cover image European Journal of Neurology

European Journal of Neurology

2026 - Volume 33
Issue 4 | April 2026
Previous Issue Next Issue

LETTER TO THE EDITOR

Response to Letter to Editor: Headache After Sealing of Cerebrospinal Fluid Leaks in Patients With Spontaneous Intracranial Hypotension

Read full article
Free access for EAN members – please log in.
Authors:
Adrian Scutelnic, Nedelina Slavova, Eric Morel, Franz Riederer, Tomas Dobrocky, Eike I. Piechowiak, Ralph T. Schär and Christoph J. Schankin
Article first published online:
17 Apr 2026 | DOI: 10.1111/ene.70452

ORIGINAL ARTICLE

Background

Parkinson's disease (PD) and multiple system atrophy (MSA) are synucleinopathies marked by α‐synuclein aggregation, while progressive supranuclear palsy (PSP) is a tauopathy. Clinical overlap between these diseases complicates diagnosis. Detection of intraneural S129 phospho‐α‐synuclein (pαSyn) via immunofluorescence staining (IF) in skin biopsies shows diagnostic promise. However, prior studies rarely addressed differentiation between synucleinopathies and tauopathies and lacked assessment of varying pαSyn burden—particularly relevant for this aim.

Methods

In this cross‐sectional study, we analyzed skin biopsies from 29 PD, 5 MSA, and 4 PSP patients. Samples obtained at C7 and Th12 were double‐immunostained with pαSyn and PGP9.5, a pan‐axonal neurite marker.

Results

Our novel method digitizes biopsy sections semi‐automatically and performs computer‐assisted 3D signal reconstruction. The resulting full volumetric quantification of intraneural pαSyn load enables burden‐dependent test results based on ROC‐derived cut‐offs. Applied as a differential diagnostic test, it showed excellent discrimination of synucleinopathies from tauopathies, achieving AUCs of 0.912 (C7) and 0.934 (Th12), with 88.2% sensitivity and 100% specificity. Intraneural pαSyn load was significantly higher in PD and MSA compared to PSP (C7  = 0.004; Th12  = 0.002), with no difference between PD and MSA.

Conclusions

This novel technique refines IF by increasing objectivity and allowing gradual pαSyn‐burden assessment, offering potential as a confirmatory differential biomarker. Validation in larger, neuropathologically confirmed cohorts of these preliminary small‐group results is warranted to fully evaluate the diagnostic and prognostic potential.

Read full article
Free access for EAN members – please log in.
Authors:
Sophia Lonczewski, Verian Bader, Louisa Ortmann, Louisa Basner, Markus Stücker, Ralf Gold, Raphael Scherbaum, Eun Hae Kwon, Konstanze F. Winklhofer and Lars Tönges
Article first published online:
17 Apr 2026 | DOI: 10.1111/ene.70525

ORIGINAL ARTICLE

Background

Staged bilateral Magnetic Resonance–guided Focused Ultrasound (MRgFUS) thalamotomy is an incisionless option for medication‐refractory essential tremor (ET). While the efficacy and safety of unilateral MRgFUS are established, evidence for bilateral treatment remains limited.

Objective

To evaluate the efficacy and safety of staged bilateral MRgFUS in a prospective single‐centre observational cohort and to perform a systematic review and meta‐analysis of the literature.

Methods

Consecutive ET patients undergoing second‐side MRgFUS were prospectively assessed. The primary efficacy endpoint was the longitudinal change in Clinical Rating Scale for Tremor (CRST) A + B scores for the treated hand after FUS2, while safety was evaluated by collecting and grading adverse events (AEs). A systematic review identified published bilateral MRgFUS series; efficacy data were meta‐analysed, while AEs were reported descriptively.

Results

Fifteen patients (60% men; mean age 74.1 ± 8.9 years) underwent FUS2 28.9 ± 22.5 months after first‐side treatment. At the 12‐month evaluation, CRST A + B decreased from 21.0 to 8.8 (−58%), CRST C from 7.3 to 1.9 (−74.2%), and QUEST from 30.5 to 9.5 (−68.7%). Head and voice tremor were reduced by 73.8% and 40.3%, respectively. AEs were predominantly mild (95.2%) and transient (88%). Cognition at 1 year was globally preserved, with a selective decline in verbal episodic memory. Meta‐analysis confirmed significant improvement in tremor severity.

Conclusion

Staged bilateral MRgFUS thalamotomy was associated with sustained tremor reduction, including midline tremor, functional improvement and acceptability, with a manageable safety profile. Overall, consistent with literature, these findings support its potential role as a therapeutic option in selected ET patients.

Read full article
Free access for EAN members – please log in.
Authors:
F. Paio, G. K. Ricciardi, G. Bulgarelli, M. Tagliamonte, E. Mantovani, C. Zucchella, T. Bovi, M. Longhi, Z. Lombardi, P. M. Polloniato, E. Zivelonghi, C. Cavedon, S. Montemezzi, A. Nicolato, F. Sala, B. Petralia, B. Bonetti, M. Tinazzi and S. Tamburin
Article first published online:
31 Mar 2026 | DOI: 10.1111/ene.70535

ORIGINAL ARTICLE

Background

Headache diaries are the gold standard for assessing preventive migraine treatments but can be burdensome. The Migraine Disability Assessment (MIDAS) and the six‐item Headache Impact Test (HIT‐6) offer alternatives for monitoring treatment response, though their effectiveness in identifying treatment responders is unclear relative to diary‐based measures. This study evaluated how well MIDAS and HIT‐6 distinguish responders from non‐responders to erenumab, and aimed to determine cut‐off scores that best align with a ≥ 50% reduction in monthly migraine days (MMDs).

Methods

This prospective, open‐label study enrolled adults with migraine who received 140 mg erenumab for 24 weeks. Treatment response was a ≥ 50% reduction in MMDs based on diary data. MIDAS and HIT‐6 were completed at baseline, Week 12, and Week 24. Discriminative ability and optimal cut‐offs were determined using receiver operating characteristic curve analysis.

Results

Among 582 participants, 300 individuals (52%) achieved a ≥ 50% reduction in MMDs. MIDAS and HIT‐6 demonstrated fair discriminative ability in identifying treatment responders, with area under the curve values ranging from 0.71 to 0.77. The optimal MIDAS cut‐offs were either a 16‐point absolute reduction (78% sensitivity, 60% specificity) or a 49% relative reduction (82% sensitivity, 64% specificity). For HIT‐6, optimal thresholds included an 8‐point reduction (53% sensitivity, 84% specificity) or a 12% relative reduction (54% sensitivity, 84% specificity). Sensitivity analyses using alternative response definitions confirmed the primary findings.

Conclusions

Although MIDAS and HIT‐6 contribute meaningful information on treatment‐related disability reduction, these retrospective tools lack sufficient precision to replace prospective headache diaries in assessing response to erenumab.

Trial Registration

NCT04603976

Read full article
Free access for EAN members – please log in.
Authors:
Janu Thuraiaiyah, Rune Häckert Christensen, Haidar M. Al‐Khazali, Messoud Ashina, Zaza Katsarava and Håkan Ashina
Article first published online:
27 Mar 2026 | DOI: 10.1111/ene.70542

EDITORIAL

Staging Language‐Led Neurodegenerative Diseases in a Language‐Based World: The Challenge of the PPA‐Squared Scale

Read full article
Free access for EAN members – please log in.
Authors:
Salvatore Mazzeo, Massimo Filippi and Maria Salsone
Article first published online:
27 Mar 2026 | DOI: 10.1111/ene.70552

ORIGINAL ARTICLE

Background

Subjective memory impairment (SMI) is used as a proxy for objective memory, although their relationship remains unclear. Moreover, SMI is suggested to be a risk factor for dementia. This study investigated associations between SMI and (1) concurrent objective memory performance, (2) early‐life general cognitive abilities (GCA), and (3) if SMI and objective memory scores were associated with distinct or overlapping sociodemographic, health, and lifestyle risk factors for dementia.

Material and Methods

2690 participants between 30 and 90 years from the general, geographical population study HUNT4 were included. SMI scores were from the Meta‐Memory‐Questionnaire. Verbal, spatial, and ability to differentiate between similar representations (pattern separation) were tested concurrently. GCA was from conscription at age 18. We implemented multiple imputation and inverse probability weighting from the entire population to account for selection bias.

Results

Higher SMI scores were associated with verbal memory and GCA, but not spatial or pattern separation memory. There was an interaction between sex and verbal memory on SMI, with men reporting higher SMI than women at similar lower verbal memory performance. Higher SMI scores were associated with higher age, blood pressure, depression, sleep, fatigue, and chronic pain, but not APOE4 or lifestyle variables. All memory tests were positively associated with each other and negatively with age. Diabetes was associated with verbal memory.

