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Article first published online:
30 Mar 2025 | DOI: 10.1111/ene.16354

ORIGINAL ARTICLE

Multivariate Pattern Analysis of fMRI Reveals Striato‐Cortical Network Changes in Myoclonus‐Dystonia

Background

Currently, the pathophysiology of myoclonus‐dystonia (M‐D) remains insufficiently understood. This study addresses this gap by adding innovative multivariate pattern analysis (MVPA) to traditional univariate analysis of functional magnetic resonance imaging (fMRI) data.

Methods

Data from 18 M‐D patients and 18 age‐matched healthy volunteers who performed a finger tapping fMRI task were analyzed. Whole‐brain univariate and searchlight (MVPA) analysis with varying hemodynamic response function (HRF) delays were employed to examine brain responses associated with the visually guided motor task.

Results

Distinguishing response patterns between M‐D patients and healthy volunteers revealed significant response reductions in the putamen, insula, and visual cortex. Compared to univariate analysis, searchlight analysis was more sensitive for brain activity patterns associated with finger tapping in both M‐D patients and healthy volunteers. At short HRF delays, increased (pre)motor cortical responses were evident in M‐D patients, whereas such responses emerged at a later HRF delay in healthy volunteers.

Conclusion

The task‐related effects observed in M‐D patients support the involvement of the basal ganglia‐thalamo‐cortical network. Notably, cerebellar involvement was not strongly implicated in our study. We postulate that inherent deficits in the putamen trigger either premature or downstream compensatory (motor) cortical effects. The potential involvement of the visual cortex in the M‐D pathophysiology is new, but its role has been suggested by a previous study investigating visual sensory processing in gene‐positive M‐D patients. Our findings, including the innovative searchlight method, pave the way for further studies investigating the complex interplay between brain regions and networks and their role in M‐D pathogenesis.

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Authors:
Ramesh S. Marapin, Bauke M. de Jong, Remco J. Renken, Elze R. Timmers, Marina A. J. Tijssen and Jelle R. Dalenberg

Article first published online:
12 Apr 2025 | DOI: 10.1111/ene.70085

ORIGINAL ARTICLE

Fatigue in the Preataxic and Ataxic Stages of Spinocerebellar Ataxia Type 3

Objective

Fatigue is a significant symptom in patients with spinocerebellar ataxia type 3 (SCA3). This study explores the role of fatigue in SCA3, examining its impact on quality of life and its potential as an indicator of disease progression.

Methods

We prospectively recruited 128 molecularly confirmed SCA3 patients and 125 sex‐, age‐, and education‐matched healthy controls (HCs). Age at onset, disease duration, length of normal and expanded CAG repeats, and 14‐item Fatigue Scale score were compared. MRIs evaluated the cerebellum and brain lesions.

Results

Our study found that the preataxic SCA3 group exhibited lower fatigue incidence and score than HCs (Incidence: 13% vs. 36%, = 0.031; FS‐14 score: 3.0 ± 2.7 vs. 5.6 ± 2.8, < 0.001). Ataxic SCA3 patients experienced significantly higher fatigue incidence and score compared to both the preataxic SCA3 group (Incidence: 63.8% vs. 13%, < 0.001; FS‐14 score: 8.1 ± 3.9 vs. 3.0 ± 2.7, < 0.001) and HCs (Incidence: 63.8% vs. 36%, < 0.001; FS‐14 score: 8.1 ± 3.9 vs. 5.6 ± 2.8, < 0.001). Moreover, fatigue severity in SCA3 correlated with disease duration and expanded CAG repeat length. Neuroanatomical correlations revealed volume reductions in cortical and cerebellar regions linked to higher physical and mental fatigue scores in SCA3 patients.

Conclusions

Monitoring fatigue effectively evaluates a patient's overall quality of life and disease progression, making it a key indicator. Future treatments can target specific brain regions, with their effectiveness being evaluated through FS‐14 assessments of fatigue changes.

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Authors:
Zhi‐li Chen, Li‐mei Xiao, Chun Li, Liang‐liang Qiu, Wei Lin, Zhi‐xian Ye, Yuan‐yuan Zhang, Zhi‐bao Zhu, Meng‐cheng Li, Min‐ting Lin, Wan‐jin Chen, Ning Wang, Ying Fu and Shi‐rui Gan

Article first published online:
03 Apr 2025 | DOI: 10.1111/ene.70093

REVIEW ARTICLE

Multimodal Neuroimaging as a SUDEP Predictor: What Is Known and What Still Needs to Be Uncovered?

Introduction

Sudden Unexpected Death in Epilepsy (SUDEP) is the most common cause of death in patients with poorly controlled epilepsy. To date, a higher risk of developing SUDEP is mainly identified by clinical factors, among which generalized tonic–clonic seizures and their frequency stand out as part of the highly debated SUDEP‐7 Scoring. This review investigates the role of neuroimaging‐based approaches as a tool to help predict SUDEP.

Methods

We carried out a systematic search of the literature to identify multimodal neuroimaging modifications (i.e., MRI, fMRI, PET, and SPECT) in patients with epilepsy who died from SUDEP. The following databases were used: PubMed and Google Scholar. The review was registered on the PROSPERO platform (Registration code: CRD42024558765).

Results

Fifteen articles were selected, investigating 104 SUDEP cases compared with 792 non‐SUDEP epileptic patients and 280 healthy controls (HC) (overall mean age 33.9 ± 1.6). Results suggest that SUDEP and non‐SUDEP cases and HC differ anatomically and functionally. In the SUDEP population, MRI data indicate relevant volume differences in the gray matter of the hippocampus and cerebellar cortices. In addition, functional imaging reveals discrepancies in network modulation within the brainstem and its relationship with several cortical structures. Although less consistent, PET and SPECT scan data point toward alterations in metabolism and perfusion in the frontal and brainstem areas.

Conclusion

The reviewed data support correlations between the occurrence of SUDEP and neuroimaging multimodal alterations that could be relevant in death prediction.

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Authors:
Paolo Quintieri, Fedele Dono, Giacomo Evangelista, Clarissa Corniello, Sara Cipollone, Sibilla De Angelis, Antonio Ferretti and Stefano L. Sensi

Article first published online:
12 Apr 2025 | DOI: 10.1111/ene.70101

ORIGINAL ARTICLE

Gene Screening Since the Advent of Biotherapies in France: A Nationwide Retrospective Survey Between 2018 and 2023

Background

Hereditary transthyretin amyloidosis (ATTRv) is a rare genetic disorder caused by mutations in the gene. Associated with various clinical phenotypes like polyneuropathy and cardiomyopathy, ATTRv has historically had poor outcomes. Recent advances in biotherapies have significantly improved these outcomes. This study aimed to assess the evolution in genetic variant screening since the advent of biotherapies in France in 2018.

Methods

This nationwide retrospective study analyzed data and genetic results from patients who underwent gene sequencing from 2018 to 2023.

Results

16,640 patients were tested during the period studied. There was a 108% increase in the number of gene sequencing performed annually between 2018 and 2023. Positive rates remained stable despite increased testing (7.09% over time). During this 6‐year period, 1,179 patients were diagnosed with a pathogenic variant of .

Conclusions

The study shows a substantial rise in genetic testing in France, likely linked to the deployment of biotherapies. These findings underscore the necessity of integrating gene sequencing into standard diagnostic procedures, especially given the effectiveness of treatments and the stability of positive rates.

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Authors:
Abd El Kader Ait Tayeb, Pauline Chazelas, Vianney Poinsignon, David Adams, Caroline Berthot, Cécile Cauquil, Claire‐Marie Dhaenens, Bruno Francou, Guillaume Jedraszak, Céline Labeyrie, Clara Laffitte Redondo, Anne‐Sophie Lia, Maureen Lopez, Alexis Proust, Franck Sturtz, Lucie Tosca, Céline Verstuyft, Andoni Echaniz‐Laguna and Jérôme Bouligand

Article first published online:
22 Apr 2025 | DOI: 10.1111/ene.70104

ORIGINAL ARTICLE

Disease Trajectories of a Large French Cohort of 142 Congenital Myopathy Patients in Adult Age

Background

Congenital myopathies (CMyo) are a group of rare inherited muscle disorders classified to date according to myopathological features on muscle biopsy. They usually present with an early onset, with a slow or non‐progressive muscle weakness. The phenotypic spectrum is wide, ranging from severe early onset forms to milder and later onset conditions. Data regarding the disease trajectory of CMyo in adult patients are lacking. Here, we describe the clinical, myopathological, and genetic features of a large cohort of adult CMyo patients to facilitate their management in adulthood.

Methods

Global data of a cohort of 142 myopathologically and genetically defined adult patients, 76 women and 66 men, followed at Institute of Myology of the Pitié‐Salpêtrière Hospital, were retrospectively analyzed focusing on muscular phenotype, cardiac, and respiratory assessment.

Results

RYR1related CMyo was the most represented entity ( = 65, 45%), followed by DNM2‐related CMyo ( = 26, 18%). Eighty‐two percent of patients presented with a prenatal, infancy or childhood onset, including delayed motor milestones. An adult onset, defined as > 18 years (median age 43 years), was identified in 15% of patients ( = 18). Fifteen percent of patients were wheelchair‐bound. The poorest respiratory outcome was found in SELENON‐related CMyo patients.

Conclusions

This observational study provides long‐term data on disease progression in CMyo. Adult CMyo patients generally presented mild motor disability at follow‐up. Nevertheless, a subset of patients experienced loss of gait and severe respiratory failure. CMyo should be considered in the differential diagnosis of adult‐onset myopathies due to the rare but possible late‐onset forms.

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Authors:
Michela Bisciglia, Gianmarco Severa, Norma Beatriz Romero, Michel Fardeau, John Rendu, Tanya Stojkovic, Pascal Laforêt, Bruno Eymard, Ana Ferreiro, Edoardo Malfatti and Anthony Béhin

Article first published online:
30 Mar 2025 | DOI: 10.1111/ene.70109

ORIGINAL ARTICLE

The Results of ADVANCE‐CIDP IVIG Trial: Intravenous Immunoglobulin 10% Therapy With GAMMAGARD LIQUID/Kiovig for Treatment of Relapse in Chronic Inflammatory Demyelinating Polyradiculoneuropathy

Background

ADVANCE‐CIDP IVIG evaluated the efficacy and safety of immune globulin infusion (human) 10% solution (IVIG 10%; GAMMAGARD LIQUID, also known as Kiovig) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) as a rescue treatment for patients relapsing during the ADVANCE‐CIDP 1 trial.

Methods

Open‐label ADVANCE‐CIDP IVIG included adult patients with confirmed CIDP relapse (≥ 1‐point increase in adjusted Inflammatory Neuropathy Cause and Treatment [INCAT] disability scores from pre‐treatment baseline) during ADVANCE‐CIDP 1, which assessed the efficacy and safety of hyaluronidase‐facilitated subcutaneous immunoglobulin (fSCIG) 10%. Patients received an induction IVIG 10% dose (2 g/kg) followed by maintenance infusions at the same monthly equivalent dose of pre‐randomization IVIG, 3‐weekly for 6 months. The primary outcome was the responder rate (≥ 1‐point decrease in adjusted INCAT scores at treatment cessation vs. pre‐IVIG 10% baseline, in patients receiving placebo in ADVANCE‐CIDP 1). Other outcomes included the responder rate across all patients relapsing on fSCIG 10% or placebo in ADVANCE‐CIDP 1, time to functional improvement (≥ 1‐point decrease in adjusted INCAT score), and change in adjusted INCAT scores and Rasch‐built Overall Disability Scale (R‐ODS) centile scores from pre‐IVIG 10% baseline.

