretation system based on a deep learning model (SCORE‐AI) validated across multicenter datasets; and a wearable‐based deep learning model for detecting generalized convulsive seizures using low‐cost smartwatches.

Results

The smartphone diagnostic tool achieved area under the curve (AUC) 0.92–0.95 with sensitivity 85.0%–97.5% for identifying epilepsy with convulsive seizures using eight binary clinical features. SCORE‐AI demonstrated expert‐level performance (AUC 0.89–0.96, accuracy 85%–92%) for automated EEG classification across multiple validation datasets. The wearable seizure detection algorithm achieved 96% sensitivity with approximately one false alarm per 8 days. All three solutions were designed for deployment on widely accessible platforms.

Conclusions

AI‐driven approaches demonstrate feasibility for addressing diagnostic and monitoring gaps in resource‐limited settings. However, implementation faces substantial challenges including infrastructure constraints, limited digital literacy, ethical considerations, and sociocultural factors. Successful deployment requires validation with large locally relevant datasets, context‐adapted solutions, task‐sharing strategies, implementation research, appropriate regulatory frameworks/certification, and community engagement to reduce the global epilepsy care gap.

Read full article
Free access for EAN members – please log in.
Authors:
Philippe Ryvlin, Sándor Beniczky, Harald Aurlien, Adriano Bernini, Gabriel Davis Jones, Symon M. Kariuki, Antoine Spahr, Jesper Tveit and Arjune Sen
Article first published online:
08 Sep 2026 | DOI: 10.1111/ene.70740

ORIGINAL ARTICLE

Background

Plasma and cerebrospinal fluid (CSF) protein biomarkers in amyotrophic lateral sclerosis (ALS) may provide insight into disease mechanisms and yield clinically useful biomarkers.

Methods

Overall, 363 proteins in plasma and CSF from 198 patients with ALS and 125 matched controls were profiled using Olink assays. Associations with disease status, survival, and functional decline, as well as longitudinal biomarker stability across the disease course were assessed, together with network and enrichment analyses. ALS risk‐associated biomarkers were externally validated in the UK Biobank (UKB).

Results

Overall, 125 proteins were significantly associated with at least one outcome (i.e., case status, risk, survival, or functional decline), and 21 were associated with three or more outcomes. NEFL was the most robust biomarker in plasma and CSF, alongside TNFRSF12A in plasma and CSF, EDA2R in plasma, and FABP4 in plasma and CSF. Most biomarkers remained stable longitudinally across the disease course. ALS risk‐associated biomarkers were replicated in UKB, in which > 3000 plasma proteins were measured in 52,990 participants, including 298 with ALS. Network and enrichment analyses highlighted their roles in immune response and extracellular‐matrix remodeling, and their enrichments in the brain and T‐cell subsets. Construction of an ALS risk‐prediction model achieved an ROC‐AUC of 0.72 in the UKB validation cohort.

Conclusions

These findings suggest candidate protein biomarkers for ALS risk stratification, early detection, and clinical therapeutic monitoring.

Read full article
Free access for EAN members – please log in.
Authors:
Lu Pan, Can Hou, Christina Seitz, Caroline Ingre, Åsa K. Hedman, Jose Laffita, Trung Nghia Vu, Yudi Pawitan, Abbe Ullgren, Solmaz Yazdani, John Andersson, Emily E. Joyce, Charilaos Chourpiliadis, Anikó Lovik, Yan Chen, Sebastian A. Lewandowski, Oscar Fernandez‐Capetillo, Myriam Barz, Kristin Samuelsson, Rayomand Press, Fredrik Piehl, Caroline Graff, Anders Mälarstig and Fang Fang
Article first published online:
05 Sep 2026 | DOI: 10.1111/ene.70741

ORIGINAL ARTICLE

Background

Congenital myasthenic syndromes (CMS) caused by pathogenic variants in , encoding the δ‐subunit of the nicotinic acetylcholine receptor (AChR), are rare, and data on genotype–phenotype correlations and long‐term outcomes are limited.

Methods

We performed a retrospective, multicenter study of nine patients with genetically confirmed ‐related CMS from specialized neuromuscular centers. Clinical, electrophysiological, genetic, and therapeutic data were systematically collected. All diagnoses were established by exome sequencing during routine clinical work‐up.

