Oral Presentations

OPR‐001

Distressing dreams, cognitive decline, and risk of dementia: A prospective study of three population‐based cohorts

A. Otaiku

UK Dementia Research Institute, Imperial College London, London, UK

Background and aims: Distressing dreams are associated with faster cognitive decline and increased dementia risk in people with Parkinson's disease (PD). Whether distressing dreams are associated with cognitive decline and dementia in people without PD is unknown. This study investigated the association between self‐reported distressing dream frequency and the risk of cognitive decline and incident dementia in community‐dwelling men and women in the general population.

Methods: Risk of cognitive decline was evaluated in 605 middle‐aged adults from the Midlife in the United States (MIDUS) study who were followed‐up over 13 years. Cognitive decline was defined as having an annual rate of decline in global cognitive function ≥1 standard deviation faster than the mean decline rate. Risk of incident all‐cause dementia was evaluated in 2600 older adults from the Osteoporotic Fractures in Men Study (MrOS) and the Study of Osteoporotic Fractures (SOF), who were followed‐up over 7 years. Distressing dream frequency was assessed in all cohorts at baseline using item 5 h of the Pittsburgh Sleep Quality Index. The association between self‐reported distressing dream frequency and later cognitive outcomes was evaluated using multivariable logistic regression.

Results: Compared with middle‐aged adults who reported having no distressing dreams at baseline, those who reported having weekly distressing dreams had a 4‐fold risk of experiencing cognitive decline (adjusted odds ratio [aOR] = 3.99; 95% CI: 1.07, 14.85). Amongst older adults, the difference in dementia risk was 2.2‐fold (aOR = 2.21; 95% CI: 1.35, 3.62).

Conclusion: Distressing dreams predict cognitive decline and all‐cause dementia in middle‐aged and older adults in the general population.

Disclosure: Nothing to disclose.

OPR‐002

Exploring family history in Alzheimer's disease: Evidence for X‐chromosome linked and recessively inherited risk factors

C. Bernardes ¹; R. Guerreiro²; J. Brás²; J. Durães¹; I. Baldeiras³; M. Lima¹; M. Almeida³; I. Santana¹; M. Tábuas‐Pereira¹

¹Neurology Department, Coimbra University Hospital Centre, Coimbra, Portugal; ²Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA; ³Center for Neuroscience and Cell Biology, Coimbra, Portugal

Background and aims: Alzheimer's Disease (AD) heritability is estimated to be around 70–80%. Yet, much of it is yet to be explained. Studying transmission patterns in different populations may help to understand factors contributing to the development of AD. In this study, we aimed to analyse family history patterns in a large cohort of Portuguese AD patients.

Methods: We collected family history from patients with AD and cognitively healthy controls over 75. We compared the proportion of subjects with AD depending on their family history (to assess X‐linked and Y‐linked associated inheritance patterns) and on the parents' birthplace (as a proxy of remote consanguinity). Linear regressions to study the association of these variables with different endophenotypes were performed.

Results: We included 3073 participants, 2183 cognitively healthy controls and 890 patients with AD. Men with a mother with dementia develop AD more frequently than women with a mother with dementia. In female patients with a CSF‐supported diagnosis of AD, paternal history of dementia is associated with lower CSF total Tau, but increased CSF phosphorylated Tau. People whose parents are from the same town have higher risk of dementia. In multivariate analysis, this proxy is associated with a lower age of onset and higher CSF phosphorylated Tau, but higher CSF amyloid‐beta42.

Conclusion: Our study gives evidence, at a population level, of X‐linked risk factors for AD. We also add evidence to remote consanguinity as a risk factor for AD.

Disclosure: Nothing to disclose.

OPR‐003

Regulation of conditioned fear memory extinction by the orexin system in the medial prefrontal cortex

P. Yi¹; M. Lin²; F. Chang ³

¹Department of Sport Management/Aletheia University, Taiwan, China; ²Graduate Institute of Brain and Mind Sciences/National Taiwan University, Taiwan, China; ³Graduate Institute of Veterinary Medicine/National Taiwan University, Taiwan, China

Background and aims: Post‐traumatic stress disorder (PTSD) disrupts discernment of trauma‐related fear memories, causing emotional distress and sleep disruptions. The orexin system, originating from the lateral hypothalamus (LH), is implicated in fear memory recall post‐extinction. Lesions in the medial prefrontal cortex (mPFC), a LH downstream projection, hinder fear memory extinction. We proposed that the LH‐mPFC pathway crucially contributes to conditioned fear memory extinction and modulates rapid eye movement (REM) sleep, impacting memory processing.

Methods: Using chemogenetic technique, we selectively manipulated the LH‐mPFC pathway by activating or inhibiting it during extinction learning, and behavior tasks were assessed. Concurrently, electrocorticography (EEG) measured sleep–wake states under these manipulations.

Results: Extinction acquisition heightened activity in both the mPFC and LH. Activating the LH‐to‐mPFC pathway maintained elevated freezing levels during fear memory extinction, while silencing initially lowered freezing levels, decreasing rapidly. This manipulation not only affected freezing expression but also influenced the formation of the extinction engram, impacting fear memory retrieval and anxiety tasks. These findings underscore the pivotal role of the LH‐to‐mPFC pathway in extinction acquisition. Pathway augmentation induced insomnia‐like features, particularly during the light period.

Conclusion: Our results suggest that the LH‐to‐mPFC orexinergic projection regulates conditioned fear memory extinction and may disrupt REM sleep, providing insights into the intricate interplay between fear regulation, memory processing, and sleep disturbances in PTSD.

Disclosure: Nothing to disclose.

OPR‐004

Significance of plasma p‐tau217 in predicting long‐term dementia risk: Insights from machine learning approaches

Z. Xiao ¹; X. Zhou¹; Q. Zhao¹; Y. Cao²; D. Ding¹

¹Institute of Neurology, Huashan Hospital, Fudan University, Shanghai, China; ²Clinical Epidemiology and Biostatistics, Department of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden

Background and aims: The role of plasma biomarkers for predicting incident dementia in the general population is still undetermined.

Methods: A total of 1857 baseline non‐demented older adults with follow‐ups within 10 years were included from a community‐based cohort. Consensus diagnoses of dementia and Alzheimer's disease (AD) were based on clinical criteria. The Recursive Feature Elimination algorithm was used to select the important features from 90 baseline candidate predictors for developing dementia and AD prediction models. Area Under the Receiver Operating Characteristic Curve (AUC) was used to evaluate models' performance. Models were validated in the testing sets and subsets.

FIGURE 1 Illustration of the candidate variables and research process.

Results: During the follow‐up of 12,716 person‐years, 207 participants developed dementia (including 145 AD). The constructed Logistic Regression, Naive Bayes, Bagged Trees, and Random Forest models showed moderate‐to‐high AUCs predicting future dementia (AUCs = 0.709–0.808) in the testing sets. Age, neuropsychological tests, and plasma p‐tau217 were the prioritized variables in all models. The models also showed robustness in diverse subgroups.

FIGURE 2 The selected models and variable importance for predicting dementia.

FIGURE 3 Subgroup analyses of the models for predicting dementia.

Conclusion: Plasma p‐tau217, combined with age and cognitive performance, showed important values in predicting incident dementia among community older adults. In the resource‐limited settings, using these variables may be convenient and cost‐effective to identify participants with high risk of dementia in the general population.

Disclosure: Nothing to disclose.

OPR‐005

Autonomic dysfunction in REM sleep behavior disorder: Heart rate variability analysis to explore neurodegeneration

M. Figorilli ¹; P. Sattar³; E. Casaglia¹; M. Mascia¹; E. Facchini²; G. Baldazzi³; N. Mandas⁴; D. Pani³; P. Mattioli⁶; L. Giorgetti⁵; D. Arnaldi⁶; M. Puligheddu¹

¹Department of Medical Sciences and Public Health, Sleep Disorder Research Center, University of Cagliari, Cagliari, Italy; ²MeDSP Lab, Department of Electrical and Electronic Engineering, University of Cagliari, Cagliari, Italy; ³MeDSP Lab, Department of Electrical and Electronic Engineering, University of Cagliari, Cagliari, Italy; Department of Medical Sciences and Public Health, Sleep Disorder Research Center, University of Cagliari, Cagliari, Italy; ⁴MeDSP Lab, Department of Electrical and Electronic Engineering, University of Cagliari, Cagliari, Italy; The Hadron Academy, Istituto Universitario di Studi Superiori IUSS, Pavia, Italy; ⁵Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DI‐NOGMI),Clinical Neurology, University of Genoa, Genoa, Italy; ⁶Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DI‐NOGMI), Clinical Neurology, University of Genoa, Genoa, Italy; Neurophysiopathology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy

Background and aims: Autonomic dysfunction is common along the alpha‐synucleinopathy continuum from prodromal stage (isolated REM sleep behavior disorder, iRBD) to overt Parkinson's disease (PD). This study aims to investigate autonomic dysregulation in iRBD, RBD‐PD and PD patients by examining sleep‐related Heart Rate Variability (HRV) parameters.

Methods: 40 iRBD (67 ± 8 y.o., 73% males), 16 PD (67 ± 10 y.o., 50% males), 30 PD‐RBD (71 ± 8 y.o., 66% males) and 24 controls (CG, 59 ± 10 y.o., 46% males) subjects were enrolled from two Italian sleep centers. A 5‐min artifact‐free ECG signal from N2, N3, and REM phases was investigated for time‐domain HRV analysis. Inter‐group significant differences have been assessed by nonparametric statistical analysis, for each sleep phase separately.

Results: When comparing iRBD and CG subjects, lower HRV parameters were observed in N2 (p < 0.025 for all) and REM (p < 0.04 for STDNN and R20) phases. iRBD showed lower HRV also when compared to PD‐RBD in N2 (p < 0.006, for STDNN, SDSD, RMSSD), and PD in N2 (p < 0.025, for STDNN, SDSD, RMSSD, pR50) and in N3 (p < 0.05, for STDNN, SDSD, RMSSD). Conversely, the PD group showed significant reduction when compared to the CG (p < 0.03), as well as a significant increase when compared to the PD‐RBD group (p < 0.05, R20 and pR20 in REM).

Conclusion: These findings suggest that the disrupted autonomic regulation is evident in the early alpha‐synucleinopathy stage during N2 and REM sleep, even more than in overt PD. Longitudinal studies are warranted to determine whether autonomic dysfunction in iRBD could serve as a prognostic biomarker, aiding in the prediction of alpha‐synucleinopathy subtypes development.

Disclosure: Nothing to disclose.

OPR‐006

NLRP3‐inflammasome inhibition reduces stroke induced inflammation and delays infarct growth before recanalization

M. Bellut

Department of Neurology, University Hospital Würzburg, Würzburg, Germany

Background and aims: The NLRP3‐inflammasome is a multiprotein complex regulating the activation of the innate immune system. NLRP3‐dysregulation has been implicated in various inflammatory and autoimmune diseases. In experimental ischemic stroke, NLRP3‐inhibition mitigated ischemia/reperfusion‐injury and secondary infarct growth after recanalization. In the present study, we examined whether NLRP3‐inhibition might alleviate stroke progression already under large vessel occlusion (LVO) before recanalization.

Methods: We occluded the middle cerebral artery in C57Bl/6‐mice for up to 4 hours and examined the NLRP3‐mRNA expression under LVO. In a subsequent experiment, C57Bl/6‐mice were prophylactically or therapeutically (after 1 h and 2 h of vessel occlusion) treated with the NLRP3‐inflammasome inhibitor MCC950. We then assessed stroke volumes, the NeuroScore, IL1b‐levels (immunoblot) and blood–brain‐barrier (BBB) integrity (albumin extravasation).

Results: We detected a 5–10‐fold upregulation of NLRP3‐mRNA expression already under LVO (n = 10/group). Its inhibition reduced stroke sizes significantly [vehicle/prophylactic/MCC950(1 h)/MCC950(2 h)‐treatment: 67.4 ± 16.4 mL/37.2 ± 10.2 mL/42.9 ± 8.4 mL/49.1 mL ± 12.1 mL] (n = 9/group). Consequently, the IL1b‐release decreased cortically by 20% (n = 9/group) while the integrity of the BBB and the NeuroScore (n = 9/group) improved significantly. We observed these improvements in both the prophylactic and therapeutic settings.

NLRP3 gene expression levels increase during pMCAO.

NLRP3 inhibition reduces infarct volume after prophylactic (MCC950 0 h) and delayed treatment, 1 h (MCC950 1 h) and 2 h (MCC950 2 h) post stroke onset.

Conclusion: As main finding we show that blocking of NLRP3 mitigates cerebral inflammation and infarct growth already under LVO and partly preserves the ischaemic penumbra, “buying time” before recanalization. This may have a major clinical impact in the future since infarct progression under LVO is a major caveat for an unfavourable clinical outcome despite successful recanalization.

Disclosure: Nothing to disclose.

OPR‐007

Antiplatelets in emergent carotid stenting after intravenous thrombolysis: A multicenter retrospective matched analysis

F. Colò ¹; A. Alexandre¹; F. Arba²; L. Scarcia³; A. Falcou⁴; M. Ruggiero⁵; M. Piano⁶; A. Zini⁷; G. Bigliardi⁸; A. Broccolini¹

¹Policlinico Universitario Agostino Gemelli, Rome, Italy; ²Careggi University Hospital, Firenze, Italy; ³Henri‐Mondor University Hospital, Créteil, France; ⁴Clinica ospedaliero‐universitaria Policlinico Umberto I, Rome, Italy; ⁵AUSL Romagna ‐ Sede Cesena, Neurology, Cesena, Italy; ⁶Niguarda, Neurology, Milan, Italy; ⁷Ospedale MAGGIORE Bologna, Bologna, Italy; ⁸Stroke Unit, Ospedale Civile di Baggiovara, Modena, Italy

Background and aims: Mechanical thrombectomy (MT) with emergent carotid stenting (eCAS) is beneficial in patients with tandem occlusion (TO). Our aim was to address safety and efficacy of different intra‐procedural antiplatelet regimens in patients undergoing eCAS after intravenous thrombolysis (IVT) and define predictors of parenchymal hemorrhage (PH).

Methods: The databases of 17 European stroke centers were screened for consecutive patients with TO who received MT with eCAS. Intra‐procedural antiplatelet therapy was categorized in: (1) low intensity regimen, (2) high intensity regimen, and (3) high intensity regimen followed by i.v. Glycoprotein IIb/IIIa inhibitors (GPI) infusion. Propensity score matching (PSM) was used to estimate differences in outcome between treatment groups. Outcome measure included the occurrence of PH type 2 and type 1 and the 90‐day mRS score 0–2.

Results: 621 patients were collected, 48.5% received IVT. After PSM there was no significant difference between IVT and non‐IVT patients under different antiplatelet regimens concerning rates of PH type 2 and type 1. Subgroup analysis showed increased rate of PH type 2 in IVT patients receiving high intensity regimen plus GPI maintenance, but without difference in clinical outcome. In multivariate analysis, presence of atrial fibrillation (OR 4.089, 95% CI 1.759–9.508), high intensity antiplatelet regimen with GPI maintenance (OR 2.364, 95% CI 1.086–5.147) and stent thrombosis (OR 2.631, 95% CI 1.160–5.970) were predictors of PH type 2.

Conclusion: Different intra‐procedural antiplatelet regimens for eCAS are safe after IVT. Increased risk of PH type 2 is associated with use of intra‐procedural GPI maintenance in IVT patients and presence of atrial fibrillation.

Disclosure: Nothing to disclose.

OPR‐008

Stroke recurrence and overall mortality in CPAP treated post‐stroke obstructive sleep apnea patients

J. Suusgaard ¹; A. West²; L. Ponsaing¹; H. Iversen²; P. Jennum¹

¹Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, Copenhagen University Hospital, Rigshospitalet, Denmark; ² Department of Neurology, Cerebrovascular Research Center Rigshospitalet, Copenhagen University Hospital, Rigshospitalet, Denmark

Background and aims: Obstructive sleep apnea (OSA) is strongly associated with stroke development and is identified in up to 70% of stroke patients. It is unclear whether treatment with continuous positive airway pressure (CPAP) reduces re‐stroke risk or mortality among post‐stroke patients. Previous studies examining the impact of CPAP on mortality in post‐stroke patients have either had limited follow‐up periods or involved small sample sizes.

Methods: We conducted a retrospective cohort study using data from the Danish National Patient Registry covering the period from 2003 to 2016, involving 1821 patients diagnosed with sleep‐disordered breathing (SDB) and a prior ischemic stroke or transient ischemic attack (TIA). Patients were categorized into three groups: CPAP adherent, CPAP non‐adherent and no CPAP treatment. By utilizing Cox hazard regression, we assessed the risk of recurrent stroke or TIA and overall mortality among these groups over a 5‐year follow‐up period.

Results: CPAP treatment improved survival rate in patients categorized as adherent compared to patients with no CPAP treatment (hazard ratio: 0.62; 95% CI: 0.50–0.76; p < 0.001). This effect persisted after adjusting for age, sex, and pre‐existing comorbidities within 3 years (the Quan updated Charlson Comorbidity Index). There was no observed reduction in the risk of recurrent stroke/TIA between the CPAP groups.

Conclusion: In this large, registry‐based study, we found that CPAP‐adherence reduced the overall mortality in post‐stroke/TIA patients with SDB. CPAP treatment did not seem to affect the risk of re‐stroke/TIA during the 5 years of follow‐up.

Disclosure: Nothing to disclose.

OPR‐009

Argatroban for ischemic stroke with early neurological deterioration: A meta‐analysis of randomized controlled trials

I. Barros Andrade ¹; V. Morbach²; V. Kendi Tsuchiya Sano³; V. Maia Arca⁴; A. de Oliveira Macena Lôbo⁵; A. Menegaz de Almeida⁶; F. Cezar Aquino de Moraes⁷; L. Henrique Geraldo⁸

¹Faculdade Santo Agostinho De Vitória Da Conquista, Bahia, Brazil; ²Feevale University, Novo Hamburgo, Brazil; ³Federal University of Acre, Rio Branco, Brazil; ⁴Neurology Department – Hospital da Clínicas UFPE, Recife, Brazil; ⁵Federal University of Pernambuco, Recife, Brazil; ⁶Federal University of Mato Grosso, Sinop, Brazil; ⁷Federal University of Para, Belém, Brazil; ⁸Department of Neurology, New York University Grossman School of Medicine, New York, USA

Background and aims: The presence of early neurological deterioration in acute ischemic stroke (AIS) underscores the urgent and intricate nature of managing this medical condition. Currently, argatroban is under investigation as a potential combination treatment, but there still a lack of evidence for its efficacy. Consequently, it becomes imperative to ascertain whether this compound contributes to improvement in neurological function following AIS.

Methods: We systematically searched databases (PubMed, Embase, Web of Science, and Cochrane) until January 10, 2024. Odds ratio (OR) and mean differences (MDs) with 95% confidence intervals (CIs) were calculated using a random‐effects model. Heterogeneity was assessed using I² statistics. The statistical analysis was performed using R software, version 4.3.1.

Results: A total of 9 studies and 2043 patients were included. As compared to the control group, Argatroban treated patients exhibited significantly improved NIHSS score at 7‐ and 90‐days post stroke (MD −0.8315, 95% CI −1.418 to −0.2449, p = 0.005; MD −0.3903, 95% CI −1.9313 to 1.1506, p = 0.62) respectively. Argatroban treatment reduced the occurrence of parenchymal hematoma (PH). There were no significant changes in the Modified Rankin Score (mRS) and symptomatic intracranial hemorrhage (sICH) occurrence in patients treated with Argatroban when compared to placebo group. Finally, patients on the placebo group had a significantly improved modified Barthel Index (mBI).

A forest plot of the change in the National Institutes of Health Stroke Scale (NIHSS) outcome of 7 days.

A forest plot of the change in the Parenchymal Hematoma (PH) outcome.

A forest plot of the modified Barthel Index (mBI) outcome.

Conclusion: Among these patients, treatment with argatroban plus drug improve NIHSS scores, most prominently at 7 days. These results demonstrate a benefit of Argatroban on reducing neurological deficits on AIS patients subject to thrombolytic therapy without increasing the risk of sICH.

Disclosure: The authors declare that they have no disclosure.

OPR‐010

Increased apnea‐hypopnea index and elevated hypoxic burden are associated with atrial fibrillation in ischemic stroke

X. Yang ¹; J. Lippert¹; I. Filchenko¹; S. Baillieul²; C. Bernasconi¹; S. Bauer‐Gambelli¹ ; A. Brill³; D. Seiffge¹; T. Reichlin⁴; M. Arnold¹; M. Schmidt¹; C. Bassetti¹

¹Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; ²Grenoble Alpes University, HP2 Laboratory, INSERM U1300 and Grenoble Alpes University Hospital, Grenoble, France; ³Department of Pulmonary Medicine, Allergology and Clinical Immunology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; ⁴Department of Cardiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

Background and aims: Sleep apnea (SA) increases the risk of cardiovascular disorders (CVD). SA is highly prevalent in stroke and is associated with an increased prevalence of atrial fibrillation (AF). Which markers of SA, the apnea‐hypopnea index (AHI) or the hypoxic burden (HB), better predict AF in stroke, remains unknown.

Methods: This cross‐sectional analysis utilized data from the Bernese Sleep & Stroke Cohort, an integral component of the Swiss Stroke Registry. During acute hospitalization, patients underwent respiratory polygraphy, leading to dichotomization into AHI+/ AHI‐ groups using a 20/h threshold. Further classification into HB+/HB‐ groups occurred with the 75% percentile as the threshold. Multivariate logistic regression assessed the associations between distinct combinations of HB and AHI (HB+/AHI+, AHI+/HB‐, and HB+/AHI‐) in comparison to HB‐/AHI‐ on prevalent AF, adjusting for various confounders.

Results: In the analysis of 1010 patients (mean age 66y, 62% males), AF was diagnosed in 197 (20%) patients. HB+ was present in 254 (25%) patients, and AHI+ was present in 360 (36%) patients. The HB+/AHI+, AHI+/HB−, HB+/AHI−, and HB−/AHI− groups constituted 20%, 16%, 5%, and 59% of the total, respectively. Compared to the HB−/AHI− group, the HB+/AHI+ group was independently associated with prevalent AF (adjusted OR: 1.68; 95% CI: 1.10–2.55). No significant difference was observed in AHI+/HB− and HB+/AHI‐ groups.

FIGURE 1 Adjusted Odds Ratios for prevalent AF across distinct combinations of HB and AHI (HB+/AHI+, HB+/AHI−, and AHI+/HB−), in comparison to the baseline group HB−/AHI−

TABLE 1 Baseline characteristics between HB−/AHI−, AHI+/HB−, HB+/AHI−, AHI+/HB+ groups.

Conclusion: In stroke, an elevated HB with an increased AHI, rather than either SA measures in isolation, is associated with a higher prevalent of AF. These findings underscore the potential of both markers in enhancing risk stratification for CVD.

Disclosure: Swiss National Science Foundation grant #320030_149752.

OPR‐011

Compensated hypogonadism identified in males with cluster headache: A prospective case‐controlled study

A. Petersen¹; D. Kristensen²; C. Westgate¹; T. Folkmann‐Hansen¹ ; N. Lund ¹; M. Barloese³; M. Søborg¹; A. Snoer¹; T. Johannsen⁴; H. Frederiksen⁴; A. Juul⁴; R. Jensen¹

¹ Department of Neurology, Danish Headache Center, University of Copenhagen, Rigshospitalet‐Glostrup, Glostrup, Denmark; ²Department of Science and Environment, Roskilde University, Denmark; ³Department of Clinical Physiology and Nuclear Medicine, Centre for Functional and Diagnostic Imaging and Research, University of Copenhagen, Hvidovre Hospital, Hvidovre, Denmark; ⁴Department of Growth and Reproduction, Copenhagen University Hospital ‐ Rigshospitalet, Copenhagen, Denmark

Background and aims: Androgens have been hypothesized to be involved in the pathophysiology of cluster headache due to the male predominance, but whether androgens are altered in patients with cluster headache remains unclear.