Results

Overall, 20 patients received IVIG 10% ( = 4 [fSCIG 10%‐relapse group]; = 16 [placebo‐relapse group]). Responder rate (95% confidence interval) was 100.0% (80.6%–100.0%) in the placebo‐relapse group and 95.0% (76.4%–99.1%) in the overall‐relapse population. Across all patients, median time to functional improvement was 25 days. At treatment cessation, mean changes from pre‐IVIG 10% baseline in adjusted INCAT and R‐ODS centile scores were −1.9 and 12.9, respectively.

Conclusions

IVIG 10% effectively treated CIDP relapse and improved functional abilities.

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Authors:
Mamatha Pasnoor, Colin Anderson‐Smits, Todd Levine, Vera Bril, Juan Marcos Solano, Konrad Rejdak, Josep Gamez, Elisabeth Chroni, Carlos Casasnovas, Enrico Marchioni, Gabriele Siciliano, Dario Cocito, K. Sivakumar, Alberto Rivero, Kim Duff, Erin Greco, Massimo Corbo, Shabbir Hasan, Amir Dori, Jens Schmidt, Jamie Wood, Zhaoyang Li and Hakan Ay

Article first published online:
17 Apr 2025 | DOI: 10.1111/ene.70110

ORIGINAL ARTICLE

Reactive Pleocytosis After Repeated Lumbar Puncture—Implications for Clinical Practice

Introduction

Lumbar puncture (LP) is a routine clinical procedure and, in some cases, is repeatedly performed for diagnostic or therapeutic reasons. The impact of repeated LP on cerebrospinal fluid (CSF) findings is not clear.

Objective

To investigate whether repeated LP is associated with reactive pleocytosis and disruption of blood–CSF barrier function and to determine the role of interval between repeated LP.

Methods

Patients with non‐inflammatory neurological disease (NIND) and at least two consecutive LP were included. Longitudinal changes in CSF white blood cell count (WBC), CSF total protein (TP), and CSF/serum albumin quotient (Q) were assessed depending on the time interval between the LP.

Results

A total of 73 patients with a median age of 35 years (25th–75th percentile: 25–45) and a female predominance of 75% had second LP after 6 (3–19) days. Twenty (27%) patients developed pleocytosis with an increase of WBC count to 8/μl (6–15) with a maximum of 30/μl. Patients with pleocytosis had the follow‐up LP significantly earlier than patients without pleocytosis, 3.5 (3–7) versus 7 (3–28) days. The majority of patients (90%) with CSF pleocytosis had the second LP within 10 days. Further repeated LP in a subgroup of patients revealed similar findings. CSF TP and Q slightly increased in patients with pleocytosis.

Conclusion

Mild “reactive” CSF pleocytosis occurred in approximately one‐third of patients after repeated LP, mostly when performed within 10 days.

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Authors:
Martin Schmidauer, Fabian Föttinger, Klaus Berek, Michael Auer, Robert Barket, Franziska Di Pauli, Nik Krajnc, Laura Stichaller, Sina Zaic, Anne Zinganell, Florian Deisenhammer, Janette Walde, Gabriel Bsteh and Harald Hegen

Article first published online:
05 Apr 2025 | DOI: 10.1111/ene.70117

GUIDELINES

European Academy of Neurology (EAN)/European Federation of Autonomic Societies (EFAS)/International Neuro‐Urology Society (INUS) Guidelines for Practising Neurologists on the Assessment and Treatment of Neurogenic Urinary and Sexual Symptoms (NEUROGED Guidelines)

Background

Urinary and sexual symptoms are common following neurological disease, and we aimed to develop multidisciplinary inter‐society evidence‐based management guidelines.

Methods

The ADAPTE framework was used, and a systematic search of guidelines published in different languages was performed. Guidelines, consensus statements, and systematic reviews were included, and guideline quality was appraised using AGREE II. Patient representatives reviewed the relevance and suitability of recommendations. A modified Delphi process integrating the Evidence to Decision framework adapted from GRADE and the Oxford Centre for Evidence Based Medicine system was used to reach consensus on recommendation wording and strength.

Results

Recommendations were drafted, using guidelines/consensus statements (59 urinary, 50 sexual), systematic reviews (8 urinary, 2 sexual) and others (7 urinary,13 sexual), and wordings/strengths achieved at least 80% consensus through 2 Delphi rounds. Eleven evidence‐based recommendations, 19 good practice statements, and 8 consensus‐based recommendations were made. Individuals with neurological diseases should be asked about urogenital symptoms and undergo targeted physical examination when appropriate. Urinary symptom assessments include urinalysis, bladder diary completion, and post‐void residual volume measurement. Treatments include fluid intake optimization, pelvic physiotherapy, tibial nerve stimulation, and oral medications. Urinary retention is managed by intermittent catheterization. Antibiotics should not be recommended to treat asymptomatic bacteriuria. Suprapubic catheterization is preferred for long‐term catheterization. A comprehensive sexual history should be taken, focusing on multidimensional factors affecting sexual health. Treatments include lubricants, vibrators, and phosphodiesterase‐5 inhibitors. Red flag symptoms warrant a shared‐care approach with specialist colleagues.

Conclusions

The 38 NEUROGED recommendations will guide neurologists to comprehensively manage urogenital symptoms reported by individuals with neurological diseases.

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Authors:
Jalesh N. Panicker, Alessandra Fanciulli, Magdalena Krbot Skoric, Tamara Kaplan, Katina Aleksovska, Ivan Adamec, Marcio Augusto Averbeck, Nicole Campese, Pietro Guaraldi, Fabian Leys, Jorge Moreno‐Palacios, Sara Simeoni, Iva Stankovic, Sarah Wright, Amit Batla, Bertil Blok, Claire Hentzen, Max Josef Hilz, Thomas M. Kessler, Helmut Madersbacher, Kannan Rajasekharan Nair, Krishnan Padmakumari Sivaraman Nair, Mahreen Pakzad, Anne Pavy‐Le Traon, Guy Peryer, Mikolaj Przydacz, Ryuji Sakakibara, Udit Saraf, Matthew Smith, Walter Struhal, Roland D. Thijs, Katarina Ivana Tudor, Marcin Tutaj, David B. Vodušek, Gregor Wenning and Mario Habek

Article first published online:
10 Apr 2025 | DOI: 10.1111/ene.70119

ORIGINAL ARTICLE

The Phenotypes of Multiple Sclerosis Differ Significantly in Relative and Excess Mortality

Background

Patients With Multiple Sclerosis (MS) Have Higher Mortality Than Matched Background Populations. We Compare Relative and Excess Mortality in MS Over the Matched Background Populations Between Primary Progressive MS (PPMS), relapsing Onset MS (ROMS), and Secondary Progressive MS (SPMS).

Methods

We included all patients from the nationwide and complete Danish MS Registry with onset 1994–2022 and compared the extra mortality of the MS phenotypes in terms of relative and excess mortality, with adjustment for sex, age at onset, disease‐modifying treatment, and number of recorded relapses. We calculated the adjusted ratios of relative and excess mortalities between PPMS and ROMS and between PPMS and SPMS.

Results

The initial course was unknown in 221, leaving 1412 cases with PPMS (which includes progressive relapsing MS) and 12,449 cases with ROMS. 627 had died during follow‐up by the end of 2022. After adjustment, both ratios between PPMS and ROMS came close to unity, indicating that the excess mortality is equal for PPMS and ROMS in the long run. The adjusted relative and additive mortalities were factors 6.05 (95% CI 4.42–8.27) and 1.90 (95% CI 1.65–2.18) higher in SPMS than in PPMS.

Conclusions

Compared with the matched population, the adjusted relative and excess mortalities are the same for PPMS and ROMS. However, SPMS had a higher relative and excess mortality than PPMS, probably in part owing to the burden of disease carried over from the pre‐progressive phase. This underlines the need for effective treatment in this later stage of the disease and more attention to comorbidity.

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Authors:
Melinda Magyari, Frederik Elberling and Nils Koch‐Henriksen

Article first published online:
17 Apr 2025 | DOI: 10.1111/ene.70122

ORIGINAL ARTICLE

Insights Into Disability and Disability Progression in People With Multiple Sclerosis Using Large‐Scale Healthcare Data

Background

Identifying predictors for disability progression is crucial for managing multiple sclerosis (MS). This study aims to explore levels of disability and informative factors for disability progression in people with MS (PwMS) using healthcare data without detailed clinical information.

Methods

We conducted a case–control/cohort study on data from Bavaria's largest health insurance organization. The dataset included records of assistive devices, nursing care, sick leaves, rehabilitation, drug therapies, and diagnoses for individuals with MS, Crohn's disease (CD), rheumatoid arthritis (RA), and controls (CTR) without these diseases. We used generalized linear models to compare healthcare service utilization between MS and other cohorts. A gradient‐boosting algorithm identified informative healthcare‐related factors associated with disability progression in PwMS, defined by increased nursing care utilization.

Results

PwMS ( = 11,961) demonstrated higher healthcare utilization than CD ( = 21,884), RA ( = 105,450), and CTR ( = 82,677) groups, even at young ages. Besides expected risk factors like age, smoking, diabetes, and psychiatric disorders, the prediction algorithm revealed that PwMS with specific gynecological disorders, upper tract infections, asthma, and thyroiditis were less likely to need higher levels of nursing care.

Conclusions

Leveraging healthcare data allows for an objective assessment of disability in PwMS and can identify informative factors for disability progression. Our approach can be applied to studies on disease progression in large cohorts without detailed clinical data and can be adapted to other diseases, disability measures, and healthcare systems. Higher utilization of healthcare resources even at young ages revealed an unmet need for improved treatment and management strategies for young adults with MS.

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Authors:
Onur Dereli, Jochen Behringer, Achim Berthele, Alexander Hapfelmeier, Bernhard Hemmer and Christiane Gasperi

Article first published online:
30 Mar 2025 | DOI: 10.1111/ene.70124

LETTER TO THE EDITOR

Letter to the Editor: ‘Causes of Hospitalisation and Mortality in Persons With Epilepsy: The EpiLink Bologna Cohort, Italy’

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Authors:
Maanini Singhvi, Leroy D'Souza, Vivekhan Raja and Rohan Nikhil Dubeer

Article first published online:
05 Apr 2025 | DOI: 10.1111/ene.70126

ORIGINAL ARTICLE

Altered Brain Iron Depositions of Spinocerebellar Ataxia Type 3: From Pre‐Symptomatic to Symptomatic Stage

Background

Spinocerebellar ataxia type 3 (SCA3) is a rare hereditary neurodegeneration disease. The iron distribution of SCA3 is poorly understood, yet quantitative susceptibility mapping (QSM) has rarely been used in SCA3.