Conclusion

In the general population, SMI was weakly linked to concurrent verbal memory and GCA in adolescence. Health, in particular mental health, was highly associated with SMI but not objective memory performance. Thus, SMI is a complement to memory testing, not a proxy.

Read full article
Free access for EAN members – please log in.
Authors:
Simon Holmvik, Daniel Radosław Sokołowski, Ragnhild Bergene Skråstad, Olav Spigset, Bjørn Heine Strand and Asta Kristine Håberg
Article first published online:
29 Mar 2026 | DOI: 10.1111/ene.70556

ORIGINAL ARTICLE

Background

Characterizing the gene–environment interactions with early pathological changes in Alzheimer's disease (AD) is critical to precision medicine.

Methods

We recruited 1007 cognitively normal participants from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study. Multiple linear regression models were applied to explore the associations between polygenic risk scores (PRSs) and cerebrospinal fluid (CSF) biomarkers of AD, the interactions between PRSs and potentially modifiable risk factors, and the relationships between lifestyle categories and CSF AD biomarkers.

Results

A higher AD‐PRS was associated with more severe amyloidosis, as indicated by pTau/Aβ42 ( = 0.091,  = 0.005) and tTau/Aβ42 ( = 0.092,  = 0.004). There were significant interactions between AD‐PRS and three modifiable risk factors (anemia, gingivitis, and anxiety) in AD biomarker ratios. Stratified analyses by AD‐PRS indicated that anemia was associated with higher pTau/Aβ42 and tTau/Aβ42 in the first and second quartiles, while gingivitis and anxiety correlated with amyloidosis in the fourth quartile (all  < 0.05). Additionally, a favorable lifestyle was associated with milder amyloidosis in the high genetic risk group.

Conclusions

AD‐PRS was associated with amyloidosis severity. The associations between modified risk factors (anemia, gingivitis, and anxiety) and biomarker ratios differed by genetic risk strata. Moreover, a healthy lifestyle was associated with less amyloid burden in individuals with high genetic risk. These findings can be used to generate hypotheses for future longitudinal studies to investigate whether targeted management of these factors influences AD pathological progression.

Read full article
Free access for EAN members – please log in.
Authors:
Ze‐Xin Guo, Xiao‐Yu He, Yi‐Jun Ge, Bing Zhao, Liang‐Yu Huang, Shi‐Dong Chen, Yan Fu, Pei‐Yang Gao, Ze‐Hu Sheng, Yi‐Ming Huang, Qiong‐Yao Li and Lan Tan
Article first published online:
08 Apr 2026 | DOI: 10.1111/ene.70558

ORIGINAL ARTICLE

Objective

To reassess the importance of transcranial magnetic stimulation (TMS), including the triple stimulation technique (TST), to detect upper motor neuron (UMN) involvement in amyotrophic lateral sclerosis (ALS).

Methods

In this single‐center prospective study, 144 consecutive patients suspected of having motor neuron disease were included over 5 years at the time of diagnosis. All patients were examined clinically and with EMG to assess UMN and lower motor neuron (LMN) involvement, and survival was ascertained 2 years after inclusion of the last patient. Our TMS protocol consisted of TST in both arms and conventional motor evoked potentials (MEP) in arms and legs to assess central motor conduction time (CMCT).

Results

The TST could be performed in 142 patients who showed central conduction failure in 63%, which was often markedly asymmetrical, and 50% had prolonged CMCT in the legs. Combining TST in the arms and conventional MEP in the legs showed central abnormalities in 77%. In 62 patients with only signs of LMN involvement at clinical and EMG assessment, the TST amplitude ratio was reduced in 45%, and combined TST to the arms and conventional MEP to the legs disclosed a central abnormality in 61%.

Conclusion

The main clinical significance was the subclinical corticospinal involvement at TMS with TST in a large proportion of patients without clinical UMN involvement. TMS with TST is a sensitive, non‐invasive electrophysiological method to detect corticospinal dysfunction in ALS.

Read full article
Free access for EAN members – please log in.
Authors:
Birgit Andersen and Christian Krarup
Article first published online:
02 Apr 2026 | DOI: 10.1111/ene.70560

LETTER TO THE EDITOR

Comment on “Screening Value of the I‐Douleur Neuropathique Four Questionnaire for Small Fiber Neuropathy in Patients With Painful Syndromes: Insights From 872 Skin Biopsies”

Read full article
Free access for EAN members – please log in.
Authors:
Mohammed Anas Mohiuddin and Mohammed Misbah Ul Haq
Article first published online:
27 Mar 2026 | DOI: 10.1111/ene.70564

REVIEW ARTICLE

Background

Retrograde trans‐synaptic degeneration (RTSD) refers to the progressive loss of retinal cells following damage to the post‐geniculate visual pathway. The advent of optical coherence tomography (OCT) has allowed the measurement and quantification of retinal layers, in turn providing compelling evidence of RTSD in stroke patients and highlighting that assessing the temporal and functional evolution of RTSD has important clinical implications.

Methods

We conducted a systematic review up until 7th July 2025 to summarize the OCT evidence on post‐stroke RTSD. Eligible articles on this topic were searched in PubMed, Web of Science, and Scopus databases. Twenty‐eight papers, involving 888 patients and 624 healthy controls, were included, and their results were systematically described and qualitatively analyzed.

Results

Overall, literature shows that RTSD is a frequent outcome of post‐chiasmatic strokes. RTSD is operationalized by measuring the thickness of the peripapillary retinal nerve fiber and macular layers. The latter appears to be a more robust structural biomarker, showing more consistent findings across studies, with its magnitude better correlating with patients' visual field defects. RTSD starts early after the stroke's onset and progresses for several years, with severity depending on lesion location and extension. Future investigations are needed to draw more robust conclusions on RTSD temporal dynamics, clarifying the relation between structural and functional loss.

Conclusions

Current literature highlights the need to consider the RTSD among the primary outcomes of post‐chiasmatic stroke, given its implications on clinical management and neurorehabilitation, making the longitudinal assessment of this degenerative process crucial for prevention.

Read full article
Free access for EAN members – please log in.
Authors:
Francesca Crespi, Giacomo Guidali, Lisa Melzi, Stefania Bianchi Marzoli and Nadia Bolognini
Article first published online:
01 Apr 2026 | DOI: 10.1111/ene.70566

SHORT COMMUNICATION

Background

Anti‐amyloid therapies, such as lecanemab or donanemab, represent the first disease‐modifying treatments approved for early Alzheimer's disease (AD) in individuals with confirmed amyloid pathology. Their implementation in routine care raises important challenges, particularly in older adults with heterogeneous functional reserve and multimorbidity. We address the role of frailty in refining clinical decision‐making for anti‐amyloid therapies.

Methods

This short communication presents a conceptual discussion informed by geriatric oncology, where frailty assessment and comprehensive geriatric assessment (CGA) are routinely used to individualize treatment in heterogeneous older populations. We describe how similar principles may be applied to anti‐amyloid monoclonal antibodies once regulatory eligibility has been established, and outline a frailty‐informed conceptual framework to support clinical decision‐making in routine care.

Results

This conceptual analysis proposes a stepwise, frailty‐informed clinical framework that integrates regulatory eligibility assessment with brief frailty screening and targeted comprehensive geriatric assessment. The framework defines differentiated clinical pathways for robust, pre‐frail, and frail individuals, linking frailty status to specific decisions regarding treatment initiation, need for prehabilitation, intensity of monitoring, and consideration of treatment deferral. By embedding frailty assessment within routine clinical workflows, the framework operationalizes evaluation of physiological reserve, anticipates treatment burden and monitoring feasibility, and provides a structured approach to individualized risk–benefit appraisal for anti‐amyloid therapies.

Conclusions

Frailty‐informed frameworks may offer a pragmatic and ethically grounded approach to support real‐world implementation of anti‐amyloid therapies, guiding treatment selection as well as longitudinal decisions on monitoring, continuation, and reassessment over time.

Read full article
Free access for EAN members – please log in.
Authors:
Miguel Germán Borda, Kevin O'Hara‐Veintimilla and Dag Aarsland
Article first published online:
05 Apr 2026 | DOI: 10.1111/ene.70567

ORIGINAL ARTICLE

Background

Risdiplam, an oral disease‐modifying therapy, has demonstrated safety and efficacy in clinical trials, but real‐world data from Asia are limited.

