cover image European Journal of Neurology

European Journal of Neurology

2025 - Volume 32
Issue 10 | October 2025
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ISSUE INFORMATION

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Article first published online:
29 Sep 2025 | DOI: 10.1111/ene.16360

SHORT COMMUNICATION

Introduction

Amyloid related imaging abnormalities effusion/edema (ARIA‐E) is seen in patients treated with antiamyloid antibodies. It resembles cerebral amyloid angiopathy (CAA) related inflammation (CAA‐ri) caused by an inflammatory response to amyloid deposition in the walls of cortical and leptomeningeal vessels in patients with sporadic CAA. Recently, temporary inflammatory imaging findings that remained clinically silent have been described in patients with iatrogenic CAA (iCAA).

Results

We describe a case of probable iatrogenic CAA (iCAA), which demonstrated radiological features of CAA‐ri that remained clinically silent and spontaneously resolved before the inaugural intracranial hemorrhage. Clinical and radiological features resembled ARIA‐E.

Discussion

This case adds to the clinical and radiological spectrum of iCAA and suggests an immune‐mediated response to amyloid deposition.

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Authors:
Ulf Jensen‐Kondering, Gregor Kuhlenbäumer and Nils G. Margraf
Article first published online:
21 Oct 2025 | DOI: 10.1111/ene.70298

REVIEW ARTICLE

Background

Moyamoya angiopathy (MMA) is a rare, progressive cerebrovascular disorder characterized by stenosis or occlusion of the terminal internal carotid arteries, leading to the development of fragile collateral vessels. Headache is a common but understudied symptom of MMA, reported in up to 75% of patients. The headache phenotype often mimics migraine or tension‐type headache, although cluster headache‐like episodes have also been described. Aims to summarize current evidence on the clinical characteristics, underlying mechanisms, and treatment strategies for headache in MMA.

Materials and Methods

A narrative review of the literature was conducted, focusing on the prevalence, phenotype, pathophysiological mechanisms, and therapeutic options for headache in MMA.

Results

The pathogenesis of headache in MMA remains unclear but is likely multifactorial, involving impaired cerebrovascular autoregulation, microvascular ischemia, and collateral vessel development. No standardized treatment exists for MMA‐related headache. Antiplatelet therapy, particularly aspirin, may offer some benefit, whereas NSAIDs and triptans require caution due to cerebrovascular risks. Emerging therapies such as calcitonin gene‐related peptide (CGRP) inhibitors and Lasmiditan show potential but lack specific data in MMA patients. Surgical revascularization, mainly through direct or combined bypass, is an established intervention for stroke prevention and may also reduce headache burden. However, postoperative outcomes are heterogeneous, with reports of both headache improvement and new‐onset headache.

Discussion and Conclusion

Headache is a frequent and clinically relevant manifestation of MMA that significantly impacts quality of life. Evidence on optimal management remains scarce, and current strategies are largely empirical. Further studies are needed to clarify pathogenic mechanisms, refine patient selection for surgical interventions, and evaluate pharmacological treatments, including novel agents, to improve clinical outcomes.

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Authors:
Nicola Rifino, Anne Hege Aamodt, Markus Wiedmann, Markus Kramer, Jana Becker, Stéphanie Guey, Francesco Acerbi, Dominique Herve and Anna Bersano
Article first published online:
02 Oct 2025 | DOI: 10.1111/ene.70316

ORIGINAL ARTICLE

Background and Objectives

Camptocormia, a pathological forward flexion of the spine, is a relatively common but often unexplained postural abnormality. Facioscapulohumeral muscular dystrophy (FSHD), one of the most prevalent adult myopathies, is caused by a contraction of D4Z4 repeats on chromosome 4 and typically presents with facial, scapular, and lower limb weakness. However, atypical phenotypes are increasingly recognized. We investigated camptocormia as a presenting feature of FSHD in a large neuromuscular cohort.

Methods

This cross‐sectional study assessed clinical, genetic, and muscle imaging features in patients with FSHD presenting with camptocormia and compared them to patients with typical FSHD.

Results

Among 87 patients with genetically confirmed FSHD, 8 (9.1%) had camptocormia as the predominant and initial manifestation. FSHD also accounted for 47% (8/17) of all cases of camptocormia due to axial myopathy. Compared to classical FSHD, camptocormic patients exhibited later disease onset, moderately contracted D4Z4 repeats, and marked axial involvement, with predominant spinal extensor weakness and relatively preserved abdominal strength. Muscle MRI revealed more severe paravertebral involvement and milder serratus anterior involvement than typically observed in FSHD.

Conclusions

Camptocormia represents a relatively frequent and distinct phenotypic variant of FSHD, particularly in older adults. Conversely, FSHD is a common cause of camptocormia due to axial myopathy. These findings expand the clinical spectrum of FSHD and underscore the importance of considering FSHD in the differential diagnosis of camptocormia, even in the absence of typical clinical signs of FSHD. Muscle imaging may assist in identifying FSHD‐associated camptocormia.