Methods

We prospectively investigated QSM of SCA3 (19 pre‐symptomatic and 41 symptomatic) and 37 healthy controls (HCs) recruited from 2018.05 to 2021.01. Group susceptibility was cross‐sectionally compared, and the associations between altered brain iron deposition and clinical symptoms, neurofilament light chain (Nfl), and fractional anisotropy of the bilateral corticospinal tracts and cerebellar peduncles were explored. 12 SCA3 participants were followed for at least a year.

Results

Compared to HCs, bilateral SN were observed with significantly increased susceptibility in pre‐symptomatic SCA3. Most of the supratentorial nuclei and the right dental nucleus had increased susceptibility in symptomatic than in pre‐symptomatic stage and were partially correlated with symptomatic severity, disease duration, and damaged cerebellar peduncles ( < 0.05) but not Nfl ( > 0.05). The left substantia nigra (SN) demonstrated the highest diagnostic efficacy in identifying pre‐ (AUC = 0.904) and symptomatic SCA3 (AUC = 0.938). The longitudinal study also confirmed the significant change in the left SN ( < 0.01).

Conclusions

Our in vivo QSM evidence demonstrates disease‐specific patterns for brain iron depositions in SCA3. Brain iron deposition abnormality is an early event of the SCA3's occurrence and development. The left SN might be a critical site for the disease's start and development.

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Authors:
Haishan Qiu, Manshi Hu, Chao Jiang, Jiale Wu, Zihuan Huang, Jiahui Liang, Runhua Sha, Wenting Zeng, Chao Wu, Jianping Chu and Jing Zhao

Article first published online:
10 Apr 2025 | DOI: 10.1111/ene.70127

ORIGINAL ARTICLE

An Investigation of Corticospinal Tract Microstructural Integrity in ARSACS Using a Profilometry MRI Analysis: Results From the PROSPAX Study

Background

Spasticity represents a core clinical feature of Autosomal Recessive Spastic Ataxia of Charlevoix‐Saguenay (ARSACS) patients. Nonetheless, its pathophysiological substrate is poorly investigated. We assessed the microstructural integrity of the corticospinal tract (CST) using diffusion MRI (dMRI) via profilometry analysis to understand its possible role in the development of spasticity in ARSACS.

Materials and Methods

In this multi‐center prospective study, data of 37 ARSACS (M/F = 21/16; 33.4 ± 12.4 years) and 29 controls (M/F = 13/16; 42.1 ± 17.2 years) acquired within the PROSPAX consortium were collected from January 2021 to October 2022 and analyzed. Differences in terms of global CST microstructural integrity were probed, as well as a possible spatial distribution of the damage along the tract via profilometry analysis. Possible correlations between clinical severity, including the Spastic Paraplegia Rating Scale (SPRS), were also tested.

Results

A significant global involvement of the CST was found in ARSACS compared to controls (all tests with < 0.001), with a spatially defined pattern of more pronounced microstructural integrity loss occurring right below and above the pons, a structure that was also confirmed to be thickened in these patients ( < 0.001). A bilateral negative correlation emerged between the microstructural integrity of the CST and clinical indices of spasticity expressed via SPRS ( = 0.02 for both CSTs).

Conclusion

A clinically meaningful microstructural involvement of CST is present in ARSACS patients, with a spatially defined pattern of damage occurring right below and above a thickened pons. An evaluation of the microstructure of this bundle might serve as a possible biomarker in this condition.

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Authors:
Alessandra Scaravilli, Gaia Mari, Ilaria Gabusi, Matteo Battocchio, Sara Bosticardo, Simona Schiavi, Benjamin Bender, Christoph Kessler, Roberta La Piana, Bart P. van de Warrenburg, Mirco Cosottini, Dagmar Timmann, Bernard Brais, Graziella Donatelli, Giovanna De Michele, Thomas M. Ernst, Stephan Klebe, Ilana Leppert, Ivana Ricca, Sara Satolli, Andreas Traschütz, Ilse Willemse, Alessandro Daducci, Rebecca Schüle, Matthis Synofzik, Filippo Maria Santorelli and Sirio Cocozza

Article first published online:
16 Apr 2025 | DOI: 10.1111/ene.70128

REVIEW ARTICLE

Epilepsy and Employment in Europe: A Systematic Review of Literature

Background

Epilepsy is a chronic disorder affecting all aspects of individual life. People with epilepsy (PwE) reach seizure control in about 60% of cases. However, social integration issues are frequently overlooked. Unemployment and underemployment are markedly more common in PwE compared with the general population. With this review, we aimed to depict the current state of the employment situation in Europe with a focus on factors that may influence it.

Methods

We performed a systematic review on epilepsy and employment as part of EpilepsyPOWER Erasmus+ project (2021‐1‐IT02‐KA220‐ADU‐000028349). Our search string was “Epilepsy AND Employment OR Job OR Work.” Using the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA 2020) guidelines, we screened 7272 articles and selected 55 articles from 1958 to 2023. We extrapolated data on employment rate and status, also considering people with specific epileptic syndromes. We finally evaluated factors contributing to employment and unemployment.

Results

Unemployment rates range from similar to twice or three times the rates of the general population, depending on the countries and years examined. When analyzing factors contributing to employment conditions, most papers highlighted the importance of seizure control and employers' attitudes.

Conclusion

Developing specific legislation and programs to include PwE in the workplace could help their social integration. Moreover, seizure control seems to be the most relevant factor influencing the possibility of getting and maintaining a good job, demonstrating the importance of providing continuous follow‐up and the best medical care to all PwE.

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Authors:
F. Narducci, G. Lippa, G. Baker, D. Walsh, F. Sofia, N. Casalino, F. Pigni, S. Louissi, I. Philipova, S. Duttenhöfer, L. Ricci, B. Sancetta, J. Lanzone, M. Tombini, V. Di Lazzaro and G. Assenza

Article first published online:
21 Apr 2025 | DOI: 10.1111/ene.70129

ORIGINAL ARTICLE

Stratifying Multiple Sclerosis Susceptibility Risk: The Role of and Infectious Mononucleosis in a Population Cohort

Background

Epstein–Barr Virus (EBV) and its clinical manifestation, infectious mononucleosis (IM), are strongly linked to MS risk. A recent in vitro study suggests that , in contrast to , may protect against MS through more effective immune responses against EBV‐infected B cells. However, the role of in MS remains unclear.

Methods

We investigated if was significantly associated with higher MS risk in individuals with a history of IM diagnosis, using 487,144 individuals from the UK Biobank's cohort. We estimated the interaction between and IM using Cox proportional hazard models, adjusting for demographics, smoking, childhood body size, older siblings, and MS‐related HLA alleles (e.g., ).

Results

allele alone was not significantly associated with IM or MS ( > 0.05). However, a significant interaction between and IM history was observed in relation to MS risk ( < 0.001). Specifically, MS risk was significantly higher in both heterozygotes (HR = 1.74 [95% CI: 1.36, 1.97], < 0.001) and homozygotes (HR = 3.01 [95% CI: 1.81, 3.88], < 0.001) with IM history, compared to homozygotes Conversely, these associations were non‐significant in individuals without IM history ( > 0.05). The estimated proportion of the combined risk attributable to interaction effects was 40% in heterozygotes and 65% in homozygotes.

Conclusions

carriers diagnosed with IM are at significantly increased risk of MS, independently from other MS‐related HLA alleles. This supports the hypothesis that may contribute to MS susceptibility due to weaker immune control over EBV infection. Incorporating into existing MHC‐based MS risk models could then enhance personalized risk assessments in individuals with IM history.

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Authors:
Andrea Nova, Davide Gentilini, Giovanni Di Caprio, Sonia Bourguiba‐Hachemi, Nicolas Vince, Pierre‐Antoine Gourraud, Luisa Bernardinelli and Teresa Fazia

Article first published online:
07 Apr 2025 | DOI: 10.1111/ene.70131

ORIGINAL ARTICLE

Alterations of Fat and Ketone Body Metabolism in ALS and SMA—A Prospective Observational Study

Background

Amyotrophic lateral sclerdosis (ALS) and spinal muscular atrophy (SMA) are motor neuron diseases associated with distinct metabolic alterations. ALS patients feature an increased resting energy expenditure (REE) causing weight loss and cachexia. In SMA, a disturbed utilization of free fatty acids has been described. These metabolic alterations negatively affect prognosis in both diseases. The objective of this study was to further characterize these changes to identify potential therapeutic targets.

Methods

Between 11/2020 and 08/2022, 112 ALS patients, 77 SMA patients, and 50 controls were recruited in the Department of Neurology of Ulm University. Standardized blood and urinary samples were collected to analyze fat and ketone metabolism.

Results

Ketone body levels were higher in ALS and SMA compared to controls. In both diseases, patients with higher BMI featured higher ketone bodies and free fatty acids compared to those with lower BMI, while in controls we found the opposite phenomenon. In SMA, more severe disease types were associated with higher ketone body levels. Compared to ALS, SMA patients featured higher ketone body and free fatty acid levels.

Conclusions

Our data suggest that already during early disease stages, ALS patients produce ketone bodies to compensate for the energy deficit. In SMA, on the other hand, the persistence of ketogenesis may indicate an upregulation of all available metabolic pathways for energy production due to the disturbance of fatty acid utilization. Therefore, the application of additional sources of energy, such as ketone bodies, might constitute a promising therapeutic option in both diseases.

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Authors:
C. Herrmann, Z. Uzelac, S. Michels, A. Weber, L. Richter, Z. Elmas, L. Jagodzinski, C. Wurster, J. Schuster, J. Dreyhaupt and J. Dorst

Article first published online:
09 Apr 2025 | DOI: 10.1111/ene.70132

ORIGINAL ARTICLE

Sex Differences in Embolic Stroke of Undetermined Source: Echocardiographic Features and Clinical Outcomes

Background

Sex differences in stroke are well‐documented, but in embolic stroke of undetermined source (ESUS) remains underexplored. This study aims to investigate sex‐related differences in clinical and cardiac features and stroke outcomes in ESUS.

Methods

Retrospective observational single‐center study including consecutive ESUS patients. Multivariate regression analyses evaluated the association between sex, echocardiographic features, and 90‐day outcomes. Cox regression assessed the independent effect of sex on ischemic stroke recurrence, all‐cause death, and atrial fibrillation detection after stroke (AFDAS).

Results

Among 556 patients, 248 (44.6%) were women, who were older and had more severe strokes. Women exhibited larger left atria (LA) as evidenced by a higher LA volume index (adjusted β‐coefficient = 2.59, 95% CI 0.53–4.65, = 0.014) and more valve abnormalities, such as mitral annulus calcification (aOR 2.72; 95% CI 1.43–5.20, = 0.002). Men showed more markers of left ventricular (LV) disease, including reduced ejection fraction < 50% (aOR 0.44; 95% CI 0.20–0.93, = 0.033) and LV wall motion abnormalities (aOR 0.37; 95% CI 0.19–0.74, = 0.005). In multivariate analyses, the female sex was independently associated with reduced all‐cause death (aHR 0.59; 95% CI 0.38–0.91, = 0.019) and showed a trend toward higher AFDAS risk (aHR 1.57; 95% CI 0.99–2.49, = 0.053). No association was found with 90‐day outcomes or stroke recurrence.

