cover image European Journal of Neurology

European Journal of Neurology

2026 - Volume 33
Issue 2 | February 2026
Previous Issue

ORIGINAL ARTICLE

Background

Sleep and sleep disorders (SD) have a major impact on brain (neurological and psychiatric), body and societal health. Despite this, the epidemiological and economic burden of SD have not been sufficiently analyzed. This study investigates the epidemiology and costs of SD across 47 European countries and identifies knowledge gaps in the literature.

Methods

Systematic literature reviews on PubMed (between January 2010 and April 2023) and expert communications identified relevant epidemiological and cost‐of‐illness (COI) studies on five major SD: insomnia, obstructive sleep apnea (OSA), narcolepsy, restless legs syndrome (RLS), and REM sleep behavior disorder (RBD). Four epidemiological parameters, including prevalence, were investigated. Economic analyses stratified direct, indirect, and informal care costs, and employed an imputation procedure that accounts for several country‐specific economic factors. Costs were expressed as purchasing power parity (PPP)‐adjusted 2019 Euros.

Results

Eleven COI and six epidemiological studies were identified. Estimated prevalence for OSA, insomnia, RLS, narcolepsy, and RBD in the adult population was 18%, 10%, 3%, 0.03%, and 0.009%, respectively. Economic data were exclusively available for high‐income Europe. OSA was the most costly SD (€184 billion), followed by insomnia (€158 billion), RLS (€79 billion), narcolepsy (€905 million), and RBD (€436 million). Direct and indirect costs contributed 48% and 52%, respectively, with no available data on informal care costs.

Conclusions

The unexpected high prevalence and substantial economic burden associated with SD contrast with the universally neglected role of sleep health and SD in public health strategies. More research on the burden of SD is needed.

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Authors:
Claudio L. A. Bassetti, Luisa S. Welter, Mateo Montes‐Martinez, Nikolai Mühlberger, Paul Boon, Thomas Berger, Günther Deuschl, Marjan Arvandi, Maria Konti, Maria Lolich, Evelina Pajediene, Rolf Fronczek, Elena Moro, Uwe Siebert and Richard Dodel
Article first published online:
14 Feb 2026 | DOI: 10.1111/ene.70463

SHORT COMMUNICATION

Background

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia surface receptor that aids in tissue repair and debris clearance. The soluble form, sTREM2, found in both blood and cerebrospinal fluid, is considered a biomarker for microglial activation. Based on the central role of microglia in MS pathogenesis, we aimed to investigate whether serum sTREM2 levels could predict disability progression in patients with primary progressive MS.

Methods

Serum levels of sTREM2 were measured at baseline using a single‐molecule array assay in a multicenter cohort of 137 primary progressive multiple sclerosis (PPMS) patients. Univariable and multivariable linear models evaluated the association between sTREM2 levels and EDSS change at 2 years, 6 years, and last follow‐up.

Results

While an association was observed at 2 years only in non‐inflammatory PPMS patients, no consistent relationship was found between sTREM2 levels and disability progression over longer follow‐up.

Conclusions

These findings suggest that serum sTREM2 may have limited value as a biomarker of disability progression in PPMS.

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Authors:
Nicolás Fissolo, Pascal Benkert, Andreu Vilaseca‐Jolonch, Yolanda Blanco, Harald Hegen, Klaus Berek, Francisco Pérez‐Miralles, Konrad Rejdak, Luisa Villar, Enric Monreal, Roberto Alvarez‐Lafuente, Franziska Bachhuber, Hayrettin Tumani, Sergio Martínez‐Yelamos, Antonio Sánchez‐López, Antonio García‐Merino, Lucía Gutiérrez, Tamara Castillo‐Triviño, Jan Lycke, Igal Rosenstein, Nieves Téllez, Roberto Furlan, Jan D. Lünemann, Michael Khalil, Jens Kuhle, Xavier Montalban and Manuel Comabella
Article first published online:
30 Jan 2026 | DOI: 10.1111/ene.70480

SHORT COMMUNICATION

Background and Purpose

Cryptogenic strokes, accounting for 25%–40% of ischemic strokes, represent a major challenge in secondary prevention due to their uncertain etiology and high recurrence risk. Identifying biomarkers to reliably distinguish cardioembolic (CE) strokes among embolic strokes of undetermined source (ESUS) could help guide therapeutic decisions. Previous studies have indicated thrombus DNA content as a potential biomarker of CE stroke etiology, but direct quantification of fibrin, another key component, has not been adequately explored.

Methods

We analyzed thrombi collected from 186 ischemic stroke patients undergoing endovascular treatment between 2019 and 2023. Thrombi were processed using a quantitative method based on ex vivo tPA‐mediated fibrinolysis followed by mechanical homogenization. Stroke etiology was classified according to TOAST criteria: 40% cardioembolic, 24% non‐cardioembolic (large artery atherosclerosis or dissection), and 36% ESUS. Biomarker content was correlated with stroke etiology, and the diagnostic performance of DNA and fibrin (D‐dimer) content was evaluated.

Results

Cardioembolic thrombi contained significantly higher levels of DNA (median [IQR]: 325.3 [177–484] ng/mg) and D‐dimer (17.5 [9.1–23.8] μg/mg) compared to non‐cardioembolic thrombi (DNA: 128 [76.4–263] ng/mg; D‐dimer: 11.4 [6.8–13.2] μg/mg), with no significant differences observed in heme or GPVI content. The combined use of thrombus DNA and fibrin (D‐dimer) content provided good discrimination between CE and non‐CE thrombi, with an area under the ROC curve of 0.79 (95% CI, 0.70–0.87).

Conclusion

DNA and fibrin content in thrombi are promising biomarkers for identifying cardioembolic stroke etiology. Prospective studies should evaluate their use in selecting ESUS patients who may benefit from anticoagulant therapy.

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Authors:
Jéromine Fasille, Mialitiana Solo Nomenjanahary, Dorothée Faille, Capucine Habay, Laurine Bedoucha, Maeva Kyheng, Julien Labreuche, Arturo Consoli, Bertrand Lapergue, Michel Piotin, Raphael Blanc, Benoit Ho‐Tin‐Noé, Mikael Mazighi, Jean Philippe Desilles and Lucas Di Meglio
Article first published online:
11 Feb 2026 | DOI: 10.1111/ene.70484

ORIGINAL ARTICLE

Background

Biallelic pentanucleotide expansions in cause cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS), and a growing spectrum of presentations. We aimed to clinically characterize a cohort of patients from Sweden with biallelic expansions in .

Methods

We retrospectively enrolled patients with homozygous expansions in from a tertiary center in Sweden, evaluating clinical and genetic data. Assessments included nerve conduction studies (NCS,  = 27), electromyography ( = 7), quantitative sensory testing ( = 18), brain MRI ( = 27), and vestibular/eye motor tests ( = 18–21).

Results

Of the 30 patients enrolled, 28 were ethnic Swedish; 17/30 from smaller regions, including eight (27%) from Norrbotten. Twenty‐two patients met the CANVAS criteria. Mean age of onset was 52 ± 12 years (range 20–70), and disease duration was 14 ± 12 years. Symptoms matched the CANVAS acronym with multisystemic features in 83%, including dysautonomia (77%), dyskinesia (36%), and bradykinesia (17%). Phenotypes overlapped with MSA‐C ( = 2) and mitochondrial ataxias ( = 1). Notably, one symptomatic patient lacked neuropathy on NCS. Annual disease progression was slow (0.3 by spinocerebellar degeneration functional score, 1.2 by SARA). At vestibular testing, 47% showed a preserved caloric response and pathologic angular VOR with a nonsignificant trend among younger patients and milder ataxia; otolith function was largely preserved.

Discussion

Our findings expand the spectrum, suggesting a founder effect in Sweden and extensive subclinical involvement. disorder should also be considered in patients with cerebellar and vestibular dysfunction but lacking neuropathy. A discordant VOR pattern may represent an incipient sign of spectrum disorder; interestingly, otolith pathways seem to be generally spared.

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Authors:
Victor Alm, Linda Säll, Kristin Samuelsson, Rayomand Press, Snjolaug Arnardottir, Anna Lindstrand, Valter Niemelä, Lilia Terinte, Frida Nordin, Per Svenningsson, Daniel Nilsson, Luca Verrecchia and Martin Paucar
Article first published online:
28 Jan 2026 | DOI: 10.1111/ene.70488

GUIDELINES

Background

Recent epidemiological studies on the general population reveal that up to 1.3% have oligo/asymptomatic hyperCKemia.