Results

Eight patients were compound heterozygous and one was homozygous for pathogenic variants, including nonsense, missense, splice‐site variants, and one microdeletion. Disease onset ranged from the neonatal period ( = 7) to adolescence ( = 2). Three patients were followed longitudinally for 22–43 years. Ocular involvement, particularly ptosis and ophthalmoparesis, was present in all patients. Generalized fatigable weakness was common, whereas bulbar and respiratory involvement occurred in a subset and reflected overall disease severity. Genotypes including a null allele or a homozygous missense variant tended to be associated with more severe phenotypes, while compound heterozygous missense variants were linked to a broader and generally milder spectrum, sometimes limited to ocular symptoms. Long‐term outcomes ranged from minimal symptoms under therapy to severe motor impairment with respiratory insufficiency, highlighting substantial interindividual variability.

Conclusions

This study expands the phenotypic and genotypic spectrum of ‐related CMS and underscores the critical role of genotype in determining disease severity. Comprehensive genetic testing, longitudinal phenotyping, and genotype‐informed management are essential for optimal diagnosis and care in this rare disorder.

Read full article
Free access for EAN members – please log in.
Authors:
David Muhmann, Göknur Haliloğlu, Maria Antonia Grimalt, Damjan Osredkar, Ana Vesperinas Castro, Silvia Cerezo Corredera, Angela Abicht, Adalet Elçin Yıldız, Johann Böhm, Ulrike Schara‐Schmidt, Anja Troha Gergeli, Berta Estevez‐Arias, Elena Cortes Vicente, Andres Nascimento, Adela Della Marina, Daniel Natera‐de Benito and Andreas Roos
Article first published online:
27 Aug 2026 | DOI: 10.1111/ene.70742

ORIGINAL ARTICLE

Background

Neurological patients represent a small yet resource‐demanding group in pediatric emergency departments (PEDs). Their pathways and resource needs remain poorly understood. This population‐based real‐world data study aims to bridge this gap.

Methods

We analyzed neurological visits from 2021 to 2023 at the sole PED serving 300,000 children using process mining and statistical analysis. Neurological visits included patients triaged for neurologist evaluation and those with neurological complaints and/or diagnosis.

Results

We identified 4854 neurological visits, constituting 5% of PED visits. Seizure and headache comprised 64% of the chief complaints; seizures dominated the highest acuity visits, while headache was linked to visits with lower acuity. Neurological patients had a nearly fivefold increased risk of requiring immediate lifesaving interventions compared to non‐neurological patients. Half of the highest acuity patients were 1–5 years old. Patient disposition was most strongly associated with acuity: 81% of highest acuity patients were admitted and 15% of them to the pediatric intensive care or surgical unit, whereas only 18% of stable patients were hospitalized. Variability of patient pathways was moderate. 87% of patients adhered to one of four most common pathways where disposition decision was made without advanced testing. Over 30 pathways were identified for patients needing advanced tests. These patients presented with higher acuity, non‐seizure complaints and increased admissions.

Conclusion

This population‐based study pioneers process mining for analyzing patient care processes and resource utilization of neurological patients at the PED. It highlights the critical nature of pediatric neurological emergencies and uncovers the variability of patient needs and pathways.

Read full article
Free access for EAN members – please log in.
Authors:
Henna Aro, Tuomo Antikainen, Mari Videman, Elina Wärnhjelm, Erika Ignatius, Pirjo Isohanni and Miika Koskinen
Article first published online:
09 Sep 2026 | DOI: 10.1111/ene.70743

LETTER TO THE EDITOR

Letter to the Editor in Reply to: “Advanced ET” Is a More Appropriate Term Than “ET‐Plus”

Read full article
Free access for EAN members – please log in.
Authors:
Luca Angelini and Matteo Bologna
Article first published online:
27 Aug 2026 | DOI: 10.1111/ene.70744

ORIGINAL ARTICLE

Background

Cluster headache (CH) is a primary headache disorder characterized by severe, unilateral headache attacks accompanied by trigemino‐autonomic symptoms. Calcitonin gene‐related peptide (CGRP) is thought to be released during CH attacks, although the role of CGRP has been questioned. In this exploratory study, we investigated tear fluid CGRP levels during experimentally induced CH attacks using glycerol trinitrate.

