cover image European Journal of Neurology

European Journal of Neurology

2026 - Volume 33
Issue 6 | June 2026
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ORIGINAL ARTICLE

Introduction

This cross‐sectional study aims to assess somatosensory function in patients with trigeminal neuralgia (TN) using quantitative sensory testing (QST) and QST‐based sensory phenotyping, and to investigate their relationship with clinical findings, including etiology (classical and idiopathic TN), type of pain (paroxysmal pain only and concomitant continuous pain), and response to pharmacological treatment.

Methods

Sixty‐five patients with classical or idiopathic TN underwent QST. Sensory alterations were quantified using ‐scores derived from normative data, and sensory profiles were identified using a validated algorithm. Clinical characteristics, presence of concomitant continuous pain, and response to first‐line sodium channel blockers were systematically recorded through a structured questionnaire.

Results

QST showed bilateral thermal hypoesthesia and pain hyperesthesia in the whole patient population. Cold detection threshold (CDT) was significantly reduced on the affected side compared to the unaffected side in patients with Classical TN. Idiopathic TN was associated with bilaterally elevated wind‐up ratio. Patients with purely paroxysmal pain showed a bilateral gain of function in heat pain thresholds. Sensory phenotyping identified mechanical hyperalgesia (49%) and thermal hyperalgesia (35%) as predominant phenotypes. A sensory loss phenotype was significantly associated with poor response to sodium‐channel blockers.

Discussion

TN is characterized by subtle and complex bilateral sensory alterations, potentially suggesting central modification of sensory processing. The finding of asymmetrical CDT reduction may indicate peripheral Aδ‐fiber dysfunction. Sensory profiling may identify subgroups with distinctive treatment responses, with sodium channel blockers being less effective in sensory loss phenotype.

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Authors:
Gianfranco De Stefano, Daniel Litewczuk, Eleonora Galosi, Giuseppe Di Pietro, Pietro Falco, Caterina Leone, Jibril Osman‐Farah, Deepti Bhargava, Francis O'Neill, Bernhard Frank, Colby T. Joncas, Raymond F. Sekula, Giulia Di Stefano and Andrea Truini
Article first published online:
01 Jun 2026 | DOI: 10.1111/ene.70553

REVIEW ARTICLE

Background

Noninvasive neuromodulation has emerged as a promising approach for acute and preventive treatment of migraine and cluster headache. This systematic review evaluates how noninvasive neuromodulation trials align with guidelines by the International Headache Society (IHS), their efficacy on IHS‐recommended outcomes, and the robustness of the supporting evidence.

Methods

A systematic search of MEDLINE, Embase, , and the WHO International Clinical Trials Registry Platform was conducted for clinical trials published between January 1990 and October 2024. Studies evaluating noninvasive neuromodulation for acute or preventive treatment of migraine or cluster headache were included based on predefined eligibility criteria. Data were analyzed with respect to study design, adherence to endpoints recommended by IHS, and efficacy of reported outcomes.

Results

Seventy trials met inclusion criteria, covering modalities such as noninvasive vagus nerve stimulation (nVNS), external trigeminal nerve stimulation (e‐TNS), single‐ and repetitive transcranial magnetic stimulation (sTMS, rTMS), and remote electrical neuromodulation (REN), among others. For migraine, acute treatment studies were mostly randomized, sham‐controlled, and blinded, while preventive trials showed greater variability. Significant heterogeneity was noted in the use of IHS‐recommended endpoints. For cluster headache, nVNS remains the only modality evaluated.

Conclusions

Noninvasive neuromodulation holds potential for acute and preventive treatment of migraine and cluster headache. However, considerable variability exists in study design, outcomes, and adherence to IHS guidelines across trials. Additional robust, sham‐controlled studies are needed to validate the clinical efficacy of these interventions.

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Authors:
Javiera Canales‐Rodríguez, Cornelius Angerhöfer, Edoardo Caronna, Bianca Raffaelli, Lucas Hendrik Overeem, Patricia Pozo‐Rosich and Uwe Reuter
Article first published online:
18 Jun 2026 | DOI: 10.1111/ene.70559

SHORT COMMUNICATION

Objectives

Radiation‐induced (radiculo)plexopathy [RI(R)P] is a debilitating delayed neurological adverse event occurring in cancer survivors years after the irradiation of the brachial or lumbar plexuses. No effective treatments have been identified to date. The objective of this work was to evaluate the effectiveness of the anti‐VEGF bevacizumab in the treatment of RI(R)P.

Methods

We retrospectively identified patients diagnosed with contrast‐enhancing RI(R)P and treated with bevacizumab in the setting of an institutionally sponsored expanded access program over the last 10 years. Clinical, radiological, and neurophysiological records were reviewed.

Results

We identified nine patients manifesting with neurophysiological‐confirmed RI(R)P (brachial plexopathy, 4; lumbosacral radiculoplexopathy, 5) after a median of 13 years from radiotherapy for their cancer. Symptoms included focal weakness, paresthesia, cramps, hypoesthesia, amyotrophy, and pain. Patients received bevacizumab at 7.5 mg/kg/q2 weeks for a median of six cycles (range, three to nine cycles). Clinical improvement was noted in three cases and clinical stabilization in two. Patients treated within 2 years since symptom onset appeared as most likely to benefit. Enhancement reduction on follow‐up MRI was associated with the clinical benefit.

Discussion

Bevacizumab could be effective in the treatment of RI(R)P, particularly when patients are managed early in their disease. Further prospective clinical trials are warranted to validate these results.

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Authors:
Alberto Picca, Timothée Lenglet, Christophe Vandendries, Jean‐Marc Simon, Mathilde Ducloie, Thierry Maisonobe, Damien Ricard and Dimitri Psimaras
Article first published online:
28 May 2026 | DOI: 10.1111/ene.70587

LETTER TO THE EDITOR

Inclusive Language for Inclusive Care—A Proposal for an LGBTQI Glossary for European Neurologists

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Authors:
Giulia Donzuso, Maria Teresa Ferretti, Francesco Pasini, Calogero Edoardo Cicero, Gennarina Arabia, Marianne de Visser, Cianán B. Russell, Dauren Ramankulov, Anja Sander and Alessandra Nicoletti
Article first published online:
28 May 2026 | DOI: 10.1111/ene.70607

ORIGINAL ARTICLE

Background

Multiple system atrophy (MSA) is characterized by progressive autonomic/motor dysfunction, but robust biomarkers do not exist. Electrochemical skin conductance (ESC) provides a noninvasive measure of sudomotor function, but its longitudinal predictive value and prognostic relevance in MSA remain insufficiently studied. We aimed to comprehensively evaluate ESC in a large longitudinal cohort.

Methods

We analyzed 175 patients with MSA followed for a mean of 4.2 ± 2.1 years. Disease severity was assessed using UMSARS Parts 1 and 2, COMPASS31, SCOPA‐AUT, and orthostatic blood pressure (BP) measurements. Hand and foot ESC were measured using Sudoscan. Cross‐sectional and longitudinal associations were examined using linear mixed‐effects models, repeated‐measures correlations, and grouped 10‐fold cross‐validation. Mortality predictors were assessed with time‐varying Cox proportional hazards models.

Results

ESC was strongly inversely associated with UMSARS 1 and 2 ( = −0.58 to −0.65;  = −0.67 to −0.75; all  < 0.0001), whereas associations with orthostatic BP, autonomic symptom scales, and disease duration were weaker or inconsistent. ESC declined significantly over time (feet −6.88 ± 0.60 μS/year; hands −5.41 ± 0.46 μS/year; both  < 0.001), paralleling UMSARS progression. ESC outperformed orthostatic BP drops in predicting UMSARS scores in mixed‐effects models and cross‐validation. Higher ESC independently predicted lower mortality, while higher UMSARS scores and greater orthostatic BP drops predicted increased risk. Median survival was 46.2 months.

Conclusions

ESC is a sensitive biomarker of disease severity, progression, and survival in MSA, substantially outperforming orthostatic BP measures. Its simplicity and prognostic value support incorporation into routine monitoring and clinical trials.

