cover image European Journal of Neurology

European Journal of Neurology

2026 - Volume 33
Issue 5 | May 2026
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ORIGINAL ARTICLE

Background

Cognitive impairment is common in multiple sclerosis (MS), yet the application of diagnostic frameworks of Neurocognitive Disorders (NCDs) is limited. Additionally, the integration of multimodal data for predicting cognitive outcomes using artificial intelligence (AI) remains underexplored. This study aimed to characterize NCDs in MS and predict cognitive worsening using an explainable deep learning model trained on MRI and clinical data.

Methods

Two‐hundred twenty‐four MS patients and 115 healthy controls (HC) underwent 3.0 T MRI and clinical assessment at baseline. MS patients also completed neuropsychological testing, including estimation of z‐cognitive reserve, at baseline and after a median follow‐up of 3.4 (interquartile range = [2.0; 6.1]) years. MS patients were classified as Mild or Major NCD according to the Diagnostic and Statistical Manual of Mental Disorders criteria at baseline, and as “stable” or “worsened” based on cognitive changes at follow‐up. A deep learning model was trained on baseline T1‐weighted MRI, demographic, clinical, and brain volumetric data to predict cognitive decline, with explainability methods used to interpret the model's decisions.

Results

At baseline, 4% of patients had Mild and 11% Major NCD. At follow‐up, 12% showed cognitive decline. The deep learning model predicted follow‐up cognitive status with 90% accuracy. Explainability models identified the most relevant predictors, in order of importance: cortical gray matter volume, age, thalamic and hippocampal volumes, T2 lesion volume, and z‐cognitive reserve.

Conclusions

The proposed multimodal AI approach demonstrated robust performance and highlighted relevant brain regions associated with cognitive worsening, underscoring its potential for personalized cognitive assessment and monitoring in MS.

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Authors:
Loredana Storelli, Damiano Mistri, Alice Mastropasqua, Marta Grosselle, Paolo Preziosa, Lucrezia Rossi, Massimo Filippi and Maria A. Rocca
Article first published online:
27 Apr 2026 | DOI: 10.1111/ene.70568

ORIGINAL ARTICLE

Background

Patients with generalized myasthenia gravis (gMG) frequently have variable and fluctuating symptoms. Treatments providing long‐term, sustained disease control are essential for improving function and health‐related quality of life.

Methods

In the phase 3 Vivacity‐MG3 study, nipocalimab improved clinical outcomes in adults with gMG when added to standard‐of‐care (SOC) therapy. These post hoc analyses further assessed the ability of nipocalimab to produce sustained responses over 24 weeks, using the following response categories for total score improvements in Myasthenia Gravis‐Activities of Daily Living (MG‐ADL) and Quantitative Myasthenia Gravis (QMG), respectively: Meaningful Clinical Improvement (MCI; ≥ 2‐ and ≥ 3‐point), Substantial Improvement (SI; ≥ 3‐ and ≥ 4‐point), Considerable Improvement (CIP; ≥ 4‐ and ≥ 5), Composite Response (CR; MG‐ADL improvement ≥ 2‐points plus QMG improvement ≥ 3‐points), and Minimal Symptom Expression (MSE; MG‐ADL 0 or 1).

Results

Significantly higher percentages of nipocalimab‐treated than placebo‐treated participants achieved MG‐ADL MCI, SI, and CIP, sustained for ≥ 12 consecutive weeks; achievement of these outcomes occurred as early as week 1 among nipocalimab‐treated participants. Similar results were observed for QMG MCI, SI, and CIP. Significantly higher percentages of nipocalimab‐treated participants achieved CR, sustained for ≥ 8 consecutive weeks versus placebo; the likelihood of achieving sustained CR for ≥ 8 weeks was higher with nipocalimab (odds ratio = 6.3). Nipocalimab‐treated participants were 4‐fold more likely to achieve MSE, sustained for ≥ 8 consecutive weeks versus placebo ( = 0.022). MSE and CR were achieved earlier among nipocalimab‐treated participants.

Conclusions

Nipocalimab treatment improves gMG symptoms earlier than placebo and provides meaningful and long‐term sustained disease control over 24 weeks among participants with gMG.

