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Article first published online:
28 Oct 2025 | DOI: 10.1111/ene.16361

ORIGINAL ARTICLE

Longitudinal Brain Atrophy Patterns in Early MOG‐Antibody Associated Disease and Relapsing Multiple Sclerosis

Background

Myelin oligodendrocyte glycoprotein antibody‐associated disease can manifest as a relapsing or monophasic condition. Although several MRI studies have shown evident gray and white matter atrophy compared to healthy controls, little is known about regional brain volume dynamics in myelin oligodendrocyte glycoprotein antibody‐associated disease over time.

Methods

In this study, we performed an explorative voxel‐based morphometry to detect brain volumetric differences between myelin oligodendrocyte glycoprotein antibody‐associated disease ( = 27), relapsing multiple sclerosis ( = 40)—both in early disease stages—and healthy controls ( = 45). Furthermore, we investigated the longitudinal brain volume changes over a 2‐year follow‐up period in myelin oligodendrocyte glycoprotein antibody‐associated disease ( = 15) and relapsing multiple sclerosis ( = 40).

Results

We identified distinct patterns of regional brain volume loss in the patient subgroups compared to healthy controls. In multiple sclerosis patients, bilateral thalamic atrophy was observed, whereas patients with myelin oligodendrocyte glycoprotein antibody‐associated disease showed atrophy of the bilateral fornix and stria terminalis. Our results confirmed longitudinal volume loss in thalamic and infratentorial regions in the relapsing multiple sclerosis group, which was partly related to clinical relapses during the 2‐year follow‐up period. In contrast, no longitudinal gray or white matter changes were found in the myelin oligodendrocyte glycoprotein antibody‐associated disease group.

Conclusions

To our knowledge, this is the first MRI study demonstrating no evidence of regional brain volume loss over time in patients with myelin oligodendrocyte glycoprotein antibody‐associated disease using voxel‐based morphometry, suggesting a different—probably not progressive—pathophysiological background compared to relapsing multiple sclerosis.

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Authors:
Theodoros Ladopoulos, David Bratek, Carolin Schwake, Ann‐Kathrin Kogel, Barbara Bellenberg, Britta Krieger, Zainab Abbas, Ralf Gold, Carsten Lukas, Ilya Ayzenberg and Ruth Schneider

Article first published online:
18 Nov 2025 | DOI: 10.1111/ene.70354

LETTER TO THE EDITOR

Letter to the Editor: Integrating Machine Learning Into Stroke Risk Stratification in AF

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Authors:
Wenwen Xu, Guoxin Zhang and Junxiong Yin

Article first published online:
01 Nov 2025 | DOI: 10.1111/ene.70368

LETTER TO THE EDITOR

Letter to the Editor: Integrating Machine Learning Into Stroke Risk Stratification in AF—Authors' Reply

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Authors:
Soundous M'Rabet, Yannick Béjot and Charles Guenancia

Article first published online:
01 Nov 2025 | DOI: 10.1111/ene.70369

SHORT COMMUNICATION

Polyneuropathy in Wild‐Type Transthyretin Amyloidosis

Introduction

Transthyretin amyloidosis (ATTR) is a systemic disorder characterized by the extracellular accumulation of amyloid fibrils, classified as either mutant (ATTRv, v for variant) or wild‐type (ATTRwt), based on the genetic sequence of the transthyretin (TTR) protein. ATTRwt primarily manifests with cardiac and osteo‐articular involvement. Nevertheless, evidence of peripheral neuropathy, besides carpal tunnel syndrome (CTS), can be found in ATTRwt patients. Although neurological complications of ATTRv have been extensively studied, to date information on peripheral nervous system (PNS) involvement in ATTRwt remains limited.

Methods

Patients with a confirmed diagnosis of ATTRwt underwent neurological examination and nerve conduction studies (NCS). In patients with confirmed polyneuropathy, we suggested a sural nerve biopsy to detect amyloid deposits.

Results

We examined 30 patients with a mean age of 81.1 years (range 60–96). The absence of lower‐limb distal tendon reflexes was shown in 53% of cases. CTS was present in 70% of cases. NCS revealed a sensory polyneuropathy in 18 patients (60%). Among the patients with neuropathy, four agreed to undergo sural nerve biopsy: in two patients, histological examination showed the presence of Congo red‐positive amyloid deposits.

Discussion

We observed a sensory neuropathy in more than half of the enrolled ATTRwt patients, supporting the systemic nature of the disease. However, the unclear pathogenesis of sensory polyneuropathy, considering the various comorbidities in the elderly population, highlights the need for further investigation. Histological confirmation of amyloid deposition in nerve tissue may provide a causal link between amyloidosis and PNS involvement.

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Authors:
Maria Ausilia Sciarrone, Francesca Vitali, Valeria Guglielmino, Angela Romano, Giovanni Siconolfi, Marco Ceccanti, Maurizio Inghilleri, Cristina Chimenti, Francesca Graziani, Rosa Lillo, Laura Libonati, Chiara Cambieri, Federica Moret, Vito Stifano and Marco Luigetti

Article first published online:
05 Nov 2025 | DOI: 10.1111/ene.70374

ORIGINAL ARTICLE

Serum Neurofilament Light Is Associated With Future Disease Activity in Clinically Isolated Syndrome and Early Multiple Sclerosis Only After Non‐Optic Neuritis Onset

Background

We compared the prognostic value of serum neurofilament light chain (sNFL) and glial fibrillary acidic protein (sGFAP) for clinical and radiologic disease activity among patients with clinically isolated syndrome or early multiple sclerosis (MS) with optic neuritis (pwON) and non‐optic neuritis (pwNON) as the first manifestation.

Methods

Patients within 7 months (pwON and pwNON) from disease onset and patients with MS with a disease duration longer than 12 months (pwMS) as controls were included. sNFL and sGFAP were analyzed at baseline and at follow‐ups using SIMOA technology. Linear mixed models and Cox regression analyses were applied.

Results

We included 165 samples of 86 patients (18 pwON, 46 pwNON, 21 pwMS). Median follow‐up time was 80 months. Mean sNFL scores were higher in pwNON (1.06) than pwON (0.53) and pwMS (0.94). In pwNON, but not pwON, higher sNFL scores were associated with an elevated risk for a subsequent attack (pwNON: HR 1.63 [95% CI 1.12 to 2.27], = 0.005; pwON: HR 0.80 [95% CI 0.51–2.27], = 0.318) and new MRI T2 lesions (pwNON: HR 1.66 [95% CI 1.31 to 2.11], < 0.001; pwON: HR 1.16 [95% CI 0.82 to 1.63], = 0.404). sGFAP scores were associated with a lower risk of a subsequent attack in pwON (HR 0.34 [95% CI 0.12 to 0.98], = 0.047).

Conclusion

sNFL but not sGFAP predicted future clinical and MRI disease activity only in pwNON, potentially suggesting that the prognostic value of sNFL may depend on the type of the first manifestation.

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Authors:
Philipp Klyscz, Klemens Ruprecht, Lina Carlotta Anderhalten, Tanja Schmitz‐Hübsch, Jens Kuhle, Tatiana Usnich, Judith Bellmann‐Strobl, Friedemann Paul, Patrick Schindler and Susanna Asseyer

Article first published online:
12 Nov 2025 | DOI: 10.1111/ene.70375

ORIGINAL ARTICLE

Alterations in Cerebrospinal Fluid Density Following Contrast Administration in Patients With Acute Ischemic Stroke

Introduction

The degree of iodine clearance from the parenchyma in acute ischemic stroke (AIS) has not been determined. The aim of our study was to measure changes in cerebrospinal fluid (CSF) density in patients with AIS relative to controls.

Methods

This is a retrospective cohort study from a single tertiary stroke center, including any patient who underwent CT angiography (CTA) and EVT and then follow‐up noncontrast CT (NCCT) after 12–36 h. Control group included nonstroke patients who underwent CTA and a NCCT after 12–36 h. The density of CSF in Hounsfield units (HU) was measured in the frontal horns of lateral ventricles and in the third ventricle and was compared between baseline and follow‐up NCCT (ΔHU), as well as between groups. Paired ‐tests and multivariable linear regression analysis were utilized for data analysis.

Results

Altogether, 134 patients with AIS and 46 controls were included. In the AIS group, we found median (IQR) ΔHU of 1 (−0.34, 2.33) compared with −0.33 (−1, 0.33) in controls ( < 0.01). Early ischemic changes and onset‐to‐recanalization times remained significant for ΔHU following multivariable analysis.

Discussion

Our findings suggest that iodine contrast administration in patients with AIS leads to increased CSF density, potentially through the glymphatic clearance systems.

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Authors:
Vadim Khasminsky, Jonathan Naftali, Gal Tsur, Rani Barnea, Ruth Eliahou, Eli Atar and Eitan Auriel

Article first published online:
05 Nov 2025 | DOI: 10.1111/ene.70381

ORIGINAL ARTICLE

Preliminary Validation of the FCD‐Q8 Tool in Functional Cognitive Disorder and Early Alzheimer's Disease: A Biomarker‐Verified Case–Control Study

Background

Differentiating functional cognitive disorder (FCD) from early Alzheimer's disease (eAD) through clinical interview alone is challenging and may lead to unnecessary testing. We aimed to assess the diagnostic accuracy of the Functional Cognitive Disorder Questionnaire‐8 (FCD‐Q8) and examine its psychometric properties.

Methods

In this cross‐sectional, phase 1 case‐control study at a tertiary memory clinic in Seville, Spain, 78 adults with memory complaints were recruited: 44 with biomarker‐verified eAD (positive CSF or amyloid PET; GDS 3–4) and 34 with FCD (negative biomarkers and clinical internal inconsistency). A blinded neuropsychologist administered the FCD‐Q8. The primary outcome was diagnostic accuracy (area under the ROC curve [AUC], sensitivity, and specificity). Secondary outcomes included internal consistency (Cronbach's with 95% CI) and item characteristics using two‐parameter logistic Item Response Theory (2PL IRT).