Conclusion

ESUS patients exhibit significant sex‐based differences in echocardiographic features, with women showing larger LA and more valve abnormalities, while men present greater LV dysfunction. Female sex is independently associated with a lower risk of long‐term mortality and a potentially higher risk of AFDAS. These findings underscore the need for individualized, sex‐specific ESUS management strategies.

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Authors:
Angelo Cascio Rizzo, Ghil Schwarz, Andrea Bonelli, Chiara Ceresa, Benedetta De Chiara, Antonella Moreo and Maria Sessa

Article first published online:
05 Apr 2025 | DOI: 10.1111/ene.70133

ORIGINAL ARTICLE

Criminal Behavior in Early Onset Neurodegenerative Diseases

Introduction

Literature on criminal behavior preceding a neurodegenerative disease diagnosis is insufficient. Some studies suggest increased crime rates among patients with frontotemporal dementia (FTD).

Methods

Patients with neurodegenerative diseases were gathered from Kuopio and Oulu University Hospitals and compared with nonselective general population data from Statistics Finland ( = 24,144). Clinical data were linked to the Finnish national register of police‐reported crimes.

Results

In total, 2424 participants with neurodegenerative diseases were included. Overall crime rates were notably higher among patients with FTD during the year before the diagnosis (9.4% for FTD, 6.3% for controls, = 0.019). There was a significant drop in the criminal rates of FTD patients 3 years after the diagnosis (4.7% in the FTD, 12.3% in controls, < 0.001).

Discussion

Criminal behavior is overrepresented in patients with FTD before the diagnosis. Criminal behavior manifesting in previously law‐abiding individuals in late adulthood should be considered a potential early symptom of a neurodegenerative disease.

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Authors:
Helmi Soppela, Mikko Aaltonen, Kalle Aho, Sami Heikkinen, Ave Kivisild, Adolfina Lehtonen, Laura Leppänen, Anna Mäki‐Petäjä‐Leinonen, Iina Rinnankoski, Laura Tervonen, Jari Tiihonen, Markku Lähteenvuo, Annakaisa Haapasalo, Anne M. Portaankorva, Päivi Hartikainen, Kasper Katisko, Johanna Krüger and Eino Solje

Article first published online:
08 Apr 2025 | DOI: 10.1111/ene.70134

ORIGINAL ARTICLE

Multiorgan Involvement and Mortality in Individuals With Adult‐Onset Myotonic Dystrophy (DM1)—A Danish Register‐Based Study I

Background and Purpose

Adult‐onset myotonic dystrophy type 1 (DM1) is characterized by a diagnostic delay due to milder symptoms than the infantile and juvenile forms. Despite this, there is a risk of negative biopsychosocial consequences, particularly due to the cognitive impact. Individuals with adult‐onset DM1 may receive less attention and have lower adherence to hospital follow‐ups, which increases the risk of adverse events and early death. The aim of this study was to provide knowledge on the time of diagnosis, multiorgan involvement, and mortality in a national cohort of individuals with adult‐onset DM1.

Methods

Data from individuals with DM1 were extracted from the Danish National Health and administrative registers in the period 1994–2022; each individual with DM1 was paired with 10 reference individuals from the general Danish population.

Results

Analyses were based on 949 individuals with DM1 and 9427 controls. The median age at diagnosis was 43 years; 40% of individuals had a parent–child relationship. Respiratory insufficiency and cataracts were the most common involvements among individuals with DM1. The average age at death was 58 years; risk of mortality was 5.87 times higher than controls ( < 0.001) and individuals with DM1 and cardiovascular disease had a higher mortality rate compared to controls (HR: 2.63, CI: 2.14–3.23, < 0.001). The risk of mortality tended to decline in the later years of the study period.

Conclusion

Despite adult‐onset DM1 often being characterized as mild, comorbidities and an excess risk of death are major concerns. This calls for attention from health professionals to improve rehabilitation and survival for this population.

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Authors:
Ulla Werlauff, Jan Håkon Rudolfsen, Henning Andersen, John Vissing, Charlotte Dahl Rossau, Pia Dreyer, Jens Olsen, Simone D. Bengtsson, Heidi Aagaard and Charlotte Handberg

Article first published online:
08 Apr 2025 | DOI: 10.1111/ene.70135

ORIGINAL ARTICLE

BRAF V600E Mutation in Ganglioglioma: Impact on Epileptogenicity and Implications for Surgical Strategy

Objective

Gangliogliomas are commonly found pathologies in patients undergoing epilepsy surgery. While resections can be curative, seizure relapses occur. Expression of CD34 and the BRAF V600E mutation are the most common molecular biomarkers found in gangliogliomas, but their influence on seizure outcomes is unclear. We therefore reviewed our experience over two decades to better describe prognostic factors.

Methods

We performed a retrospective chart review of all patients operated on for ganglioglioma at our institution since the year 2000. We included patients with preoperative epilepsy and a minimum follow‐up of 1 year. Available tumor specimens were immunohistochemically stained for CD34 and BRAF V600E.

Results

We included 62 patients with epilepsy operated for ganglioglioma. Lesionectomies were performed in 32 (51.6%), extended resections in 21 (33.9%), and partial resections in 9 cases (14.5%). Residual tumor mass on postoperative MRI was diagnosed in 21 patients (33.9%). CD34 reactivity was found in 57 patients (91.9%) and the BRAF V600E mutation was detected in 30 patients (48.4%). Patients with a BRAF V600E mutation were younger at the time of epilepsy onset (9.1 years vs. 15.2 years) and surgery (14.5 years vs. 23.7 years). Residual tumor was the largest risk factor for seizure relapses (hazard ratio 8.45) and the BRAF V600E mutation also increased this risk (hazard ratio 3.94).

Conclusions

BRAF V600E status in patients with ganglioglioma‐associated epilepsy is a potential biomarker to stratify the risk for seizure relapse after surgery. BRAF V600E‐positive patients might benefit from a more aggressive surgical strategy.

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Authors:
Matthias Tomschik, Eva Horner, Alexandra Lang, Florian Mayer, Thomas Czech, Gregor Kasprian, Ekaterina Pataraia, Amedeo A. Azizi, Martha Feucht, Karl Rössler, Christine Haberler and Christian Dorfer

Article first published online:
05 Apr 2025 | DOI: 10.1111/ene.70136

ORIGINAL ARTICLE

Population‐Based Versus Hospital‐Based Data in Amyotrophic Lateral Sclerosis—A Factor to Consider?

Background

Over the past years, some studies in amyotrophic lateral sclerosis (ALS) have provided heterogeneous findings regarding demographic and clinical data as well as the impact of various prognostic factors. It is well known that these inconsistencies might be caused by a selection bias in hospital‐based data sets. In this study, we sought to further characterize this selection bias.

Methods

We compared hospital‐based data from the ALS center at Ulm University (UC; = 3833; 1997–2021) with the population‐based ALS registry Swabia (SR; = 852; 2010–2020).

Results

Patients from UC were younger (age of onset 60.9 [IQR 52.4–68.9] vs. 65.0 [57.0–72.7]), had a higher share of males (60.5% vs. 56.3%), a longer diagnostic delay (10.5 [IQR 6.4–18.4] months vs. 6.9 [IQR 3.4–12.1] months), a higher prevalence of the “definite” category according to El Escorial diagnostic criteria (60.9% vs. 11.2%), a higher share of familial cases (12.9% vs. 6.3%), a slower progression rate (points of ALS functional rating scale revised lost per month −0.54 [IQR −1.02 to −0.28] vs. −0.79 [IQR −1.47 to −0.43]), and (among all deceased patients) a higher share of percutaneous endoscopic gastrostomy (26.7% vs. 17.7%) and non‐invasive ventilation (34.3% vs. 25.3%).

Conclusions

The observed differences likely indicate a selection bias in hospital‐based data, which may be attributed, among others, to the willingness to travel large distances to a specialized center, the desire to participate in clinical studies, and the attitude toward life‐prolonging measures. These differences must be considered when interpreting and generalizing study results from hospital‐based populations.

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Authors:
Johannes Dorst, Jens Dreyhaupt, Deborah Wernecke, Ulrike Weiland, Özlem Parlak, Maximilian Wiesenfarth, Zeynep Elmas, Christine Herrmann, Hansjörg Bäzner, Axel Boertlein, Silke Dempewolf, Christian Foerch, Martin Hecht, Andreas Kohler, Christian Opherk, Katharina Althaus, Monika Clauer‐Bredt, Alfred Lindner, Wolfgang Ruf, David Brenner, Simon Witzel, Raphael S. Peter, Joachim Schuster, Albert C. Ludolph, Angela Rosenbohm and Gabriele Nagel

Article first published online:
04 Apr 2025 | DOI: 10.1111/ene.70137

ORIGINAL ARTICLE

Predictors of Recovering Full Consciousness: Results From a Prospective Multisite Italian Study

Background

Improving prognostication in patients with a prolonged disorder of consciousness (pDoC) is among the most challenging issues in neurorehabilitation. The aim of this Italian multisite prospective longitudinal study was to identify valuable predictors of the complete recovery of consciousness (emergence from Minimally Conscious State, eMCS) at 3 months (T1) from the admission in intensive rehabilitation units (IRUs) in pDoC (T0).

Methods

Patients with Unresponsive Wakefulness Syndrome (UWS) or MCS admitted within 3 months of injury to 4 Italian IRUs were included. Demographic, clinical, and neurophysiological data were collected at T0, and a clinical diagnosis of consciousness (UWS, MCS−, MCS+) was established at T0 and T1 using the Coma Recovery Scale‐Revised (CRS‐R).

Results

One hundred forty‐three patients were initially included and 131 completed follow‐ups at T1: (76 males; median age: 69 years [IQR = 23]; VS/UWS: 51, MCS−: 29, MCS+: 51; etiology: 33 traumatic, 14 anoxic, 24 ischemic, 55 hemorrhagic, 5 other; median time post‐injury: 40 days [IQR = 23]). At T1, 77 patients were eMCS, and 10 improved their clinical diagnosis. Among the clinical and neurophysiological independent variables, a higher CRS‐R visual sub‐score and the presence of EEG reactivity to eye opening at T0 were the best independent predictors of eMCS. Out of 77 eMCS, 18 reached a moderate disability (Glasgow Outcome Scale Extended‐GOSE > 4), while the others persisted with a severe disability (GOS‐E ≤ 4).

Conclusions

A multimodal assessment can help identify patients who achieve functionally relevant improvements and thus better support clinicians when communicating with caregivers.

Trial Registration

registration number: NCT04495192

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Authors:
Bahia Hakiki, Piergiuseppe Liuzzi, Anna Maria Romoli, Francesca Draghi, Daniela Maccanti, Agnese De Nisco, Rachele Burali, Tanita Toci, Antonello Grippo, Maenia Scarpino, Andrea Mannini, Alfonso Magliacano, Anna Estraneo, Angela Comanducci, Jorge Navarro, Caterina Tramonti, Valentina Carli, Pietro Balbi, Claudio Macchi and Francesca Cecchi

Article first published online:
24 Apr 2025 | DOI: 10.1111/ene.70138

REVIEW ARTICLE

Generics, Biosimilars and Follow‐On Non‐Biologic Complex Drugs for Multiple Sclerosis: A Narrative Review of the Regulatory and Clinical Implications for European Neurologists

Background

Multiple sclerosis (MS) places substantial socioeconomic burden on patients due to its early onset and progressive nature, but healthcare systems are also impacted by the high costs of disease‐modifying treatments (DMTs). The use of generics (for conventional drugs), biosimilars (for biologics) or follow‐on versions of non‐biologic complex drugs (NBCDs) can help to reduce the cost of MS care and improve patient access. This review describes the European regulatory processes for these DMT ‘copies’ and the available data in people with MS.