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Authors:
Paulo Bastos, Marc Kermorgant, Fabienne Ory‐Magne, Clémence Leung, Margherita Fabbri, Olivier Rascol, Alexandra Foubert‐Samier, David Bendetowicz, Wassilios G. Meissner and Anne Pavy‐le‐Traon
Article first published online:
19 Jun 2026 | DOI: 10.1111/ene.70620

ORIGINAL ARTICLE

Background

In Duchenne muscular dystrophy (DMD), cardiac causes account for approximately 30% of all deaths. Therefore, evaluating cardiac function in older patients is important. In addition, current recommendations advise screening for arrhythmias when left ventricular dysfunction is identified; however, the evidence base underpinning this recommendation in DMD is limited. Furthermore, large‐scale cohort studies with substantial adult representation are lacking.

Methods

To characterize arrhythmia profiles of patients with DMD, we analyzed 1018 Holter electrocardiographic recordings from 167 patients with DMD (age: 9–44 years).

Results

Bradyarrhythmia and supraventricular tachyarrhythmia were rare; nonsustained ventricular tachycardia (NSVT) and ≥ 720 premature ventricular complexes per 24 h were detected in 85 (8.3%) and 124 (12.2%) recordings, respectively. Logistic regression identified reduced left ventricular function as the strongest associated factor for NSVT. Although statistically nonsignificant, risk increased with age, nonuse of noninvasive positive‐pressure ventilation, and a Dp140‐deficient genotype. A Dp116‐deficient genotype was associated with lower odds of NSVT.

Conclusions

Given that NSVT may trigger sudden cardiac death in susceptible patients with underlying cardiac disease, regular Holter electrocardiographic monitoring is warranted in patients at high risk of NSVT.

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Authors:
Ryo Sugiyama, Eri Takeshita, Yu Aihara, Yuko Shimizu‐Motohashi, Shoki Izumi, Mari Oba and Hirofumi Komaki
Article first published online:
02 Jun 2026 | DOI: 10.1111/ene.70621

ORIGINAL ARTICLE

Background

While most people fully recover after mild traumatic brain injury (mTBI), a substantial minority experience persistent symptoms and incomplete recovery. This may be prevented by early interventions specifically targeting patients at risk of incomplete recovery. The UPFRONT‐model was developed to identify patients at risk of poor functional outcome. This study aimed to externally validate the UPFRONT‐model in an independent sample.

Methods

A prospective, longitudinal, multicenter cohort study with 126 mTBI patients recruited from emergency and neurology departments (ED) of six hospitals in the Netherlands was performed. Predictors in the UPFRONT‐model included educational level, Glasgow Coma Scale (GCS), neck pain at injury, alcohol intoxication, Post Traumatic Amnesia (PTA), pre‐injury mental health, anxiety, depression, coping, and the number and severity of post‐traumatic complaints. Functional recovery at 6 months was assessed using the Glasgow Outcome Scale Extended (GOS‐E). The external validity of the UPRFONT model was assessed with measures of calibration and discrimination.

Results

The model showed acceptable discriminative ability (AUC = 0.74), comparable to the development sample (AUC = 0.77). However, calibration revealed systematic underestimation of recovery (predicted: 46%; observed: 75%), with a calibration intercept of 1.52 and a slope of 0.70. Despite differences in some predictor effects, psychological variables were robust and consistent across samples.

Conclusion

The UPFRONT‐model demonstrated solid discriminative performance in an external cohort, but tended to underestimate the likelihood of complete recovery. Further validation and optimization are needed before clinical implementation. The model holds promise for early identification of at‐risk patients, enabling targeted interventions following mTBI.

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Authors:
Robin van Pinxteren, Marilien C. Marzolla, Melloney L. M. Wijenberg, Caroline M. van Heugten, Frits H. M. van Osch, Joukje van der Naalt, Jacoba M. Spikman, Marieke E. Timmerman and Jeroen J. Roor
Article first published online:
19 Jun 2026 | DOI: 10.1111/ene.70626

REVIEW ARTICLE

Background

We used network meta‐analyses to evaluate the pharmacological interventions for Hereditary Transthyretin‐related Amyloidosis with Polyneuropathy (ATTRv‐PN).

Methods

We searched Medline, Embase, and Cochrane (June 2025) for randomized trials assessing pharmacological interventions in ATTRv‐PN adults. Two reviewers independently screened, extracted data, and assessed risk of bias. Primary efficacy outcomes were mNIS+7 and Norfolk‐QoL‐DN. Primary safety outcome was serious adverse events (SAE). We used Bayesian hierarchical models. Evidence certainty was assessed using GRADE.

Results

Six trials ( = 989) were included (3 at high‐risk of bias). Participant ages and disease duration ranged from 52.8 to 62.0 and 1.4 to 3.9 years, respectively. For mNIS+7, data were available for all interventions except tafamidis. All demonstrated statistically significant improvements versus placebo. Vutrisiran (standardized mean difference [SMD] vs. placebo: −1.66; 95% credible interval [CrI]: −2.13 to −1.17) and patisiran (SMD vs. placebo: −1.56; 95% CrI: −1.88 to −1.25) demonstrated improvements compared with diflunisal, eplontersen, and inotersen. For Norfolk‐QoL‐DN, data were available for all interventions except diflunisal. All except tafamidis demonstrated statistically significant improvements versus placebo. Patisiran (MD vs. placebo: −17.39; 95% CrI: −23.22 to −11.57), vutrisiran (MD vs. placebo: −16.99; 95% CrI: −25.24 to −8.72), and eplontersen (MD vs. placebo: −15.56; 95% CrI: −21.97 to −9.15) demonstrated improvements compared with tafamidis. For SAE, there were no differences between active interventions versus placebo. Confidence in the evidence varied from very low to moderate.

Conclusion

Gene‐silencing therapies were more efficacious, although these findings should be regarded as hypothesis‐generating given the scarcity of data, lack of head‐to‐head trials, and clinical heterogeneity across trials.

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Authors:
Gonçalo S Duarte, Tiago Luís Gonçalves Neves Machado, Filipe B Rodrigues, Isabel Conceição, Davide Pareyson and João Nuno Marques Parracho Guerra da Costa
Article first published online:
10 Jun 2026 | DOI: 10.1111/ene.70627

ORIGINAL ARTICLE

Background

Almost 75% of patients with relapsing multiple sclerosis (pwRMS) with suboptimal response to other disease‐modifying therapies (DMTs) showed no evidence of disease activity (NEDA‐3) when treated with ocrelizumab in a large single‐arm multicentre trial over 2 years. We aimed to assess the 4‐year effectiveness and safety of ocrelizumab in pwRMS who entered a 2‐year extension trial.

Methods

PwRMS completing CASTING were eligible to rollover into LIBERTO if available in the country of residence. PwRMS received ocrelizumab every 24 weeks; the same frequency was used for clinical assessments. Primary endpoint was the proportion of patients who had NEDA‐3 over 4 years. Safety was assessed by rate and nature of adverse events (AEs).

Results

A total of 439 pwRMS rolled over to LIBERTO, of which 68.1% completed the study; most patients discontinued from LIBERTO due to country‐specific changes in reimbursement but most remained on ocrelizumab outside the trial. Over 4 years, 79.5% of patients showed no 24‐week confirmed disability progression, 87.5% no relapses, and 90.0% no radiological activity. A total of 65.6% of patients ( = 290) showed NEDA‐3, with the proportion of patients achieving NEDA‐3 yearly remaining above 84.8%. Over 4 years, infections (72.9% of patients) and infusion‐related reactions (44.2%) were the most reported AEs. Serious AEs were reported in 9.3% of patients. Five (1.1%) patients discontinued due to AEs.

Conclusions

Findings suggest that switching to ocrelizumab is safe for patients with early RRMS and suboptimal response to previous DMTs, resulting in significant and durable control of disease activity.

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Authors:
Patrick Vermersch, Ralph H. B. Benedict, Bart Van Wijmeersch, Gary Cutter, llya Kister, Celia Oreja‐Guevara, Aksel Siva, Heinz Wiendl, Jens Wuerfel, Bouchra El Azzouzi, Thomas Kuenzel, Regine Buffels, Licinio Craveiro, Petra Dirks and Giancarlo Comi
Article first published online:
22 Jun 2026 | DOI: 10.1111/ene.70628

ORIGINAL ARTICLE

Objective

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is characterized by heterogeneous clinical presentations and the absence of validated imaging biomarkers. Although several quantitative MRI (qMRI) parameters have been investigated individually, their respective diagnostic and clinical relevance remains unclear.