Objective

This guideline aims to provide updated, evidence‐based recommendations on investigating persons older than 18 years.

Methods

The guideline followed EAN standard operating procedures and was developed according to the GRADE methodology. Fourteen neuromuscular experts from the EAN neuromuscular group were joined by a methodologist and a patient representative. There are two types of recommendations: evidence‐based recommendations, based on published studies, and consensus statements if the quality of evidence is poor.

Results

We recommend that: (1) Persistent oligo/asymptomatic hyperCKemia with a CK > 1.5 ULN be investigated (Consensus statement); (2) Neurogenic and non‐neuromuscular causes of hyperCKemia be excluded (Expert opinion); (3) A Dried Blood Spot (DBS) be done (Strong recommendation); (4) A NCS/EMG to identify whether there is a myopathy or neuropathy be performed (Weak recommendation); (5) A resting lactate and fasting acyl‐carnitine assays, if a metabolic myopathy is suspected, be done (Consensus statement); (6) A skeletal muscle MRI be performed to guide/interpret genetic testing (Strong recommendation); (7) NGS is recommended over sequential gene testing (Consensus statement); (8) NGS is recommended over muscle biopsy (Strong recommendation); (9) A muscle biopsy may be offered, if genetic testing is uninformative and one or more applies: a genetic variant of unknown significance (VUS), suspected metabolic myopathy, suspected inflammatory myopathy, abnormal muscle MRI, a CK ≥ 3 ULN, a family history of muscle disease or age, less than 25 years (Expert opinion).

Conclusions

An evidence‐based guideline is suggested for when and how to investigate adults with oligo/asymptomatic hyperCKemia.

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Authors:
T. Kyriakides, K. Aleksovska, C. Angelini, Z. Argov, K. G. Claeys, M. de Visser, M. FIlosto, I. Jovanovic, A. Kostera‐Pruszczyk, M. J. Molnar, S. Sacconi, J. Schaefer, G. Siciliano, J. J. Vilchez, B. Schoser and A. Toscano
Article first published online:
31 Jan 2026 | DOI: 10.1111/ene.70493

REVIEW ARTICLE

Background

Despite clear diagnostic criteria established in 2017, delivering and explaining the diagnosis of persistent postural‐perceptual dizziness (PPPD) can be challenging.

Methods

We outline a step‐by‐step approach to clearly explain the diagnosis, underlying mechanisms and treatment options to patients with PPPD, followed by a brief overview of current treatment approaches. This approach is adapted from the Cambridge‐Calgary Consultation Model and previous recommendations for functional neurological disorders but is mainly based on our expertise accrued over decades and input from patients with PPPD.

Results

The practical clinical framework for the assessment and management of PPPD includes structured history‐taking, bedside examination and patient‐centred communication strategies aimed at improving diagnostic confidence and therapeutic engagement.

Conclusion

Our experience indicates that the clinical approach used may shape patients' understanding, engagement and overall management trajectory in PPPD. Good communication is essential for the diagnosis and management of this condition.

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Authors:
Hüseyin Nezih Özdemir, Jasmin Charlton, Elvira Cortese, Arianna Di Stadio, David Herdman and Diego Kaski
Article first published online:
09 Feb 2026 | DOI: 10.1111/ene.70494

ORIGINAL ARTICLE

Background

Reversible cerebral vasoconstriction syndrome (RCVS) is a neurovascular disorder with unclear pathophysiology, particularly concerning systemic endothelial function. Understanding arterial stiffness could shed light on potential systemic vascular involvement in RCVS.

Objective

This study aimed to investigate systemic endothelial dysfunction in patients with RCVS by assessing arterial stiffness using pulse wave velocity (PWV).

Methods

We conducted a prospective, age‐ and sex‐matched, 1:1 case–control study from January 2020 to January 2023 at Nantes University Hospital. Patients diagnosed with definite RCVS according to ICHD‐3 criteria were enrolled as cases; controls were matched individuals without RCVS. All participants underwent PWV measurement as a noninvasive marker of arterial stiffness. Follow‐up PWV assessments were performed in RCVS patients at 1 and 3 months after onset.

Results

Sixty‐two subjects with a mean age of 49.8 years (70% female) were included. One‐third of RCVS cases had secondary triggers. Mean systolic and diastolic blood pressures were 130.8 ± 24.0 mmHg and 80.6 ± 1.4 mmHg, respectively, with 29% of patients presenting acute hypertension. No systemic organ dysfunction was observed in cardiac, renal, or hepatic assessments. PWV values at the acute stage showed no significant difference between patients and controls (7.0 vs. 6.4 m.s,  = 0.8701). PWV increased transiently from 7.7 to 9.2 m.s at 1 month but returned to 8.1 m.s by 3 months, without statistically significant overall changes ( = 0.5331).

Conclusion

Systemic arterial stiffness, as measured by PWV, remains normal and stable throughout the course of RCVS even during the acute phase and recovery.

Trial Registration

, NCT04463212

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Authors:
Pacôme Constant dit Beaufils, Laëtitia Barbin, Morgane Pere, Clarisse Colleu, Jérôme Connault, Cécile Préterre, Benoît Guillon and Solène de Gaalon
Article first published online:
27 Jan 2026 | DOI: 10.1111/ene.70495

ORIGINAL ARTICLE

Background

Myasthenia gravis (MG) is an autoantibody‐mediated neuromuscular disease often co‐occurring with other autoimmune diseases (ADs). We aimed to determine the temporal relationship between other ADs and MG.

Methods

We conducted a nationwide, population‐based case–control study of MG patients and 10 age‐, sex‐, and index date‐matched controls from 1985 to 2020. We used conditional logistic regression to estimate odds ratios (ORs) for AD diagnoses preceding MG, and Cox regression to calculate hazard ratios (HRs) for ADs succeeding MG. Analyses were stratified by sex, age group (≤ 50 and > 50 years), baseline comorbidity, and time intervals (0–5 and 5–10 years) before and after MG.

Results

Our study population included 2110 MG cases (1060 females) and 21,100 matched controls, with 27.4% ≤ 50 years old. Before the index date, 5.2% of MG patients and 2.7% of controls were diagnosed with another AD, yielding an OR of 1.9 (95% CI 1.5–2.3). After MG diagnosis, 5.0% of MG patients and 2.7% of controls received an AD diagnosis (HR 2.1, 95% CI 1.2–2.6), with an overrepresentation of patients ≤ 50 years or younger, females, and patients with a low comorbidity level. Most diagnoses occurred within 5 years before MG onset. The strongest associations were observed for autoimmune thyroiditis, systemic lupus erythematosus, and pernicious anemia.

Conclusion

MG patients are twofold more likely to be diagnosed with another AD, especially MG patients ≤ 50 years and women, suggesting a shared autoimmune predisposition. Understanding the AD spectrum associated with MG could improve diagnostic accuracy and treatment strategies.

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Authors:
Josefine Jul Jarbæk Nielsen, Lotte Sahin Levison and Henning Andersen
Article first published online:
11 Feb 2026 | DOI: 10.1111/ene.70498

ORIGINAL ARTICLE

Background

Small‐fibre neuropathy (SFN), which is defined by the sole involvement of small sensory fibres, often leads to neuropathic pain. The diagnosis of SFN relies on clinical, neurophysiologic, and morphologic abnormalities. A decrease in intraepidermal nerve fibre density (IENFD) on a skin biopsy specimen is considered useful in the diagnosis of SFN in the appropriate clinical context. The self‐administered Douleur Neuropathique 4 (I‐DN4) questionnaire, designed to differentiate neuropathic from somatic pain, shows high sensitivity and specificity but has not been specifically investigated with regard to SFN.

Methods

This retrospective study examined the diagnostic accuracy of I‐DN4 for SFN in 872 patients who were systematically assessed at the time of skin biopsy according to local standards of routine care, after excluding central nervous system diseases and other peripheral nerve disorders by careful clinical examination and medical history.

Results

An I‐DN4 score of ≥ 3 had a sensitivity of 93% and a specificity of 18.13% for diagnosing SFN. ROC analysis revealed an AUC of 0.53, indicating no discriminative ability for this condition. There were no correlations between the I‐DN4 scores and the adjusted IENFD or proximo‐distal IENFD ratio. Only the sensation of burning was a moderate predictor of SFN risk (odds ratio [OR] = 1.65; 95% confidence interval [CI], 1.04–2.68;  = 0.038). Hypoesthesia to pinprick was also associated with a moderate risk of a reduced IENFD at the distal leg (OR = 1.52; 95% CI, 1.03–2.25;  = 0.040).

