cover image European Journal of Neurology

European Journal of Neurology

2026 - Volume 33
Issue 3 | March 2026
Previous Issue

REVIEW ARTICLE

Background

Migraine and sleep disturbances share a bidirectional relationship, influencing each other's frequency and severity. The aim of this systematic review is to examine the effects of migraine‐targeted interventions on both migraine outcomes and sleep parameters (including sleep quality and insomnia symptoms), as well as the effects of sleep‐focused interventions on both sleep and migraine outcomes.

Methods

Following PRISMA 2020 guidelines, a systematic search was conducted across six databases (PubMed, Medline, Scopus, Embase, PsycINFO, CINAHL) for studies published until December 5, 2023. Eligible studies included Randomized Clinical Trials, Controlled Clinical Trials, and observational studies assessing migraine and/or sleep‐targeted interventions in adults. The risk of bias was evaluated using RoB 2 and ROBINS‐E tools.

Results

Twenty‐three studies (1941 participants) were included. Pharmacological treatments such as erenumab, amitriptyline, propranolol, and onabotulinumtoxinA reduced migraine frequency and pain intensity, with variable effects on sleep quality. Melatonin showed no significant impact. Among non‐pharmacological treatments, percutaneous electrical nerve stimulation, greater occipital nerve block, green light therapy, binaural beats, mindfulness, and dietary modifications improved both migraine symptoms and sleep. Digital Cognitive‐Behavioral Therapy for Insomnia (CBT‐I) significantly reduced headache days and improved sleep parameters, whereas evidence on standard CBT‐I was mixed.

Limitations

Study heterogeneity, small sample sizes, and variability in outcome measures limit generalizability. Few studies focused on sleep‐targeted interventions and their effects on migraine, highlighting a research gap.

Conclusions

Integrated approaches combining migraine and sleep interventions show promise for symptom management. Further research is needed to refine treatment strategies and assess long‐term effects.

Registration

CRD42024617217.

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Authors:
Marco Sforza, Ilaria Mariani, Federica Fazzini, Federica Genovese, Andrea Salibba, Massimo Filippi, Paola Proserpio, Andrea Galbiati, Roberta Messina and Luigi Ferini‐Strambi
Article first published online:
24 Mar 2026 | DOI: 10.1111/ene.70420

ORIGINAL ARTICLE

Objectives

This study evaluated the natural history of giant cerebral arteriovenous malformations (AVMs) over 6 cm and compared long‐term outcomes of interventional treatment versus conservative management.

Materials and Methods

Patients with AVMs > 6 cm were identified from a national multicenter prospective registry (MATCH). Rupture risk factors were analyzed with uni‐ and multivariate models. Propensity score matching balanced intervention and conservative groups. The primary outcome was long‐term hemorrhagic stroke or death; secondary outcomes included obliteration rates and neurological status. Subgroup and sensitivity analyses assessed robustness.

Results

From August 2011 to December 2021, 380 patients with giant AVMs were enrolled. Annual rupture risk was 2.4% for unruptured lesions, 9.4% for previously ruptured, and 3.6% overall. Ventricular involvement (OR = 3.61) and draining vein stenosis (OR = 2.61) were independent hemorrhage risk factors. Over a mean follow‐up of 7.3 years, intervention did not significantly reduce hemorrhagic stroke or death compared to conservative management but was associated with higher hemorrhagic stroke risk (HR = 2.04) and neurological deterioration, despite higher obliteration rates (39.1%). Stratified analysis suggested microsurgery and embolization alone were less favorable, while embolization plus radiosurgery more effectively reduced hemorrhagic stroke or death. Subgroup analysis indicated conservative management was preferable for higher S‐M grades, unruptured AVMs, and eloquent brain regions.

Conclusion

The annual rupture rate of giant AVMs (> 6 cm) is approximately 3.6%. Interventional treatment for giant AVMs is not superior to conservative management, and the risks of hemorrhagic stroke and neurological deterioration remain substantial—particularly for unruptured, high‐grade, or eloquently located AVMs.

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Authors:
Nan Li, Yukun Zhang, Chengzhuo Wang, Heze Han, Li Ma, Ruinan Li, Zhipeng Li, Haibin Zhang, Kexin Yuan, Anqi Li, Qinghui Zhu, Yongenbo Su, Dezhi Gao, Hengwei Jin, Youxiang Li, Shibin Sun, Yuanli Zhao, Shuo Wang, Yu Chen, Hao Wang, Xiaolin Chen and Jizong Zhao
Article first published online:
06 Mar 2026 | DOI: 10.1111/ene.70485

ORIGINAL ARTICLE

Background

Intracranial High‐Resolution Vessel Wall (HRVW) MRI is sometimes used alongside standard ischemic stroke (IS) work‐up, yet its clinical and therapeutic interests remain debated. We aimed to assess the intracranial HRVW‐MRI findings in IS patients and their impact on the IS etiologic classification as well as on treatment modifications.

Methods

We retrospectively analyzed consecutive patients who underwent an intracranial HRVW‐MRI within 2 weeks from stroke onset at a single comprehensive stroke center. The HRVW‐MRI was considered for IS patients with intracranial stenosis or of undetermined origin following standard IS work‐up. We compared IS etiology according to the TOAST classification before and after HRVW MRI and identified treatment changes.

Results

Among the 316 included patients (mean age = 65 years ±16.9), HRVW‐MRI was performed to evaluate intracranial stenosis in 134 (42%), and IS of undetermined etiology without stenosis in 177 (56%). HRVW‐MRI modified the TOAST classification in 17% of cases. Following HRVW‐MRI, the proportion of strokes attributed to presumed atheromatous origin increased from 28.2% to 38.3% ( < 0.001), and those due to other determined etiologies rose from 7.3% to 12.7% ( < 0.001), while undetermined strokes decreased from 50.9% to 35.4% ( < 0.001). Etiological reclassifications were comparable in the subgroups of patients with intracranial stenosis and those with initially undetermined etiology. HRVW‐MRI prompted therapeutic changes in 7% of cases.

Conclusion

HRVW‐MRI significantly affected the IS etiologic classification and had implications in subsequent therapeutic management. Further prospective studies are warranted to determine the clinical utility of HRVW‐MRI in IS etiological work‐up.

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Authors:
Grace Adwane, Alexia Tran, Pierre seners, Julien Savatovsky and Michael Obadia
Article first published online:
06 Mar 2026 | DOI: 10.1111/ene.70492

ORIGINAL ARTICLE

Introduction

Peripheral demyelinating neuropathies impair gait and increase fall risk, particularly under cognitively demanding conditions. While gait disturbances in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and Charcot–Marie–Tooth disease type 1A (CMT1A) are well documented, their differential responses to cognitive dual‐tasking remain poorly understood.

Methods

In this prospective study, 62 patients (31 CIDP, 31 CMT1A) performed 10‐m barefoot walking trials under three conditions: natural walking, low dual‐task (answering factual questions), and high dual‐task (introspective questions about illness impact). Gait parameters, including speed, stride length, stride time, foot and heel clearance, were measured using a motion capture system. Group, condition, and interaction effects were analyzed using linear mixed‐effects models.

Results

Both groups showed significant reductions in gait speed and stride length under dual‐task conditions. Compared to CMT1A, CIDP patients exhibited more pronounced slowing and increased stride time, especially during high dual‐tasking. Heel clearance decreased significantly in CIDP, with a group × condition interaction, while CMT1A patients maintained more stable gait patterns. Foot clearance at peak swing declined in both groups without intergroup differences.

Discussion

These results suggest that CIDP patients adopt a more cautious gait under cognitive load, reflecting reduced automatism and adaptability. In contrast, CMT1A patients appear to benefit from long‐term compensatory strategies developed over the disease course. Moreover, the CIDP patients decreased their heel clearance during dual‐task, increasing the fall risk.

Conclusion

Dual‐task gait analysis reveals distinct adaptations in hereditary and acquired neuropathies. Parameters such as heel clearance and stride time may serve as functional markers to guide diagnosis and rehabilitation.