Methods: We performed a prospective, case‐controlled study in adult males with cluster headache. Sera were measured for hormones including testosterone, luteinizing hormone (LH), and sex hormone‐binding globulin in 60 participants with episodic cluster headache (during a bout and in remission), 60 participants with chronic cluster headache, and 60 age‐ and sex‐matched healthy controls. Free testosterone (fT) was calculated according to the Vermeulen equation. Shared genetic risk variants were assessed between cluster headache and testosterone concentrations.

Results: The mean fT/LH ratio was reduced by 35% (95% CI: 21%–47%, p < 0.0001) in patients with chronic cluster headache and by 24% (95% CI: 9%–37%, p = 0.004) in patients with episodic cluster headache compared to controls after adjusting for age, sleep duration, and use of acute medication. Androgen concentrations did not differ between bouts and remissions. Furthermore, a shared genetic risk allele, rs112572874 (located in the intron of the microtubule associated protein tau (MAPT)), between fT and cluster headache was identified.

Violin plot of free testosterone/luteinizing hormone (fT/LH) ‐ratio in serum in participants with different types of cluster headache and in healthy, sex‐ and age‐ matched controls.

Linear regression of the free testosterone/luteinizing hormone (fT/LH) ‐ratio in serum as a function of age.

Shared genetic risk variants of cluster headache and serum free testosterone concentration.

Conclusion: Our results demonstrate that the male endocrine system is altered in patients with cluster headache to a state of compensated hypogonadism, and this is not an epiphenomenon associated with sleep or the use of acute medication. Together with the identified shared genetic risk allele, this may suggest a pathophysiological link between cluster headache and fT.

Disclosure: Nothing to disclose.

OPR‐012

Cluster tics in cluster headache: A cross‐sectional and controlled study

M. Carney¹; S. Maarbjerg¹; M. Søborg ¹; N. Lund¹; J. Worm¹; L. Bendtsen¹; R. Jensen¹; A. Petersen

Department of Neurology, Danish Headache Center, University of Copenhagen, Rigshospitalet‐Glostrup, Glostrup, Denmark

Background and aims: This explorative study aimed to investigate the lifetime prevalence of cluster tics in patients with cluster headache, characterize cluster tics, including identifying possible associations to different clinical characteristics, and further investigate specific traits associated with cluster tics compared to trigeminal neuralgia.

Methods: A total of 424 patients with cluster headache were included in this controlled cross‐sectional cohort study based on a semi‐structured interview. The comparator cohort consisted of 576 patients diagnosed with trigeminal neuralgia, who had previously participated in a standardized, purpose‐built, semi‐structured interview.

Results: Cluster tics were reported in 200 out of 424 (47%) of patients with cluster headache. The odds of experiencing cluster tics were higher for males compared to females (OR: 1.93, 95% CI: 1.27–2.96, p = 0.002), and for patients with chronic cluster headache compared to patients with episodic cluster headache (OR: 1.74, 95% CI: 1.15–2.62, p = 0.008). We found that cluster tics presented as orbital pain in 70% of patients, and that, in comparison to trigeminal neuralgia paroxysms, the odds of a paroxysm being a cluster tic was low if the attack was triggerable (OR: 0.02, 95% CI: 0.01–0.04, p < 2e‐16).

Odds ratios (OR) for having been diagnosed with trigeminal neuralgia (TN) prior to interview when presenting with specific attack traits, adjusted for age and sex.

Conclusion: The lifetime prevalence of cluster tics in patients with cluster headache was 47%. The cluster tics were associated with the chronic cluster headache, and in contrast to the paroxysms in TN, cluster tics were associated to male sex, often had an orbital location of pain and were non‐serial and non‐triggerable.

Disclosure: Nothing to disclose.

OPR‐013

Vascular compression in trigeminal neuralgia discloses trigeminal root somatotopic organization

G. De Stefano ¹; D. Litewczuk¹; E. Ripiccini²; S. Maarbjerg³; G. Di Pietro¹; P. Falco¹; C. Leone¹; E. Galosi¹; A. Truini¹; G. Di Stefano¹

¹Department of Human Neuroscience, Sapienza University of Rome, Italy; ²Advanced Quantum Architecture Laboratory, Swiss Federal Institute of Technology of Lausanne, Switzerland; ³Danish Headache Center, Rigshospitalet, Glostrup, Denmark

Background and aims: In Trigeminal Neuralgia pain is localized in the distribution of one or more branches of the trigeminal nerve. A hallmark of TN is the presence of discrete skin areas able to trigger pain attacks when touched. In classical TN, trigeminal reflexes are normal but it is possible to recognize a vascular compression with morphological changes of trigeminal nerve root.

Methods: We enrolled 53 patients with clinically defined TN, normal trigeminal reflexes testing, and evidence of neurovascular compression at 3‐Tesla MRI. From MRI images we measured the polar coordinates of the impacting vessel on the trigeminal root circumference and then correlate it with pain distribution, trigger zones and latencies of the early components of the trigeminal reflexes.

Results: Pain in V1, V2 and V3 is associated, respectively, with vascular compression in the medial, superior and lateral aspect of the nerve (p < 0.05). Cutaneous trigger zones are associated with corresponding region of the circumference (p < 0.05). Increased latency of the R1 component of the blink reflex is associated with medial compression, while increased latency of the SP1 component of the masseter inhibitory reflex is associated with inferomedial compression when the reflex is evoked from the infraorbital nerve, and with lateral compression when it is evoked from the mental nerve (p < 0.05).

Relative frequency of location of neurovascular compression along the root circumference as derived by MRI data of TN patients with pain limited to one trigeminal division, V1 (left), V2 (middle) or V3 (right).

Relative frequency of location of neurovascular compression along the root circumference as derived by MRI data of TN patients reporting as trigger zones the forehead (left), the cheek (middle) or the jaw (right).

Mean latency of the early component of the trigeminal reflexes in patients with MRI evidence of neurovascular compression along a given zone of the trigeminal root. Reflexes were evoked from V1 (left), V2 (middle) and V3 (right).

Conclusion: Our study showing that pain distribution, trigger zones and increased latencies of the early components of the trigeminal reflexes are correlated with specific sites of neurovascular compression along trigeminal root circumference discloses its somatotopic organization.

Disclosure: Nothing to disclose.

OPR‐014

Endogenous pain control mechanisms during the migraine cycle and in chronic migraine with/without medication overuse

G. Cosentino ¹; E. Antoniazzi²; C. Cavigioli²; E. Guaschino²; N. Ghiotto²; G. Sances³; R. De Icco¹; M. Todisco²; C. Tassorelli¹

¹IRCCS Mondino Foundation, University of Pavia, Italy; ²IRCCS Mondino Foundation, Pavia, Italy; ³Headache Science & Neurorehabilitation Center, Pavia, Italy

Background and aims: The offset analgesia (OA) phenomenon refers to the disproportionately large decrease in the perceived pain following a slight decrease in intensity of a noxious warm stimulus. This is considered as expression of activation of the endogenous pain‐modulation system, whose dysfunction is could be involved in the pathophysiology of episodic migraine (EM) and chronic migraine (CM) with or without medication overuse (MO).

Methods: We enrolled 67 subjects with EM (in different phases of the migraine cycle), 30 patients with CM with/without MO, and 30 healthy controls. All subjects underwent an experimental paradigm consisting of 3 stimulus offset trials (OT) and 3 constant temperature trials (CT) at the level of the supraorbital region. Visual analogue scale (VAS) values were recorded during the OT and CT.

Results: Interictal EM patients and CM patients with MO did not show the OA phenomenon. A paradoxical pronociceptive facilitation during the offset trial was observed in the CM group without MO and in the preictal and ictal EM subjects. The OA phenomenon was restored in in the postictal phase. Only in patients with CM with MO we observed lack of adaptation to pain during the CT. The magnitude of VAS changes during the offset trials negatively correlated with scores at 12‐item Allodynia Symptom Checklist, migraine disability assessment (MIDAS), and depression section of the Hospital Anxiety and Depression Scale (HADS).

Conclusion: A dysfunction in the endogenous pain‐modulation system may play a role in the recurrence of migraine attacks and in the process of migraine transformation from episodic to chronic pattern.

Disclosure: none.

OPR‐015

Cortical inflammation in migraine measured with quantitative magnetic resonance imaging: A REFORM study

R. Christensen ¹; H. Ashina¹; H. Al‐Khazali¹ ; M. Pineda²; R. Rahmanzadeh²; N. Hadjikhani³; C. Granziera²; F. Amin¹; M. Ashina¹

¹Department of Neurology, Danish Headache Center, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark; ²Translational Imaging in Neurology (ThINk) Basel, Department of Biomedical Engineering, Faculty of Medicine, University Hospital Basel and University of Basel, Basel, Switzerland; ³Gillberg Neuropsychiatry Centre, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg, Sweden

Background and aims: We aimed to investigate cortical inflammation using a novel quantitative, multimodal magnetic resonance imaging (MRI) technique in adult participants with migraine compared to age‐ and gender‐matched healthy controls.

Methods: Participants underwent a single MRI session. Cortical quantitative T2 (qT2), quantitative T1 (qT1), and ADC values, considered surrogate markers of neuroinflammation, were measured in the cortical ribbon and compared between participants with migraine (with and without aura) and healthy controls. A general linear model was used with a vertex‐wise threshold of p < 0.05 and a cluster‐wise threshold of p < 0.05, adjusted for age and gender.

Results: A total of 296 participants with migraine (103 with aura and 180 with chronic migraine) and 155 age and gender matched healthy controls were included in the analysis. Participants with migraine had increased qT2 in the left occipital cortex compared to healthy controls (p < 0.0001). In participants with migraine with aura, the increased qT2 was more widespread and located bilaterally in the occipital cortices compared to healthy controls (left, p < 0.0001; right, p = 0.004). Exploratory analysis revealed higher ADC values within the qT2 clusters in participants with migraine with aura than in controls (p = 0.01). No significant differences were observed in qT1 values between the two groups.

Conclusion: Cortical inflammation is more prevalent in migraine with aura than in migraine without aura. The increased qT2 values in the occipital cortices of participants with migraine with aura are likely extracellular edema, as suggested by the concomitant ADC increase. These results support the importance of cortical inflammation in migraine pathogenesis, particularly in migraine with aura.

Visual abstract.

Disclosure: The study was funded by the Lundbeck Foundation Professor Grant (R310‐2018–3711). Funding sources had no influence on study design, patient inclusion, or data interpretation. H.A. reports personal fees from Teva, outside of the submitted work. C.G. is supported by: The University Hospital Basel (USB), as the employer of Cristina Granziera has received the following fees, which were used exclusively for research support: (i) advisory board and consultancy fees from Actelion, Novartis, Sanofi‐Genzyme, Jannsen, and F. Hoffmann‐La Roche; (ii) speaker fees from Biogen, F. Hoffmann‐La Roche, Novartis, Jannsen, and Genzyme‐Sanofi; (iii) research support by F. Hoffmann‐La Roche. F.M.A. has received personal fees from Pfizer, Teva, Lundbeck, Novartis, Eli Lilly, outside of the submitted work. M.A. is a consultant, speaker, or scientific advisor for AbbVie, Allergan, Amgen, Eli Lilly, Lundbeck, Novartis, and Teva and a primary investigator for ongoing AbbVie/Allergan, Amgen, Eli Lilly, Lundbeck, Novartis, and Teva trials. Messoud Ashina has no ownership interest and does not own stocks of any pharmaceutical company. Messoud Ashina serves as associate editor of Cephalalgia, associate editor of the Journal of Headache and Pain, and associate editor of Brain. R.C., H.M.A., M.O‐P., R.R., and N.H. report no relevant conflicts of interest.

OPR‐016

Peripherin: A novel early diagnostic and prognostic biomarker in Amyotrophic Lateral Sclerosis

A. Bombaci; G. De Marco; F. Casale; G. Fuda; P. Salamone; G. Marchese; A. Calvo; A. Chiò

“Rita Levi Montalcini” Department of Neuroscience, University of Turin, Turin, Italy

Background and aims: motor neuron diseases (MND) are complex and heterogeneous neurodegenerative diseases. Biomarkers could help in early diagnosis, in defining patients' prognosis, and stratification. The most studied and promising biomarkers are neurofilaments (Nfs). A particular type of Nfs is peripherin, mainly expressed in neurons of the peripheral nervous system. There are no studies in literature led in humans evaluating peripherin in plasma.

Methods: sandwich‐ELISA was used to quantify plasma peripherin from 120 ALS MND (including 12 ALS/FTD and 10 PLS), 9 HSP, 46 MND‐mimics (including myelopathy, radiculopathy, axonal neuropathies, Hirayama disease, IBM, benign fasciculation syndrome, functional syndrome, myasthenia, post‐polio syndrome) and 38 healthy‐controls (HCs). Plasma was collected at the time of diagnosis or some months earlier. 46 ALS were evaluated longitudinally. ALSFRSr, MRC, spirometry, genetic tests, disease progression rate (PR), blood examinations, neuropsychological tests were performed. We analysed data using Kruskal–Wallis, ANCOVA and Cox regression analysis.

Results: peripherin plasma levels is different between groups (p < 0.0001); Bonferroni's correction shows higher levels of peripherin in MND compared to MND‐mimics and HCs. Comparing ALS with PLS and HSP peripherin resulted to be higher (p < 0.001). Differences are confirmed co‐variating for age and sex. ROC curve shows a good capability of peripherin to discriminate MND from MND mimics (AUC = 0.79).

Peripherin levels in MND, MND‐mimics and healthy controls.

Conclusion: peripherin plasma levels result to be increased in MND (in particular in classic ALS) compared to MND mimics since the early phases of the disease. Further multicentre studies, testing together other fluid biomarkers, are needed to better explain role of peripherin in diagnosis and prognosis in MND.

Disclosure: Nothing to disclose.

OPR‐017

Rate of change in upper and lower motor neuron burden is associated with survival and in amyotrophic lateral sclerosis

A. Maranzano ¹; F. Gentile²; A. Doretti¹; E. Colombo¹; A. Wall¹; V. Patisso³; A. De Lorenzo³; C. Gendarini³; C. Cinnante⁴; C. Morelli¹; S. Messina¹; M. Treddenti³; V. Silani¹; F. Verde¹; N. Ticozzi¹

¹Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy; ²IRCCS Ospedale San Raffaele, Division of Genetics and Cell Biology, Milan, Italy; ³Neurology Residency Program, Università degli Studi di Milano, Milan, Italy; ⁴Section of Neuroradiology, Department of Radiology and Diagnostic Imaging, IRCCS Istituto Auxologico Italiano, Milan, Italy

Background and aims: The role of upper (UMN) and lower motor neuron (LMN) involvement in amyotrophic lateral sclerosis (ALS) has been extensively studied in relation to clinical phenotype and survival. Conversely, it is not known whether the rate of change in UMN (ΔUMN) and LMN (ΔLMN) signs provides useful information on ALS evolution.

Methods: A retrospective inpatient cohort of 1000 ALS patients was evaluated. Burden of UMN and LMN signs was assessed using the Penn Upper Motor Neuron Score and Lower Motor Neuron Score, respectively. The time interval between symptom onset and first evaluation was used to quantify ΔUMN and ΔLMN values. Survival, time from symptom onset to percutaneous endoscopic gastrostomy (PEG), and to non‐invasive ventilation (NIV) were used as outcome measures. For a subset of patients, we compute the ENCALS survival model.

Results: ΔUMN and ΔLMN values are negatively associated with survival (ΔUMN: HR = 1.30; ΔLMN: HR = 4.22) time to PEG (ΔUMN: HR = 1.34; ΔLMN: HR = 4.46) and time to NIV (ΔUMN: HR = 1.23; ΔLMN: HR = 5.0). A cut‐off value of 0.195 for ΔLMN was identified to predict patients with estimated short vs. prolonged survival. ENCALS groups characterized by shorter survival were significantly associated with higher ΔUMN and ΔLMN scores when compared to those with longer survival.

Multivariate Cox regression investigating the effect of RoC in LMNS and PUMNS after adjusting for variables that are known to be associated with survival in ALS.

ROC curve illustrating the reliability of variable RoC in LMNS in predicting patients with short (survival <36 months) vs. prolonged (survival >36 months) survival.

Distribution of RoC in PUMNS (A), RoC in LMNS (B), PUMNS (C) and LMNS (D) among different ENCALS survival groups.

Conclusion: ΔUMN and ΔLMN might represent reliable clinical indexes to estimate disease evolution and survival in ALS patients. Indeed, these two measures provide distinct clinical information in addition to that derived from the total burden of UMN and LMN signs at first evaluation.

Disclosure: Alessio Maranzano, Francesco Gentile, A. Doretti, Eleonora Colombo, Aoife Wall, Mauro Treddenti, Valerio Patisso, Alberto De Lorenzo, Claudia Gendarini, Claudia Maria Cinnante, Claudia Morelli, Stefano Messina, Federico Verde report no disclosure. Vincenzo Silani received compensation for consulting services and/or speaking activities from AveXis, Cytokinetics, Italfarmaco, LiquidWeb, Srl and Novartis Pharma AG. He receives or he has received research support from the Italian Ministry of Health, AriSla, and E‐Rare Joint Translational Call. He is on. the Editorial Board of Amyotrophic Lateral Sclerosis and Frontotemproal Degeneration, European Neurology, American Journal of Neurodegenerative Disease and Frontiers in Neurology. Nicola Ticozzi received compensation for consulting services from Amylyx Pharmaceutical and Zambon Biotech SA. He received research funding from the Italian Ministry of Health and AriSLA. He is associate editor of Frontiers in Aging Neuroscience.

OPR‐018

Circulating endocannabinoid signatures of disease activity in amyotrophic lateral sclerosis

G. Senerchia ¹; F. Piscitelli²; R. Dubbioso¹

¹Department of Neurosciences, Reproductive Sciences and Odontostomatology, Federico II University, Naples, Italy; ²Endocannabinoid Research Group, Institute of Biomolecular Chemistry (ICB), National Research Council (CNR), Pozzuoli, Italy

Background and aims: Evidence from the preclinical model of amyotrophic lateral sclerosis (ALS) has consistently demonstrated altered levels of circulating endocannabinoids (eCBs) that may contribute to disease activity and course. Results from human studies are sparse and inconclusive. Main aim of this study was to determine the association between eCB levels and disease activity in patients with ALS.

Methods: Serum concentrations of the eCBs 2‐arachidonoylglycerol (2‐AG) and N‐arachidonoylethanolamine (AEA), and related lipids palmitoylethanolamine (PEA), oleoylethanolamine (OEA), eicosapentaenoyl‐ethanolamide (EPA‐EA), 2‐docosahexaenoyl‐glycerol (2‐DHG) and docosahexaenoyl‐ethanolamide (DHA‐EA) were measured in samples from 65 ALS patients, 32 healthy controls (HC) and 16 neurological disease controls (NALS). Moreover, 46 ALS patients underwent a longitudinal study. Disease activity and progression were correlated with eCBs levels.

Results: Circulating eCBs were higher in ALS than in HC (p < 0.001), but not compared to NALS. Across clinical stages, ALS patients showed increased levels of PEA, OEA, and EPA‐EA (p < 0.02), which were confirmed by the longitudinal study (p < 0.03). Serum PEA and OEA levels were independent predictors of survival and OEA was higher in patients complaining of appetite loss. Cluster analysis revealed two distinct profiles of circulating eCBs associated with two patterns of disease activity (severe vs. mild). Patients belonging to the “severe” cluster showed significantly higher levels of OEA and lower levels of 2‐DHG compared to NALS and HC.

Comparison of circulating eCBs levels among the three groups: ALS, NALS and HC.

Circulating eCBs levels across ALS clinical stages and their association with survival.

Cluster analysis of circulating eCBs and clinical correlates of cluster membership.

Conclusion: Specific circulating eCBs profiles are indicative of different disease activities. This study paves the way for an individually‐designed rather than a “one‐fit‐all” targeting the eCB system for therapeutic purposes.

Disclosure: Nothing to disclose.

OPR‐019

Skin innervation across ALS clinical stages: New biomarkers of disease progression and survival

R. Dubbioso ¹; V. Provitera²; V. Iuzzolino¹; G. Senerchia¹; F. Manganelli¹; M. Nolano²

¹Department of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples Federico II, Naples, Italy; ²Istituti Clinici Scientifici Maugeri IRCCS, Skin biopsy lab, Neurological Rehabilitation Unit of Telese Terme Institute, Telese Terme, Italy

Background and aims: Aims of this study were to assess sensory involvement by applying a morpho‐functional approach on a large population of ALS patients stratified according to King's stages and to correlate these findings with the severity and prognosis of the disease.

Methods: We recruited 149 ALS patients and 41 healthy controls (HC). Patients underwent clinical questionnaires, nerve conductions studies (NCS) and 3 mm‐punch skin biopsy from leg, thigh and fingertip. We assessed intraepidermal nerve fibers (IENF) and Meissner corpuscles (MC) density by applying indirect immunofluorescence technique. Moreover, a subset of 65 ALS patients underwent a longitudinal study with repeated skin biopsies. Serum Neurofilament light chain (NfL) levels were measured in 40 patients.

Results: Sensory symptoms and sensory NCS abnormalities were present in 32.2% and 24% of patients, respectively, and increased across clinical stages. Skin biopsy showed a significant loss of IENF and MC in ALS compared with HC (all p < 0.001). Across the clinical stages, we found a progressive reduction in MC (p = 0.004) and an increase in IENF (all p < 0.027). Interestingly, the MC density inversely correlated with NfL level (r = −0.424, p = 0.012), and survival analysis revealed that low MC density, higher NfL levels, and increasing IENF over time were associated with a poorer prognosis (all p < 0.024).

Morpho‐functional assessment of peripheral nerve fibers across ALS clinical stages Bar dot plots showing (A) a significant reduction from King's stage 1 to stage 4 in the sensory nerve action potential (SNAP) recorded from the fifth finger (p = 0.034)

Cutaneous innervation across King's ALS clinical staging and in the longitudinal study. Confocal images of punch biopsies from hairy and glabrous skin in ALS patients (A, B, D, E, G, H, J, K, L) versus controls (C and F). Green, nerve fibres; blue, epide.

Kaplan–Meier survival curves based on morphological and NfL data, and skin biopsy longitudinal study Kaplan–Meier curves of survival probability among ALS patients stratified by median value of (A) Meissner corpuscles (MC) density (n/mm2), (B) serum neuro.

Conclusion: In patients with ALS, peripheral sensory involvement worsens in parallel with motor disability. Furthermore, the correlation between skin innervation and disease activity may suggest the use of skin innervation as a putative prognostic biomarker.

Disclosure: Nothing to disclose.