Methods

Active episodic and chronic CH patients were screened at study Day 1 and eligible patients received sublingual glycerol trinitrate 0.9 mg at study Day 2. Headache characteristics and tear fluid were sampled before and after intake of GTN. Tear fluid CGRP levels were analyzed using a commercial CGRP ELISA (Cusabio, Wuhan, China).

Results

89 episodic (eCH) and chronic cluster headache (cCH) patients were screened. Of these, 18 CH patients (eCH  = 11, 42.6 ± 10.0 years) were included in the analysis. Of 16 CH patients reported an experimentally induced CH attack, tear fluid CGRP levels significantly increased from “baseline” to “headache” (“baseline”: 2.34 ± 3.22 ng/mL, “headache”: 3.70 ± 5.60 ng/mL;  = 0.019). Tear fluid CGRP levels increased significantly more in participants with an intense headache attack (NRS ≥ 5: +2.65 ± 3.51 ng/mL) compared to participants with a mild intensity (NRS < 5: +0.07 ± 0.83 ng/mL,  = 0.015).

Conclusion

Our study results support the role of CGRP in the pathophysiology of CH. Further studies with a larger study sample and investigation of other neuropeptides are needed to better understand the underlying mechanisms.

Read full article
Free access for EAN members – please log in.
Authors:
Katharina Kamm, Maria Angelhuber, Adrian Marius Le Prince, Andreas Straube and Ruth Ruscheweyh
Article first published online:
08 Sep 2026 | DOI: 10.1111/ene.70745

ORIGINAL ARTICLE

Background

The dual syndrome hypothesis distinguishes frontostriatal and posterior cortical cognitive subtypes in Parkinson's disease with mild cognitive impairment (PD‐MCI), which are associated with distinct cognitive profiles and different risks of dementia.

Objective

To characterize dopaminergic‐ and cholinergic‐related structural MRI patterns across cognitive subtypes of PD‐MCI.

Methods

A total of 182 non‐demented patients with Parkinson's disease (PD) and 38 healthy controls (HC) were included. Based on comprehensive neuropsychological assessments, PD patients were classified as having normal cognition (PD‐NC,  = 112), PD‐MCI with frontostriatal deficits ( = 20), posterior cortical deficits ( = 28), or mixed deficits ( = 22). All participants underwent T1‐weighted MRI. Normalized volumetric measures of subcortical nuclei (caudate, putamen, globus pallidus, and thalamus) and the basal forebrain were obtained.

Results

Distinct subtype‐specific patterns of subcortical and basal forebrain atrophy were observed. PD‐MCI patients with posterior cortical deficits showed significant atrophy of cholinergic nucleus 4 (Ch4) compared with HC and PD‐MCI patients with frontostriatal deficits. In contrast, PD‐MCI patients with frontostriatal deficits exhibited atrophy of the caudate nucleus and putamen relative to HC. The mixed deficits subtype showed putamen and thalamic atrophy compared with HC. In addition, basal forebrain Ch4 volume was significantly associated with visuospatial performance in PD‐MCI patients.

Conclusions

Different PD‐MCI subtypes exhibit distinct patterns of dopaminergic‐ and cholinergic‐related structural alterations on MRI. Posterior cortical deficits are predominantly associated with cholinergic basal forebrain degeneration, whereas frontostriatal deficits are linked to dopaminergic involvement. These findings support the neural heterogeneity underlying cognitive impairment in PD.

Read full article
Free access for EAN members – please log in.
Authors:
Xueqin Bai, Haoxin Chen, Qiuyue Li, Shiwei Zhang, Shuangli Chen, Andan Qian, Ronghui Zhou, Yitong Cheng, Chenglong Xie, Zhen Wang, Yunjun Yang and Meihao Wang
Article first published online:
09 Sep 2026 | DOI: 10.1111/ene.70746

POSITION PAPER

Background

The therapeutic landscape of generalised myasthenia gravis (gMG) has evolved substantially with the approval of targeted immunotherapies, including complement C5 inhibitors (C5‐I) and neonatal Fc receptor inhibitors (FcRn‐I). While pivotal trials have demonstrated marked efficacy in defined subgroups, real‐world experience reveals more heterogeneous outcomes and raises questions about optimal patient selection, therapy sequencing and integration into clinical practice. In Germany and Austria, early access following regulatory approval has facilitated clinical experience over recent years. This expert opinion paper aims to combine current evidence with clinical experience to guide the use of C5‐I and FcRn‐I in everyday care.