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Authors:
Loïc Dupont, Romain Thomas, Loïc Danjoux, Madeline Cailleret, Jean‐Baptiste Davion, Luc Defebvre, Arnaud Delval and Céline Tard
Article first published online:
24 Mar 2026 | DOI: 10.1111/ene.70518

EDITORIAL

Screening of Atrial Fibrillation in Cryptogenic Ischemic Stroke—Does Timing Make the Difference?

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Authors:
Olli P. Suomalainen and Jukka Putaala
Article first published online:
25 Mar 2026 | DOI: 10.1111/ene.70526

ORIGINAL ARTICLE

Background

Insulin resistance and impaired insulin secretion are hallmarks of type 2 diabetes (T2D) and may influence risks of complications including dementia. We investigated dementia risk across T2D subgroups defined by beta‐cell function and insulin sensitivity.

Methods

We used Homeostasis Model Assessment‐2 indices of beta‐cell function (HOMA2‐B) and insulin sensitivity (HOMA2‐S) to classify 7221 individuals with recently diagnosed T2D into insulinopenic (low HOMA2‐B, high HOMA2‐S), classical (low HOMA2‐B, low HOMA2‐S), and hyperinsulinemic (high HOMA2‐B, low HOMA2‐S) subgroups. Incident dementia was ascertained by validated hospital diagnosis codes and dementia‐specific medication over 13 years. Absolute risks were estimated using the Aalen‐Johansen estimator and adjusted hazard ratios (aHRs) using Cox regression.

Results

Over a median follow‐up of 9 years, 179 (2.5%) developed dementia. The 10‐year risk (95% CI) was 3.8% (2.4%–5.8%) in the insulinopenic subgroup versus 2.8% in both classical (2.3%–3.5%) and hyperinsulinemic (2.0%–3.8%) subgroups. Compared with classical T2D, aHRs (95% CI) were 1.31 (0.83–2.09) for insulinopenic and 1.10 (0.78–1.54) for hyperinsulinemic T2D. No robust associations with dementia were observed with insulin resistance (HOMA‐IR) or C‐peptide levels, although compared to the lowest C‐peptide levels (quartile 1), aHRs (95% CI) were decreased at 0.67 (0.45–1.01) in quartile 2, 0.73 (0.48–1.09) in quartile 3, and 0.89 (0.59–1.33) in quartile 4.

Conclusions

We found no clear associations between T2D subgroup, insulin resistance, or C‐peptide level at T2D diagnosis and dementia risk. The numerically higher risk in those with lower insulin secretion was statistically imprecise and warrants further study.

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Authors:
Nicole Jacqueline Jensen, Astrid Kousholt, Jens Steen Nielsen, Jacob Stidsen, Allan Vaag, Reimar Wernich Thomsen, Jørgen Rungby and Frederik Pagh Bredahl Kristensen
Article first published online:
28 Feb 2026 | DOI: 10.1111/ene.70527

ORIGINAL ARTICLE

Background

The in vivo detection of phosphorylated‐α‐synuclein (pS129‐α‐syn) via immunofluorescence in cutaneous nerve fibers has emerged as a promising biomarker for diagnosing synucleinopathies, including Parkinson's disease, dementia with Lewy bodies and multiple system atrophy (MSA). However, the variability in biopsy protocols, particularly regarding the choice and number of anatomical sites, limits standardisation and clinical applicability.

Objective

To evaluate the diagnostic accuracy of different biopsy site combinations for pS129‐α‐syn detection in a large cohort of patients with confirmed synucleinopathies, to identify a sampling strategy that ensures high sensitivity while reducing patient burden, promoting methodological standardisation and clinical applicability.

Methods

In this 10‐year retrospective study, data from 227 patients with Lewy Body Diseases (LBD) ( = 194) or MSA ( = 33), who were identified as positive based on the three anatomical sites (two samples from each site: the cervical region (CE), thigh (TH) and distal leg (LEG)) skin biopsies protocol, were analysed. Diagnostic sensitivity was calculated for each site and combination, stratified by sex and disease duration.

Results

The results showed that the CE + LEG combination yielded the highest diagnostic sensitivity in both the LBD (97.68%) and MSA (100%) cohorts, independent of sex and duration. The TH site offered minimal additional diagnostic value when combined with CE and LEG.

Conclusions

CE + LEG dual‐site skin biopsy provides high diagnostic accuracy for both LBD and MSA, making it a less invasive yet effective alternative to the tri‐site protocols (six samples). The distinct deposition patterns observed between disease subtypes warrant further investigation to enhance the biomarker's diagnostic and pathophysiological relevance.

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Authors:
Cecilia Delprete, Alex Incensi, Alessandro Furia, Cosmanna Ragucci, Riccardo Bari, Veria Vacchiano, Maria Pia Giannoccaro, Giovanni Rizzo, Rocco Liguori and Vincenzo Donadio
Article first published online:
18 Mar 2026 | DOI: 10.1111/ene.70528

ORIGINAL ARTICLE

Introduction

Monitoring individuals with peripheral neuropathies is challenging due to limited availability and time resources of neurologists, especially for rare genetic forms. This highlights the need for innovative methods to quantify disease severity efficiently and enable telemedical settings. In this study, we explored the feasibility of visual grading of gait disability as a novel approach for remote disease monitoring, using genetic neuropathies (Charcot Marie Tooth Disease, short CMT) as a model.

Methods

We prospectively evaluated 53 participants with CMT using a battery of clinical examination scores, and patient reported outcome measures (PROMs), as well as semi‐standardized sagittal‐plane videos of participants walking a 4‐m runway for 5 ± 2 min cross‐sectionally, and developed the Visual Gait Assessment Scale in Polyneuropathy (vGASP) to grade the severity of gait abnormality.

Results

Three independent raters evaluated the score as easily understandable and quick. The vGASP was internally consistent (inter‐class coefficient of 0.9) and valid when correlating with validated clinical outcome measures (Spearman's ρ = 0.6–0.8).

Conclusions

The vGASP may offer a time‐effective solution for remote monitoring of patients in CMT and potentially other gait‐affecting polyneuropathies.

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Authors:
Helena F. Pernice, Emanuele Piazza, Eleonora Asaad, Paul J. Wetzel and Katrin Hahn
Article first published online:
20 Mar 2026 | DOI: 10.1111/ene.70532

ORIGINAL ARTICLE

Background

Delays in the provision of care to patients experiencing seizures can result in evolution into status epilepticus (SE) and admission to the intensive care unit (ICU). However, data on specific response times and its implications remain sparse. Our aim is to report the time intervals of care delivery in patients with urgent seizures and evaluate its impact on the diagnosis of SE and the requirement for ICU admission.

Methods

A consecutive cohort analysis was conducted across two tertiary hospitals between December 2022 and March 2024. Of 1493 emergency episodes, 1139 cases were analyzed after excluding non‐epilepsy diagnoses and incomplete data. Demographic data and time intervals (seizure onset, extra‐hospital emergency activation, hospital admission, and EEG performance) were recorded. Associations between these intervals and SE diagnosis or ICU admission were evaluated.

Results

From our sample, 236 patients were diagnosed with SE, and 128 required ICU admission. Patients with SE had longer commute times (55 vs. 48 min,  = 0.040) and higher rates of prehospital anti‐seizure drug administration ( < 0.001). Delays in EEG acquisition were associated with increased ICU admissions (22.1 vs. 16.5 h,  < 0.001). In multivariable analysis, prehospital treatment showed a strong association with SE (OR = 24.5,  < 0.001). Commute to hospital (OR = 4.95,  0.001) and seizure‐to‐EEG timelapse (OR = 5.05,  0.001) were associated with ICU admission.

Conclusion

Pre‐hospital treatment administration, commute home to hospital and delayed EEG acquisition are associated with SE diagnosis and ICU admission, underscoring the need to optimize urgent care protocols for epileptic seizures.

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Authors:
Jacint Sala Padró, Elena Fonseca, Manuel Quintana, Guillermo Hernández Pérez, Samuel López‐Maza, Daniel Campos‐Fernández, Laura Abraira, Estevo Santamarina, Misericòrdia Veciana de las Heras, Merce Falip Centellas and Manuel Toledo
Article first published online:
04 Mar 2026 | DOI: 10.1111/ene.70533

ORIGINAL ARTICLE

Background

Vasculitic neuropathy (VN) is a disease in which vessel inflammation happens and injures peripheral nerves. Despite increasing awareness, features of VN in mainland China are still understudied.