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Authors:
Tuan Vu, Said R. Beydoun, Richard J. Nowak, Hans Katzberg, Maria Ait‐Tihyaty, Kavita Gandhi, John J. Sheehan, Sheryl Pease, Ibrahim Turkoz, Bernie Sattin, Zia Choudhry, Sindhu Ramchandren and Carlo Antozzi
Article first published online:
19 May 2026 | DOI: 10.1111/ene.70599

ORIGINAL ARTICLE

Background

Long‐term outcome data for stiff person spectrum disorder (SPSD) remain limited and sustained response to treatment varies.

Methods

In this retrospective cohort study, we included patients with probable or definite SPSD (Mayo Clinic criteria), evaluated at Mayo Clinic (12/1995‐07/2024) with ≥ 5 years of follow‐up after diagnosis. Primary outcome measures included the modified Rankin scale (mRS) and use of gait aids.

Results

Fifty‐four patients were included, 41 (76%) were female; median age at onset was 45 years (16–78). Most were antibody‐positive (51 [94%]), with high‐titer (serum, ≥ 20 nmol/L) GAD65‐IgG in 45 (83%). Nine patients had a stiff‐limb presentation (17%). The median interval from onset to diagnosis was 2 years (0–34), and median follow‐up was 9 years (5–26). Most patients (46 [85%]) received immune therapy; 37 (82%) reported improvement. All patients had significant impairment (mRS ≥ 2) at nadir, with 31 (57%) losing functional independence (mRS ≥ 3) and 40 (75%) requiring bilateral gait assistance. The median time from onset to nadir was 6 years (0–39). At last follow‐up, most (37 [69%]) were functionally independent (mRS ≤ 2), including 8 (15%) with minimal restrictions (mRS ≤ 1). Bilateral gait assistance was needed in 22 (41%). Among 40 patients with ≥ 10 years of follow‐up, 22 (56%) had an mRS ≤ 2 and 25 (63%) required a gait aid at last follow‐up. Poor outcome in this population was associated with bilateral gait assistance at nadir and older age ( < 0.05).

Conclusions

Although over half of SPSD patients lose functional independence at disease nadir, many regain independence and achieve well‐controlled symptoms.

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Authors:
Georgios Mangioris, Andrew McKeon, James H. Bower, Nisa Vorasoot, Divyanshu Dubey, Eoin P. Flanagan, Sean J. Pittock and Anastasia Zekeridou
Article first published online:
22 May 2026 | DOI: 10.1111/ene.70609

ORIGINAL ARTICLE

Background

Congenital insensitivity to pain with anhidrosis (CIPA) is an autosomal recessive disorder caused by variants in the gene (encoding TrkA). The identification and functional analysis of these variants are essential for elucidating the genetic basis of the disease and improving diagnostic efficiency. In this study, we investigated four unrelated Chinese families with CIPA.

Methods

We employed next‐generation sequencing to identify the causative genetic variants in 13 individuals (5 affected and 8 unaffected) from four unrelated Chinese families. A comprehensive bioinformatics and in vitro functional analyses were subsequently performed to assess the pathogenicity of the identified variants.

Results

We identified seven variants in the gene, including two novel variants (c.2285C > A and c.1990_1993delinsTGCT). Functional characterization of five variants (four missense: c.632 T > A, c.1942C > T, c.2122G > A and c.2285C > A; and one indel: c.1990_1993delinsTGCT) revealed that they disrupted distinct steps within the nerve growth factor (NGF)‐TrkA pathway, including TrkA glycosylation and phosphorylation, NGF‐TrkA binding, and downstream signaling pathway.

Conclusions

Our findings expand the mutational spectrum of with two novel variants associated with CIPA and delineate the specific step(s) within the NGF‐TrkA pathway affected by each variant, thereby establishing a link between genotype and the observed phenotypic severity. This study provides a crucial theoretical and experimental foundation for the future development of personalized therapies for CIPA patients.

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Authors:
Yaqiong Ren, Yue Cao, Fangfang Cheng, Jin Dai, Yuan Zhang, Xinxin Wang, Jiali Chen, Lijun Zhou, Xiaoxiang Song and Hongying Wang
Article first published online:
25 Apr 2026 | DOI: 10.1111/ene.70610

ISSUE INFORMATION

Issue Information

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Article first published online:
25 Apr 2026 | DOI: 10.1111/ene.70611

REVIEW ARTICLE

Background

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a relevant differential diagnosis for progressive polyneuropathy, with effective treatment options available. In case of an ambiguous diagnosis, supportive tests like nerve imaging are recommended. However, MRI is considered of limited use by the current guidelines. This meta‐analysis provides an analysis of current data on morphological MRI features in CIDP.