Methods

Twenty‐eight CIDP patients (21 typical, 7 multifocal) were prospectively enrolled and compared with 13 age‐ and sex‐matched healthy controls and 17 patients with symptomatic hereditary transthyretin amyloid neuropathy (vATTR). All participants underwent 1.5 T qMRI of the sciatic and tibial nerves and of the thigh and leg muscles. Nerve and muscle volume, magnetization transfer ratio (MTR), fat fraction (FF), and T2 relaxation time were extracted. Clinical assessment included ONLS, RODS, and MRC sum score, while electrophysiological evaluation included fibular compound motor action potentials and tibialis anterior MUNIX. Imaging parameters were compared between groups and correlated with clinical and neurophysiological measures.

Results

CIDP patients showed significant differences compared with controls in both nerve and muscle metrics. Nerve volume was increased and MTR decreased at both sciatic and tibial levels ( < 0.005). At the muscle level, leg muscles showed increased fat fraction and decreased MTR, while T2 values and muscle volume did not differ significantly. MTR showed the strongest correlations with disability scores and MUNIX. Compared with vATTR patients, CIDP patients had lower sciatic nerve MTR, whereas vATTR patients exhibited larger nerve volumes and more pronounced muscle abnormalities.

Conclusions

Nerve volume appears to be a sensitive diagnostic marker, while MTR may reflect disease burden. A multiparametric qMRI approach may improve diagnosis and monitoring in CIDP.

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Authors:
A. Guérémy, E. Fortanier, C. P. Michel, G. Corazza, A. Ogier, A. Trabelsi, A. Grapperon, A. Verschueren, E. Salort‐Campana, M. Guye, E. Delmont, D. Bendahan and S. Attarian
Article first published online:
25 Jun 2026 | DOI: 10.1111/ene.70631

ORIGINAL ARTICLE

Background and Aims

The safety and effectiveness of mechanical thrombectomy (MT) in patients with cervical artery dissection (CeAD) remain uncertain. This study aimed to evaluate the safety, recanalization rates, and functional outcomes of MT in LVO‐AIS patients with and without CeAD.

Methods

Retrospective multicenter study based on data prospectively collected from June 2021 to June 2024. CeAD‐related LVO‐AIS patients treated with MT were compared with matched anterior and posterior circulation AIS patients without CeAD. Primary outcomes included procedural adverse events, recanalization rates, and favorable functional outcomes at 3 months. A meta‐analysis of similar studies from 2015 to 2025 was conducted to support generalizability.

Results

Of 1861 LVO‐AIS patients, 164 (8.7%) patients had a CeAD. Despite a higher prevalence of tandem occlusion (63.0% vs. 20.0%, SDM: 0.99), CeAD patients showed similar rates of overall procedural adverse events (17.7% vs. 16.3%,  = 0.684), recanalization rates (90.0% vs. 87.5%,  = 0.563), and 90‐day favorable functional outcome (59.1% vs. 58.5%,  = 0.917) as compared to non‐CeAD patients. Additionally, CeAD patients had a significantly lower mortality rate at 90 days (4.3% vs. 13.1%,  = 0.023). A subgroup analysis of posterior circulation LVO‐AIS showed no significant differences in safety and clinical outcomes. Meta‐analysis of six studies suggested better MT outcomes in CEAD‐related LVO‐AIS ( < 0.001, with  = 60.02% [13.48–83.33 95% CI]).

Conclusions

Despite procedural challenges, this multicenter study has shown that in both anterior and posterior circulation CeAD‐related LVO‐AIS, MT is as safe as in non‐CeAD stroke patients, achieves high recanalization rates, and is associated with similar favorable functional outcomes.

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Authors:
Francesco Favruzzo, Marialuisa Zedde, Luca Weis, Rosario Pascarella, Alessia Giossi, Michele Besana, Francesco Valletta, Manuel Cappellari, Benedetto Petralia, Mauro Gentile, Andrea Zini, Luigi Simonetti, Stefano Vallone, Maria Giulia Mosconi, Maurizio Paciaroni, Andrea Fiacca, Aurelia Zauli, Pietro Caliandro, Iacopo Valente, Ludovica Ferraù, Paolo La Spina, Agostino Tessitore, Roberto Menozzi, Chiara Ferraro, Francesco Causin, Alessandro Pezzini and Claudio Baracchini
Article first published online:
22 Jun 2026 | DOI: 10.1111/ene.70632

ORIGINAL ARTICLE

Introduction

To investigate the association of intracranial atherosclerotic disease (ICAD), alone and comorbid with cerebral small vessel disease (SVD), with ischemic or hemorrhagic events in patients receiving antithrombotic therapy.

Patients and Methods

In this prospective, multicenter, observational study, baseline brain MRI was performed to assess SVD (white matter hyperintensities, cerebral microbleeds, lacunes, enlarged perivascular spaces [PVS]), nonlacunar infarcts, and ICAD. SVD burden was defined as SVD score > 2. ICAD was classified as normal‐to‐mild, moderate, and severe stenosis‐to‐occlusion. The outcomes were any ischemic event, ischemic stroke, major bleeding, intracranial hemorrhage, and all‐cause mortality. We assessed associations of ICAD with outcomes via Cox regression and mediation analyses, adjusting for SVD burden.

Results

Among 5250 patients (mean age: 71 ± 11 years, 33% women), 3947 (75%) received antiplatelets and 1304 (25%) anticoagulants at baseline. ICAD was normal‐to‐mild in 3781 (72%), moderate in 571 (11%), and severe‐to‐occluded in 894 (17%). SVD burden was observed in 1400 (27%). ICAD was associated with a higher frequency of non‐lacunar infarcts and a lower frequency of PVS. There was no graded association between ICAD severity and SVD burden. During a median follow‐up of 2 years, 278 ischemic events, 197 ischemic strokes, 97 major bleedings, 55 intracranial hemorrhages, and 217 deaths occurred. Severe‐to‐occluded ICAD independently increased the risk of any ischemic event (adjusted hazard ratio: 1.39 [1.03–1.86]) and mortality (2.01 [1.48–2.74]); coexisting SVD burden further increased the risk of all outcomes. ICAD directly affected ischemic events, while mortality was mainly driven by its additive interaction with SVD.

Conclusions

ICAD increases the risk of any ischemic events and, with comorbid SVD, contributes to hemorrhagic events and excess mortality.

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Authors:
Kaori Miwa, Masatoshi Koga, Kanta Tanaka, Yusuke Yakushiji, Makoto Sasaki, Kohsuke Kudo, Sohei Yoshimura, Masafumi Ihara, Shigeru Fujimoto, Tadashi Terasaki, Yukako Yazawa, Yoshinari Nagakane, Hiroshi Yamagami, Kazutoshi Nishiyama, Yoshiki Yagita, Shinichi Yoshimura, Teruyuki Hirano and Kazunori Toyoda
Article first published online:
02 Jun 2026 | DOI: 10.1111/ene.70635

ISSUE INFORMATION

Issue Information

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Article first published online:
28 May 2026 | DOI: 10.1111/ene.70636

ORIGINAL ARTICLE

Objectives

The aim of this study was to determine if people with MS (pwMS) experience a different income development from controls, and if so, at what age, and at what time in the disease course.

Methods

We examined income development for pwMS compared to matched controls in a Norwegian cohort. We assessed the impact of both age and time from diagnosis on income using linear mixed‐effects models.

Results

Men with MS (mwMS) had, on average, a lower income trajectory compared to controls at an earlier age than women with MS (wwMS) (49 vs. 55 years). For men, the gap was increasing throughout the entire working age, while women were catching up with their controls close to retirement age. Although the absolute difference from controls is larger for mwMS than wwMS from age 50, the difference between the sexes is only statistically significant from age 60. The income increase rate was lower for both mwMS and wwMS compared to controls after being diagnosed with MS. For mwMS, the difference is evident 2 years after diagnosis, and for wwMS, 5 years after diagnosis. The average income loss experienced by mwMS was double that of women from 6 years after diagnosis, but the difference was not statistically significant when comparing the sexes.

Conclusions

PwMS have lower income development than controls. Men lose income earlier in life and earlier in the disease course than women.