Objective

To characterize the clinical, pathological features and outcomes of VN in mainland China, and evaluate clinicopathological correlations:

Methods

We retrospectively reviewed records of VN patients diagnosed pathologically between June 1999 and December 2024, including demographic data, clinical manifestations, biopsy features, and outcomes.

Results

112 patients were totally included. All presented with axonal sensorimotor neuropathy, most commonly involving the tibial (90.63%) and peroneal (87.50%) nerves. Systemic VN (SVN) showed more frequent transmural inflammatory cell infiltration (ICI) than non‐systemic VN (NSVN) ( = 0.046). Eosinophilic granulomatosis with polyangiitis (EGPA) was more common in VN without ICI than VN with ICI ( = 0.008). In SVN, the ICI‐positive exhibited more severe distal upper limb weakness ( = 0.042) and higher thrombosis rates ( = 0.001) than ICI‐negative. Of the 63 patients followed, 62 received glucocorticoids with or without immunosuppressants. Thirteen died from multi‐organ complications (12 SVN and 1 NSVN), while others achieved remission. The 5‐year all‐survival rate was 80.23% (95% CI 66.83%– 88.66%).

Conclusions

This first large cohort of VN in mainland China delineates its clinical–pathological features. EGPA showed a lower diagnostic yield on biopsy, suggesting diverse mechanisms of vascular injury. Nerve biopsy remains the diagnostic gold standard. The overall prognosis of VN is relatively favorable, emphasizing the need for early recognition and treatment.

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Authors:
Xiaoyu Zhou, Didi Shan, Bin Wu, Fuchen Liu, Dong Zhang, Pengfei Lin, Wei Li, Yuying Zhao, Chuanzhu Yan and Jingwen Xu
Article first published online:
14 Mar 2026 | DOI: 10.1111/ene.70540

ORIGINAL ARTICLE

Background

Surgical intervention is recommended in idiopathic intracranial hypertension (IIH) for fulminant or treatment‐refractory cases, yet data on outcomes remain limited, particularly regarding indication‐specific effects. This study evaluated outcomes and indications for surgery in IIH, aiming to identify predictors of favorable or adverse results.

Methods

A retrospective multi‐center study was conducted by the Danish‐Austrian IIH Consortium (DASH‐IIH). Databases from three centers (Vienna, Odense, Copenhagen) were screened for persons with IIH (pwIIH) fulfilling revised Friedman criteria who underwent surgery and had ≥ 6 months of follow‐up. Outcomes at 6 months included visual function, headache improvement (≥ 50%), papilledema resolution, and severe adverse events. Multivariable regression was used to adjust for confounders.

Results

Of 1310 pwIIH, only 3.6% required surgery overall. Thirty‐six pwIIH were included (100% female; mean age 32.5 years; median BMI 37.0; median CSF opening pressure 41 cmHO). Of these, 27 (75%) underwent CSF diversion and 9 (25%) optic nerve sheath fenestration (ONSF). The primary indication for surgery was acute visual deterioration in 83.3% and refractory headache in 16.7%. Visual function improved in 41.7%, papilledema resolved in 89.7%, and headache improved in 30.6%. No significant differences in outcomes were found between CSF diversion and ONSF. Importantly, no visual improvement occurred in cases operated for headache alone, and the odds of headache improvement were significantly lower in this group (OR 0.11,  = 0.012).

Conclusion

CSF diversion and ONSF are effective in IIH with acute visual threat, improving vision and, to a much lesser extent, headache. Refractory headache alone appears insufficient indication for surgical intervention.

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Authors:
Gabriel Bsteh, Nadja Skadkær Hansen, Sina Zaic, Steffen Hamann, Johanne Juhl Korsbæk, Nik Krajnc, Stefan Macher, Laleh Dehghani Molander, Klaus Novak, Therese Wallentin Steenfos, Marianne Wegener, Berthold Pemp, Rigmor Højland Jensen, Dagmar Beier, Kaare Fugleholm, Marianne Juhler, Karl Kirchner, Martin Michl, Christoph Mitsch, Nina Müller, Petersen Bibi Gronemann, Andreas Reitner, Christoph Stapf, Christian Wöber and Karin Zebenholzer
Article first published online:
04 Mar 2026 | DOI: 10.1111/ene.70541

LETTER TO THE EDITOR

Letter to the Editor Regarding Kortazar‐Zubizarreta et al. ‘The Risk of Transmission of Genetic Prion Diseases Is Greater Than 50%’

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Authors:
Akin Nihat, Tze How Mok, Eric Vallabh Minikel, John Collinge and Simon Mead
Article first published online:
02 Mar 2026 | DOI: 10.1111/ene.70543

ORIGINAL ARTICLE

Background

The aim was to evaluate the diagnostic, therapeutic, nutritional, and complication‐related impact of a university‐led neurogenic dysphagia outpatient clinic.

Methods

We retrospectively analyzed all patients seen at the University Hospital Frankfurt Neurogenic Dysphagia Outpatient Clinic (January 2021–July 2023). Data included demographics, neurological diagnoses, Functional Oral Intake Scale (FOIS), Penetration–Aspiration Scale (PAS) from Flexible Endoscopic Evaluation of Swallowing (FEES), nutritional status, therapy adjustments, and pneumonia requiring hospitalization. We quantified diagnostic revisions, therapeutic/nutritional interventions, and modeled pneumonia risk using logistic regression.

Results

Among 255 patients (mean age 65.9 years; 60.0% men), Parkinsonian syndromes (18.0%) and stroke (12.9%) were most frequent. Complications included weight loss (32.8%), choking (20.0%), and pneumonia (12.6%). Primary diagnosis changed in 38.8% of patients. Of 110 patients with initially unexplained dysphagia, 70.9% received a neurological diagnosis, most often ALS and Parkinsonian syndromes (each 19.5%). Therapy recommendations changed in 42.0% of patients, including symptomatic and disease‐modifying treatments; nutritional management was dynamic (new PEG in 16.1%; removal in 50.0% of existing PEGs); 42.9% of tracheostomized patients were decannulated. Frailty (OR 1.49,  = 0.005) and PAS 8 (OR 3.67,  = 0.007) independently predicted pneumonia.

Conclusion

A dedicated outpatient dysphagia clinic enhances diagnostic precision, optimizes therapy, and supports individualized nutritional and airway management. FEES‐based phenotyping strengthens differential diagnostics and enables the identification of previously unrecognized neurological syndromes. Silent aspiration and frailty identify patients at the highest pneumonia risk. Dysphagia should be regarded as an independent therapeutic target within disease‐specific neurological treatment, and dysphagia outpatient clinics should be integrated into standard neurological care pathways.

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Authors:
Bendix Labeit, Jasmin Bach, Elena Harborth, Rainer Dziewas, Sven G. Meuth, Christian Grefkes, Laurent Willems and Sriramya Lapa
Article first published online:
26 Feb 2026 | DOI: 10.1111/ene.70544

ORIGINAL ARTICLE

Background

This study aimed to compare the real‐world efficacy and safety of rituximab and inebilizumab in patients with aquaporin‐4 immunoglobulin G (AQP4‐IgG) seropositive neuromyelitis optica spectrum disorder (NMOSD).

Methods

This retrospective study included patients treated with rituximab or inebilizumab at two tertiary hospitals in China between January 2015 and June 2025. Propensity score matching was conducted to reduce between‐group imbalance. The primary endpoint was time to first confirmed relapse. Secondary outcomes included changes in annualized relapse frequency, EDSS scores, and serum IgG and AQP4‐IgG levels. Safety profiles were also assessed.

Results

A total of 276 patients were analyzed (rituximab: 211; inebilizumab: 65), yielding 61 well‐balanced pairs after propensity score matching. In terms of efficacy, clinical outcomes and AQP4‐IgG dynamics were comparable between groups in pre‐ and post‐matching analyses, although inebilizumab exhibited a significantly greater reduction in serum IgG levels at 6 months. Safety profiles differed. Rituximab was associated with a higher incidence of overall adverse events, driven primarily by infusion‐related reactions, whereas other adverse events remained comparable.