Results

Participants had a mean age of 67.5 years (SD ± 7.1); 59% were female. The FCD‐Q8 demonstrated good diagnostic accuracy with an AUC of 0.87 (95% CI 0.78–0.95). At a cut‐off ≥ 5, sensitivity was 76.5% and specificity 88.6%. Internal consistency was moderate ( = 0.61; 95% CI 0.47–0.70). 2PL IRT analysis showed that items related to checking behaviours were the most discriminative (difficulty 3.70), while questions on compound statements and premorbid self‐appraisal were the least discriminative. Attending the clinical interview alone was the most difficult item (1.47).

Conclusion

The FCD‐Q8 demonstrated good diagnostic utility to distinguish FCD from eAD in biomarker‐verified populations. These findings support progression to a subsequent prospective validation phase, which could further establish its clinical and research applicability.

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Authors:
Ernesto García‐Roldán, Ángela Almodóvar‐Sierra, Andrea Luque‐Tirado, Alba Marta Marín Cabañas, María Bernal Sánchez‐Arjona and Emilio Franco‐Macías

Article first published online:
29 Oct 2025 | DOI: 10.1111/ene.70383

ORIGINAL ARTICLE

Clusters of Comorbidities in Multiple Sclerosis and Their Influence on Healthcare Resource Usage

Introduction

MS patients are at increased risk of comorbidities and use more healthcare resources. Multimorbidity approached as the number of conditions is flawed by classifying patients with different needs as equal. We aimed to explore how comorbidities cluster and their impact on healthcare resource usage.

Methods

We used latent‐class models of up to 10 clusters in a population‐based sample of MS patients. The optimal number of clusters was determined using model metrics and similarity/entropy measures, and cluster stability was assessed by bootstrapping. Sociodemographic characteristics and healthcare‐resource usage according to the clusters assigned were compared to each other and to patients without comorbidities using univariable and adjusted linear regression models.

Results

In 5548 MS cases, of which 60% had comorbidities, the optimal number of comorbidity clusters was two, comprising a high frequency of cardiovascular comorbidities and psychiatric disorders. Patients in the cardiovascular cluster were older, and in the psychiatric cluster were more frequently female. After adjusting for sociodemographic variables, healthcare resource usage was higher for patients with comorbidities, particularly for nurse (1.1 more average yearly visit; [95% CI 0.41–1.8]; = 0.002), primary care (1.8 more visits; [95% CI 1.4–2.1]; < 0.001), and medication dispensation (336 more dosage units; [95% CI 260–402]; < 0.001) in the cardiovascular cluster, and annual sick‐leave days (3.8 more days; [95% CI 0.25–7.3]; = 0.036) in the psychiatric cluster.

Discussion

We observed clustering of comorbidities around cardiovascular comorbidities and mental disorders, which impacted healthcare resource usage differently. Further research is needed to assess the influence of these clusters on the prognosis of MS.

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Authors:
Simón Cárdenas‐Robledo, Susana Otero‐Romero, Juan David García, Nuria López, Pere Carbonell‐Mirabent, Marta Rodríguez, Claudia Guío‐Sánchez, René Carvajal, Maria Angels Passarell‐Bacradit, Jaume Sastre‐Garriga, Xavier Montalban and Mar Tintoré

Article first published online:
05 Nov 2025 | DOI: 10.1111/ene.70386

ORIGINAL ARTICLE

Robotic Extended Thymectomy in Late‐Onset Myasthenia Gravis: A 21‐Year Retrospective Cohort Study of 172 Patients

Background

The safety and feasibility of robotic‐assisted (RATS) thymectomy for myasthenia gravis (MG) with onset age ≥ 50 years remain unverified, particularly in very late‐onset MG (V‐LOMG).

Methods

Patients were classified into late‐onset MG (LOMG, 50–64) and very late‐onset MG (V‐LOMG ≥ 65) based on age of onset. Composite neurological remission (CNR) included complete stable remission (CSR), pharmacologic remission (PR), and minimal manifestations‐0 (MM‐0), while favorable outcomes comprised CNR and MM1‐3.

Results

Among 1041 patients, 172 with MG onset at ≥ 50 years who underwent RATS extended thymectomy were included in the final analysis. The LOMG group comprised 104 patients (45.2% male), while the V‐LOMG group included 68 patients (60.3% male). V‐LOMG patients had more preoperative MG crises, shorter onset‐to‐thymectomy intervals, heavier thymic specimens, and less hyperplasia. In ocular‐onset MG, generalization was more frequent in LOMG than in V‐LOMG. No significant differences were found in other baseline characteristics, perioperative parameters, postoperative complications, and adverse composite outcomes. At a 5.1‐year mean follow‐up, the V‐LOMG group had slightly higher CSR (7.4% vs. 6.7%), CNR (16.2% vs. 11.5%), and favorable outcome rates (52.9% vs. 45.2%) than the LOMG group, with no statistical significance. Both groups, especially V‐LOMG (16.0 mg vs. 2.1 mg, < 0.001), showed a significant corticosteroid dose reduction at the last follow‐up, confirming the steroid‐sparing effect of thymectomy.

Conclusions

RATS extended thymectomy appears to be a safe and feasible treatment for patients with MG of onset at age ≥ 50 years, including those with V‐LOMG, demonstrating a significant steroid‐sparing effect while maintaining favorable neurological outcomes.

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Authors:
Luyu Huang, Feng Li, Zhongmin Li, Hongbin Zhang, Aron Elsner, Julia Strauchmann, Marco Nicolas Andreas, Tomasz Dziodzio, Aina Lask, Jens Neudecker, Daipeng Xie, Lintong Yao, Shaowei Wu, Haiyu Zhou, Andreas Meisel and Jens‐C. Rueckert

Article first published online:
05 Nov 2025 | DOI: 10.1111/ene.70388

ORIGINAL ARTICLE

Deceleration Capacity as a Marker of Autonomic Cardiac Modulation in Prodromal and Manifest Parkinson's Disease, Multiple System Atrophy, and Progressive Supranuclear Palsy

Background

Degenerative parkinsonian syndromes, including the alpha‐synucleinopathies (aSYN) Parkinson's disease (PD), and multiple system atrophy (MSA), and the tauopathy progressive supranuclear palsy (PSP), are characterized by motor and non‐motor symptoms. The later subsume autonomic dysfunction, which may appear early or progress with the disease. Cardiac dysfunction varies by syndrome and can also occur in isolated REM sleep behavior disorder (iRBD), a prodromal stage of aSYN. Overlapping motor features make early differentiation challenging. Heart rate variability (HRV) analysis is a noninvasive tool for evaluating cardiac autonomic function, with deceleration capacity (DC) as a sensitive parasympathetic marker. This study compares HRV and DC across parkinsonian syndromes to assess their potential in early diagnosis and differentiation.

Methods

Using standardized 30‐min resting ECG recordings in the early morning, we analyzed HRV parameters in five groups: iRBD ( = 10), PD ( = 10), MSA ( = 10), PSP ( = 9), and healthy controls (HC, = 10). Evaluated HRV parameters included HRV index (HRVI), reflecting overall variability, and DC.

Results

As expected, DC was significantly lower in MSA (3.82 ± 1.38) and unexpectedly even lower in PSP (3.19 ± 2.77), compared to HC (9.66 ± 4.67) and PD (7.55 ± 2.48). These findings are novel for PSP. HRVI was significantly reduced in PSP, while other HRV parameters showed no significant differences.

Conclusions

Deceleration capacity (DC) reduction in MSA and PSP suggests pronounced cardiac parasympathetic dysfunction. DC may support differentiation between PD and atypical syndromes, but larger studies are needed for validation. Given the impact of autonomic dysfunction on quality of life and mortality, comprehensive autonomic testing should be included in the diagnostic workup.

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Authors:
Elisabeth Ruppert, Nuria Mix, Karl Kesper, Axel Bauer, David Vadasz, Vincent Ries, Elisabeth Sittig, Ulrich Koehler, Annette Janzen and Wolfgang H. Oertel

Article first published online:
30 Oct 2025 | DOI: 10.1111/ene.70395

REVIEW ARTICLE

Corneal Confocal Microscopy to Diagnose Peripheral Neuropathy: A Systematic Review and Meta‐Analysis

Background and Objectives

Peripheral neuropathy (PN) may be diagnosed late or may remain undiagnosed. Studies have shown that measurement of corneal nerve fiber length (CNFL) using corneal confocal microscopy (CCM) may have diagnostic utility in diabetic and other peripheral neuropathies.

Methods

The main databases [CENTRAL, Embase (Ovid), and PubMed] were searched for peer‐reviewed literature. Gray literature searching was undertaken using the ProQuest Dissertations & Theses database. The updated Preferred Reporting Items for Systematic Reviews and Meta‐Analysis guidelines were used by two authors independently for screening and data extraction. The primary outcome of CNFL was represented by the standardized mean difference and 95% confidence interval, and differences between healthy controls (HC), patients with sub‐clinical (PN−), and clinical (PN+) peripheral neuropathy were assessed. Sensitivity analysis was performed to assess the risk of bias.

Results

We identified = 52 eligible studies ( = 2995 participants) reporting CNFL across 34 different conditions associated with PN. CNFL was significantly lower in PN+ patients compared to HC (standardized mean difference −1.12, 95% confidence interval −1.32 to −0.33, < 0.00001), in PN− patients compared to HC (−0.78, −0.99 to −0.57, < 0.00001), and in PN+ compared to PN− patients (−0.93, −1.53 to −0.33, = 0.002). The results remained significant following sensitivity analysis to adjust for the risk of potential detection bias. The results remained significant independent of the choice of a random or fixed effects model.

Conclusions

This systematic review and meta‐analysis shows that CNFL has utility in the diagnosis of peripheral neuropathies.

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Authors:
Ioannis N. Petropoulos, Omar A. Madani, Hoda Y. Gad, Ziyad R. Mahfoud, Georgios Ponirakis, Ross MacDonald and Rayaz A. Malik

Article first published online:
07 Nov 2025 | DOI: 10.1111/ene.70396

REVIEW ARTICLE

Recent Advances in Interventions Targeting Remyelination and a Systematic Review of Remyelinating Effects of Approved Disease‐Modifying Treatments for Multiple Sclerosis

Background

Regenerative strategies in progressive multiple sclerosis (MS) pose a significant unmet need. Combining immunomodulatory treatment with remyelinating interventions to target the complex underlying pathogenesis appeals as the next frontier in MS therapeutic developments. Therefore, it is important to identify which disease‐modifying treatments (DMT) with proremyelinating properties are most promising for future use in combination treatments. This systematic review provides an overview of preclinical and clinical research on remyelination, focusing on the effects of currently available FDA and EMA‐approved DMT

Methods

The search was conducted in accordance with the “Synthesis without meta‐analysis” (SWiM) reporting guideline. The protocol was registered at PROSPERO prior to the search.