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Authors:
Eleonora Torchia, Patrick Vandeputte, Mauro Monforte, Charlène Gillet, Christophe Verny, Rafaelle Bernard, Giorgio Tasca and Marco Spinazzi
Article first published online:
02 Oct 2025 | DOI: 10.1111/ene.70332

ORIGINAL ARTICLE

Background and Purpose

Titin is critical for sarcomere structure and function, and mutations in this gene cause titinopathies, a group of neuromuscular disorders. Muscle MRI is a key tool for diagnosing and understanding these conditions. This study aims to compare the muscle involvement patterns in two autosomal dominant, adult‐onset titinopathies: Tibial Muscular Dystrophy (TMD) and Hereditary Myopathy with Early Respiratory Failure (HMERF).

Methods

In this multicenter, cross‐sectional study, lower limb MRI scans were analyzed for 17 patients with TMD and 15 with HMERF. Clinical and demographic data were collected from medical records. Muscle fat replacement was assessed using a modified Mercuri score for 30 muscles per patient. Two independent evaluators reviewed the images. Heatmaps were used to visualize asymmetry and patterns of fat replacement. Statistical analysis included Cliff's delta and random forests to distinguish muscle involvement between TMD and HMERF, and Spearman's rho to explore correlations between fat replacement and disease duration.

Results

HMERF showed extensive, severe fat replacement, particularly in muscles like the semitendinosus, obturator externus, and gluteus minimus, with distinct intramuscular patterns. In contrast, TMD presented more localized fat replacement, primarily affecting the tibialis anterior and extensor digitorum longus. Both conditions exhibited mixed patterns of muscle replacement and preservation. Random forests confirmed differential muscle involvement, and fat replacement correlated with disease duration more strongly in HMERF than in TMD.

Conclusions

This systematic MRI analysis reveals distinct muscle involvement patterns in TMD and HMERF, providing insights into the differential progression of these titinopathies.

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Authors:
David Gómez‐Andrés, Laura Costa‐Comellas, Jordi Díaz‐Manera, Katrin Õunap, Mireia Álvarez‐Molinero, Gabriela Urcuyo, Marco Savarese, Francina Munell and Bjarne Udd
Article first published online:
30 Sep 2025 | DOI: 10.1111/ene.70348

REVIEW ARTICLE

Abstract

Hereditary choreas are a clinically and genetically heterogeneous group of monogenic disorders in which chorea constitutes the core or an early‐dominant feature. These conditions result from various genetic mutations affecting the structures and pathways involved in movement control, primarily the caudate and putamen, ultimately impairing the basal ganglia circuits involved in the regulation of movement, cognition, and behavior. This review focuses on the main forms of hereditary choreas, including Huntington's disease, neuroacanthocytosis syndromes, Huntington's disease phenocopies, benign hereditary chorea, and other less common genetic disorders presenting with chorea. We discuss the clinical, genetic, and pathophysiological features of each condition, alongside key aspects of phenomenology, examination, and complementary tests—including laboratory findings—to guide phenotype‐driven genetic testing. We detail the characteristic features of key disorders while also highlighting less common but emerging conditions. This review aims to assist neurologists in recognizing and diagnosing hereditary choreas efficiently, including guidance on the selection of appropriate genetic tests, thereby reducing diagnostic delays, informing accurate counseling, and facilitating access to disease‐specific interventions and clinical trials.

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Authors:
Jesús Pérez‐Pérez, Gonzalo Olmedo‐Saura, Saül Martínez‐Horta, Sara Bernal, Javier Pagonabarraga and Jaime Kulisevsky
Article first published online:
17 Oct 2025 | DOI: 10.1111/ene.70357

ORIGINAL ARTICLE

Background and Objectives

Recognition of autoimmune encephalitis (AIE) can be difficult as typical radiological or cerebrospinal fluid abnormalities may be lacking. We investigated the yield of comprehensive diagnostic testing for anti‐neuronal antibodies in patients suspected of encephalitis in an acute setting.

Methods

In a prospective multicenter cohort, we included patients suspected of encephalitis in whom a lumbar puncture was performed. We retrospectively selected patients from this cohort in whom no infectious cause was identified and an autoimmune CNS disease was considered. Immunohistochemistry was performed on the CSF samples as an index test to screen for anti‐neuronal antibodies, and confirmatory cell‐based assays were performed.

Results

Between 2017 and 2021, 723 episodes were included in 707 patients. The median age was 55 years, and 347 (48%) of the episodes occurred in women. In 59 of 723 episodes (8%), a clinical diagnosis of autoimmune CNS disease was made. Twenty‐three (3%) of them fulfilled the diagnostic criteria for possible AIE, and 9 (1%) had antibody‐positive AIE (five anti‐NMDAR encephalitis, two anti‐LGi1 encephalitis, one anti‐Ma2 encephalitis and anti‐CV2 encephalitis). Extensive antibody testing identified no additional anti‐neuronal antibodies in the remaining 47 episodes.

Discussion

In a cohort of patients with a suspected encephalitis presenting in an acute setting, the incidence of possible AIE was low, and in only one‐third of possible AIE episodes an anti‐neuronal antibody was detected. Anti‐neuronal antibody testing beyond what was done in the clinical setting did not yield additional cases of antibody‐positive AIE.

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Authors:
Liora ter Horst, Juliette Brenner, Ingeborg E. van Zeggeren, Diederik van de Beek, Maarten J. Titulaer, Matthijs C. Brouwer, J. Citroen, B. M. van Geel, S. G. B. Heckenberg, K. Jellema, M. I. Kester, J. Killestein, B. B. Mook, Y. C. Resok and K. E. B. van Veen
Article first published online:
10 Oct 2025 | DOI: 10.1111/ene.70359

ORIGINAL ARTICLE

Background

The definition of conduction block (CB) is variable in multifocal motor neuropathy (MMN). In current criteria, excessive temporal dispersion (TD) may preclude the recognition of CB and the diagnosis of MMN.