Conclusions

In our real‐world study of 276 patients, rituximab and inebilizumab demonstrated comparable efficacy in the medium term but differed in their safety profiles, with a significantly higher incidence of infusion‐related reactions observed in the rituximab group.

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Authors:
Ying Cui, Zihao Yu, Hengri Cong, Hao Zhang, Yutong Shi, Ai Guo, Yujing Li, Dongmei Jia, Chao Zhang, Kaibin Shi, Fu‐Dong Shi and Wei Jiang
Article first published online:
27 Feb 2026 | DOI: 10.1111/ene.70545

ORIGINAL ARTICLE

Background

Diagnosing cardioembolic stroke/transient ischemic attack (TIA) rapidly remains a major challenge. Current emergency cardiac assessments often provide insufficient data. This study tests whether bolus tracking, a readily available technique during brain CTA, can be leveraged to quickly identify reduced ejection fraction (EF) and potential cardioembolic etiology in acute stroke patients.

Patients and Methods

We retrospectively analyzed CTA and echocardiography data from acute ischemic stroke/TIA patients across two comprehensive stroke centers. We measured total transit time (TTT) based on aortic attenuation values of 40 Hounsfield Units (T40HU) and 100 HU (T100HU) obtained during routine CTA. ΔT100–T40HU, representing the time difference required for aortic contrast enhancement to increase from 40 to 100 HU, was also calculated as a key parameter. EF was measured by transthoracic echocardiography using the Simpson biplane method.

Results

In a cohort of 443 patients, we found a statistically significant inverse correlation between EF and T40HU, T100HU, and ΔT100–T40HU. Notably, ΔT100–T40HU demonstrated good discriminatory ability for identifying heart failure (AUROC = 0.88) and poor discriminatory ability for cardioembolic stroke (AUROC = 0.66). Multivariate analysis further confirmed that T40HU, T100HU, and ΔT100–T40HU were independent predictors of both heart failure and cardioembolic stroke based on the TOAST classification criteria.

Conclusion

Bolus tracking during CTA provides a reliable and easily accessible radiological tool for the identification of heart failure and cardioembolic stroke, enabling a faster diagnostic workup and facilitating appropriate selection of further diagnostic investigations within the acute emergency setting.

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Authors:
Simone Bellavia, Pier Andrea Rizzo, Irene Scala, Jacopo Di Giovanni, Agostino Meduri, Aldobrando Broccolini, Giacomo Della Marca, Simona Scalise, Adriana Paladini, Francesca Colò, Simona Gaudino, Paolo Calabresi, Marcella Caggiula and Giovanni Frisullo
Article first published online:
05 Mar 2026 | DOI: 10.1111/ene.70546

SHORT COMMUNICATION

Background

Neuroinflammatory and systemic immune mechanisms are increasingly recognized as contributors to migraine pathophysiology. However, peripheral markers of inflammation remain underexplored. This study aimed to evaluate systemic immune alterations in patients with migraine through complete blood count (CBC) parameters and derived inflammatory indices, comparing findings with healthy controls (HCs).

Methods

We conducted a cross‐sectional analysis of peripheral blood samples, assessing leukocyte subtypes including absolute and relative (percentage‐%) values, hemoglobin, and platelet levels. Inflammatory indices, including neutrophil‐to‐lymphocyte ratio (NLR), platelet‐to‐lymphocyte ratio (PLR), and systemic immune‐inflammation index (SII), were calculated. Migraine features were collected.

Results

A total of 409 subjects were included: 179 HCs, 194 with episodic migraine (EM), and 36 with chronic migraine (CM). Regarding inflammatory indices, SII significantly differed among EM, CM, and HCs ( = 0.024). In particular, in post hoc analyses, it was significantly higher in CM (514.20 ± 250.57) vs. HCs (423.14 ± 221.69) ( = 0.019) and in CM compared to EM (448.28 ± 266.53,  = 0.044). Similarly, neutrophil% significantly differed among the three groups ( = 0.022), and was higher in patients with CM (58.69 ± 9.57) vs. HCs (54.81 ± 8.86,  = 0.019) and in patients with CM vs. EM (55.39 ± 9.77,  = 0.016). Lymphocyte% differed among the three groups ( = 0.047), and it was lower in CM (31.51 ± 8.27) vs. HCs (34.55 ± 8.24,  = 0.047).

Conclusions

Systemic immune dysregulation appears to be associated with migraine, particularly CM. Alterations in neutrophil and lymphocyte distributions, as well as increased SII, may represent peripheral correlates of central neuroinflammation. These findings suggest that simple, routinely available blood‐derived markers could help identify inflammatory endophenotypes in migraine, warranting validation in larger, prospective studies.

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Authors:
Marina Romozzi, Federico Tosto, Annalisa Gentile, Flavia Bianchi, Giada Giuliani, Caterina Ermio, Sonia Di Tella, Luigi Francesco Lannone, Paolo Calabresi and Catello Vollono
Article first published online:
20 Mar 2026 | DOI: 10.1111/ene.70547

ORIGINAL ARTICLE

Background

Cervical artery dissection (CeAD) is a major cause for stroke in young adults. A timely association with minor‐to‐moderate unimposing cervical trauma, which is often sports‐related, is common in CeAD. Our goal was to assess whether physical activity puts patients at risk post‐CeAD.

Methods

Pooled data from two prospective observational CeAD cohorts with in‐person follow‐up of at least 1‐year post‐CeAD were assessed. Changes in physical activity were recorded using patient‐reported assessment of change in activity compared to pre‐CeAD. Baecke score‐derived sports index was applied to address the association between physical activity intensity and our outcomes. Outcomes were (1) recurrent dissection and (2) cerebral ischemia upon follow‐up.

Results

A total of 648 CeAD patients were recorded. Physical activity‐specific follow‐up data were available in 333 (59.7%). The median follow‐up duration was 6.5 (IQR 3.1, 10.9) years with 17/333 (5.1%) suffering CeAD recurrence and 22/33#3 (6.6%) experiencing cerebral ischemia. A total of 197 of 333 (59.2%) patients reported a change in physical activity post‐CeAD (127 [64.5%] decrease, 70 [35.5%] increase). Neither overall change, increase, or decrease of physical activity was associated with recurrent CeAD or cerebral ischemia ( > 0.2 throughout). However, regular performance of higher‐intensity sports, assessed via Baecke score‐derived sports index, associated in trend to dissection recurrence (OR 3.43 [0.86, 13.64];  = 0.080).

Conclusions.

CeAD patients should be reassured that regaining physical activity after CeAD is safe. However, moderation on exertion should be discussed on an individual patient basis.

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Authors:
Lukas Mayer‐Suess, Josefin Kaufmann, Christopher Traenka, Silvia Felicetti, Sebastian Kaufmann, Benjamin Dejakum, Lukas S. Enz, Gudrun Ratzinger, Simon Truessel, Elke R. Gizewski, Stefan Kiechl, Stefan Engelter and Michael Knoflach
Article first published online:
25 Feb 2026 | DOI: 10.1111/ene.70548

ISSUE INFORMATION

Issue Information

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Authors:
Article first published online:
25 Feb 2026 | DOI: 10.1111/ene.70549

ORIGINAL ARTICLE

Background and Purpose

Transcranial Doppler (TCD) detects microembolic signals (MES), reflecting ongoing cerebral embolization. MES have been studied across stroke subtypes and may clarify etiology, monitor treatment, and predict recurrence. We aimed to determine the prevalence of MES in acute ischemic stroke (AIS), explore clinical and laboratory associations, and assess their role in etiological workup.

Methods

We conducted a prospective single‐center study over 3 years including anterior circulation AIS patients within 24 h of onset. Stroke subtype was classified by TOAST criteria. Bilateral middle cerebral artery TCD monitoring was performed for 30 min to detect and quantify MES.

Results

Among 136 patients (mean age 60.1 ± 12.4 years), MES were detected in 22 (16.2%; 95% CI: 10.4%–23.5%). MES(+) patients had more often multiple‐territory infarcts (36.4% vs. 10.5%,  = 0.005), newly detected atrial fibrillation (13.6% vs. 0.9%,  = 0.013), and cancer‐associated stroke (18.2% vs. 0.9%,  = 0.002), whereas cryptogenic etiology was less common (18.2% vs. 41.2%,  = 0.041). MES were absent in lacunar stroke. MES positivity correlated with higher D‐dimer levels (median 932 vs. 456 ng/mL,  < 0.001), and MES counts correlated strongly with D‐dimer values (Spearman coefficient: 0.393,  < 0.001).