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Authors:
Anne Høgset, Cecilia Smith Simonsen, Heidi Øyen Flemmen, Cathrine Brunborg, Line Broch, Pål Berg‐Hansen and Elisabeth Gulowsen Celius
Article first published online:
28 May 2026 | DOI: 10.1111/ene.70638

ORIGINAL ARTICLE

Objectives

To examine the association between optic nerve lesion volume (ONLV) on double inversion recovery (DIR) MRI and other imaging biomarkers of disease burden in multiple sclerosis (MS), including white matter hyperintensities (WMHs), T1‐weighted hypointensities, and brain volumetrics. The study explores whether ONLV reflects more severe neurodegenerative MS profile.

Materials and Methods

In this cross‐sectional study, 212 MS patients underwent 3 T MRI, including 3D T1W, FLAIR, and DIR sequences. Optic nerve lesions were segmented on DIR and quantified volumetrically. Patients were categorized by optic nerve involvement: none ( = 59), unilateral ( = 60), bilateral ( = 93). WMHs were analyzed using AI‐based tool. T1W hypointensities and brain volumetrics were extracted using FreeSurfer and AI algorithm applied to 3D T1W and FLAIR images. Multivariate models were adjusted for multiple covariates.

Results

ONLV positively correlated with periventricular ( = 0.365,  < 0.001), deep ( = 0.165,  = 0.005), and juxtacortical ( = 0.163,  = 0.007) WMHs. Bilateral involvement was associated with higher WMH burden, increased T1W hypointensities ( = 10.91,  < 0.001). ONLV was associated with greater white matter atrophy ( = −107.02,  = 0.016); after adjustment for age, this association was attenuated, while bilateral optic nerve involvement emerged as predictor of gray matter atrophy. Periventricular WMHs also correlated with global cortical and subcortical gray matter loss.

Conclusions

ONLV is associated with greater lesion load and neurodegeneration in MS. Longitudinal studies are needed to confirm prognostic value of ONLV as a candidate biomarker of disease severity.

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Authors:
Adrian Korbecki, Tomasz Konopczyński, Oktawian Hawro, Aleksandra Blachucik, Krzysztof Winiarczyk, Kamil Litwinowicz, Agata Zdanowicz‐Ratajczyk, Michał Sobański, Justyna Korbecka, Justyna Chojdak‐Łukasiewicz, Anna Pokryszko‐Dragan, Joanna Bladowska and Anna Zimny
Article first published online:
04 Jun 2026 | DOI: 10.1111/ene.70639

ORIGINAL ARTICLE

Background

Essential tremor (ET) is a common movement disorder characterized by heterogeneous features, though the rate and pattern of worsening are variable. Longitudinal data combining clinical and objective motor measures remain limited, resulting in uncertainty regarding trajectories and predictors of progression in ET.

Methods

Twenty‐two patients from a previously established ET/ET‐plus cohort underwent a third clinical and kinematic evaluation almost seven years after baseline. Kinematic analysis assessed postural, kinetic, rest tremor, and finger‐tapping performance. Longitudinal changes were evaluated using non‐parametric statistics and linear mixed‐effects models adjusting for clinical covariates.

Results

Over time, tremor worsened overall. Kinematic measures indicated a selective increase in kinetic tremor severity, while rest and postural tremor amplitude remained stable. Clinically, tremor spread to a greater number of body regions. Soft neurological signs increased over time and were associated with greater tremor spread. Cognitive performance showed only a mild decline, partly related to age and affective symptoms. Higher baseline tremor severity was associated with greater worsening of kinetic tremor, and lower baseline cognitive scores with changes in postural tremor.

Conclusions

ET progression is heterogeneous and often non‐linear. Kinematic measures were particularly sensitive in capturing worsening of kinetic tremor, the most disabling clinical feature. The accumulation of soft neurological signs and their association with tremor spread support the notion of ET‐plus as a more advanced disease stage with broader cerebral involvement. Independent of disease progression, there were strong aging‐related effects. Future multimodal longitudinal studies may clarify how aging interacts with disease trajectories in essential tremor.

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Authors:
Luca Angelini, Daniele Birreci, Anna Sofia Grandolfo, Martina De Riggi, Davide Costa, Adriana Martini, Sara Cirinei, Simone Aloisio, Giulia Paparella, Rick C. G. Helmich and Matteo Bologna
Article first published online:
01 Jun 2026 | DOI: 10.1111/ene.70646

ORIGINAL ARTICLE

Background

There are no clear guidelines for enzyme replacement therapy (ERT) use and obstetric management in pregnant patients with Pompe disease receiving ERT. This study aims to explore outcomes and challenges for these patients.

Methods

We included French and Dutch patients who became pregnant during ERT. Main outcomes were pregnancy (ERT management, obstetric delivery, neonatal outcomes) and clinical results (6‐min walk test [6MWT], forced vital capacity [FVC] in supine and upright positions, infusion associated reactions [IARs]).

Results

Data from 11 patients (median age at pregnancy onset 33 years) with 14 pregnancies were studied. One pregnancy ended in early miscarriage, and 12/13 live births reached term. Eight pregnancies had an induced birth or planned C‐section, 6/8 due to maternal condition (e.g., increased dyspnea or preference medical team to ensure patient's safety). ERT was continued in eight pregnancies, with three patients receiving an adjusted dose based on their increased weight. ERT was interrupted early in five pregnancies because of trial participation or safety concerns. No IARs were reported during pregnancy or after restart of ERT. Of the patients with clinical data during pregnancy, a (mild) decline was observed in 6/7 pregnancies for 6MWT, 3/10 for upright FVC, and 6/9 for supine FVC. Most patients recovered from their decline during pregnancy within 2 years.

Conclusion

In patients who continued ERT during pregnancy, it appeared to be safe, with no documented adverse effects for mother or child. While most patients experienced a mild worsening of clinical condition during pregnancy, the majority recovered well postpartum.

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Authors:
Maudy T. M. Theunissen, Zohra Hayat, Françoise Bouhour, Johanna M. P. van den Hout, Jean‐Baptiste Noury, Emmeline Lagrange, Aurélie Jouy, Nadjib Taouagh, Pieter A. van Doorn, Ans T. van der Ploeg, Pascal Laforêt and Nadine A. M. E. van der Beek
Article first published online:
25 Jun 2026 | DOI: 10.1111/ene.70648

ORIGINAL ARTICLE

Background

Genetic Creutzfeldt‐Jakob Disease (gCJD) is an autosomal dominant prion disease caused by heterozygous pathogenic variants in the gene. It is relatively prevalent in Israel due to a large cluster of individuals from Libyan Jewish origin harboring the p.Glu200Lys variant. In our experience, increasing awareness, expanded reproductive options, and the emergence of research initiatives have led more asymptomatic relatives to seek presymptomatic testing. Since gCJD is a highly penetrant and fatal condition, the decision to pursue testing involves complex medical, psychological, ethical, and familial considerations.

Methods

An Israeli multidisciplinary expert panel, familiar with gCJD, collaborated to formulate a structured approach to the genetic testing process of at‐risk individuals.

Results

We describe the core components of the recommended presymptomatic testing process, in a real‐world setting. We focus on referral considerations, eligibility and timing of testing, psychological assessment, a stepwise approach for the testing process, results disclosure, post‐result support, and implications for family planning.

Conclusions

Based on the valuable experience of professionals who address these issues in clinical practice, the proposed framework aims to provide a comprehensive structured methodology for clinicians and care teams supporting individuals at risk for gCJD. It may serve as a model for the testing process of other late‐onset monogenic neurodegenerative diseases, in Israel and worldwide.

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Authors:
Dror Shir, Noa Bregman, Aya Bar David, Talya Nathan, Orly Goldstein, Tanya Gurevich, Avner Thaler, Anat Mirelman, Tamara Shiner, Mali Gana Weisz, Shiri Shkedi‐Rafid, Gael Ganz, Hagit Shani, Elon Pras, Odelia Chorin, Gia Sorkin, Keren Markus‐Bustani, Shlomzion Kahana Merhavi, Mor Shechory‐Stahl, Miri Yanoov Sharav, Michal Dicastro, Dorin Trigubov, Dalit Barel, Esther Kahana, Avi Fellner, Amos Korczyn, Hagit Baris Feldman, Lior Greenbaum and Nurit Omer
Article first published online:
23 Jun 2026 | DOI: 10.1111/ene.70649

REVIEW ARTICLE

Objectives

The acute imbalance syndrome (AIS) refers to acute‐onset and persistent vertigo, dizziness and/or imbalance without nystagmus, reflecting a subset of the acute vestibular syndrome (AVS) with or without nystagmus. While AVS with nystagmus is well characterized and the approach to these patients is validated, much less is known about patients presenting with AIS. This systematic review synthesizes current epidemiologic and clinical evidence on AIS.