Methods

We retrospectively studied the electrophysiological data of 47 consecutive subjects with MMN and of 69 consecutive controls with upper limb‐onset motor neuron disease, from three neuromuscular centres in the United Kingdom and Korea.

Results

Compared to CB defined by compound muscle action potential (CMAP) area reduction (CB‐Area) > 30%, CB defined by CMAP amplitude reduction (CB‐amp) > 30% was more sensitive (78.7% vs. 63.8%; McNemar's Test:  = 0.008), but less specific versus controls (90.1% vs. 96.7%; McNemar's Test:  = 0.001). CB‐amp > 30% offered greater diagnostic accuracy than CB‐Area > 30% (Youden's Index: 0.688 vs. 0.606). TD showed a sensitivity of 59.6% and specificity of 94.3%. F‐wave prolongation or absence showed a sensitivity of 42.6% and specificity of 96.9%. Considering CB‐amp > 30% or TD or F‐wave prolongation or absence, as independent electrodiagnostic markers of MMN, improved diagnostic sensitivity from 78.7% to 91.5% compared to CB‐amp > 30% alone (McNemar's Test:  = 0.031), also offering optimal accuracy (Youden's Index: 0.816). Within this three‐parameter combination, CB defined by CMAP amplitude reduction > 30% offered similar sensitivity, specificity and accuracy to when defined by CMAP amplitude reduction > 50%.

Conclusions

CB‐amp has higher sensitivity and accuracy than CB‐Area for the electrodiagnosis of MMN. Consideration of TD or F‐wave prolongation or absence, as independently diagnostic of MMN, in addition to CB‐amp > 30% alone, may improve electrophysiological sensitivity as well as accuracy.

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Authors:
Yusuf A. Rajabally, Young Gi Min, Ahmad Al‐Areed, Woohee Ju, Ramamurthy Arunachalam, Jung‐Joon Sung and Chinar Osman
Article first published online:
02 Oct 2025 | DOI: 10.1111/ene.70361

ORIGINAL ARTICLE

Background

Distinct angiographic characteristics may explain clinical differences between European and East Asian MMD cohorts. This study aimed to investigate this hypothesis and explore angiographic risk factors for stroke within a Danish nationwide cohort.

Methods

We reviewed radiologic studies within a nationwide cohort of patients diagnosed with MMD from 13 clinical departments across six hospitals in Denmark between 1994 and 2017. We followed these patients until 2023, investigating angiographic progression and risk factors for stroke.

Results

The cohort comprised 50 patients (33 females and 17 males). Radiographic films were retrieved from 43 patients. Twenty patients were followed with DSA and 35 patients with MRA; the latter with a median interval of 4 years between the first and most recent investigations. Twelve (24%) and 38 (76%) patients had unilateral and bilateral MMD. In 90% of cases, the ICA was involved in the stenotic changes. 34% of cases showed angiographic progression, and one case progressed from unilateral to bilateral MMD (8%). Chronic ischaemic lesions were seen in 93% of patients. There was a trend towards a higher stroke risk in patients with angiographic progression (25% vs. 13%,  = 0.66), and no statistical difference in stroke risk between patients with uni‐ and bilateral MMD (HR 0.98, 95% CI 0.20–4.78).

Conclusions

Our findings do not support the assertion of a distinct European MMD variety. Among the risk factors explored, there was a trend towards a higher stroke risk in patients with angiographic progression.

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Authors:
Peter Birkeland, Jesper Kelsen, Anabel Diaz, Jens Lauritsen, Paul von Weitzel‐Mudersbach and Sanja Karabegovic
Article first published online:
30 Sep 2025 | DOI: 10.1111/ene.70364

ORIGINAL ARTICLE

Background

While structural and functional connectivity changes in multiple sclerosis (MS) are well documented, their complex interplay remains poorly understood. This study identifies co‐fluctuating patterns of structural and functional changes in MS using an MRI‐based multimodal fusion approach and assesses the added value to clinical outcomes.

Methods

Linked independent component analysis (ICA) was applied to spatial maps of white matter (WM) lesions, fractional anisotropy (FA), gray matter (GM) volume, and functional network connectivity to detect regions with differential co‐fluctuations. Graph theory (GT) was then used to reveal clusters of interconnected brain regions. Linear mixed‐effect models targeted regions with significantly different co‐fluctuating patterns between MS and HC. Multivariate stepwise regressions analyzed the associations between co‐fluctuating patterns and disability and cognitive dysfunction.

Results

The study included 147 patients with MS and 57 HC. Significant co‐fluctuating patterns of decreased FA, increased lesion probability in the thalamic radiation and corpus callosum, GM atrophy in sensorimotor and thalamic areas, and enhanced functional connectivity in the temporal parietal network distinguished MS from HC ( < 0.001). GT revealed eight brain sub‐networks of spatially connected clusters. Regional‐ and modality‐specific loadings and GT changes explained physical (adjusted  = 0.51,  < 0.001) and cognitive (adjusted  = 0.44,  < 0.001) disability better than traditional MRI measures (adjusted  = 0.12–0.33,  < 0.001).