Conclusions

MES were detected in one‐sixth of anterior circulation AIS patients, but were absent in lacunar stroke. Their presence was associated with multiple‐territory infarcts, newly detected atrial fibrillation, and cancer‐related stroke. MES counts correlated with D‐dimer levels, supporting their role as markers of ongoing cerebral embolization and underlying prothrombotic state, with potential utility in revealing occult embolic mechanisms.

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Authors:
Eleni Bakola, Lina Palaiodimou, Aikaterini Theodorou, Maria Chondrogianni, Georgia Papagiannopoulou, Anna Keramida, Stella Fanouraki, Angeliki‐Erato Sterpi, Apostolos Safouris, Theodore Karapanayiotides, João Sargento‐Freitas, Claudio Baracchini, Branko Malojčić, Anastasios Bonakis, George P. Paraskevas, Andrei V. Alexandrov and Georgios Tsivgoulis
Article first published online:
27 Feb 2026 | DOI: 10.1111/ene.70550

LETTER TO THE EDITOR

Transmission Ratio Distortion in Genetic Prion Diseases: Clarifying Methodological Considerations

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Authors:
Izaro Kortazar‐Zubizarreta, Africa Manero‐Azua, Hasier Eraña, Joaquín Castilla and Guiomar Perez de Nanclares
Article first published online:
25 Feb 2026 | DOI: 10.1111/ene.70551

SHORT COMMUNICATION

Background

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an extremely rare autosomal recessive disease caused by variants in the thymidine phosphorylase gene (), primarily characterized by severe gastrointestinal and neurological symptoms. The complete phenotype of MNGIE has not been linked to any gene other than .

Methods

We describe two identical twins who exhibited delayed psychomotor development, infantile bilateral cataract, congenital demyelinating polyneuropathy, and severe progressive gastrointestinal dysmotility with recurrent pseudo‐obstruction episodes, along with diffuse supratentorial leukoencephalopathy that mainly overlaps with classic ‐related MNGIE. During the course of the disease, one patient developed Wernicke encephalopathy, triggered by chronic malnutrition related to recurrent gastrointestinal pseudo‐obstruction. This patient later suffered from a catastrophic stroke‐like episode, resulting in massive cerebral edema and brain death at the age of 38.

Results

Next‐generation sequencing (NGS) using a custom‐targeted mitochondrial gene panel identified two compound heterozygous variants in the gene: the paternal variants p.Thr251Ile and p.Pro587Leu, occurring , and the novel maternal variant p.Arg853Gly. Quantification of mtDNA by real‐time PCR on skeletal muscle DNA detected significant depletion, but no multiple deletions were detected with mtDNA analysis by long‐range PCR and Nanopore sequencing.

Conclusions

These cases showed a very distinctive phenotype, with some MNGIE‐like features, expanding the clinical and genetic spectrum of the ‐related diseases. Additionally, they highlighted the importance of monitoring for thiamine deficiency in mitochondrial patients with severe gastrointestinal dysmotility who experience sudden clinical deterioration.

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Authors:
Giuliana Capece, Luca Caumo, Sara Volta, Pietro Riguzzi, Elena Sogus, Angela Petrosino, Sara Vianello, Daniele Sabbatini, Leonardo Salviati, Renzo Manara, Carlo Viscomi, Gianni Sorarù, Luca Bello and Elena Pegoraro
Article first published online:
17 Mar 2026 | DOI: 10.1111/ene.70554

ORIGINAL ARTICLE

Background

Recent studies describe an association between sertraline and acquired late‐onset multiple acyl coenzyme A dehydrogenase deficiency (MADD), a rare disorder affecting fatty acid metabolism. MADD was previously considered solely a genetic disorder caused by recessive pathogenic variants mainly in the gene.

Methods

A nationwide population‐based registry search was conducted to identify adult patients with sertraline‐associated MADD in Sweden 2014–2024. Patients with muscle biopsy reports of lipid storage myopathy or biochemical investigations showing acylcarnitine profile suggesting MADD were included. Medical records were retrospectively reviewed.

Results

We identified 40 (30/10 female/male) . Median age at symptom onset was 42 years and muscle weakness was the most common first symptom. All patients reported muscle symptoms during the disease course. Extra‐muscular symptoms, including sensory disturbance (29 patients) and fatigue (18 patients), were common. Most had lipid accumulation in muscle fibers, an abnormal acylcarnitine profile, a myopathic electromyography pattern, and elevated creatine kinase. Cyanocobalamin, folic acid, and proton‐pump inhibitors were the most frequent other medications at diagnosis. Five patients carried a heterozygous variant. All patients were treated with riboflavin. Almost all (38/39) experienced clinical improvement. Acylcarnitine profile improved in all patients (31/31) with available data. The mean incidence was 1.24 patients per 100,000 adults receiving sertraline treatment per year.

Conclusions

Acquired MADD associated with sertraline is the most common type of adult‐onset MADD in Sweden. The disease is generally responsive to riboflavin treatment. Patients presenting with muscle symptoms during sertraline therapy should undergo adequate evaluation to exclude MADD.

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Authors:
Sofie Sunebo, Emil Nilsson, Martin Engvall, Carola Hedberg‐Oldfors, Yan Shen, Inger Nennesmo, Olof Danielsson, Anders Oldfors, Hanna Appelqvist and Ulrika Lindgren
Article first published online:
11 Mar 2026 | DOI: 10.1111/ene.70555

CASE REPORT

Background

Monoclonal gammopathy‐associated myopathies (MGAMs) include light chain (AL) amyloid myopathy, sporadic late‐onset nemaline myopathy (SLONM), and vacuolar myopathy with monoclonal gammopathy and stiffness (VAMMGAS). These subtypes usually occur separately, although rare overlap has been described. We report a patient with monoclonal gammopathy and concurrent SLONM and excessive glycogen accumulation, resembling VAMMGAS but with distinct features.

Methods

Case report with clinical, electrophysiological, pathological, and therapeutic characterization of a patient with IgG‐kappa monoclonal gammopathy and coexisting SLONM and glycogen accumulation within muscle fibers.

Results

A 69‐year‐old man developed subacute progressive axial and limb weakness, head drop, dysphagia, and weight loss. Examination showed proximal/distal weakness, neck extensor weakness, and lumbar hyperlordosis. EMG revealed myopathic motor unit potentials without electrical myotonia or complex repetitive discharges. Serum studies identified IgG‐kappa monoclonal protein with elevated kappa light chain and ratio. Muscle biopsy demonstrated nemaline rods (1% of fibers) and scattered fibers with non‐rimmed vacuoles (0.3% of fibers) containing PAS‐positive, diastase‐labile material consistent with concurrent SLONM and glycogen storage myopathy‐like pathology. Genetic testing for congenital nemaline and glycogen storage myopathies was negative. Plasma‐cell directed therapy with daratumumab, lenalidomide, and dexamethasone led to rapid functional improvement and M‐protein reduction. Further gains followed autologous stem cell transplantation.

Conclusion

This case expands the MGAM spectrum, highlighting co‐occurrence of SLONM and an excessive glycogen accumulation responsive to immunotherapy and transplantation. These findings suggest a spectrum of related disease processes. Recognition of this combined pathology is clinically important, as affected patients may benefit from targeted immunotherapy or stem cell transplantation.

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Authors:
Felipe J. S. Jones, Ikreet Cheema, Ruple S. Laughlin, Eli Muchtar and Teerin Liewluck
Article first published online:
05 Mar 2026 | DOI: 10.1111/ene.70557

ORIGINAL ARTICLE

Background

Neurocardiac autonomic impairment with reduced heart rate variability (HRV) has been linked to SARS‐CoV‐2 infection and may persist in patients with post‐COVID‐19 syndrome. We synthesised meta‐analytic data on HRV in post‐COVID‐19 syndrome.