Methods

This prospective study followed 34 symptomatic SMA patients (24 adults, 10 children) over 36 months of risdiplam treatment. The cohort included 5 patients with SMA type 1, 25 with SMA type 2, and 4 with SMA type 3, with ages ranging from 6.9 to 50.9 years. Most (91%) were wheelchair users, and 74% had scoliosis managed by bracing or spinal surgery. Twenty‐five patients (22 adults, 3 children) were treatment naïve, and 9 patients (2 adults, 7 children) switched from nusinersen. Motor function was assessed at baseline, 6, 12, 24, and 36 months using MFM‐32, RULM, ATEND, and HFMSE. In pediatric patients, HRQOL was evaluated using PedsQL Neuromuscular Module and PedsQL Generic Core scale. HRQOL of their parents was assessed with PedsQL Family Impact Module.

Results

After 36 months, MFM‐32 score was significantly improved in those switching therapies [ = 0.042], while both MFM‐32 and RULM scores were significantly improved in treatment‐naïve group [ = 0.005 and  = 0.043]. Parents experienced HRQOL gains in their Physical domain (2 years: PedsQL Family Impact Module,  = 0.038). Pediatric patients showed improvement in the Communication domain (3 years: PedsQL Neuromuscular Module,  = 0.042). Risdiplam was generally well tolerated; however, two adults discontinued due to adverse effects. Moreover, two adult patients died during treatment.

Conclusions

This study fills Asian real‐world data gaps, stresses the importance in monitoring in severe SMA, and underscores the need for larger, long‐term safety and efficacy studies.

Read full article
Free access for EAN members – please log in.
Authors:
Pak On Patrick Yee, Hayley Hoi Ning Ip, Michael Kwan Leung Yu, Pui Kei Cheng, Wilfred Hing Sang Wong, Patrick Pak Hei Ng, Nathan Sheung Tat Kwong, Priscillia Lam, Mei Wun Cheung, Angel Tung, Stephen Chan, Shirley Ng, Wai Lan Yeung, Sheila Wong, Yuen Gao, Shirley Pang and Sophelia Hoi Shan Chan
Article first published online:
24 Mar 2026 | DOI: 10.1111/ene.70574

ORIGINAL ARTICLE

Introduction

The COVID‐19 pandemic accelerated the adoption of digital health solutions in healthcare. Phenylketonuria (PKU) is a rare condition requiring chronic management and frequent assessments, making it a useful model for examining how digital health tools support patient and caregiver education, communication with healthcare professionals and facilities, and patient care pathways.

Methods

Patient representatives and expert clinicians developed qualitative, co‐designed ad hoc surveys during virtual workshops. From October 2023 to March 2024, the surveys were available online through EUSurvey English, Spanish, and German, and distributed to PKU patients in Spain, Germany, and Ireland by national PKU patient associations.

Results

The survey co‐design process identified crucial topics significant to key stakeholders in rare disease management. Diverse perspectives emerged on the roles and utility of digital tools: (1) rare disease patients may prefer hybrid care models combining face‐to‐face and digital interactions; (2) digital tools were perceived as particularly useful for supporting information exchange, education, preparation for clinical visits, and patient engagement.

Conclusions

This paper examines unmet needs in digital care pathways for PKU from the perspectives of patients, caregivers, and clinicians. Findings provide important insights into the needs of patients with rare diseases and the most effective channels for engaging and communicating with them. Although clinical and cost‐effectiveness were not evaluated, these findings could guide future research and policy discussions on incorporating digital solutions into rare diseases patient care pathways.

Read full article
Free access for EAN members – please log in.
Authors:
Sara Cannizzo, Vinciane Quoidbach, Bernadette Sheehan‐Gilroy, Tobias Hagedorn, Agata Bak, Suzanne L. Dickson, Eileen P. Treacy, Alvaro Hermida, Anita MacDonald, Eva Venegas, James O'Byrne, Maurizio Scarpa, Francjan Van Spronsen, Eric Lange, Tim Buckinx, Ahmad Monavari, Stephan vom Dahl, Leopoldo Trieste and Giuseppe Turchetti
Article first published online:
09 Apr 2026 | DOI: 10.1111/ene.70575

ORIGINAL ARTICLE

Background

Cerebral small vessel disease (CSVD) is a common incidental MRI finding in patients with transient ischemic attack (TIA) and stroke and has been linked to cognitive decline. This study investigated the prevalence of CSVD imaging biomarkers in TIA patients and their association with cognitive performance over 3 years.

Methods

We included 246 TIA patients from the INSPiRE‐TMS study (: NCT01586702). CSVD was assessed on baseline 3 T MRI using a composite score (0–4) including white matter hyperintensities (WMH), lacunes, cerebral microbleeds (CMBs), and enlarged perivascular spaces (PVS). Cognitive performance was evaluated using the Montreal Cognitive Assessment (MoCA) at baseline and annually for 3 years.

Results

At least one CSVD imaging biomarker was present in 58.5% of patients. Lacunes (36.6%) were the most common, followed by PVS (28.1%), WMH (19.5%), and CMBs (17.9%). Higher CSVD‐score was independently associated with greater cognitive decline over 3 years ( = −0.52, 95% CI −0.95– −0.08,  = 0.020), along with older age ( = −0.08, 95% CI −0.13 to −0.03,  = 0.001). CMB burden was the strongest predictive component of the CSVD‐score ( = 0.42, 95% CI −0.63 to −0.22,  < 0.001). CSVD‐score was particularly associated with decline in the domain (adjusted of −0.18, 95% CI −0.32 to −0.04,  = 0.015).

Conclusion

CSVD imaging markers are present in over half of TIA patients and are independently associated with cognitive decline up to 3 years, with the strongest effect on . Whether the presence of CMBs is the strongest predictive imaging biomarker of cognitive decline in TIA patients requires confirmation in further studies.

Read full article
Free access for EAN members – please log in.
Authors:
Paula Roesen, Uchralt Temuulen, Ana Sofia Rios, Ramanan Ganeshan, Tim Bastian Braemswig, Ahmed Khalil, Kersten Villringer, Thomas Ihl, Huma Fatima Ali, Pimrapat Gebert, Ulrike Grittner, Michael Ahmadi, Laurent Puy, Charlotte Cordonnier, Matthias Endres, Heinrich J. Audebert and Anna Kufner
Article first published online:
26 Mar 2026 | DOI: 10.1111/ene.70578

ORIGINAL ARTICLE

Background

This exploratory analysis of the NEURO‐TTRansform Phase 3 trial evaluated the efficacy of eplontersen in patients with hereditary transthyretin (ATTRv) amyloidosis with polyneuropathy by genetic variant.

Methods

Changes from baseline in NEURO‐TTRansform primary endpoints serum transthyretin (TTR) at Week 65, modified Neuropathy Impairment Score+7 (mNIS+7) composite score, and Norfolk Quality of Life‐Diabetic Neuropathy (Norfolk QoL‐DN) total score at Week 66 were evaluated in patients with early‐onset (aged < 50 years) and late‐onset (aged ≥ 50 years) Val30Met (p.Val50Met) or non‐Val30Met ATTRv amyloidosis with polyneuropathy. Secondary endpoints from NEURO‐TTRansform were also evaluated by genetic variant.

Results

In total, 144 patients with early‐onset ( 54) or late‐onset ( 31) Val30Met or non‐Val30Met ( 59), ATTRv amyloidosis with polyneuropathy were randomized to eplontersen. A further 60 patients from NEURO‐TTR with early‐onset ( 16) or late‐onset ( 17) Val30Met or non‐Val30Met ( 27), served as a historical placebo group. The mean percentage difference (95% confidence interval) in serum TTR was −79.9 (−87.8, −72.0), −85.0 (−93.3, −76.6), and −70.6 (−77.7, −63.5) with eplontersen versus placebo in the early‐ and late‐onset Val30Met, and non‐Val30Met groups, respectively. Across subgroups, the change from baseline to Week 66 in mNIS+7 composite score was generally well maintained, and the Norfolk QoL‐DN total score improved with eplontersen versus worsening with placebo. The Polyneuropathy Disability score was maintained in most patients. From baseline to Week 65, the modified body mass index was maintained with eplontersen compared to a marked reduction (worsening) for placebo.

Conclusions

Findings were suggestive of consistent benefits in reducing neuropathy impairment and improving QoL with eplontersen versus historical placebo, across variants.