Methods

A panel of 18 neurologists from Germany and Austria, including two paediatric neurologists, evaluated study data and real‐world experiences. Through structured discussion and a consensus process, they developed evidence‐ and experience‐based recommendations on integrating targeted immunotherapies into existing treatment algorithms.

Results

The panel provides practical recommendations for managing (highly) active gMG in adults, focusing on C5‐I (eculizumab, ravulizumab, zilucoplan) and FcRn‐I (efgartigimod, rozanolixizumab). The statements cover initiation criteria, sequencing and switching within and between drug classes and transitions to intensified immunomodulatory therapies (rituximab, apheresis, intravenous or subcutaneous immunoglobulin), as well as special considerations for juvenile MG.

Conclusions

This expert statement provides a practice‐oriented framework integrating current evidence and clinical experience to support individualised therapeutic decision‐making in gMG.

Read full article
Free access for EAN members – please log in.
Authors:
Andreas Meisel, Adela Della Marina, Paolo Doksani, Tim Hagenacker, Christoph Kleinschnitz, Heidrun H. Krämer, Jan D. Lünemann, Sven G. Meuth, Tobias Ruck, Ulrike Schara‐Schmidt, Christiane Schneider‐Gold, Benedikt Schoser, Michael Schroeter, Charlotte Schubert, Jörn Peter Sieb, Fritz Zimprich, Jana Zschüntzsch and Sarah Hoffmann
Article first published online:
09 Sep 2026 | DOI: 10.1111/ene.70747

CORRECTION

Correction to “A Population‐Based Study of Posterior Reversible Encephalopathy Syndrome and Reversible Cerebral Vasoconstriction Syndrome During Pregnancy and Puerperium”

Read full article
Free access for EAN members – please log in.
Authors:
Article first published online:
04 Sep 2026 | DOI: 10.1111/ene.70748

LETTER TO THE EDITOR

Response Shift and Item Interpretation: Two Caveats for Using Minimal Symptom Expression as a Treatment Goal in Generalised Myasthenia Gravis

Read full article
Free access for EAN members – please log in.
Authors:
Hai‐Feng Li, Qi Li, Yu‐Zhou Guan and Huan Yang
Article first published online:
11 Sep 2026 | DOI: 10.1111/ene.70749

ORIGINAL ARTICLE

Background

Spinal cord injury (SCI) results in neurodegeneration both at and above the lesion site. While cervical cord atrophy is well characterised in populations of mixed cervical, thoracic and/or lumbar injuries, the remote morphological changes in cervical cord following thoracic SCI remain unclear. The present study aimed to quantify cervical spinal cord morphology at C2–C3 in individuals with complete thoracic SCI and compare these metrics to matched controls.

Methods

Participants were 52 adults with complete thoracic SCI and 55 neurologically healthy, able‐bodied controls matched for age and sex. Extracted cervical metrics included mean cross‐sectional area (CSA), antero‐posterior (AP) and right–left (RL) diameters, eccentricity, solidity, orientation and cord length. Group differences were assessed using linear mixed models adjusted for age, sex and scanning sites. Impacts of experiencing SCI‐related chronic neuropathic pain on these metrics were explored.

Results

Compared to controls, the thoracic SCI group showed significantly reduced cervical CSA and AP/RL diameters, consistent with remote atrophy, and increased eccentricity, indicating a more flattened cord profile. Solidity, orientation and cord length showed no group differences, supporting metric reliability and absence of segmentation artefacts. Although no difference was evident among the SCI groups, those experiencing chronic neuropathic pain had larger eccentricity than controls.

Conclusions

Complete thoracic SCI is associated with significant remote cervical cord degeneration, even in the absence of direct cervical injury. Results highlight that neurodegenerative processes propagate along ascending and descending spinal pathways. Cervical morphometry metrics, particularly CSA and eccentricity, may represent biomarkers of distal neurodegeneration following thoracic SCI and inform future therapeutic strategies.