Methods

We searched databases in PubMed, Scopus, Web of Science, and Google Scholar and reported findings following PRISMA guidelines. We included prospective and retrospective case–control and cohort studies on qualitative or quantitative assessment of cervical and lumbar nerve roots in CIDP. The size and morphological appearance of nerve roots were compared between affected vs. non‐affected subjects.

Results

We included 11 studies with qualitative and 15 with quantitative outcome measures. Odds ratios indicated hypertrophy, hyperintensity, and gadolinium enhancement in CIDP patients. Quantitative analysis confirmed larger nerve root diameters averaging at 5 mm in the cervical and 7 mm in the lumbosacral area. Few studies investigated the cross‐sectional area and volume of nerve roots, confirming larger values in CIDP patients.

Conclusions

Plexus imaging provides valuable adjunctive support in the diagnosis of CIDP and our analysis revealed greater diagnostic significance for lumbar nerve roots. Yet its utility must be interpreted with nuance because of data heterogeneity and potential imaging mimics simulating CIDP features on MRI. Future advancements should focus on refining imaging techniques and developing quantitative metrics to enhance diagnostic specificity. The integration of imaging modalities with clinical and electrophysiological findings remains essential in diagnosis of CIDP.

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Authors:
Karolina M. Gausmann, Rebecca A. May, Thorsten Sichtermann, Nicole M. Heussen, Jörg B. Schulz and Robert Brunkhorst
Article first published online:
28 May 2026 | DOI: 10.1111/ene.70612

ORIGINAL ARTICLE

Background

Cerebral amyloid angiopathy (CAA) frequently co‐occurs with Alzheimer's disease (AD), complicating diagnosis in patients with cognitive impairment. The CSF biomarker profile of CAA remains poorly understood, particularly with AD co‐pathology. We aimed to characterize CSF biomarkers in CAA, assess diagnostic accuracy, and examine associations with neuroimaging markers.

Methods

We included 261 participants from a hospital‐based cohort, recruited from memory clinic outpatients and neurology inpatients. Groups comprised healthy controls (HC,  = 35), CAA without AD co‐pathology (CAA‐nonAD,  = 27), CAA with AD co‐pathology (CAA‐AD,  = 30), and AD ( = 169). CSF Aβ40, Aβ42, p‐tau181, and t‐tau were quantified using automated immunoassays. Group differences were tested using ANCOVA adjusted for age and sex. ROC analyses with 10‐fold cross‐validation and bootstrapping assessed diagnostic performance. Associations between CSF biomarkers and CAA‐related MRI markers were examined using ANCOVA.

Results

Aβ40 concentrations were lower in CAA‐nonAD and CAA‐AD compared to AD and HC (‐value < 0.05). Aβ42 was reduced in CAA‐AD and AD versus HC, with no difference between CAA‐nonAD and AD. p‐tau181 and t‐tau were elevated in AD and CAA‐AD compared with CAA‐nonAD and HC (‐value < 0.05). Aβ40 showed the highest diagnostic accuracy for CAA (AUC = 0.73; 95% CI: 0.66–0.80), followed by Aβ42 (AUC = 0.71; 95% CI: 0.64–0.78). In AD patients, Aβ42 best discriminated coexisting CAA (AUC = 0.77). Higher CAA‐SVD burden scores were associated with lower Aβ40 (‐value < 0.05).

Conclusions

CSF Aβ40 and Aβ42 provide complementary diagnostic value for identifying CAA, both in isolation and with AD co‐pathology. Reduced Aβ40 is associated with greater CAA‐related vascular burden, supporting its role as a marker of vascular amyloid pathology.

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Authors:
Aida Fernández‐Lebrero, Joan Jiménez‐Balado, Greta García‐Escobar, José Contador, Isabel Estraguès‐Gázquez, Laia Peraferrer‐Montesinos, Antoni Suárez‐Pérez, Rosa María Manero‐Borràs, Brigitte Beltrán, Ludovica Gramegna, Ana Rodríguez Campello, Abel Palacio‐Gili, Oriol Grau, Marc Suárez‐Calvet, Angel Ois, Albert Puig‐Pijoan and Irene Navalpotro‐Gómez
Article first published online:
20 May 2026 | DOI: 10.1111/ene.70613

EDITORIAL

Cognitive Impairment Beyond Neurodegenerative Dementias: New Frontiers for Cognition in Neurological Disease

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Authors:
Paulo Caramelli and Isabel Pavão Martins
Article first published online:
29 Apr 2026 | DOI: 10.1111/ene.70614

ORIGINAL ARTICLE

Background

Posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS) are related neurovascular conditions, with pregnancy as a shared risk factor. In this study, we aimed to describe shared and distinctive risk factors and outcomes in patients with pregnancy‐associated PRES and/or RCVS.