Conclusions

Our multimodal MRI approach revealed co‐fluctuating regional patterns of lesions, structural disconnection, and functional hyperconnectivity in MS, offering a more comprehensive explanation of clinical outcomes than traditional MRI metrics.

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Authors:
Jian Zhang, Marco Battaglini, Rosa Cortese, Maria Laura Stromillo, Marzia Mortilla, Ludovico Luchetti, Giordano Gentile, Emilio Portaccio, Maria Pia Amato, Menno M. Schoonheim and Nicola De Stefano
Article first published online:
29 Sep 2025 | DOI: 10.1111/ene.70367

LETTER TO THE EDITOR

Treating Sight Threatening Papilloedema in Idiopathic Intracranial Hypertension: Temporary Versus Permanent Intervention

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Authors:
Gabriele Berman, Michael Lowe, Georgios Tsermoulas and Susan P. Mollan
Article first published online:
02 Oct 2025 | DOI: 10.1111/ene.70370

LETTER TO THE EDITOR

Renal Cell Carcinoma With Unknown Primary in the Femur: The Loch Ness Monster?

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Authors:
Mustafa Güngör Albayrak, Berkay Yalçınkaya, Ahmet Furkan Çolak, Ebrar Yazıcı and Alp Çetin
Article first published online:
06 Oct 2025 | DOI: 10.1111/ene.70371

ORIGINAL ARTICLE

Background

Functional movement disorders (FMDs) are common within functional neurological disorders, yet understudied in Asian populations, particularly in China. Understanding FMDs across diverse cultural and ethnic contexts is crucial for elucidating disease mechanisms and optimizing treatment strategies. This study aimed to characterize FMDs among Chinese Han individuals and identify key prognostic factors.

Methods

We enrolled 119 FMD patients from 22 centers across China. Data collected included demographics, clinical manifestations, neuropsychological assessments, and treatment details. Statistical analyses including ANOVA, chi‐square tests, logistic regression, and so on were used to analyze the clinical characteristics and potential prognostic predictors of FMD patients in China.

Results

Patients showed a mean onset age of 45.3 years, female (58.8%), and a possible bimodal age distribution (peaks at 20–30 and ≥ 60 years). Mixed phenotypes (32.8%) and tremor (29.4%) were most common, with high rates of anxiety (61.3%) and depression (53.8%), and 38.7% clinical symptom remission. Physical therapy may be a potential protective factor (OR = 0.077,  < 0.001), while trauma history (OR = 7.863, = 0.002) and higher baseline CGI scores (OR = 1.933, = 0.002) predicted poorer outcomes.

Conclusion

This first multi‐center study of FMDs in China highlights a potential tendency toward a bimodal distribution, female predominance, and abnormal scores on psychiatric scales. Notably, physical therapy represents a potential protective factor, while trauma history may be a risk factor. Our findings identify the clinical profile and prognostic factors of FMDs in the Chinese population, offering valuable insights for clinical practice and future research.

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Authors:
Jin‐Tao Wang, Ou‐Mei Cheng, Gang Xu, Shun‐Liang Xu, Xue‐Dong Liu, Sha Ma, Wei Huang, Wei Chen, Xing‐Yue Hu, Yi‐Ming Liu, Hong Lu, Yu‐Kai Wang, Yue‐Fei Shen, Xiao‐Ling Pan, Qing Huang, Mao‐Wen Ba, Han Wang, Yun‐Lan Du, Alexander Lehn, Xian‐Wen Chen and Gang Wang
Article first published online:
10 Oct 2025 | DOI: 10.1111/ene.70372

ORIGINAL ARTICLE

Background

Chronic pain is characterized by persistent and often debilitating symptoms, yet its underlying neural mechanisms remain poorly understood. This study investigates alterations in brain oscillations and connectivity in chronic pain patients using electroencephalography (EEG), aiming to identify potential neural signatures of chronic pain.

Methods

This cross‐sectional study analyzed EEG data from 42 chronic pain patients and 42 healthy controls to identify differences in oscillatory activity and network connectivity. Connectivity analyses were corrected for multiple comparisons using network‐based statistics. Machine learning techniques were employed to evaluate the potential of these neural signatures as biomarkers for chronic pain.

Results

Chronic pain patients exhibited decreased power in high‐frequency bands. Conversely, functional connectivity analysis revealed widespread enhancements in gamma synchronization in chronic pain patients. Dynamic connectivity analysis demonstrated that chronic pain patients had significantly increased gamma synchronization within the default mode network (DMN), particularly in a dominant state characterized by stronger intra‐cingulate connections. A machine learning model effectively differentiated patients from controls, achieving robust accuracy of 75.5% ± 6.9%, with sensitivity of 75.3% ± 12.6% and specificity of 80.0% ± 10.5%, primarily driven by the DMN connectivity features. Correlation analysis indicated that the connection between the left posterior cingulate and caudal anterior cingulate within the DMN was positively correlated with pain duration ( = 0.021,  = 0.354).

Conclusion

Enhanced gamma synchronization within the DMN plays a critical role in the pathophysiology of chronic pain. DMN gamma synchronization may serve as a valuable neural marker for chronic pain, providing new insights into its underlying mechanisms.