Trial Registration

ClinicalTrials.gov: NCT04136184, NCT01737398

Read full article
Free access for EAN members – please log in.
Authors:
Julian D. Gillmore, David Adams, Markus Weiler, Ahmad Masri, Laura Obici, Jonatan Nåtman, T. Jesse Kwoh, Barry Reicher, James Revkin, Márcia Waddington Cruz, Morie Gertz and Chi‐Chao Chao
Article first published online:
30 Mar 2026 | DOI: 10.1111/ene.70580

LETTER TO THE EDITOR

Systematic Review and Meta‐Analysis of Secondary Treatment Failure and Immunogenicity with Botulinum Neurotoxin A in Multiple Indications—Comment on Recommending IncobotulinumtoxinA as First‐Line to Prevent Secondary Treatment Failure [Letter]

Read full article
Free access for EAN members – please log in.
Authors:
Fabiano Nadson Magacho‐Vieira
Article first published online:
31 Mar 2026 | DOI: 10.1111/ene.70581

ORIGINAL ARTICLE

Introduction

Cognitive complaints are often considered early indicators of Alzheimer's disease (AD) and commonly lead to memory clinic consultations. Prior studies suggest stronger associations between cognitive complaints and mood than with objective cognition, but this interplay remains poorly understood. Using a machine learning–supported approach, we aimed to (1) identify key predictors of cognitive complaints, and (2) compare the value of gamified versus standard neuropsychological testing in detecting subtle deficits.

Methods

In this international multi‐center study, 98 participants (57 females; mean age 71.9, range 55–86) from three memory clinics completed the Cognitive Failures Questionnaire (CFQ), mood and apathy questionnaires, the tablet‐based gamified Adaptive Cognitive Evaluation Explorer (ACE‐X), and standard neuropsychological tests. Predictors of CFQ scores were examined using elastic net regression and the Boruta algorithm, followed by linear mixed‐effects modeling.

Results

Greater mood symptoms were associated with more cognitive complaints, whereas increasing age was linked to fewer complaints. Study center accounted for additional variance. The final model explained a substantial proportion of variance (conditional R = 0.48, marginal R = 0.33). Participants had lower z‐scores on ACE‐X compared to standard testing, but neither predicted the severity of cognitive complaints.

Discussion

Mood and age were main predictors of cognitive complaints in memory clinic patients. Although ACE‐X yielded lower normative scores than standard tests, neither cognitive measure was linked to complaints. These findings highlight the importance of systematically assessing mood, adopting personalized approaches when evaluating subjective and objective cognition, and the potential value of gamified assessments for screening populations at risk of AD.

Read full article
Free access for EAN members – please log in.
Authors:
Florian W. Sander, Marie Pittet, Valeria Manera, Christine Krebs, Esther Brill, Andrea Brioschi‐Guevara, Philippe Ryvlin, Joaquin A. Anguera, Adam Gazzaley, Philippe Robert, Stefan Klöppel, Jean‐François Démonet, Giulia Binarelli and Arseny A. Sokolov
Article first published online:
22 Apr 2026 | DOI: 10.1111/ene.70583

ORIGINAL ARTICLE

Background

Cognitive dysfunction is a disabling feature of migraine, affecting attention, memory, and executive functions. Differences between episodic and chronic migraine, as well as between interictal and ictal periods, remain unclear. We aimed to compare interictal cognitive performance in episodic and chronic migraine with healthy controls and to evaluate intra‐individual changes during attacks.

Methods

In this cross‐sectional study with within‐subject repeated measures, migraine patients (32 EM, 32 CM) and 30 matched healthy controls underwent standardized cognitive testing (Mini Mental State Examination, Clock Drawing Test, Stroop Test, Digit Span Forward/Backward Tests) assessing attention, short‐term and working memory, and executive function along with Beck Depression Inventory. Migraine cohorts were evaluated interictally (≥ 72 h attack‐free) and again within the first 3 h of an untreated spontaneous migraine attack.

Results

Interictally, CM patients demonstrated significant impairments in attention, short‐term memory, and working memory compared to healthy controls. EM patients, however, showed no cognitive dysfunction except for working memory. During migraine attacks, all cognitive domains deteriorated significantly in both groups. The magnitude of cognitive decline during an attack did not differ between EM and CM. Attack severity was associated with greater cognitive decline during attacks in the general migraine group, but this association was more pronounced in EM than in CM.

Conclusions

Migraine is a neurobiological disorder with cognitive consequences that extend beyond pain. Our findings highlight the importance of incorporating cognitive assessment into routine migraine management and reveal the need for longitudinal studies to elucidate the underlying mechanisms of cognitive dysfunction in migraine.

Read full article
Free access for EAN members – please log in.
Authors:
Esra Kochan Kizilkilic, Bekir Burak Kılboz and Serap Üçler Yaman
Article first published online:
26 Mar 2026 | DOI: 10.1111/ene.70584

ORIGINAL ARTICLE

Purpose

To examine the association between newly prescribed fluoroquinolones (FQ) and the occurrence of polyneuropathy and certain neuropsychiatric events.

Methods

German statutory health insurance‐based cohort study (2013–2019) of patients exposed to FQ compared to different reference antibiotics. Patients with an incident antibiotic prescription were followed up for 365 days after initial dispensing. Outcomes were defined by incident diagnoses of polyneuropathy/other peripheral nervous system‐related diseases (PNS), depression/other affective disorders (DEP), mood‐related symptoms (MOOD), somnolence/stupor/coma (SSC), and consciousness‐related symptoms (CONSCIOUS). Piece‐wise exponential additive mixed models adjusted for person‐time, age, comorbidities, year, and quarter of cohort entry were applied.

Results

The outcome‐specific cohorts included 10.7–14.3 million antibiotic episodes of which 1.7% had incident PNS, 4.8% DEP, 1.5% MOOD, 0.6% SSC, 0.8% CONSCIOUS. Relative risks for these outcomes ranged from 1.04 to 1.10 for FQ versus reference antibiotics. Stratified by gender and age groups, relative risk for PNS was high in ≤ 39‐year‐old males (aHR = 1.31 [95% 1.19; 1.45]), for MOOD and CONSCIOUS in 40–69‐year‐old females (aHR = 1.12 [1.08; 1.15], aHR = 1.14 [1.09; 1.19]) for DEP in ≥ 70‐year‐old males (aHR = 1.16 [1.14; 1.19]), whereas relative risk for SSC was high in ≤ 39‐year‐old females (aHR = 1.24 [1.10; 1.40]). FQ‐associated PNS was mainly comprised of drug‐induced polyneuropathy (aHR = 1.68 [1.58; 1.79]). Relative risks for each endpoint varied by choice of active comparator.

Conclusions

FQ episodes were associated with an increased risk for neurological and neuropsychiatric events, especially within the first 92 days after initial dispensing. Risk estimates vary by age and gender subgroups.

Read full article
Free access for EAN members – please log in.
Authors:
Julia Wicherski, Jonas Peltner, Cornelia Becker, Katrin Schüssel, Gabriela Brückner, Andreas Schlotmann, Helmut Schröder, Winfried V. Kern and Britta Haenisch
Article first published online:
25 Mar 2026 | DOI: 10.1111/ene.70585

ORIGINAL ARTICLE

Background

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. We assessed changes in the mortality from ALS in Finland from 1987 to 2022.

Methods

Numbers of deaths caused by ALS (ICD‐10 code G12.2) and population sizes by sex, age group, and year were obtained from Statistics Finland. Crude and age‐standardized mortality rates were calculated. The annual percentage change was estimated using Poisson regression, and joinpoint regression was used to identify changes in trend during the study period.

Results

Mortality from ALS increased in Finland from 1987 to 2022. The age‐standardized ALS mortality in the entire population was 2.24/100,000 in 1987 and 4.21/100,000 in 2022. The male: female ratio in mortality was 1.18. The age‐standardized mortality increased on average by 1.7% (95% CI 1.5%–2.0%) annually. In men, the age‐standardized mortality increased on average by 1.2% (95% CI 0.9%–1.6%) annually and in women by 2.0% (95% CI 1.6%–2.3%). The largest increase occurred in the oldest age group (70+ years), with an average annual increase of 2.4% (95% CI 2.0%–2.8%). In joinpoint regression, no changes in trend were identified overall or in men, but in women, the annual percentage change (APC) was 5.5% (95% CI 3.0%–8.0%) in 1987–1997 and 1.0% (95% CI 0.5%–1.4%) during 1997–2022.

Conclusion

Similar to some other countries, mortality from ALS has increased in Finland, nearly doubling in 35 years. Further research on possible reasons is needed.