Conclusions

I‐DN4 is not an effective standalone tool for screening SFN in patients with painful syndromes.

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Authors:
Simon Frachet, Emilie Soust, Laurence Richard, Aurore Danigo, Claire Demiot and Laurent Magy
Article first published online:
11 Feb 2026 | DOI: 10.1111/ene.70499

ORIGINAL ARTICLE

Objective

To explore pathological findings on magnetic resonance imaging (MRI) and their diagnostic implications in early‐stage neuroborreliosis (NB).

Method

Adult patients from the Danish neuroinfections cohort (DASGIB, 2015–2019) with confirmed NB, symptom duration < 6 months, and MRI performed within 14 days of diagnosis were included. MRIs were retrospectively reinterpreted by an unblinded neuroradiologist.

Results

In 116 patients, 123 MRIs were performed (99 brain, 44 spine, 46 with contrast). White matter lesions (WML) were common, but non‐specific and associated with increasing age ( < 0.001). Six patients showed WML not typical for small vessel disease. Acute infarctions occurred in four patients. Encephalitis was clinically diagnosed in five patients; one showed brainstem FLAIR hyperintensities. In 45 contrast‐enhanced brain scans, leptomeningeal enhancement was identified in 6 (13%) and cranial nerve enhancement in 29 (64%). There was poor correlation between facial palsy and enhancement. Spinal cord lesions (1.6–14 cm) were identified in 10 of 44 scans (23%) without symptoms of transverse myelitis. Among 13 contrast‐enhanced spine scans, 8 showed leptomeningeal enhancement (61%), and 8 showed nerve root enhancement (61%). Most enhancements did not match symptoms.

Conclusion

Pathological findings were found in 35 of 46 patients with contrast‐enhanced MRIs. Key findings included cranial nerve, spinal nerve root, and leptomeningeal enhancement—often without clinical correlation. Spinal cord lesions were relatively frequent; cerebral infarction was rare. While key findings can support the diagnosis, their absence does not exclude NB.

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Authors:
Mathilde Ørbæk, Nitesh Shekhrajka, Rosa Maja Møhring Gynthersen, Jacob Bodilsen, Lykke Larsen, Merete Storgaard, Christian Brandt, Lothar Wiese, Birgitte Rønde Hansen, Hans R. Luttichau, Aase Bengaard Andersen, Helene Mens, Henrik Nielsen, Klaus Hansen and Anne‐Mette Lebech
Article first published online:
09 Feb 2026 | DOI: 10.1111/ene.70500

ORIGINAL ARTICLE

Background

Cognitive impairment and depression are common comorbidities in people with epilepsy (PWE). This study investigated the extent to which the severity of depression affects specific cognitive domains and quality of life (QOL) in PWE.

Methods

In 732 PWE (age 18–82 years), Beck Depression Inventory (BDI) scores were correlated with performance in several cognitive domains (attention/executive functions, motor function, memory, language, visuo‐construction) and with QOL (using QOLIE‐10), individually and as superordinate compounds reflecting the range and intensity of general impairment.

Results

Forty‐five percent of patients had mild‐to‐severe depression. Cognitive domains were impaired in 43%–62% of patients. Depression correlated strongly with poorer QOL ( = 0.65). In contrast, its correlations with cognition were significantly weaker ( = 0.07–0.17), explaining less than 3% of the variance across all domains. The strongest correlation was with attention/executive functions. The overall impact of depression on the range and severity of cognitive impairments was mediated by its effect on these executive functions. The minimum BDI score difference required for a clinically significant cognitive difference (> 1 SD) was domain‐specific, ranging from 6 points for attention to 13 points for language. A 16‐point difference was needed for a significant change in QOL.

Conclusion

In PWE, depression has a severe primary impact on quality of life. Its direct effect on cognition, however, is minor. When a cognitive effect is present, it suggests hypofrontality impacting attention, executive functions, and motor skills, predominantly in the most severely depressed patients (BDI > 29). The influence of depression on global cognitive impairment is mediated through this executive dysfunction.

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Authors:
Christoph Helmstaedter, Christian Hoppe, Rainer Surges, Randi von Wrede and Juri‐Alexander Witt
Article first published online:
04 Feb 2026 | DOI: 10.1111/ene.70501

ORIGINAL ARTICLE

Background

Myelin oligodendrocyte glycoprotein antibody‐associated disease (MOGAD) is a rare antibody‐mediated inflammatory demyelinating disorder. In 2023, new international consensus diagnostic criteria were agreed. This study uses these criteria to describe epidemiological features of MOGAD in a population‐based cohort of patients from south Wales, UK.

Methods

Retrospective review of case notes on all positive MOG‐IgG results in South Wales between 01 January 2011 and 30 June 2024 was undertaken, 2023 diagnostic criteria applied and standardised clinical features recorded. Paediatric MOGAD was defined as age at onset < 16 years and adult MOGAD ≥ 16 years. The incidence period was between 01 January 2015 and 31 December 2023.

Results

Seventy‐six prevalent cases were identified: 53 adults and 23 children. Minimum estimated prevalence of MOGAD in south Wales on 30 June 2024 was 76/1,974,110 population (3.85/100,000 population; 95% CI 3.03–4.82). Paediatric prevalence was 6.59/100,000 population (95% CI 4.18–9.89) and adult prevalence 3.26/100,000 population (95% CI 2.44–4.27). Sex ratio was almost equal in males and females. The most frequent presentations were optic neuritis in adults (62.3%) and ADEM in children (34.8%); 64.5% had a monophasic disease course over a median follow‐up of 38 months (IQR 13–63). Mean annual incidence was 3.39 (95% CI 2.58–4.39) per million population.

Conclusions

This regional study provides updated prevalence and incidence rates for MOGAD since the introduction of 2023 diagnostic criteria in a stable south Wales, UK population.

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Authors:
Sophie Voase, Patrick Waters, Stephen Jolles, Gillian Ingram, Owen Pearson, Johann te Water Naudé, Katharine Harding, Mark Woodhall, Ray Wynford‐Thomas, Callum Wood, Emma Tallantyre and Neil P. Robertson
Article first published online:
09 Feb 2026 | DOI: 10.1111/ene.70502

ORIGINAL ARTICLE

Introduction

Management of multiple sclerosis (MS) revolves around timely initiation of effective disease‐modifying therapy. Here we investigate the additive predictive value of age‐adjusted normalised neurofilament light chain (NfL) concentrations when combined with a clinicodemographic model of treatment response.

Methods

Data were obtained from three sources: the University Hospital Basel, the SET cohort in Prague, and EIMS and IMSE cohorts from Sweden. NfL samples were collected within 90 days of baseline, age‐adjusted and normalised using a reference population. Principal component analysis reduced the dimensionality of clinicodemographic predictors. Cox proportional hazards models estimated cumulative hazards of relapse, 6‐month confirmed disability worsening and 9‐month confirmed disability improvement, with and without NfL. Uno's concordance index compared prediction accuracy across pooled and treatment‐specific models.

Results

The study included 1716 individuals across three therapies: interferon β ( = 554), fingolimod ( = 307) and natalizumab ( = 369). Clinicodemographic characteristics were associated with relapse and disability outcomes. While NfL showed no association in the pooled cohort, in the natalizumab group, higher NfL predicted lower probability of disability improvement (HR = 0.819, 95% CI: 0.814–0.823). Pooled models predicted outcomes with moderate accuracy (relapse: 63.4%, disability worsening: 56.4%, improvement: 67.7%), with minimal contribution from NfL. In treatment‐specific models, NfL‐inclusive accuracy ranged from 51.3%–62.2% (relapse), 54.3%–60.3% (worsening) and 65%–67.9% (improvement), closely matching models without NfL.

Conclusion

In well‐characterised MS patients treated with interferon β, fingolimod or natalizumab, clinicodemographic information provides modest prognostic value; however, NfL adds minimal incremental utility.

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Authors:
Nahid Moradi, Sifat Sharmin, Charles B. Malpas, Jens Kuhle, Pascal Benkert, David Leppert, Eva Kubala Havrdová, Dana Horáková, Pavlína Kleinová, Tomas Uher, Ali Manouchehrinia, Jan Hillert, Tomas Olsson, Ingrid Kochum, Bruce V. Taylor, Michael Barnett, Trevor J. Kilpatrick, Katherine Buzzard and Tomas Kalincik
Article first published online:
02 Feb 2026 | DOI: 10.1111/ene.70505

REVIEW ARTICLE

Background

Many Parkinson's disease patients receiving oral levodopa/carbidopa experience a troublesome wearing off effect. Higher doses to mitigate OFF‐time are limited by adverse effects occurring at peak dopamine levels, particularly dyskinesia. A novel strategy to reduce OFF‐time without increasing peak dopamine levels is the continuous subcutaneous infusion of levodopa/carbidopa, or their prodrug equivalents foslevodopa/foscarbidopa.