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Authors:
Zhaoshun Jiang, Fei Tao, Feidong Lv, Zhibo Xu, Xiaolei Wang, Yuxi Cai, Xiyu Du, Fafa Sun, Lina Yi, Songbin Liu, Xixue Zhang, Yongjun Zheng and Weidong Gu
Article first published online:
10 Oct 2025 | DOI: 10.1111/ene.70373

ORIGINAL ARTICLE

Background

The association between amyotrophic lateral sclerosis (ALS) and monoclonal gammopathy has been proposed, but evidence on its prevalence, clinical relevance, and treatment response remains limited, especially in Asian populations. This study aimed to investigate the prevalence of monoclonal gammopathy in Korean patients with ALS and evaluate the impact of immunotherapy.

Methods

This registry‐based study analyzed Korean patients with ALS at a tertiary referral hospital (2005–2023). All patients underwent electrophoresis and immunofixation electrophoresis to detect monoclonal gammopathy. Clinical progression was assessed using ALSFRS‐R scores, disease progression rate (ΔFS), survival analysis, and electrophysiological evaluations.

Results

Among 2400 patients with ALS, monoclonal gammopathy was identified in 1.0% (25/2400). Prevalence increased with age, 1.9% in patients aged ≥ 65 years and 0.7% (13/1755) aged < 65 years. Patients with ALS and monoclonal gammopathy were older (63.2 vs. 57.1;  = 0.01) and predominantly male (7.3:1 vs. 1.5:1;  < 0.01). Immunotherapy targeting monoclonal gammopathy did not significantly affect disease progression (pre‐treatment ΔFS 1.00 ± 1.23 vs. post‐treatment ΔFS 0.94 ± 0.86;  = 0.46) or survival outcomes (median survival 55.0 vs. 57.0 months; log‐rank  = 0.93). Nerve conduction study did not correlate with clinical outcomes. IgM monoclonal gammopathy demonstrated later slower disease progression (initial ΔFS, overall ΔFS;  < 0.05) compared to IgA and IgG subtypes.

Conclusion

Monoclonal gammopathy in Korean patients with ALS was not more prevalent than in the general population, and immunotherapy did not impact ALS progression or survival. Clinical features may vary by immunoglobulin subtype. This collectively suggests minimal clinical significance of monoclonal gammopathy in ALS.

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Authors:
Hyunkee Kim, Ji‐Eun Uhm, Jinseok Park, Yong sung Kim, Wonjae Sung, Sanggon Lee, Seung Hyun Kim and Ki‐Wook Oh
Article first published online:
21 Oct 2025 | DOI: 10.1111/ene.70376

LETTER TO THE EDITOR

Lifestyle and Occupational Risk Factors in the Development of Motor Neurone Disease

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Authors:
Nethmi Nuwanji Amarasekera
Article first published online:
10 Oct 2025 | DOI: 10.1111/ene.70377

LETTER TO THE EDITOR

Letter to the Editor: Clinical Characteristics in Danish Children and Adults Diagnosed With Neuroborreliosis: A Retrospective Study From January 2016 to January 2024

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Authors:
Ayesha Qayyum and Umar Aziz
Article first published online:
18 Oct 2025 | DOI: 10.1111/ene.70378

LETTER TO THE EDITOR

Letter to the Editor: Clinical Characteristics in Danish Children and Adults Diagnosed With Neuroborreliosis: A Retrospective Study From January 2016 to January 2024

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Authors:
Laiba Saher
Article first published online:
18 Oct 2025 | DOI: 10.1111/ene.70379

LETTER TO THE EDITOR

Concerns Regarding “Small Fiber Morphology and Function in Inclusion Body Myositis—A Multimodal Assessment Including Confocal Corneal Microscopy”

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Authors:
Muhammad Owais, Muhammad Huzaifa Sabir and Muhammad Nouman Javed
Article first published online:
21 Oct 2025 | DOI: 10.1111/ene.70380

REVIEW ARTICLE

Background

Reliable biomarkers for amyotrophic lateral sclerosis (ALS) are urgently needed due to diagnostic and prognostic challenges. This systematic review and meta‐analysis aimed to synthesize recent evidence on the utility of blood and cerebrospinal fluid (CSF) biomarkers for ALS.

Methods

We systematically reviewed studies published from January 1, 2019 to March 25, 2025, that evaluated blood or CSF biomarkers for ALS. Eligible studies reported diagnostic performance, group‐level biomarker values, hazard ratios (HRs) for survival, or correlations with functional rating scales or disease progression rates. Study quality was assessed using the QUADAS‐2 and QUIPS frameworks. Random‐effects models were employed to pool summary receiver operating characteristic (SROC) curves, HRs, standardized mean differences, and correlation coefficients.

Results

We included 47 studies in the SROC analysis and 27 in the HR analysis, covering 9078 participants (5556 ALS and 3522 controls). Neurofilament light chain (NfL) consistently demonstrated the highest diagnostic accuracy (sensitivity/specificity: 0.81–0.87 vs. ALS mimics) and high prognostic value (pooled HRs: 2.8–4.3) in both blood and CSF. CSF chitinases and the p‐tau/t‐tau ratio showed moderate utility. Other biomarkers, including interleukins, had limited clinical relevance. Most studies showed moderate to high risk of bias, with methodological heterogeneity and limited transparency.