Read full article
Free access for EAN members – please log in.
Authors:
Milla Laine, Jani Raitanen and Anssi Auvinen
Article first published online:
05 Apr 2026 | DOI: 10.1111/ene.70586

ORIGINAL ARTICLE

Background and Purpose

Mitochondrial Encephalomyopathy, Lactic acidosis and Stroke‐like episodes (MELAS) is a rare multisystem mitochondrial disorder with clinical heterogeneity. Diagnostic criteria and management strategies for MELAS and mitochondrial stroke‐like episodes (SLE) remain inconsistent. This work provides international consensus recommendations on the definition, diagnosis, and management of MELAS and SLE in pediatric and adult populations.

Methods

An international Delphi consensus process was conducted within the European Reference Network for Neuromuscular Diseases (ERN EURO‐NMD), in collaboration with the US Mitochondrial Medicine Society, the ERN for Hereditary Metabolic Disorders (MetabERN), and patient representatives. Following a systematic literature review, 54 statements addressing diagnostic definitions and management of MELAS were evaluated. Statements not reaching consensus were revised and re‐evaluated during a face‐to‐face meeting.

Results

Consensus supported defining MELAS as a clinical syndrome characterized by one or more SLE in the context of mitochondrial dysfunction caused by a pathogenic mitochondrial DNA variant, particularly m.3243A>G in . The use of terms such as “MELAS‐like” or “MELAS spectrum” was discouraged. The panel agreed that the efficacy of L‐arginine, L‐taurine, L‐citrulline, coenzyme Q, vitamins, and other supplements remains unproven and requires validation in clinical trials. Antiseizure medications should be initiated promptly when seizures are suspected during SLE, and intravenous corticosteroids may be beneficial acutely. Multidisciplinary management of neurological, neuropsychiatric, and systemic complications was endorsed.

Conclusions

This international consensus provides updated definitions and practical guidance for the diagnosis and management of MELAS and SLE, aiming to harmonize clinical practice and inform future evidence‐based research.

Read full article
Free access for EAN members – please log in.
Authors:
Michelangelo Mancuso, Marcello Bellusci, Valerio Carelli, Irenaeus de Coo, Daria Diodato, Felix Distelmaier, Omar Hikmat, Michio Hirano, Rita Horvath, Amel Karaa, Thomas Klopstock, Mary Kay Koenig, Cornelia Kornblum, Chiara La Morgia, Piervito Lopriore, Mika Henrik Martikainen, Robert McFarland, Olimpia Musumeci, Robert D. S. Pitceathly, Guido Primiano, Shamima Rahman, Fernando Scaglia, Andrew Schaefer, Manuel Schiff, Luisa Semmler, Costanza Lamperti and Serenella Servidei
Article first published online:
18 Apr 2026 | DOI: 10.1111/ene.70588

SHORT COMMUNICATION

Objectives

To measure intra‐observer and interobserver correlations and reading times for visual and artificial intelligence algorithm‐assisted reading (innerve) of intraepidermal small nerve fiber density (IENFD) in skin biopsies.

Methods

We retrospectively selected 40 skin biopsy slides with PGP9.5/col4 double‐immunofluorescence labeling. The slides were scanned and read by two experienced observers (O1 and O2), on two occasions (visual reading 1 ‐VR1‐ and 2 ‐VR2‐). They were then read after predetection with the Innerve algorithm (assisted reading ‐AR‐). IENFD and reading time were evaluated to assess reliability and time saved.

Results

Intra‐observer reliability was evaluated by calculating intraclass correlation coefficient (ICC). The ICC obtained were 0.95 (O1)/0.99 (O2) for the two VR and 0.96 (O1)/0.99 (O2) for VR1/AR. Inter‐rater ICC between O1 and O2 was 0.88, 0.87, and 0.93 for VR1, VR2, and AR, respectively. AR reading time was 1.96 times faster for O1 and 1.03 times slower for O2. Subgroup analyses revealed an interobserver ICC significantly > 0.7 ( < 0.05), with ICC > 0.9 regardless of sex and skin pigmentation.

Discussion

Innerve is an innovative and reliable AI tool for IENFD determinations on skin biopsies, making such analyses—which were considered time‐consuming and difficult—easier for small‐fiber neuropathy diagnosis.

Read full article
Free access for EAN members – please log in.
Authors:
C. Labeyrie, A. Lorenzo de Brionne, O. Trassard, V. Blot, O. Petit, D. Hervault, D. Medernach, O. Morassi, C. Guettier, D. Adams, N. Brunel and C. Adam
Article first published online:
08 Apr 2026 | DOI: 10.1111/ene.70589

POSITION PAPER

Background

Despite the advent of Disease Modifying Therapies (DMTs) for Alzheimer's Disease (AD), the approval and commercialization of anti‐amyloid monoclonal antibodies has been slow and contentious, particularly in Europe. The primary source of debate is the discrepancy between robust biological effects—namely, effective β‐amyloid clearance—and modest clinical improvements, which, although statistically significant, often fail to reach the minimal clinically important difference (MCID) compared to placebo.

Methods

This paper highlights a confounding factor in the interpretation of the results of clinical trials: limited sensitivity of neuropsychological outcome measures. These tools, developed in the 1980s and only marginally updated, are not suited to detect subtle but meaningful cognitive changes in early disease stages.

Results

The ADAS‐Cog, the most commonly used cognitive endpoint, suffers from a substantial ceiling effect, impairing its ability to capture cognitive decline over short durations in prodromal populations. Likewise, functional scales such as the CDR‐SB are inherently insensitive in mild cognitive impairment (MCI), as functional independence is, by definition, preserved. Moreover, the use of composite multidomain scales with high baseline scores may mask domain‐specific improvements, further limiting a drug's capacity to reach MCID thresholds.

Conclusion

Methodological limitations risk undervaluing the therapeutic impact of treatment, particularly in trials targeting early or preclinical phases where changes are subtle and domain‐specific. Urgent reconsideration of outcome measures is necessary to ensure accurate assessment of clinical efficacy and to avoid prematurely discarding potentially beneficial therapies.

Read full article
Free access for EAN members – please log in.
Authors:
Simona Luzzi and Julie S. Snowden
Article first published online:
01 Apr 2026 | DOI: 10.1111/ene.70590

LETTER TO THE EDITOR

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

Read full article
Free access for EAN members – please log in.
Authors:
Katarina Rukavina, Marianne de Visser, Elena Moro, Kailash Bhatia, Paul Boon, Jana Midelfart‐Hoff, Matilde Leonardi, Irena Rektorova, Gereon R. Fink, Nathalie Nasr, Alicia Gonzalez‐Martinez, Claudio L. A. Bassetti, Ulf Kallweit, Michael Crean, Patrick Cras, Ludo Vanopdenbosch, Astri Arnesen, Joke Jaarsma, Alexander Bernhard Kowski, Simone Veronese and David Oliver
Article first published online:
03 Apr 2026 | DOI: 10.1111/ene.70591

ORIGINAL ARTICLE

Background

Epidemiological studies carried out on progressive supranuclear palsy (PSP) provide heterogeneous data. Our aim has been to analyze incidence, point prevalence, survival, and time to diagnosis of PSP in Navarre, a northern Spanish region.

Methods

This is a population‐based observational retrospective study from 2010 to 2022. Data from various sources of health information were reviewed to identify all potential diagnoses of PSP, validated through medical records reviews. Patients were included if they fulfilled the 2017 Movement Disorder Society (MDS) criteria and were classified into the different PSP phenotypes.

Results

A total of 226 prevalent PSP cases were identified. Age‐standardized point prevalence rate at January 1, 2023, was 7.52/100,000 inhabitants, and age‐standardized annual incidence rate (IR) for the period was 2.41/100,000 person‐years. PSP‐Richardson syndrome (RS) phenotype showed significantly higher prevalence and incidence rates compared to PSP non‐RS phenotypes. Joinpoint regression for overall incidence showed a significant increase until 2018 and thereafter a significant steep decline. Joinpoint regression for prevalence showed a statistically significant annual decline from 2018 onwards. Mortality rate experienced a peak in 2020. Median time to diagnosis was 37 months, and the median survival from clinical symptom onset was 89 months. PSP‐RS was associated with reduced time to diagnosis and reduced survival compared to the PSP non‐RS phenotypes.

Conclusions

This study represents the first population‐based epidemiological study of PSP in Spain and the first with application of the new MDS diagnostic criteria in Europe, providing detailed incidence, prevalence, and mortality data that are in accordance with other European studies.