OPR‐020

Heterogeneous real‐life strategies in therapeutic approach of chronic inflammatory demyelinating polyradiculoneuropathy

A. De Lorenzo ¹; P. Doneddu²; F. Manganelli³; D. Cocito⁴; R. Fazio⁵; A. Mazzeo⁶; A. Schenone⁷; C. Briani⁸; V. Di Stefano⁹; M. Filosto¹⁰; G. Marfia¹¹; G. Cosentino¹²; A. Clerici¹³; G. Antonini¹⁴; L. Benedetti¹⁵; G. Piscosquito¹⁶; M. Carpo¹⁷; G. Lauria Pinter¹⁸; G. Siciliano¹⁹; G. Cavaletti²⁰; M. Lucchetta²¹; T. Rosso²²; M. Luigetti²³; M. Inghilleri²⁴; E. Nobile‐Orazio²⁵

¹Neuromuscular and Neuroimmunology Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy; Università degli Studi di Milano, Milano, Italy; ²IRCCS Humanitas Research Hospital, Rozzano (Milano), Milano, Italy; ³Department of Neuroscience, Reproductive Sciences and Odontostomatology, University of Naples ‘Federico II’, Napoli, Italy; ⁴Department of Neuroscience, University of Turin, Torino, Italy; ⁵Division of Neuroscience, Department of Neurology, Institute of Experimental Neurology (INSPE), San Raffaele Scientific Institute, Milano, Italy; ⁶Department of Clinical and Experimental Medicine, Unit of Neurology, University of Messina, Messina, Italy; ⁷Neurology Clinic, IRCCS Ospedale Policlinico San Martino Genova, Genova, Italy; Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa and IRCCS AOU San Martino‐IST, Genova, Italy; ⁸Neurology Unit, Department of Neuroscience, University of Padua, Padova, Italy; ⁹Department of Biomedicine, Neuroscience, and Advanced Diagnostic (BiND), University of Palermo, Palermo, Italy; ¹⁰Center for Neuromuscular Diseases and Neuropathies, Unit of Neurology, ASST ‘Spedali Civili’, University of Brescia, Brescia, Italy; ¹¹Dysimmune Neuropathies Unit, Department of Systems Medicine, Tor Vergata University of Rome, Roma, Italy; ¹²Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy; IRCCS Mondino Foundation, Pavia, Italy; ¹³Neurology Unit, Circolo & Macchi Foundation Hospital, University of Insubria, Varese, Italy; ¹⁴Unit of Neuromuscular Diseases, Department of Neurology Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, ‘Sapienza’ University of Rome, Sant'Andrea Hospital, Roma, Italy; ¹⁵Neurology Clinic, IRCCS Ospedale Policlinico San Martino Genova, Genova, Italy; ¹⁶Department of Medicine and Surgery, Neurology Unit, University Hospital “San Giovanni di Dio e Ruggi d'Aragona”, University of Salerno, Salerno, Italy; ¹⁷Department of Neurology, ASST Bergamo Ovest‐Ospedale Treviglio, Treviglio, Italy; ¹⁸Unit of Neuroalgology, IRCCS Foundation ‘Carlo Besta’ Neurological Institute, Milano, Italy; Department of Medical Biotechnology and Translational Medicine, Milan University, Milano, Italy; ¹⁹Neurology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; ²⁰Università di Milano‐Bicocca, Monza, Italy; ²¹UOC Neurologia, Ospedale Santa Maria della Misericordia, Rovigo, Italy; ²²UOC di Neurologia, Ospedale San Bassano, Vicenza, Italy; ²³Neurology Department, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, Italy; ²⁴Neurodegenerative Diseases Unit, Department of Human Neuroscience, Sapienza University, Policlinico Universitario Umberto I, Roma, Italy; ²⁵Neuromuscular and Neuroimmunology Unit, IRCCS Humanitas Research Hospital, Milan, Italy; Department of Medical Biotechnology and Translational Medicine, Milan University, Milan, Italy

Background and aims: Despite the existence of therapeutic recommendations in the 2010 EFNS/PNS and 2021 EAN/PNS guidelines for managing Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP), the sequence of therapy to be used remains unsettled.

Methods: A comparative analysis was conducted, examining therapeutic strategies and responses in 524 CIDP patients from tertiary referral centers included in a large national database.

Results: Intravenous immunoglobulins (IVIg) emerged as the most commonly used first‐line therapy (53%), followed by steroids (33%) and plasmapheresis (3%). A consistent proportion of patients (8%) received combined first‐line therapy with IVIg and steroids or (3%) monotherapy with immune suppressants. In acute‐onset CIDP, IVIg and plasmapheresis were often used. There were also differences in relation to the early or late age at onset and to CIDP variants. Immune suppressants were often used as maintenance monotherapy (10%). There was a substantial variability among different centers in the choice of first‐ and second‐line therapy, number of therapies performed, use of immunosuppressants and subcutaneous immunoglobulin (SCIg). A consistent proportion of patients responded to IVIg (86%) or steroid (85%) when used as second line therapy and only 7% of the patients failed to respond to two first‐line therapies. There was no distinctive features between responder and not responder patients beside a more frequent ataxia at onset and greater disability at enrollment.

Conclusion: The absence of specific indications from guidelines may explain the notable heterogeneity in the therapeutic choice in CIDP patients. Therapeutic response significantly decreases after two failed attempts, but the identification of non‐responders remains challenging.

Disclosure: Nothing to disclose.

OPR‐021

Serum neurofilament light chain as a biomarker in Guillain‐Barré syndrome: Origin and prognostic value

B. Hafsteinsdóttir ¹; H. Zetterberg²; M. Axelsson¹; J. Lycke¹

¹Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; ²Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, The University of Gothenburg, Mölndal, Sweden

Background and aims: Our objective was to determine the origin serum neurofilament light chain (sNfL) and the utility of the sNfL Z‐score, NfL ratio and NfL index as prognostic biomarkers in Guillain‐Barré syndrome (GBS).

Methods: We included 96 patients with GBS between 1989 and 2014 in Western Sweden. Outcome measures were GBS disability scale (GBSDS) at 3 and 12 months and the need of respiratory support. Receiver operator characteristics curves were calculated for sNfL Z‐score for the risk of respiratory support and GBSDS >2 at 3 months. NfL ratio and NfL index were compared with healthy controls (HC), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS).

Results: The sNfL Z‐score was higher for respiratory support (median 3.7, IQR 3.2–4.0 vs. median 2.7, IQR 1.6–3.5), GBSDS >2 at 3 months (median 3.5, IQR 3.2–4.0, vs. median 2.6, IQR 1.7–3.4) and 12 months (median 3.6, IQR 3.5–3.8, vs. median 2.6, IQR 1.8–3.5). No association was seen between NfL ratio or index and outcome. The area under the curve for the sNfL Z‐score was 0.75 (95% CI 0.61–0.89) for respiratory support and 0.76 (95% CI 0.58–0.93) for GBSDS >2 at 3 months. The NfL ratio and index were lower in GBS than HC, MS, and ALS.

ROC curves for sNfL Z‐score. AUC for GBSDS >2 at 3 months was 0.76 (95% CI 0.59–0.93, p = 0.009). AUC for respiratory support 0.75 (95% CI 0.61–0.89, p = 0.004). ROC = receiver operator characteristics; AUC = area under curve.

(A) NfL ratio in healthy controls (HC), Guillain‐Barré syndrome (GBS), multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). (B) NfL index in GBS, MS and ALS presented as median, interquartile range and individual values. The columns represent.

Conclusion: The sNfL Z‐score at onset is a promising predictive biomarker for prognosis in GBS. Our results suggest that peripheral nerves are a significant contributor to sNfL in GBS.

Disclosure: The study was supported by grants from the Swedish State Support for Clinical Research (ALFGBG‐722081), NEURO Sweden, NEURO Gothenburg, the Edit Jacobson Foundation, the Rune and Ulla Amlövs Foundation for Neurological Research, the MS Research Foundation of the Swedish MS Society, the Gothenburg Society of Medicine, and grants from Berit Linnea and Ragnar Bakken Foundation. Henrik Zetterberg has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work) Jan Lycke has received travel support and/or lecture honoraria and has served on scientific advisory boards for Amgen, Almirall, Biogen, Bristol Myers Squibb, Celgene, Genesis Pharma, Janssen, Merck, Novartis, Roche, Sanofi and Sandoz; and has received unconditional research grants from Biogen and Novartis, and financial research support from Sanofi.

OPR‐022

Activin‐IIB‐receptor inhibition prevents muscle atrophy and hastens motor recovery in experimental autoimmune neuritis

F. Kohle¹; I. Gerlach ¹; M. Koch²; I. Klein¹; G. R Fink¹; G. Gatto¹; M. Schroeter¹; H. C Lehmann³

¹Department of Neurology, Faculty of Medicine, University of Cologne and University Hospital Cologne, Cologne, Germany; ²Center for Biochemistry, Institute for Dental Research and Oral Musculoskeletal Research, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; ³Department of Neurology, Hospital Leverkusen, Leverkusen, Germany

Background and aims: Muscle atrophy due to neuronal denervation is a significant determinant of the functional outcome in immune‐mediated neuropathies after cessation of autoinflammation. Activin‐IIB receptors (ActIIBR) are critically involved, and the blockade of these receptors has recently been explored in primarily degenerative muscular diseases. We examined the potential of ActIIBR blockade on motor recovery in the experimental autoimmune neuritis (EAN) animal model.

Methods: EAN was induced using myelin P253‐78 protein in female Lewis rats. With the beginning of the recovery phase at day 18 post immunization, rats were treated with either sham, 1.25 mg/kg body weight, or 5 mg/kg body weight of a synthesized ActIIBR antibody subcutaneously every fourth day. Functional motor outcome was assessed using a neuritis score, grip strength, and balance beam paired with cinematic tracing until day 30. Nerve conduction studies, histological analyses of the sciatic nerve and the tibialis anterior muscle, real‐time PCR, and muscle proteomics were performed.

Results: Treatment with 5 mg/kg ActIIBR‐antibody ameliorated EAN severity at day 30 (p‐value: <0.0001). The grip strength nearly returned to baseline. No group differences were seen for nerve conduction studies and cellular inflammation in the sciatic nerve. Histologically, an increased cross‐sectional area and ferret's diameter were observed. Muscle proteomics indicated alteration of the pAKT pathway, leading to a reduced expression of Atrogin1‐ and MuRF1 (p‐values: 0.014 and 0.038).

Treatment with 5 mg/kg of the ActIIBR antibody enhances functional recovery after EAN.

ActIIBR inhibition prevents muscle atrophy and induces muscle hypertrophy without affecting cellular inflammation of the sciatic nerve.

Proteomics and real‐time PCR analysis of the tibialis anterior muscles revealing reduced muscle degradation by downregulation of Atrogin‐1 and MuRF‐1 via ActIIBR‐inhibition.

Conclusion: Blockade of the ActIIBR prevents muscle atrophy via Atrogin‐1 and MuRF‐1 downregulation, thereby hastening motor recovery in EAN. Further studies are warranted to investigate the role of ActIIBR blockade in autoimmune neuropathy.

Disclosure: FK was supported by the Cologne Clinician Scientist Program (CCSP), Project No. 413543196. I. Gerlach, I. Klein, M. Koch, G. R. Fink, G. Gatto, H.C. Lehmann and M. Schroeter reported no disclosures related to this study.

OPR‐023

Intracutaneous amyloid deposition predicts ulterior nerve conduction studies deterioration in ATTRv carriers

N. Schulz ¹; D. Beauvais²; C. Cauquil¹; C. Labeyrie¹; C. Adam³; V. Algalarrondo⁴; D. Adams¹; G. Beaudonnet¹

¹Department of Neurology, CHU Bicêtre, Le Kremlin‐Bicêtre, France; ²Department of Neurology, CHU Bordeaux, Bordeaux, France; ³Department of Pathology, CHU Bicêtre, Le Kremlin‐Bicêtre, France; ⁴Department of Cardiology, CHU Bichat, Paris, France

Background and aims: Hereditary transthyretin amyloidosis (ATTRv) is an autosomal dominant systemic disease, leading to harmful tissue protein deposition, mainly in the heart and nerves, with an overall poor prognosis. While new disease‐modifying treatments are being developed, it appears crucial to find markers of disease onset and progression for optimal timing in treatment initiation. Nerve conduction studies offer an objective, reproducible and non‐invasive although late mean of following large nerve disease.

Methods: We studied 107 ATTRv carriers with normal nerve conduction studies (NCS) and sought to find elements predictive of ulterior NCS decline, defined as a 20% decrease of the average of the bilateral sural and fibular sensory nerve action potential (SNAPs).

Results: During a median follow‐up of 5 years, 15/107 (14%) carriers presented a NCS deterioration. On univariate analysis, intracutaneous amyloid deposition (ICAD) (HR = 10.8, 95% CI(3.1 to 34.5), p < 0.0001) and difference of age with age of disease onset in proband (HR = 1.1, 95% CI(1.0 to 1.1), p = 0.002) were significantly associated with ulterior NCS decline. After multivariate analysis, skin amyloid deposition remained significantly and strongly associated with further worsening (HR = 10.3, 95% CI (2.4 to 45.5), p = 0.0014). EOVal30Met genotype, presence at baseline of cardiac denervation, skin denervation, an interventricular septum thickness superior to 12 mm, abnormal short‐term heart rate variability, abnormal SUDOSCAN or neurological physical examination were not significantly associated with electric deterioration on univariate testing.

Conclusion: ATTRv carriers with intracutaneous amyloid deposition at initial evaluation were more likely to present NCS deterioration during follow‐up compared to those without. Search of ICAD should be recommended during follow‐up of asymptomatic carriers.

Disclosure: Nothing to disclose.

OPR‐024

Neuropathy in anti‐MAG+/− IgM gammopathy: Population analysis and evaluation of old and innovative severity measures

D. Tornabene ¹; G. Cosentino¹; M. Todisco²; G. Tammam¹; E. Antoniazzi²; M. Gastaldi²; S. Scaranzin²; C. Morandi²; R. De Icco¹; M. Corrado¹; V. Grillo²; M. Varettoni³; E. Vegezzi²; E. Marchioni²; L. Diamanti²

¹Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy; ²IRCCS C. Mondino Foundation, Pavia, Italy; ³IRCCS Policlinico San Matteo Foundation, Pavia, Italy

Background and aims: IgM Monoclonal Gammopathy (IgM‐MG) often coexists with peripheral polyneuropathy. Distal demyelinating polyneuropathy (DADS) with anti‐MAG antibodies is the best‐known variant. Lack of appropriate endpoints poses challenges in assessing treatment efficacy. We provide a thorough clinical and paraclinical characterization of 38 anti‐MAG+/− subjects with IgM‐MG and evaluate various traditional and innovative measures of disease severity.

Methods: Participants underwent detailed collection of haematological, neurological, and therapeutic history, anti‐MAG reactivity testing, and extensive electrodiagnostic assessment including Terminal Latency Index (TLI) determination. A broad clinical evaluation comprised multiple scales (mRS, ONLS, Berg Balance Scale, INCAT‐SS, IRODS), functional tests (9‐holes peg test, grip strength determination, 10‐metres and 2‐minutes walking test), and the EuroQoL questionnaire. A balance assessment was performed through posturography (i.e. the tracking of a standing subject's centre‐of‐gravity movement).

Results: 24 subjects exhibited anti‐MAG reactivity, with 21 displaying electrodiagnostic signs of demyelination. Of the 14 seronegative individuals, one showed electrodiagnostic signs consistent with DADS. TLI reduction was found in at least some nerve in many demyelinating cases, but it was frequently unassessable due to nerve inexcitability or entrapment. Attached charts illustrate the performance of each assessment as a measure of disease severity.

Comparison of disease measures in subject stratified by mRS class (left) and by a Berg balance score value (right). A Berg score of 45 or lower is predictive of a high risk of falls (Shumway‐Cook et al., Physical Therapy, 1997).

Pearson correlation coefficient for each disease measure and IRODS (left) and Berg (right) scores.

Performance of the posturography measures “length” (above) and “area” (below) as disability indexes. Data for the “open eyes” test are shown.

Conclusion: The correlation between anti‐MAG antibodies and “DADS” neuropathy is robust but not universal. TLI can help the diagnosis, but not every nerve will have an index <0.25 and its utility is limited by inexcitability or false positives due to median nerve entrapment at the wrist. Posturography emerges as a potential objective, quantitative outcome for future trials.

Disclosure: Nothing to disclose.

OPR‐025

Prediction of the global functional outcome of intensive inpatient rehabilitation after stroke using machine learning

A. Sodero; S. Campagnini; M. Baccini; A. Grippo; B. Hakiki; C. Castagnoli; P. Liuzzi; C. Macchi; A. Mannini; F. Cecchi

IRCCS Fondazione Don Carlo Gnocchi onlus, Firenze, Italy

Background and aims: Prognostic data‐driven solutions could support the outcome prediction and, eventually, the optimisation of the rehabilitation pathway. We aimed at the development, cross‐validation, and external validation of machine learning‐based prognostic models for the prediction of the global functional outcome of patients undergoing intensive inpatient rehabilitation after stroke.

Methods: Patients addressing an evidence‐based intensive inpatient rehabilitation pathway within 30 days from stroke from two multicentric prospective studies were enrolled. Data related to standardized comprehensive multidimensional assessment were collected and fed within the model for feature selection (figure 1). The outcome of interest was the modified Barthel Index(mBI) at discharge. Different algorithms were optimised, nested cross‐validated, externally tested, and interpretability techniques were applied for the analysis of the contributions of predictors.

FIGURE 1 Analysis pipeline.

Results: Total numbers of 220 and 180 patients were considered for training and test sets, respectively (figure 2). Respectively a 50.9% and 56.7% of women, 79.5% and 78.9% of ischaemic, and a median [IQR] age of 80.0 [15.0] and 78.0 [17.0] were registered on the two datasets. The Support Vector Machine obtained the best validation performances and a median absolute error of 11.5 [15.0] and 9.2 [13.0] on the internal and external testing, respectively. The baseline variables providing with the main contributions to the predictions resulted in mBI, motor upper‐limb score, age, and cognitive score (figure 3).

FIGURE 2 Flow chart of the study.

FIGURE 3 Contributions of the predictors to the outcome prediction aggregated among each fold. In panels A‐C, bar plots of the global contributions are presented, whilst in panels B‐D, beeswarm plots with patient‐wise contributions are presented. The res.

Conclusion: Our results indicate the suitability of this solution for supporting clinicians in formulating a functional prognosis at the admission to intensive inpatient post‐stroke rehabilitation and in promptly identifying features potentially predicting an unfavourable outcome.

Disclosure: Nothing to disclose.

OPR‐026

In‐hospital death matters: A machine learning approach to anterior circulation mechanical thrombectomy

I. Petrović ¹; S. Broggi²; O. Tomašević³; A. Balenović¹; I. Milosavljević¹; M. Ivanišević⁴; M. Killer‐Oberpfalzer⁵ ; J. Mutzenbach⁵; C. Hecker⁵; S. Rajić¹; S. Pikija⁵

¹Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia; ²ASST dei Sette Laghi, Neurology and Stroke Unit, Varese, Italy; ³Faculty of Technical Sciences, Department of Systems, Signals and Control Engineering, University of Novi Sad, Novi Sad, Serbia; ⁴Faculty of Medicine, University of Belgrade, Belgrade, Serbia; ⁵Department of Neurology, Christian Doppler University Hospital, Paracelsus Medical University of Salzburg, Salzburg, Austria

Background and aims: Although the popularity of mechanical thrombectomy (MT) has grown significantly in the past decade, there is still a literature gap concerning post‐procedural in‐hospital mortality, the main contributing factors, and the possibility of predicting it. The aim was to employ interpretable machine learning (ML), which could potentially aid in understanding existing ambiguities.

Methods: This retrospective study included 602 anterior circulation ischemic stroke patients who underwent MT. Patients were divided into two groups: (I) died (n = 133), in which the fatal outcome occurred during the in‐hospital stay, and (II) survived (n = 469). Python 3.10.9 was used for the machine learning model build‐up, and based on the input features, two models were constructed: (I) the preMT model, which consisted of baseline features, and (II) the postMT model, which included baseline and MT‐related features. The ML models' training, internal evaluation, and performance testing followed feature selection. Interpretation frameworks explained the decision‐making process.

Summarized steps of the analysis. After a two‐step process of feature selection, with univariate feature selection (UFS) as the first step, and Recursive Feature Elimination (RFE) as the second, models were trained, evaluated, and tested.

Results: For the preMT model (AUC = 0.792), selected features were age, baseline NIHSS value, neutrophil‐to‐lymphocyte ratio (NLR), INR, vessel type, peripheral arterial disease (PAD), baseline glycemia, and premorbid modified Rankin scale (pre mRS), while in the postMT model (AUC = 0.837), added features included puncture to procedure end time (PET), and onset to puncture time (OPT).

(A) Evaluation metrics of the preMT model and the receiver operating characteristic curves (ROCs) of 4 classifiers; (B) The SHAP (Shapley Additive Explanations) analysis graph; (C) Local Interpretable Model‐Agnostic Explanations (LIME) plot.

(A) Evaluation metrics of the postMT model and the receiver operating characteristic curves (ROCs) of 4 classifiers; (B) The SHAP (Shapley Additive Explanations) analysis graph; C) Local Interpretable Model‐Agnostic Explanations (LIME) plot.

Conclusion: To the best of our knowledge, this study represents a pioneer research that utilized interpretable models for predicting in‐hospital death following anterior circulation MT. The constructed models need further extensive evaluation before they can be practically applied.

Disclosure: Nothing to disclose.

OPR‐027

Ethnic differences in access to care and treatment in patients with suspected acute stroke: A retrospective cohort study

I. Scala ¹; J. Di Giovanni¹; P. Rizzo¹; S. Bellavia¹; M. Monforte²; A. Broccolini²; P. Calabresi²; M. Covino³; G. Frisullo²

¹Catholic University of Sacred Heart, Roma, Italia; ²Department of Neuroscience, Sensory Organs and Chest, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy; ³Emergency Department, IRCCS Fondazione Policlinico Universitario Agostino Gemelli, Rome, Italy

Background and aims: Data concerning unequal healthcare access of acute stroke patients based on ethnicity or race are inconclusive in Europeans. The primary objective was to evaluate the effect of geographic origin/race on access to acute stroke care and treatments. Secondly, we evaluated the effect of geographic origin/race on stroke risk factors, outcomes, and admission for stroke mimics.

A graphic representation of the geographical origin of the included population. The percentages refer to the number of patients from various continents compared to the total number of non‐Western Europeans.

Methods: In this retrospective, cohort study, we enrolled adult patients admitted to the emergency department of a comprehensive stroke center for suspected stroke. Based on geographic origin, patients were divided into two groups: Western Europeans (WE) and non‐Western Europeans (nWE). For each nWE subjects, we included four sex‐ and age‐propensity score matched patients in the WE group. We then divided patients in three further subgroups (White/Black/Asian) based on race. Univariate comparisons were performed using Mann–Whitney, Kruskal‐Wallis, and χ ²‐tests, as appropriate. Logistic regression was used to perform the adjusted analyses.

Results: 618 patients were enrolled in the nWE group and 2444 in the WE group. Belonging to the nWE group is an independent predictor of lower likelihood of receiving intravenous thrombolysis (p = 0.005). Considering Black/Asian/White subgroups, ED accesses for stroke mimics were less frequent among racial minority groups (p = 0.038). Furthermore, Black and Asian individuals had a higher incidence of brain hemorrhages than Whites (p = 0.003). No differences in stroke outcomes were found.

TABLE 1 Results of the multivariate logistic regression for the prediction of thrombolytic treatment.

Conclusion: Racial and ethnic disparities in healthcare are a challenging issue even in universal healthcare systems, likely due to differences in socioeconomic status, and they and should be addressed promptly through education campaigns of healthcare personnel.

Disclosure: Nothing to disclose.