Results

Fifty‐seven articles on preclinical research, three randomized controlled trials (RCTs), 29 non‐randomized clinical studies, and eight reviews were included. Preclinical research suggested neuroprotective properties of various DMT. However, convincing evidence of true remyelination, either by influencing oligodendrocyte lineage cells in cell cultures or histological analysis in vivo, could only be found in studies investigating glatiramer acetate, teriflunomide, Fingolimod, Siponimod, Ponesimod, and alemtuzumab. Clinical trials using surrogate markers of myelin repair, such as advanced imaging and electrophysiological techniques, demonstrated promising results with glatiramer acetate, Fingolimod, Siponimod, natalizumab, alemtuzumab, and ocrelizumab. However, we found insufficient proof to claim that changes in these surrogate markers can be explained by remyelination alone.

Conclusions

Future proof‐of‐concept clinical trials investigating remyelinating agents in MS should consider combining outcome measures into composite endpoints. Furthermore, research efforts should be dedicated to novel biomarkers to assess repair mechanisms in MS.

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Authors:
Anna‐Victoria De Keersmaecker, Eline van Doninck, Inez Wens, Yousra El Ouaamari, Veronica Popescu, Guy Laureys, Melissa Cambron, Miguel D'Haeseleer, Lander Willem, Judith Derdelinckx, Tatjana Reynders and Barbara Willekens

Article first published online:
11 Nov 2025 | DOI: 10.1111/ene.70397

REVIEW ARTICLE

Childhood and Adolescent Environmental Risk Factors for Multiple Sclerosis: A Systematic Review With Meta‐Analysis

Background

We aimed to provide updated evidence from the current literature regarding pediatric environmental factors associated with the risk of developing multiple sclerosis (MS).

Methods

Articles were searched in PubMed, SciVerse ScienceDirect, and Web of Science. We included all clinical studies assessing the occurrence of MS at any age in association with the exposure to any environmental risk factor during childhood or adolescence. The main outcome was the occurrence of MS. The quality assessment was performed with the critical appraisal checklist for case–control studies. Pooled unadjusted effect sizes (OR) were calculated and reported with a 95% CI from random‐effects meta‐analysis.

Results

The review included 87 studies conducted across 20 countries. The studies analyzed diverse environmental risk factors, including infections, vaccinations, tobacco exposure, body mass index, and other pediatric exposures. EBV infection showed a significant positive association with MS risk (ES = 2.38, 95% CI = 1.80–3.15). Breastfeeding showed limited protective associations, and various adverse social experiences like bullying and sexual abuse were linked to increased MS risk. Active smoking during childhood/adolescence and obesity during these periods were associated with higher MS risk, while normal body mass index was protective. Antibiotic and chemical exposures, as well as vitamin D deficiency, were linked to higher MS risk. The review highlighted substantial heterogeneity and identified publication bias in studies on infections and vaccinations.

Conclusions

Environmental risk factors for MS are important during childhood and adolescence. The first 20 years are a key window for prevention and should be seen as an opportunity.

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Authors:
Bruno Kusznir Vitturi, Maria Cellerino, Daniele Boccia, Emmanuelle Leray, Jorge Correale, Ruth Dobson, Ingrid van der Mei, Kazuo Fujihara and Matilde Inglese

Article first published online:
28 Oct 2025 | DOI: 10.1111/ene.70398

ORIGINAL ARTICLE

Impact of Erenumab on Comorbid Depression, Anxiety, and Sleep Quality in Migraine: A Registry for Migraine (REFORM) Study

Background

Migraine frequently co‐exists with psychiatric comorbidities, including anxiety, depression, and sleep disturbances. Erenumab, a monoclonal antibody targeting the calcitonin gene‐related peptide receptor, effectively reduces migraine frequency, but its impact on psychiatric symptoms remains unclear. This study evaluated the effects of erenumab on anxiety, depression, and sleep quality in individuals with migraine.

Methods

This non‐randomized, single‐arm, open‐label trial was conducted within the prospective Registry for Migraine (REFORM). Adults with migraine received 140‐mg erenumab monthly for 24 weeks. Anxiety, depression, and sleep‐related symptoms were evaluated at baseline, Week 12, and Week 24 using the hospital anxiety and depression scale (HADS) and the Pittsburgh sleep quality index (PSQI). Participants were stratified by treatment response during Weeks 13–24 (≥ 50% reduction in monthly migraine days) and psychiatric history.

Results

Among 675 participants completing ≥ 12 weeks, the proportion at risk for anxiety decreased from 30.1% (196/651) at baseline to 22.8% (136/597) at Week 24, and for depression from 24.9% (162/651) to 18.3% (109/597, both < 0.001). Poor sleep quality decreased from 66.1% (429/649) to 56.3% (333/592, < 0.001). Only ≥ 50% responders (300/582, 51.5%) achieved significant improvements in anxiety, depression, and sleep‐related symptoms (All < 0.001), whereas < 50% responders did not improve significantly (All > 0.05). Improvements were significant in both subgroups with and without psychiatric history (All < 0.001).

Conclusions

Erenumab treatment is associated with improvement in anxiety, depression, and sleep‐related symptoms, specifically in treatment responders. These benefits appear mediated by migraine control rather than direct pharmacological effects.

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Authors:
Bianca Raffaelli, Janu Thuraiaiyah, Rune Häckert Christensen, Haidar M. Al‐Khazali, Håkan Ashina, Josefin Snellman, Tina Maio‐Twofoot and Messoud Ashina

Article first published online:
07 Nov 2025 | DOI: 10.1111/ene.70402

ORIGINAL ARTICLE

Olfactory Dysfunction as a Window Into the Heterogeneity of Parkinson Disease

Background

While olfactory dysfunction is common in Parkinson disease (PD), its neural basis and clinical implications remain to be clarified. We investigated the neural substrates and clinical profiles, particularly non‐motor symptoms (NMSs), associated with olfactory function.

Methods

This retrospective study included 259 drug‐naïve patients with PD who underwent the Cross‐Cultural Smell Identification Test (CC‐SIT), comprehensive autonomic function test, neuropsychological assessments, and the Neuropsychiatric Inventory Questionnaire (NPI‐Q) at diagnosis. NMS profiles were compared across olfactory groups defined by CC‐SIT scores (normosmia [ = 45], hyposmia [ = 143], anosmia [ = 74]). Associations between olfaction and clinical/imaging variables were assessed using correlation and path analyses. Cox proportional hazards models were employed to evaluate the risk of developing motor complications or PD dementia according to olfactory status.

Results

CC‐SIT scores correlated with Composite Autonomic Severity Scale scores (rho = −0.219, = 0.001), NPI‐Q scores (rho = −0.269, < 0.001), and cognitive performance in memory (rho = 0.288, < 0.001) and frontal/executive domains (rho = 0.205, = 0.001). Dopaminergic depletion in the caudate nucleus and limbic atrophy emerged as neural substrates underlying olfactory dysfunction, mediating the association between olfaction and cognitive/neuropsychiatric symptoms. Anosmia was associated with increased risk of developing PD dementia compared to normosmia (hazard ratio [HR]: 2.579; 95% confidence intervals [CI]: 1.137–5.851) and hyposmia (HR: 2.783; 95% CI: 1.437–5.390). Anosmia was associated with higher risk of developing freezing of gait (HR: 2.571; 95% CI: 1.077–6.134) compared to normosmia.

Conclusions

Olfactory dysfunction serves as a multifaceted clinical marker associated with convergent degeneration of nigrostriatal and limbic pathways, offering insights into PD phenotypic variance and its prognostic implications.

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Authors:
Yeeun Sun, Han Kyu Na, So Hoon Yoon, Quynh Phuong Vo, Chan Wook Park, Jung Hyun Lee, Yun Young Choi, Han Soo Yoo, Young H. Sohn, Chul Hyoung Lyoo and Phil Hyu Lee

Article first published online:
04 Nov 2025 | DOI: 10.1111/ene.70404

ORIGINAL ARTICLE

Compound Muscle Action Potential (CMAP) Amplitude Trajectories and Pattern in Adults with 5q‐Spinal Muscular Atrophy Receiving Nusinersen Therapy: A Multicenter, Binational Observational Study

Background

This study aimed to evaluate changes in compound muscle action potential (CMAP) amplitude in adults with spinal muscular atrophy (SMA) undergoing nusinersen treatment and its association with motor function improvements.

Methods

This multicenter study assessed median, ulnar, and peroneal CMAP over a follow‐up of up to 4.5 years using linear mixed models. Motor function was measured using the Revised Upper Limb Module (RULM) and the Hammersmith Functional Motor Scale Expanded (HFMSE). Correlations between CMAP and motor function scores were analyzed.

Results

Seventy‐eight patients (27 ambulatory, 51 non‐ambulatory) were included. Baseline ulnar CMAP ≥ 2.0 mV distinguished SMA type 3 from type 2 with 91.3% sensitivity and 88.9% specificity (AUC 0.96, 95% CI 0.92–1.0), while baseline median nerve CMAP ≥ 6.5 mV showed 91.7% sensitivity and 77.3% specificity (AUC 0.84, 95% CI 0.72–0.96). No significant changes over time were observed in median, ulnar, and peroneal CMAP amplitudes ( > 0.05). CMAP trajectories did not differ between SMA types 2 and 3 ( > 0.05). No significant difference in the change in RULM or HFMSE at any time point was observed between SMA patients with baseline median nerve CMAP < 5 mV and those with CMAP of ≥ 5 mV ( > 0.05). No significant correlations were found between changes in median nerve CMAP and HFMSE or RULM ( > 0.05).