Methods

A PubMed literature search was undertaken in March 2024, using the terms ‘biosimilar’, ‘generic’, ‘non‐biologic complex drug’, ‘NBCD’ and ‘follow‐on’ in association with ‘multiple sclerosis’.

Results

Our literature search identified three clinical studies with generic treatments for MS (two with generic fingolimod and one with generic dimethyl fumarate), 11 studies with biosimilars (eight with biosimilar interferon formulations, one with natalizumab and two with rituximab biosimilars) and six studies with follow‐on glatiramer acetate. The data showed that the generics, biosimilars and follow‐on NBCDs had similar clinical efficacy and tolerability profiles to the originator drugs, although the quality and quantity of the research varied between DMTs.

Conclusions

In Europe, there are robust regulatory processes for generics, biosimilars and follow‐on NBCDs, in order to ensure that these agents can be considered equally effective and safe as the originator DMT. Physicians caring for people with MS should familiarise themselves with the evidence so that they can have informed conversations about the potential use of these agents.

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Authors:
Thomas Berger, Markus Zeitlinger, Veronica Popescu, Melinda Magyari, Laura Airas, Mona Alkhawajah, Maura Pugliatti, Magd Zakaria, Carlo Pozzilli, Jelena Drulovic, Bart Van Wijmeersch, Patrick Vermersch and Celia Oreja‐Guevara

Article first published online:
15 Apr 2025 | DOI: 10.1111/ene.70140

LETTER TO THE EDITOR

PET Beta‐Amyloid Tracer Uptake in Leukoencephalopathies: Comparing Metachromatic Leukodystrophy and CADASIL

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Authors:
Chiara Benzoni, Marco Moscatelli, Anna Bersano, Angelo Del Sole and Ettore Salsano

Article first published online:
10 Apr 2025 | DOI: 10.1111/ene.70141

LETTER TO THE EDITOR

Comment on: Associations of Inflammatory Markers With Neurological Dysfunction and Prognosis in Patients With Progressive Stroke

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Authors:
Xinmin Zhao and Weixin Zhang

Article first published online:
21 Apr 2025 | DOI: 10.1111/ene.70145

ORIGINAL ARTICLE

Robotic Thymectomy for Myasthenia Gravis: Analysis of the Surgical and Neurological Outcomes After a 20 Years' Experience

Background

Evidence supporting robotic thymectomy for myasthenia gravis is generally based on small sample‐size studies, heterogeneous in patient selection and in reporting outcomes. Therefore, this study was conducted to assess the surgical and neurological outcomes of robotic thymectomy in myasthenic patients and to identify prognostic factors associated with symptoms' remission through a large cohort of patients operated in a 20 years' period.

Methods

A retrospective analysis of a prospectively maintained database was conducted for all patients undergoing robotic thymectomy for myasthenia gravis between 2002 and 2022. Myasthenia Gravis Foundation of America (MGFA) recommendations were used to report the neurological outcomes. Complete remission and overall improvement were evaluated using Cumulative Incidence Functions, while the effect of preoperative variables on the probability of remission was estimated with Cox models.

Results

In total, 267 patients underwent robotic thymectomy. Median operative time was 135 min and there were 7 (2.6%) open conversions. Clinical follow‐up (median 83 months) showed a 5‐year probability of complete remission of 18% and of overall improvement of 84%. Complete remission was negatively associated with age (HR 0.97, 95% CI 0.95–0.99, = 0.001) and preoperative use of pyridostigmine (HR 0.34, 95% CI 0.15–0.81, = 0.014), while severe MGFA class did not reach significance (HR 0.55, 95% CI 0.3–1.01, = 0.052). Instead, there was a benefit in patients operated on in later years (HR 1.11, 95% CI 1.04–1.18, = 0.01).

Comment

Robotic thymectomy is a safe procedure. Long‐term neurological follow‐up demonstrated an improvement in most patients, also in subgroups that historically showed worse outcomes.

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Authors:
Giovanni M. Comacchio, Marco Schiavon, Luca Bello, Marco Mammana, Eleonora Faccioli, Elena Pegoraro, Giulia Lorenzoni, Giorgio Cannone, Giuseppe Cataldi, Giulia Pagliarini, Alessandro Rebusso, Samuele Nicotra, Dario Gregori, Maria Carlotta Marino, Giuliana Capece, Pietro Riguzzi, Federica Pezzuto, Fiorella Calabrese, Andrea Dell'Amore and Federico Rea

Article first published online:
15 Apr 2025 | DOI: 10.1111/ene.70147

ORIGINAL ARTICLE

Raised Intracranial Pressure in Seizures Induced by Electroconvulsive Therapy

Background

Increased intracranial pressure (ICP) can be observed immediately upon seizure activity in craniotomized patients in neurosurgical practice. However, it is not commonly included in models of pathomechanisms contributing to morbidity and mortality in epilepsy. A main contributor to this may be the fact that measuring ICP noninvasively during a seizure is technically challenging. The optic nerve sheath diameter (ONSD) represents a promising, noninvasive option to monitor relative ICP changes. We therefore measured ONSD in patients undergoing electroconvulsive therapy (ECT).

Methods

Twenty‐seven ECT‐induced seizures from nine consecutive patients underwent ONSD measurement at baseline after induction of anesthesia (t0), during injection of suxamethonium (sux) (t1), after injection of sux (t2), during the electrically induced seizure (t3), and after the electrically induced seizure (t4). A linear mixed model was applied.

Results

An increase in ONSD of > 0.2 mm from t0 to t3 was observed in all patients and in all ECT‐induced seizures except one. ONSD increased significantly during the succinylcholine‐induced fasciculations, T, ( = 0.535 mm, < 0.001) and during the electrically induced seizure, T, ( = 1.02 mm, < 0.001). ONSD returned to baseline after the fasciculations, T, ( = 0.091 mm, = 0.443) and after the seizure, T, ( = 0.103 mm, = 0.379).

Conclusions

This investigation shows generalized convulsive seizures are associated with a transient but pronounced increase in ONSD, suggesting a temporary increase in ICP.

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Authors:
Jochem K. H. Spoor, Rutger V. A. Hollestelle, Tom K. Birkenhager, Marie‐Claire Y. De Wit, Iain K. Haitsma, Irene M. J. Mathijssen, Marie‐Lise C. van Veelen, Marcel A. Kamp, Esther Pluijms, Markus Klimek, Rinze Neuteboom, Iscander M. Maissan and Maxine Dibué

Article first published online:
16 Apr 2025 | DOI: 10.1111/ene.70149

ORIGINAL ARTICLE

Factors Distinguishing Nonsystemic Versus Systemic Vasculitic Peripheral Neuropathy: A Retrospective Cohort Study

Background

Prompt differentiation of nonsystemic vasculitic neuropathy (NSVN) from systemic vasculitic neuropathy (SVN) without antineutrophil cytoplasmic antibodies or organ involvement (SVN‐) is challenging but crucial given the differences in management. Our primary objective was to identify predictors of SVN‐ versus NSVN.

Methods

We retrospectively identified patients seen at either of two centers for histologically definite or probable vasculitic neuropathy diagnosed as SVN‐ or NSVN. Clinical, electromyographic, laboratory, and histological data at diagnosis and last follow‐up were collected.

Results

We included 98 patients, of whom 46 (47%) had NSVN and 52 (53%) SVN‐. Symptoms and neurophysiological findings did not significantly differ between the two groups. By univariate analysis, compared to the NSVN group, the SVN‐ group had more patients with C‐reactive protein ≥ 10 mg/L (44.2% vs. 17.4%, < 0.01), antinuclear antibodies (42.3% vs. 21.7%, = 0.04), and low C3 or C4 (23.1% vs. 4.3%, = 0.02). All three associations were confirmed by multivariate analysis. By multivariate analysis adjusted for symptom duration, muscle vasculitis also was associated with SVN‐ (OR, 8.33; 95% CI, 2.63–25.00; < 0.01).

Conclusion

Simple, readily available laboratory and histological variables may help to rapidly distinguish SVN from NSVN.

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Authors:
Edouard Berling, Thierry Maisonobe, Olivier Morassi, Andoni Echaniz‐Laguna, Christian Denier, Adrien Le Guillou, Mathilde Duschene, Céline Labeyrie and Clovis Adam

Article first published online:
10 Apr 2025 | DOI: 10.1111/ene.70150

ORIGINAL ARTICLE

Change in Structural Connectivity Following Stereotactic Thermocoagulation in Mesial Temporal Lobe Epilepsy Patients

Aims

To examine the association between postoperative lesions in distinct ROIs of the brain and the impact that their ablation would have on the structural and functional brain connectivity relative to outcomes.

Methods

We retrospectively reviewed 21 patients with refractory unilateral MTLE. The percentage of each ablated gray matter region of interest (ROIs) was calculated, using a voxel‐by‐voxel comparison. The percentage of the affected fibers was calculated by assessing the neuronal change reflected by a decrease in anisotropy in the repeat scans (i.e., pre and postoperative). Graph theory analysis was used to investigate the change in the pre and postoperative structural and functional networks between the seizure‐free and non‐seizure‐free groups.

Results

Fifteen patients (71.42%) were seizure‐free and six (28.57%) were non‐seizure‐free at a 12 to 48 months (23.80 ± 8.93) follow‐up. Four patients (19.04%) reported memory decline following RFTC. The seizure‐free group showed a larger ablation volume of both the amygdala ( = 0.024) and rhinal cortex ( = 0.035), and an alteration in structural connectivity networks metrics ( < 0.05) compared to the non‐seizure‐free group.

Conclusions

Our study shows that a higher ablation of both the amygdala and rhinal cortex led to improved structural connectivity and was associated with better outcomes. Our results provide insight into some essential elements of brain connectivity networks in MTLE and might contribute to the generation of novel evidence that could improve SEEG‐guided RFTC interventions in MTLE patients.

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Authors:
Stéphane Jean, Rifeng Jiang, Yihai Dai, Weitao Chen, Weihong Liu, Donghuo Deng, Panashe Tevin Tagu, Xiaoqiang Wei, Shan Chen, Xinrong Fang and Shiwei Song

Article first published online:
21 Apr 2025 | DOI: 10.1111/ene.70153

ORIGINAL ARTICLE

Voxel‐Based Lesion Symptom Mapping to Predict Poststroke Epilepsy After Mechanical Thrombectomy

Introduction

Poststroke epilepsy (PSE) is an important long‐term complication after stroke. Data regarding predictors of PSE in patients with large‐vessel occlusion stroke receiving mechanical thrombectomy (MT) are scarce. Voxel‐based lesion symptom mapping on brain MRI might be a valuable tool in the risk prediction of PSE. This study aims to assess PSE risk after acute stroke treated with MT via voxel‐ and volumetric‐based analyses.