Conclusions

NfL is the most validated biomarker for ALS diagnosis and prognosis, in both blood and CSF. However, its limited accuracy when used alone carries a considerable risk of misclassification. Future studies should adopt prevalence‐specific strategies and integrate biomarkers within multimodal frameworks to enhance diagnostic and prognostic precision.

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Authors:
Kazuki Obara, Daisuke Ito, Christer Nilsson, Shorena Janelidze, Alexander Santillo, Masahisa Katsuno and Niklas Mattsson‐Carlgren
Article first published online:
27 Oct 2025 | DOI: 10.1111/ene.70382

ORIGINAL ARTICLE

Background

Sleep disorders co‐existing with cerebral small vessel disease (CSVD) are prevalent in older adults, both of which are established risk factors for cognitive decline. Here, we aimed to explore the role of glymphatic function in linking CSVD and sleep quality to cognitive decline in community‐dwelling older adults from a new perspective.

Methods

This cohort study included participants from the Shanghai Aging Study (SAS) who underwent clinical interviews, neuroimaging, and neuropsychological assessments. Diffusion tensor image analysis along the perivascular space (DTI‐ALPS) index was employed to evaluate the glymphatic function. Mediation and interaction analyses were performed to investigate the potential mediating role of DTI‐ALPS in the associations between CSVD burden/sleep quality and cognitive impairment, as well as their interaction effects.

Results

258 participants were included in cross‐sectional analysis (mean age 68.5 years, 54.7% female), with 133 followed up after a 7‐year interval. At baseline, DTI‐ALPS index simultaneously mediated the associations between CSVD score/PSQI and cognitive impairment. Interaction analyses revealed that poor sleep quality had a more significant impact on cognitive impairment among participants at high risk of CSVD. Longitudinally, while no significant mediating effect was observed, both baseline DTI‐ALPS and CSVD burden were significantly correlated with longitudinal MMSE changes.

Conclusions

Our study suggested that glymphatic function, as assessed by DTI‐ALPS, may play a crucial role in linking CSVD burden and sleep quality to cognitive decline in community‐dwelling older adults. We also emphasized the importance of individualized sleep management for individuals at high risk of CSVD.

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Authors:
Rong Zhou, Weiyi Zhong, Yiwei Xia, Yunqing Ying, Yi Wang, Lumeng Yang, Jiajie Xu, Jinyi Cao, Zonghui Liang, Xiaoxiao Wang, Qiang Dong, Ding Ding and Xin Cheng
Article first published online:
17 Oct 2025 | DOI: 10.1111/ene.70384

ORIGINAL ARTICLE

Background

Multiple sclerosis (MS) is a major cause of disability, particularly among young adults, with fatigue affecting up to 95% of patients. Despite the availability of disease‐modifying therapies (DMTs), their impact on MS‐related fatigue (MSF) remains uncertain. This study investigates changes in fatigue levels among individuals with relapsing–remitting MS (RRMS) following the initiation of highly effective therapies (HETs).

Methods

A systematic search of MEDLINE, PubMed, Scopus, and PsycINFO identified studies involving adults with RRMS treated with HETs and assessed using validated fatigue measures at baseline and follow‐up. Data on demographics, MS duration, DMT type, and fatigue scores were extracted. Meta‐analyses using a random‐effects model calculated standardized mean differences (SMD) in fatigue scores post‐treatment.

Results

Eighteen studies comprising 4138 RRMS patients and 3806 person‐years of follow‐up were included. The overall SMD was −0.34 (95% CI −0.47 to −0.21), indicating a small but significant reduction in fatigue. Continuous treatments (e.g., natalizumab, ocrelizumab, fingolimod) showed significant improvements, while immune reconstituting therapies (e.g., alemtuzumab) did not. Among fatigue domains, only physical fatigue showed a significant reduction, particularly with natalizumab (SMD = −1.25; 95% CI −2.43 to −0.06) and when assessed using the fatigue scale for motor and cognitive functions scale (SMD = −1.52; 95% CI −2.87 to −0.17).

Conclusion

MS‐related fatigue levels, especially in its physical aspect, decrease after the initiation of HET. This finding reinforced the role of neuroinflammation in driving fatigue and highlighted the need for domain‐specific research and treatment strategies.

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Authors:
C. Sales, R. Patel, T. Wijeratne, A. Bruestle and N. Cherbuin
Article first published online:
22 Oct 2025 | DOI: 10.1111/ene.70385

EDITORIAL

Cardioembolic Breakthrough Stroke: When Anticoagulation Fails, Is Left Atrial Appendage Closure the Next Step?

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Authors:
Lina Palaiodimou and Georgios Tsivgoulis
Article first published online:
15 Oct 2025 | DOI: 10.1111/ene.70387

ORIGINAL ARTICLE

Background and Objectives

Glymphatic dysfunction occurs in Parkinson's disease (PD), but its status in prodromal PD (pPD) is unclear. Using the diffusion tensor imaging along perivascular spaces (DTI‐ALPS) index as an indirect proxy, this study aims to evaluate glymphatic‐related changes in a pPD cohort and to explore their relationship with symptoms, gray matter volume, and risk of phenoconversion.