Methods

Our systematic review and meta‐analysis were guided by PRISMA standards. We used MEDLINE, Embase and Web of Science to identify non‐randomised studies of HRV in patients with post‐COVID‐19 syndrome, conducted more than 3 months after infection and compared with healthy controls. The search covered the period from 01/2020 to 09/2023. We pooled data on the following HRV parameters: standard deviation of normal‐to‐normal intervals (SDNN), root mean square of successive differences (rMSSD) and low‐frequency to high‐frequency ratio (LF/HF ratio). We applied a random effects model to account for heterogeneity. Risk of bias was assessed.

Results

From 856 initially identified records, we included 11 studies with a total of 1162 participants (593 post‐COVID‐19 patients and 565 healthy controls). We observed a trend toward lower HRV in post‐COVID patients compared to controls, with small to medium effects for SDNN (SMD: 0.26, 95% CI: −0.03 to 0.56,  = 0.09), rMSSD (SMD: 0.11, 95% CI: −0.15 to 0.36,  = 0.41) and LF/HF ratio (SMD: –0.271, 95% CI: −0.61 to 0.07,  = 0.12). Moderate to high statistical heterogeneity of the effects was observed (I = 83% for SDNN and 78% for rMSSD) and nine of 11 studies had a high risk of bias.

Conclusion

This meta‐analysis suggests a possible association between post‐COVID condition and alterations in neurocardiac autonomic function.

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Authors:
Daniela Schoene, Stefanie Deckert, Kristian Barlinn, Hagen B. Huttner, Markus Kösters and Timo Siepmann
Article first published online:
11 Mar 2026 | DOI: 10.1111/ene.70561

ORIGINAL ARTICLE

Background

Calcitonin gene‐related peptide monoclonal antibodies (CGRP mAbs) are effective for migraine prophylaxis; however, real‐world evidence beyond 1 year remains limited.

Methods

This single‐center, retrospective observational cohort study in Japan included 307 migraine patients who received CGRP mAbs (erenumab, galcanezumab, or fremanezumab) for ≥ 3 months between April 2022 and February 2025 for an effectiveness analysis. Outcomes included monthly migraine days (MMDs), ≥ 50% responder rates, adverse events (AEs), and treatment persistence. Patients were categorized as nonresponders or responders: early (≥ 50% MMD reduction by Month 3), late (Months 4–5), and ultralate (after Month 6).

Results

Significant MMD reductions were observed across 24 months. The ≥ 50% response rates were 45.9%, 57.0%, 63.6%, and 71.0% at 3, 6, 12, and 24 months, respectively. AEs occurred in 12.6% and were mild. Early responders had the lowest baseline MMDs and Migraine Disability Assessment (MIDAS) scores; nonresponders had the highest baseline MMDs and MIDAS scores and the highest rates of comorbid medication overuse headache (MOH) and psychiatric disorders. Compared with early responders, late and ultralate responders had higher baseline MMDs, higher MIDAS scores, higher rates of MOH, and more prior preventive failures. Additionally, ultralate responders presented the highest rates of photophobia and pulsatile headache and the fewest psychiatric comorbidities. Effectiveness appeared similar among the three CGRP mAbs. Treatment continuation rates were 68.3%, 58.0%, and 50.6% at 12, 18, and 24 months, respectively.

Conclusion

CGRP mAbs were associated with a long‐term reduction in migraine frequency and favorable tolerability.

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Authors:
Keisuke Suzuki, Shiho Suzuki, Saro Kobayashi, Mukuto Shioda, Hiroaki Fujita, Yasuo Haruyama and Koichi Hirata
Article first published online:
09 Mar 2026 | DOI: 10.1111/ene.70562

POSITION PAPER

Introduction

Generalized myasthenia gravis (gMG) is a chronic autoimmune neuromuscular disorder characterized by fluctuating muscle weakness and exertional fatigue, often requiring long‐term immunosuppressive or biologic treatment. Although international guidelines recommend achieving minimal manifestations as the primary treatment goal, the lack of a standardized measurement approach has limited its application in clinical settings and trials. Minimal Symptom Expression (MSE), defined as a Myasthenia Gravis Activities of Daily Living (MG‐ADL) score of 0 or 1, has recently emerged as a practical, patient‐centric endpoint that reflects minimal functional burden and aligns with regulatory priorities around patient‐reported outcomes.

Results

This position paper examines the rationale for MSE as a clinically meaningful, actionable treatment target in gMG. We summarize the strengths of the underlying MG‐ADL scale and highlight phase 3 trial data showing that MSE is attainable with biologic therapies, including complement and neonatal Fc receptor inhibitors. Data also suggest that achieving MSE correlates with improvements in physician‐assessed outcomes and quality of life metrics. However, inconsistencies in how sustained MSE is defined and reported limit comparability across trials.

Conclusion

MSE, as a patient‐centric endpoint, can be used alongside clinician‐assessed measures and safety measures to support an integrated treatment goal that encompasses both efficacy and tolerability for the treatment of gMG. Future research should further define the clinical utility of MSE and sustained MSE and incorporate stakeholder input to validate MSE as a part of an integrated treatment goal in both clinical trials and real‐world clinical practice.

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Authors:
Andreas Meisel, Akiyuki Uzawa, Cynthia Z. Qi, Dustin Nowacek, Jeff Guptill and James F. Howard
Article first published online:
19 Mar 2026 | DOI: 10.1111/ene.70563

ORIGINAL ARTICLE

Background

Parvovirus B19 (B19V) infection has been associated with neurological complications. Rarely, patients present with multiple mononeuropathy (MM). The present study aimed to better characterize the clinical, electrophysiological, and prognostic features of patients with B19V‐related MM.

Methods

This retrospective, observational, multicenter study included patients with B19V‐related MM diagnosed between January 2015 and January 2025 in seven university hospitals in France and Switzerland.

Results

Twenty‐one patients were included. Twelve were female (57%). All were immunocompetent. The median age at symptom onset was 40 years [IQR: 31–44]. All patients experienced sensory symptoms, 19 (90%) reported neuropathic pain, nine (43%) developed motor weakness, and seven (33%) had cranial nerve involvement. The most frequently involved nerves were the median (14 patients, 67%), fibular ( = 13; 62%), and ulnar ( = 10; 48%) nerves. B19V IgM antibodies were present in 12/20 patients (60%), and all 21 patients were positive for IgG. B19V DNA was detected in blood by PCR in 20 patients (95%). Nerve biopsy showed necrotizing small‐vessel vasculitis in one patient (17%), perivascular lymphocytic and macrophagic infiltrates in five (83%), and B19V DNA was detected by PCR in all four tested nerves. Most patients received immunomodulatory treatment ( = 19; 90%). MM relapse occurred in four patients (19%). A partial recovery was observed in 17/20 patients (85%), two remained stable (10%), and one achieved complete recovery (5%).

Conclusions

B19V infection should be systematically investigated in patients presenting with MM, especially in young individuals (including children) with predominantly sensory symptoms, predominant upper limb nerve involvement, and/or cranial nerve involvement.

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Authors:
Julian Theuriet, Maud Michaud, Guillaume Fargeot, Céline Labeyrie, Anaïs Grosset, Maude Bucy, Ludivine Kouton, Florian Hubben, Véronique Manel, Florent Cluse, Adrien Bohic, Nicolas Rodriguez, Philippe Petiot, Geneviève Billaud, Vincent Fabry, Pascal Cintas, Thierry Maisonobe, Karine Viala, Rabab Debs, Dimitri Psimaras, Sarah Leonard‐Louis, Benjamin Terrier, Alina Dorobat, Céline Tard, Stéphane Darteyre, Alex Vicino, Marie Théaudin, Clovis Adam, Françoise Bouhour, Timothée Lenglet, Grégory Destras, Nathalie Streichenberger and Antoine Pegat
Article first published online:
20 Mar 2026 | DOI: 10.1111/ene.70565

ORIGINAL ARTICLE

Background

Optimal timing for treatment discontinuation in myasthenia gravis (MG) patients achieving minimal symptom expression (MSE) remains undefined.

Methods

This prospective cohort study enrolled 196 MG patients from the Huashan MG Registry who achieved MSE and subsequently discontinued all treatments. Cox regression was used to identify prognostic factors for relapse. Among these, 20 patients experienced two discontinuation events and were analyzed separately for their second discontinuation.