Methods

In this bi‐center study from two tertiary‐care stroke centers, we included consecutive acute ischemic stroke patients who had received MT between 2011 and 2017, and had postinterventional brain MRI as well as long‐term follow‐up data available. Infarct volume and location were assessed on MRI. Following semiautomated lesion outlining and generation of binarized lesion masks, lesion symptom mapping was applied to identify relevant topographical lesion patterns in PSE.

Results

Of 348 analyzed patients, 97 cases had to be excluded due to insufficient image quality and inaccurate registration results. Finally, lesion maps from 251 patients (median age: 66, 45.4% women) were considered for lesion symptom mapping, including maps from 26 patients with PSE (10.4%). Mean infarct volume was higher in PSE patients (119.2 cm vs. 43.9 cm, < 0.0001). Lesion symptom mapping identified the orbitofrontal region, the operculum, and the temporal pole as brain regions associated with PSE.

Conclusion

Apart from infarct volume, lesion symptom mapping on postinterventional brain MRI identified specific brain regions associated with PSE after large vessel occlusion stroke. This information might be helpful for PSE risk stratification and follow‐up care in this specific population.

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Authors:
Joachim Gruber, Stefan Ropele, Daniela Pinter, Christian Enzinger, Raimund Helbok, Hannes Deutschmann, Michael Sonnberger, Markus Kneihsl, Tim J. von Oertzen and Thomas Gattringer

Article first published online:
10 Apr 2025 | DOI: 10.1111/ene.70154

ORIGINAL ARTICLE

Brain‐Derived Tau as an Outcome Marker in Guillain‐Barré Syndrome: A Retrospective Cohort Study

Background and Objectives

Biomarkers for predicting disease severity and outcome in Guillain‐Barré syndrome (GBS) are scarce. We aimed to determine if brain‐derived tau in serum (sBD‐tau) and cerebrospinal fluid (CSF BD‐tau) are associated with long‐term outcome and disease severity in GBS.

Methods

In this retrospective study of 100 GBS patients, we measured sBD‐tau and CSF BD‐tau at diagnosis. Outcome was defined as GBS disability scale (GBSDS) > 2 and overall neuropathy limitation scale (ONLS) at 12 months, disease severity as respiratory support and ONLS at nadir. BD‐tau levels were compared between groups and correlated with ONLS scores. Regression analyses and receiver operator characteristic curve analyses were performed for GBSDS > 2 at 12 months.

Results

BD‐tau levels were higher for GBSDS > 2 at 12 months in serum and CSF. Odds ratio for sBD‐tau was 1.9 (95% CI 1.08–3.2, = 0.03) and for CSF BD‐tau was 5.9 (95% CI 1.4–25, = 0.02). Area under curve for sBD‐tau was 0.75 (95% CI 0.57–0.9, < 0.001) and for CSF BD‐tau was 0.78 (95% CI 0.65–0.9, = 0.001). ONLS at 12 months correlated with sBD‐tau ( = 0.34 [95% CI 0.12–0.53], = 0.002) and CSF BD‐tau ( = 0.33 [95% CI 0.08–0.54], = 0.01). Statistically significant difference in BD‐tau levels was not seen for respiratory support or ONLS at nadir.

Conclusion

BD‐tau at GBS onset is associated with long‐term outcome but not disease severity. Because BD‐tau is essentially a CNS biomarker, our results suggest that CNS involvement influences recovery.

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Authors:
Brynhildur Hafsteinsdóttir, Fernando Gonzalez‐Ortiz, Nina Gleisner, Ellen Alpsten, Jan Lycke, Igal Rosenstein, Lenka Novakova, Kaj Blennow, Tomas Bergström, Henrik Zetterberg and Markus Axelsson

Article first published online:
16 Apr 2025 | DOI: 10.1111/ene.70155

ORIGINAL ARTICLE

Time Trends in Incidence of Motor Neuron Diseases in France: A Comprehensive 14‐Year Nationwide Study (2010–2023)

Background

Changes over time in the incidence of Motor Neuron Disease (MND) remain uncertain. We aimed to examine time trends in the incidence and survival of MND over 14 years using the Système National des Données de Santé, a nationwide French administrative database.

Methods

We utilized a published algorithm that integrates riluzole prescriptions and hospital discharge to identify incident MND cases from January 1, 2010, to December 31, 2023. Crude and standardized incidences were calculated per 100,000 person‐years. Multivariate Poisson regression models determined time trends in MND incidence by age and sex. Survival was analyzed using Kaplan–Meier methods and Cox proportional hazards models to calculate adjusted hazard ratios for different time periods.

Results

A total of 30,028 incident cases were identified. Crude incidence rose from 2.99 to 3.49 cases per 100,000 person‐years between 2010 and 2019, reflecting an annual increase of 1.7% (IRR 1.017, 95% CI 1.012–1.021). After accounting for population aging, there was still an annual increase of 0.7% (IRR: 1.007 [95% CI 1.002–1.012]) between 2010 and 2019. From 2020 to 2023, observed incidence rates deviated from the expected trend, particularly in 2022, which showed a 15% decrease. The median survival time after diagnosis was 18.1 months (2010), 17.8 months (2015), and 15.6 months (2019).

Conclusions

Although population aging explains much of the rise in case numbers, it does not fully account for the increase. Mortality rates remained stable between 2010 and 2015, but the COVID‐19 pandemic had a notable impact, leading to reduced incidence and survival rates.

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Authors:
Octave Guinebretiere, Quentin Calonge, Gaelle Bruneteau, Maria‐Del‐Mar Amador and Thomas Nedelec

Article first published online:
16 Apr 2025 | DOI: 10.1111/ene.70156

ORIGINAL ARTICLE

Long‐Term Efficacy and Safety of Ravulizumab in Adults With Anti‐Acetylcholine Receptor Antibody‐Positive Generalized Myasthenia Gravis: Final Results From the Phase 3 CHAMPION MG Open‐Label Extension

Background

Ravulizumab, an anti‐complement C5 monoclonal antibody, was efficacious with acceptable safety in the randomized controlled period (RCP) and interim open‐label extension (OLE) periods of the CHAMPION MG phase 3 trial in adults with anti‐acetylcholine receptor antibody‐positive (AChR‐Ab+) generalized myasthenia gravis (gMG). Here, we report final results from the OLE.

Methods

Patients who completed the 26‐week RCP could enter the OLE and receive ravulizumab for up to 4 years. Efficacy and safety were assessed throughout the OLE.

Results

Among all ravulizumab‐treated patients ( = 169; median [range] ravulizumab treatment, 759.0 [14.0, 1265.0] days), 161 entered the OLE (ravulizumab‐ravulizumab: = 78; placebo‐ravulizumab: = 83). Sustained improvements were observed in Myasthenia Gravis Activities of Daily Living (MG‐ADL) total scores (ravulizumab‐ravulizumab, least squares mean [95% CI] change from RCP baseline at week 164: −4.0 [−5.3, −2.8]; < 0.0001; placebo‐ravulizumab, change from OLE baseline after 138 weeks of treatment: −2.1 [−3.3, −0.9]; = 0.0005). One hundred and forty‐one out of 160 (88.1%) patients achieved a ≥ 2‐point improvement in MG‐ADL total score, and 59/141 (41.8%) achieved a score of 0 or 1; once achieved, 32/59 (54.2%) sustained this status for > 50% of their remaining time in the study. Similar improvements were observed in Quantitative Myasthenia Gravis and Myasthenia Gravis Quality of Life‐15 revised scores, and Neurological Quality of Life Fatigue subscale scores. Clinical deterioration event rates were reduced in the OLE versus placebo in the RCP. Corticosteroid usage was reduced in the OLE. Ravulizumab was well tolerated; no meningococcal infections were reported.

Conclusion

Ravulizumab demonstrated clinically meaningful and durable efficacy and safety in adults with AChR‐Ab+ gMG.

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Authors:
Tuan H. Vu, Renato Mantegazza, Djillali Annane, Masahisa Katsuno, Andreas Meisel, Michael W. Nicolle, Vera Bril, Rasha Aguzzi, Glen Frick and James F. Howard

Article first published online:
16 Apr 2025 | DOI: 10.1111/ene.70158

ORIGINAL ARTICLE

Global Temporal Trends and Projections of Stroke Among Women of Childbearing Age: An Age–Period–Cohort Analysis Based on the Global Burden of Disease Study 2021

Background

Stroke is a major global health concern, particularly for women of childbearing age (WCBA), who face unique biological and sociodemographic risks. This study analyzes temporal trends in stroke incidence, prevalence, disability‐adjusted life‐year (DALY), and deaths among WCBA at global, regional, and national levels over the past three decades, using age–period–cohort (APC) modeling.

Methods

Stroke burden data for WCBA from 1992 to 2021 across 204 countries were extracted from the Global Burden of Disease (GBD) 2021 study. An APC model assessed annual percentage changes in stroke burden (net drift), age group‐specific trends (local drift), and relative risks associated with age, period, and cohort factors. Future stroke burden was projected using Bayesian APC models through 2030.

Results

From 1992 to 2021, global stroke incidence cases among WCBA increased from 638,478 to 779,371, but ASIR and AS‐DALYs declined. High‐SDI regions consistently had the lowest stroke rates, while middle‐ and low‐SDI regions, particularly China and India, accounted for a significant portion of global cases. Despite declines in some regions, countries like the Philippines and Pakistan exhibited rising trends. Projections to 2030 indicate a continued increase in stroke incidence cases, with higher rates expected in middle‐income countries due to emerging risk factors like obesity and gestational diabetes.

Conclusions

While ASIR and AS‐DALYs declined globally, rising incidence case numbers and persistent disparities highlight the need for targeted prevention and policy strategies, particularly in low‐ and middle‐income regions, to reduce the stroke burden among WCBA.

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Authors:
Dong Tang, Zheng Huang, Shifu Li, Qian Zhang, Mengjun Li, Yangzong Zhou, Kangtai Su and Fenghua Chen

Article first published online:
12 Apr 2025 | DOI: 10.1111/ene.70159

REVIEW ARTICLE

Acupuncture Versus Standard Medical Care in the Prophylactic Treatment of Migraine: A Systematic Review and Meta‐Analysis

Background

Although innovative pharmacological therapies for migraine prevention are now available, they may not be suitable or effective for all patients due to concerns about tolerability and the varying complexity of the underlying condition. This study systematically reviewed and meta‐analyzed acupuncture's effects on migraine prophylaxis compared to standard medical care, focusing on study heterogeneity and issues related to sham interventions.

Methods

Following the PRISMA guidelines and using the PICO model, the study searched PubMed, Scopus, CNKI, and VIP database from December 1965 to September 2024. Studies evaluating acupuncture's clinical efficacy for migraine prophylaxis, including clinical trials, observational studies, case series, and case reports, were considered. An additional search was conducted on the database from the beginning of indexing up to September 2024 to include ongoing studies. Quality control and bias assessment were performed. Primary outcomes focused on acupuncture's efficacy and safety versus pharmacological treatments in reducing migraine frequency and intensity. The impact on patients' quality of life was also evaluated.