OPR‐028

Polysomnographic parameters as predictors of outcome in patients with ischemic stroke: A preliminary report

M. de Scisciolo; E. Rollo; G. Della Marca; V. Brunetti

Dipartimento di Neuroscienze, Organi di Senso e Torace, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy

Background and aims: Limited literature exists on sleep architecture in ischemic stroke (IS). This study aims to assess whether macrostructure and microstructure sleep parameters can predict outcomes in patients with IS.

Methods: Seventy‐seven with IS admitted to the Stroke Unit were prospectively collected. Patients underwent 24 hour polysomnography within seven days from the stroke. Macro and micro (Cycling Alternating Pattern ‐ CAP) sleep architecture and respiratory parameters were analyzed. Three‐month modified Ranking Scale(mRS) was used as the outcome measure. Sleep parameters were analyzed between groups with excellent (mRS = 0–1) and poor outcome (mRS = 2–6) using univariate and multivariate approaches, correcting for potential confounders (sex, age, NIHSS, pre‐stroke mRS).

Results: The study group showed a median age of 73 years (IQR = 20), and an admission NIHSS = 12 (IQR = 11). Forty‐three patients had excellent outcome (55.8%). Median total sleep time (TST) was 374 minutes (IQR = 104). Patients with excellent outcome showed higher REM sleep [13.0% (IQR = 8.6) vs. 6.9% (IQR = 7.5); p = 0.002)], higher N1 stage of NREM sleep [13.3% (IQR = 10.5) vs. 8.2% (IQR = 5.7; p = 0.001)], higher number or sleep cycles [3 (IQR = 2) vs. 1 (IQR = 3); p = 0.030)], shorter daytime sleep [10 (IQR = 75) vs. 75 minutes (IQR = 126); p = 0.005)], and higher CAP rate [43.7% (IQR = 25.0) vs. 24.9% (IQR = 30.8); p = 0.001)]. None of the analyzed respiratory parameters were associated with outcome. Multivariate analysis confirmed that higher CAPrate(p = 0.030) and less daytime sleep(p = 0.017) were associated to excellent outcome.

Conclusion: Macro and, mostly, microstructure parameters of sleep in ischemic stroke seem to be correlated with outcome, in particular higher CAP rate is associated with better outcome. Further investigations are needed to reinforce these findings.

Disclosure: Nothing to disclose.

OPR‐029

Amyloid PET as biomarker of white matter damage in recently diagnosed multiple sclerosis and its clinical relationship

J. Barrios‐López ¹ ; A. Piñeiro‐Donis² ; E. Triviño‐Ibáñez³ ; P. Casa Nova‐Leitao Moreira¹; F. Segovia‐Román⁴ ; B. Marín‐Romero⁵ ; M. Pérez‐García⁶

¹Neurology Department, Hospital Universitario Virgen de las Nieves, Granada, Spain; ²Nuclear Medicine Department, Hospital Universitario Virgen de las Nieves, Granada, Spain; ³Nuclear Medicine Department, Hospital Universitario Virgen de las Nieves, Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain; ⁴Department of Signal Theory, Networking and Communications, University of Granada, Granada, Spain; ⁵ Neurology Department, Hospital Universitario Virgen de las Nieves, Granada, Spain; ⁶Radiology Department, Hospital Universitario Virgen de las Nieves, Granada, Spain

Background and aims: White matter (WM) demyelination in multiple sclerosis (MS) can be measured in vivo using amyloid positron emission tomography (PET). Our aim was to evaluate amyloid uptake in damaged (DWM) and normal‐appearing WM (NAWM) of MS patients and the relation to their clinical status.

Methods: This prospective longitudinal study enrolled patients with recent MS onset between March to May 2023. Participants underwent a neurological examination, disability (EDSS), neuropsychological (SDMT) and quality of life (EQ‐5D) assessment, brain MRI and 18F‐florbetaben PET in early (0–10′) and late phase (90′) post‐i.v., MRI and PET images were co‐registered and results are presented as standardized uptake values (SUV), using cerebellum (SUVRc) and NAWM (SUVRwm) as the reference region.

Results: Ten patients were included (35.10 ± 11.32 years; 70% female). We found, both in early‐ and late‐phase, a lower mean SUVR in DWM compared to NAWM (p < 0.01) in all patients. SUVRwm correlated with EQ‐5D index (r:0.652, p = 0.041). A trend toward lower SUVRwm was observed in the highly active onset group compared to non‐ highly active group (0.62 ± 0.43 vs.. 3.62 ± 3.20, p > 0.05). Considering only highly active onset patients, SUVRwm correlated with EDSS score (rho = −0.896, p = 0.0031). The lesions analysis showed a correlation between SUVmean in DWM with EDSS and SDMT scores (rho: −0.534, p = 0.004 and rho: 0.670, p = 0.006, respectively); and SUVRc with SDMT (rho: 0.585, p = 0.022).

Standardized uptake values (SUV) analysis by co‐registered MRI and amyloid PET images.

Active lesion analysis by MRI and amyloid PET images.

Conclusion: Preliminary results of this work in progress suggest that amyloid PET could be a promising tool to monitor myelin changes in MS and may have a predictive role in disease activity and progression.

Disclosure: This work has received funding from the call for “NEURO‐RECA grants for scientific research in neurology in 2021” with file number NEURORECA‐0007‐2022.

OPR‐030

Validation of an automated deep learning algorithm for the identification of confluent Multiple Sclerosis lesions

M. Pasca ¹; L. Marchi²; A. Mariottini²; B. Lambert³; P. Rubini³; S. Doyle³; H. Dehaene³; A. Tucholka³; P. Roca³; S. Filippini⁴; L. Massacesi²

¹Department of Neurology, “F. Ferrari” Hospital, Casarano, Lecce, Italy; ²Department of Neurosciences, Drug and Child Health, University of Florence, Florence, Italy; ³Pixyl, Grenoble, France; ⁴Department Neurology, Florence, Italy

Background and aims: Lesion count is a crucial biomarker in Multiple Sclerosis diagnosis and follow‐up. Deep Learning (DL) models are a powerful aid for this task, providing an automated segmentation of lesions. These models tend to underestimate the true number of lesions, and segment confluent lesions as a single connected component. To improve the accuracy of the lesion counting, a novel post‐processing algorithm named LesDiv that can recognize individual lesions component in confluent lesions has been validated, automatically identifying single lesion center using the input FLAIR and lesion probability map produced by the DL segmentation model.

Methods: 60 MS patients with 440 clusters of lesions were included. Two neurologists, with expertise in Multiple Sclerosis MRi analysis, independently performed ground truth sub‐lesion counts and delineations. To compare the algorithm with alternative methods, an alternative pipeline that uses the Hessian filter instead of the LoG (described by Dworkin et al.), named Hessian Division, was implemented.

Flowchart of our proposed LesDiv algorithm.

Results: The analysis showed excellent reliability between the two human experts in terms of sublesion counting and delineation: Mean Absolute Error (MAE) = 0.45, Pearson Coefficient (R ²) = 0.88, Dice = 0.526. LesDiv showed good reliability with the analysis performed by the two human experts: MAE = 0.75, R ²= 0.75, Dice = 0.52, compared with Expert 1 analysis. Hessian Method showed a lower reliability with the two experts: MAE = 0.99, R ² = 0.67, Dice = 0.48 compared with Expert 1 analysis.

Illustration of expert counts and automated counts.

Comparison of experts and automated counts. MAE = Mean Average Error. R2 = Pearson correlation coefficient.

Conclusion: Lesion segmentation in MS is a complex and time‐consuming analysis. LesDiv is an automated deep learning algorithm, that showed significant correlation with human analysis in the identification of single lesions from confluent MS lesions.

Disclosure: Nothing to disclose.

OPR‐031

Cellular soma and neurite density abnormalities in multiple sclerosis paramagnetic rim and core‐sign lesions

P. Preziosa ¹; E. Pagani²; A. Meani²; M. Margoni³; M. Rubin¹; M. Palombo⁴; M. Rocca¹; M. Filippi⁵

¹Neuroimaging Research Unit, Division of Neuroscience, and Neurology Unit, IRCCS San Raffaele Scientific Institute, and Vita‐Salute San Raffaele University, Milan, Italy; ²Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; ³Neuroimaging Research Unit, Division of Neuroscience, Neurology Unit, and Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; ⁴Cardiff University Brain Research Imaging Centre, School of Psychology, and School of Computer Science and Informatics, Cardiff University, Cardiff, UK; ⁵Neuroimaging Research Unit, Division of Neuroscience, Neurology Unit, Neurorehabilitation Unit, and Neurophysiology Service, IRCCS San Raffaele Scientific Institute, and Vita‐Salute San Raffaele University, Milan, Italy

Background and aims: In multiple sclerosis (MS), susceptibility‐weighted imaging (SWI) may reveal white matter lesions (WML) with a paramagnetic rim (“paramagnetic rim lesions” [PRLs]) or diffuse hypointensity (“core‐sign lesions”), reflecting different stages of WML evolution. Using soma and neurite density imaging (SANDI) model on diffusion‐weighted magnetic resonance imaging (MRI), we characterized the microstructural abnormalities of MS PRLs and core‐sign lesions and their clinical relevance.

Methods: Forty MS patients and 20 healthy controls (HC) underwent a 3 T brain MRI. Using SANDI, the fractions of neurite (fneurite) and soma (fsoma) and size of soma (rsoma) were quantified in PRLs (including their core and rim separately), and core‐sign lesions identified on SWI.

Results: Among 1811 WMLs, 122 (6.7%) core‐sign lesions and 97 (5.4%) PRLs were identified. Compared to HC and MS normal‐appearing white matter, all MS WML showed significantly lower fneurite and fsoma and higher rsoma (FDR‐p < 0.001). Compared to isointense WML, core‐sign lesions showed a significantly higher fneurite, and lower fsoma and rsoma (FDR‐p < =0.001). Compared to isointense WML and core‐sign lesions, PRLs showed a significantly lower fneurite, higher fsoma, and higher rsoma (FDR‐p ≤ 0.005). The PRL‐core showed significantly lower fneurite, and higher rsoma than PRL‐rim (FDR‐p < 0.001). Lower PRL fneurite (β < = − 0.006, FDR‐p ≤ 0.015) and higher rsoma (β > =0.032, FDR‐p < =0.024) were significantly associated with a longer disease duration and more severe disability.

Conclusion: In PRLs, the significant and clinically‐relevant neurite loss and increased soma fraction and size possibly reflect increased astrogliosis and activated microglia. Core‐sign lesions exhibit milder axonal loss, microglia density and astrogliosis, supporting their less destructive nature.

Disclosure: P Preziosa received speaker honoraria from Roche, Biogen, Novartis, Merck, Bristol Myers Squibb, Genzyme, Horizon and Sanofi. He has received research support from Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla (FISM). E Pagani, A Meani, M Rubin, M Palombo have nothing to disclose. M Margoni reports grants and personal fees from Sanofi Genzyme, Merck Serono, Novartis and Almiral. MA Rocca received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, Roche; speaker honoraria from AstraZaneca, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Horizon Therapeutics Italy, Merck Serono SpA, Novartis, Roche, Sanofi and Teva; research support from MS Society of Canada, Italian Ministry of Health, Italian Ministry of University and Research, and FISM. M. Filippi received compensation for consulting or speaking activities from Alexion, Almirall, Biogen, Bayer, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA; participation in Advisory Boards for Alexion, Biogen, Bristol‐Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi‐Aventis, Sanofi‐Genzyme, Takeda; scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol‐Myers Squibb, Lilly, Novartis, Sanofi‐Genzyme; he receives research support from Biogen Idec, Merck‐Serono, Novartis, Roche, Italian Ministry of Health, Italian Ministry of University and Research, and FISM.

OPR‐032

Discriminating MS from MOGAD using deep learning attention maps

R. Cortese ¹; M. Battaglini¹; A. Jacob²; J. Palace³; F. Paul⁴; R. Marignier⁵; C. de Medeiros Rimkus⁶; M. Filippi⁷; M. Rocca⁷; A. Rovira⁸; J. Sastre‐Garriga⁹ ; Y. Liu¹⁰; C. Gasperini¹¹; C. Tortorella¹¹; M. Amato¹²; S. Groppa¹³; S. Llufriu¹⁴; C. Lukas¹⁵; P. Sowa¹⁶; A. Pröbstel¹⁷; C. Granziera¹⁷; B. Stankoff¹⁸; F. Barkhof¹⁹; O. Ciccarelli²⁰; N. De Stefano¹

¹Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy; ²Department of Neurology, Cleveland Clinic, Abu Dhabi, United Arab Emirates; ³Department of Clinical Neurology, John Radcliffe Hospital, Oxford, UK; ⁴Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité ‐ Universitaetsmedizin Berlin, Berlin, Germany; ⁵Service de Neurologie, Sclérose en Plaques, Pathologies de la Myéline et Neuro‐inflammation, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Lyon, France; ⁶Universidade de São Paulo, Faculdade de Medicina, Departamento de Radiologia e Oncologia, São Paulo SP, Brazil; ⁷Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; ⁸Section of Neuroradiology, Department of Radiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.; ⁹Servei de Neurologia. Centre d'Esclerosi Múltiple de Catalunya, (Cemcat). Vall d'Hebron Institut de Recerca, Vall d'Hebron Hospital Universitari, Universitat Autònoma de Barcelona, Barcelona, Spain; ¹⁰Department of Radiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; ¹¹Department of Neurosciences, S. Camillo‐Forlanini Hospital, Rome, Italy; ¹²Department NEUROFARBA, University of Florence, Italy; ¹³Department of Neurology, University Medical Center of the Johannes Gutenberg University Mainz, Germany; ¹⁴Neuroimmunology and Multiple Sclerosis Unit and Laboratory of Advanced Imaging in Neuroimmunological Diseases (ImaginEM), Hospital Clinic Barcelona, Fundació de Recerca Clínic Barcelona‐IDIBAPS and Universitat de Barcelona, Barcelona, Spain; ¹⁵Institute of Neuroradiology, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany; ¹⁶Division of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway; ¹⁷Departments of Neurology, Biomedicine and Clinical Research, and Research Center for Clinical Neuroimmunology and Neuroscience Basel, University Hospital and University of Basel, Kantonsspital, Basel, Switzerland; ¹⁸Sorbonne University, Paris Brain Institute, ICM, Pitié Salpêtrière Hospital, Paris, France; ¹⁹Radiology & Nuclear medicine, VU University Medical Centre, Amsterdam, The Netherlands; ²⁰MR Research Unit, Department of Neuroinflammation, Queen Square MS Centre, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK

Background and aims: Relapsing remitting multiple sclerosis (RRMS) and myelin‐oligodendrocyte antibody‐associated disease (MOGAD) are distinct diseases, but their differentiation can be challenging in clinical practice due to overlapping clinical and MRI features. The application of deep learning (DL)‐models to MRI is a promising approach to provide a structurally based classification of diseases, while the study of DL‐derived attention maps may indicate the most relevant anatomical regions for DL‐stratification. We aimed to build a MRI‐based DL‐model to differentiate RRMS from MOGAD and to assess group differences using probability attention maps (PAM).

Methods: In this cross‐sectional study, we analysed 345 FLAIR brain MRIs from RRMS (n.201, 117F, mean [SD] age: 39 years [±11], median EDSS: 2 [0–8], mean [SD] disease duration: 93 months [±94]) and MOGAD (n.144, 81F, mean [SD] age: 41y [±13], median EDSS: 2 [0–8.5], mean [SD] disease duration: 71 months [±96]), retrospectively collected from 17 centres. Patients were divided into three independent groups (training, validation, external test sets). The study design is illustrated in Figure 1.

FIGURE 1 Schematic representation of the study design.

Results: A DL discriminatory model between the two diseases was built (accuracy/specificity/ sensitivity: 84%/85%/84%) and successfully validated in the external test set without retraining (accuracy/specificity/sensitivity: 72%/68%/76%). PAM revealed the relevant role of insula (nV: 271, z‐score: 3.10), hippocampus (nV: 839, z‐score: 3.44), periventricular areas (nV: 669, z‐score: 3.47) for RRMS, while the selective role of the cingulate cortex (nV: 2360, z‐score: 2.71) for the identification of MOGAD (Figure 2).

FIGURE 2 Topographical distributions of the areas significantly contributing to the differentiation between patients with RRMS and with MOGAD.

Conclusion: We developed a DL‐model to accurately differentiate RRMS from MOGAD on FLAIR MRI. PAM provided additional clues on how damage is distributed in the two diseases.

Disclosure: The present research was conducted thanks to the 2019 ECTRIMS‐MAGNIMS fellowship (awarded to R.C.). The Authors have nothing to disclose in relation to this work.

OPR‐033

Rehabilitation of attention with a tablet‐based app in pediatric Multiple Sclerosis: A randomized, multicenter study

C. Masciulli ¹; E. Portaccio¹; B. Goretti²; C. Niccolai²; M. Simone³; R. Viterbo⁴; M. Zaffaroni⁵; L. Pippolo⁵; E. Cocco⁶; G. Fenu⁶; M. Flautano⁷; C. Celico⁷; M. Pardini⁸; G. Mancardi⁸; R. Guerrini⁹; F. Melani⁹; F. Giovannelli⁹; M. Rocca⁷; M. Filippi⁷; M. Trojano³; M. Amato¹

¹Department of NEUROFARBA, University of Florence, Florence, Italy; ²Department of Neurology, Don Carlo Gnocchi Foundation, Florence, Italy; ³Department of Precision and Regenerative Medicine and Jonic Area, University ‘Aldo Moro’ of Bari, Bari, Italy; ⁴Department of Translational Biomedicine and Neurosciences – DiBraiN, University “Aldo Moro” of Bari, Italy, Bari, Italy; ⁵Neuroimmunology Unit ‐ Multiple Sclerosis Center, Hospital of Gallarate, ASST della Valle Olona, Gallarate, Italy; ⁶Multiple Sclerosis Centre, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy; ⁷Neurology Unit and MS Center, IRCCS San Raffaele Scientific Institute; Neuroimaging Research Unit, Division of Neuroscience; Neurorehabilitation Unit and Neurophysiology Service; Vita‐Salute San Raffaele University, Milan, Italy; ⁸Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy/IRCCS AOU San Martino‐IST, Genoa, Italy; ⁹Paediatric Neurology Unit and Laboratories, Neuroscience Department, Meyer Children's Hospital IRCCS, Florence, Italy

Background and aims: Cognitive impairment affects approximately 30% of pediatric onset Multiple Sclerosis (POMS) patients with a negative impact on everyday life1. The aim of this study was to evaluate the feasibility and effectiveness of a home‐based, computer‐assisted training of attention in patients with POMS.

Some studies have highlighted a particular involvement of language in patients with POMS, which is commonly spared in adults. Additionally, a lower intelligence quotient (IQ) has been observed in patients with an earlier onset of the disease.

Methods: Inclusion criteria were diagnosis of MS, age 9–18 years, impairment on at least one attention test. Subjects were randomized to specific training (ST) or non‐specific training (n‐ST), delivered through a customized module based on attention exercises in COGNI‐TRAcK2. The main feature of the ST is the implementation of working load algorithms and procedures for intensiveness regulation. The effectiveness of the ST on attention was primarily assessed on the Symbol Digit Modalities Test (SDMT)3 using an analysis of variance for repeated measures. Secondary objectives included effectiveness on other cognitive tests and everyday‐life activities. The evaluations were performed at baseline, end of training, 3‐month follow‐up.

Results: 22 relapsing–remitting patients were included: data of 8 subjects in n‐ST and 4 subjects in ST were available. As for the primary outcome, SDMT score improved in the ST group (from 31.2 at baseline to 42.4 after 3 months, p = 0.043). This effect was evident also in Trial Making Test B (p = 0.047). There was no benefit in other neuropsychological measures.

As for the primary outcome, mean score on the SDMT improved in the ST group (from 31.2 + 9.8 at baseline to 42.4 + 18 at the end of training, p = 0.524) and remained stable in the n‐ST group (from 32 + 7.3 at baseline to 35.5 + 9.7 at the end of training, p = 0.284).

The positive effect of ST was also evident in Trail Making Test B, which improved in each group of patients: in ST group from 113.5 + 16.3 at baseline to 54 + 8.5 at the end of treatment (p = 0.047) and in n‐ST group from 97 + 39 at baseline to 76.7 + 41.4 at the.

Conclusion: These preliminary findings point to a potential benefit of a home‐based, computer‐assisted training of attention in patients with POMS. Early rehabilitation in POMS can mitigate the negative impact of cognitive impairment in patient's lifestyle and school activities.

Disclosure: C. Masciulli nothing to disclose; E. Portaccio received fees from Biogen, Merck Serono, Sanofi, Teva and Novartis; R. G. Viterbo received speaker honoraria from Biogen Idec and Teva; M. Zaffaroni received honoraria from Almirall, Biogen Idec, Genzyme, Merck Serono, Novartis and Teva; M. Pardini received research support from Novartis and Nutricia and honoraria from Merk and Novartis, G. Mancardi received honoraria from Bayer Schering, Biogen Idec, Sanofi‐Aventis, and Merck Serono Pharmaceuticals, R. Guerrini received honoraria from Biocodex, UCB, Eisai Inc, ValueBox, and Viropharma, M. Rocca received honoraria from Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche, and Teva, M. Filippi received fees from Almiral, Alexion, Bayer, Biogen, Celgene, Eli Lilly, Genzyme, Merck‐Serono, Novartis, Roche, Sanofi, Takeda, and Teva Pharmaceutical Industries; M. Trojano received honoraria from Biogen, Sanofi, Merck, Roche, and Novartis; M.P. Amato received honoraria from Biogen Idec, Merck Serono, Bayer Schering Pharma, and Sanofi Aventis.

OPR‐034

Ambulatory 24‐h continuous polysomnography as diagnostic tool for narcolepsy type 1 in adult and pediatric patients

F. Biscarini ¹; C. Zenesini²; L. Vignatelli²; F. Citeroni²; S. Vandi¹; L. Barateau³; Y. Dauvilliers³; G. Plazzi⁴; F. Pizza¹

¹Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio‐Emilia, Italy; ²IRCCS Istituto delle Scienze Neurologiche di Bologna, Italy; ³Sleep‐Wake Disorders Unit, Department of Neurology, Gui‐de‐Chauliac Hospital, CHU Montpellier, Montpellier, France; ⁴Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio‐Emilia, Italy

Background and aims: Narcolepsy type 1 (NT1) is diagnosed on average 10 years after the onset. We evaluated the contribution of 24‐hour continuous polysomnography (PSG) as an alternative tool for the diagnosis of NT1 in adults and children.

Methods: Consecutive patients evaluated at the Bologna Narcolepsy Center from 2013 to 2022 for suspected hypersomnia were included. The 807 participants underwent 48‐hour ambulatory PSG monitoring preceding the multiple sleep latency test (MSLT). The accuracy of night1 and day2 PSG was tested for the diagnosis of NT1 (n = 322), employing the 2023 international criteria as the standard reference for the ROC curve analysis.

Results: The detection of daytime‐sleep‐onset REM period (SOREMP) ≥1, with an area under the curve (AUC) of 0.84 (95% CI, 0.82–0.87), 84.4% sensitivity and 84.5% specificity, resulted superior to nighttime‐PSG measures, including nighttime‐SOREMP (p < 0.001) and comparable to 24‐hour‐SOREMP count. In the entire cohort, the combination of daytime‐SOREMP ≥1 with cataplexy provided 78.9% sensitivity and 98.4% specificity, with AUC 0.89 (95% CI 0.86–0.91) superior to the combination of nighttime‐SOREMP with cataplexy (AUC 0.78, 95% CI 0.76–0.81, p < 0.001) and not inferior to MSLT criteria for narcolepsy (AUC 0.90, 95% CI 0.88–0.92). These results were confirmed separately in adult and pediatric patients, except that, in pediatric patients (130/243 with NT1), nighttime‐SOREMP (AUC 0.86, 95% CI 0.82–0.90) was not inferior to daytime‐SOREMP ≥1.