Discussion

CMAP amplitudes remained stable during nusinersen treatment, with no differences in trajectories between SMA types 2 and 3. Our findings suggest that while CMAP amplitude correlates with disease severity, it may not serve as a sensitive biomarker of treatment response in adult SMA patients.

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Authors:
Bogdan Bjelica, Camilla Wohnrade, Alma Osmanovic, Olivia Schreiber‐Katz, Sonja Koerner, Katja Kollewe, Sebastian Haeckl, Maren Freigang, Isabell Cordts, Benedikt Becker, Charlotte Vogt, Mohamad Tareq Muhandes, René Günther, Marcus Deschauer, Jan C. Koch, Matthias Tuerk, Martin Regensburger, Christoph Neuwirth and Susanne Petri

Article first published online:
01 Nov 2025 | DOI: 10.1111/ene.70405

SHORT COMMUNICATION

Efficacy and Safety of Plasmapheresis in Children With Acute Transverse or Flaccid Myelitis, and Guillain‐Barré Syndrome

Background

Acute transverse myelitis (ATM), acute flaccid myelitis with polio‐like myeloradiculitis (AFM) and Guillain‐Barré syndrome (GBS) are severe neuroimmune disorders associated with high morbidity. First‐line treatments include corticosteroids and intravenous immunoglobulins (IVIg), but they may be insufficient. Therapeutic plasma exchange (TPE) and immunoadsorption (IA) are second‐ or third‐line options in pediatrics, despite their recognized efficacy in adults. Data on pediatric use remain limited. This study aimed to evaluate the efficacy and safety of apheresis in children with ATM, GBS or AFM.

Methods

We conducted a retrospective monocentric study at Necker University Hospital, including pediatric patients diagnosed with ATM, GBS or AFM who underwent TPE/IA between 2014 and 2024. Functional outcomes were assessed using the modified Rankin Scale (mRS) at five time points, from peak disease severity to last follow‐up. Safety was evaluated based on severe adverse events.

Results

Among 23 children (6 years [Q1‐Q3]), 20 received TPE and 3 IA. 17 of 23 patients (74%) showed significant improvement by the end of treatment. The median mRS was 5 (IQR 4–5) before apheresis, improving to 4 (IQR 2–4) at the end of TPE/IA, and decreasing to 2 at 6 months. Brainstem function fully recovered in all surviving patients. Among 14 children with sphincter dysfunction, 5 (36%) still required intermittent catheterization. No treatment discontinuations occurred, but two patients died, one from venous air embolism, one after life‐sustaining treatment limitation.

Conclusion

TPE and IA appear effective in pediatric ATM, AFM and GBS. Larger studies are needed to confirm long‐term efficacy and refine treatment guidelines.

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Authors:
Alix Fleurance, Laure Joseph, Laurène Dehoux, Christine Barnerias, Marie Hully, Manoelle Kossorotoff, Eugénie Sarda, Emmanuel Cheuret, Nathalie Bach, Charles De Marcellus, Florine Perez, Maxime Colmard, Pierre Meyer, Mikael Jokic, Olivia Boyer, Cyril Gitiaux, Mehdi Oualha, Isabelle Desguerre and Mélodie Aubart

Article first published online:
18 Nov 2025 | DOI: 10.1111/ene.70406

ORIGINAL ARTICLE

The Medical Burden of Drug‐Resistant Epilepsy in an Outpatient Clinic of a Tertiary Hospital: A Prospective Study Based on Real‐World Evidence

Objective

Drug‐resistant epilepsy (DRE) leads to a range of medical and social consequences, which contribute to a high disease burden. We aimed to describe factors associated with an increased medical burden in DRE.

Methods

We designed a longitudinal prospective study including adult people with epilepsy (PWE) who visited at least once in an outpatient clinic of a tertiary hospital during 2023. Demographic and clinical data were collected. Emergency department (ED) consultations and antiseizure medications (ASM) were documented at each visit. Information comes from a structured data warehouse integrated into an electronic health record designed for the follow‐up of PWE and used systematically in clinical practice. Patients were categorized into drug‐responsive or drug‐resistant epilepsy (DRE) according to the ILAE criteria.

Results

Of 2835 patients (51% men) and 4935 outpatient visits, 785 (27.7%) had DRE. Drug resistance was more common in focal epilepsy (29.7% vs. 19.6% in generalized epilepsy; < 0.001), in younger patients (44.1 ± 17.8 vs. 51.1 ± 20.7 years; < 0.001), and with a younger onset (24.3 ± 22.4 vs. 42.4 ± 26 years; < 0.001). DRE accounted for a higher rate of outpatient consultations [median per patient/year: 2 (1–3) vs. 1 (1, 2); < 0.001], ED consultations (25.5% vs. 16.9%; < 0.001) and traumatic injury resulting from seizures (1.7% vs. 0.5%; = 0.01). ASM changes were more frequent in DRE (61.1% vs. 32.2, %; < 0.001).

Significance

Systematic data collection using electronic health records enables comprehensive identification of epidemiological and clinical factors associated with DRE. Earlier age at onset and focal epilepsy contribute to a higher disease burden, along with more frequent follow‐up visits and increased adjustments in ASM.

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Authors:
Maria Grávalos, Jordi Mayol, Elena Fonseca, Manuel Quintana, Samuel López‐Maza, Daniel Campos‐Fernández, Laura Abraira, Estevo Santamarina and Manuel Toledo

Article first published online:
07 Nov 2025 | DOI: 10.1111/ene.70407

ORIGINAL ARTICLE

Abnormal Sleep in Chronic Inflammatory Demyelinating Polyneuropathy

Background and Objectives

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a dysimmune disease leading to sensorimotor deficits due to peripheral nerve dysfunction, but recently additional non‐sensorimotor symptoms (NSMS) were increasingly recognized. In this context, we compared the sleep behavior in persons with versus without CIDP and discussed the results with respect to further NSMS.

Methods

Twenty‐five CIDP patients and 27 controls took part in this prospective, cross‐sectional study. Clinically, sensorimotor disability (RODS), affective state (DESC‐I), and fatigue levels (FSMC scores) were assessed. Regarding sleep–wake behavior, they wore actigraphic devices over 14 consecutive days and completed sleep diaries, chronotype questionnaires, and the Pittsburgh Sleep Quality Index (PSQI). The actigraphic data were analyzed with respect to sleep efficiency, wake after sleep onset (WASO), sleep onset latency, total sleep duration, intradaily variability (IV), and interdaily stability (IS).

Results

Patients with CIDP reported significantly worse subjective sleep quality ( < 0.001). They also showed higher levels of fatigue ( < 0.001) and depressiveness ( = 0.046). The actigraphic results showed significantly reduced WASO ( = 0.012), especially early in the morning and immediately preceding waking up ( = 0.010). The sleep abnormalities were not linked to the raised clinical data ( > 0.05).

Discussion

Beyond subjectively reduced sleep quality, actigraphic data show that persons with CIDP have lowered sleep efficacy and experience increased nocturnal arousals. This suggests that sleep disturbance is a genuine aspect of CIDP adding to the underrecognized problem of NSMS in this condition.

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Authors:
Oliver L. Steiner, Claudia Angela and Fabian Klostermann

Article first published online:
05 Nov 2025 | DOI: 10.1111/ene.70408

LETTER TO THE EDITOR

Sex and Gender Transition of People With Multiple Sclerosis: A Real‐World Perspective

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Authors:
Pasquale Paletta, Paola Mosconi, Roberto Bergamaschi, Claudia Santucci, Vito Lepore and Eleonora Tavazzi

Article first published online:
25 Nov 2025 | DOI: 10.1111/ene.70409

ORIGINAL ARTICLE

Motor and Cognitive Fatigue in Chronic Inflammatory Demyelinating Polyneuropathy

Background

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is the most prevalent dysimmune disease of sensorimotor nerves. However, based on various non‐sensorimotor symptoms (NSMS), the concept of a purely peripheral condition has recently been challenged. Against this background, we aimed to differentiate motor and cognitive components of fatigue as the most prominent NSMS in CIDP.

Methods

Cognitive and motor fatigue constructs were assessed in 47 CIDP patients and 31 healthy controls (HC) using the Fatigue Scale for Motor and Cognitive Functions (FSMC). The results were referred to score data for sensorimotor disability as well as for depressiveness, sleep quality, and alertness, describing functional levels potentially related to fatigue. Further, they were analyzed with respect to serum neurofilament light chain (sNfL), a biomarker of disease progression and potentially central involvement in CIDP.

Results

CIDP patients reported significantly higher scores of total ( < 0.001), motor ( < 0.001), and cognitive ( = 0.005) fatigue compared to HC. Within the CIDP group, motor fatigue was more pronounced than cognitive fatigue compared to HC ( < 0.001). Although alertness levels did not differ significantly between the groups, poorer alertness correlated with cognitive fatigue in the CIDP cohort ( = 0.02). Notably, only functional disability and depressiveness served as predictors for both fatigue components ( < 0.05). sNfL levels showed no significant association with fatigue.

Discussion

These findings show that the burden of CIDP is not sufficiently described by sensorimotor disability. A clinically relevant NSMS aspect of the disease is fatigue in motor as well as cognitive dimensions.

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Authors:
Oliver L. Steiner, Claudia Angela, Rohat Geran and Fabian Klostermann

Article first published online:
28 Oct 2025 | DOI: 10.1111/ene.70410

ORIGINAL ARTICLE

Optimized Kappa‐Index Test Protocol to Detect Intrathecal Immunoglobulin Synthesis in Multiple Sclerosis

Background

Kappa free light chain (KFLC)‐based Kappa‐index (K‐index) can substitute oligoclonal banding (OCB) to detect intrathecal immunoglobulin synthesis. Cutoffs for positive results vary; therefore, further comparison of different approaches is necessary to optimize K‐index for diagnostic utilization.

Methods

We analyzed 432 paired CSF/serum samples and selected 77 OCB‐positive patients with multiple sclerosis (MS), clinically isolated syndrome (CIS) that did not progress to MS in > 10 years, and other neuroinflammatory diseases (non‐MS). K‐index subtests were measured on the Optilite platform (The Binding Site) and OCB with isoelectric focusing on the Hydrasys platform (Sebia).