Results

At the end of the selection process, 15 studies were eligible. Acupuncture showed no statistically significant difference as a prophylactic treatment for migraine in reducing the frequency of migraine days or pain intensity but did reduce the use of analgesics while improving patients' quality of life.

Conclusion

Current evidence supports acupuncture as an adjunctive therapy in migraine prophylaxis, but challenges such as protocol heterogeneity, dropout biases, the complexities of sham‐controlled trials, and the lack of comparison data with newer innovative treatments not yet considered warrant further research.

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Authors:
Francesca Pistoia, Simone Cesarano, Gennaro Saporito, Maria Albanese, Cecilia Lucenti, Secondo Scarsella, Aldo Liguori and Federica Umani Ronchi

Article first published online:
16 Apr 2025 | DOI: 10.1111/ene.70160

LETTER TO THE EDITOR

Homogeneous ALS Cohorts in Terms of Etiology, onset type, and Vaccination Status Are Required to Assess the Outcome of Their COVID Infection

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Authors:
Josef Finsterer

Article first published online:
21 Apr 2025 | DOI: 10.1111/ene.70161

LETTER TO THE EDITOR

In Response to “Homogeneous ALS Cohorts in Terms of Etiology, Onset Type and Vaccination Status Are Required to Assess the Outcome of Their COVID Infection”

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Authors:
Pilar H. García‐Casanova, Pablo Pérez‐Martínez, Teresa Sevilla, Rosalía Doménech, Montserrat León and Juan F. Vázquez‐Costa

Article first published online:
21 Apr 2025 | DOI: 10.1111/ene.70162

ORIGINAL ARTICLE

Real‐World Dual Antiplatelet Therapy Use Exceeds Randomized Trials Boundaries With Possible Safety Issues in Patients With Large Artery Atherosclerosis—Insights From the READAPT Study

Background and Aim

According to randomized controlled trials (RCTs), dual antiplatelet therapy (DAPT) is more effective for secondary prevention of ischemic events attributable to large artery atherosclerosis (LAA) than other mechanisms. We investigated whether real‐world application may impact DAPT effectiveness and safety in the REAl‐life study on short‐term Dual Antiplatelet treatment in Patients with ischemic stroke or Transient ischemic attack (READAPT, NCT05476081).

Methods

READAPT was an observational multicenter study including patients with minor ischemic stroke or TIA treated with short‐term DAPT. At 90 days, we assessed primary effectiveness (ischemic recurrence, severe bleeding, or vascular death) and safety (severe to moderate bleeding) outcomes. We explored associations between LAA and outcomes using Cox regression. Within patients with and without LAA, outcomes were compared between subgroups based on age, NIHSS score (for ischemic stroke patients), ABCD score (for TIA patients), presence and number of MRI acute lesions, and DAPT regimen characteristics.

Results

Among 1920 analyzed patients (of 2278 enrolled), 452 had LAA. Unlike RCTs, 21.2% of patients with LAA had NIHSS > 5, and 48.2% received DAPT > 30 days. Patients with LAA had higher bleeding rates (3.5% vs. 2.1%, = 0.004), primarily hemorrhagic infarctions and moderate bleeding, than those without LAA. However, primary effectiveness outcomes were similar (4.9% vs. 3.5%, = 0.201) between the groups. In patients with LAA, prolonged DAPT (> 21 days), multiple MRI lesions, age ≥ 65, and loading doses increased bleeding risk.

Conclusions

The real‐world DAPT use in patients with LAA exceeds RCTs boundaries with possible drawbacks on treatment safety.

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Authors:
Eleonora De Matteis, Federico De Santis, Matteo Foschi, Michele Romoli, Tiziana Tassinari, Valentina Saia, Silvia Cenciarelli, Chiara Bedetti, Chiara Padiglioni, Bruno Censori, Valentina Puglisi, Luisa Vinciguerra, Maria Guarino, Valentina Barone, Marialuisa Zedde, Ilaria Grisendi, Ilaria Maestrini, Maria Rosaria Bagnato, Marco Petruzzellis, Domenico Maria Mezzapesa, Pietro Di Viesti, Vincenzo Inchingolo, Manuel Cappellari, Mara Zenorini, Paolo Candelaresi, Vincenzo Andreone, Giuseppe Rinaldi, Alessandra Bavaro, Anna Cavallini, Stefan Moraru, Maria Grazia Piscaglia, Valeria Terruso, Marina Mannino, Alessandro Pezzini, Giovanni Frisullo, Francesco Muscia, Maurizio Paciaroni, Maria Giulia Mosconi, Andrea Zini, Ruggiero Leone, Carmela Palmieri, Letizia Maria Cupini, Michela Marcon, Rossana Tassi, Enzo Sanzaro, Cristina Paci, Giovanna Viticchi, Daniele Orsucci, Anne Falcou, Susanna Diamanti, Roberto Tarletti, Patrizia Nencini, Eugenia Rota, Federica Nicoletta Sepe, Delfina Ferrandi, Luigi Caputi, Gino Volpi, Salvatore La Spada, Mario Beccia, Claudia Rinaldi, Vincenzo Mastrangelo, Francesco Di Blasio, Paolo Invernizzi, Giuseppe Pelliccioni, Maria Vittoria De Angelis, Laura Bonanni, Giampietro Ruzza, Emanuele Alessandro Caggia, Monia Russo, Agnese Tonon, Maria Cristina Acciarri, Sabrina Anticoli, Cinzia Roberti, Giovanni Manobianca, Gaspare Scaglione, Francesca Pistoia, Alberto Fortini, Antonella De Boni, Alessandra Sanna, Alberto Chiti, Leonardo Barbarini, Marcella Caggiula, Maela Masato, Massimo Del Sette, Francesco Passarelli, Maria Roberta Bongioanni, Danilo Toni, Stefano Ricci, Simona Sacco, Raffaele Ornello, Maurizio Acampa, Maria Cristina Acciarri, Paola Ajdinaj, Sergio Altomare, Chiara Alessi, Vincenzo Andreone, Stefania Martina Angelocola, Sabrina Anticoli, Federica Assenza, Maria Rosaria Bagnato, Leonardo Barbarini, Chiara Bassi, Valentina Barone, Maraia Cristina Baruffi, Alessandra Bavaro, Mario Beccia, Chiara Bedetti, Simone Bellavia, Simone Beretta, Giorgia Bernabè, Leonardo Biscetti, Novella Bonaffini, Laura Bonanni, Maria Roberta Bongioanni, Gian Luca Bruzzone, Martina Caccamo, Marcella Caggiula, Valentina Cameriere, Paolo Candelaresi, Alessandro Canessa, Luigi Caputi, Nicoletta Giuseppa Caracciolo, Patrizio Cardinali, Anna Cavallini, Emanuele Alessandro Caggia, Roberto Cappellani, Manuel Cappellari, Silvia Cenciarelli, Bruno Censori, Alberto Chiti, Letizia Maria Cupini, Maria Vittoria De Angelis, Antonella De Boni, Chiara De Fino, Cristina De Luca, Antonio De Mase, Eleonora De Matteis, Manuela De Michele, Federico De Santis, Massimo Del Sette, Francesco Di Blasio, Ivo Giuseppe De Franco, Anna Di Giovanni, Filomena Di Lisi, Pietro Di Viesti, Susanna Diamanti, Marina Diomedi, Anna Falcou, Claudia Faini, Ciro Alberto Fasolino, Delfina Ferrandi, Carlo Ferrarese, Thomas Fleetwood, Alberto Fortini, Matteo Foschi, Giovanni Matteo Fratta, Giovanni Frisullo, Antonio Genovese, Serena Gallo Cassarino, Debora Galotto, Maurizio Giorelli, Alessia Giossi, Ilaria Grisendi, Maria Guarino, Vincenzo Inchingolo, Paolo Invernizzi, Salvatore La Spada, Ruggiero Leone, Federica Letteri, Enrico Maria Lotti, Ilaria Maestrini, Marina Mannino, Giovanni Manobianca, Michela Marcon, Maela Masato, Vincenzo Mastrangelo, Chiara Menichetti, Elisabetta Menegazzo, Domenico Maria Mezzapesa, Daniela Monaco, Stefan Moraru, Maria Giulia Mosconi, Francesco Muscia, Federica Naldi, Serena Nannucci, Patrizia Nencini, Raffaele Ornello, Daniele Orsucci, Cristina Paci, Maurizio Paciaroni, Chiara Padiglioni, Carmela Palmieri, Silvia Paolucci, Giulio Papiri, Rosario Pascarella, Francesco Passarelli, Giuseppe Pelliccioni, Francesco Perini, Marco Petruzzellis, Francesca Pistoia, Eleonora Potente, Emanuele Puca, Valentina Puglisi, Pietro Querzani, Stefano Ricci, Maria Chiara Ricciardi, Claudia Rinaldi, Giuseppe Rinaldi, Annalisa Rizzo, Cinzia Roberti, Michele Romoli, Eugenia Rota, Monia Russo, Giampietro Ruzza, Elisa Sacchini, Simona Sacco, Valentina Saia, Alessandra Sanna, Enzo Sanzaro, Davide Sassos, Gaspare Scaglione, Irene Scala, Alessandro Pezzini, Eleonora Sgarlata, Emanuele Spina, Roberto Tarletti, Rossana Tassi, Tiziana Tassinari, Valeria Terruso, Pierluigi Tocco, Danilo Toni, Agnese Tonon, Laura Tudisco, Martina Valente, Maria Grazia Vittorini, Gloria Valcamonica, Luisa Vinciguerra, Marco Vista, Giovanna Viticchi, Gino Volpi, Marialuisa Zedde, Mara Zenorini, Andrea Zini, Cecilia Zivelonghi and Antonio Zito

Article first published online:
23 Apr 2025 | DOI: 10.1111/ene.70163

ORIGINAL ARTICLE

Faster Decay of Cerebrospinal Fluid Red Blood Cells and Total Protein Predict Good Functional Outcome After Subarachnoid Hemorrhage

Introduction

Prognostication after subarachnoid hemorrhage (SAH) is essential to guide clinical management and improve patient care.

Objective

To investigate whether decay rates of cerebrospinal fluid (CSF) red blood cells (RBC) and total protein (TP) after SAH predict functional outcome at 3 months.

Methods

Patients with SAH treated at the Neurological Intensive Care Unit Innsbruck with a first CSF sample (CSFfirst) within 72 h after admission and at least one subsequent sample were eligible for inclusion. Decay rates of RBC and TP were measured between CSFfirst and each subsequent measurement (Weeks 1–3). Modified Rankin Scale scores at 3 months ≤ 2 were defined as good functional outcomes.

Results

A total of 97 patients with a median age of 61 years [25th; 75th percentile: 52;71] and a median Hunt and Hess score of 4 [3;5] were included. Daily RBC decay rates decreased over time, while daily TP decay rates were highest in Week 1, showed a nadir in Week 2, and increased again in Week 3. In multivariable analysis, higher RBC (adjusted odds ratio (adjOR): 1.13, 95% confidence interval (95% CI): 1.02–1.26, = 0.025) and TP (adjOR: 1.01, 95% CI: 1.00–1.01, = 0.031) decay rates at Week 3 predicted a good functional outcome at Month 3. RBC and TP decreasing below 1180 cells/μL and 127.5 mg/dL, respectively, at Week 3 were associated with good functional outcome at Month 3 (adjOR: 11.04, 95% CI: 3.21–38.02, < 0.001 and 6.03, 1.68–21.67, = 0.006).