FIGURE 1 Receiver operating characteristic (ROC) curve analysis for diagnosis of narcolepsy type 1 of the polysomnographic variables from daytime (A), nighttime (B), daytime and nighttime combined (C), and all the variables together (D).

TABLE 1 Receiver operating characteristic (ROC) curve analysis for the diagnosis of narcolepsy type 1, in different age groups.

Conclusion: Continuous daytime‐PSG is accurate for identifying NT1 in all age groups and appears superior to nighttime‐PSG and not inferior to 24‐hour monitoring. Daytime‐PSG, applicable outside sleep laboratory settings, can anticipate the diagnosis of NT1 in both adults and children.

Disclosure: Nothing to disclose.

OPR‐035

Survival differences between genders in PDHA1‐related pyruvate dehydrogenase deficiency

K. Merkevicius; J. Mayr; S. Wortmann

University Children's Hospital, Salzburger Landeskliniken (SALK), Paracelsus Medical University (PMU), Salzburg, Austria

Background and aims: Pyruvate dehydrogenase complex deficiency (PDHD) is the prototypic inborn error of mitochondrial metabolism, leading to neurodevelopmental disorder with lactic acidosis, CNS structural abnormalities. Disease causing variants in the X‐linked PDHA1 are the most common genetic cause of PDHD, consequently, mainly males should be affected. In the literature, both genders are reported. We here assess the gender differences in survival in PDHA1‐ related PDHD.

Methods: Affected individuals with PDHA1‐ related PDHD were recruited via literature review (n = 512) and international collaboration (n = 418). All variants were (re)classified according to NM_000284.3 reference transcript, interpreted via American College of Medical Genetics (ACMG) criteria. (Likely) benign variants were excluded. Survival probability was assessed using Kaplan–Meier estimator.

Results: In total, 930 cases with known gender and genotype were included (females 51.6%, n = 480), harbouring a total of 324 different PDHA1 disease causing variants. The overall median survival was 12.5 years (95% Confidence interval (95% CI) 8–20 years; n = 317). Males had significantly (p < 0.001) lower survival probability than females, median survival in males and females were 3.6 years (95% CI 2.5–9.42; n = 146) and 22 years (95% CI 16.0–30.0; n = 159), respectively. Males with neonatal or infantile presentation had significantly lower survival probability than females with neonatal (p < 0.001; n = 136) or infantile (p < 0.001; n = 83) presentation.

Conclusion: Interestingly, we found equal number of cases between both genders, males had significantly lower survival probability. In females, X‐inactivation could lead to milder phenotypes with better survival even with the same genotype as in males. Some males with severe phenotype could result in spontaneous pregnancy termination explaining similar frequency.

Disclosure: This abstract is part of a larger study analysing the genotypical and phenotypical landscape of PDHA1‐related PDHD. This study was made possible through large collaboration with more than 150 different specialists worldwide.

OPR‐037

Clinical and instrumental gait phenotyping in subjects with GLUT‐1 deficiency syndrome

M. Corrado ¹; R. De Icco¹; V. Grillo¹; V. De Giorgis¹; V. Vacchini²; C. Varesio²; M. Celario²; D. Trabassi³; S. Castiglia³; M. Serrao³; C. Tassorelli³

¹Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy; ²Department of Child Neurology and Psychiatry, IRCCS Mondino Foundation, Pavia, Italy; ³Department of Medical and Surgical Sciences and Biotechnologies, “Sapienza” University of Rome, Polo Pontino, Latina, Italy

Background and aims: Gait disturbances and movement disorders are frequent in patients with GLUT‐1 deficiency syndrome (GLUT1‐DS), a rare disease also characterized by seizures and cognitive dysfunction. This study aimed to assess the ability of a set of instrumental gait indexes to identify gait disorders in GLUT1‐DS, and to detect potential correlations with the clinical phenotype and biochemical parameters.

Methods: We recorded a 30‐meter gait of 16 subjects with GLUT1‐DS and of 16 matched healthy subjects (HS). We performed gait analysis with an inertial sensor. Based on trunk acceleration we calculated: spatio‐temporal gait parameters, pelvic kinematics, harmonic ratios (HR), recurrence quantification analysis (RQA), stride length coefficient of variation (CV), the longest short‐term Lyapunov's exponent (sLLE), and the log dimensionless jerk score (LDLJ). Along with the instrumental gait recording, we performed a comprehensive clinical and biochemical phenotyping.

Results: GLUT 1‐DS (mean age 19.1 ± 13.7 years) showed lower values of HR and single support (SS) phase (Figure 1; p < 0.05), indicating impaired gait smoothness. Moreover, they showed higher values of CV and sLLE (Figure 2; p < 0.01), suggestive of higher dynamic instability and variability of gait. The CV negatively correlated with ketonemia (r = −0.61, p < 0.05). Nine subjects (52%) had clinically evident gait disorders, mainly characterized by choreo‐ataxic gait.

FIGURE 1 Differences in time of single support (SS) and harmonic ratio (HR) between HS (orange) and GLUT1‐DS (green).

FIGURE 2 Differences in coefficient of variation (CV, i.e. variability of stride length) and the longest short‐term Lyapunov's exponent (sLLE) between HS (orange) and GLUT1‐DS (green).

Conclusion: GLUT1‐DS exhibited multiple alterations in the trunk acceleration‐derived gait indexes, which were suggestive of impaired gait stability and smoothness. Interestingly, increased gait variability correlated with low ketonemia, possibly suggesting this feature as a marker of poor therapeutic adherence.

Disclosure: Nothing to disclose.

OPR‐038

Long‐term outcomes of Phase‐1 study of neural stem cell transplantation in progressive multiple sclerosis

M. Azzimonti ¹; I. Gattuso²; E. Pagani³; A. Genchi⁴; L. Storelli³; L. Moiola²; V. Martinelli²; P. Vezzulli⁵; E. Brambilla⁶; A. Falini⁷; G. Martino⁸; M. Rocca¹; M. Filippi⁹

¹Neuroimaging Research Unit, Division of Neuroscience, and Neurology Unit, IRCCS San Raffaele Scientific Institute, and Vita‐Salute San Raffaele University, Milan, Italy; ²Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; ³Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; ⁴Neurology Unit, and Neuroimmunology Unit, Institute of Experimental Neurology, IRCCS San Raffaele Scientific Institute, Milan, Italy; ⁵Neuroradiology Unit and High Field MRI Center, IRCCS San Raffaele Scientific Institute, Milan, Italy; ⁶Neuroimmunology Unit, Institute of Experimental Neurology, IRCCS San Raffaele Scientific Institute, Milan, Italy; ⁷Neuroradiology Unit and High Field MRI Center, IRCCS San Raffaele Scientific Institute, and Vita‐Salute San Raffaele University, Milan, Italy; ⁸Neuroimmunology Unit, Institute of Experimental Neurology, IRCCS San Raffaele Scientific Institute, and Vita‐Salute San Raffaele University, Milan, Italy; ⁹Neuroimaging Research Unit, Division of Neuroscience, Neurology Unit, Neurorehabilitation Unit, and Neurophysiology Service, IRCCS San Raffaele Scientific Institute, and Vita‐Salute San Raffaele University, Milan, Italy

Background and aims: Human fetal neural progenitor/stem cells (hfNPCs) transplant feasibility and safety in progressive multiple sclerosis (PMS) has been demonstrated in STEMS, a phase I clinical trial (NCT03269071). Higher dose of hfNPCs was associated with significantly lower rates of brain and gray matter (GM) atrophy after 2 years. We present long‐term (LT) follow‐up (FU) of STEMS trial.

Methods: Patients underwent clinical (comprehensive of Expanded Disability Status Scale [EDSS] and Symbol Digit Modalities Test [SDMT]) and brain MRI evaluation at minimum 4.5 year FU. New T2‐hyperintense and Gd‐enhancing lesions were counted. T2‐lesion volume (T2LV), percentage brain (PBVC), GM (PGMVC) and white matter (PWMVC) volume changes were estimated.

Results: FU was available for 11/12 patients (median duration 5.6 years). At LT, EDSS and SDMT were significantly worsened compared to 2 year FU (p < =0.08). Five (45%) patients showed new T2‐hyperintense lesions, whereas T2LV was unchanged (p = 0.07); no patient showed Gd‐enhancing lesions. Brain, GM and WM volumes were decreased at LT compared to 2‐year FU. Interestingly, atrophy rates at LT were lower compared to the first 2‐year changes (significant for PGMVC: 2‐years vs. baseline = −0.76%; LT vs. 2‐years = −0.47%, p = 0.04). No significant correlation was found between number of injected hfNPCs and variation of EDSS, SDMT or MRI measures.

Conclusion: Although no clear dose–response effect has been found in hampering disability, cognition or brain atrophy progression, lower rates of GM atrophy were found at LT FU, which could imply that hfNPCs maintain their neuroprotective effect over time.

Disclosure: M Azzimonti, I Gattuso, E Pagani, A Genchi, L Storelli, P Vezzulli, E Brambilla, A Falini, and G Martino have nothing to disclose. L Moiola compensation for speaking activities and/or consulting services from Merck, Biogen, Novartis, Roche, Sanofi, and TEVA. V Martinelli compensation for speaking and/or consultancies and support for participation in congresses from Biogen, Merck‐Serono, Novartis, Genzyme and TEVA Pharmaceutical Industries. MA Rocca consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, Roche; speaker honoraria from AstraZaneca, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Horizon Therapeutics Italy, Merck Serono SpA, Novartis, Roche, Sanofi and Teva; research support from MS Society of Canada, Italian Ministry of Health (IMH), Italian Ministry of University and Research, and FISM. M. Filippi compensation for consulting or speaking activities from Alexion, Almirall, Biogen, Bayer, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA; participation in Advisory Boards for Alexion, Biogen, Bristol‐Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi‐Aventis, Sanofi‐Genzyme, Takeda; scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol‐Myers Squibb, Lilly, Novartis, Sanofi‐Genzyme; he receives research support from Biogen Idec, Merck‐Serono, Novartis, Roche, IMH, Italian Ministry of University and Research, and FISM.

OPR‐039

Parental smoking exposure and risk for multiple sclerosis among adults: The EnvIMS study

C. Ferri ¹; N. Merli²; K. Myhr³; T. Riise⁴; C. Wolfson⁵; M. Pugliatti⁶

¹Department of Neuroscience, S. Anna University Hospital, Ferrara, Italy; ²Department of Neuroscience and Rehabilitation, University of Ferrara, Italy. S. Anna University Hospital, Ferrara, Italy; ³Department of Clinical Medicine, University of Bergen, Norway; The Norwegian Multiple Sclerosis Registry and Biobank, Department of Neurology, Haukeland University Hospital, Bergen, Norway; ⁴Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway/The Norwegian Multiple Sclerosis Competence Centre, Department of Neurology, Haukeland University Hospital, Bergen, Norway; ⁵Department of Epidemiology, Biostatistics, and Occupational Health, School of Population and Global Health, McGill University, Montreal, Quebec, Canada; ⁶Department of Neuroscience and Rehabilitation, University of Ferrara, Italy; S. Anna University Hospital, Ferrara, Italy

Background and aims: Active smoking is a known risk factor for Multiple sclerosis (MS) development and poor prognosis. However, the impact of past exposure to parental smoking (ParS), including maternal smoking during pregnancy (MSDP) is not well defined. We aimed to investigate how these types of early age exposures affect MS risk among adults.

Methods: Using the data collected by the EnvIMS study, a large multinational case–control population‐based study, we investigated the association between MS and smoking habit, MSDP and maternal/paternal smoking (MaS, PaS) in Canadian, Italian, and Norwegian populations. Data were collected with EnvIMS‐Q, designed to investigate environmental exposures during early life stages. Adjusted odds ratios (aOR) for index age and participants' smoking status are presented with 95% confidence intervals (95% CI).

Results: We included 1565 Canadian, 2040 Italian, and 2674 Norwegian subjects. An association between MS and MSDP and MaS was observed among Norwegians: aOR 1.38 (1.12, 1.71) and 1.39 (1.17, 1.65), respectively. A tendency for PaS to be associated with MS was found among Canadians: aOR 1.21 (0.97, 1.51). No significant association to ParS (any) was detected in the Italian population.

Conclusion: Selective exposure to ParS at early age may differentially increase MS risk in the general population and independently from the subject's past/current smoking habit. The developmental origin of health and disease (‘DOHaD’) theory may help interpret these findings. The absence of an association between MS and past exposure to ParS in other populations may reflect its smaller effect on MS risk compared to other factors.

Disclosure: The authors declare no conflict of interest. The EnvIMS study was supported by Fondazione Italiana Sclerosi Multipla, FISM, grants n. 2007/R/14, and n. 2008/R/19; Financially supported by the European Union – Next Generation EU – NRRP M6C2 – Investment 2.1 Enhancement and strengthening of biomedical research in the NHS ‐ PNRR‐MAD‐2022‐12,376,868.

OPR‐040

Retinal layer thinning differentiates disease‐modifying treatment effects in relapsing MS when using a rebaseline

G. Bsteh ¹; H. Hegen³; N. Krajnc²; P. Altmann¹; M. Auer³; K. Berek³; B. Kornek¹; F. Leutmezer¹; S. Macher¹; T. Monschein¹; M. Ponleitner¹; P. Rommer¹; C. Schmied¹; K. Zebenholzer¹; G. Zulehner¹; T. Zrzavy¹; F. Deisenahmmer³; F. Di Pauli³; B. Pemp⁴; T. Berger¹

¹Department of Neurology, Medical University of Vienna, Vienna, Austria; ²Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, Vienna, Austria; ³Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria; ⁴Department of Ophthalmology, Medical University of Vienna, Vienna, Austria

Background and aims: We aimed to investigate whether retinal layer thinning measured by optical coherence tomography (OCT) can differentiate effects of disease‐modifying treatment (DMT) in relapsing MS (RMS) using a rebaseling concept.

Methods: From an ongoing prospective observational study, we included RMS patients, who 1) had an OCT scan 6–12 months after DMT start (rebaseline), 2) ≥1 follow‐up OCT ≥12 months after rebaseline, and 3) adhered to the DMT during follow‐up. Differences between DMT substances in thinning of peripapillary retinal nerve fiber layer (pRNFL) and macular‐ganglion‐cell‐plus‐inner‐plexiform layer (GCIPL) were analyzed using mixed‐effects linear regression adjusting for age, sex, disease duration and relapses during follow‐up.

FIGURE 1 Study design.

Results: Of 291 RMS patients (mean age 30.8 years [SD 7.9], 72.9% female, median disease duration 9 months [6–94], median rebaseline‐to‐last‐follow‐up‐interval 37 months [12–87]). Mean annualized percent loss rates (%/year) of retinal layer thinning in reference to dimethyl‐fumarate (n = 84, GCIPL 0.28, pRNFL 0.53) were similar under teriflunomide (n = 18, GCIPL 0.34, pRNFL 0.59, not significant [ns]), glatiramer acetate (n = 24, GCIPL 0.32, pRNFL 0.56, ns) and interferon beta (n = 13, GCIPL 0.33, pRNFL 0.60, ns), appeared slightly lower under sphingosine‐phosphate‐1‐receptor modulators (n = 27, GCIPL 0.19 [p = 0.093], pRNFL 0.42 [p = 0.097]) and cladribine (n = 23, GCIPL 0.20 [p = 0.095], pRNFL 0.42 [p = 0.099]), and were significantly lower under natalizumab (n = 47, GCIPL 0.09, pRNFL 0.24; p < 0.001 respectively) and anti‐CD20 monoclonal antibodies (n = 55, GCIPL 0.10, pRNFL 0.23; p < 0.001 respectively).

FIGURE 2 Annualized pRNFL loss differentiates disease‐modifying treatment effects in RMS.

Figure 23 Annualized GCIPL loss differentiates disease‐modifying treatment effects in RMS.

Conclusion: Applying a rebaseling concept, retinal layer thinning differentiates DMT effects in RMS and, thus, may be a useful biomarker to mediate DMT efficacy on neuroaxonal degeneration – at least on a group level.

Disclosure: Gabriel Bsteh: has participated in meetings sponsored by, received speaker honoraria or travel funding from Biogen, Celgene/BMS, Lilly, Merck, Novartis, Roche, Sanofi‐Genzyme and Teva, and received honoraria for consulting Biogen, Celgene/BMS, Novartis, Roche, Sanofi‐Genzyme and Teva. He has received unrestricted research grants from Celgene/BMS and Novartis.

OPR‐041

Longitudinal changes in the periplaque area of paramagnetic rim lesions may be associated with remyelination failure

N. Krajnc ¹; V. Schmidbauer²; J. Leinkauf²; N. Gantner²; L. Haider²; G. Bsteh¹; G. Kasprian²; F. Leutmezer¹; B. Kornek¹; P. Rommer¹; T. Berger¹; H. Lassmann³; S. Hametner⁴; A. Dal‐Bianco¹

¹Department of Neurology, Medical University of Vienna, Vienna, Austria; ²Medical University of Vienna, Department of Biomedical Imaging and Image‐guided Therapy, Vienna, Austria; ³Center for Brain Research, Medical University of Vienna, Vienna, Austria; ⁴Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria

Background and aims: Paramagnetic rim lesions (PRLs) are an emerging imaging biomarker in multiple sclerosis (MS) associated with a more severe disease course.

Methods: In this prospective longitudinal study, quantitative MRI metrics of PRLs, lesions with diffuse susceptibility‐weighted imaging (SWI)‐hypointense signal (DSHLs) and SWI‐isointense lesions (SILs), their surrounding periplaque area (PPA) and normal‐appearing white matter (NAWM) were measured in people with MS (pwMS) using the multi‐dynamic multi‐echo (MDME) sequence post‐processing software “SyMRI” at baseline, after 1 and 2 years.

Results: In 15 pwMS, 18 PRLs, 31 DSHLs and 63 SILs were identified; four (26.7%) patients had no PRLs. After 2 years, intralesional T1 relaxation times increased significantly only in SILs (1200.7 (172.6) vs. 1278.6 (245.7), p = 0.002) but not in PRLs and DSHLs (1648.6 (402.1) vs. 1810.2 (564.6), p = 0.154; 1532.5 (402.1) vs. 1741.4 (328.1), p = 0.086, respectively). In the PPA, significantly shorter T1 relaxation times were observed for both DSHLs (790.8 (83.2) vs. 767.9 (45.9), p = 0.012) and SILs (747.5 (45.7) vs. 730.6 (51.2), p = 0.007) but not for PRLs (786.7 (52.9) vs. 795.2 (30.3), p = 0.591). Patients with PRLs also showed no shortened T1 relaxation times in the NAWM (685.0 (46.0) vs. 690.7 (18.5), p = 0.830) in contrast to patients without PRLs (676.1 (42.9) vs. 643.3 (19.4), p < 0.001).

Longitudinal changes in PRLs, DSHLs and SILs, their surrounding PPA and NAWM.

Conclusion: Significantly shorter T1 relaxation times in DSHL PPA and SIL PPA, but not in PRL PPA after 2 years may again point to remyelination failure in and around PRLs. T1‐quantification based on MDME in and around lesions may become a useful and applicable routine marker for silent progression in pwMS.

Disclosure: The project is supported by the Multiple Sklerose Forschungsgesellschaft.

OPR‐042

CVS, CL and PRL for the diagnostic and prognostic workup of MS

S. Borrelli ¹; M. Martire²; A. Stölting¹; C. Vanden Bulcke¹; E. Pedrini²; F. Guisset¹; C. Bugli³; H. Yildiz⁴; L. Pothen⁴; S. Elands⁵; V. Martinelli²; B. Smith⁶; S. Jacobson⁶; R. Du Pasquier⁷; V. van Pesch⁸; M. Filippi²; D. Reich⁶; M. Absinta²; P. Maggi¹

¹Neuroinflammation Imaging Lab (NIL), Institute of NeuroScience, Université catholique de Louvain, Brussels, Belgium; ²Vita‐Salute San Raffaele University, Milan, Italy; ³Plateforme technologique de Support en Méthodologie et Calcul Statistique, Université catholique de Louvain, Brussels, Belgium; ⁴Department of Internal Medicine and Infectious Diseases, Cliniques Universitaires Saint‐Luc, Université catholique de Louvain, Brussels, Belgium; ⁵Department of Neurology, Hôpital Erasme, Hôpital Universitaire de Bruxelles, Université libre de Bruxelles, Brussels, Belgium; ⁶National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, MD, USA; ⁷Neurology Service, Department of Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland; ⁸Department of Neurology, Cliniques Universitaires Saint‐Luc, Université catholique de Louvain, Brussels, Belgium

Background and aims: The diagnosis of multiple sclerosis (MS) can be challenging in clinical practice. We evaluated the diagnostic performance, alone or in combination, of the central vein sign (CVS), cortical lesions (CL), and paramagnetic rim lesions (PRL), as well as their association with clinical outcomes.

Methods: This multicenter study included: (1) a cross‐sectional analysis of CVS (proportion of CVS‐positive lesions, or simplified determination of CVS in three/six lesions ‐ Select3*/Select6*), CL, and PRL in 185 MS/100 non‐MS cases on 3T‐MRI‐brain images, including 3D T2‐FLAIR, T2*‐EPI magnitude and phase, DIR, and MPRAGE; (2) a longitudinal analysis in 61 MS cases of progression independent of relapse and MRI activity (PIRA).

Results: The presence of ≥41% CVS‐positive lesions/≥1 CL/≥1 PRL (optimal cut‐offs) had 96%/94%/93% specificity, 97%/80%/60% sensitivity, and 0.99/0.88/0.77 area under the curve (AUC), respectively, to distinguish MS from non‐MS cases. Select3*/Select6* showed 93%/95% specificity, 97%/89% sensitivity, and 0.95/0.92 AUC. The combination of CVS, CL, and PRL improved the diagnostic performance, especially when Select3*/Select6* were used (93%/93% specificity, 98%/97% sensitivity, 0.99/0.98 AUC; p = 0.002/p < 0.001). Both CL and PRL were associated with higher MS disability and severity. After 2 years follow‐up, cases with >4 PRL at baseline were more likely to experience PIRA (OR 17.8, 95% CI: 2.2–144.7; p = 0.007), whereas no association was observed between other MRI measures and PIRA, including the number of CL.

Conclusion: The combination of CVS, CL, and PRL can improve MS differential diagnosis. CL and PRL also correlate with clinical measures of poor prognosis, with PRL being a predictor of PIRA.

Disclosure: S. Borrelli is supported by the Funds Claire Fauconnier, Ginette Kryksztein & José and Marie Philippart‐Hoffelt, managed by the King Baudouin Foundation. A. Stölting has the financial support of the Fédération Wallonie Bruxelles ‐ Fonds Spéciaux de Recherche (F.S.R.). C. Vanden Bulcke has the financial support of the Fédération Wallonie Bruxelles ‐ Fonds Spéciaux de Recherche (F.S.R.). D.S. Reich is supported by the intramural Research Program of NIH/NINDS. M. Absinta is supported by research grants from the Conrad N. Hilton Foundation (Marylin Hilton Bridging Award for Physician‐Scientists, grant #17313), the International Progressive MS alliance (21NS037), the Roche Foundation for Independent Research, the Cariplo Foundation (grant #1677), the FRRB Early Career Award (grant #1750327), and the National MS Society (NMSS RFA‐2203‐39,325). P. Maggi research activity is supported by the Fondation Charcot Stichting Research Fund 2023, the Fund for Scientific Research (F.R.S, FNRS; grant #40008331), Cliniques universitaires Saint‐Luc “Fonds de Recherche Clinique” and Biogen.