Methods

In this retrospective, nationwide, population‐based cohort study, the national healthcare registers were utilized to identify women with PRES and/or RCVS during pregnancy or puerperium during 1987–2016. Subsequent pregnancies, vascular events, and deaths until 2022 were identified. Medical records were reviewed to classify cerebrovascular events and collect clinical details.

Results

In total, 27 patients had pregnancy‐associated PRES and/or RCVS (18 PRES; 5 PRES + RCVS; 4 RCVS) during 1987–2016, resulting in an incidence of 1.52 per 100,000 (95% Cl 1.02–2.18) deliveries. All patients with PRES ± RCVS had preeclampsia with severe features during late pregnancy or early puerperium. In contrast, isolated RCVS showed a weaker association to preeclampsia and occurred in late puerperium, with a median puerperal day of 26 (IQR 11–45). Altogether, 40.7% of all patients had a stroke, 90.9% of which were hemorrhagic. Preeclampsia was diagnosed in 90.9% of stroke patients. Maternal mortality was 3.7%, whereas perinatal mortality was 7.4%. At 3 months, 92.3% had a good recovery (mRS 0–2). During follow‐up, stroke recurrence was 3.7% and 33.3% had subsequent uneventful, full‐term pregnancies.

Conclusions

Pregnancy‐associated PRES and RCVS are potentially life‐threatening, rare conditions that can result in hemorrhagic stroke. PRES ± RCVS is strongly associated with preeclampsia with severe features, whereas puerperal RCVS seems to be a separate, later‐occurring condition.

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Authors:
Vest Teresa, Verho Liisa, Rantanen Kirsi, Aarnio Karoliina, Korhonen Aino, Richardt Anna, Gissler Mika, Tikkanen Minna, Laivuori Hannele and Ijäs Petra
Article first published online:
30 Apr 2026 | DOI: 10.1111/ene.70615

ORIGINAL ARTICLE

Background

Elevated blood pressure (BP) after spontaneous intracerebral hemorrhage (ICH) is associated with poor outcomes, but the prognostic value of prehospital BP, particularly in relation to onset‐to‐arrival time, remains unclear. We investigated time‐dependent associations of prehospital BP, arrival BP, and their early difference with in‐hospital outcomes.

Methods

We conducted a retrospective cohort study using a prospectively maintained stroke registry at a tertiary medical center in Taipei, Taiwan (2016–2022). Adults (≥ 18 years) with spontaneous ICH transported by emergency medical services within 24 h of symptom onset and with available prehospital BP were included. First prehospital and hospital‐arrival BP were analyzed. Outcomes were in‐hospital mortality and stroke in evolution (SIE) within 72 h of hospital admission. Patients were stratified by onset‐to‐arrival time (< 3 vs. ≥ 3 h). Multivariable logistic regression and restricted cubic splines were applied.

Results

Six hundred ninety patients were included (mean age 64.7 years, 63.1% male; 336 < 3 h, 354 ≥ 3 h). In patients arriving ≥ 3 h, higher prehospital systolic BP, mean arterial pressure, and pulse pressure were independently associated with increased odds of in‐hospital mortality, and higher arrival pulse pressure was also associated with mortality. Associations with SIE and early BP differences were weaker and were attenuated in fully adjusted models. Restricted cubic spline showed no nonlinear associations. No significant associations between BP measures and outcomes were observed in patients arriving < 3 h.

Conclusions

Higher prehospital BP was associated with increased in‐hospital mortality among patients presenting ≥ 3 h after onset, whereas such associations are not evident within 3 h.

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Authors:
Chun‐Ju Lien, Jui Wang, Chih‐Hao Chen, Tzu‐Hsuan Weng, Sung‐Chun Tang, Li‐Kai Tsai, Ying‐Chih Ko, Yu‐Kang Tu, Jiann‐Shing Jeng and Ming‐Ju Hsieh
Article first published online:
16 May 2026 | DOI: 10.1111/ene.70616

ORIGINAL ARTICLE

Background and Purpose

Functional stroke‐like episodes (FSMs) are an increasingly recognised stroke mimic with demographic and clinical characteristics that differ from acute ischaemic strokes (AISs) but have unclear long‐term outcomes.