Results

OCB positive cases had a higher K‐index than OCB negative. The MS group had a higher K‐index than CIS ( = 0.0066) and non‐MS ( < 0.0001). A K‐index over 80.9 suggests MS over CIS, and 61.4 suggests MS over non‐MS. Different values to mimic undetectable CSF KFLC levels resulted in different cutoffs against positive OCB. Using the limit of detection (LOD) of the assay and fixing sensitivity and specificity to 95% to establish the gray area, the cutoffs were < 4.45 (negative) and > 12.92 (positive). When undetectable CSF KFLC was also considered negative, specificity against OCB was 99.7% and sensitivity 92.7%, leaving 6% for gray area OCB verification testing.

Conclusions

Published K‐index cutoffs vary due to different settings of CSF KFLC results below LOD. Using a reflex approach, where samples within a certain K‐index gray area are subjected to OCB verification testing, and where samples with CSF KFLC below LOD are considered negative, was the most efficient laboratory algorithm. K‐index may also have prognostic value in MS.

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Authors:
Joel Björklund, Outi Itkonen, Pasi Nokelainen, Mika Siuko, Emilia Österlund‐Tauriala, Pentti J. Tienari and Mikko Anttonen

Article first published online:
03 Nov 2025 | DOI: 10.1111/ene.70411

ORIGINAL ARTICLE

Cognitive Reserve in Amyotrophic Lateral Sclerosis: A 2‐[F]FDG‐PET Study on Sex‐Related Differences

Background

Cognitive reserve (CR) applies to ALS‐related cognitive impairment and education is a CR proxy. The influence of sex on CR in ALS is unclear.

Methods

We compared brain 2‐[F]FDG‐PET metabolism of male (m‐ALS, = 95) and female (f‐ALS, = 95) patients, matched for age, education, onset, and King's stage, with no significant difference in ECAS scores. In each group, clusters showing a negative/positive correlation with education were used as seed regions in an interregional correlation analysis (IRCA) to evaluate connectivity. We identified the seed regions including age, onset, King's stage and ECAS as covariates.

Results

M‐ALS showed a relative hypometabolism compared to f‐ALS in bilateral frontotemporal regions. In f‐ALS brain metabolism positively correlated with education in the left fusiform gyrus, cerebellum and pons. The IRCA showed a positive correlation of the seed region with the cerebellum, pons, right fusiform gyrus and cuneus, and the left precuneus, and a negative correlation with the frontal lobes and caudate nuclei. In m‐ALS brain metabolism negatively correlated with education in the left frontotemporal and insular cortices. The IRCA showed a positive correlation of the seed region with bilateral frontotemporal and cingulate cortices, and the right parietal cortex, and a negative correlation with bilateral cerebellum and motor cortex, and the left lingual gyrus.

Conclusions

M‐ALS showed relative frontotemporal hypometabolism compared to f‐ALS, suggesting a male prevalence of CR. In m‐ALS the negative correlation of education with left frontotemporal and insular metabolism supports the CR hypothesis. In f‐ALS the positive correlation of cerebellar metabolism with education suggests compensatory mechanisms, also supported by the IRCA.

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Authors:
Antonio Canosa, Stefano Callegaro, Umberto Manera, Rosario Vasta, Sara Cabras, Francesca Di Pede, Filippo De Mattei, Francesca Palumbo, Barbara Iazzolino, Anastasia Dei Giudici, Enrico Matteoni, Grazia Zocco, Emilio Minerva, Alessandra Maccabeo, Giorgio Pellegrino, Daniela Pascariu, Maurizio Grassano, Francesco Ciresi, Marcella Testa, Giulia Polverari, Paolina Salamone, Giovanni De Marco, Claudia Paolantonio, Giulia Marchese, Cristina Moglia, Andrea Calvo, Adriano Chiò and Marco Pagani

Article first published online:
07 Nov 2025 | DOI: 10.1111/ene.70412

ORIGINAL ARTICLE

The Impact of Pregnancy on Functional Neurological Disorder (FND)

Background

Functional neurological disorder (FND) commonly affects women of reproductive age, yet little is known about its interaction with pregnancy and childbirth. We aimed to explore FND symptom changes during pregnancy, delivery and the postpartum period and understand women's experiences of care.

Methods

We conducted a cross‐sectional online survey of women with FND who had experienced pregnancy. The questionnaire was co‐designed with clinicians and individuals with lived experience.

Results

Of 111 respondents, 61 had experienced pregnancy after FND onset. Among 88 who provided onset data, 24% reported symptom onset during pregnancy, delivery, or postpartum, with 1 in 10 reporting onset specifically during the peripartum period. Seven participants described symptom onset or worsening following neuraxial (epidural/spinal) anaesthesia. On a group level, there was no significant change in FND symptoms across pregnancy phases or postpartum. FND symptoms did not worsen with vaginal delivery versus caesarean section. However, women who experienced hyperemesis gravidarum, daily headaches, or instrumented vaginal delivery were more likely to report FND symptom worsening. Although 35% expressed concern about FND during pregnancy and 13% changed pregnancy plans because of FND, the majority reported no difficulties with infant care or breastfeeding. Most participants (85%) received no FND‐specific advice regarding pregnancy, and health professionals were generally perceived to have limited knowledge of FND.

Conclusions

While FND symptoms remain stable for most women during pregnancy, a subgroup experiences significant changes or new onset. There is an urgent need for prospective studies and for developing educational resources to guide care in this understudied area.

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Authors:
Alexander Lehn, Ingrid Hoeritzauer, Caoimhe McLoughlin, Jon Stone, Syeda Farah Zahir, Jan Coebergh, Yvonne Leavy, Adam Morton and David Palmer

Article first published online:
05 Nov 2025 | DOI: 10.1111/ene.70413

ORIGINAL ARTICLE

Joint Modelling of Growth and Motor Function Centiles in Corticosteroids Treated Boys With Duchenne Muscular Dystrophy

Background

Corticosteroid (CS) treated boys with DMD display higher rates of height stunting, higher weight gain, improved motor function scores and delayed loss of ambulation compared to untreated patients. However, the relationship between growth and motor function has historically been understudied due to modelling complexities.

Methods

In this analysis, we use the newly developed motor function centiles for the NSAA, RFF and 10MWR. We consider each combination of growth (height and weight SD) and motor function using multivariate regression models controlling for differential CS treatment (prednisolone/deflazacort, daily/intermittent). This allows inference on the growth and motor function outcomes separately and on the relationship between the outcomes.

Results

We consider 559 steroid‐treated boys with DMD between the ages of 5 and 16 over 1643 assessments. Better motor function trajectories were observed in those treated with daily CS, with the deflazacort daily group displaying a positive NSAA centile trajectory (annual change of 0.07 SD). There was a mild, negative pairwise correlation between the annual changes in NSAA and 10MWR Scores, and height and weight Scores, ranging from −0.25 to −0.36. This indicated that patients with a milder weight gain or more severe height stunting trajectory with respect to their CS treatment were more likely to exhibit a more favourable NSAA or 10MWR trajectory over time.

Conclusions

This work describes the complex relationships between motor function, CS treatment and growth and provides insights for conversations about the relative benefits and negative effects of CS.

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Authors:
Georgia Stimpson, Deborah Ridout, Amy Wolfe, Evelin Milev, Emer O’Reilly, Adnan Manzur, Anna Sarkozy, Francesco Muntoni, Giovanni Baranello, A. Childs, A. Henderson, A. Majumdar, A. Murugan, A. Parkes, A. Saxena, A. Schofield, A. Schugal, A. Shah, A. Skippen, A. Wolfe, A. Y. Manzur, A. Sarkozy, C. Adams, C. Bettolo, C. de Goede, C. Frimpong, C. Lilien, C. Martos, C. Rylance, C. Smith, C. Wood, D. Baskaran, D. Krishnakumar, D. Moat, D. O’Donogue, D. Roberts, E. Bartram, E. Dowling, E. Groves, E. Milev, E. O’Reilly, E. Reading, E. Robinson, E. Stephen, E. Whitehouse, E. Wraige, E. Wright, E. Chan, F. Flint, F. Muntoni, F. Taylor, G. Ambegaonkar, G. Baranello, G. Cobb, G. Nicfhirleinn, G. Robertson, G. Tasca, H. Beattie, H. Chase, H. Davis, H. English, H. Jarvis, H. Jungbluth, H. McMurchie, H. Ramjattan, I. Guarino, I. Horrocks, I. Hughes, J. Burslem, J. Diaz‐Manera, J. Dunne, J. McFetridge, J. McVeigh, J. Moores, J. Moustoukas, J. Palmer, J. Sodhi, J. Taylor, J. TeWaterNaude, J. Tewnion, J. Watson, J. Watts‐When, J. Wong, J. Sheehan, K. Baxter, K. Payne, K. Pysden, K. Shill, K. Skone, K. Stevenson, K. Stewart, K. Strachan, K. Torne, K. Wong, L. Abbott, L. Locke, L. Servais, L. Wills, L. Pallant, M. Atherton, M. DiMarco, M. Elseed, M. Guglieri, M. Illingworth, M. James, M. Khries, M. Main, M. Main, M. Ong, M. Prasad, M. Sa, M. Vanegas, M. Scoto, N. Bhangu, N. Birchall, N. Burnett, N. Emery, N. Hussain, N. Mills, P. Brink, P. Fenty, P. Munot, R. Karuvattil, R. Keetley, R. Madhu, R. Mohamed, R. Muni‐Lofra, R. Noble, R. Rabb, R. Sullivan, R. Tomlinson, S. Brown, S. Clark, S. Geary, S. Gregson, S. Joseph, S. McKenzie, S. Ramdas, S. Sanchez Marco, S. Sedehizadeh, S. Tirupathi, S. Walker, S. Warner, S. Williamson, S. Robb, T. Leyland, T. Willis, V. Crook, V. Gowda, V. Robinson, V. Straub, V. Velmurugan, W. Girshab, Y. Balla and Z. Lambat

Article first published online:
07 Nov 2025 | DOI: 10.1111/ene.70414

ORIGINAL ARTICLE

Stroke in Fabry Disease: Identification of Risk Factors for Stroke in a Large Single‐Centre Cohort

Objectives

Risk factors for stroke in Fabry disease (FD) are not precisely known. This study presents a retrospective cohort analysis from one reference centre in the United Kingdom to determine risk factors for stroke and to develop a predictive model.