OPR‐043

Neuron‐specific Enolase in Status Epilepticus versus Generalized Periodic Discharges after cardiac Arrest (NEXT‐CAT)

Morotti Colleoni ¹; M. Pozzi²; S. Tagliabue¹; E. Bianchi³; M. Normanno¹; F. Pasini¹; G. Cereda¹; A. Giglio¹; A. Stabile¹; G. Pederzoli¹; S. Diamanti¹; J. Di Francesco¹; L. Stanzani¹; A. Coppo²; L. Avalli²; C. Ferrarese¹; G. Foti²; S. Beretta¹

¹Department of Neurology, Fondazione IRCCS San Gerardo dei Tintori, University of Milano‐Bicocca, Monza, Italy; ²Department of Intensive Care, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy; ³Mario Negri Institute for Pharmacological Research IRCCS, Milano, Italy

Background and aims: The aim of our study was to analyse the distribution of NSE levels according to specific EEG patterns in post‐cardiac arrest patients.

Methods: We conducted a prospective cohort study in patients after cardiac arrest admitted to the ICU, with at least one NSE value between 24 and 72 hours and at least one off‐sedation EEG within 72 hours after cardiac arrest. Subjects were categorized in four independent EEG patterns (benign, epileptiform non‐GPDs, GPDs, malignant non‐epileptiform). Kruskal‐Wallis test and Mann–Whitney tests were used to compare the NSE levels distribution among the four EEG patterns and in GPDs versus epileptiform non‐GPDs patterns.

Results: We recruited 341 patients from 2011 to 2023. A benign EEG pattern was observed in 161 (47%), an epileptiform pattern in 84 (25%), GPDs in 43 (13%) and a malignant pattern in 53 (15%). The median NSE level were 34 ng/mL for the benign EEG pattern, 45.8 ng/mL for the epileptiform pattern, 144 ng/mL for GPDs and 320.8 ng/mL for the malignant one. The distribution of NSE levels was statistically different among the four EEG patterns (H = 152.4, p < 0.0001). NSE levels were approximately 100 ng/mL higher in patients with a GPDs pattern, compared to an epileptiform non‐GPDs pattern (absolute difference 98.2 ng/mL, 95% CI 66.2–126.7; p < 0.0001).

The NSE levels distribution among the four EEG patterns.

Conclusion: The level of the prognostic biomarker NSE is higher in patients after cardiac arrest with GPDs compared to epileptiform activity. A more aggressive therapeutic approach could be justified for patients with epileptiform non‐GPDs activity after cardiac arrest.

Disclosure: Nothing to disclose.

OPR‐044

Electroencephalographic and epileptological natural history in metachromatic leukodystrophy: A longitudinal study

G. Cutillo ¹; G. Fanelli¹; A. Zambon¹; M. Vabanesi¹; G. Cecchetti¹; A. Bellini¹; S. Recupero³; M. Sarzana³; F. Ciotti³; U. Del Carro¹; M. Natali Sora¹; C. Baldoli²; A. Aiuti³; F. Fumagalli³; M. Filippi¹

¹Neurology Unit and Neurophysiology Service, IRCCS Ospedale San Raffaele, Milan, Italy; ²Neuroradiology Unit, IRCCS Ospedale San Raffaele, Milan, Italy; ³Pediatric Immunohematology Unit and BMT Program, IRCCS San Raffaele Scientific Institute, Milan, Italy

Background and aims: Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by mutations in the ARSA gene. Few data are available on its epileptological history.

Methods: Single‐center, retrospective and prospective observational study on MLD patients enrolled in a natural history protocol (January 2000–December 2023). Data including clinical histories, EEG tracings, MRI evaluations and functional scales were collected.

Results: Fifty patients, 25 late infantile (LI), 12 early juvenile (EJ), 7 late juvenile (LJ), 6 adult‐onset (AD), were included. Median follow‐up was 4 years (IQR: 2–8; range: 1–20), with 360 EEG tracings. Epilepsy was documented in 76% (38/50) of patients: 80% (20/25) of LI, 100% (13/13) of EJ, 50% of AD (3/6) and 43% of LJ (3/7). Epilepsy occurred on average 30 months after disease onset in LI, 35 months in EJ, 108 months in LJ and 109 months in AD. Main seizure types reported were focal and focal‐to‐bilateral tonic–clonic seizures, often drug‐resistant. Status epilepticus was reported in 34% (13/38) of patients, coinciding with epilepsy onset in 4/38. Disease subtypes presented distinct EEG patterns: LI presented rapid background deterioration, frequent seizures, and low‐voltage rapid activity bursts. Among Juvenile‐onset patients, divergent patterns were observed, with EJ having more similarities with LI group and LJ displaying a slower progression. AD presented disorganized backgrounds with sporadic focal anomalies.

Baseline features and demographics of the patients included in the analysis, recapitulating the results section.

Conclusion: Epilepsy represent a significant comorbidity in MLD, especially LI and EJ groups, often presenting with drug‐resistant seizures. MLD subtypes present different EEG evolution, hence this could represent a tool to further characterize patients, disease progression and treatment response.

Illustrative EEG epochs of four patients in advanced diseases stages. A (LI), B (EJ), C (LJ), D (AD). Different subtype shows different degrees of background disorganization and focal anomalies.

Disclosure: The study was supported by Telethon Foundation, IRCCS San Raffaele Scientific Institute, GlaxoSmithKline (GSK), and Orchard Therapeutics. The authors have no relevant disclosure related to the present work.

OPR‐045

EpilepsyPOWER a project to favor inclusion of people with epilepsy in workplaces

F. Narducci ¹; G. Baker²; D. Walsh³; N. Casalino⁴; B. Borin⁴; F. Pigni⁵; S. Louissi⁵; M. Kateva⁶; S. Duttenhöfer⁷; M. Tombini¹; V. Di Lazzaro¹; G. Assenza¹

¹Campus Bio‐Medico University, Department of Medicine and Surgery, Unit of Neurology, Neurophysiology, Neurobiology and Psichiatry, Rome, Italy; ²University of Liverpool, Department of Molecular and Clinical Pharmacology, Liverpool, UK; ³International Bureau of Epilepsy, Dublin, Ireland; ⁴Luiss Business School, Rome, Italy; ⁵Grenoble Ecole de Management, Grenoble, France; ⁶Chamber of Commerce and Industry Vratsa, Vratsa, Bulgaria; ⁷emcra GmbH, Berlin, Germany

Background and aims: Despite good seizure control, unemployment and underemployment are more common among people with epilepsy (pwE), for several reasons. The EpilepsyPOWER is a European project, involving five Countries (Italy, Bulgaria, France, Ireland, Germany), aimed to improve PwE's workplace inclusion.

Methods: For this project, we made a systematic review on epilepsy and employment, selecting 55 articles from 1958 to 2023, analyzing employment rate and determinants of employment/unemployment. We reviewed legislation in involved countries and developed two anonymous surveys asking for PwE's employment condition, and higher education institutions (HEI) general knowledge and attitudes about epilepsy.

Results: For all considered countries, we have not found any specific job legislation. Unemployment rates ranged from similar to twice or three times the general population and above all factors, seizure control and employers' attitudes contributed mostly to unemployment. We collected 567 answers from PwE and 291 from HEI. Unemployment rates were: 7.9% in Italy, 6.7% Ireland, 8.5% France, 15% Germany, 9% Bulgaria; people fully employed: 42.9% in Italy, 53% Ireland, 31.7% France, 40% Germany, 47.9% Bulgaria. In Italy, 24.2% of pwE did not disclose their condition, whereas in Bulgaria 48.5%. HEI individuals correctly defined epilepsy as a neurological disorder, treatable in most cases. Although most respondents have seen a seizure, in some countries, they did not know how to give first aid.

Conclusion: Exploring pwE work conditions and HEI perspectives could help to spread a culture of inclusion and fight marginalization of pwE in workplaces, allowing them to attain correct employment.

Disclosure: Nothing to disclose.

OPR‐046

An internationally derived core outcome set for adult epilepsy treatment trials: The EPSET Project

J. Mitchell ¹; A. Noble²; P. Williamson²; T. Marson²; EPSET Project Ineternational Working Group³

¹The Walton Centre NHS FT, UK; ²University of Liverpool, UK; ³EPSET Project

Background and aims: A Core Outcome Set (COS) is a standardised list of outcomes that should be reported as a minimum in all trials. In epilepsy, the choice of outcomes measured varies widely among existing studies, particularly in randomised controlled trials (RCTs). We have developed an internationally derived COS specific to adult epilepsy treatment trials.

Methods: We performed a rapid review of the qualitative literature exploring experiences of people with epilepsy and reviewed outcomes already measured in phase 3 and 4 epilepsy specific RCTs, to generate an outcome long‐list. In collaboration with the ILAE Big Data Commission and an international group of healthcare providers, researchers, and people with epilepsy we have performed a grouping and rationalisation process and taken 42 individual outcomes to a two‐stage, online Delphi survey followed by consensus meeting.

Long List of Outcomes for EPSET consensus process.

Results: 490 people with epilepsy, their representatives, healthcare professionals and researchers have completed the Delphi surveys in 7 languages, representing the global perspective. Inconclusive outcomes were discussed, and the final outcomes ratified at international online consensus meeting. The ratified COS includes a minimum set of seizure and non‐seizure outcomes, that should be measured and reported as a minimum in all future clinical trials.

Outcomes achieving consensus for inclusion in the COS after each Delphi round.

Conclusion: The EPSET Project has identified a COS for adults with epilepsy and derived inter‐ national consensus. This will ensure that meaningful outcomes are measured in future clinical trials, that the results of trials are relevant to people with epilepsy and facilitate systematic review and meta‐analysis.

Disclosure: Nothing to disclose related to the submitted work.

OPR‐047

Heart rate variability exhibits a reduced vagal output in patients with status epilepticus developing Tako‐Tsubo

S. De Angelis; P. Quintieri; F. Dono; D. Liviello; S. Cipollone; G. Evangelista; S. Consoli; M. Russo; M. Dasara; F. Anzellotti; S. Sensi

Department of Neurosciences, Imaging and Clinical Sciences, “G. d'Annunzio” University of Chieti‐Pescara, Chieti, Italy

Background and aims: Tako‐tsubo cardiomyopathy (TTC) is an impairment of systolic function, mainly targeting the left ventricle with clinical manifestations closely resembling that of acute coronary syndrome. Although its aetiology has been related to a massive catecholamine release driven by physical and psychological stressors, certain neurologic conditions like status epilepticus (SE) also seem to increase susceptibility to TTC. However, clinical factors linking the SE to TTC are still missing. This study aims to provide reliable criteria to be employed as predictors of TTC in epileptic patients.

Methods: In this study, we examined Heart Rate Variability (HRV) changes in three patients presenting with TTC immediately after an SE. HRV analysis was performed on a 5‐minute EKG recording in resting state during and after SE. HRV variability was evaluated according to time and frequency domains and non‐linear analysis.

Results: During SE, a leaning towards cardiovagal output reduction was observed, as indicated by decreased RMSSD, HF, and SD1. In addition, an increased LF/HF ratio was also observed, an index that correlates with an overall increased risk of mortality. These imbalances tend to attenuate with SE resolution.

Conclusion: Data from our cohort suggest that HRV variations play a role in predicting cardiac dysfunction (and TTC) in epileptic patients. These data support the notion of a distinct undergoing interplay between sympathetic and cholinergic stimuli on myocardial motility in people with epilepsy.

Disclosure: Nothing to disclose.

OPR‐048

Status epilepticus in patients with brain tumors and metastases: A multicenter cohort study of 208 patients

A. Strzelczyk ¹; J. Rickel¹; D. Zeeb²; S. Knake²; H. Urban¹; J. Konczalla¹; K. Weber¹; P. Zeiner¹; A. Pagenstecher²; E. Hattingen¹; A. Kemmling²; E. Fokas¹; S. Adeberg²; R. Wolff¹; M. Sebastian¹; T. Rusch²; M. Ronellenfitsch¹; K. Menzler²; L. Habermehl²; M. Czabanka¹; C. Nimsky²; L. Timmermann²; C. Grefkes¹; J. Steinbach¹; F. Rosenow¹

¹Goethe‐University Frankfurt; ²Philipps‐University Marburg

Background and aims: Brain tumors and metastases account for approximately 10% of all status epilepticus (SE) cases. This study described the clinical characteristics, treatment, and short‐ and long‐term outcomes of this population.

Methods: This retrospective, multi‐center cohort study analyzed all brain tumor patients treated for SE at the university hospitals of Frankfurt and Marburg between 2011 and 2017.

Results: The 208 patients (mean 61.5 ± 14.7 years of age; 51% male) presented with adult‐type diffuse gliomas (55.8%), metastatic entities (25.5%), intracranial extradural tumors (14.4%), or other tumors (4.3%). The radiological criteria for tumor progression were evidenced in 128 (61.5%) patients, while 57 (27.4%) were newly diagnosed with tumor at admission and 113 (54.3%) had refractory SE. The mean hospital length of stay (LOS) was 14.8 days (median 12.0, range 1–57), 171 (82.2%) patients required intensive care (mean LOS 8.9 days, median 5, range 1–46), and 44 (21.2%) were administered mechanical ventilation. All patients exhibited significant functional status decline (modified Rankin Scale) post‐SE at discharge (p < 0.001). Mortality at discharge was 17.3% (n = 36), with the greatest occurring in patients with metastatic disease (26.4%, p = 0.031) and those that met the radiological criteria for tumor progression (25%, p < 0.001).

Conclusion: SE occurrence contributed to a decline in functional status in all cases, regardless of tumor type, tumor progression status, and SE refractoriness, while long‐term mortality was increased in those with malignant tumor entities, tumor progressions, and refractory SE.

Disclosure: Nothing to disclose.

OPR‐049

CAG repeats within non‐pathological range in the HTT gene influence plasma NfL levels in prodromal Alzheimer's disease

C. Crucitti ¹; S. Mazzeo¹; A. Ingannato¹; G. Giacomucci¹; J. Balestrini¹; V. Moschini²; C. Morinelli²; G. Galdo¹; F. Emiliani¹; D. Frigerio¹; D. Piazzesi²; S. Bagnoli¹; S. Padiglioni²; V. Berti³; S. Sorbi¹; V. Bessi¹; B. Nacmias¹

¹Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Italy; ²Research and Innovation Centre for Dementia‐CRIDEM, Azienda Ospedaliero‐Universitaria Careggi, Florence, Italy; ³Department of Biomedical, Experimental and Clinical Sciences “Mario Serio”, University of Florence, Florence, Italy

Background and aims: HTT gene is involved in axon trafficking. It contains a key region of CAG repeats which is responsible, when expanded beyond 39 repeats, of Huntington's disease (HD). Expansions ranging from 27 to 35 are termed as intermediate alleles (IAs). Previous studies showed that increasing repeat length below the HD threshold in HTT confers advantageous changes, stabilizing the interaction with the brain‐derived neurotrophic factor. Moreover, CAG repeats seem to affect cognitive performances of patients with Subjective Cognitive Decline (SCD) and Mild Cognitive Impairment (MCI). Here, we aimed to explore the association between CAG repeats, Alzheimer's Disease (AD) CSF biomarkers and plasma neurofilament light chain (NfL) in patients with SCD and MCI.

Methods: We included 95 patients (36 SCD and 59 MCI) who underwent neuropsychological investigation, plasma NfL analysis, CSF biomarkers analysis, Apolipoprotein E (APOE) and HTT genotype analysis. Patients were classified as prodromal AD if they had at least one positive Aβ biomarker and positive p‐tau, otherwise they were defined as non‐AD.

Results: We tested the association between plasma NfL and CAG repeats: in prodromal AD, this relationship was described by a quadratic model (R ² 0.243, p = 0.009) as the NfL concentration decreases as the CAG repeat number increases up to 26 repeats (confirmed after age, diagnosis and CAG repeat number adjustment). There was no association in non‐AD patients.

Conclusion: The number of CAG repeats, below the IA threshold, may play a role in SCD and MCI modulating the neurodegeneration due to AD, implying the potential of HTT ‘s involvement in the disease's pathophysiology.

Disclosure: Nothing to disclose.

OPR‐050

Sleep and cognition: Insights from sleep microarchitecture

I. Filchenko ¹; A. Eberhard‐Moscicka² ; S. Duss¹; M. Aktan Süzgün¹; C. Bernasconi¹; M. Schmidt¹; C. Bassetti¹

¹Department of Neurology, University Hospital, Inselspital, Bern, Switzerland; ²Department of Psychology, University of Bern, Bern, Switzerland

Background and aims: Sleep plays a pivotal role in cognition [Kong, 2023], however, to date little is known about the link between sleep microarchitecture and different cognitive domains [Qin, 2023]. This exploratory analysis aimed to comprehensively investigate this link.

Methods: The “Sleep and cognitive functioning” study included volunteers in good or excellent health condition (Eastern Cooperative Oncology Group grade of 0–1). Demographics, medical history, sleep architecture by polysomnography (electroencephalography [EEG] was recorded either with 6 electrodes or 256 electrodes [high‐density EEG, hd‐EEG]) and cognition were assessed at study inclusion (Figure 1A). Associations between cognition and sleep microarchitecture were explored using multiple linear regression with adjustment for age and arousal index.

Study design (A) and population (B).

Results: 60 participants were included (median age: 52.7 years old, interquartile range (IQR) [32.9, 64.6]; 55% men; hd‐EEG in 52%; Figure 1B). EEG analysis as based on 6 electrodes or their hd‐EEG equivalents showed limited associations between cognition and sleep microarchitecture (e.g., working and visual memory with high SS density; Figure 2), whereas high‐density EEG analysis identified multiple associations of interest with a distinct topography (e.g., visual memory with high EEG spectral power in beta band involving the right posterior region; Figure 3).

Associations between cognition and sleep microarchitecture (basic analysis).

Selected associations between cognition and sleep microarchitecture (topographic analysis).

Conclusion: While these results confirm previous findings, they also expand our understanding about the link between sleep microarchitecture and cognition by providing valuable insights for the involvement of specific cortical regions. This knowledge may serve as a basis for targeted interventions to improve sleep‐related cognitive function.

Disclosure: European Stroke Research foundation 2021.

OPR‐051

Neurotransmitters circuitry dysfunction in the Alzheimer's disease continuum

L. Argenti ¹; M. Losa¹; L. Lombardo¹; E. Peira²; S. Raffa³; G. Sambuceti³; F. Massa¹; S. Garbarino⁴; D. Arnaldi⁵; S. Morbelli⁶; A. Chincarini²; B. Orso¹; M. Pardini¹

¹Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy; ²Istituto Nazionale di Fisica Nucleare (INFN), Genoa, Italy; ³Department of Health Science (DISSAL), University of Genoa, Genoa Italy; ⁴Life Science Computational Laboratory, IRCCS Ospedale Policlinico San Martino, Genova, Italy; ⁵Neurophysiopatology Unit, IRCCS Ospedale Policlinico S. Martino, Genoa, Italy; ⁶Nuclear Medicine Unit, AOU Città Della Salute e Della Scienza di Torino, Turin, Italy

Background and aims: The modulation of neurotransmitters circuitry in Alzheimer's disease (AD) holds promise as a potential focus for pharmacological intervention. We aimed to study the progression of neurotransmitter's networks dysfunction associated to the accumulation of misfolded proteins throughout the AD continuum.

Methods: We enrolled 90 AD patients (72.8 ± 7.02 yo) and 42 Healthy Controls (HC, 70 ± 8.53 yo). All patients had a brain [18F]FDG‐PET scan and MMSE available. As amyloidosis biomarker, 50 patients performed CSF exam and 40 an amyloid‐PET. Patients were divided in two groups based on MMSE score (MMSE <24, n = 24; MMSE ≥24, n = 66) to study different disease stages. We performed a voxel‐based analysis between AD patients and HC: in the whole group, in MMSE <24 and MMSE ≥24 groups, separately. Using JuSpace toolbox we explored the correlation between [18F]FDG‐PET images and PET maps of glutamate (mGluR5), GABA (GABA‐a), dopamine (D1, D2, FDOPA), serotonin (SERT, 5HT1a, 5HT1b, 5HT2a, 5HT4), noradrenaline (NAT) and choline (VAChT).

Results: In the whole AD group, the distribution of brain hypometabolism was associated with areas of 5HT2a and mGluR5 density (p = 0.029, p = 0.034 respectively). This remained significant in the MMSE <24 group (p = 0.006). In the whole group, 5HT2a density correlates with a lower MMSE score and greater cerebral amyloid burden.

Conclusion: The spatial pattern of brain hypometabolism in AD is related to the distribution of specific neurotransmitters. We can speculate that areas with elevated expression of receptors involved may be more susceptible to synaptic damage, as evidenced by brain hypometabolism.

Disclosure: Nothing to disclose.

OPR‐052

Universal prevention of dementia in Italy: A document analysis of the 21 Italian Regional Prevention Plans

S. Salemme ¹; D. Marconi²; S. Pani³; V. Casigliani⁴; A. Ancidoni⁵; G. Zamboni⁶; G. Lazzeri²; N. Vanacore⁵; G. Bellomo⁵

¹School of Advanced Studies, University of Camerino, Camerino, Italy; ²Post Graduate School of Public Health, University of Siena, Siena, Italy, Siena, Italy; ³University of Cagliari, Cagliari, Italy; ⁴University of Pisa, Pisa, Italy; ⁵National Center for Disease Prevention and Health Promotion, National Institute of Health, Rome, Italy; ⁶Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy

Background and aims: An estimated 40% of dementia cases could be prevented through interventions targeting 12 modifiable risk factors (RFs) at different stages of life. We characterized the subnational population approaches to the prevention of dementia implemented in Italy.

Methods: We conducted a document analysis of the 21 Regional Prevention Plans (RPPs) for 2020–2025. We categorized the dementia‐specific preventive interventions according to (i) type of RF targeted, (ii) target age, and (iii) target population. Indirect potential beneficial effects of interventions were defined by critically reviewing published literature on plausible relationships between RFs. Furthermore, we developed and applied to all RPPs a checklist evaluating key elements of situational analysis and prevention planning.

Results: Physical inactivity was the only RF covered by all RPPs, as a direct target of 117/248 interventions for dementia prevention. Smoking was targeted in more than 50% of RPPs, while less than 50% covered alcohol consumption and obesity. Only 25% of RPPs had dementia‐specific interventions for social isolation, hypertension, and diabetes. Two RPPs targeted air pollution and only one TBI. No RPP directly covered low education, depression or hearing loss for dementia prevention. Total scores of the checklist ranged from a minimum score of 7 to a maximum of 28/63.

TABLE 1 Subnational coverage of potentially modifiable risk factors for cognitive decline.

Sankey Chart of the dementia‐specific preventive interventions.

Checklist scores by RPP.

Conclusion: While interventions on cardiovascular RFs can synergistically affect multiple noncommunicable diseases, their prevalence may suggest that policymakers are not fully aware of RFs more specific to dementia (e.g., social isolation and hearing loss). Therefore, policymakers, public health workers, and dementia experts should closely cooperate for the development of these policies.

Disclosure: Nothing to disclose.