Materials and Methods

We report retrospective data on consecutive patients with FSM who underwent acute perfusion‐CT (PCT) admitted to Lausanne University Hospital (2003–2017). We compared them to all contemporaneous AISs undergoing PCT from the Acute‐STroke‐Registry‐and‐Analysis‐of‐Lausanne (ASTRAL).

Results

Twenty‐five FSMs and 3201 control‐AISs were included. FSM patients were significantly younger (median 43 vs. 73 years, adjusted odds ratio (OR) 0.92), had a higher incidence of psychiatric disorders (OR 5.33/17.07), and over half had a prior history of neurological and non‐neurological functional disorders. FSM patients more often presented decreased vigilance (OR = 9.28) and sensory deficits (OR = 3.87), and less visual field defects (OR = 0.14) and dysarthria (OR = 0.20). FSM patients showed no significant changes on plain‐CT and PCT. Acute revascularisation rates were similar in both groups (48% vs. 43%). Follow‐up at 3‐months revealed significant handicap in 41% of patients, similar to the control group in propensity‐score‐matched analysis, and lower mortality (0% vs. 20%, 0.04). After a median of 9 years follow‐up, FSM patients failed to functionally improve further and 55% experienced additional functional neurological events.

Conclusion

In this single‐centre cohort of consecutive FSMs undergoing acute PCT, we identified distinctive demographic and clinical features, normal CT‐based neuroimaging, but still a high thrombolysis rate. Long‐term observation revealed a high rate of recurrent functional events and persistent disability, suggesting the need for more effective treatment and regular follow‐up.

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Authors:
Filipa Bastos, Davide Strambo, Alexander Salerno, Vincent Dunet, Selma Aybek and Patrik Michel
Article first published online:
06 May 2026 | DOI: 10.1111/ene.70617

ORIGINAL ARTICLE

Background

Plasma phosphorylated tau 217 (p‐tau217) has emerged as a promising Alzheimer's disease (AD) biomarker, yet its longitudinal associations with neurodegeneration and cognitive decline remain inadequately characterized in Chinese populations, and ethnicity‐specific diagnostic thresholds are lacking for optimal clinical application.

Methods

A total of 541 participants (402 cognitively unimpaired [CU]; 139 cognitively impaired [CI]) from the Sino Longitudinal Study on Cognitive Decline (SILCODE) cohort were enrolled. Cross‐sectional and longitudinal associations of plasma p‐tau217 with amyloid‐β (Aβ) pathology, neurodegeneration, and cognition were evaluated. Diagnostic thresholds were derived using receiver operating characteristic analysis, and Cox regression assessed prognostic value for clinical progression.

Results

Cross‐sectionally, baseline p‐tau217 was associated with greater Aβ burden, neurodegeneration, and poorer cognition in the whole cohort and CI group; in the CU group, associations were confined to amyloid measures. Longitudinally, accelerated p‐tau217 accumulation was associated with faster neurodegeneration and cognitive decline in the whole cohort, with stage‐dependent patterns: nominal associations with neurodegenerative markers in CU and prominent cognitive associations in CI. Plasma p‐tau217 demonstrated high diagnostic accuracy for amyloid positivity (AUC = 0.891; cutoff: 0.529 pg/mL). Threshold‐based stratification effectively differentiated individuals by Aβ burden, neurodegeneration, and cognitive trajectories. Elevated baseline p‐tau217 predicted higher progression risk (Whole cohort: HR = 2.66 [1.28–5.53],  = 0.009; CU: HR = 2.44 [1.07–5.59],  = 0.034).

Conclusion

Plasma p‐tau217 serves as a valuable diagnostic and prognostic biomarker for AD, even among CU individuals, and the ethnicity‐specific threshold of 0.529 pg/mL enhances its clinical applicability for early detection and risk stratification in Chinese populations.