Read full article
Free access for EAN members – please log in.
Authors:
P. Arrondo Gómez, E. Vicente, G. Martí‐Andrés, J. Sánchez Ruiz de Gordoa, I. Gastón, P. Clavero, R. Valentí, J. Delfrade and M. E. Erro
Article first published online:
02 Apr 2026 | DOI: 10.1111/ene.70592

ISSUE INFORMATION

Issue Information

Read full article
Free access for EAN members – please log in.
Authors:
Article first published online:
24 Mar 2026 | DOI: 10.1111/ene.70593

ORIGINAL ARTICLE

Background

Progressive supranuclear palsy (PSP) is a rare neurodegenerative tauopathy characterized by early postural instability and vertical gaze palsy. Mitochondrial dysfunctions have been increasingly implicated in the pathogenesis of neurodegenerative disorders, including PSP. We investigated mitochondrial DNA copy number (mtDNA‐CN) alterations in the peripheral blood of PSP patients, assessing its potential as a biomarker for disease onset and progression.

Methods

We measured mtDNA‐CN in a cohort of clinically diagnosed PSP patients and age‐matched healthy controls using quantitative real‐time PCR. We evaluated differences across clinical phenotypes and age groups.

Results

PSP patients exhibited a significant reduction in ND3‐CN compared to healthy controls ( < 0.0001). This depletion remained consistent across age groups, suggesting that mitochondrial impairment in PSP is independent of physiological aging. Although not statistically significant, ND3‐CN levels were lower in PSP‐parkinsonism (PSP‐P) patients compared to those with Richardson's syndrome (PSP‐RS). Interestingly, in PSP‐RS patients, ND3‐CN levels tended to increase with age, potentially reflecting an age‐related compensatory mitochondrial response to chronic neuroinflammation.

Conclusions

Our findings support the involvement of mitochondrial dysfunction in PSP pathogenesis, suggesting that peripheral mtDNA‐CN may serve as a non‐invasive biomarker for disease monitoring. Further studies in larger cohorts are warranted to validate its prognostic potential in different PSP phenotypes.

Read full article
Free access for EAN members – please log in.
Authors:
Luigi Citrigno, Annamaria Cerantonio, Monica Gagliardi, Radha Procopio, Alessia Felicetti, Anna Aureli, Maurizio Morelli and Grazia Annesi
Article first published online:
17 Apr 2026 | DOI: 10.1111/ene.70594

ORIGINAL ARTICLE

Background

Aberrant iron homeostasis is increasingly recognized as a key pathological feature in progressive multiple sclerosis (MS). Although the source of excess brain iron remains unclear, haemoglobin is one possible source. To test this hypothesis, we conducted a case–control study to determine whether erythrocytes are more fragile in people with progressive MS (PwPMS) and examined associations between erythrocyte fragility and brain atrophy.

Methods

PwPMS and control individuals were recruited from two centres. Two measures of erythrocyte fragility were assessed at baseline: the Median Corpuscular Fragility (MCF) and haemolysis curve slope. A subset of PwPMS in one centre underwent MR imaging at the same time as osmotic fragility testing and annually for three years thereafter.

Results

A total of 174 participants were included (75 PwPMS, 99 controls), with MRI data available for 44 PwPMS. No significant differences in the MCF were observed between PwPMS and controls in either the full or age‐matched cohorts. However, the haemolysis curve slope in PwPMS was less steep than healthy controls (median PwPMS = −24.76, controls = −28.73,  = 0.017), consistent with a subpopulation of fragile erythrocytes, with a similar trend in the age‐matched subset ( = 0.056). Erythrocyte fragility was associated with normalized whole brain volume at the time of osmotic fragility testing and up to three years thereafter.

Conclusions

Extracellular haemoglobin from lysis of an erythrocyte subpopulation may contribute to neurodegeneration in progressive MS. Further research is warranted to elucidate the interplay between erythrocyte health, inflammation and neurodegeneration, which may open avenues for novel therapeutic strategies.

Read full article
Free access for EAN members – please log in.
Authors:
Carmen Jacob, Thomas E. Williams, Charlotte M. Stuart, Aviva Witkover, Simon Hametner, Hans Lassmann, Charles R. M. Bangham, Jeremy Chataway and Ian Galea
Article first published online:
17 Apr 2026 | DOI: 10.1111/ene.70595

ORIGINAL ARTICLE

Introduction

Generalized myasthenia gravis (gMG) may progress to life‐threatening myasthenic crises (MC) requiring mechanical ventilation. Standard therapy includes intravenous immunoglobulins (IVIg), plasmapheresis (PLEX), immunoadsorption (IA), and high‐dose corticosteroids. This study aimed to evaluate the real‐world effectiveness of complement‐inhibitors (C5‐I) in patients refractory to the standard treatment of MC (termed therapy‐refractory MC).

Methods

This multicentre, retrospective study included patients with acetylcholine‐receptor‐antibody positive (AChR‐ab+) gMG experiencing MC or severe exacerbations (MGFA IVb/V) treated with eculizumab or ravulizumab in the intensive or intermediate care unit (ICU/IMC). The primary outcome was the proportion of patients discharged from ICU/IMC within six weeks after C5‐I initiation (German Clinical Trials Registry; DRKS00032104).

Results

Among 17 identified cases, seven had thymoma‐associated MG (TAMG) and 10 had late‐onset MG; median age was 77 years. Five patients required non‐invasive and 12 invasive ventilation; nine underwent tracheotomy. Therapies included IVIg, PLEX, IA, and corticosteroids. Rituximab was added in two cases. Twelve patients received eculizumab and five ravulizumab. Median hospitalization before C5‐I initiation was 32 days (IQR 22–50) and median ICU‐stay was 17 days (IQR 4.5–35) thereafter. Fourteen patients (82%) reached the primary outcome. Two patients died due to bacterial sepsis; no meningococcal infection was observed.

Conclusion

In MC or severe exacerbations insufficiently responsive to standard treatment with IVIg and PLEX/IA, add‐on C5‐I therapy may represent an effective therapeutic approach. Importantly, TAMG, a subtype typically excluded from interventional trials yet often requiring more intensive therapy, also demonstrated clinical improvement. These findings warrant further systematic evaluation of C5‐I as adjunctive therapy for AChR‐ab+ therapy‐refractory MC.

Read full article
Free access for EAN members – please log in.
Authors:
Lea Gerischer, Maike Stein, Alice Schneider, Hanna Tangen, Johanna Loris, Stefanie Glaubitz, Jana Zschüntzsch, Ulrich Hofstadt‐van Oy, Charlotte Schubert, Christoph Heesen, Melina Schlag, Tim Hagenacker, Menekse Oeztuerk, Tobias Ruck, Paolo Doksani, Carla Dusemund, Meret Herdick, Julia Herzig‐Nichtweiß, Philipp Mergenthaler, Frauke Stascheit, Amani Suboh, Lisa Schwarz, Sarah Hoffmann, Andreas Meisel and Sophie Lehnerer
Article first published online:
15 Apr 2026 | DOI: 10.1111/ene.70596

ORIGINAL ARTICLE

Background

Recent post‐marketing studies have indicated a possible association between anti‐CGRP receptor monoclonal antibodies (anti‐CGRP‐mAbs) used for migraine prophylaxis and an increased risk of hypertension (HT).

Methods

We performed a retrospective real‐world exploratory study, including individuals with a confirmed diagnosis of migraine who were treated with erenumab, an anti‐CGRP receptor (r)‐mAb, for at least 12 months. Inclusion was limited to individuals with complete clinical records and regular follow‐up, with at least one visit every 3 months and data available to assess treatment outcomes. Patients were excluded if they had previously received anti‐CGRP mAbs or gepants for migraine prevention before starting the current therapy, were on any concomitant baseline migraine preventive treatment, or did not complete the 12‐month follow‐up visits.

Results

One hundred twenty‐five participants were eligible and included in the analysis. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were compared between baseline and follow‐up visits, conducted every 3 months for up to 24 months while the patient was on treatment. Individuals treated with erenumab initially received 70 mg, administered subcutaneously every 4 weeks. Throughout the 12‐month treatment period, blood pressure (BP) measurements remained stable and within normal physiological ranges, indicating no significant hypertensive effect. Analysis across multiple visits showed that SBP ranged from 118 to 121 mmHg, while DBP stayed between 78 and 80 mmHg. Erenumab treatment over 24 months in 54 patients demonstrated stable BP with no notable hypertensive effects.

Conclusions

This study did not find sufficient evidence that treatment with erenumab leads to the development of HT.