Results

Over a mean follow‐up of 111.10 months, 108 patients (55.1%) experienced relapse. Multivariate analysis identified four independent prognostic factors: onset age ≥ 50 years as a risk factor (HR 1.68, 95% CI 1.04–2.70,  = 0.032), and rituximab administration (HR 0.43, 95% CI 0.17–0.89,  = 0.015), treatment duration ≥ 14.3 months (HR 0.54, 95% CI 0.34–0.85,  = 0.008), and time from MSE to discontinuation ≥ 6.1 months (HR 0.51, 95% CI 0.32–0.83,  = 0.007) as protective factors. Infection, fatigue, and psychological stress were common relapse triggers.

Conclusions

Complete treatment discontinuation after MSE in MG carries substantial relapse risk. Individualized discontinuation decisions incorporating younger onset age, prior rituximab use, adequate treatment and consolidation duration may optimize outcomes.

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Authors:
Dingxian He, Chong Yan, Baitong Wang, Yanlei Yang, Shengying Gu, Jianying Xi, Sushan Luo and Chongbo Zhao
Article first published online:
13 Mar 2026 | DOI: 10.1111/ene.70569

ORIGINAL ARTICLE

Background/Objectives

Immunoglobulin (Ig) therapy is the first‐line treatment and often the single option for a substantial number of diseases. Still, Ig supply and use have experienced restrictions, aggravated during the COVID‐19 pandemic. This study assessed the clinical and economic implications of Ig use under restrictive conditions in neurological diseases and immunodeficiencies in Spain.

Methods

Hospitalization cases in neurological disorders and immunodeficiencies in which Ig is the main therapeutic option, identified by ICD‐10 codes, were retrieved from the Spanish Minimum Basic Data Set for 2019 and 2022. Comorbidities and outcomes were analyzed along with hospitalization rates and characteristics, like the length of stay (LoS) and costs, among others. Therapeutic plasma exchange (TPE) use was evaluated as the alternative treatment of choice in the conditions analyzed.

Results

In 2022 compared to 2019, hospitalizations due to relapses remained stable in patients with neurological conditions. Comorbidity and complications increased significantly in this group, as well as LoS, mofrtality ( < 0.05 for all), and TPE rates ( = 0.003). These changes were not identified for immunodeficiencies, which only experienced a decrease in hospitalization rates ( < 0.001). Hospital costs increased in both groups (7.97% in neurological conditions and 2.41% in immunodeficiencies).

Conclusions

In a period in which access to Ig may have been limited, neurological patients, but not patients with immunodeficiencies, show an increase in LoS and mortality, as well as an increased TPE. These results suggest that modifying the management strategy of patients with neurological disorders requiring Ig due to restrictive conditions could have negatively impacted their clinical outcomes.

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Authors:
Luis Querol, J. Bruno Montoro‐Ronsano, Pere Soler‐Palacín, Jonathan Galduf, Óscar Martínez‐Pérez and Helena Díaz‐Cuervo
Article first published online:
15 Mar 2026 | DOI: 10.1111/ene.70570

ORIGINAL ARTICLE

Background

In the DELIVER trial, eptinezumab administration was associated with sustained reductions in headache frequency and migraine‐related impact in participants for whom previous preventive treatments have failed. This analysis evaluated long‐term maintenance of initial ≥ 50% and ≥ 75% migraine response.

Methods

DELIVER was a 24‐week, randomized, double‐blind, placebo‐controlled trial with a 48‐week dose‐blinded extension. For participants with initial ≥ 50% or ≥ 75% reduction in monthly migraine days—defined as response following their first dose (Weeks 1–12) or first and second dose (Weeks 1–24)—maintenance of ≥ 50% or ≥ 75% migraine response was assessed for each subsequent 12‐week dosing interval. Proportions of severe migraine attacks, 6‐Item Headache Impact Test (HIT‐6) total score, migraine‐specific Work Productivity and Activity Impairment (WPAI:M) presenteeism subscore, and Patient Global Impression of Change (PGIC) categories were also evaluated in Weeks 1–12 responders.

Results

Of participants with ≥ 50% migraine response over Weeks 1–12, 61.0% (69/113, 100 mg) and 73.8% (93/126, 300 mg) maintained response over the entire 72‐week treatment period; ≥ 50% responders (Weeks 1–24) and ≥ 75% responders (Weeks 1–12 and 1–24) showed similar trends. Weeks 1–12 responders (≥ 50% and ≥ 75%) experienced sustained reductions in migraine severity, HIT‐6 total score, and presenteeism subscore, with most reporting improvements per the PGIC.

Conclusions

For both eptinezumab doses, ≥ 50% or ≥ 75% migraine response over Weeks 1–12 or 1–24 was maintained for the entire 72‐week treatment period for many participants. An initial response within the first two doses of eptinezumab can indicate long‐term improvements.

Trial Registration

(Identifier: NCT04418765; URL: ); EudraCT (Identifier: 2019–004497‐25; URL: )

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Authors:
Jessica Ailani, Messoud Ashina, Susanne F. Awad, Xin Ying Lee, Line Pickering Boserup, Seema Soni‐Brahmbhatt, Bjørn Sperling and Richard B. Lipton
Article first published online:
15 Mar 2026 | DOI: 10.1111/ene.70571

ORIGINAL ARTICLE

Background

The potential link between myasthenia gravis (MG) and COVID‐19 infection or vaccination remains unclear. This study aimed to evaluate the relationship between these factors and new‐onset MG.

Methods

A case–control study was conducted using Clalit Health Services' database. We applied a ML algorithm to reduce diagnostic misclassification. The study examined adults with new onset MG, aged 18 or older, between January 2020 and December 2022 for COVID‐19 infection (Cohort I) and between January 2021 and December 2022 for Pfizer‐BioNTech COVID‐19 vaccine (Cohort II). For each new MG case, three controls matched by age, sex, and index date were selected. Prior exposure to either infection or vaccination was assessed within 90 and 180 days for cases and controls.

Results

In cohort I, 253 new MG cases were identified. A multivariate logistic regression model showed an odds ratio (OR) of 1.44 (95% CI 0.708–2.92) within 90 days post‐infection and 1.67 (95% CI 0.98–2.84) within 180 days. In cohort II, 177 new MG cases were detected, with an OR of 1.76 (95% CI 1.049–2.95) within 90 days post‐vaccination and 2.45 (95% CI 1.51–3.95) within 180 days.

Conclusion

This study suggests no significant increased risk of new‐onset MG following COVID‐19 infection, but the Pfizer‐BioNTech vaccine appears to be associated with a higher risk of developing MG, particularly within 180 days of vaccination.

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Authors:
Tasneem Kab, Keshet Pardo, Mark A. Hellmann, Itay Lotan, Yitzhak Friedman, Tzipora Shochat and Adi Wilf‐Yarkoni
Article first published online:
19 Mar 2026 | DOI: 10.1111/ene.70572

ORIGINAL ARTICLE

Background

Paramagnetic rim lesions (PRLs) are emerging MRI biomarkers of smoldering inflammation in multiple sclerosis with prognostic relevance. However, their prevalence in the early stages of the disease remains underexplored.

Objective

This prospective cohort study investigated the prevalence, anatomical distribution, and clinical significance of PRLs in newly diagnosed relapsing MS patients with high disease activity and explored their associations with conventional and non‐conventional MRI measures, serum neurofilament light chain (sNfL), and clinical outcomes.

Methods

We enrolled treatment‐naïve patients who had received an MS diagnosis in the previous 12 months. Patients underwent 3 T brain and spinal MRI including susceptibility‐weighted imaging at baseline, 6, and 12 months, along with neurological and cognitive assessments and sNfL sampling.

Results

The cohort consisted of 21 patients, with a mean age of 31 and median disease duration of 9 months (IQR 4–17). Median EDSS score was 1.5. All patients presented with spinal cord lesions and 38% showed Gd + lesions. PRLs were detected in 76%, with a mean of 4.9 lesions per subject. Higher PRL burden correlated with greater T2 lesion volume and cortical lesion count, higher EDSS, reduced SDMT scores, and elevated baseline sNfL. PRLs remained stable over 12 months despite treatment; two new PRLs emerged at month 12. sNfL levels were higher in patients with ≥ 4 PRLs and decreased in all during follow‐up.