Objectives

Assess whether subcutaneous infusion therapies safely reduce OFF‐time and improve quality of life scores compared to oral levodopa/carbidopa.

Methods

We searched MEDLINE, Embase, CENTRAL and ICTRP up to 28th October 2024 for clinical trials comparing subcutaneous infusions of levodopa or foslevodopa to oral levodopa in Parkinson's disease.

Results

Screening of 1114 records identified seven studies in which 725 patients received subcutaneous infusion regimens of levodopa/carbidopa (ND0612) (407 patients) or foslevodopa/foscarbidopa (318 patients). Moderate quality evidence indicated subcutaneous infusion reduced the daily duration of OFF‐time by 1.98 h ( = 0.0004). Moderate quality evidence indicated improvements in health‐related quality of life score PDQ‐39 ( = 0.0003) and sleep score PDSS‐2 ( = 0.02), but an increase in the rate of treatment‐emergent adverse events, mostly related to the infusion site ( = 0.04).

Conclusions

Subcutaneous infusion therapies produce a clinically and statistically significant reduction in the duration of OFF‐time experienced by patients with Parkinson's disease, compared to oral levodopa/carbidopa. Patient experience is improved by a statistically, but not clinically, significant degree. There are increased adverse events, mostly related to the infusion site. Overall, subcutaneous infusion regimens could provide a meaningful alternative for Parkinson's disease patients who experience severe motor fluctuations with existing levodopa formulations.

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Authors:
Matthew Burton, Duncan Marsden, Dhruv Harish, Peter Morris, Carl Heneghan, Ailsa Butler and David Nunan
Article first published online:
29 Jan 2026 | DOI: 10.1111/ene.70506

ORIGINAL ARTICLE

Background

Ocrelizumab and natalizumab are highly effective disease‐modifying treatments for relapsing–remitting multiple sclerosis (RRMS). Direct comparison of effectiveness is crucial for optimizing treatment decisions and improving patient outcomes. The aim was to compare any difference in effectiveness of ocrelizumab and natalizumab on disease activity and progression in RRMS.

Methods

This was a national multicenter comparative effectiveness research study using data from the nationwide population‐based registry of MS cases in Denmark. Patients were included from January 2018 to April 2023 with a history of RRMS treated with ocrelizumab or natalizumab. Inverse probability of treatment weighting based on propensity scores was applied. Main outcomes were the comparison of annualized relapse rate (ARR), time to first progression independent of relapse activity (PIRA), and time to first occurrence of new/enlarging T2 or contrast‐enhancing lesions on cerebral MRI scans.

Results

We found no statistically significant differences in the ARR between ocrelizumab‐treated ( = 542) and natalizumab‐treated ( = 384) patients (mean [95% CI] ARR of 0.071 [0.057–0.088] and 0.071 [0.054–0.092], respectively) and in the ARR ratio (0.996, 95% CI [0.687–1.444],  = 0.983). Similarly, we did not find differences between the two groups in terms of time to first PIRA (HR, 1.34; 95% CI, 0.88–2.02;  = 0.17) and time to first inflammatory activity in MRI scans (HR, 1.04; 95% CI, 0.74–1.25;  = 0.78).

Conclusions

The study could not demonstrate a difference in effectiveness of ocrelizumab and natalizumab treatment in this nationwide population‐based registry study in risk of relapses, disability progression, and MRI activity.

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Authors:
Camilla Maersk‐Moller, Luigi Pontieri, Morten Leif Munding Stilund, Jeppe Romme Christensen, Lars Kristian Storr, Victoria Hansen, Jakob Schäfer, Arkadiusz Weglewski, Katerina Quinto Romani, Henrik Boye Jensen, Zsolt Illes, Victoria Papp, Tobias Sejbaek, Mai Bang Poulsen, Matthias Kant, Caroline Winther Torring, Finn Sellebjerg and Melinda Magyari
Article first published online:
28 Jan 2026 | DOI: 10.1111/ene.70507

ORIGINAL ARTICLE

Background

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the accumulation of misfolded alpha‐synuclein (α‐Syn) and the subsequent loss of dopaminergic neurons. Identifying reliable and non‐invasive biomarkers is crucial for accelerating early diagnosis and monitoring disease progression. To this aim, we longitudinally investigated α‐Syn in salivary extracellular vesicles (SEVs) in PD patients and the correlation with clinical outcomes.

Methods

SEVs were isolated from PD patients and healthy controls (HCs) saliva using differential ultracentrifugation followed by morphological and molecular characterization. The levels of both total (α‐Syn) and oligomeric (α‐Syn) α‐Syn were quantified by ELISA.

Results

We found a significant increase in both α‐Syn and α‐Syn in PD‐derived SEVs compared to HCs, and receiver operating characteristic analysis revealed that α‐Syn displayed higher sensitivity (65%) for discriminating PD from HCs compared to α‐Syn (59%). Moreover, α‐Syn levels correlated negatively with Mini‐Mental State Examination scores and were higher in patients with motor fluctuations. Finally, we found that α‐Syn levels did not change after one‐year follow‐up in patients when also the clinical parameters remained unaltered.

Conclusions

These results establish for the first time that SEVs‐associated α‐Syn is a promising, sensitive and non‐invasive biomarker for PD diagnosis and clinical correlation studies, bearing higher sensitivity than α‐Syn. Moreover, α‐Syn levels closely followed the clinical outcomes in PD patients. Finally, these findings strengthen the rationale for the further exploration of SEVs to disclose still unavailable accessible biomarkers for multiple neurological diseases.

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Authors:
Antonia Gurgone, Vita Cardinale, Marta M. Tangari, Serena Budicin, Debora Comai, Claudia Ledda, Leonardo Lopiano, Giovanni Camussi, Maurizio Zibetti and Maurizio Giustetto
Article first published online:
28 Jan 2026 | DOI: 10.1111/ene.70508

ORIGINAL ARTICLE

Background

Cranial nerve involvement is a well‐recognized feature in Guillain–Barré syndrome (GBS) but remains less well understood in chronic forms of autoimmune neuropathies. Earlier studies of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) were conducted before updated diagnostic criteria and the recognition of autoimmune nodopathy (AN), which may limit the interpretation of their findings.

Methods

We retrospectively analyzed 582 patients with chronic autoimmune neuropathies—CIDP ( = 431), multifocal motor neuropathy (MMN) ( = 64), anti‐myelin‐associated glycoprotein (MAG) neuropathy ( = 54), and AN ( = 33)—from 4 Korean and 1 UK centers. Patients with cranial nerve involvement were identified and described. CIDP patients with cranial nerve involvement (cranial+ CIDP) were compared with those without (cranial− CIDP).

Results

Cranial nerve involvement was observed in 8.8% (38/431) of CIDP and 24.2% (8/33) of AN patients but was absent in MMN (0/64) and anti‐MAG neuropathy (0/54). Facial palsy was overall the most common manifestation (CIDP: 45%, AN: 50%). Patients with AN more frequently exhibited bilateral optic neuropathy (50%) and facial diplegia (38%), while CIDP patients more often showed trigeminal neuropathy and oculomotor nerve palsy (both 32%). Compared with cranial− CIDP, cranial+ CIDP patients were more often younger, of variant subtypes (especially multifocal), presented (sub)acutely with preceding infection/vaccination, followed by relapsing–remitting rather than progressive courses, and achieved greater improvement despite greater pre‐treatment disability.

Conclusions

Cranial nerve involvement serves as a diagnostic clue in chronic autoimmune neuropathies, particularly in identifying AN and CIDP. Cranial+ CIDP appears to represent a distinct subset with partial overlap to GBS, suggesting unique underlying mechanisms.

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Authors:
Young Gi Min, Hyunjin Kim, Hee Jo Han, Byeol‐A Yoon, Jong Kuk Kim, Woohee Ju, Seok‐Jin Choi, Sung‐Min Kim, Ki Hoon Kim, Young Nam Kwon, Seung Woo Kim, Eun‐Jae Lee, Young‐Min Lim, Kabir K. Nazeer, Yusuf A. Rajabally, Ha Young Shin and Jung‐Joon Sung
Article first published online:
09 Feb 2026 | DOI: 10.1111/ene.70512

ORIGINAL ARTICLE

Background

Myasthenic crisis (MC) affects 10%–20% of myasthenia gravis patients and is life‐threatening with significant economic burden, yet its long‐term outcomes remain poorly understood. This prospective multicentre study aimed to evaluate 1‐year clinical outcomes after MC.