Read full article
Free access for EAN members – please log in.
Authors:
Christian Lampl, Reem Suliman, Viktoria Tischler‐Strasser, Antoinette MaassenVanDenBrink and Taoufik Alsaadi
Article first published online:
09 Apr 2026 | DOI: 10.1111/ene.70597

ORIGINAL ARTICLE

Background

The worsening of headaches or the occurrence of new headaches can occur after coil embolization. Although the frequency of headaches is reported to be greater when a stent is used, this phenomenon is poorly understood. Therefore, we aimed to evaluate the incidence and intensity of headache in patients treated with non‐stent‐assisted coil embolization (NSCE) versus stent‐assisted coil embolization (SACE) for unruptured intracranial aneurysms (UIAs).

Methods

In this prospective comparative cohort study, a total of 186 patients treated with coil embolization for UIAs between June 2018 and March 2022 were classified into NSCE or SACE groups. A Cox proportional hazards model was used to identify risk factors for occurrence of headache, and changes in headache intensity over time were assessed using a linear mixed‐effects model.

Results

Headaches occurred in 71.0% (132/186) of patients after coil embolization. During the 3‐month follow‐up, headaches after coil embolization were more common in patients who underwent SACE (adjusted hazard ratio, 1.57;  = 0.02). Female sex, cilostazol medication use, and pre‐existing headache were also independently associated with the occurrence of headache after coil embolization. Changes in numeric rating scale (NRS) scores according to stent placement status and trends in NRS scores over time based on stent placement status were not statistically significant.

Conclusions

Patients treated with SACE were more likely to experience headache after coil embolization than those treated with NSCE were. However, changes in headache intensity over time were not significantly different between the groups.

Read full article
Free access for EAN members – please log in.
Authors:
Seung Pil Ban, O‐Ki Kwon, Young Deok Kim, Hwan Seok Shim, Seung Bin Sung, Jae Seung Bang, Si Un Lee, Sang Hyo Lee, Tae Won Choi, Eun‐A Jeong, Hye Ju Jeon and Seunghyun Won
Article first published online:
09 Apr 2026 | DOI: 10.1111/ene.70598

CASE REPORT

Background

Subacute oculomotor dysfunction encompasses a broad differential diagnosis, including autoimmune, infectious, vascular, and neoplastic etiologies. Primary skull base diffuse large B‐cell lymphoma (DLBCL) is a rare but treatable cause of cranial nerve dysfunction and may present subtly on conventional neuroimaging.

Methods

We report an 80‐year‐old man with subacute diplopia, dysfunction of multiple cranial nerves, left‐sided ptosis, and headache. Diagnostic workup included cranial imaging, cerebrospinal fluid (CSF) analysis with cytology and flow cytometry, neurophysiological studies, serum diagnostics, and dedicated MRI of the skull base. Transsphenoidal biopsy was performed following identification of an infiltrative lesion.

Results

Initial investigations including cranial CT, CSF analysis, and serum diagnostics were unremarkable. Dedicated skull base MRI revealed a diffuse infiltrating mass involving the clivus, petrous bone, occipital condyles, and perisellar/posterior pituitary region, with anatomical correlation to multiple cranial nerves. Mildly elevated prolactin levels suggested a stalk effect. Histological analysis confirmed DLBCL (NOS, GCB type). Treatment with corticosteroids followed by dose‐adjusted R‐CHOP resulted in complete clinical remission and radiologically confirmed tumor regression.

Conclusions

This case illustrates a rare presentation of primary bony skull base DLBCL with perisellar infiltration, highlighting the diagnostic challenges of complex oculomotor dysfunction. Dedicated skull base MRI is essential in the workup of unexplained cranial neuropathy. CSF‐based molecular markers may complement the diagnostic approach in similar presentations.

Read full article
Free access for EAN members – please log in.
Authors:
Paul Philipp Kastner, Pia Lena Niederau, Georgios Pantazis and Katharina Seystahl
Article first published online:
24 Apr 2026 | DOI: 10.1111/ene.70600

ORIGINAL ARTICLE

Background

Psychotic disorders and use of antipsychotics prior to or after ischemic stroke (IS) may be associated with poor outcomes. However, data on antipsychotic use in young IS patients are limited. We aimed to characterize young patients purchasing antipsychotics prior to IS or de novo post‐stroke, and to examine their association with long‐term outcomes.

Methods

We analyzed data from the Helsinki Young Stroke Registry, including 1008 consecutive patients aged 15–49 with first‐ever IS 1994–2007. We considered patients without antipsychotic purchases as non‐users, those with at least one purchase any time before IS as prior users, and those who had purchases at any time after IS (but not before) as de novo users. Cox regression models assessed the association of antipsychotic purchases with any recurrent vascular event or all‐cause mortality.

Results

Of 966 included IS survivors (62.6% male, median age 44), 55 (5.7%) purchased antipsychotics before and 67 (6.9%) after index IS. Compared with de novo or non‐users, prior users more often had other/unknown socioeconomic status, a history of psychiatric hospitalization, drug abuse, smoking, heavy drinking, more severe stroke symptoms on admission, and limb paresis at discharge. Antipsychotics purchased before IS were associated with a heightened hazard of endpoint events when adjusted for sociodemographics and cardiovascular comorbidities. The association was not found for de novo users.

Conclusions

Around 6% of young IS patients had a history of antipsychotic use, while a similar proportion initiated antipsychotics post‐stroke. Pre‐stroke antipsychotic use was associated with recurrent vascular events and mortality.

Read full article
Free access for EAN members – please log in.
Authors:
Jenna Broman, Karoliina Aarnio, Hanna Granroth‐Wilding, Ivan Marinkovic, Markku Kaste, Turgut Tatlisumak and Jukka Putaala
Article first published online:
20 Apr 2026 | DOI: 10.1111/ene.70601

ORIGINAL ARTICLE

Background

Cerebrospinal fluid (CSF) kappa free light chains (KFLC) is a sensitive marker of intrathecal immunoglobulin synthesis and is incorporated into the 2024 McDonald criteria for multiple sclerosis (MS). How disease‐modifying therapies (DMTs) influence KFLC dynamics and their association with treatment response remains unclear.

Objective

To determine whether intrathecal KFLC synthesis changes during DMT and whether these changes are associated with clinical outcomes.

Methods

Patients with treatment‐naïve relapsing–remitting MS were prospectively enrolled at the Sahlgrenska MS Center (Gothenburg, Sweden). Paired CSF and serum samples were collected at baseline and after 12 months of treatment with dimethyl fumarate (DMF) or natalizumab (NTZ). KFLC index was calculated as [(CSF KFLC/serum KFLC)/(CSF albumin/serum albumin)]. Treatment response was assessed using no evidence of disease activity‐3 (NEDA‐3) and progression independent of relapse and MRI activity (PIRMA).

Results

Forty‐eight patients were included (DMF  = 26, NTZ  = 22). NTZ reduced KFLC index from a median 117.4 (63.6–171.9) at baseline to 78.8 (39.4–104.0) at 12 months (adjusted  = 0.003), corresponding to a median decline of −51.0 (IQR −82.1 to −24.7), whereas DMF produced no meaningful change. In NTZ‐treated patients maintaining NEDA‐3 or without PIRMA, KFLC index declined markedly (both  < 0.01). Change in KFLC index predicted outcomes, yielding an AUC of 1.0 for NEDA‐3 and 0.79 for non‐PIRMA.

Conclusions

Natalizumab appears to reduce intrathecal KFLC synthesis, and a decline in KFLC index may reflect effective suppression of CNS humoral immunity. ΔKFLC index could serve as a sensitive biomarker of treatment response and disease stability in MS.

Read full article
Free access for EAN members – please log in.
Authors:
Igal Rosenstein, Markus Axelsson, Magnus Johnsson, Clas Malmeström, Hlin Kvartsberg, Henrik Zetterberg, Jan Lycke and Lenka Novakova
Article first published online:
17 Apr 2026 | DOI: 10.1111/ene.70602

ORIGINAL ARTICLE

Background

Neuralgic amyotrophy (NA) causes acute episodes of neuropathic pain in the upper limbs, followed by weakness and atrophy. NA can be idiopathic (INA) or hereditary (HNA). The gene has been linked to HNA. This study aimed to characterize the clinical and prognostic features of patients with ‐related HNA.

Methods

This retrospective multicenter study included all adult patients diagnosed with ‐related HNA in France from January 2012–June 2025. INA patients were included as controls.

Results

Twelve patients with ‐related HNA and 25 with INA were included. A family history of NA (75%) and dysmorphic features (50%) were reported exclusively in the group. The median age at neurological episode was significantly lower in the group (26.0 years) than in the INA group (38.5 years;  < 0.01). Multiple episodes were more frequent in the group (75%) than in the INA group (24%;  < 0.01). Distal upper‐limb nerves were more frequently affected in ‐related HNA episodes than in INA episodes. Sensory symptoms were significantly more frequent in ‐related HNA episodes (57%) than in INA episodes (22%;  < 0.01). A higher proportion of ‐related HNA patients had a modified Rankin Scale score ≥ 2 (42%) compared with INA patients (16%), although this difference did not reach statistical significance ( = 0.12).