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Authors:
Ruixian Li, Jie Yang, Wenhui Chai, Hongwei Liu, Xuanqian Wang, Shuyu Zhang, Hongtao Cai, Jinghua Wang, Tengfei Guo and Ying Han
Article first published online:
22 May 2026 | DOI: 10.1111/ene.70618

ORIGINAL ARTICLE

Object

Glutamic acid decarboxylase antibody‐associated neurological disease (GADAND) is a rare autoimmune disorder with elusive immunogenetic underpinnings. We aimed to investigate HLA associations with GADAND susceptibility in a Chinese cohort.

Methods

We performed HLA genotyping at the HLA‐A, ‐B, ‐C, ‐DRB1, ‐DQA1, and ‐DQB1 loci in 62 Chinese patients with GADAND and compared them with 990 healthy controls. Haplotype frequencies were estimated using the expectation–maximization (EM) algorithm. Allele and haplotype associations with disease susceptibility and clinical phenotypes were assessed.

Results

We identified the HLA class I haplotype A*11:01 ~ B*40:01 ~ C*07:02 as a susceptibility haplotype for GADAND (OR = 10.22, 95% CI 3.86–25.57,  = 0.003), and the association was stronger for the extended haplotype including DQA1*01:03 (OR = 25.61, 95% CI 4.99–89.11,  < 0.001). Three haplotypes showed suggestive but non‐significant associations: B*44:02 ~ C*05:01 (OR = 8.32, 95% CI 2.52–24.48,  = 0.069), DQA1*01:03 ~ DQB1*06:01 ~ DRB1*08:03 (OR = 3.15, 95% CI 1.67–5.63,  = 0.066), and DQA1*05:05 ~ DQB1*03:01, which showed a suggestive protective effect (OR = 0.15, 95% CI 0.018–0.556,  = 0.088). T1DM risk haplotypes, including DQA1*03:01 ~ DQB1*03:02 ~ DRB1*04:03 (OR = 5.04, 95% CI 1.18–16.62,  = 0.744) and DQA1*05:01 ~ DQB1*02:01 ~ DRB1*03:01 (OR = 2.50, 95% CI 1.07–5.24,  = 0.829), were more frequent in GADAND patients, and A*11:01 ~ B*40:01 ~ C*07:02 was enriched in those with comorbid AITD. No statistically significant associations were identified between HLA haplotypes and clinical phenotypes.

Conclusions

The haplotype A*11:01 ~ B*40:01 ~ C*07:02 was associated with GADAND susceptibility in the Chinese population, implicating T cell involvement. T1DM‐associated haplotypes were overrepresented in GADAND, and A*11:01 ~ B*40:01 ~ C*07:02 was enriched in comorbid AITD, suggesting HLA as a shared immunogenetic basis for autoimmune comorbidities. No significant HLA associations with clinical phenotypes were identified, warranting validation in larger cohorts.

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Authors:
Lin Bai, Haitao Ren, Qiang Lu, Han Zhang, Yang Yu, Zhuo Yang, Xinzhuang Yang, Siyuan Fan, Xinhua Wan, Yicheng Zhu, Hongzhi Guan and Meng Xiao
Article first published online:
11 May 2026 | DOI: 10.1111/ene.70619

ORIGINAL ARTICLE

Background

B‐cell–depleting anti‐CD20 therapies are among the most effective disease‐modifying treatments for relapsing–remitting multiple sclerosis (RRMS). Rituximab (RTX) is widely used off‐label, while ocrelizumab (OCR) is approved for RRMS; yet comparative real‐world evidence between the two remains limited.

Methods

We conducted a retrospective registry‐based cohort study using the Finnish MS Registry, including adult RRMS patients treated with RTX or OCR between 2018 and 2024 at two university hospitals. Propensity score matching (1:1) was applied to balance baseline characteristics. Primary outcomes were annualized relapse rate (ARR) during follow‐up and relapse‐free survival. Secondary outcomes included MRI activity, disability progression, adverse events, and longitudinal plasma immunoglobulin G (IgG) levels.

Results

Of 636 screened patients, 191 met inclusion criteria and 112 patients (56 RTX, 56 OCR) were included after matching. Median follow‐up was 3.1 years for RTX and 2.6 years for OCR. ARR was low and similar in both groups (mean 0.03), and relapse‐free survival did not differ (log‐rank  = 0.95; HR 0.95, 95% CI 0.21–4.33). MRI activity remained largely stable, with no significant differences in T2 lesion changes. Adverse events were infrequent and mild. IgG declined modestly in both groups (mean−13%), with values below the reference range in 4.5% of patients and no association with infections. No disease reactivation was observed among patients switching from OCR to RTX.