Methods

We analyzed data from the Parkinson's Progression Marker Initiative, including 51 healthy controls (HC), 83 individuals with pPD, and 202 with de novo PD (dnPD). The pPD cohort underwent ≥ 4‐year follow‐up. Cross‐sectional analyses compared the DTI‐ALPS index across three groups and examined associations between the DTI‐ALPS index and clinical features/gray matter volume in the pPD cohort. For longitudinal analysis, the relationship of DTI‐ALPS index with the risk of phenoconversion was assessed via Kaplan–Meier and Cox regression.

Results

DTI‐ALPS index was significantly reduced in pPD and dnPD vs. HC ( < 0.001). In pPD, lower DTI‐ALPS index correlated with: higher anxiety (STAI:  = −0.46,  = 0.02), elevated CSF p‐tau ( = 0.52,  = 0.04) and ‐tau ( = 0.42,  = 0.03), lower volumes of right temporal pole ( = 0.03), left thalamus ( = 0.01), right superior occipital gyrus ( = 0.04), and higher volume of left posterior central gyrus ( = 0.03). Among 83 pPD subjects, 10 phenoconverted to PD. Each standard deviation decrease in DTI‐ALPS increased conversion risk by 13% (adjusted HR = 0.87, 95% CI 0.83–0.92;  = 0.018).

Conclusion

Reduced DTI‐ALPS index in pPD—which may reflect altered glymphatic function—is associated with accelerated phenoconversion and correlates with clinical symptoms and cortico‐thalamic structural changes.

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Authors:
Amei Chen, Zhanyu Kuang, Pek‐Lan Khong, Junxiang Huang, Jinyu Wen, Yoon Seong Choi, Yongzhou Xu, Peng Wu and Xinhua Wei
Article first published online:
25 Oct 2025 | DOI: 10.1111/ene.70389

LETTER TO THE EDITOR

Authors' Reply to the Comment by L. Saher and Drs. Qayyum and Aziz Dalton on the Article “Clinical Characteristics in Danish Children and Adults Diagnosed With Neuroborreliosis: A Retrospective Study From January 2016 to January 2024”

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Authors:
Christian Stenør, Nina Vindegaard Sørensen, Malini Vendela Sagar, Anne‐Mette Lebech, Anders Hougaard and Al‐Hasan Hussein Dos
Article first published online:
20 Oct 2025 | DOI: 10.1111/ene.70390

REVIEW ARTICLE

Background

Migraine is a global public health burden, with characteristics of stabbing pain, hypersensitivity and vegetative symptoms, affecting one billion people with multiple risk factors and potential pathophysiological mechanisms, including neuroinflammation. Periodontitis is a multifactorial disease that affects the dental supporting tissues (gingiva, periodontal ligament, root cementum, and alveolar bone), which in advanced stages can cause tooth loss. This pathology can have systemic implications, and its association with migraine offers a promising area of research to understand and treat both conditions. The aim of this study was to review the scientific evidence that links both pathologies.

Material and Methods

A systematic review and meta‐analysis was carried out using four databases (PubMed, Web of Science, Scopus, and Embase). A total of 197 articles were retrieved; after applying the selection criteria, a total of 8 articles were included in the review and 6 in the meta‐analysis, which were combined using the Random Forest model.

Results

An OR of 1.8 with a 95% confidence interval = 1.4–2.32 was estimated. The meta‐analysis showed a significant OR by Z‐test = 4.55 ( < 0.001). Regarding publication bias, an intercept was obtained using Egger's regression method equivalent to 2.83 with a 95% confidence interval = 1.31–4.36 ( = 0.007). After qualitative analysis, we found risk factors (such as smoking and stress) and comorbidities (obesity, diabetes, hormonal disorders, among others) that could be involved in this association.

Conclusions

Through this meta‐analysis, we have seen how there is a statistically significant relationship between periodontitis and migraine.

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Authors:
Gabriel Bernat Camps‐Plomer, Cecilia Fabiana Márquez‐Arrico, José Enrique Iranzo‐Cortés and José María Montiel‐Company
Article first published online:
22 Oct 2025 | DOI: 10.1111/ene.70391

LETTER TO THE EDITOR

Unraveling the Military Service–MND Connection: Time Frame, Exposures, and Phenotypic Considerations

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Authors:
Christian Messina
Article first published online:
21 Oct 2025 | DOI: 10.1111/ene.70392

ORIGINAL ARTICLE

Background

Tension‐type headache (TTH) is one of the most prevalent headache disorders worldwide, yet its underlying pathophysiological mechanisms remain poorly understood. Previous research suggests a potential link between myofascial factors, such as trapezius muscle stiffness, and headache severity. This study investigates the association between upper trapezius muscle stiffness and headache severity in patients with TTH.

Methods

We conducted a cross‐sectional analysis of 203 patients diagnosed with TTH, evaluating muscle stiffness using a portable muscle hardness meter and headache severity using the Headache Impact Test‐6 (HIT‐6) and Migraine Disability Assessment Scale (MIDAS). Logistic regression analysis was performed to identify correlations between muscle stiffness and headache severity, adjusting for age, sex, and other clinical variables.

Results

The mean muscle stiffness values were 32.5 ± 5.8 on the left and 31.3 ± 5.6 on the right. HIT‐6 scores positively correlated with muscle stiffness ( = 0.148), chronic TTH ( = 0.304), and age ( = −0.203). Significant clinical symptoms associated with headache severity included weakness ( = 0.154) and a heavy eyelid sensation ( = 0.154). However, shoulder stiffness and neck pain were not significantly associated with headache severity. Triggers such as stress and weather changes were also identified as significant predictors of headache severity.