Read full article
Free access for EAN members – please log in.
Authors:
Yann Quidé, Negin Hesam‐Shariati, Zina Trost, Thiago Folly de Campos, William R. Willoughby, Mark Bolding, Rachel E. Cowan, Pauline Zahara and Sylvia M. Gustin
Article first published online:
10 Sep 2026 | DOI: 10.1111/ene.70750

ORIGINAL ARTICLE

Objective

To investigate whether selective radiofrequency thermocoagulation (RFTC) targeting mesiotemporal structures, while sparing the piriform cortex (PC), can achieve seizure freedom in drug‐resistant mesial temporal lobe epilepsy (MTLE), and to assess whether said seizure freedom is associated with an indirect disconnection of the PC within the epileptogenic network.

Methods

A retrospective analysis was performed on 32 patients (mean age 27.81 ± 13.37 years) with drug‐resistant MTLE who underwent stereoelectroencephalography (SEEG)‐guided RFTC. Volumetric and structural connectivity (SC) analyses were conducted using pre‐ and postoperative T1‐weighted (T1W) and diffusion‐weighted imaging (DWI). The regions of interest (ROIs) targeted included the hippocampus, amygdala, rhinal cortex, and parahippocampal cortex, while the PC was spared. Network metrics assessed pre‐ and postoperative SC changes.

Results

At a mean follow‐up of 40.63 ± 16.36 months, 25 patients (78.1%) became seizure free (SF). SF patients had significantly greater ablation volumes in the amygdala ( = 0.026) and rhinal cortex ( = 0.023) compared to non‐seizure‐free (NSF) patients. SF patients showed significant postoperative reductions in SC across all mesiotemporal ROIs, including the spared PC ( ≤ 0.020). NSF patients exhibited no significant SC changes.

Conclusions

Seizure freedom following SEEG‐guided RFTC is associated with widespread disruption of SC in mesiotemporal networks, including the spared PC. These findings support the hypothesis that seizure freedom following the ablation of key mesiotemporal ROIs can induce an indirect disconnection of the PC through its connected nodes, offering a safer therapeutic option for MTLE.

Read full article
Free access for EAN members – please log in.
Authors:
Stéphane Jean, Paul Edisie Donkor, Xiaoqiang Wei, Yihai Dai, Jifeng Gong, Qingfang Xiao, Weitao Chen, Weihong Liu, Xinrong Fang and Shiwei Song
Article first published online:
11 Sep 2026 | DOI: 10.1111/ene.70751

SHORT COMMUNICATION

Objectives

pathogenic variants are associated with ALS, frontotemporal dementia, spastic ataxia, spasticity, ataxia, Parkinson's disease, female infertility, macrothrombocytopenia, and myopathy. Four recently reported patients with neonatal/childhood onset myopathy had also a decrement on repetitive nerve stimulation (RNS), but such a finding was not further characterized. We describe a patient with a pathogenic variant with adulthood‐onset genetic myasthenic syndrome accompanied by myopathy and infertility to highlight the neuromuscular junction defect as the main feature of the patient's phenotype.

Methods

We reviewed the patient's clinical and laboratory findings and performed transcriptomic analysis on the patient's muscle.

Results

A 53‐year‐old woman with infertility of unknown etiology manifested fatigability and proximal upper limb muscle weakness in her mid‐30s, followed by lower limb involvement. Her examination showed proximal muscle weakness and fatigability but spared facial muscles. CK values were mildly elevated. Anti‐AChR, MuSK, P/Q‐type calcium channel, and LRP4 antibodies were absent. 2 Hz RNS showed decrement (−14% to −48%) in limb muscles that improved with 3,4‐dyaminopyridine (3,4‐DAP). Facilitation (231%) occurred in the trapezius. Muscle biopsy showed patchy loss of oxidative enzyme reactivity and no C5b9 or IgG at neuromuscular junctions. Whole genome sequencing identified a heterozygous known pathogenic variant (c.850G>A, p.Glu284Lys). Patient improved with 3,4‐DAP and albuterol.

Discussion

TUBA4A p.Glu284Lys can lead to treatable myasthenic syndrome with postsynaptic and likely presynaptic involvement, as suggested by the patient's electrophysiological findings and response to therapy. This patient expands the ‐disorder spectrum to include overlapping myasthenic syndrome‐myopathy and shows that neuromuscular disease and infertility can occur within the same patient.