Conclusions

While not completely sensitive or specific, certain features may prompt clinicians to suspect a ‐related form when assessing a patient with NA: young age, dysmorphic features, a family history of NA, repeated episodes, sensory symptoms, and distal nerve involvement affecting the upper limbs.

Read full article
Free access for EAN members – please log in.
Authors:
Julian Theuriet, Isabelle Quadrio, Frédéric Fer, Pauline Monin, Adrien Bohic, Alice Gravier‐Dumonceau, Vianney Poinsignon, Emilien Delmont, Emmanuelle Salort‐Campana, Shahram Attarian, Sylvain Nollet, Philippe Petiot, Solène Ronsin, Stéphane Peysson, Pierre Lozeron, Françoise Bouhour, Philippe Corcia, Antoine Pegat and Tanya Stojkovic
Article first published online:
16 Apr 2026 | DOI: 10.1111/ene.70603

SHORT COMMUNICATION

Background

The French National Rare Diseases Registry (BNDMR) was established in 2007 to ensure access to optimal care standards for all patients with rare diseases in dedicated reference centres. The objective of this retrospective cohort study was to describe patients with myasthenia gravis (MG) in the BNDMR.

Methods

All patients aged ≥ 18 years in the BNDMR with a confirmed diagnosis of MG visiting a reference centre at least once between 2007 and 2021 (inclusive) were included. Diagnosis was defined through ORPHA:589 or ORPHA:391490 disease codes. Patients were followed for ≥ 12 months until 31 December 2022 (or until death). Data were collected on demographics and disease history. Mortality was estimated using Kaplan–Meier survival analysis. Healthcare resource utilisation at the reference centre was documented.

Results

Overall, 3963 patients were analysed. Mean follow‐up duration was 6.1 ± 3.8 years. The median interval between diagnosis and inclusion was 3.8 months [IQR: 1.5–7.5] and the median age at symptom onset was 52.0 [IQR: 34.0–69.0] years. Survival probability was 82.7% at 10 years, and higher in women than men ( < 0.001; logrank test). The mean interval between visits was 4.1 months. The mean number of overnight or day hospitalisations per patient was 2.6 ± 3.4 and the mean number of physician consultations per patient per year was 1.7 ± 1.1.

Conclusion

This national registry study provides reference data for patients in France with a confirmed diagnosis of MG. However, all patients with MG are still not managed in dedicated reference centres.

Read full article
Free access for EAN members – please log in.
Authors:
Jean‐Philippe Camdessanche, Andoni Echaniz‐Laguna, Guilhem Solé, Cécile Blein, Mariana Ciumas, Claude Messiaen, Anne‐Sophie Jannot and Shahram Attarian
Article first published online:
22 Apr 2026 | DOI: 10.1111/ene.70604

ORIGINAL ARTICLE

Background

Optic nerve involvement in Multiple Sclerosis (MS) can be detected with Optical Coherence Tomography (OCT) based on intereye difference (IED). We aimed to assess optic nerve involvement in a large real‐world MS cohort applying the 2024 McDonald IED cut off criteria, and to investigate OCT–MRI concordance.

Methods

OCT measurements of peripapillary‐retinal‐nerve‐fiber‐layer (pRNFL) and ganglion‐cell‐inner‐plexiform‐layer (GCIPL) thickness were analyzed in 740 MS patients. Clinical histories of optic neuritis (ON) were reviewed. Three‐dimensional double inversion recovery MRI sequences for optic nerve assessment were available for 240 patients.

Results

The IED cutoff (GCIPL ≥ 4 μm or pRNFL ≥ 6 μm) demonstrated 83% sensitivity and 55% specificity for identifying prior ON. In the MRI subgroup, it yielded 67% sensitivity and 83% specificity for detecting asymptomatic optic nerve lesions. MRI identified lesions in 46% of patients without a prior history of ON, whereas OCT‐IED was positive in 40%, resulting in an overall OCT–MRI concordance of 77%. Among asymptomatic patients ( = 164), 25 were OCT‐negative/MRI‐positive (11 with bilateral optic nerve involvement) and 15 were OCT‐positive/MRI‐negative, mostly with isolated GCIPL or pRNFL asymmetry.

Conclusions

The 2024 McDonald IED cutoff demonstrates high sensitivity for prior ON but reduced sensitivity for subclinical optic nerve involvement. MRI appears slightly more sensitive, with both modalities providing complementary information on optic nerve pathology.

Read full article
Free access for EAN members – please log in.
Authors:
Gualco Alessandro, Boffa Giacomo, Razzetta Chiara, Lapucci Caterina, Cipriano Emilio, Nasone Lorenza, Sirito Tommaso, Al Qudsi Sabrina, Garbarino Sara, Saitta Laura, Campi Cristina, Iester Michele, Cellerino Maria and Inglese Matilde
Article first published online:
18 Apr 2026 | DOI: 10.1111/ene.70605

POSITION PAPER

Background

Noncommunicable diseases are the leading cause of death and disability worldwide, although many of their detrimental health effects can be prevented by lifestyle changes. Despite growing public and individual recognition of the importance of prevention, adherence to recommended measures is limited. We refer to this discrepancy between knowledge and action, specifically in relation to preventive lifestyle behavior, as .

Methods

This paper presents a narrative synthesis and aims to provide a conceptual framework for communication with patients and the public that includes neurobiological and evolutionary perspectives. It discusses interactions between neural reward systems, executive control mechanisms, and contemporary environmental triggers, including nutrition, exercise, sleep, and stress, as examples of the six pillars of lifestyle medicine.

Results

We propose that can serve as a didactic label in communication with patients and the public to explain the mismatch between evolved neural mechanisms and the modern environment. Rather than a sole failure of willpower, non‐adherence to preventive lifestyle measures is partly founded in a conflict within neural circuitry. Patient education regarding the brain's underlying processes and their influence on behavior has the potential to enable individuals to actively redesign their actions, train their reward systems, and thus reinforce healthy behavior.

Conclusion

Integrating a narrative on neurobiological mechanisms into public health and clinical practice strategies should thus be aimed at helping bridge the gap between intention and sustainable preventive behavior. This conceptual framework provides a basis for supporting patients and the public in achieving lifestyle goals and improving the effectiveness of preventive measures.

Read full article
Free access for EAN members – please log in.
Authors:
Daniela Berg, Mareike Krause, Eva Schaeffer and Gesine Hermann
Article first published online:
21 Apr 2026 | DOI: 10.1111/ene.70606

ORIGINAL ARTICLE

Background

Although treatment goals in migraine prevention have moved beyond the benchmark of a 50% reduction in monthly attacks, residual disease burden is still evaluated based on residual headache frequency. However, migraine‐related symptoms can persist despite headache freedom, leading to so‐called unclear days that may meaningfully contribute to interictal burden.

Methods

In this prospective, real‐world study, patients with chronic or high‐frequency episodic migraine treated with CGRP‐monoclonal antibodies (CGRP‐mAbs) were followed for six months. Interictal burden was assessed using the Migraine Interictal Burden Scale (MIBS‐4) alongside the monthly unclear and crystal clear days. Patients achieving optimal (< 4 monthly attacks) or modest (4–6 monthly attacks) migraine control were stratified according to the presence of “residual interictal burden” (MIBS‐4 ≥ 3).

Results

Two hundred patients were included. CGRP‐mAbs treatment was associated with a reduction in MIBS‐4 scores and an increase in crystal clear days ( < 0.001). Despite optimal or modest migraine control, 45.1% of patients at month 3 and 27.2% at month 6 continued to exhibit a substantial “residual interictal burden”. Patients with “residual interictal burden” showed significantly more unclear days and fewer crystal clear days compared with those without residual interictal migraine burden, while no differences were observed in residual headache days, concomitant preventive treatments, or cephalalgiophobia.

Discussion

Even when migraine attacks are adequately controlled, residual interictal burden may remain and seems to be predominantly associated with unclear days rather than with residual attacks. Assessing crystal clear and unclear days provides a complementary, patient‐centered perspective on treatment response and interictal recovery in migraine.

Read full article
Free access for EAN members – please log in.
Authors:
Marcello Silvestro, Ilaria Orologio, Raffaele Ornello, Francesca Trojsi, Alessandro Tessitore, Simona Sacco and Antonio Russo
Article first published online:
24 Apr 2026 | DOI: 10.1111/ene.70608