Methods

This study enrolled patients with MC between December 2018 and October 2024 and prospectively followed at 1, 2, 3, 6, and 12 months post‐MC. Outcome measures included Myasthenia Gravis Foundation of America (MGFA) postintervention status (PIS) classification at 1 year after MC, all‐cause mortality, and complications.

Results

The cohort comprised 277 patients with 282 MC episodes with a follow‐up duration of 29.16 ± 15.93 months. The in‐hospital mortality was 5.05% (14/277), while the all‐cause mortality was 15.16% (42/277). The leading causes of death were septic shock (35.7%) and multiple organ failure (21.4%). Among 247 patients with complete 1‐year follow‐up, 79.76% (197/247) achieved favorable outcomes. MG‐ADL scores reduced from 21.3 ± 2.1 at baseline to 5.5 ± 1.5 at 6 months, and 2.8 ± 1.1 at 1 year post‐MC ( < 0.01). Multivariable analysis identified older age at crisis (OR 1.03,  = 0.003), thymoma comorbidity (OR 1.84,  = 0.041), higher comorbidity burden (Charlson Comorbidity Index ≥ 3, OR 2.68,  = 0.003), and prolonged ICU stay (OR 1.03,  = 0.002) as independent predictors for minimal symptom expression non‐responders. The most frequent chronic complications included infections (15.2%; predominantly fungal pathogens), gastrointestinal disorders (8.3%), and osteoporosis/fractures (5.1%).

Conclusions

This is the first prospective cohort study to report clinical outcomes in MG patients at post‐MC stage, highlighting the importance of disease monitoring and early intervention to improve patient‐centred care.

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Authors:
Xiao Huan, Ran Chen, Lei Jin, Yuan Wang, Yafang Xu, Lei Yang, Caihua Xi, Jianming Zheng, Lijun Luo, Song Yang, Jianquan Shi, Yanping Liu, Zhe Ruan, Wanlong Wu, Wei Li, Yaoxian Yue, Yarong Li, Wenji Jia, Huahua Zhong, Chong Yan, Jie Song, Jianying Xi, Song Tan, Qilong Jiang, Zhangyu Zou, Chongbo Zhao, Sushan Luo, Yuzhou Guan, Yuwei Da, Huan Yang, Ting Chang, Yuge Wang, Bitao Bu, Hongyu Zhou, Chunsheng Yang, Hua Zhang, Hui Deng and Ruisheng Duan
Article first published online:
27 Jan 2026 | DOI: 10.1111/ene.70513

SHORT COMMUNICATION

Introduction

Hemiplegic migraine (HM) is a rare subtype of migraine with aura, characterized by transient, unilateral motor weakness. Due to its rarity, treatment strategies are lacking. Monoclonal antibodies targeting the calcitonin gene‐related peptide (CGRP) pathway have emerged as a potential therapeutic option.

Case Report

A 64‐year‐old man was admitted to an Austrian stroke unit with acute aphasia, right‐sided hemiplegia, and reduced consciousness. MRI showed no ischemia or hemorrhage. Cerebrospinal fluid analysis revealed pleocytosis (146 cells/μL) without signs of infection. By Day 4, the patient showed improving hemiparesis and new‐onset hemicranial headache. Aphasia resolved by Day 14 and hemiparesis by Day 21. The patient's history included non‐Hodgkin lymphoma with cerebral relapse, treated with whole‐brain irradiation and stem cell transplantation in 2007, and a history of migraine with aura. Differential diagnoses such as SMART syndrome and HaNDL were considered, but the improvement of symptoms following headache onset and the prior migraine history supported the diagnosis of sporadic hemiplegic migraine (SHM). Genetic testing revealed no mutations associated with familial HM. Initial treatment with lamotrigine was followed by monthly fremanezumab (225 mg). No further HM attacks occurred over 6 months of follow‐up.

Conclusion

This case illustrates the diagnostic complexity of SHM and adds to the growing body of anecdotal observations suggesting that CGRP monoclonal antibodies may be a promising preventive treatment for patients with HM. Further studies are needed to evaluate their efficacy in this rare migraine subtype.

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Authors:
Julian Frederic Hotz, Lisa Kaindl, Stefan Krebs, Marion Vigl, Julia Ferrari, Christian Neumann, Robert Han, Lavinia Ritscher, Marek Sykora and Paolo Gallmetzer
Article first published online:
27 Jan 2026 | DOI: 10.1111/ene.70514

ISSUE INFORMATION

Issue Information

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Article first published online:
26 Jan 2026 | DOI: 10.1111/ene.70515

ORIGINAL ARTICLE

Objectives

To investigate the prevalence of probable REM sleep behavior disorder (pRBD) in essential tremor (ET), identify associated risk factors, and evaluate its effects on motor and non‐motor symptoms.

Methods

Clinical data were collected from 1297 ET patients across multicenter. pRBD was assessed using the RBD Questionnaire‐Hong Kong (RBDQ‐HK). Risk factors associated with pRBD were identified through multivariable logistic regression. Furthermore, a meta‐analysis was conducted to synthesize existing estimates of pRBD/RBD prevalence in ET.

Results

In this study, pRBD was identified in 11.6% of ET patients. Meta‐analysis yielded pooled prevalence estimates of 16% for pRBD (ES = 0.16, 95% CI [0.10–0.21]) and 14% for RBD (ES = 0.14, 95% CI [0.07–0.21]). ET patients with pRBD were older (59.89 ± 13.99 vs. 54.63 ± 16.59 years,  < 0.001) and had a later tremor onset (47.55 ± 15.98 vs. 43.15 ± 17.62 years,  = 0.007) compared with those without pRBD. ET‐pRBD patients also exhibited a higher frequency of midline tremor (54.67% vs. 43.93%,  = 0.003), rest tremor (27.33% vs. 16.04%,  = 0.001), and elevated Non‐Motor Symptom Scale (NMSS) scores (20.30 ± 18.50 vs. 10.43 ± 12.42,  < 0.001). Multivariable logistic regression identified lower educational attainment (OR = 0.93,  = 0.002) and higher NMSS scores (OR = 1.03,  < 0.001) as independent risk factors.

Conclusions

pRBD is prevalent in ET and independently associated with lower education and increased non‐motor symptom burden. Recognition of pRBD may help identify an ET subgroup with distinctive clinical features.

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Authors:
Yuzheng Wang, Mingqiang Li, Runcheng He, Xiaomei Duan, Liang Jin, Dong Chang, JuanWan, Meiqi Jiang, Jiayi Wu, Mingshan Cai, Sheng zeng, Mei Yuan, Heng Wu, Chunyu Wang, Guohua Zhao, Qiying Sun and Beisha Tang
Article first published online:
09 Feb 2026 | DOI: 10.1111/ene.70516

ORIGINAL ARTICLE

Background

Vascular risk factors are associated with increased disease activity and disability progression in multiple sclerosis (MS). This has been studied mainly in cohorts with relapsing–remitting MS. However, the association between vascular comorbidities (VCM) and clinical disability in secondary progressive MS (SPMS) is less well studied. Our aim was to investigate the association between VCM, non‐VCM, comorbidity burden and both physical and cognitive performance in SPMS.

Methods

Longitudinal analysis of 445 patients from the MS secondary progressive multi‐arm trial (MS‐SMART)–a multi‐arm multicentre phase‐2b randomised placebo‐controlled trial of three agents in SPMS (NCT01910259). VCM (hypertension and hyperlipidaemia) and non‐VCM (asthma, hypothyroidism and osteoporosis) were recorded. A comorbidity score was also determined (0, 1, ≥ 2). Physical disability and processing speed were assessed at baseline, 48‐ and 96 weeks. Multiple linear regression and mixed models were used to investigate the cross‐sectional and longitudinal relationships between baseline VCM, non‐VCM, comorbidity score and clinical outcome measures.