Methods

MEDLINE and Embase (2000–2024) were searched for English‐language original articles addressing acute imbalance, vertigo/dizziness and reporting on nystagmus and/or AVS/AIS. Two reviewers independently screened articles and extracted predefined parameters. The review was registered with PROSPERO (CRD42024623068).

Results

Forty studies ( = 11,731 patients) were included, with 2730 patients being classified as AVS. Prevalence of AVS (with/without nystagmus) amongst all acutely dizzy patients was 16.4% and 50.5%, respectively, in two studies. 49.4% of central AVS cases were classified as AIS. Whereas AIS presentation was rare in AICA strokes (9%), fractions reached 40% (PICA), 57% (SCA), and 62% (PCA) for other vascular territories. Data on underlying causes in noncentral AIS was limited, with dysautonomia, drug intoxication, and heart disease being most frequently identified.

Conclusions

With almost 50% of central AVS cases presenting as AIS, this emphasizes the importance of selecting bedside testing appropriately, focusing on algorithms such as STANDING or graded truncal instability. Patients presenting with AIS have a distinct differential diagnosis than those with AVS with nystagmus, mostly due to the distribution of noncentral causes. Promoting awareness of AIS and its diagnostic approach should be prioritized in emergency and acute neurological settings.

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Authors:
Konstantin Schmidt, Andreas Zwergal, Diego Kaski and Alexander Andrea Tarnutzer
Article first published online:
01 Jun 2026 | DOI: 10.1111/ene.70651

ORIGINAL ARTICLE

Background

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of various malignancies. The resulting activation of the immune system may lead to neurological immune‐related adverse events (n‐irAEs). Here, we retrospectively characterized severe n‐irAEs in a monocentric cohort.

Methods

We screened an in‐house registry of the Medical University of Vienna, Austria, including all patients treated with ICIs between 2007 and 2023. Patients who underwent a neurological evaluation were identified, and their medical records were reviewed. Cases with severe (i.e., grade ≥ 3) n‐irAEs were analyzed. We report clinical and demographic characteristics, neurological manifestations, treatment and outcomes.

Results

Ten out of 2043 screened patients (i.e., 0.5%) developed severe n‐irAEs. In most cases ( = 7), neurological manifestations involved the neuromuscular system and/or peripheral nerves, including myasthenia/myositis ( = 5), polyneuropathy ( = 1), and facial nerve palsy ( = 1). Central nervous system involvement included aseptic meningitis, myelitis, and stroke (each  = 1). The number of ICI cycles prior to n‐irAE onset varied, with a median of 3 cycles (range 1–43). The median time from the last infusion to symptom onset was 7 days (range 2–24). n‐irAEs led to ICI discontinuation and/or immunomodulatory treatments in 9 patients. Clinical improvement was observed in 7 of 10 cases. No deaths were attributed to ICI‐related toxicity.

Conclusion

Our findings indicate that severe n‐irAEs are rare. Nonetheless, clinicians should remain vigilant for delayed‐onset neurotoxicity, even after long treatment exposure. Most patients showed clinical improvement following ICI discontinuation and/or immunomodulatory treatments.

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Authors:
Anna Grisold, Angelika M. Starzer, Sara Silvaieh, Martin Krenn, Marie‐Bernadette Aretin, Manuela Schmidinger, Julia M. Ressler, Stephan Polterauer, Thomas Berger, Matthias Preusser and Anna S. Berghoff
Article first published online:
02 Jun 2026 | DOI: 10.1111/ene.70652

ORIGINAL ARTICLE

Background

UNC13A is a genetic modifier of amyotrophic lateral sclerosis (ALS) in European populations, but its role in Chinese patients remains incompletely characterized. We investigated the spectrum of UNC13A variation and its impact on disease risk and progression in a Chinese ALS cohort.

Methods

We performed an integrated genetic analysis of 1,533 Chinese ALS patients and 1,405 controls, including rare variant burden testing, genome‐wide survival analysis, haplotype mapping, and conditional analyses. An integrated clinical‐genetic prognostic score was developed and validated.

Results

Rare deleterious UNC13A variants were not associated with ALS risk. We identified two independent haplotype blocks with distinct clinical impacts. Block 1 (tagged by rs75421007) was associated with reduced baseline muscle strength ( = 0.030), while Block 2 (tagged by rs78549703), a brain‐specific splicing QTL, was the primary driver of survival heterogeneity. The European variant rs12608932 showed a survival association in single‐marker analysis ( = 0.024), but conditional analyses revealed its effect was not independent of Block 2. An integrated prognostic score combining clinical factors and Block 2 haplotype stratified patients into low‐, intermediate‐, and high‐risk groups (median survival: 52.6, 37.1, and 32.0 months;  < 0.001), with decision curve analysis confirming clinical utility.

Conclusions

This study delineates UNC13A genetic architecture in Chinese ALS, identifying two independent haplotype blocks that differentially influence disease severity and survival. The Block 2 haplotype, which includes a brain sQTL, is a major determinant of survival heterogeneity and may inform patient stratification in future studies.

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Authors:
Cailin He, Ziqin Liu, Yanchun Yuan, Linxin Tang, Meirong Wang, Yongchao Li, Qianqian Zhao, Ling Weng, Juan Du, Hanjun Wu, Fan Hu, Renshi Xu, Jifeng Guo, Lu Shen, Beisha Tang and Junling Wang
Article first published online:
01 Jun 2026 | DOI: 10.1111/ene.70653

ORIGINAL ARTICLE

Objectives

To compare response (reduction in headache frequency and differences in patient‐reported outcomes) between Erenumab and OnabotulinumtoxinA from two phase‐IV trials after 6 months of treatment.

Materials/Methods

A prospective cohort study included two parallel cohorts of chronic migraine patients treated with either Erenumab 140 mg/month or OnabotulinumtoxinA 195 U every 3 months. Participants had no additional preventive therapies or comorbid psychiatric or chronic pain conditions. Baseline data collected included demographics, monthly headache (MHD) and migraine days (MMD), impact scales (MIDAS, HIT‐6, MSQ), and anxiety/depression scores (BAI, BDI‐II). Assessments were repeated at 6 months. Baseline characteristics were balanced. Efficacy analysis (measured by reduction in MHD/MMD and impact scales) was conducted using paired ‐test, and linear regression models compared treatment‐related changes between groups.

Results

A total of 114 patients were analyzed (57 per group), with no significant baseline differences. Both treatments produced significant reductions in headache frequency at 6 months (Erenumab: −7.93 MHD and −5.36 MMD,  < 0.001; OnabotA: −6.00 MHD and −4.31 MMD,  < 0.001), without statistically significant differences between therapies. Significant improvements were observed in HIT‐6 and MSQ scores in both cohorts ( < 0.05). The Erenumab group showed significant reductions in MIDAS, BDI, and BAI scores ( < 0.05). Differences between treatments were significant for MIDAS improvements at three and 6 months ( < 0.05).

Conclusion

Erenumab and OnabotulinumtoxinA are effective preventive treatments for chronic migraine. No significant differences were found in the magnitude of headache reduction at 3 or 6 months when comparing both treatments.

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Authors:
María Garcés‐Pellejero, Marta Torres‐Ferrús, Rut Mas‐de‐les‐Valls, Edoardo Caronna, Alicia Alpuente, Eulalia Giné‐Ciprés and Patricia Pozo‐Rosich
Article first published online:
25 Jun 2026 | DOI: 10.1111/ene.70654

LETTER TO THE EDITOR

Gastrointestinal Pseudo‐Obstruction Is Not an Uncommon Phenotypic Manifestation of POLG1 Variants

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Authors:
Josef Finsterer
Article first published online:
01 Jun 2026 | DOI: 10.1111/ene.70655

ORIGINAL ARTICLE

Background

Progression independent of relapse activity (PIRA) has been shown to account for a majority of the disability accumulation in relapsing–remitting multiple sclerosis (RRMS) patients treated with disease‐modifying therapies. While comorbidities are common in MS and linked to disability progression, their role in PIRA remains unclear. We investigated whether comorbidities at treatment initiation could predict PIRA in RRMS patients receiving B‐cell depleting therapy.