Read full article
Free access for EAN members – please log in.
Authors:
Margherita Milone, Stefan Nicolau, Zhiyv Niu, Teerin Liewluck, Eric J. Sorenson, Xin‐Ming Shen, C. Michael Harper and William J. Litchy
Article first published online:
11 Sep 2026 | DOI: 10.1111/ene.70753

REVIEW ARTICLE

Background

Neurological and psychiatric disorders pose a persistent global health burden, with conventional therapies often providing inadequate relief. Transcranial ultrasound stimulation (TUS) has attracted considerable attention as a non‐invasive neuromodulation technique offering high spatial resolution and the distinctive capacity to modulate deep brain regions.

Methods

This review synthesizes recent basic and clinical research on TUS across neurological and psychiatric disorders, and consolidates emerging evidence on its mechanisms, therapeutic applications, and safety considerations.

Results

Emerging evidence suggests that TUS may drive sustained neural remodeling—including synaptic plasticity, neurogenesis, and anti‐neuroinflammatory effects—raising the possibility that TUS could eventually contribute to disease‐modifying strategies. However, disease modification by TUS has not yet been demonstrated in humans; the evidence supporting this possibility is derived predominantly from preclinical studies and remains a hypothesis requiring confirmation in large‐scale, controlled clinical trials. Building on these frameworks, we further propose a working hypothesis—termed mechanotransduction‐to‐oscillation encoding—which posits a nonlinear encoding relationship between the pulse repetition frequency of TUS and the intrinsic oscillatory properties of the stimulated region.

Conclusion

This hypothesis remains largely speculative and is offered as a conceptual framework to generate testable predictions and guide future investigations. Together, these frameworks provide a cohesive strategy for advancing TUS from an exploratory neuromodulation technique toward a potentially clinically translatable precision intervention, while acknowledging that significant technical and clinical hurdles remain.

Read full article
Free access for EAN members – please log in.
Authors:
Yunjie Sui, Mingyue Wei, Robert Chen and Xue Xia
Article first published online:
15 Sep 2026 | DOI: 10.1111/ene.70754

ORIGINAL ARTICLE

Background

The onset of amyotrophic lateral sclerosis (ALS) is preceded by non‐motor signs detectable many years before motor symptom onset. We recently showed that early ALS patients and presymptomatic carriers of ALS‐associated gene mutations display altered sleep macroarchitecture, characterised by increased wakefulness and decreased non‐REM sleep, together with altered microarchitecture, particularly reduced slow oscillations and sleep spindles. Here we aimed at determining whether sleep alterations are progressive in premanifest carriers of ALS‐associated gene mutations.

Methods

This longitudinal observational cohort study included presymptomatic first‐degree relatives of ALS patients carrying pathogenic gene mutations ( = 18) and noncarrier family members ( = 3). Sleep macroarchitecture and sleep microarchitecture were assessed using standardised polysomnography and electroencephalographic analyses at baseline and in a follow‐up examination after 2.3 ± 1.5 years.

Results

In all carriers, sleep alterations were more severe at follow‐up compared to the initial examination, for both macro‐ and microarchitecture. The progression of sleep alterations was seemingly independent of proximity to motor onset, whether evaluated by increased neurofilament levels or phenoconversion during the study period.

Conclusions

Sleep macro‐ and microarchitectural abnormalities progressively worsen during the premanifest phase of ALS. These findings suggest that polysomnography‐derived sleep measures and their neurochemical correlates may serve as sensitive, noninvasive surrogate biomarkers of disease progression in clinically silent ALS. This could support disease prevention, for example, by the antisense oligonucleotide tofersen in patients carrying SOD1 mutations.

Read full article
Free access for EAN members – please log in.
Authors:
Christina Lang, Simon J. Guillot, Antje Knehr, Patrick Weydt, Johannes Dorst, Hayrettin Tumani, Albert C. Ludolph, Luc Dupuis and Matei Bolborea
Article first published online:
21 Sep 2026 | DOI: 10.1111/ene.70755

ORIGINAL ARTICLE

Background

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease marked by considerable variability in survival times. This retrospective study aims to evaluate the prognostic value of a broad range of variables by conducting a comprehensive survival analysis on longitudinal data from RAP‐ALS, a clinical trial investigating the effects of rapamycin in ALS patients ( = 63).