Conclusions

Decay rates of CSF RBC and TP after SAH are associated with functional outcomes.

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Authors:
Anna Berek, Klaus Berek, Philipp Kindl, Franziska Di Pauli, Alois J. Schiefecker, Bettina Pfausler, Raimund Helbok, Florian Deisenhammer, Ronny Beer, Harald Hegen and Verena Rass

Article first published online:
24 Apr 2025 | DOI: 10.1111/ene.70164

ORIGINAL ARTICLE

High Agreement Across Laboratories Between Different Alpha‐Synuclein Seed Amplification Protocols

Background

Seed amplification assays (SAA) detect alpha‐synuclein (aSYN) pathology in patient biomatrices such as cerebrospinal fluid (CSF)—potentially even before clinical manifestations. As CSF‐based SAA are approaching broader use in clinical trials and research, ensuring that different laboratories obtain the same results becomes increasingly important.

Methods

In this cross‐laboratory, cross‐aSYN‐recombinant substrate and cross‐protocol round‐robin test, we compared SAA results from a common set of 38 CSF samples measured independently in four research laboratories of the German Center for Neurodegenerative diseases. Three laboratories (A–C) used an assay protocol adapted from Parchi's group at ISNB (Bologna, Italy); laboratory D used an assay protocol adapted from Amprion Inc. Two different manufacturers of aSYN protein were used as substrates for the SAA reaction.

Results

Qualitative results were identical in at least three of the four laboratories for 37 out of 38 samples (20 positive, 17 negative). Fleiss Kappa for all four laboratories was 0.751 ( = 12, < 0.001). For each laboratory, agreement with laboratory A was > 92%. For the number of positive replicates, Fleiss Kappa was 0.45 for a score of zero positive replicates and 0.42 for a score of four positive replicates.

Conclusions

The qualitative SAA results showed a high level of agreement across research laboratories, aSYN monomers, and assay protocols. Small differences between laboratories were systematic, consistent with the notion that SAA reports biologically relevant properties. These results also underline that round‐robin tests can be helpful in assessing and ensuring SAA quality across laboratories.

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Authors:
Stefan Bräuer, Maximilian Weber, Christian Deuschle, Kühlwein Julia, Luis Concha‐Marambio, Alexander M. Bernhardt, Vaibhavi Kadam, David Mengel, Wolfgang P. Ruf, Jan Kassubek, Iñaki Schniewind, Sandra Kuhs, Marcello Rossi, Piero Parchi, Johannes Levin, Karin M. Danzer, Matthis Synofzik, Kathrin Brockmann and Björn H. Falkenburger

Article first published online:
16 Apr 2025 | DOI: 10.1111/ene.70165

ORIGINAL ARTICLE

Intraepineurial Fat Fraction: A Novel MR Neurography‐Based Biomarker in Transthyretin Amyloidosis Polyneuropathy

Introduction

Hereditary transthyretin amyloid polyneuropathy (ATTRv‐PN) is a rare and progressive neurodegenerative disorder characterized by axonal neuropathy and amyloid deposits. Early detection of disease onset and progression is crucial for timely therapeutic intervention. Quantitative MRI (qMRI) can be used to measure potential biomarkers. Intraepineurial fat fraction (ieFF) may reflect lipid droplets in amyloid deposits as described in histological studies or the replacement of nerve fiber loss with fatty‐rich interfascicular epineurium. This study investigates the potential utility of ieFF as a novel imaging‐related biomarker in differentiating ATTRv‐PN, asymptomatic carriers (ATTRv‐C), and healthy controls (HCs).

Methods

Fifty‐three patients with TTR mutations were imaged (31 ATTRv‐PN patients, 22 ATTRv‐C, and 24 HC) and both clinical and electrophysiological parameters were quantified. 3D volume, ieFF, and magnetization transfer ratio (MTR) were quantified in sciatic and tibial nerves using qMRI.

Results

Symptomatic ATTRv‐PN patients exhibited significantly higher ieFF in both sciatic (32.4% IQR [24.4–38.1]) and tibial nerves (13.7%, IQR [9.97–20.7]) compared to controls (sciatic 22.3%, IQR [16.6–28.5]; tibial 9.74%, IQR [6.36–12.5]) ( < 0.05). ieFF values were positively correlated in both uni and multivariate analyses with the main clinical scores and electrophysiological measures. ATTRv‐C also showed increased ieFF values compared to controls ( < 0.05). Comparatively, MTR and nerve volumes exhibited less pronounced differences across groups.

Conclusion

This study demonstrates that ieFF effectively differentiates symptomatic and asymptomatic ATTRv patients from HC and correlates strongly with electrophysiological and clinical severity parameters. Furthermore, we compare ieFF with conventional qMRI biomarkers, highlighting its superior potential for monitoring nerve structural impairment.

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Authors:
Eva Sole Cruz, Etienne Fortanier, Constance P. Michel, Emilien Delmont, Annie Verschueren, Marc‐Adrien Hostin, David Bendahan and Shahram Attarian

Article first published online:
21 Apr 2025 | DOI: 10.1111/ene.70168

ORIGINAL ARTICLE

The Many Faces of REM Sleep Behavior Disorder. Providing Evidence for a New Lexicon

Background

People with idiopathic/isolated REM sleep behavior disorder (iRBD) are highly heterogeneous, showing mild motor, cognitive, and dysautonomia symptoms. The aim of this study is to unveil the clinical heterogeneity of iRBD with a specific reference to overlapping features with prodromal Parkinson's disease (pPD) and prodromal dementia with Lewy bodies (pDLB) labels.

Methods

People with a polysomnography‐confirmed diagnosis of iRBD were enrolled and followed over time. At baseline, pPD and pDLB criteria were assessed.

Results

Among the 285 iRBD people (68.2 ± 7.6 years, 81% males), due to additional signs or symptoms, 49.8% fulfilled pPD criteria only, 5.6% pDLB criteria only, and 14.4% subjects fulfilled both pPD and pDLB criteria. Conversely, about one third of iRBD people (30.2%) did not meet either pPD or pDLB criteria. At follow‐up (40.6 ± 43.6 months), 28.8% subjects phenoconverted, developing PD (56.1%), DLB (39%), or multiple system atrophy (4.9%). Subjects with iRBD fulfilling either pPD or pDLB criteria, or both, have an increased risk of phenoconversion (adjusted hazard ratio, aHR 2.34, 95% confidence interval, CI 1.24–4.41). On the opposite, subjects not fulfilling prodromal criteria have a significantly reduced short‐term phenoconversion likelihood (aHR 0.43, 95% CI 0.23–0.81). Notably, pPD and pDLB criteria did not predict PD and DLB diagnoses, respectively.

Conclusions

People with iRBD are highly heterogeneous, and the presence of other concomitant signs and symptoms is frequent, leading to faster phenoconversion. Thus, the terms idiopathic and isolated may be poorly appropriate and possibly even confounding. These results pave the way to a more appropriate new lexicon for people with RBD.

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Authors:
Dario Arnaldi, Pietro Mattioli, Beatrice Orso, Federico Massa, Matteo Pardini, Silvia Morbelli, Flavio Nobili, Michela Figorilli, Elisa Casaglia, Martina Mulas, Michele Terzaghi, Elena Capriglia, Gaetano Malomo, Michela Solbiati, Elena Antelmi, Fabio Pizza, Francesco Biscarini, Monica Puligheddu and Giuseppe Plazzi

Article first published online:
21 Apr 2025 | DOI: 10.1111/ene.70169

ORIGINAL ARTICLE

Quantitative MRI Assessment Using Variable Echo Time Imaging of Peripheral Nerve Injury in ATTRv Amyloidosis Patients

Background and Purpose

Early detection of peripheral nerve damage in patients with hereditary transthyretin amyloidosis (ATTRv) has become essential for the prompt initiation of effective, recently approved therapies. In our study, we propose a new variable echo time (vTE) MRI sequence as a non‐invasive method to detect nerve injury in ATTRv patients and to establish a novel potential imaging marker of neuropathy that correlates with disease severity and abnormal results of NCS.

Methods

In this cohort study, twenty patients with clinically confirmed ATTRv polyneuropathy (PNP) and twenty‐one healthy volunteers underwent 3 T MRI. vTE was performed on the right thigh to include the proximal tract of the sciatic nerve. The cross‐sectional area of the whole sciatic nerve, inner epineurium, and endoneurial fascicles was segmented, and the corresponding pseudo‐T2* was extrapolated from the two acquired echoes of the vTE.

Results

Significantly higher fascicles pT2* ( = < 0.001), total cross‐sectional area (CSA: = 0.017) and fascicular area ( = < 0.001) were found in the ATTRv group compared to healthy controls. Fascicles pT2* also correlated with previously validated clinical outcome measures such as Polyneuropathy Disability Scoring System (PND score = < 0. 001), Neuropathy Impairment Score (NIS = 0.030) and NIS items related to the lower limbs, and with nerve conduction parameters, demonstrating the ability to discriminate ATTRv patients with different degrees of PNP from HC.

Conclusion

In conclusion, the vTE sequence provides novel and reliable imaging markers capable of detecting early nerve microstructural changes related to disease onset and severity.

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Authors:
Carlo Asteggiano, Matteo Paoletti, Elisa Vegezzi, Xeni Deligianni, Francesco Santini, Niels Bergsland, Nico Papinutto, Massimiliano Todisco, Giuseppe Cosentino, Andrea Cortese, Laura Obici, Giovanni Palladini and Anna Pichiecchio

Article first published online:
23 Apr 2025 | DOI: 10.1111/ene.70172

ORIGINAL ARTICLE

Primary Neurolymphomatosis: A Literature Review

Background

Primary neurolymphomatosis (PNL) is a rare clinical entity resulting from direct lymphomatous infiltration into the peripheral nervous system. Its diagnosis is challenging as the hematological condition is unknown at the onset of neurological symptoms.

Methods

We report two of our own cases and the first extensive review of published cases of PNL to delineate its clinical features, paraclinical investigation results, progression, and treatment response more precisely. We extracted demographic data, clinical presentation, results of the investigations performed, type and number of treatments, overall survival, and progression‐free survival.

Results

We describe 301 cases of PNL in patients with a mean age of 57.9 years, 61% of whom were men. The most common clinical presentation was an often painless asymmetric neuropathy. Other presentations included multifocal neuropathy preferentially affecting the sciatic and peroneal nerves, radiculopathy, brachial plexus lesions, cauda equina syndrome, and cranial nerve palsy. Systemic signs and deterioration of clinical status were uncommon.

Conclusions

This literature review provides an overview of the available data concerning PNL presentation and progression.

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Authors:
Sahar Chakroun, Alice Faucher, Antoine Gueguen, Jehane Fadlallah, Emilie Corvilain, Nathalie Kubis and Pierre Lozeron

Article first published online:
23 Apr 2025 | DOI: 10.1111/ene.70173

European Journal of Neurology

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LETTER TO THE EDITOR

Letter to the Editor: ‘Causes of Hospitalisation and Mortality in Persons With Epilepsy: The EpiLink Bologna Cohort, Italy’

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