Methods

This population‐based cohort study included RRMS patients initiating rituximab between August 2010 and April 2019, without relapses during six‐year follow‐up. PIRA was defined as confirmed disability worsening (Expanded Disability Status Scale). We performed hypothesis‐driven analysis of pre‐specified comorbidities and data‐driven analysis of all ICD‐10 codes from secondary care. Comorbidity‐PIRA associations were assessed using adjusted logistic regression. Predictive performance for elastic net, random forest, XGBoost, and neural networks was evaluated as the area under the curve (AUC) and Brier score through nested cross‐validation.

Results

Among 2837 patients, 563 (20%) experienced PIRA within 6 years. The most prevalent comorbidities were depression/anxiety (36%), hypertension (15%), and headache (8%). No pre‐specified comorbidities were statistically significant predictors of PIRA. Among all diagnosis codes, only neuromuscular bladder dysfunction reached significance after multiple comparison correction. Predictive models demonstrated modest performance (AUC 0.563–0.652) and adding comorbidities did not improve prediction.

Conclusions

In this rituximab‐treated RRMS cohort, comorbidities at therapy start were not associated with higher PIRA risk when accounting for MS‐associated disability. The association with bladder dysfunction likely reflects spinal tract engagement rather than an independent comorbidity effect.

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Authors:
Peter Alping, Anton Öberg Sysojev, Fredrik Piehl and Thomas Frisell
Article first published online:
01 Jun 2026 | DOI: 10.1111/ene.70656

ORIGINAL ARTICLE

Background

The F64L variant is among the most frequent TTR mutations in Italy, typically associated with a predominantly neurologic phenotype and limited cardiac involvement.

Methods

Data from 181 ATTRv patients in the multicenter Patisiranitaly database treated with Patisiran since 2020 were analyzed. Neurologic impairment scores, Norfolk QoL‐DN, and cardiac parameters were compared between F64L ( = 56), V30M ( = 37), and non‐F64L ( = 125) patients at baseline and during follow‐up. Cluster analysis was applied to identify patient subgroups based on these variables.

Results

F64L represented 30.9% of the cohort. Compared to non‐F64L patients, F64L patients had a higher prevalence of neurologic onset and neurologic phenotype, a thinner interventricular septum, and lower NT‐proBNP levels. Cluster analysis segregated patients into two distinct groups, predominantly reflecting F64L vs. non‐F64L status and corresponding neurologic severity. F64L patients showed milder cardiac involvement compared to V30M patients. Longitudinal repeated‐measures ANOVA showed stable clinical and instrumental measures.

Conclusions

F64L is characterized by predominant neurologic involvement and milder cardiac involvement in this Patisiran‐treated cohort. Mutation‐specific diagnostic and follow‐up strategies are essential to capture its natural history and treatment response.

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Authors:
Marco Ceccanti, Pietro Guaraldi, Angela Romano, Giovanni Antonini, Alessandro Barilaro, Chiara Briani, Marco Burattini, Micol Gianoli, Giulia Carlini, Vittoria Cianci, Marco Currò Dossi, Daniela Di Lisi, Antonio Di Muzio, Adele Ratti, Massimiliano Filosto, Sabrina Gasverde, Chiara Gemelli, Luca Gentile, Mariangela Goglia, Luca Leonardi, Simone Longhi, Antonio Lotti, Fiore Manganelli, Anna Mazzeo, Sofia Maria Augello, Giammarco Milella, Giuseppina Novo, Davide Pareyson, Silvia Fenu, Giovanni Palumbo, Cristina Petrelli, Loris Poli, Luca Guglielmo Pradotto, Massimo Russo, Alessandro Salvalaggio, Maria Ausilia Sciarrone, Luigi Sellitti, Matteo Tagliapietra, Stefano Tozza, Mariagiovanna Castiglia, Mara Turri, Lorenzo Verriello, Cristina Chimenti, Francesca Vitali, Filippo Brighina, Nicasio Rini, Maurizio Inghilleri, Roberto D'Angelo, Domenico Abelardo, Chiara Cambieri, Laura Libonati, Federica Moret, Marco Luigetti and Vincenzo Di Stefano
Article first published online:
01 Jun 2026 | DOI: 10.1111/ene.70657

LETTER TO THE EDITOR

Letter to the Editor: Gastrointestinal Pseudo‐Obstruction Is Not an Uncommon Phenotypic Manifestation of Variants—Authors' Reply

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Authors:
Giuliana Capece, Renzo Manara, Leonardo Salviati, Carlo Viscomi, Luca Bello and Elena Pegoraro
Article first published online:
01 Jun 2026 | DOI: 10.1111/ene.70658

ORIGINAL ARTICLE

Background

Delaying time to requiring a wheelchair in people living with MS is an important treatment goal to maintain quality of life and guard against increased healthcare costs. In this post hoc analysis, the effects of siponimod versus placebo on time to sustained Expanded Disability Status Scale (EDSS) ≥ 7.0 over the core part of the Phase 3 EXPAND study were assessed.

Methods

The time to sustained EDSS ≥ 7.0 (time to requiring a wheelchair) was analysed for participants with secondary progressive multiple sclerosis (SPMS). Analyses were based on a While on Treatment (WOT) set that censored participants if entering open‐label treatment. Subgroup analyses were conducted in participants with active versus non‐active SPMS (defined based on pre‐study/baseline criteria), and in participants with baseline EDSS 6.5.

Results

In the overall EXPAND population, siponimod reduced the risk of reaching sustained EDSS ≥ 7.0 (requiring a wheelchair) by 40% (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.41–0.88;  = 0.009) versus placebo; the reduction in risk was 51% (HR, 0.49; 95% CI, 0.29–0.81;  = 0.005) versus placebo in participants with active SPMS and 22% (HR, 0.78; 95% CI, 0.42–1.45;  = 0.437) in non‐active SPMS.

Conclusion

Siponimod reduced the risk of requiring a wheelchair in participants with SPMS versus participants receiving placebo, with a greater effect in those with active disease. Time to requiring a wheelchair is a highly relevant treatment goal and an important indicator of treatment effect in patients with SPMS.

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Authors:
Patrick Vermersch, Sophie Arnould, Ralf Gold, Ludwig Kappos, Robert Fox, Amit Bar‐Or, Bruce A. C. Cree, Soudeh Ansari, Daniela Piani Meier, Goeril Karlsson, Nicolas Rouyrre and Gavin Giovannoni
Article first published online:
08 Jun 2026 | DOI: 10.1111/ene.70659

ORIGINAL ARTICLE

Background

Respiratory failure is the main cause of death in Amyotrophic lateral sclerosis (ALS), in which the physiological sigh reflex is impaired due to inspiratory muscle weakness. Aim of this study is to assess the tolerability, safety, and effectiveness of adding a sigh cycle to non‐invasive mechanical ventilation (NIMV) settings in ALS patients.

Methods

In this randomized, blind‐controlled proof‐of concept study, 44 consecutive ALS patients with indication for NIMV were randomized to: Group I: NIMV with Sigh cycles; Group II: NIMV without Sigh. The primary outcome was the reduction in the Oxygen Desaturation Index (ODI); secondary outcomes included: Overnight Oximetry (OvOx), Arterial blood gas (ABG), and Visual Analog Scale (VAS; 0–10) scores to assess sleep quality, symptom intensity, mask interface, and NIMV tolerance. Assessments were conducted at baseline, after NIMV adaptation (T1) and at 1‐month follow‐up (T2).

Results

The Sigh cycle was safe and well tolerated. No significant group differences were observed at T1 or T2 in the primary outcome ODI (median ΔODI: Group A:–4.2; Group B:–4.6:  = 0.54), as well as in the OvOx parameters and pO and pCO ABG values. At T2, secondary analysis showed a significant difference in HCO₃ in favor of the Sigh arm (ΔHCO: −1.60 vs. 1.35 mmol/L,  = 0.042). Exploratory Cox‐regression models suggested a potential independent effect of SIGH on survival.

Conclusions

Sigh is safe, well tolerated in ALS patients. Although this study did not reach the primary outcome, we also cannot rule out that sigh doesn't benefit the patient.