Methods

Covariates were classified as risk or protective factors according to their hazard ratios. Regularized Cox regression was utilized to select the best‐performing multivariate models in cross‐validation. Longitudinal measures were incorporated by modeling covariates as time‐dependent. Survival times of treated C9orf72 mutation carriers ( = 6) were further investigated through log‐rank tests and restricted mean survival time analysis.

Results

Univariate analyses confirmed several previously established prognostic factors. Multivariate regularized Cox models incorporated neurofilaments, creatinine, clinical scores, and markers of immune activation. Moreover, the inclusion of time‐varying covariates allowed us to investigate late‐stage risk factors, such as the neutrophil‐to‐lymphocyte ratio. Additionally, the analysis indicated a protective effect in treated C9orf72 mutation carriers (log‐rank test,  = 0.026), which was confirmed after comparing this treatment subgroup with an independent C9orf72+ cohort ( = 40; RMST test,  = 0.04).

Conclusions

The survival analysis confirmed the role of previously identified prognostic factors, while suggesting that high‐performing multivariate models should integrate multiple ALS pathological hallmarks. Moreover, the observed longer survival among C9orf72 mutation carriers contrasts with prior reports. Due to the small sample size and potential confounding factors, the observed benefits in treated C9orf72 patients should be considered exploratory, supporting evaluation in a larger, genetically stratified trial.

Read full article
Free access for EAN members – please log in.
Authors:
Alex De Nardi, Alessio Paris, Mario Lauria, Ilaria Martinelli, Elisabetta Zucchi, Cecilia Simonini, Jessica Mandrioli and Luca Marchetti
Article first published online:
19 Sep 2026 | DOI: 10.1111/ene.70756

ORIGINAL ARTICLE

Background

Chitinases, including chitotriosidase (CHIT1) and chitinase‐3‐like protein 1 (CHI3L1), are markers of neuroinflammation, a key process in amyotrophic lateral sclerosis (ALS). Tear fluid (TF) can be collected non‐invasively and may represent a promising alternative to CSF or blood to study chitinases.

Methods

TF was collected from 50 ALS patients and 50 control subjects using Schirmer strips. CHIT1 and CHI3L1 levels in TF, serum, and CSF were quantified using ELISA. Serum NfL was measured using SIMOA. The frequency of a 24 bp‐duplication polymorphism in the CHIT1 gene influencing CHIT1 expression was assessed by PCR.

Results

No group differences in the distribution of the CHIT1 polymorphism were detected. Carriers of the polymorphism in both ALS and controls showed lower CHIT1 levels in serum and TF. CHI3L1 levels in TF were higher in ALS patients compared to controls ( = 0.007), consistent with changes in CSF but not serum. In ALS, males showed higher TF CHIT1 values compared to females ( = 0.009). Combining TF chitinase values with serum NfL values improved discrimination between ALS and controls.

Conclusions

Chitinases are detectable in TF, and CHI3L1 levels recapitulate changes observed in CSF, highlighting its potential for non‐invasive longitudinal assessment. Furthermore, chitinase values in TF, together with serum NfL, may act complementarily by capturing distinct aspects of the disease, neuroinflammation and axonal damage. These results suggest TF chitinases and serum NfL could complementarily contribute to the diagnosis and monitoring of the disease, and call for further evaluation of TF as a biomarker source in ALS.

Read full article
Free access for EAN members – please log in.
Authors:
Lara Wenz, Lena‐Sophie Scholl, Nya Reinhardt, Ricarda von Heynitz, Vincent Gmeiner, Petra Rau, Philipp Jie Müller, Andreas W. Wolff, Emily Feneberg, Antonia F. Demleitner and Paul Lingor
Article first published online:
19 Sep 2026 | DOI: 10.1111/ene.70757

LETTER TO THE EDITOR

Re: “Palliative Care in Europe: Safeguarding Compassion Amidst Changing End‐Of‐Life Policies and Expanding Access to Medically Assisted Dying Position Statement on Behalf of the European Academy of Neurology, the European Federation of Neurological Associations and OneNeurology” by Rukavina Et al.