Methods

Patients > 18 years old were included in the study and were followed from their first visit until March 2019. The main outcome of the survival analysis was time to stroke. The independent risk factors were evaluated using a multivariate Cox regression.

Results

Of 414 patients, 368 were included in the survival analysis. 227 (61.7%) were female, with a median baseline age of 42.7 (IQR 27.8–54.8) for males and 39.9 (26.6–51.2) years for females. 56 (39.7%) males and 64 (28.2%) females had the N215S genotype. 41 patients had a stroke at baseline (11.2%), rising to 69 (18.8%) at the end—66.7% lacunar, 18.9% anterior circulation, 13% posterior circulation and 1.4% venous thrombosis. Median follow‐up was 10.4 years. Median time to stroke in males and females was 43 (43–43) and 58 (58–59) years, respectively. In the multivariate analysis, a concomitant autoimmune disease was associated with an increased risk of stroke, while glomerular filtration rate > 90 and N215S genotype were associated with a decreased risk.

Interpretation

Sex was not associated with stroke, despite males being more severe. These results might help stratify patients and are of interest not only to metabolic physicians, but to general stroke physicians too.

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Authors:
David Moreno‐Martinez, Sara Lucas‐Del‐Pozo, Lucia Lavalle, Uma Ramaswami, Lionel Ginsberg, Guillem Pintos‐Morell and Derralynn A. Hughes

Article first published online:
07 Nov 2025 | DOI: 10.1111/ene.70415

ORIGINAL ARTICLE

Rituximab in New‐Onset Generalized Myasthenia Gravis: Long‐Term Follow‐Up of the RINOMAX Clinical Trial

Background

The placebo‐controlled RINOMAX trial (NCT02950155) demonstrated superiority up to 12 months of rituximab over standard‐of‐care in new‐onset generalized myasthenia gravis (MG), but benefit–risk over longer time frames remains unknown.

Methods

RINOMAX included 47 participants with a Quantitative Myasthenia Gravis (QMG) score ≥ 6. Twenty‐five patients were randomized to a single intravenous infusion of 500 mg rituximab, and 22 to placebo of which 16 received rituximab after the double‐blinded phase (7 ± 2.9 months). Data were extracted from the Swedish MG registry to track hospitalizations, treatments including rescue, and disease activity scores.

Results

Compared to the placebo arm, lower mean time‐weighted QMG scores at 12 months (mean difference [MD]: 2.9, 95% CI: 0.9, 4.9; = 0.005) and 24 months (MD: 2.6, 95% CI: 0.3, 4.9; = 0.027) were observed in the RTX arm. The incidence rate of rescue from 48 weeks up to 5 years was numerically higher in the placebo arm than RTX (0.16 vs. 0.09/person‐year; = 0.121). Compared to delayed RTX, early exposure displayed lower QMG, risk of hospitalization (HR 0.24, 95% CI 0.07, 0.83), and rescue (HR 0.46, 95% CI 0.14, 1.57), but also the six patients never receiving RTX showed lower hospitalization risk (HR 0.08, 95% CI 0.01, 0.96). Corticosteroid doses were low globally throughout. Overall, 12.5% and 18.8% and of patients with early and delayed RTX, respectively, suffered a severe infection.

Conclusion

Disease activity and treatment burden, including hospitalization and rescue treatments, remained low, indicating a potential benefit of rituximab on the long‐term disease trajectory. Infection risk with B cell depletion, however, remains a concern.

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Authors:
Jing Wu, Ann Eriksson‐Dufva, Anna Budzianowska, Amalia Feresiadou, William Hansson, Max Albert Hietala, Irene Håkansson, Rune Johansson, Daniel Jons, Ivan Kmezic, Christopher Lindberg, Jonas Lindh, Fredrik Lundin, Ingela Nygren, Anna Rostedt Punga, Rayomand Press, Kristin Samuelsson, Peter Sundström, Oskar Wickberg, Thomas Frisell, Susanna Brauner and Fredrik Piehl

Article first published online:
05 Nov 2025 | DOI: 10.1111/ene.70418

ORIGINAL ARTICLE

Miglustat in Alzheimer's Disease Associated With Heterozygous Mutation: Exploratory Case Series and Preliminary Findings

Introduction

Several studies have previously demonstrated an increased risk of dementia and brain amyloid deposition in individuals with heterozygous mutations. Moreover, in a recent study, we identified the first family with autosomal dominant late‐onset Alzheimer's disease (AD) caused by a heterozygous mutation. Unfortunately, there are currently no effective treatments available for this condition. Miglustat, which impacts the metabolism of oxysterols, has been shown to exert an anti‐amyloidogenic effect in a human cellular model of AD.

Methods

In our exploratory uncontrolled study, three patients from the previously published family were orally treated with miglustat for 12 months. They underwent monthly clinical evaluations and routine blood tests. Additionally, neuropsychological evaluations, brain amyloid‐PET imaging, and biochemical analyses on plasma and CSF were performed.

Results

All three patients achieved clinical stability, showed a sustained reduction in serum oxysterol levels, and experienced a marked decrease in brain amyloid burden.

Discussion

Based on our preliminary observations and hypothesis‐generating findings, along with the growing evidence suggesting AD as a lipid disorder, miglustat should be further tested in a larger cohort of heterozygous mutated patients and probably evaluated as a potential disease‐modifying treatment for AD.

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Authors:
Diego Lopergolo, Daniele Gasparini, Silvia Bianchi, Barbara Pucci, Domenico Tripodi, Valerio Leoni, Andrea Chincarini, Stelvio Sestini, Henrik Zetterberg, Nicola De Stefano and Andrea Mignarri

Article first published online:
11 Nov 2025 | DOI: 10.1111/ene.70419

ORIGINAL ARTICLE

Impact of Collateral Circulation on Poststroke Epilepsy After Mechanical Thrombectomy for Large Vessel Occlusive Stroke: A Multicenter Cohort Study

Background

Acute ischemic stroke (AIS) represents a significant etiology of acquired epilepsy in adults. However, there remains a paucity of evidence concerning predictive factors for poststroke epilepsy (PSE) among patients undergoing mechanical thrombectomy (MT). We aimed to evaluate the association between poor collateral circulation and the risk of PSE.

Methods

This multicenter cohort study included AIS patients who underwent MT (2017–2022) at three tertiary centers. Adjusted Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for PSE risk. Subgroup analyses, sensitivity analyses, and competing risk analyses were also performed.

Results

We included 1167 patients (mean age: 62 years; 46.5% female). PSE frequency was higher in the poor collateral circulation group compared to the control group (13.0% vs. 4.2%, < 0.001). Patients with inadequate collateral circulation (ASITN/SIR < 2) showed significantly increased risks of both 12‐month PSE and 60‐month PSE development (HR > 1, < 0.05) compared to those with adequate collateral status (ASITN/SIR ≥ 2) following MT for AIS.

Conclusions

Poor collateral circulation is associated with PSE and may help identify individuals at high risk for PSE.

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Authors:
Peng Jiang, Zongzhi Jiang, He Sui, Mingyang Du, Qi Guo, Zhaoshi Zheng, Fuli Wang, Zhanhao Mo and Songyan Liu

Article first published online:
21 Nov 2025 | DOI: 10.1111/ene.70421

SHORT COMMUNICATION

Glycolipid Antibodies in Patients With Chronic Idiopathic Axonal Polyneuropathy and Gluten Neuropathy

Objective

To evaluate the presence of IgM and IgG antibodies in the serum of patients with chronic idiopathic axonal polyneuropathy (CIAP) and gluten neuropathy (GN) using a newly developed microarray technique.

Methods

Sera from 42 CIAP patients, 32 GN patients, and 79 healthy controls were tested for IgM and IgG antibodies against 16 single glycolipids and their 120 heteromeric complexes. Positivity rates were analyzed using the 95th percentile from controls.

Results

IgM positivity against 8 heteromeric complexes was more frequent in CIAP patients (16.7% to 28.6%) compared to controls, while GN patients showed higher rates (18.8% to 46.9%) across 15 complexes. GN patients had a higher rate of IgM positivity against the GM2:GT1b complex than CIAP patients (46.9% vs. 21.4%). IgG antibodies against seven antigens were also more prevalent in CIAP (16.7% to 26.2%) and GN patients (18.8% to 28.1%) than controls. GN patients showed a higher rate of IgG positivity against the GM1:Sulfatide complex than CIAP patients (15.6% vs. 0%).

Conclusions

This is the first study to report increased antibody detection rates against peripheral nerve glycolipids, both individually and in complexes. The findings suggest that a significant proportion of CIAP and GN patients may have an autoimmune pathogenesis, potentially targetable by immunotherapy.

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Authors:
Panagiotis Zis, Artemios Artemiadis, Susan Halstead, Georgios M. Hadjigeorgiou, Hugh Willison and Marios Hadjivassiliou

Article first published online:
03 Nov 2025 | DOI: 10.1111/ene.70422

ORIGINAL ARTICLE

Individual Alpha Frequency as an EEG Biomarker of Drug‐Related Cognitive Burden in Epilepsy

Background

EEG alpha rhythm is well‐proven to correlate with cognitive performance in healthy subjects. We aimed to evaluate the potential of EEG background activity, quantified as individual alpha frequency (IAF), as a biomarker of cognitive impairment induced by antiseizure medications (ASMs) in people with epilepsy (PwE).

Methods

We conducted a cross‐sectional study (S1) and a prospective longitudinal study (S2). In S1, PwE underwent EEG recording and concurrent EpiTrack assessment. In S2, EEG and EpiTrack were performed before and 6 months after initiating cenobamate. Correlation analyses assessed the association between EpiTrack scores and IAF (S1) and their changes post‐cenobamate (S2). ANOVA and ANCOVA were used to compare IAF between cognitively impaired and unimpaired PwE. Logistic regression evaluated the incremental value of IAF combined with clinical variables to identify cognitive improvement following ASM modification.