Conclusions

In this population‐based Finnish real‐world study, RTX and OCR demonstrated comparable effectiveness and safety in RRMS, supporting RTX as a rational alternative to OCR in routine clinical practice.

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Authors:
Maiju Savolainen, Merja Soilu‐Hänninen, Henriikka Nurmi, Matias Viitala, Pentti Tienari, Sari Atula and Sini M. Laakso
Article first published online:
16 May 2026 | DOI: 10.1111/ene.70625

ORIGINAL ARTICLE

Background and Objective

The incidence of ischemic stroke (IS) in young adults (18–50 years) has been rising, in parallel with a growing prevalence of traditional vascular risk factors in this population. Understanding these trends critical for prevention and treatment strategies. This study aimed to analyze temporal trends in classical vascular risk factors among young adults hospitalized with IS in Spain between 2000 and 2022, and to forecast their prevalence through 2027.

Methods

A retrospective analysis was conducted using hospital discharge data from the Spanish National Inpatient Database. Patients aged 18–50 years diagnosed with IS between 2000 and 2022 were included. Temporal trends were assessed using ordinary least squares regression and stationarity was evaluated with the Augmented Dickey–Fuller test. Short‐term forecasts (2023–2027) were generated using a cross‐validated time‐series framework comparing multiple univariate models. Model selection was based on out‐of‐sample root mean squared error.

Results

A total of 57,427 young adults with IS were identified. Incidence increased from 7 to 15 per 100,000 population between 2000 and 2022. Increases were observed in obesity (5.2%–15.2%), dyslipidemia (20.8%–29.7%), and illicit substance use (1%–13.5%). Obstructive sleep apnea, patent foramen ovale, and other congenital heart diseases also showed upward trends, while hypertension and diabetes remained relatively stable. Short‐term forecasts suggest a sustained burden through 2027.

Conclusions

The increasing burden of modifiable vascular risk factors and cardiac comorbidities among young IS patients underscores the urgent need for public health strategies focused on early detection, lifestyle modification, and prevention in this population.

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Authors:
Tania Garrido‐Hernández, Laura Amaya‐Pascasio, Adrián Aparicio‐Mota, José María López‐Martín and Patricia Martínez‐Sánchez
Article first published online:
18 May 2026 | DOI: 10.1111/ene.70633

ORIGINAL ARTICLE

Background

Pain is a frequent and disabling symptom in patients with Functional Motor Disorders (FMD), yet its clinical correlates and impact have not been characterized in large, representative cohorts. The aims of this study were to identify clinical predictors and correlates of pain intensity and interference among FMD patients.

Methods

We conducted a cross‐sectional analysis within the Italian Registry of Functional Motor Disorders, including 466 adults with FMD recruited from 25 movement disorders centers. Pain was assessed using the Brief Pain Inventory (BPI), which captures pain experienced during the 24 h prior to assessment, alongside sociodemographic, clinical, and psychometric data on depression, anxiety, alexithymia, fatigue, and quality of life.

Results

Pain was reported by 78.8% of participants. Fibromyalgia strongly predicted pain, whereas comorbid epilepsy was linked to reduced risk. The presence of pain was associated with a poorer self‐reported sense of physical health. Among patients with pain, higher intensity and interference were associated with younger age, Restless Legs Syndrome, Irritable Bowel Syndrome, physical trauma as a precipitating factor for FMD, anxiety, and poorer physical and mental health. Painkillers were prescribed to 41.6% of patients, yet 39.27% reported pain despite medications, and 39.48% had pain while not receiving analgesics.

Conclusions

Pain is highly prevalent in FMD when assessed over the previous 24 h and is frequently reported in patients who are either not receiving analgesics or continue to experience pain despite treatment. Multiple factors influence its intensity and interference in daily life. Longitudinal studies are needed to clarify causal relationships and to inform pain management strategies.

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Authors:
Veronica Nisticò, Benedetta Demartini, Christian Geroin, Enrico Marcuzzo, Angela Sandri, Luigi Michele Romito, Roberto Eleopra, Lucia Tesolin, Francesco de Bertoldi, Alessandra Nicoletti, Giovanni Mostile, Nicola Modugno, Enrica Olivola, Andrea Pilotto, Alessandro Magliozzi, Tommaso Ercoli, Giovanni Defazio, Martina Petracca, Carlo Dallocchio, Rosa De Micco, Marcello Esposito, Roberto Erro, Roberto Ceravolo and Michele Tinazzi
Article first published online:
18 May 2026 | DOI: 10.1111/ene.70634

ORIGINAL ARTICLE

Background

The cause of facial pain often remains unknown after ruling out dental disorders and arterial compression of the trigeminal nerve. New pathologic models and treatment options are needed.