Read full article
Free access for EAN members – please log in.
Authors:
Eugenio Pucci, Alessandra Solari, Gianluigi Mancardi, Leandro Provinciali, Nicola Ticozzi and Alessandro Padovani
Article first published online:
17 Sep 2026 | DOI: 10.1111/ene.70758

ORIGINAL ARTICLE

Background

The relationship between intrathecal kappa free light chain (κ‐FLC) synthesis and retinal layer atrophy in multiple sclerosis (MS) is unknown.

Objective

To investigate whether the κ‐FLC index is associated with peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell plus inner plexiform layer (GCIPL) thickness.

Methods

Patients with newly diagnosed clinically isolated syndrome or relapsing MS and available cerebrospinal fluid (CSF) analysis and optical coherence tomography (OCT) were included. Clinical and magnetic resonance imaging (MRI) data were also assessed. κ‐FLC concentrations were measured by nephelometry, and the κ‐FLC index was calculated as (CSF κ‐FLC/serum κ‐FLC)/albumin quotient.

Results

A total of 100 patients at a median age of 33 (25th–75th percentile: 25–39) years and a female predominance (58%) were included. In multivariable linear regression analysis adjusted for age, sex, disease duration, number of T2‐hyperintense and number of contrast‐enhancing MRI lesions, the κ‐FLC index was associated with pRNFL (log‐transformed κ‐FLC index: : −2.51; 95% confidence interval [CI]: −4.01, −1.01;  = 0.001) and GCIPL thinning (log‐transformed κ‐FLC index: : −1.24, 95% CI: −2.32, −0.17;  = 0.024).

Conclusions

Intrathecal plasma cell activity, as measured by the κ‐FLC index, is associated with neuroaxonal damage, as reflected by pRNFL and GCIPL atrophy.

Read full article
Free access for EAN members – please log in.
Authors:
Klaus Berek, Martin Schmidauer, Fabian Föttinger, Michael Auer, Thomas Berger, Franziska Di Pauli, Luisa Velez Escola, Thomas Hofer, Barnabas Kremser, Stephanie Mangesius, Jan P. Nolte, Marie‐Christine Pali, Berthold Pemp, Katharina Stock, Markus Tiefenthaler, Janette Walde, Anne Zinganell, Florian Deisenhammer, Gabriel Bsteh and Harald Hegen
Article first published online:
19 Sep 2026 | DOI: 10.1111/ene.70759

ORIGINAL ARTICLE

Background

The timing of ischemic stroke and intracerebral hemorrhage (ICH) onsets follow distinct daily patterns, but it remains unclear whether these patterns influence ICH outcomes.

Methods

Consecutive data were obtained from the prospective stroke inpatient quality assurance registry of Hesse, Germany from 2015 to 2023. Patients with ICH were grouped according to the time of symptom onset: morning (5:00 AM to 10:59 AM), midday (11:00 AM to 4:59 PM), evening (5:00 PM to 10:59 PM), and night (11:00 PM to 4:59 AM). The primary outcome was global disability at discharge, analyzed using ordinal logistic regression. Secondary outcomes included mortality and complications during hospitalization. To account for potential confounding, the analysis incorporated both inverse probability weighting (IPW) and propensity score matching (PSM) based on baseline characteristics.

Results

After exclusions, 5665 patients underwent final analysis. Peak ICH incidences occurred around 8:30 AM and 5:00 PM with a minimum at approximately midnight. Patients experiencing ICH during the evening and particularly at night had higher discharge disability, compared to those with symptom onset in the morning or midday. Unadjusted analyses found daily variations in mortality and in‐hospital complications that were no longer significant after adjustment by PSM or IPW.

Conclusion

Our study confirms the daily pattern previously observed in ICH onset, with peak onset during daytime. Functional outcomes were worse in evening and night onset ICH patients. These findings underscore the potential for chronobiologically informed prevention and treatment strategies and the need for further research into time‐dependent pathophysiology and care delivery.

Read full article
Free access for EAN members – please log in.
Authors:
Franziska Lieschke, Eng H. Lo, Emiri T. Mandeville, Christian Foerch, Elizabeth B. Klerman, Jeffrey L. Saver, Erik Maronde, Jan Hendrik Schaefer, Ferdinand O. Bohmann, Thorsten Steiner, Marco Stein, Björn Misselwitz and Daniel T. Marggrander
Article first published online:
19 Sep 2026 | DOI: 10.1111/ene.70762