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Authors:
Nilo Riva, Paride Schito, Tommaso Russo, Ottavia Eleonora Ferraro, Gianluca Durante, Andrea Tettamanti, Elisa Riboldi, Teuta Domi, Laura Pozzi, Angelo Quattrini, Mauro Comola, Federica Agosta, George Cremona and Massimo Filippi
Article first published online:
23 Jun 2026 | DOI: 10.1111/ene.70660

REVIEW ARTICLE

Background and Purpose

Central disorders of hypersomnolence (CDH) are, except for Narcolepsy Type 1 (NT1), difficult to diagnose and manage because of overlapping features and the lack of reliable biomarkers. Machine learning (ML) has the potential to improve diagnosis by detecting subtle physiological patterns and distinguishing between CDH subtypes. This review systematically explores current ML applications in CDH, assesses their limitations, and suggests future directions.

Methods

Following PRISMA guidelines, MEDLINE, Embase, PsycINFO, IEEE Xplore, CINAHL, Web of Science, and Google Scholar (up to June 2025) were searched for studies using ML to classify or characterize CDH in adults. ML methods, data types, and diagnostic outcomes were extracted and analyzed.

Results

Out of 3274 studies, 41 met the inclusion criteria (37 peer‐reviewed articles and 4 preprints). Data sources included neuroimaging (fMRI, PET), sleep assessments (MSLT, polysomnography), demographics, and standardized questionnaires. Supervised ML reliably identified known features, including early REM onset, hypocretin deficiency, and spectral EEG changes, showing strong performance for NT1 but limited generalizability across other CDH subtypes. Although many studies reported high accuracy, clinical relevance was often limited by rigid diagnostic labels that may not reflect the true complexity of CDH. Unsupervised learning uncovered heterogeneous phenotypes and exposed limitations in existing diagnostic labels.

Conclusion

ML has the potential to improve CDH diagnosis. Deep learning models are promising for feature extraction; however, their black‐box nature and high data requirements hinder clinical application. Future advancements depend on large, diverse datasets, multimodal and longitudinal data, and close collaboration between clinicians and data scientists.

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Authors:
Annina Helmy, Livia G. Fregolente, Marc von Gernler, Rafael Morand, Julia van der Meer, Markus Schmidt, Stavroula Mougiakakou, Athina Tzovara and Claudio L. A. Bassetti
Article first published online:
04 Jun 2026 | DOI: 10.1111/ene.70661

ORIGINAL ARTICLE

Background

Essential tremor (ET) is a prevalent movement disorder affecting the upper limbs, yet the neural basis of hand‐specific motor dysfunction remains incompletely understood. Most fMRI studies have not explicitly addressed lateralization of tremor‐related brain activity. This study used both multivariate pattern analysis (MVPA) and univariate general linear modeling (GLM) to characterize brain network engagement during right‐ and left‐hand movements in ET.

Methods

Eighteen right‐handed ET patients and 18 age‐matched healthy volunteers performed alternating right‐ and left‐hand finger‐tapping tasks during fMRI. Whole‐brain GLM assessed subject‐level BOLD activation, and searchlight MVPA quantified subject‐level local decoding performance. Group‐level analyses compared activation and decoding patterns between groups, and associations with hand‐specific tremor severity were examined within the ET group.

Results

During right‐hand finger‐tapping, ET patients exhibited bilateral motor network engagement. GLM revealed reduced BOLD activity in the thalami and right supramarginal gyrus, while MVPA showed decreased decoding in the right supramarginal gyrus. In left‐hand finger‐tapping, a more lateralized pattern emerged, with diminished activation and decoding performance in the right thalamus and right supramarginal gyrus. Left cerebellar involvement differed between tasks and showed putative compensatory engagement, and right insular activity was associated with tremor severity during task performance. Overall, cortical alterations were predominantly right lateralized across both hands.

Conclusions

ET is associated with hand‐specific differences in task‐related network engagement, involving cerebello–thalamo–cortical and higher‐order sensorimotor regions. Right‐hand movements engaged more bilateral motor circuits, whereas left‐hand movements showed relatively stronger right‐hemispheric involvement, suggesting lateralized task‐related network alterations in ET.

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Authors:
Alma S. Torres‐Torres, Jelle R. Dalenberg, A. M. Madelein van der Stouwe, Bauke M. de Jong, Remco J. Renken, Giorgia Sciacca and Marina A. J. Tijssen
Article first published online:
14 Jun 2026 | DOI: 10.1111/ene.70662

REVIEW ARTICLE

Background

Multiple sclerosis (MS) is commonly stratified into activity‐based subgroups to inform treatment decisions and health technology assessments (HTAs). However, the terminology and criteria used to define these subgroups, particularly ‘active’, ‘highly active’ and ‘rapidly evolving severe’ (RES) disease, are inconsistent across clinical trials and regulatory guidance, leading to ambiguity in practice and restricted treatment access. Our objectives were to review how activity‐based subgroups in MS are defined across NICE technology appraisals (TAs) and the randomised controlled trials (RCTs) that inform them, and to propose a preliminary framework for standardised terminology.

Methods

We identified and reviewed NICE TAs of disease‐modifying therapies (DMTs) for MS and the RCTs included in those appraisals. We extracted and compared definitions used to characterise activity‐based MS subgroups, and classified them by key components such as relapse history, MRI findings and treatment status. We summarised our findings and highlighted points of consensus and controversy.

Results

Definitions varied widely, especially for ‘highly active’ RRMS and active SPMS. While most TAs used consistent criteria for ‘active’ and ‘RES’ RRMS disease, definitions in RCTs were heterogeneous. We identified frequent overlaps in terminology and proposed a simplified framework comprising three distinct but overlapping subgroups for RMS: active RRMS/RRMS, highly active RRMS (HARRMS) and rapidly evolving severe RRMS (RES‐RRMS).

Conclusions

Standardised definitions are urgently needed to improve evidence synthesis, inform regulatory guidance and ensure equitable treatment access. We propose a formal consensus process to consolidate this framework for use in future research, HTAs and treatment pathways.

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Authors:
Catalina Lopez Manzano, Claire M. Rice, Emma Tallantyre, Chris Cooper, Hanyu Wang, Eve Tomlinson, Ayman Sadek, Ananya Rao‐Middleton, Howard Thom and Penny Whiting
Article first published online:
10 Jun 2026 | DOI: 10.1111/ene.70663

ORIGINAL ARTICLE

Background

Moyamoya angiopathy (MMA) is a cerebrovascular disease treated by surgical revascularization. This study aimed to present long‐term outcomes of European MMA patients after surgical revascularization.

Methods

MMA patients treated surgically between 1998 to 2023 were included. Follow‐up comprised clinical and radiological examinations and electronic questionnaires. Patient data were analyzed retrospectively, and logistic regressions were performed to identify predictors of unfavorable outcomes.

Results

A total of 276 patients with 428 surgically treated hemispheres were included. The mean age was 35.0 ± 17.2 years, including 192 women and 84 men, predominantly of Caucasian ethnicity (88.0%). Ischemia (82.2%) and hemorrhage (10.1%) were the most common symptoms at onset. Most adults (80.9%) were treated with combined bypass surgery via mini‐craniotomy. Within 30 days, complications occurred in 6.3% of surgeries, and the perioperative stroke risk was 2.6%. A total of 148 patients underwent in‐house follow‐up. No mRS scores ≥ 5 were observed, with 86.3% of patients achieving a score of 0–2, alongside a bypass patency rate of 95.7% and a stroke risk of 0.3% per patient‐year. Preoperative stroke and silent ischemic MRI lesions were identified as predictors of an unfavorable outcome. Additionally, 201 patients were followed up electronically. No mRS scores ≥ 5 were observed, with 87.9% of patients achieving a score of 0–2. Moreover, 90.7% were independent in daily life, but only 50.5% returned to work or school.

Conclusions

Combined bypass surgery yielded favorable outcomes with low complication and stroke rates. Patients with preoperative stroke require closer follow‐up, and individualized strategies are needed to address persistent functional impairments.