OPR‐053

Neuromodulation of the mediodorsal nucleus during MRgFUS thalamotomy demonstrates a causal role in reward learning

W. Gilmour¹; G. Mackenzie¹; I. Barnard¹; J. Macfarlane²; S. Khan³; A. Kanodia⁴; M. Canty⁵; T. Littlechild⁵; V. Marshall⁵; E. Newman⁵; J. Farah⁶; M. Radon⁶; A. Marcerollo⁶; D. Steele¹; T. Gilbertson ¹

¹Division of Imaging Science and Technology, Ninewells Hospital & Medical School, University of Dundee, Dundee, UK; ²Medical Physics, Ninewells Hospital & Medical School, Dundee, UK; ³Department of Neurosurgery, Edinburgh Royal Infirmary, Edinburgh, UK; ⁴Department of Radiology, Ninewells Hospital & Medical School, Dundee, UK; ⁵Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK; ⁶The Walton Centre NHS Foundation Trust for Neurology and Neurosurgery, Liverpool, UK

Background and aims: Evidence from basic neuroscience increasingly supports a specific role for the Medial Dorsal (MD) thalamic nucleus influencing decisions that guide reward‐based learning. As common clinical syndromes of impulsivity, apathy and executive dysfunction can be explained by abnormal reward‐learning across multiple clinical groups. Neuromodulation target MD nucleus may represent a potential future therapeutic intervention for disorders of cognitive control.

Methods: Thirty‐five patient's undergoing MRgFUS thalamotomy for Essential Tremor targeted at ventral intermediate nucleus (Vim) performed pre‐and post‐operative (<24 hours) cognitive testing using the 4‐armed restless bandit task. Outcome measures of task performance included probability of choosing the most rewarding bandit (Prew) and choice perseveration (Pstay). In 23 patients, post‐operative masks of (< 24 hours) oedema extension into the MD nucleus were used to analyse the relationship with cortical functional connectivity and it's influence on decision making.

FIGURE 1 Restless bandit reinforcement learning task. (A) example of fluctuating reward payout for each of the four bandits in the task (B) example trial with screenshots of computer graphics.

Results: Post‐thalamotomy, patients used a greater proportion of perseverative choices (Pstay) pre: 0.67 ± 0.07, post: 0.75 ± 0.0.05, rmANOVA, F = 11.05, p < 0.001). Task performance indexed by choices to the best bandit (Prew) was unaffected by thalamotomy (rmANOVA, F = 3.02, p = 0.07). Cortical functional connectivity with thalamotomy oedema extension into the MD nucleus predicted the extent to which the thalamotomy increased Pstay in individual patients (rho = 0.64, p = 0.001).

FIGURE 1 Behavioural effects of thalamotomy on task performance. Analysis binned into six‐ 50 trial blocks (A) probability of choosing the highest value bandit (B) Probability of choosing the same bandit on two consecutive trials (Pstay).

FIGURE 3 (A) Probabalistic analysis of overlap between thalamotomy (n = 23) oedema (heatmap) with the medialdorsal thalamic nucleus (grey overlay) onto standard brain template in MNI space. (B) R map correlation and (B) cortical connectivity map.

Conclusion: MRgFUS thalamotomy can be used as an opportunity to study cognitive thalamic nuclear function. An experimental design for intra‐operative thermal neuromodulation is proposed to causally map the different contributions of the thalamic nuclei to cognitive control.

Disclosure: TG has received honoraria from GE Healthcare Europe. AM has received research funding from Boston scientific, Medtronic and Insightec.

OPR‐054

Substantia Nigra and subthalamic nucleus deep brain stimulation for freezing of gait in Parkinson's disease

C. Ledda ¹; C. Artusi¹; S. Gallo²; D. Rinaldi³; C. Campisi¹; V. Rousseau⁴; C. Thalamas⁵; R. Barbosa⁵; F. Ory‐Magne⁵ ; C. Brefel‐Courbon⁵ ; O. Rascol⁶; A. de Barros⁷; E. Harroch⁶; M. Zibetti¹; M. Rizzone¹; A. Romagnolo¹; G. Imbalzano¹; L. Lopiano¹; J. Houeto⁸; M. Fabbri⁶

¹Department of Neurosciences Rita Levi Montalcini, University of Turin, Turin, Italy; ²Neurology Unit, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy; ³Department of Neuroscience, Mental Health and Sense Organs (NESMOS), Sapienza University of Rome, Rome, Italy; ⁴Service de Pharmacologie Médicale et Clinique, Centre Hospitalier Universitaire et Faculté de Médecine de Toulouse, Toulouse, France; ⁵Service de Neurologie, Centre Hospitalier Universitaire, Toulouse, France; ⁶Centre Expert Parkinson de Toulouse, CHU, Toulouse, France; ⁷Department of Neurosurgery, Toulouse University Hospital, Toulouse, France; ⁸Department of Neurology, NS‐Park/F‐CRIN network, Limoges University Hospital; Inserm, U1094, EpiMaCT ‐ Epidemiology of chronic diseases in tropical zone, Limoges, France

Background and aims: Freezing of gait (FoG) is a debilitating symptom of Parkinson's disease (PD) with limited response to dopaminergic medication and subthalamic deep brain stimulation (STN‐DBS). Substantia nigra pars reticulata (SNr) stimulation could improve FoG.

Methods: Two double‐blind, cross‐over, randomized trials, following an identical protocol were conducted involving STN‐DBS treated PD patients with severe FoG. Participants received: standard high frequency (HF) STN‐DBS (S), combined HF‐STN and SNr stimulation (C1), and combined HF‐STN and low‐frequency SNr stimulation (C2), for 1 month each in a randomized order. The primary endpoint was the change in the New Freezing of Gait Questionnaire (NFOG‐Q) score. Secondary analyses were performed on motor complications, axial symptoms, activities of daily living, psychiatric symptoms, sleep, and patient preference.

Stimulation method for S, C1, C2.

Results: Fifteen patients received at least one combined stimulation. No statistically significant difference in NFOG‐Q scores was found between S, C1, and C2; one‐third of patients showed a clinically significant improvement (≥8 points) with combined stimulations. Motor complications improved significantly with C1 and C2 compared to S (C1 vs. S: 3.6 ± 3.8 vs. 4.9 ± 3.8, p = 0.046; C2 vs. S: 2.7 ± 3.1 vs. 4.9 ± 3.8, p = 0.005). At the end of the study, 80% of patients chose combined STN‐SNr stimulation. All adverse events were manageable.

Scores after one moth of the following stimulation setting: C1, C2, and S.

VTA of the STN and of the SNr for all patient included in the study in the stimulation setting C1/C2.

Conclusion: Our study did not show a statistically significant improvement in NFOG‐Q, but one‐third of patients experienced a clinically meaningful FoG improvement. Moreover, SNr stimulation was both safe and effective in addressing motor complications., highlighting the importance of further exploration into the effects of combined STN‐SNr stimulation.

Disclosure: Nothing to disclose.

OPR‐055

Effectiveness and safety of levodopa‐entacapone‐carbidopa infusion in Parkinson's disease. A real‐world data study

D. Santos‐García ¹ ; L. López‐Manzanares² ; I. Muro²; P. Lorenzo²; R. García‐Ramos³ ; C. Morata‐Martínez⁴ ; R. Baviera‐Muñoz⁴ ; I. Martínez‐Torres⁴ ; M. Álvarez‐Sauco⁵ ; J. Suárez‐Muñoz⁶ ; J. Martínez‐Castrillo⁷ ; A. Perona⁸; J. Salom⁹; I. Legarda¹⁰; M. Valero‐García¹⁰ ; E. Cubo¹¹; N. López‐Ariztegui¹² ; D. Alonso‐Modino¹³ ; R. Espinosa¹⁴; M. Mata¹⁵

¹CHUAC (Complejo Hospitalario Universitario de A Coruña), A Coruña, Spain; ²Hospital Universitario La Princesa, Madrid, Spain; ³Hospital Clínico Universitario San Carlos, Madrid, Spain; ⁴Hospital Universitario la Fe, Valencia, Spain; ⁵Hospital General Universitario de Elche, Spain; ⁶Hospital Dr. Negrín, Las Palmas de Gran Canaria, Spain; ⁷Hospital Universitario Ramón y Cajal, Madrid, Spain; ⁸Complejo Hospitalario Universitario de Albacete, Spain; ⁹Hospital Clínico Universitario de Valencia, Spain; ¹⁰Hospital Universitario Son Espases, Palma de Mallorca, Spain; ¹¹Hospital Universitario de Burgos, Spain; ¹²Hospital Universitario de Toledo, Spain; ¹³Hospital Universitario de la Candelaria, Santa Cruz de Tenerife, Spain; ¹⁴Hospital Universitario de Jerez, Spain; ¹⁵Hospital Infanta Sofía, Madrid, Spain

Background and aims: Levodopa‐entacapone‐carbidopa intestinal gel (LECIG) infusion is a recently developed device‐aided therapy for advanced Parkinson's disease (PD) patients. Our aim was to present real world data (RWD) about the use of LECIG in PD patients from Spain.

Methods: A multicenter observational retrospective study of the first patients to start LECIG in Spain was performed. All neurologists with an experience of at least 2 patients treated until November 1, 2023 were invited to participate. RWD about effectiveness and safety from the medical records (V0, pre‐LECIG; V1, LECIG starting; V2, post‐LECIG follow‐up) with a total of 246 variables was collected.

Results: Fifty‐one PD patients (58.8% males; 69.7 ± 9.7 years old) from 15 Spanish centers with a mean disease duration of 13.8 ± 6.2 years were included (Table 1). Fourteen patients (27.5%) were switched directly from levodopa‐carbidopa intestinal gel. The mean treatment duration was 140.7 ± 83.7 days (range, 10–302). The mean daily OFF time decreased from 5.1 ± 3 at baseline (pre‐LECIG) to 1.9 ± 1.6 (post‐LECIG) (N = 45; p < 0.0001). Global improvement was observed in more than 85% of the patients (Figure 1). No significant change was detected in the levodopa equivalent daily dose from V0 to V2 (Figure 2). Only 2 patients (3.9%) received 24‐hour infusion and 11 (21.6%) required more than 1 cartridge per day. Eighteen patients (35.3%) had at least one adverse event related to LECIG and/or the device system. Three patients (5.9%) discontinued LECIG (Table 2).

TABLE 1 Data about sociodemographic aspects, comorbidities, antiparkinsonian drugs and other therapies at baseline (V0) and LECIG starting at V1.

TABLE 2 Adverse events collected by the neurologist in patients receiving LECIG from V1 (starting LECIG) to V2 (follow‐up visit; 140.7 ± 83.7 days, range from 10 to 302).

Conclusion: LECIG was safe and effective in advanced PD patients.

Disclosure: The authors report no conflict of interest.

OPR‐056

sGFAP – A potential biomarker for disease activity in essential tremor?

L. Gattermeyer‐Kell ; M. Khalil; P. Opriessnig; D. Kern; S. Franthal; M. Kögl; P. Katschnig‐Winter; R. Schmidt; C. Enzinger; P. Schwingenschuh

Department of Neurology, Medical University of Graz, Graz, Austria

Background and aims: Essential tremor (ET) constitutes a heterogeneous syndrome and possible neurodegeneration has been debated. We recently linked serum‐NfL to cognitive decline in ET‐patients with short disease duration (DD). Serum‐glial fibrillary acidic protein (sGFAP) hitherto remains unstudied in ET.

Methods: Data from 36 ET‐patients and 36 age, sex and body‐mass‐index‐matched healthy controls were analyzed. sGFAP was quantified by single‐molecule‐array in baseline (BL) and follow‐up (FU; 5 years) blood samples. ET‐patients underwent clinical evaluation (Fahn‐Tolosa‐Marin‐Tremor‐Clinical‐Rating‐Scale‐Total‐Score, FTM‐TS).

Results: BL and FU sGFAP did not differ between groups. In ET‐patients, low BL FTM‐TS was associated with higher sGFAP‐increase during the observational period (rs = −0.551, p = 0.002). Shorter DD correlated with low BL FTM‐TS and trended towards higher sGFAP‐increase (rs = −0.344, p = 0.068). Stratification in DD below/above median (10.7 years) showed higher sGFAP‐increase in short DD patients (39.6 vs. 12.6 pg/mL, p = 0.020). In short DD patients, high BL sGFAP correlated with high FU FTM‐TS (rs = 0.672, p = 0.006) and FTM‐TS‐increase (rs = 0.590, p = 0.021). Stratification of ET‐patients according to sGFAP‐level below/above median (124.2 pg/mL) revealed that high sGFAP‐patients were older at BL (70.0 vs. 60.7 years, p < 0.001) and disease onset (62.6 vs. 49.9 years, p < 0.001) than low sGFAP‐patients. Annual sGFAP‐increase correlated with annual FTM‐TS‐increase in the high (rs = 0.587, p = 0.027) but not in the low sGFAP‐group. In patients with high sGFAP and short DD (n = 8), annual sGFAP‐increase correlated with annual FTM‐TS‐increase (rs = 0.738, p = 0.037).

Conclusion: This study shows elevated sGFAP in elderly, late‐onset ET‐patients. sGFAP‐increase is higher in earlier vs. later disease stages and correlates with worsening motor function, suggesting sGFAP as a possible biomarker of ET disease activity.

Disclosure: Nothing to disclose.

OPR‐057

Modelling pathology progression in Parkinson's disease phenotypes

M. Passaretti ¹; H. Zhao²; M. Mijalkov¹; B. Zufiria Gerboles¹; A. Canal Garcia¹; J. Sun¹; D. Vereb¹; N. Rivera³; G. Volpe²; M. Bologna⁴; J. Pereira¹

¹Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden; ²University of Gothenburg, Department of Physics, Soft Matter Lab, Gothenburg, Sweden; ³Department of Medicine Solna, Respiratory Medicine Division, Karolinska Institutet, Stockholm, Sweden; ⁴Sapienza University of Rome, Department of Human Neurosciences, Rome, Italy

Background and aims: Understanding the relationship between phenotypic heterogeneity and the spread of pathology in Parkinson's disease (PD) is challenging. The α‐Synuclein Origin site and Connectome (SOC) model postulate that α‐synuclein aggregation first localization and spreading determine disease evolution. Accordingly, two PD subtypes were proposed: brain‐first‐PD, from central nervous system, and body‐first‐PD, from peripheral nervous structures. We aim to use the SOC model to differentiate PD phenotypes predicting disease progression.

Methods: 1120 de novo‐ PD patients, 910 prodromal‐cases, and 263 healthy controls were included from the Parkinson's progression markers initiative. Patients and prodromal‐cases with REM behavior disorder and/or autonomic symptoms at baseline were classified as body‐first, otherwise as brain‐first. All subjects underwent longitudinal (12‐years) clinical protocol and magnetic resonance imaging.

Results: Body‐first‐PD (667) demonstrated higher motor burden and complications, worse cognitive evolution, and more severe depression compared to brain‐first‐PD. Body‐first‐PD showed bilateral medial and lateral temporal atrophy (amygdala, para‐hippocampus, temporoparietal junction), cerebellum and brainstem. Brain‐first‐PD patients demonstrated circumscribed atrophy of the left hemisphere (angular gyrus, sensory‐motor cortex, inferior frontal gyrus). Body‐first‐prodromal‐cases (519) demonstrated similar results to body‐first‐PD, i.e. greater motor and cognitive impairment, involving the same domains, and grey matter atrophy in lateral temporal areas.

Conclusion: Consistent with the SOC model, the study results indicate that body‐first‐PD and prodromal‐cases had worse disease progression and more severe brain atrophy compared to brain‐first. The results underscore the importance of PD patient phenotyping since the prodromal phases. Hence, the application of the model would enable tailored therapeutic approaches and disease prevention interventions in high‐risk individuals.

Disclosure: Nothing to declare.

OPR‐058

Thoracic spinal cord stimulation may improve bradykinesia and rigidity in gait impaired Parkinson's disease

M. Højholt Terkelsen ¹; V. Hvingelby¹; E. Johnsen²; M. Møller²; E. Hvid Danielsen²; T. Henriksen³; A. Nørgaard Glud⁴; Y. Tai⁵; A. Møller Andersen⁴; A. Knudsen⁴; K. Meier⁴; P. Borghammer¹; E. Moro⁶; J. Hedemann Sørensen⁴; N. Pavese¹

¹Department of Clinical Medicine — Department of Nuclear Medicine and PET Center, Aarhus University, Aarhus, Denmark; ²Department of Neurology, Aarhus University Hospital, Aarhus, Denmark; ³Department of Neurology, Bispebjerg Hospital, Copenhagen, Denmark; ⁴Department of Neurosurgery, Aarhus University Hospital, Aarhus, Denmark; ⁵Department of Neurosciences, Imperial College Healthcare NHS Trust, London, UK; ⁶Grenoble Alpes University, CHU of Grenoble, Division of Neurology, Grenoble Institute of Neuroscience, Grenoble, France

Background and aims: Gait impairment in Parkinson's disease (PD) is debilitating and often resistant to available therapies. Recently, spinal cord stimulation (SCS) has been suggested to be effective. Nevertheless, existing literature on SCS for gait problems is limited and possible mechanisms of action remain to be elucidated. This study is part of the SCS therapy for patients with PD and gait problems (STEP‐PD) trial (ClinicalTrials.gov: NCT05110053), and here we aim to evaluate the effect on lower body motor symptoms and gait.

Methods: Fourteen non‐demented PD patients with gait impairment were included in the trial. The Movement Disorder Society‐Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) was assessed before surgery and at 6‐ and 12‐month follow‐ups. Total motor score, lower body and gait (LBG) subscore, and the sum of lower body bradykinesia and rigidity items (Table 1) were compared using paired t‐test. Mean differences with 95% confidence intervals are presented.

TABLE 1 Details of the Movement Disorder Society‐Unified Parkinson Disease Rating Scale (MDS‐UPDRS) scores presented. LBG, lower body gait.

Results: Thirteen patients were treated with active SCS for 6 months and eight patients were treated for 1 year. While the total motor score improved slightly after both 6 months (−2.85 points [−7.07;1.38]) and 12 months (−5.63 points [−14.03;2.78]), the LBG subscore improved by −3.38 points (−4.83;‐1.93), p = 0.0003, after 6 months and −5.25 points (−8.93;‐1.57), p = 0.0118, after 12 months. Furthermore, lower body bradykinesia and rigidity improved by −2.31 points (−3.75; −0.86), p = 0.0046, after 6 months and −3.88 points (−7.17; −0.58), p = 0.027, after 12 months.

Conclusion: SCS may ameliorate lower body bradykinesia and rigidity in gait‐impaired PD patients. Furthermore, our results suggest that extended treatment duration could yield a greater improvement.

Disclosure: KM's institution (Aarhus University Hospital) has received travel support from Boston Scientific.

OPR‐059

Role of brain 2‐[18F]FDG‐PET for the differential diagnosis between ALS and ALS‐mimics

G. Zocco ¹; A. Martino²; A. Giuliani³; C. Moglia¹; R. Vasta¹; M. Grassano¹; S. Cabras¹; F. Di Pede¹; P. Salamone¹; G. Marchese¹; F. Casale¹; G. Polverari⁴; U. Manera¹; M. Pagani⁵; A. Calvo¹; A. Chiò¹; A. Canosa¹

¹ALS Centre, ‘Rita Levi Montalcini’ Department of Neuroscience, University of Turin, Turin, Italy; ²Department of Business and Management, LUISS University, Rome, Italy; ³Environment and Health Department, Istituto Superiore di Sanità, Rome, Italy; ⁴Positron Emission Tomography Centre AFFIDEA‐IRMET S.p.A., Turin, Italy; ⁵Institute of Cognitive Sciences and Technologies, C.N.R., Rome, Italy

Background and aims: The combination of brain and spinal cord 2‐[18F]FDG‐PET has shown a 81.5% accuracy in discriminating ALS and ALS‐mimics in a published study. We investigated the potential role of brain 2‐[18F]FDG‐PET as a single marker to discriminate ALS and ALS‐mimics.

Methods: Our dataset included 663 ALS cases and 40 patients referred for suspected ALS but for whom an alternative diagnosis was made (ALS‐mimics) who underwent brain 2‐[18F]FDG‐PET at diagnosis at the ALS Centre of Turin between 2009 and 2019. We randomly collected 40 ALS cases and calculated Laplacian scores in this group. This is an algorithm for the selection of features, which correspond to the voxels. It constructs a nearest neighbour graph. Laplacian score seeks those features that respect this graph structure. We retained the top features and performed feature extraction form the two groups (ALS and mimics). Then, we randomly split the sample composed of ALS and mimics in a training set (80%) and a test set (20%). The training set was used to train the classifier (Support Vector Machine) and the test set was used to evaluate the performance of the model. The procedure was randomly repeated 10 times for internal validation.

Results: SVM showed 85% specificity and 81% sensitivity on the test set, with an error rate of 17%. The classification was based on three cerebellar clusters, situated in left anterior lobe, right uvula and right culmen.

Conclusion: Our data support the possible role of brain 2‐[18F]FDG‐PET as a single diagnostic marker to discriminate ALS and ALS‐mimics.

Disclosure: Nothing to disclose.

OPR‐060

Morphometric analysis of spinal motor neuron degeneration in sporadic amyotrophic lateral sclerosis

H. Aizawa ¹; S. Nagumo²; T. Hideyama²; H. Kato²; S. Kwak²; H. Terashi²; Y. Suzuki³; T. Kimura³

¹Department of Neurology, Sanno Hospital, Tokyo, Japan; ²Department of Neurology, Tokyo Medical University, Tokyo, Japan; ³Department of Neurology, Asahikawa Medical Center, Asahikawa, Japan

Background and aims: To clarify the relationship between TDP‐43 pathology and spinal anterior horn motor neuron (AHMN) atrophy in sporadic amyotrophic lateral sclerosis (SALS).

Methods: The subjects were 8 SALS and 12 disease controls. Formalin‐fixed specimens of lumbar spinal cord samples were paraffin‐embedded and sectioned at the level of the fourth lumbar spinal cord with a thickness of 4 μm. Using a microscope (BZ‐X800), the long diameter of neurons with nucleoli was measured in spinal AHMNs stained with anti‐SMI‐32 antibody. AHMNs were divided into medial and lateral nuclei for statistical processing. Among spinal AHMNs double‐fluorescently stained with TDP‐43 and anti‐nucleoporin p62 (NUP62) antibodies against the nuclear membrane, we also measured the long diameter of AHMNs with TDP‐43 in both the nucleus and cytoplasm, which are considered as initial lesions of TDP‐43 pathology.

Results: The long diameter of the lumbar spinal AHMNs in SALS was smaller in the medial nucleus (42.54 ± 9.33 micrometer, n = 24) and the lateral nucleus (49.41 ± 13.86, n = 129) than in controls (medial nucleus 55.84 ± 13.49, n = 85, p < 0.001; lateral nucleus 62.39 ± 13.29, n = 756, p < 0.001, Mann–Whitney test). All 21 motor neurons with early TDP‐43 pathology were in the lateral nucleus, and their long diameter (67.60 ± 18.3) was not significantly different from controls.

Histogram of spinal motor neurons.

TDP‐43 pathology and motor neuron atrophy.

Long diameter of motor neurons.

Conclusion: Motor neuron atrophy in SALS does not occur at the initial stages of TDP‐43 pathology, and TDP‐43 pathology has already progressed in the atrophic motor neurons.

Disclosure: Nothing to disclose.