Results

We enrolled 100 PwE (42 ± 18 years) in S1 and 33 PwE (45 ± 15 years) in S2. IAF correlated significantly with EpiTrack scores in S1 ( = 0.21, = 0.03), and IAF changes mirrored EpiTrack improvements post‐cenobamate in S2 ( = 0.34, = 0.04). Cognitively impaired PwE displayed significantly lower IAF independent of age, seizure frequency, epileptiform activity, and pharmacological load ( = 0.01–0.005). Adding IAF to clinical variables significantly improved the logistic model's accuracy in predicting cognitive improvement post‐treatment (AUC: 0.83 ± 0.04 vs. 0.71 ± 0.04, = 0.005).

Conclusions

EEG background activity, assessed via IAF, is sensitive to cognitive impairment related to ASMs in PwE, demonstrated in both cross‐sectional and longitudinal contexts. IAF is thus a promising, simple, cost‐effective biomarker to monitor cognitive burden in clinical epilepsy management.

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Authors:
G. Assenza, B. M. Sancetta, G. Lippa, M. Nesta, L. Ricci, C. Liguori, G. Testone, M. Fernandes, G. Di Mauro, V. Di Lazzaro and M. Tombini

Article first published online:
26 Nov 2025 | DOI: 10.1111/ene.70423

ORIGINAL ARTICLE

Reference‐Group Adjusted Behavioural Dysfunction Questionnaire Score Discriminates Highly Behavioural‐Variant Frontotemporal Dementia From Major Depressive Disorder and Alzheimer's Disease Dementia

Background

Given the fact that behavioural variant frontotemporal dementia (bvFTD) is characterised by behavioural disorders, the assessment of these disorders is essential for early diagnosis of bvFTD. In this regard, the recently developed Behavioural Dysfunction Questionnaire (BDQ) that captures the bvFTD‐specific behavioural disorders is promising in discriminating mild‐stage bvFTD from other neurodegenerative and psychiatric disorders. In this study, we aimed to increase the discriminatory power of the BDQ by adaptation of its scoring depending on the reference group to bvFTD.

Methods

In this combined prospective and retrospective cross‐sectional study, data of 241 patients [i.e., 50 patients with mild‐stage bvFTD, 71 patients with major depressive disorder (MDD) and 120 patients with mild‐stage Alzheimer's disease dementia (ADD)] were analysed. We calculated the BDQ score in two ways: (1) as the average score of the domains' mean scores and (2) by adjusting the scoring depending on the reference group by using machine learning techniques, validated by fivefold cross‐validation.

Results

The adjusted BDQ score showed a higher (bvFTD vs. MDD) or similar (bvFTD vs. ADD) discriminatory power than the unadjusted BDQ score, with a considerably smaller difference between cut‐offs with at least 90% sensitivity and at least 90% specificity.

Conclusions

We recommend using adjusted BDQ scores when MDD or ADD are the reference groups to bvFTD. Similar approaches should be taken for other reference groups to bvFTD to best reflect the thinking of clinicians who have specific reference groups in mind as differential diagnoses to bvFTD.

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Authors:
Anna Semenkova, Olivier Piguet, Andreas Johnen, Matthias L. Schroeter, Jannis Godulla, Christoph Linnemann, Markus Baumgartner, Markus Otto, Ansgar Felbecker, Steven Wezel, Reto W. Kressig, Manfred Berres and Marc Sollberger

Article first published online:
10 Nov 2025 | DOI: 10.1111/ene.70424

REVIEW ARTICLE

Measures of Comorbidities and Frailty in Multiple Sclerosis—Systematic Review on Evidence and Applicability of Utilized Scoring Systems in Clinical Routine and Real‐World Data

Background

In multiple sclerosis (MS), comorbidities and frailty are receiving increasing attention influencing disease course, treatment and quality of life. The objective of this literature review is to evaluate the evidence, strengths and weaknesses of assessment tools for comorbidities and frailty in people with MS (pwMS).

Methods

We conducted a comprehensive systematic literature review including studies published between 2014 and 2024 with original data or systematic reviews on measures of comorbidity or frailty in pwMS using PRISMA 2020 methodology. Measures were investigated focusing on underlying evidence, validity, clinical usefulness and applicability. The quality of evidence was assessed using the GRADE approach.

Results

Out of 4185 studies screened, 31 met inclusion criteria for comorbidity and 9 for frailty measures. We identified several frailty and comorbidity scores that have been investigated in the context of pwMS. For comorbidities these were the Charlson Comorbidity Index ( = 14 studies), Elixhauser Comorbidity Index ( = 6), Self‐administered comorbidity questionnaire ( = 3) and an MS‐adapted version (SRQ‐MS, = 8). For frailty, the Frailty Index ( = 8), Fried Frailty ( = 1) and Tilburg Frailty Indicator ( = 1) were identified. Quality of evidence for scores in the specific context of pwMS was graded as mostly very low to low. Applicability in clinical routine care and to real‐world data was rated from low to moderate.

Conclusion

Out of the comorbidity and frailty scales currently available, no single scale has displayed sufficient evidence to warrant routine use. Further validation and standardization are required to ensure their applicability in real‐world use.

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Authors:
Marie Louise Aicher, Fabian Föttinger, Robert Hoepner, Andrew Chan, Thomas Berger and Gabriel Bsteh

Article first published online:
10 Nov 2025 | DOI: 10.1111/ene.70425

ORIGINAL ARTICLE

AXIN1, STAMBP, ST1A1, CDCP1, and SIRT2 Validated as Myasthenia Gravis Biomarkers: A Comparative Proteomic Study With MS, CIDP, and Controls

Background and Purpose

Myasthenia gravis (MG) lacks disease‐specific biomarkers that can support monitoring of disease activity or guide treatment decisions. This study aimed to validate serum inflammatory proteins as MG‐specific biomarkers by comparing their specificity to controls and individuals with other autoimmune neurological disorders, including multiple sclerosis (MS) and chronic inflammatory demyelinating polyneuropathy (CIDP).

Methods

In this multicentre cross‐sectional study, serum from 200 acetylcholine receptor antibody seropositive (AChR+) MG patients, 192 matched controls, 93 MS patients, and 51 CIDP patients was analyzed using a 92‐plex inflammation panel (Olink PEA). Logistic regression, principal component analysis, and Boruta machine learning algorithms identified differentially expressed proteins. MG subgroups were defined by age at onset, disease severity, and immunosuppressive treatment.

Results

Fourteen proteins significantly distinguished MG from controls, including AXIN1 (OR: 0.24), IL7 (OR: 9.38), ST1A1 (OR:0.42), IL10 (OR:3.62), CASP‐8 (OR:1.61), and TNFSF14 (OR:0.50) (Bonferroni‐corrected < 0.00135). AXIN1, ST1A1, STAMBP, CDCP1, and SIRT2 were specific for MG, separating it from MS and CIDP. Shared markers across disorders included IL6, IL8, STAMBP, and TNFSF14. A 15‐protein profile, including FGF‐23 and CXCL9, correlated with MG severity. Subgroup analyses revealed distinct protein patterns by age and treatment. TRANCE and CD6 were reduced in immunosuppressed patients, whereas EN‐RAGE, IL10, and TNFRSF9 varied in those receiving biologicals.

Conclusions

This study validates the MG‐specific serum proteomic biomarkers AXIN1, STAMBP, ST1A1, CDCP1, and SIRT2 and identifies signatures associated with severity, onset, and treatment. These findings support the use of blood‐based biomarkers for monitoring and stratification in MG clinical trials and care.

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Authors:
Amol K. Bhandage, Sarah Hoffmann, Carla Dusemund, Frauke Stascheit, Yu‐Fang Huang, Niclas Eriksson, Katja Gabrysch, Andreas Meisel and Anna Rostedt Punga

Article first published online:
14 Nov 2025 | DOI: 10.1111/ene.70426

ORIGINAL ARTICLE

Spatiotemporal Brain Dynamics During Cyclic Seizures of Super‐Refractory Status Epilepticus

Background

Cyclic seizures (CS) are defined by the periodic recurrence of epileptic activity and may offer critical insights into the mechanisms of seizure termination. Previous studies have reported increased network synchronization during the final stages of seizures. The objective of this study was to investigate hypersynchronization at the termination of cyclic seizures and to characterize its spatial distribution.

Material and Methods

To quantify brain synchronization, we calculated the imaginary coherence in a low‐frequency band (LF‐iCOH) at different ictal phases. Synchronization was calculated at both scalp regions and electrode levels. A total of 10 patients were selected, and 1230 seizures from 468 h of EEG monitoring were analyzed.

Results

Eight patients exhibited a significant increase in LF‐iCOH at seizure termination in both regional and electrode‐level analyses, with varying topographies. Hypersynchronization at the end of seizures was predominantly observed in the anterior and centrotemporal regions compared to the posterior regions.

Discussion

Terminal hypersynchronization was observed in all patients with focal to bilateral seizures and one patient with focal seizures, and was not observed in patients with localized focal seizures. The diverse topographies of terminal hypersynchronization observed suggest that this process is not related to any specific scalp area or seizure onset zone. These results suggest a common mechanism of seizure termination in the continuum of single seizures to the most severe form of SE.

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Authors:
Alexandre Ledos, Gaspard Martet, Maeva Le Goïc, Sophie Demeret, Mario Chavez and Virginie Lambrecq

Article first published online:
26 Nov 2025 | DOI: 10.1111/ene.70428

ORIGINAL ARTICLE

Very High Dose Immunoglobulin Treatment for Chronic Inflammatory Demyelinating Polyneuropathy: A Multicentre UK Study

Background

Immunoglobulin dosing is individualised in chronic inflammatory demyelinating polyneuropathy (CIDP).

Methods

We retrospectively compared differences in presentation/outcomes/side effects in subjects on very high dose immunoglobulin defined as ≥ 2 g/kg every 3 weeks (‘Group A’) and subjects on ≤ 1 g/kg every 3 weeks (‘Group B’), from 2 UK centres.