Conclusions

Paramagnetic rim lesions (PRLs) are detectable early in RMS and correlate with a more severe clinical and radiological profile. The combined assessment of PRLs and CLs may improve disease monitoring and guide personalized treatment.

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Authors:
Alessandra Cicia, Matteo Lucchini, Gianluca Di Fiore, Luca Ausili Cefaro, Assunta Bianco, Viviana Nociti, Vincenzo Carlomagno, Simona Gaudino and Massimiliano Mirabella
Article first published online:
20 Mar 2026 | DOI: 10.1111/ene.70573

REVIEW ARTICLE

Background

Painful diabetic neuropathy affects ~20%–40% of individuals with diabetes, driven by peripheral small nerve fiber damage and modulated by spinal cord and brain mechanisms. Corneal nerve imaging using corneal confocal microscopy (CCM) and skin biopsy to quantify intraepidermal nerve fiber density (IENFD) are objective measures of small nerve fiber damage.

Objectives

CCM and IENFD were assessed for their ability to distinguish painful from painless diabetic neuropathy.

Methods

Following PROSPERO‐registered protocol and PRISMA guidelines, PubMed, Embase, and Web of Science were searched for studies on corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL), and IENFD in patients with painful and painless diabetic neuropathy. Standardized mean difference (SMD) with 95% confidence intervals (CI) was pooled using random‐effects meta‐analyses.

Results

Seven studies ( = 683) showed lower CNFD (SMD −0.50, 95% CI −0.96 to −0.03,  = 0.03) and CNFL (SMD −0.32, 95% CI −0.59 to −0.05,  = 0.02) in painful compared to painless DPN, with no difference in CNBD. Ten studies ( = 664) demonstrated lower IENFD in painful compared to painless DPN (SMD −0.31, 95% CI −0.59 to −0.02,  = 0.03, 69%). In three studies assessing both CCM and IENFD ( = 161), CNFD ( < 0.0001), CNBD ( = 0.01), CNFL ( = 0.0001), and IENFD ( = 0.008) were significantly lower in painful compared to painless DPN.

Conclusion

Both CCM and skin biopsy demonstrate small nerve fiber loss in painful compared to painless DPN, supporting their value in identifying alterations in small nerve fiber structure in painful DPN.

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Authors:
Hoda Y. Gad, Grazia Devigili, Ingemar Merkies, Ian Gilron, Ross MacDonald, Giuseppe Lauria and Rayaz A. Malik
Article first published online:
19 Mar 2026 | DOI: 10.1111/ene.70576

INVITED REVIEW

Background

Artificial Intelligence (AI) is rapidly emerging as a transformative tool in medical research and practice. In neuro‐oncology, AI may help to enhance diagnostic accuracy and reproducibility, manage complex multi‐modal data, and facilitate personalized treatment.

Methods

This review aims to provide an overview of AI applications in the analysis of histopathological and molecular data of brain tumors.

Results

Key applications in histopathology include molecular biomarker prediction from H&E stained slides, tumor classification, grading, and prognostication. In molecular pathology, the machine learning‐driven DNA methylation‐based classification of CNS tumors has already become an integral part of the most recent WHO classification. This framework is continuously refined by ongoing research identifying novel tumor types. Two examples of emerging applications are Stimulated Raman Histology (SRH) and nanopore sequencing. SRH enables an intraoperative AI‐powered assessment of the histopathological phenotype. Nanopore sequencing can be used for fast molecular profiling of CNS tumors, including intraoperative methylation‐based subtyping. Despite these significant advances, the clinical translation of AI tools faces some challenges, including the limited dataset availability, standardization and representativeness; the lack of robust external validation in many published studies; and the limited model interpretability. These challenges are currently being tackled by efforts to compile multi‐institutional pathological datasets and by advances in explainable AI.

Conclusions

AI holds promise for advancing personalized neuro‐oncology by improving diagnostic accuracy and accelerating existing workflows. Its potential to democratize access to precision diagnostics hinges on efforts to reduce the costs of digital infrastructure and facilitate specialized training.

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Authors:
Thomas Roetzer‐Pejrimovsky, Nicole Amberg, Georg Widhalm and Romana Höftberger
Article first published online:
19 Mar 2026 | DOI: 10.1111/ene.70577

ORIGINAL ARTICLE

Background

Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by progressive muscle weakness due to SMN protein deficiency. While effective therapies exist, their impact on slowly progressive adult SMA patients remains unclear. Reliable biomarkers for monitoring disease progression and treatment response are urgently needed. This pilot study evaluated the utility of longitudinal quantitative muscle MRI (qMRI) to monitor disease progression in adult SMA patients treated with nusinersen over an extended period.

Methods

Nine adult patients with genetically confirmed 5q‐SMA underwent whole‐body muscle MRI and clinical assessment, including the Hammersmith Functional Motor Scale‐Expanded (HFMS‐EXP), Revised Upper Limb Module (RULM), and 6 min walk test (6MWT). Muscular fat fraction (mFF) was quantified in 20 muscles over a median follow‐up of 54 months.

Results

Baseline mFF correlated strongly with clinical measures (HFMS‐EXP:  = −0.90,  = 0.001; 6MWT:  = −0.96,  < 0.001), but not with age at onset or age at MRI. Over the observation period, a significant increase in mFF was detected (averaged annual increase of all studied muscles: 0.47%,  = 0.011), accentuated in the lower leg muscles. In contrast, clinical measures showed no consistent change. Consequently, no significant correlations were found between changes in mFF and clinical scores.

Conclusions

This study provides the longest reported longitudinal qMRI assessment in adult SMA patients treated with nusinersen, demonstrating that mFF progressively increases despite stable clinical scores. The results suggest that qMRI may be a sensitive and objective biomarker for detecting subtle disease progression in adult SMA, potentially surpassing clinical measures.

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Authors:
Alexander Mensch, Benjamin Troppa, Ilka Schneider, Caroline Deborah Stapf, Anna Katharina Koelsch, Thomas Kendzierski, David Strube, Sebastian Plutz, Max Obenauf, Karl‐Stefan Delank, Torsten Kraya, Markus Otto, Dietrich Stoevesandt and Steffen Naegel
Article first published online:
23 Mar 2026 | DOI: 10.1111/ene.70579

REVIEW ARTICLE

Background

There is an unmet need for the clinically relevant ALS biomarkers to facilitate an accurate diagnosis in suspected cases, monitor disease progression and evaluate response to therapy in clinical trials. While the MND/ALS literature is dominated by innovative brain studies, motor disability in ALS is primarily driven by neurogenic muscle change impacting mobility, dexterity, respiratory and bulbar function.

Methods

With the intention of raising awareness of muscle‐derived imaging markers in ALS, a systematic review has been conducted. Study designs, imaging methods, data interpretation frameworks, and cohort characteristics were systematically evaluated to identify innovative approaches and barriers to clinical implementation.

Results

A total of 219 studies were screened and 73 original studies selected for systematic review; 37 muscle MRI studies and 36 studies using ultrasound, PET or CT. All of the selected studies successfully captured ALS‐associated muscle degeneration and their methods included the evaluation of muscle dimensions (thickness/volumes  = 34), ‘acute’ denervation (water content,  = 15), fasciculation counts ( = 14), ‘chronic’ neurogenic change (fat content,  = 21), metabolic changes ( = 4), diffusion alterations ( = 8) and echo intensity changes ( = 13).

Conclusions

Despite the huge impact of lower motor neuron dysfunction on the patients' independence, survival and quality of life, muscle imaging is a glaringly overlooked frontier of MND/ALS research. This is a missed opportunity, as a variety of non‐invasive quantitative muscle imaging techniques have been successfully used in other neurological conditions; these protocols are easy to implement on commercial MRI and ultrasound platforms and recent studies have demonstrated their ease of use and potential clinical utility.

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Authors:
Alison Toomey, Jana Kleinerova, Ee Ling Tan, We Fong Siah and Peter Bede
Article first published online:
23 Mar 2026 | DOI: 10.1111/ene.70582