Results

The cohort was predominantly female (67%), median Expanded Disability Status Scale (EDSS) 6.0. 13% and 9% had hypertension and hyperlipidaemia (VCM), respectively. 7%, 9% and 5% had asthma, hypothyroidism and osteoporosis (non‐VCM), respectively. Co‐morbidity counts were 0,63%; 1, 23% and with > = 2, 11%. In cross‐sectional models, both hypertension ( = 0.36, 95% CI 0.18–0.54) and an increased comorbidity count ( = 0.47, 95% CI 0.28–0.67) were associated with higher EDSS scores. In longitudinal models, hyperlipidaemia ( = 0.22, 95% CI 0.02–0.42) and increased comorbidity count ( = 0.21, 95% CI 0.01–0.41) were associated with increased EDSS scores over 48/96 weeks. No associations were seen with the non‐VCM.

Conclusion

VCM and also increased comorbidity burden per se are associated with increased disability. Disability worsening over 96 weeks was most evident in those with hyperlipidaemia and increased comorbidity burden.

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Authors:
Nevin A. John, Yingtong Li, Floriana De Angelis, Ferran Prados Carrasco, Jon Stutters, Anisha Doshi, Alberto Calvi, Domenico Plantone, Thomas Williams, Thanh Phan, Jeremy Chataway, Sebastien Ourselin, Marie Braisher, Tiggy Beyene, Vanessa Bassan, Alvin Zapata, Siddharthan Chandran, Peter Connick, Dawn Lyle, James Cameron, Daisy Mollison, Shuna Colville, Baljean Dhillon, Moira Ross, Gina Cranswick, Allan Walker, Lorraine Smith, Gavin Giovannoni, Sharmilee Gnanapavan, Richard Nicholas, Waqar Rashid, Julia Aram, Helen Ford, Sue H. Pavitt, James Overell, Carolyn Young, Heinke Arndt, Martin Duddy, Joe Guadagno, Nikolaos Evangelou, Matthew Craner, Jacqueline Palace, Jeremy Hobart, Basil Sharrack, David Paling, Clive Hawkins, Seema Kalra, Brendan McLean, Nigel Stallard and Roger Bastow
Article first published online:
09 Feb 2026 | DOI: 10.1111/ene.70517

ORIGINAL ARTICLE

Background

Intraneural perineurioma (INP) is a rare, benign peripheral nerve sheath tumour that typically presents in adolescence or early adulthood as a slowly progressive, motor‐predominant mononeuropathy or plexopathy. Although its clinicoradiological and histopathological features are well characterised, the genetic basis remains incompletely defined.

Methods

We retrospectively analysed 10 patients with histologically confirmed INP diagnosed between February 2015 and December 2024. Demographic and clinical data, MRI/MR neurography findings and histopathology (immunohistochemistry and electron microscopy) were analysed. Targeted Sanger sequencing of TRAF7 exons 17–18 (WD40 domain) was performed. Interphase FISH with an EWSR1 (22q12) probe was performed on archival FFPE tissue in a subset.

Results

All patients exhibited progressive motor deficits, with at least one muscle group graded ≤ 2 on the MRC scale. Sensory symptoms were present in 8/10 and pain in 4/10. MRI demonstrated fusiform nerve enlargement and homogeneous gadolinium enhancement in all cases, with T2 hyperintensity in 9/10. A pathogenic p.His521Arg variant was identified in 2/9 evaluable tumours (22.2%). Tendon transfer was performed in 7/10 patients as a reconstructive strategy to improve motor function, resulting in heterogeneous functional outcomes.

Interpretation

The MRI triad of fusiform enlargement, T2 hyperintensity and homogeneous enhancement strongly supports INP diagnosis and may obviate biopsy in typical cases. Our hotspot‐limited assay detected mutations in only 22.2%, underscoring methodological limitations and probable genetic heterogeneity. Despite an indolent imaging appearance, INP frequently causes severe functional impairment requiring reconstructive surgery. Early recognition, structured functional monitoring and risk‐adapted intervention are essential to optimise outcomes.

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Authors:
Eduardo Boiteux Uchôa Cavalcanti, Alessandra de La Rocque Ferreira, Nilo Sakai Júnior, Francineide Sadala de Souza, Heveline Becker de Moura, Eni Braga Da Silveira, Graciela Maria Barbosa Lacerda Martins and Marcio de Mendonça Cardoso
Article first published online:
09 Feb 2026 | DOI: 10.1111/ene.70519

ORIGINAL ARTICLE

Introduction

Rituximab is effective and widely used as long‐term treatment in aquaporin‐4‐IgG‐positive neuromyelitis optica spectrum disorder (AQP4‐IgG+ NMOSD). However, infections remain a significant concern during rituximab treatment.

Methods

We conducted a retrospective multicenter cohort study within the NMO Study Group (NEMOS) in Germany, analyzing demographic and clinical data from people with AQP4‐IgG+ NMOSD receiving rituximab or azathioprine by retrospective chart, and compared infection occurrence and severity. For rituximab‐treated patients, we collected laboratory data (blood lymphocytes, B‐cell counts, serum IgG, IgM, and IgA levels), assessed risk factors for infections, and determined the probability of infection within a 3‐month window before and after the laboratory assessment.

Results

In 92/170 rituximab and in 12/33 azathioprine treatment episodes, one or more infections were documented. Rituximab and azathioprine showed comparable types and risk of infection (HR = 1.24, 95% CI: 0.68–2.25). Rituximab‐treated individuals older than 60 years had a higher risk of infection (HR = 1.62, 95% CI: 1.02–2.57). Hypogammaglobulinemia (IgG < 6.0 g/L: OR = 2.27, 95% CI: 1.15–4.48; IgM < 0.3 g/L: OR = 2.08, 95% CI: 1.05–4.09) predicted infections and the occurrence of both low IgG and IgM serum levels further increased the risk of infection (OR = 2.77, 95% CI: 1.10–6.98) during rituximab treatment. Low IgG and IgA serum levels as well as lymphopenia predicted infection‐related hospitalizations.

Conclusion

Age > 60 years and immunoglobulin serum levels during rituximab treatment may serve as predictors for infection and help to individualize treatment decisions in NMOSD.

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Authors:
Daniel Engels, Mariella Herfurth, Joachim Havla, Patrick Schindler, Klemens Ruprecht, Carolin Schwake, Marius Ringelstein, Katinka Fischer, Charlotte Schubert, Insa Schiffmann, Martin W. Hümmert, Katrin Giglhuber, Sven Jarius, Ioannis Vardakas, Matthias Grothe, Thorleif Etgen, Clemens Warnke, Jasmin Naumann, Frank Hoffmann, Makbule Senel, Brigitte Wildemann, Achim Berthele, Corinna Trebst, Vivien Häußler, Orhan Aktas, Ilya Ayzenberg, Judith Bellmann‐Strobl, Florian Then Bergh and Tania Kümpfel
Article first published online:
04 Feb 2026 | DOI: 10.1111/ene.70520

CASE REPORT

Objectives

To describe a patient with chronic ataxic neuropathy with disialosyl antibodies (CANDA) with clinical and neurophysiological improvement after zanubrutinib therapy.

Methods

A 62‐year‐old man started complaining of sensory symptoms in his hands and feet extending over time to the knees and elbows. Nerve conduction studies were consistent with diffuse sensory axonal ganglionopathy. Blood tests revealed an IgM 𝜆 paraprotein expression of Waldenström's macroglobulinemia. Anti‐MAG and anti‐neuronal antibodies were negative. Anti‐ganglioside IgM antibodies (GD1b; GD2, GD3, GT1a, GT1b, GQ1b) were positive. Neurological examination disclosed pinprick and tactile hypoesthesia with stocking‐glove distribution. The patient was responsive to intravenous immunoglobulin (IVIg) but reported end‐dose fluctuations. Rituximab was started but soon discontinued for clinical worsening, so IVIg therapy was resumed.

Results

The patient was started on zanubrutinib, a second generation Bruton's tyrosine kinase (BTK) inhibitor, while continuing IVIg with global improvement and absence of end of dose efficacy. After 15 months, besides a clinical and hematological amelioration, a dramatic neurophysiological improvement also occurred. Antibodies to IgM GM1 and GM2 were not detectable, whereas anti‐disialosyl antibodies GD1a and GD1b persisted unchanged.

Discussion

To the best of our knowledge, this is the first patient with Waldenström‐associated CANDA with clinical, hematological, and neurophysiological benefit after zanubrutinib therapy.

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Authors:
Benedetta Tierro, Andrea Visentin, Alessandro Salvalaggio, Gabriella Cacchiò, Nicolò Danesin, Susanna Ruggero, Francesco Logullo and Chiara Briani
Article first published online:
24 Feb 2026 | DOI: 10.1111/ene.70521

ORIGINAL ARTICLE

Background

Spinal cord injury (SCI) is associated with substantial morbidity, premature mortality, and reduced life expectancy. However, population‐based survival data that include both traumatic and non‐traumatic cases are limited.