Method

Review of 30 patients with unexplained facial pain who were diagnosed with internal jugular vein (IJV) entrapment.

Results

Mean age 48.8 ± 12.8 years, duration of symptoms 68.4 ± 100.4 months, women (28/30, 93%). Symptom laterality: left only (11/30, 37%), right only (8/30, 27%), bilateral equally (7/30, 23%), left worse than right (3/30, 10%), right worse than left (1/30, 3%). Facial pain lateralized to the side of underlying venous compression in 19/30 (63%) patients or was unilateral with underlying bilateral compressions in 9/30 (30%). The IJV obstructed at the atlas (lateral process of the atlas, styloid process, posterior belly digastric muscle), between muscles in the mid‐neck (sternocleidomastoid, omohyoid, and anterior scalene), and at the thoracic outlet. This led to dilation of the superior petrosal sinus that abuts the trigeminal nerve and shunting through vertebral veins that congested the lower brainstem and cervical spinal cord where the spinal trigeminal nucleus originates and descends. Targeting the IJV obstruction with physical therapy, neurotoxin injections in the neck, and surgical decompression significantly improved facial pain in most patients (20/30, 67%) but was too advanced in some to achieve meaningful relief.

Conclusion

Increasing awareness of venous outflow obstruction as a contributor to facial pain could explain complex regional neurological symptoms, provide an option beyond oral medications, and lead to earlier diagnosis when the pathology is amenable to treatment.

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Authors:
K. Chan, M. Gharib, J. Karam, S. Won and Y. H. Cha
Article first published online:
26 May 2026 | DOI: 10.1111/ene.70645

ORIGINAL ARTICLE

Background

Data on the association between physical activity (PA) and cryptogenic ischaemic stroke (CIS) in young adults are scarce. We investigated the relationship between PA levels and early‐onset CIS, stratified by the presence of a high‐risk patent foramen ovale (PFO).

Methods

Patients aged 18–49 years with first‐ever CIS and sex‐ and age‐matched stroke‐free controls were recruited from 19 European centres. PA was assessed using the short International Physical Activity Questionnaire and expressed as Metabolic Equivalents, categorized into percentiles (bottom 10%, 10%–25%, 25%–75% [reference], 75%–90%, top 10%). Associations between PA and CIS were analyzed using conditional logistic regression adjusted for age, education level, traditional risk factors, and non‐traditional risk factors.

Results

Altogether, 533 patients (median age 41 [interquartile range 34–46]; 47.3% women) and 533 controls were included. Scoring in the top 10% of PA was independently associated with CIS: adjusted odds ratio 2.07; 95% confidence interval 1.22‐3.51. Comparing patients without high‐risk PFO to all controls, the top 10% PA category (1.78; 1.07‐2.94) and the bottom 10% category (1.76; 1.06‐2.92) were associated with CIS. No independent association was observed in patients with high‐risk PFO.

Conclusions

PA in the top 10% was associated with an increased risk of early‐onset CIS in the overall study population. Among patients without a high‐risk PFO, both the bottom 10% and top 10% of PA were consistently associated with elevated CIS risk. These findings highlight the need to better understand the mechanisms through which both low and high activity levels may predispose to stroke.

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Authors:
Shakar Kutal, Nilufer Yesilot, Tomi Sarkanen, Petra Redfors, Annika Nordanstig, Pauli Ylikotila, Marialuisa Zedde, Ulla Junttola, Lauri Tulkki, Kristina Ryliskiene, Radim Licenik, Phillip Ferdinand, Dalius Jatužis, Liisa Kõrv, Janika Kõrv, Alessandro Pezzini, Juha Sinisalo, Mika Lehto, Eva Gerdts, Jaana Autere, Ana Catarina Fonseca, André Paula, Ulrike Waje‐Andreassen, Bettina von Sarnowski, Tiina Sairanen, Turgut Tatlisumak, Juha Huhtakangas, Pekka Jäkälä, Jukka Putaala and Nicolas Martinez‐Majander
Article first published online:
28 May 2026 | DOI: 10.1111/ene.70650