Conclusions

Increased trapezius muscle stiffness positively correlates with greater headache severity in TTH patients. Weakness and heavy eyelid sensation may serve as important clinical indicators of headache severity, offering potential insights for improved diagnosis and management.

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Authors:
Daisuke Shimada, Eiichi Ishikawa, Takuya Kawai, Yoichi Harada, Toru Hatayama, Takuji Kono, Koichi Okamura, Toshitsugu Terakado, Kiyotaka Toyoda, Shohei Iijima, Yuta Sasaki and Satoru Miyawaki
Article first published online:
27 Oct 2025 | DOI: 10.1111/ene.70393

ORIGINAL ARTICLE

Background and Objectives

Mortality in Late‐Onset Pompe Disease (LOPD) has been associated with the rapid progression of respiratory and motor impairment. However, an in‐depth approach to the exact causes of death in these patients is still lacking.

Methods

In this retrospective cohort study, we analyzed the cause of death and the comorbidities of all deceased patients from the French Late‐Onset Pompe Disease registry.

Results

By the time of the last extraction, 60 patients diagnosed with LOPD and monitored were registered as deceased in the French national registry, out of a total of 260 patients included. The median age of death was 70.5 years, while the median age of diagnosis was 58 years. The causes of death were divided into disease‐related, accounting for 46.6% of deaths, and non‐disease‐related, comprising 28.3% of total deaths. Fifteen patients (25%) died of an unknown cause. The most frequent etiology of disease‐related death was respiratory failure ( = 14), while for the non‐disease‐related group, malignant neoplasm was the most common ( = 8). Patients in the non‐disease‐related death group had significantly higher forced vital capacity (FVC) values compared to those in the disease‐related death group (54.7% vs. 38%). Treatment‐wise, the median period elapsed from diagnosis to ERT introduction was higher in the disease‐related group.

Discussion

This is the first study to focus on the specific causes of death of LOPD patients. The majority of the LOPD deaths in the French registry were attributed to respiratory failure and malignant neoplasms.

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Authors:
Diana Maria Chitimus, Céline Tard, Maxime Fournier, Françoise Bouhour, Anthony Béhin, Emmanuelle Salort‐Campana, Emmeline Lagrange, Anne‐Laure Kaminsky, Armelle Magot, Stéphane Beltran, Jean‐Baptiste Noury, Laurent Magy, Guilhem Solé, Dimitri Renard, Marco Spinazzi, Florence Demurger, Pascal Cintas, Aleksandra Nadaj‐Pakleza, Joelle Deibener‐Kaminsky, Guillaume Bassez, Nadjib Taouagh, Azzedine Arrassi, Claire Lefeuvre, Sharam Attarian, Dalil Hamroun, Pascal Laforêt, Fatima Bouibede, Catherine Caillaud, Jean‐Baptiste Davion, Isabelle Durieu, Andoni Echaniz‐Laguna, Florence Esselin, Roseline Froissart, Pierre Yves Garcia, D. P. Germain, Karima Ghorab, Jean‐Yves Hogrel, Guillaume Nicolas, Rolland Jaussaud, Elsa Krim, Marion Masingue, Sylvain Nollet, Adeline Not, David Orlikowski, Thierry Perez, Frédéric Taithe, Ségolène Toquet, Fabien Zagnoli, Prigent Hélène, Michaud Maud, Sacconi Sabrina, Caroline Espil, Caroline Paricio, Charlene Gillet, Eva Diab, Frederic Huet, Juliette Ropars, Karine Mention, Magali Gorce, Marcel Maillet‐Vioud and Ulrike Walther‐louvier
Article first published online:
27 Oct 2025 | DOI: 10.1111/ene.70394

LETTER TO THE EDITOR

Authors' Response to the Letter on “The Added Benefit of Intra‐Arterial Thrombolysis After Successful Recanalization by Endovascular Treatment: A Systematic Review and Meta‐Analysis of Randomized‐Controlled Clinical Trials”

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Authors:
Lina Palaiodimou, Nikolaos M. Papageorgiou and Georgios Tsivgoulis
Article first published online:
25 Oct 2025 | DOI: 10.1111/ene.70399

LETTER TO THE EDITOR

Reply to Owais Et al. Concerns Regarding “Small Fiber Morphology and Function in Inclusion Body Myositis—A Multimodal Assessment Including Confocal Corneal Microscopy”

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Authors:
Dietrich Sturm, Anne‐Katrin Güttsches, Matthias Vorgerd, Peter Schwenkreis, Andrea Westermann, Tineke Greiner, Jan Vollert, Lynn Eitner, Christoph Maier, Johannes Forsting and Elena Enax‐Krumova
Article first published online:
21 Oct 2025 | DOI: 10.1111/ene.70400

LETTER TO THE EDITOR

Letter to the Editor Regarding “The Added Benefit of Intra‐Arterial Thrombolysis After Successful Recanalization by Endovascular Treatment: A Systematic Review and Meta‐Analysis of Randomized‐Controlled Clinical Trials” Recently Published by Palaiodimou and Colleagues

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Authors:
Senta Frol, Adnan H. Siddiqui, René Chapot and Wim H. van Zwam
Article first published online:
25 Oct 2025 | DOI: 10.1111/ene.70401