Methods

We retrospectively analyzed all 587 Salzburg residents diagnosed with SCI between 2013 and 2023. Cases were identified from hospital records and verified through the Austrian mortality registry. Crude mortality rates (CMRs) at 1‐, 2‐, and 5‐year intervals, standardized mortality ratios (SMRs), and life expectancy (LE) differences compared with the general population were calculated by age, sex, and injury type. Causes of death were classified as natural or external.

Results

Of 587 patients, 488 (83%) had non‐traumatic and 99 (17%) traumatic SCI; median age at onset was 62 years. By January 2025, 138 patients (24%) had died, predominantly from cardiovascular and neoplastic causes. CMRs increased steeply with age, rising from 10.5 per 100,000 at 1 year to 19.4 at 5 years. SMRs were markedly elevated in younger patients (e.g., age 30–44: 71.7 at 1 year) and decreased with advancing age. Life expectancy was consistently lower than in the general population, with the greatest reductions in younger and middle‐aged males with non‐traumatic injuries (e.g., 50‐year‐old males: LE difference 3.4 years at 1 year).

Conclusions

SCI substantially reduces life expectancy, with younger individuals experiencing disproportionate relative mortality and older adults bearing the highest absolute risk. These findings highlight the need for tailored long‐term strategies, including preventive measures for younger patients and comprehensive chronic disease management for older populations.

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Authors:
Mahdi Safdarian, Aljoscha Thomschewski, Stefan Leis, Laura Schnetzer, Georg Zimmermann, Wolfgang Voelckel, Thomas Freude and Eugen Trinka
Article first published online:
02 Feb 2026 | DOI: 10.1111/ene.70522

REVIEW ARTICLE

Introduction

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder marked by mucocutaneous telangiectasias, recurrent epistaxis, and visceral arteriovenous malformations (AVMs). Neurologic risks include brain AVMs and hemorrhagic stroke. Several rare genetic and sporadic syndromes (“HHT‐like” syndromes) share overlapping vascular features, complicating diagnosis. Differentiating these conditions is essential for accurate neurovascular risk assessment.

Methods

A comprehensive literature review (PubMed, Scopus, Embase, Google Scholar; 1990–2025) targeted cerebrovascular manifestations of HHT and related syndromes. Key entities included Wyburn–Mason syndrome, Cobb syndrome, Klippel–Trénaunay syndrome (KTS), neurofibromatosis type 1 (NF1), PHACE(S) syndrome, capillary malformation–AVM (CM‐AVM), Parkes Weber syndrome (PWS), juvenile polyposis/HHT overlap (JP‐HHT), HHT type 5 (BMP9/GDF2), PTEN hamartoma tumor syndrome (PHTS), and blue rubber bleb nevus syndrome (BRBNS). Data on gene variants, lesion types, neuroimaging, stroke risk, and neurologic outcomes were synthesized.

Results

High‐flow cerebrovascular malformations similar to HHT are prominent in Wyburn–Mason syndrome, CM‐AVM, and PWS, conferring a substantial hemorrhagic stroke risk. NF1 and PHACE(S) primarily feature occlusive arteriopathies linked to ischemic events. KTS, BRBNS, and PHTS predominantly show low‐ or mixed‐flow anomalies with lower CNS hemorrhagic risk but increased thrombotic complications. JP‐HHT carries added gastrointestinal cancer risk via SMAD4 variants, while HHT type 5 often presents incompletely. Genetic testing and tailored neuroimaging are critical for differentiation.

Conclusions

Although many syndromes mimic HHT, few combine mucosal telangiectasias, high‐flow AVMs, and recurrent hemorrhage. Integrating clinical, imaging, and genetic data enables precise diagnosis, risk stratification, and personalized management.

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Authors:
Matteo Palermo and Carmelo Lucio Sturiale
Article first published online:
18 Feb 2026 | DOI: 10.1111/ene.70523

ORIGINAL ARTICLE

Background

Brain abscesses rarely complicate bacterial meningitis while their clinical characteristics and outcomes have not been systematically assessed. We studied prevalence, pathogen distribution, clinical characteristics including treatment, and outcomes of brain abscess in bacterial meningitis patients.

Methods

In a prospective Dutch national cohort of community‐acquired bacterial meningitis (January 2006 to October 2023), we identified patients with a brain abscess diagnosed by the treating physician. Presence of abscesses was confirmed by re‐evaluation of the cranial imaging.

Results

Of the 2918 episodes included, 56 were complicated by a brain abscess (prevalence 1.9%, 95% confidence interval [CI] 1.5–2.5). For the prevalence of abscesses among meningitis episodes was 1.1% (95% CI 0.7%–1.6%) while it was 3.6% (95% CI 2.6%–5.0%) for other bacteria. Prevalence was highest in meningitis caused by the group (11/21, 52.4%), (1/10, 10.0%), (8/175, 4.6%), (1/22, 4.5%), and group A streptococcus (3/79, 3.8%). Prevalence increased between 2006–2014 and 2015–2023, with a ratio of 1.8 (95% CI 1.7–2.1). In meningitis patients with abscesses, 14‐day survival was 94% and 40 of 56 (71%) patients had an unfavourable outcome. In 9 of 56 (16%) patients the abscess was treated with a neurosurgical intervention (extra‐ventricular CSF drain or abscess aspiration). All received prolonged antibiotic treatment.

Conclusions

Most brain abscesses among meningitis patients were caused by pneumococci, but non‐pneumococcal streptococci had the highest risk for abscesses. Patients with abscesses had a high risk for an unfavourable outcome.

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Authors:
Fabian D. Liechti, Evelien H. G. M. Drost, Merijn W. Bijlsma, Matthijs C. Brouwer and Diederik van de Beek
Article first published online:
25 Feb 2026 | DOI: 10.1111/ene.70524

ORIGINAL ARTICLE

Background

Hereditary transthyretin (ATTRv) amyloidosis is a rare, genetically heterogeneous disease leading to an unstable configuration of transthyretin (TTR) and hence irregular deposition of TTR amyloid fibrils. The disease predominantly affects the peripheral nervous system, resulting in a progressive sensorimotor polyneuropathy (ATTRv‐PN), but can also involve the cardiac and other organ systems. The mRNA silencers patisiran and inotersen effectively reduce serum TTR levels, thereby improving neurologic disability and quality of life in patients with ATTRv‐PN. This real‐world study investigated long‐term efficacy and tolerability of both compounds in patients with ATTRv‐PN.

Methods

This retrospective study from a German single‐referral center assessed the effects of treatment with patisiran or inotersen on clinical parameters of 35 patients with ATTRv‐PN treated at the Amyloidosis Center of Heidelberg University Hospital for up to 6 years after therapy start. The study included analyses of serum TTR levels, NT‐proBNP, creatinine and modified body mass index (mBMI), and reported side effects throughout the observational period.

Results

Both silencers stably reduced serum TTR levels by 81.1% ( = 0.0039, patisiran) and 82.8% ( = 0.0039, inotersen), respectively, after 8 to 15 months compared to mean baseline. NT‐proBNP, creatinine, and mBMI values remained stable during treatment. With patisiran, a lower rate of reported adverse effects was observed. Grade 1 thrombocytopenia was reported primarily for inotersen‐treated patients.

Conclusions

Our findings confirm long‐term treatment with silencers in a real‐world setting is safe, consistently reducing serum TTR levels, stabilizing neurologic symptoms, cardiac and renal functions, and nutritional parameters.

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Authors:
Marilin S. Koch, Fabian aus dem Siepen, Ute Hegenbart, Stefan Schönland and Markus Weiler
Article first published online:
18 Feb 2026 | DOI: 10.1111/ene.70529

ORIGINAL ARTICLE

Background

We evaluated the real‐world efficacy, tolerability, treatment retention, and quality‐of‐life effects of cenobamate in paediatric drug‐resistant epilepsy.

Methods

We retrospectively studied 78 paediatric patients with drug‐resistant epilepsy treated with cenobamate for ≥ 3 months at a tertiary epilepsy centre. We assessed seizure frequency, adverse effects, cognitive/behavioural outcomes, and changes in concomitant antiseizure medications. The primary efficacy endpoint was a ≥ 50% reduction in seizure frequency. We assessed safety through reported adverse events and clinical improvement using the Clinical Global Impression–Improvement (CGI‐I) scale. We used Kaplan–Meier analyses to assess responder rates and treatment retention over 18 months.