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Authors:
Robert Mertens, Ibrahim Efe, Friedrich Mrosk, Kristin Lucia, Mohammad Asif Iqbal, Kerstin Rubarth, Lukas Mödl, Erin Dirk Sprünken, Lucius Fekonja, Güliz Acker and Peter Vajkoczy
Article first published online:
12 Jun 2026 | DOI: 10.1111/ene.70664

ORIGINAL ARTICLE

Background

Functional neurological disorder (FND) is a disabling condition often presenting with motor impairments, including gait disturbance and postural instability. Data on the prevalence and predictors of falls in people with FND are limited. This study aimed to investigate the prevalence of self‐reported falls among individuals with motor FND and identify factors associated with falling.

Methods

Adults with motor FND were recruited from a tertiary neurology centre in London, UK, December 2021 to August 2024. Participants reported falls within the previous 6 months and completed assessments of sensory impairment, mobility, pain, fatigue, depression and anxiety. Group differences between recurrent fallers (≥ 2 falls) and those with one or no falls were examined, and logistic regression analyses identified predictors of recurrent falls.

Results

One hundred participants (81% female, mean age 43.7 ± 14.2 years) were included. Falls were reported by 62%, and 56% reported recurrent falls. Among fallers, 64% reported injuries including bruising (39%), laceration (8%) and fracture (6%). Recurrent fallers had poorer plantar sensation and vibration detection, as well as worse scores for anxiety, depression, pain and functional mobility. A multivariable regression model indicated that absent plantar sensation (OR = 5.30, 95% CI [1.37, 20.44],  = 0.015), greater pain severity (OR = 1.25, 95% CI [1.05, 1.48],  = 0.011) and greater anxiety (OR = 1.09, 95% CI [1.004, 1.18],  = 0.040) were associated with increased odds of recurrent falls.

Conclusion

Falls are common among individuals with motor FND. Absent plantar sensation, pain and anxiety were independently associated with recurrent falls, supporting a multidimensional approach to falls assessment and rehabilitation.

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Authors:
Zahra Mohammadi, Amirreza Keyvanfar, Rory Higgins, Jon Stone, Jan Coebergh, Mark J. Edwards and Glenn Nielsen
Article first published online:
10 Jun 2026 | DOI: 10.1111/ene.70665

LETTER TO THE EDITOR

DN4 Is Not a Screening Tool for Small Fiber Neuropathy: An Expected Result

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Authors:
Jean‐Pascal Lefaucheur
Article first published online:
18 Jun 2026 | DOI: 10.1111/ene.70666

SHORT COMMUNICATION

Background and Purpose

Familial cerebral cavernous malformations (fCCM) may cause focal neurological deficits (FND) due to hemorrhagic or non‐hemorrhagic events and epileptic seizures (ES). With the widespread use of magnetic resonance imaging (MRI) and genetic testing, diagnosis is now frequently established at a presymptomatic stage, before any clinical manifestation. However, the subsequent risk of a first clinical event in these individuals remains poorly defined.

Methods

We conducted a cohort‐based analysis of retrospectively collected longitudinal data from 79 patients with fCCM who were asymptomatic at diagnosis (median age, 41.7 years) and managed in a national referral center.

Results

Over 649.6 patient‐years (median follow‐up, 4.0 years), 23 patients (29%) experienced a first clinical event. Post‐diagnostic event‐free survival was approximately 97% at 1 year, 79% at 5 years, and 69% at 10 years. Incidence rates for a first event were 35.4 per 1000 person‐years for any first event (FND or ES), 23.1 per 1000 person‐years for a first FND, and 15.4 per 1000 person‐years for a first ES. Male sex was independently associated with higher risk (HR 4.20; 95% CI, 1.60–11.04;  = 0.0036).

Conclusions

These data provide pragmatic post‐diagnostic risk estimates to guide counseling and surveillance in asymptomatic fCCM.

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Authors:
Constantina Rodica Popa, Dominique Hervé, Nassira Alili, Estelle Dubus, Abbas Taleb, Fanny Fernandes, Florence Riant, Elisabeth Tournier Lasserve, Louis Lambert, Hugues Chabriat and Stéphanie Guey
Article first published online:
23 Jun 2026 | DOI: 10.1111/ene.70669

ORIGINAL ARTICLE

Background

Whether serial electrophysiology may be useful in chronic inflammatory demyelinating polyneuropathy (CIDP), in remission off treatment, is unknown.

Methods

We retrospectively studied electrophysiological findings during active disease and post‐remission, in subjects with CIDP, at 2 UK neuropathy centres.

Results

We included 24 consecutive subjects. Eighteen (75%) had typical CIDP, 3 (12.5%) motor CIDP and 3 (12.5%) distal CIDP. Mean age was 61.3 years (SD: 15.8). Mean interval between electrophysiological study during active disease and post‐remission was 63.25 months (SD: 52.0). Mean distal motor latency improved for median ( < 0.001), ulnar ( < 0.001), fibular ( = 0.01) and tibial ( = 0.002) nerves. Mean motor conduction velocity improved for median ( < 0.001), ulnar ( < 0.001) and fibular ( = 0.012) nerves. Mean minimum F‐wave latency improved for median ( = 0.003), ulnar ( = 0.002), and tibial ( = 0.027) nerves. The proportion of nerves showing conduction block was greater during active disease than post‐remission (26/66 vs. 10/67;  = 0.002). Criteria for demyelination were initially fulfilled by all subjects, but not post‐remission (24/24 vs. 14/24;  = 0.006). Electrophysiological quasi‐normalisation correlated with shorter pre‐treatment disease duration ( = 0.002). Amplitude of functional improvement correlated with fibular nerve motor amplitude at first study ( = 0.024).

Conclusions

Electrophysiological quasi‐normalisation may occur in a third of subjects with typical CIDP in clinical remission off treatment and may be more likely with prompt diagnosis/treatment. Amelioration may be observed in all tested nerves. Initial fibular nerve motor amplitude may predict clinical improvement amplitude. The value of electrophysiology for prognostication/disease monitoring/management may merit further study in CIDP. Further research is warranted for subjects with variant and possible CIDP.

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Authors:
Yusuf A. Rajabally, Joumana Freiha, Roshan Iqbal, David Allen and Chinar Osman
Article first published online:
24 Jun 2026 | DOI: 10.1111/ene.70670

ORIGINAL ARTICLE

Background

Falls affect over 30% of stroke survivors within the first year, yet lesion‐related mobility and gait impairments underlying fall risk remain poorly understood. This study aimed to identify lesion‐derived functional networks associated with impaired mobility, gait, and fall risk in subacute stroke, and to determine whether disruption to these networks is associated with falls during the six‐month follow‐up.

Methods

We analyzed data from 94 patients with disabling subacute ischemic stroke from the prospective Baptize cohort, an imaging sub‐cohort of the multicenter PHYS‐STROKE trial. Principal component (PC) analysis reduced seven mobility‐related and four gait‐related baseline variables into two composites: PC1‐Mobility and PC1‐Gait, explaining 56% and 82% of variance, respectively. PC1‐Mobility indexed global disability, whereas PC1‐Gait reflected spatiotemporal walking capacity. Lesion network mapping (LNM) identified functional networks associated with each domain. Patient‐reported falls up to six months post‐enrollment were the primary endpoint.

Results

LNM revealed that the mobility‐related network predominantly involved cortical regions, whereas the gait‐related network was linked to subcortical and infratentorial connectivity. In binary multivariable logistic regression, network similarity scores were not associated with falls; only older age was significant (adjusted OR 1.08, 95% CI 1.02–1.16,  = 0.01). LNM of fall occurrence identified a cortical network with significant spatial overlap with the mobility‐related network ( < 0.001).

Conclusion

This exploratory, hypothesis‐generating study identified distinct functional networks for post‐stroke mobility and gait impairment. Falls may be more closely linked to disruptions in cortical networks supporting voluntary motor control and whole‐body coordination than to subcortical gait‐modulating structures, potentially informing fall risk stratification and targeted prevention.

Trial Registration

identifiers: BAPTISe: NCT01954797, PHYS‐STROKE: NCT01363856

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Authors:
Anna Kufner, Yunyou Tang, Uchralt Temuulen, Ghadir Abbas, Torsten Rackoll, Ulrike Grittner, Daniel Kroneberg, Benedikt Weigl, Andrea A. Kühn, Martin Reich, Alexander H. Nave and Matthias Endres
Article first published online:
24 Jun 2026 | DOI: 10.1111/ene.70678