Results

One‐hundred and eight subjects with CIDP received immunoglobulins. Group A consisted of 12 subjects (11.1%). Mean dose was 2.63 g/kg every 3 weeks (SD: 0.71). Six subjects (50%) had typical CIDP, 3 (25%) had motor CIDP, and 3 (25%) had multifocal CIDP. Group B consisted of 40 subjects (37%) on a mean dose of 0.47 g/kg every 3 weeks (SD: 0.16). Compared to subjects from Group B, subjects from Group A had greater pre‐treatment disability ( = 0.029), more common associated autoimmune disease ( = 0.034), worse post‐treatment outcome ( = 0.005) and a longer time to maximal improvement ( = 0.041). No differences were found between the two groups for age/gender/weight/acuteness of presentation/side‐effects. Occurrence of any side‐effect ( = 0.005), and of thromboembolic complication ( = 0.022), were associated with presence of another autoimmune disease.

Conclusions

Very high dose immunoglobulin may be partially effective in a minority of subjects with CIDP. Subjects treated with very high dose immunoglobulin may have greater pre‐treatment disability, be more likely to have another autoimmune disease, have worse post‐treatment outcomes, and take longer to reach maximal improvement, than subjects on lower doses. Concurrent autoimmune disease may increase immunoglobulin‐induced thromboembolic risk. Earlier consideration of alternative therapies may be more appropriate than immunoglobulin dose escalation in subjects with suboptimal immunoglobulin response.

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Authors:
Yusuf A. Rajabally, Joumana Freiha, Young Gi Min and Chinar Osman

Article first published online:
18 Nov 2025 | DOI: 10.1111/ene.70429

ORIGINAL ARTICLE

Retrospective In Silico Analysis of Routine Laboratory Data Supports a Specific Association of Epstein–Barr Virus and Multiple Sclerosis

Background

We conducted a retrospective in silico analysis of routine laboratory data (RISAROLDA) to study the association of Epstein–Barr virus (EBV) and multiple sclerosis (MS).

Methods

Patients with MS and 10 different inflammatory/neoplastic diseases were identified by ICD10 codes. Results of routine laboratory testing for antibodies to EBV, measles, mumps, rubella, herpes simplex virus, varicella zoster virus and cytomegalovirus were extracted using a digital tool.

Results

Among 10,669 patients with MS and 42,222 controls, EBV serologies were available from 492 (4.6%) patients with MS and 1918 (4.5%) controls. While all but three patients with an ICD10 diagnosis of MS were EBV seropositive, closer inspection of the three EBV seronegative patients revealed they were misdiagnosed with MS, resulting in a 100% EBV seroprevalence in the remaining 489 patients with MS. In contrast, EBV seroprevalences were lower in all other diseases (78.6%–97.8%). Serum antibodies to the Epstein–Barr nuclear antigen‐1, but not to the viral capsid antigen, were higher in patients with MS than in all other diseases. In patients with MS, seroprevalences of all other common viruses were lower than those of EBV, but the frequency of intrathecal production of antibodies to EBV was lower than that of other common viruses.

Conclusions

These findings suggest that the association of EBV and MS is specific for MS as compared to various other inflammatory/neoplastic diseases and that a negative EBV serology might be a marker for the absence of MS. RISAROLDA is a powerful approach for the screening of real‐world laboratory data.

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Authors:
Mario Rodomonti, Florence Pache, Carolin Otto, Patrick Schindler, Bettina Eberspächer, Rohat Geran, Marco Puthenparampil, Paolo Gallo, Brigitte Wildemann, Sven Jarius, Hebun Erdur and Klemens Ruprecht

Article first published online:
12 Nov 2025 | DOI: 10.1111/ene.70430

ORIGINAL ARTICLE

Novel Mutations in Exon 363 With Different Phenotypes Including a Founder Mutation in Eastern Europe

Background

Titin, the largest human protein, is essential for sarcomere structure and function. The gene, spanning 364 exons, undergoes extensive alternative splicing thus producing multiple isoforms. The M‐band region, encoded by exons 359–364, plays a critical role in sarcomere integrity and mechanical stability. Exon 363 is of interest due to its involvement in titinopathies. Pathogenic truncating variants in this exon have been linked to recessive myopathies, including and mainly young‐onset recessive distal titinopathy.

Methods

A multicenter study was conducted on six patients from five unrelated families with confirmed recessive titinopathy and truncating variants in exon 363. Clinical evaluations were performed. Genetic testing and segregation analysis confirmed the phase of the variants.

Results

A novel truncating variant c.107578C>T, p.(Gln35860Ter) was identified in four unrelated patients of Eastern European ancestry, all carrying a second pathogenic variant in a canonical exon. These patients exhibited juvenile/young‐adult onset recessive distal titinopathy with progressive lower limb weakness, frequently asymmetric muscle involvement, and no cardiac or respiratory complications. A Belgian family presented with a congenital myopathy caused by a novel frameshift deletion c.107430delA, p.(Ser35811AlafsTer32) in exon 363, in compound heterozygosity with a truncating variant in exon 208. These patients showed a more severe phenotype.

Conclusions

This study expands the spectrum of TTN‐related myopathies, emphasizing exon 363's pathogenic significance. Truncating exon 363 variants contribute to young onset recessive distal and sometimes early onset titinopathy with contractures, and the phenotype severity is influenced by the second variant's location and exon usage.

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Authors:
Veronica Sian, Maria Francesca Di Feo, Sergei Kurbatov, Anna Vihola, Helena Luque, Fedor Konovalov, Stojan Peric, Cathrina Duffy, Cornelia Kornblum, Kristl G. Claeys, Peter Hackman, Bjarne Udd and Marco Savarese

Article first published online:
17 Nov 2025 | DOI: 10.1111/ene.70433

SHORT COMMUNICATION

Nerve Root Enhancement and Elevated Cerebrospinal Fluid Protein in Four Patients With ‐Linked Amyotrophic Lateral Sclerosis

Introduction

The () gene has been implicated in both sporadic and familial forms of amyotrophic lateral sclerosis (). We report four ALS cases carrying pathogenic or likely pathogenic variants, characterized by albuminocytologic dissociation and nerve root enhancement.

Methods

We present the results of the diagnostic work‐up, including lumbosacral magnetic resonance imaging (MRI) with gadolinium, electromyography (EMG), and cerebrospinal fluid (CSF) analysis. We also assessed the relationship between the albumin quotient (Q‐Alb)—an index of blood–brain barrier (BBB) dysfunction—and the disease progression rate (DPR) in 12 ‐linked ALS patients (including the four described above) and in a cohort of 137 non‐genetic ALS (NgALS) cases.

Results

The four patients presented with spinal onset (progressive lower limb weakness). The EMG ultimately showed diffuse subacute neurogenic changes, while CSF analysis revealed albuminocytologic dissociation. Lumbosacral MRI demonstrated contrast enhancement of the cauda equina roots. Immunomodulatory treatment was administered due to suspected immune‐mediated neuropathy, but all patients continued to deteriorate. Genetic testing revealed pathogenic or likely pathogenic variants in the gene, confirming the diagnosis of ALS. CSF Q‐Alb and protein levels were similarly distributed between ‐linked and NgALS patients. Q‐Alb and CSF protein levels showed a positive correlation with DPR in ‐linked patients (Rho = 0.625, = 0.03; Rho = 0.755, = 0.005), but not in NgALS patients.

Conclusion

Albuminocytologic dissociation and nerve root enhancement may occur in ‐related ALS, expanding the spectrum of atypical ALS phenotypes.

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Authors:
Veria Vacchiano, Cosmanna Ragucci, Giovanni Rizzo, Vitantonio Di Stasi, Francesca Pastorelli, Rita Rinaldi, Federica Provini, Emanuela Postiglione, Alessia Fiorentino, Valerio Carelli and Rocco Liguori

Article first published online:
12 Nov 2025 | DOI: 10.1111/ene.70434

REVIEW ARTICLE

Systematic Review of Immune and Symptomatic Treatments for Stiff‐Person Syndrome

Background and Purpose

This systematic review evaluated the effectiveness and safety of immune and symptomatic treatments in patients with stiff‐person syndrome (SPS).

Methods

A systematic search of PubMed, Embase, and the Cochrane Library was conducted up to September 30, 2024 in accordance with the PRISMA guidelines. All studies that involve SPS patients treated with symptomatic pharmacotherapy or immunotherapy and where the outcome is reported were included in the initial screening. Case reports were excluded. Two independent reviewers carried out study selection, bias assessment with the Murad et al. tool for case series, ROBINS‐I for observational studies or RoB‐2 for randomised trials, and data extraction into a predefined template. All available efficacy and safety data were recorded. A narrative synthesis was conducted to address the heterogeneity of the studies.

Results

Thirty‐six studies were included. Most of the included studies consisted of small‐scale studies, with 21 case series, 10 cohort studies and only five randomised controlled trials. Outcome assessments varied across the reviewed studies. Most studies assessed measures with subjective self‐report and/or through clinical observations. Spasms and stiffness were assessed in around 60% of studies. Walking ability and pain were evaluated in less than half of studies. Only 10 (28%) studies assessed functional improvement using a valid and reliable tool. The present review highlights the paucity of data and the heterogeneity in SPS treatment responses and underscores the need for individualised therapeutic strategies.

Conclusions

Standardised assessment methods in clinical practice are necessary to benefit understanding and approval of future therapy strategies.

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Authors:
Timothée Lenglet, Jérôme Honnorat and Shahram Attarian

Article first published online:
22 Nov 2025 | DOI: 10.1111/ene.70435

LETTER TO THE EDITOR

Clarifying Order and Carry‐Over Effects in Sequential MRgFUS Thalamotomy and Pallidothalamic Tract Ablation

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Authors:
Mickael Aubignat

Article first published online:
18 Nov 2025 | DOI: 10.1111/ene.70444

LETTER TO THE EDITOR

Response to: Disentangling Facioscapulohumeral Muscular Dystrophy Disability From Age and Comorbidities: A Call for Refined Stratification

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Authors:
Sjan Teeselink and Karlien Mul

Article first published online:
25 Nov 2025 | DOI: 10.1111/ene.70448

European Journal of Neurology

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LETTER TO THE EDITOR

Letter to the Editor: Integrating Machine Learning Into Stroke Risk Stratification in AF

LETTER TO THE EDITOR

Letter to the Editor: Integrating Machine Learning Into Stroke Risk Stratification in AF—Authors' Reply

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