Results

A ≥ 50% seizure reduction was achieved in 67.9% of patients including 6.4% who became seizure‐free. Polytherapy was simplified in 38% overall and in 56.6% of responders. Adverse events occurred in 43.6% of patients, were mostly mild, and led to discontinuation in only one patient (1.3%). CGI‐I indicated clinical improvement in 24.4%. Kaplan–Meier analysis showed sustained response in 93% of initial responders at 18 months. Treatment retention remained high: 94.7% at 3 months, 89.6% at 12 months, and 86.8% at 18 months. Median follow‐up was 12 months (range 3–18), with 60.3% followed for ≥ 12 months and 41% for the full 18 months.

Conclusions

Our study confirms and extends recent evidence on the efficacy and favourable tolerability of cenobamate in paediatric drug‐resistant epilepsy. We observed functional improvements and polytherapy simplification, suggesting broader therapeutic benefits. These findings warrant prospective validation in specific paediatric epilepsy syndromes and may help support regulatory approval for paediatric use.

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Authors:
Tiziana Pisano, Simona Balestrini, Alessandra Boncristiano, Saverio Caini, Martina Lombardini, Erica Scuma, Mara Cavallin, Luca Bartolini, Simona Pellacani, Carmen Barba and Renzo Guerrini
Article first published online:
18 Feb 2026 | DOI: 10.1111/ene.70530

ORIGINAL ARTICLE

Background

New drug trials in drug resistant epilepsy are typically powered to detect changes in seizure frequency as the primary endpoint, without integrating other treatment‐associated benefits and harms. We developed Epilepsy‐DOOR, a consumer‐codesigned outcome measure, which combines seizure frequency with quality of life and adverse event measures. This study evaluated Epilepsy‐DOOR in previously completed phase 3 clinical trials of adjunctive brivaracetam in patients with drug resistant epilepsy.

Methods

Epilepsy‐DOOR was derived for each participant who completed the randomised controlled trial of three Phase 3 trials of brivaracetam (N01252, N01253, N01254). Win odds were estimated for Epilepsy‐DOOR and its individual components: change in seizure frequency, quality of life, and adverse event severity for treatment with brivaracetam over placebo for each dose in each study. Odds ratio was estimated for responder rate.

Results

In N01252, Epilepsy‐DOOR demonstrated benefit of 100 mg brivaracetam (Win odds 1.42, 95% CI 1.03, 1.97) but not smaller doses over placebo, in line with the results when using responder rate (odds ratio 1.14, 95% CI 1.02, 1.29). In studies N01253 and N01254, benefit as assessed by Epilepsy‐DOOR did not attain statistical significance, despite benefits at some doses when measuring seizure responder rate.

Conclusion

Epilepsy‐DOOR showed similar effect sizes but slightly reduced power when compared with responder rate. This reduced power is due to the appropriate reflection of adverse events by Epilepsy‐DOOR. Epilepsy‐DOOR provides a more holistic measure of anti‐seizure medication treatment effects, balancing relative benefits and harms, and has potential as a future endpoint in clinical trials in epilepsy.

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Authors:
Lucy Vivash, Hannah Johns, Terence J. O′Brien and Leonid Churilov
Article first published online:
10 Feb 2026 | DOI: 10.1111/ene.70531

REVIEW ARTICLE

Background

In myasthenia gravis (MG) with acetylcholine receptor (AChR) antibodies, epidemiology, disease mechanisms, diagnosis, and treatment depend on age. MG with debut after 65 years has an increasing incidence and prevalence but is underrepresented in clinical studies.

Methods

This is a systematic review of very late onset MG and MG in patients above 65 years with focus on epidemiology, pathogenesis, diagnosis, clinical characteristics, and treatment.

Results

Both innate and adaptive immune responses are influenced by age. The increase in MG incidence in the very old is probably caused by unknown environmental factors. Both patients' and doctors' diagnostic delays are substantial for very late onset MG. Comorbidities are frequent and can lead to misdiagnosis. MG needs to be considered as a potential diagnosis in all elderly patients with newly localized or generalized muscle weakness. AChR antibodies have near 100% diagnostic specificity and 80% sensitivity in this age group. Very late onset MG is often mild and with an excellent response to pyridostigmine and first‐line immunosuppressive therapy. One in five has a debut with life‐threatening respiratory insufficiency. Rituximab, complement inhibitors, and FcRn blockers can be used on the same indications as for younger MG patients. MG in the very old is a fluctuating disease with the need of frequent adjustments of drug therapy.

Conclusions

Very late onset MG and MG in the very old should be treated actively with symptomatic and immunosuppressive drugs, physical activity programs, and general support. The treatment aim should be pharmacological remission or minimal manifestations only.

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Authors:
Nils Erik Gilhus
Article first published online:
21 Feb 2026 | DOI: 10.1111/ene.70534

SHORT COMMUNICATION

Background

Axial myopathies present with late onset selective paravertebral weakness causing bent spine/camptocormia or dropped head, and the genetic basis remains currently only partially understood. Truncating variants in (TTNtv) are found in about 1% of the general population and, when biallelic, cause recessive titinopathies. Also, TTNtv located in cardiac exons are known to confer an increased risk of cardiomyopathy, with incomplete penetrance.

Methods

We retrospectively analyzed 55 Finnish adults with late‐onset axial myopathy evaluated at the Tampere Neuromuscular Center (2015–2025). Clinical, imaging, and histopathological data were collected, and genetic testing was performed using the MYOcap targeted next‐generation sequencing panel.

Results

Heterozygous TTNtv were identified in 9 of 55 patients (16%), representing a significant enrichment compared with the general population (odds ratio = 14.1; ≈5 × 10). The variants were ultra‐rare, distributed across different exons expressed in skeletal muscle, and five were absent from gnomAD. Mean age at onset was 60 ± 11 years; six patients were female, and five reported a positive family history. Camptocormia was the main presentation, with muscle MRI showing a consistent fatty‐fibrous replacement of paravertebral muscles in all cases. Muscle biopsies revealed either myopathic or myofibrillar changes without a uniform pattern.

Conclusions

Heterozygous TTNtv are significantly enriched in patients with late‐onset axial myopathy, suggesting a potential contribution to this phenotype. These findings broaden the clinical spectrum of titin‐related diseases and support inclusion of in genetic testing for idiopathic axial myopathies.

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Authors:
Maria Francesca Di Feo, Giuliana Capece, Marco Savarese, Bjarne Udd, Manu Jokela and Johanna Palmio
Article first published online:
17 Feb 2026 | DOI: 10.1111/ene.70537

ORIGINAL ARTICLE

Aim

Treating infective endocarditis (IE) complicated by neurological events remains challenging and often requires case‐by‐case decisions. Identifying predictors of postoperative complications is key to effective risk assessment and management.

Methods

Data from 191 patients who underwent cardiac surgery for IE were analyzed. Patients were grouped based on the presence or absence of preoperative neurological events (ischemic stroke, TIA, or intracerebral hemorrhage). Univariate and multivariate logistic regression analyses were used to identify predictors of postoperative neurological complications.

Results

Patients with preoperative neurological events underwent surgery later (33 ± 25 vs. 23 ± 23 days,  = 0.022), had larger vegetations (1.27 ± 1.88 vs. 0.68 ± 1.08 cm,  = 0.029), and more extracranial embolism (55% vs. 10%,  < 0.001). Patients with prior neurological complications developed more new cerebral embolic events (65% vs. 3.3%,  < 0.001), intracerebral bleeding (20% vs. 1.3%,  < 0.001), required longer ventilation (64 ± 89 vs. 59 ± 136 h,  = 0.013), and were more frequently discharged to neurological rehabilitation (26% vs. 9%,  = 0.008). Preexisting stroke or bleeding significantly increased the risk of cerebral embolism (OR 133.7), prolonged ventilation (OR 2.56), intracerebral bleeding (OR 420), and discharge to neurological rehabilitation (OR 4.71). Independent predictors of new postoperative neurological events were preoperative TIA (OR 19.45), cerebral embolism (OR 10.59), and leukocytosis (OR 8.36). Thirty‐day mortality did not differ between groups (8.3% vs. 7.5%,  = 1.0).

Conclusion

Patients with preoperative neurological complications remain at high risk for neurological deterioration in the postoperative course.

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Authors:
George Awad, Bahar Wakeli, Sam Varghese, Boris Kuzmin, Anke Lux, Priya Veluswamy, Mohammad Fadel, Jens Wippermann, Maximilian Philipp Scherner and Max Wacker
Article first published online:
19 Feb 2026 | DOI: 10.1111/ene.70539