OPR‐061

Genome‐wide directional effects of transcription factor binding on Amyotrophic Lateral Sclerosis

M. Torrieri ¹; M. Grassano²; A. Chiò²; M. Basso³; A. Calvo²

¹Academic Neurology Unit, San Luigi Gonzaga University Hospital, Orbassano, Italy; ²ALS Centre, RIta Levi Montalcini Department of Neuroscience, University of Turin, Turin, Italy; ³Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy

Background and aims: The transcription factor (TF) c‐myc has been shown to be elevated in many neurological disorders, including neurodegenerative diseases. We observed an increased activity of c‐myc in astrocytes in TDP‐43 mice models of Amyotrophic Lateral Sclerosis (ALS), being related to a reduction in survival, probably due to the release of an altered protein cargo by astrocytes. The aim of our study was to test the role of TFs in the pathogenesis of ALS.

Methods: We used signed LD profile (SLDP) regression to test the activity of TFs in large case–control GWAS of both ALS and frontotemporal dementia (FTD) [1,2]. SLDP regression is a validated method used to identify genome‐wide directional effects of signed functional annotations on polygenic disease risk [3]. We ran SLDP regression using the 382 available TF annotations for both ALS and FTD gene data sets. Results were significant at a per‐trait FDR <5%. A positive association implies a greater binding of the TFs, leading to greater expression; likewise, a negative association implies a lower binding of the TFs, leading to lower expression.

Results: We used GWAS summary statistics obtained from 12.577 ALS patients (vs. 23.475 healthy controls) and 3.526 FTD patients (vs. 9.402 healthy controls). We detected 38 and 14 significant associations respectively in ALS and FTD (Tables 1 and 2). Particularly, genetic variants determining a greater binding of c‐myc were associated with an increased risk of ALS, but not FTD.

TABLE 1 SLDP regression for ALS gene data set. Significant associations obtained from 12.577 ALS patients (vs. 23.475 healthy controls) are shown. We detected 38 significant positive associations at per‐trait FDR <5%.

TABLE 2 SLDP regression for FTD gene data set. Significant associations obtained from 3.526 FTD patients (vs. 9.402 healthy controls) are shown. We detected 14 significant associations at per‐trait FDR <5%, Only 1 of these associations was negative.

Conclusion: An increased activity of c‐myc could be a specific pathogenetic mechanism in ALS, leading to premature motor neurons death.

Disclosure: Nothing to disclose.

OPR‐062

Early‐onset amyotrophic lateral sclerosis (EO‐ALS): A different phenotype with a higher resilience?

S. Pierro ¹; A. Maranzano²; F. Gentile³; A. Manini⁴; A. Brusati⁵; S. Peverelli²; E. Colombo²; A. Doretti²; A. Bertini¹; J. Spagliardi¹; A. Di Maio¹; F. Duca¹; C. Morelli²; S. Messina²; L. Maderna²; A. Ratti⁵; V. Silani²; F. Verde²; N. Ticozzi²

¹Neurology Residency Program, Università degli Studi di Milano, Milan, Italy; ²Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy; ³IRCCS Ospedale San Raffaele, Division of Genetics and Cell Biology, Milan, Italy; ⁴Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy; ⁵Department of Medical Biotechnology and Molecular Medicine, Università degli Studi di Milano, Milan, Italy

Background and aims: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with a mean age of onset around 60 years. Evidence from the literature suggests the existence of a distinct clinical phenotype associated with earlier age at onset (EO‐ALS). Here we aim to define the clinical phenotype of EO‐ALS in comparison to late‐onset ALS (LO‐ALS).

Methods: We studied a cohort of 1165 ALS patients, divided in two groups: EO‐ALS (onset 20–45 years), and LO‐ALS (onset >45 years). Clinical phenotype, survival outcome measures and serum biomarkers were compared in the two groups Significant p‐value was set at <0.05.

Results: We found that EO‐ALS patients had significant predominance of males (72.5% vs. 60.9%, p = 0.010), familial ALS (15.3% vs. 9.5%, p = 0.037), spinal‐onset (82.4% vs. 70.7%, p = 0.047), progressive muscular atrophy phenotype (11.7% vs. 3.9%, p = 0.00009). In the EO‐ALS group, 1.5% had a cerebellar‐ALS‐plus phenotype (p = 0.00004). Interestingly, a lower progression rate (median: 0.47 vs. 0.61, p = 0.011) and prolonged survival (median values: 117.3 vs. 49.7 months, p < 0.001) were observed in EO‐ALS as well as a longer diagnostic delay (17.8 vs. 12.5 months, p < 0.001). Finally, in EO‐ALS serum GFAP was lower (median: 84.02 vs. 122.36 pg/mL, p = 0.011), and CPK was higher (median: 262 vs. 160 U/L, p < 0.001).

TABLE 1 Demographic and clinical characteristics of the study cohort, classified into the two main groups.

FIGURE 1 Kaplan–Meier plots of survival probabilities for EO‐ALS (green line) and LO‐ALS (blue line). Median values: 117.3 months for YO‐ALS and 49.7 months for AO‐ALS. +: censored cases.

Conclusion: Findings from our study indicate that EO‐ALS is associated with prolonged survival, suggesting that different pathogenetic mechanisms or enlarged motor neurons reserve might be at play in this group of patients. Compared to previous studies, we did not confirm the previously reported higher frequency of the upper motor neuron predominant phenotype in the EO‐ALS group.

Disclosure: Simone Pierro, Alessio Maranzano, Francesco Gentile, Arianna Manini, Alberto Brusati, Silvia Peverelli, Eleonora Colombo, Alberto Doretti, Alessandro Bertini, Jacopo Spagliardi, Alessandro Di Maio, Filippo Duca, Claudia Morelli, Stefano Messina, Luca Maderna, Federico Verde and Antonia Ratti report no disclosure. Vincenzo Silani received compensation for consulting services and/or speaking activities from AveXis, Cytokinetics, Italfarmaco, LiquidWeb, Srl and Novartis Pharma AG. He receives or he has received research support from the Italian Ministry of Health, AriSla, and E‐Rare Joint Translational Call. He is on the Editorial Board of Amyotrophic Lateral Sclerosis and Frontotemproal Degeneration, European Neurology, American Journal of Neurodegenerative Disease and Frontiers in Neurology. Nicola Ticozzi received compensation for consulting services from Italfarmaco, Biogen, Amylyx Pharmaceutical and Zambon Biotech SA. He received research funding from the Italian Ministry of Health and AriSLA. He is associate editor of Frontiers in Aging Neuroscience.

OPR‐063

Longitudinal progression of subcortical structural damage in amyotrophic lateral sclerosis

E. Spinelli ¹; A. Ghirelli¹; S. Basaia²; E. Canu²; V. Castelnovo²; T. Russo³; P. Schito³; Y. Falzone³; N. Riva⁴; M. Filippi⁵; F. Agosta¹

¹Neuroimaging Research Unit, Division of Neuroscience, and Neurology Unit, IRCCS San Raffaele Scientific Institute, and Vita‐Salute San Raffaele University, Milan, Italy; ²Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; ³Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; ⁴Neurorehabilitation Unit, and Experimental Neuropathology Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; ⁵Neuroimaging Research Unit, Division of Neuroscience, Neurology Unit, Neurorehabilitation Unit, and Neurophysiology Service, IRCCS San Raffaele Scientific Institute, and Vita‐Salute San Raffaele University, Milan, Italy

Background and aims: Converging evidence suggests an early involvement of subcortical structures in the course of neuropathological progression of amyotrophic lateral sclerosis (ALS). Our aim was to explore the longitudinal evolution of structural damage to subcortical and hippocampal structures in a cohort of incident ALS patients.

Methods: Twenty‐four patients with ALS and 34 healthy controls underwent at least two longitudinal clinical evaluations and brain MRI scans on a 3 T scanner (median follow‐up time = 0.96 years). Segmentation of subcortical and hippocampal structures was obtained. ANOVA models were performed between groups at baseline. Linear mixed effect models were used to test longitudinal trajectories of atrophy.

Results: At baseline, ALS patients showed significant bilateral reduction of hippocampal volumes compared with controls (left: p = 0.05; right: p = 0.038), and a trend toward significance for atrophy in the right thalami (p = 0.08). Baseline volumes of the basal ganglia were comparable between patients and controls. Longitudinally, ALS patients showed a significant reduction of grey matter volumes of the left pallidum (p = 0.01) and right putamen (p = 0.02).

Conclusion: Our results suggest a different temporal involvement of hippocampal and subcortical structures in the course of ALS, with an early involvement of hippocampi and thalami followed by a subsequent progression of damage to the basal ganglia. We highlight the importance of subcortical structural alterations for a more comprehensive understanding of ALS, supporting the use of MRI for tracking disease progression. Funding. This study was supported by: European Research Council (StG‐2016_714388_NeuroTRACK); Foundation Research on Alzheimer Disease; Next Generation EU/National Recovery and Resilience Plan, Investment PE8‐Project Age‐It.

Disclosure: EG Spinelli, A Ghirelli, V Castelnovo, T Russo, P Schito, Y Falzone, N Riva have nothing to disclose. S Basaia research support from Italian Ministry of Health (IMH). E Canu research support form Italian Ministry of Health. M Filippi consulting or speaking activities or advisory boards for Alexion, Almirall, Biogen, Bayer, Bristol‐Myers Squibb, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA; scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol‐Myers Squibb, Lilly, Novartis, Sanofi‐Genzyme; research support from Biogen Idec, Merck‐Serono, Novartis, Roche, IMH, Italian Ministry of University and Research, and FISM. F Agosta received speaker honoraria from Biogen Idec, Italfarmaco, Roche, Zambon and Eli Lilly, and has received research supports from IMH, Italian Ministry of University and Research, ARiSLA, ERC, EU Joint Programme – Neurodegenerative Disease Research, and Foundation Research on Alzheimer Disease.

OPR‐064

Relevance of paramagnetic rim and cortical lesions in MS at diagnosis: Exploring the clinical practice biomarker toolkit

A. Miscioscia; M. Puthenparampil; A. Zolin; G. Zanotelli; G. Scialpi; A. Berardi; F. Rinaldi; P. Perini; P. Gallo

Department of Neuroscience, Padova University Hospital, Padova, Italy

Background and aims: In multiple sclerosis (MS), imaging biomarkers aid the disease characterization at the time of diagnosis and support the appropriate treatment choice. The presence of paramagnetic rim lesions (PRLs) and cortical lesions (CLs) is not routinary evaluated in clinical practice. In this study, we investigated the association between a broad range of imaging biomarkers available and the clinical disability in MS patients at diagnosis.

Methods: 45 RRMS (mean disease duration: 9.6 months) underwent brain and spinal cord 3 T‐MRI and OCT. Susceptibility‐weighted imaging (SWI) and double inversion recovery (DIR) sequences were used to manually segment respectively PRLs and CLs. Neuroimaging metrics extracted are shown in Table 1. Regression models assessed the relationship of the lesion and atrophy metrics with physical disability (Expanded Disability Status Scale [EDSS]) and cognitive impairment (Symbol Digit Modalities Test [SDMT]).

Results: PRL and spinal cord lesion volume and count most strongly predicted EDSS. Only CL volume and count were significantly associated with SDMT score at diagnosis. In a regression model including non‐rim WML and PRL volume (or count), only the latter was significantly associated with EDSS along with spinal cord volume (or count). In the same model with the two WML phenotypes grouped together, the WML volume (or count) did not reach the significance.

TABLE 1 Demographics, clinical and radiological characteristics.

FIGURE 1 Probability maps of the spinal cord (a), non‐rim white matter (b), paramagnetic rim (d), and cortical lesions (d).

TABLE 2 Relationship between neuroimaging biomarkers and clinical disability. Multivariate linear regression models.

Conclusion: PRLs and spinal cord lesions describe the best association with physical disability in MS patients at diagnosis. CLs best correlate with cognitive performance. SWI and DIR sequences and the assessment of PRLs and CLs might add pivotal information at the first MS patient assessment.

Disclosure: Nothing to disclose.

OPR‐065

Evaluation of neuronal and glial serum biomarkers in patients with MOGAD: the MULTIMOGAD study

J. Villacieros‐Álvarez ¹ ; S. Mariotto²; C. Espejo¹; A. Dinoto²; G. Arrambide¹; R. Bernard‐Valnet³ ; P. Kerschen⁴; S. Alsaint⁵; V. Dyon⁵; X. Montalbán¹; M. Tintoré¹; Á. Cobo‐Calvo¹ ; R. Marignier⁵

¹Neurology Department and Multiple Sclerosis Centre of Catalonia (Cemcat), Vall Hebron University Hospital, Vall Hebron Research Institute. Barcelona (Spain). Uniiversitat Autónoma de Barcelona, Barcelona, Spain; ²Neurology Unit, Department of Neurosciences, Biomedicine, and Movement Sciences, University of Verona, Verona, Italy; ³Neurology Service, Lausanne University Hospital (Centre Hospitalier Universitaire Vaudois), University of Lausanne, Lausanne, Switzerland; ⁴Centre Hospitalier de Luxembourg, Luxembourg‐Ville, Luxembourg, France; ⁵Service de Neurologie, Sclérose en Plaques, Pathologies de la Myéline et Neuro‐Inflammation‐Hospices Civils de Lyon, Hôpital Neurologique Pierre Wertheimer, Bron Cedex, France

Background and aims: The role of serum biomarkers to evaluate MOGAD prognosis is limited. We aim to characterize serum neuro‐glial biomarkers and analyze their usefulness to predict relapses and disability in MOGAD.

Methods: Retrospective longitudinal study included MOGAD and age‐matched multiple sclerosis (MS) patients with serum samples obtained within 3 months from disease onset. Clinical and laboratory data were collected. Serum neurofilament light‐chain (sNfL) and glial fibrillary acidic protein (sGFAP) levels were determined using Simoa. A descriptive comparison between MOGAD and MS groups was performed. Within MOGAD group, Spearman test was built to assess correlations between baseline serum biomarkers and disability at sampling, as well as Cox and linear regression analyses to predict time to second relapse and disability, respectively.

Results: Eighty‐nine MOGAD and 32 MS patients were included. In MS, female were more predominant (p = 0.020), had lower EDSS at onset (p = 0.046), and higher presence of oligoclonal bands (p = 0.001). Baseline sNfL levels were higher in MOGAD compared to MS (p = 0.018). In MOGAD patients, sNfL (rho 0.289; p = 0.008) and sGFAP (rho 0.32; p = 0.003) correlated with EDSS at sampling. sGFAP levels were associated with EDSS at last follow‐up in univariate (p = 0.017), but lost significance in multivariate analysis. In multivariate Cox analysis, higher baseline sNfL values increased the risk of having a second relapse in MOGAD patients presenting with optic neuritis (hazard‐ratio 5.88 [95% CI 1.56; 22.20]; p = 0.009).

TABLE 1 Demographic and clinical characteristics.

TABLE 2 Univariate and multivariate regression models assessing the association of baseline sGFAP and sNfL levels with EDSS at last follow‐up in MOGAD patients.

FIGURE 1 Correlation analyses between EDSS at sampling and baseline sNfL (A) and sGFAP (B). Kaplan–Meier survival curves comparing time to relapse between MOGAD patients with high or low sNfL levels in the whole cohort (C) and in the subgroup of ON (D).

Conclusion: In MOGAD patients, the neuro‐axonal and astrocytic damage is related with disability at sampling. Neuro‐axonal damage predicts a relapsing disease course in the subgroup of patients with optic neuritis.

Disclosure: Villacieros‐Álvarez has received grant from Instituto de Salud Carlos III, Spain; FI21/00282 Cobo‐Calvo has received grant from Instituto de Salud Carlos III, Spain; JR19/00007.

OPR‐066

Profiling and modelling cellular senescence in progressive multiple sclerosis brains

M. Martire ¹; F. Fagiani²; E. Pedrini²; D. Maric³; D. Reich⁴; M. Filippi⁵; M. Absinta²

¹Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; ²Translational Neuropathology Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; ³Flow and Imaging Cytometry Core Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; ⁴Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; ⁵Neurology Unit and Division of Neuroscience, IRCCS San Raffaele Scientific Institute and Vita‐Salute San Raffaele University, Milan, Italy

Background and aims: Senescent cells accumulate in age‐related diseases. Whether these cells actively contribute to the tissue dysfunction leading to progressive MS is unknown. Here, we investigate the spatial distribution of senescent cells in MS brains, and we model post‐inflammatory senescence using 3D hiPSC‐derived organoids.

Methods: We performed single‐nucleus RNA‐sequencing (snRNAseq) on 31 samples of cortex and white matter (WM) from progressive MS cases (n = 10, mean age = 49) and controls (n = 4, mean age = 54); SenMayo gene set was applied to the snRNAseq datasets to identify senescent cells. As validation, multiplex immunofluorescence (26 primary antibodies, including the senescence marker p16INK4A+) was performed on 7 MS‐tissue blocks. To model inflammation‐induced senescence, we exposed 3D hiPSC‐derived organoids to the CSF (10% for 24 h) from MS patients and processed by scRNAseq.

Results: In the snRNAseq datasets, endothelia were the most prominent cells featuring senescence signatures in all WM lesion stages (3‐fold change [FC] increase) and MS cortex (2.3‐FC). Compared to control brain, senescent microglia were twice as abundant at the chronic active lesion (CAL) edge and MS cortex; senescent astrocytes predominated in the lesion core (2‐FC), CAL edge (2.6‐FC), and MS cortex (2‐FC). Consistently, MS brains displayed a higher number of p16INK4A+ cells compared to control, enriched within areas with chronic inflammation and at the ventricular ependyma. Using organoids, we observed that the short‐term inflamed‐CSF exposure promoted microglial senescence (4.2‐FC relative to untreated organoids).

Conclusion: Inflammation‐associated cellular senescence is pronounced in progressive MS and might potentially exacerbate tissue dysfunction, with key translational implications.

Disclosure: MSM has got nothing to disclose. FF has got nothing to disclose. ED has got nothing to disclose. DM has got nothing to disclose. MA received consultancy honoraria from Abata Therapeutics, Biogen, Sanofi‐Genzyme and GSK. DSR has received research funding from Abata Therapeutics and Sanofi‐Genzyme. MF is Editor‐in‐Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology; received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche, Sanofi; speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck‐Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA; participation in Advisory Boards for Alexion, Biogen, Bristol‐Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi‐Aventis, Sanofi‐Genzyme, Takeda.

OPR‐067

Factors influencing postpartum activity in multiple sclerosis patients: A prospective study and intervention strategy

C. Oreja‐Guevara ; C. Martin‐Romero; I. Gomez‐Estevez; L. García‐Vasco; E. Alba‐Suarez

Neurology, Hospital Clínico San Carlos, Idissc, Madrid, Spain

Background and aims: Postpartum relapses in multiple sclerosis (MS) patients significantly impact family planning decisions, often leading to cautious reproductive choices. Neurologists frequently advise these individuals on managing their condition during and after pregnancy. Objective: to analyze the factors influencing postpartum disease activity in MS patients. Additionally, we assessed the effectiveness of a proactive strategy designed to reduce postpartum relapses.

Methods: We conducted a prospective longitudinal study involving pregnant women with MS, starting in 2015. We collected and analyzed demographic, clinical, and radiological data before pregnancy, during pregnancy, and in the postpartum period. We implemented a specific strategy to minimize postpartum relapses, including initiating treatment after delivery for active patients and conducting cranial MRI scans 2 months postpartum.

Results: The study included 128 women, with a mean age of 35 years (range 25–47). Pre‐pregnancy, 28.3% had experienced relapses in the 2 years leading up to pregnancy, and similar proportions exhibited new T2 lesions (28.3%) and gadolinium‐enhancing lesions (21.6%). During pregnancy, 10% experienced relapses, with 7% having clinical relapses and 22% developing new T2 lesions within 6 months postpartum. Notably, 41.4% of patients received DMT treatment within 15 days postpartum, leading to reduced postpartum relapses. Significant correlations were found between postpartum relapses and relapse history, number of relapses, and gadolinium‐enhancing lesions.

Conclusion: This study highlights the importance of a targeted postpartum management strategy in reducing MS relapses. The proactive approach, involving early DMT treatment and postpartum MRI scans, effectively reduced postpartum relapses, demonstrating the potential for improved outcomes in MS patients considering pregnancy.

Disclosure: nothing to disclose related to the abstract.

OPR‐068

Disconnection of cerebellar motor areas and motor impairment in multiple sclerosis

F. Romanò ¹; B. Signoracci¹; P. Preziosa²; M. Margoni³; E. Pagani¹; M. Rocca²; M. Filippi⁴

¹Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; ²Neuroimaging Research Unit, Division of Neuroscience, and Neurology Unit, IRCCS San Raffaele Scientific Institute, and Vita‐Salute San Raffaele University, Milan, Italy; ³Neuroimaging Research Unit, Division of Neuroscience, Neurology Unit, and Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; ⁴Neuroimaging Research Unit, Division of Neuroscience, Neurology Unit, Neurorehabilitation Unit, and Neurophysiology Service, IRCCS San Raffaele Scientific Institute, and Vita‐Salute San Raffaele University, Milan, Italy

Background and aims: The cerebellum is often affected in patients with multiple sclerosis (MS). It contains two motor representations: the anterior (ACMA, lobules I–V) and posterior (PCMA, lobule VIII) cerebellar motor areas. We assessed atrophy and T2‐hyperintense lesion loads in these areas and their association with motor impairment.

Methods: Eighty‐nine MS patients and 65 healthy controls (HC) underwent a functional assessment (gait function and hand dexterity) and structural MRI acquisition at 3.0 T. Cerebellar lobules were segmented using the SUIT atlas. Between‐groups comparisons and age/sex‐corrected partial correlations were assessed.

Results: Compared to HC, ACMA and PCMA were atrophic in MS (p < 0.001), with similar reductions between the two areas. More than 60% of MS patients had lesions in either motor lobule. ACMA volume was lower than PCMA in HC and MS (p < 0.001), whereas T2‐hyperintense lesion load was higher in ACMA than PCMA in MS (p = 0.040). Patients with lesions in both areas had worse motor performance than those without lesions in either area (p < 0.001 for all). Patients with lesions only in the ACMA or PCMA had similar motor abilities. In patients, lower ACMA and PCMA volumes correlated with worse left‐hand dexterity (p < 0.001), whereas higher T2‐hyperintense lesion load in both ACMA and PCMA correlated with worse performance in all motor tests (r range = −0.358; −0.445, p < =0.001 for all).

Conclusion: The non‐homogeneous distribution of lesions suggests an increased susceptibility of the ACMA to focal demyelinating lesions. Considering correlation analyses, disconnection of cerebellar motor areas, rather than localised lobular atrophy, seems to better explain motor impairment in MS.

Disclosure: F. Romanò, B. Signoracci and E. Pagani have nothing to disclose. P. Preziosa received speaker honoraria from Roche, Biogen, Novartis, Merck, Bristol Myers Squibb, Genzyme, Horizon and Sanofi, and research support from Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla (FISM). M. Margoni reports grants and personal fees from Sanofi Genzyme, Merck Serono, Novartis and Almiral. MA Rocca received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, Roche; speaker honoraria from AstraZaneca, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Horizon Therapeutics Italy, Merck Serono SpA, Novartis, Roche, Sanofi and Teva; research support from MS Society of Canada, Italian Ministry of Health, Italian Ministry of University and Research, and FISM. M. Filippi received compensation for consulting or speaking activities services from Alexion, Almirall, Biogen, Bayer, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA; participation in Advisory Boards for Alexion, Biogen, Bristol‐Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi‐Aventis, Sanofi‐Genzyme, Takeda; scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol‐Myers Squibb, Lilly, Novartis, Sanofi‐Genzyme; he receives research support from Biogen Idec, Merck‐Serono, Novartis, Roche, Italian Ministry of Health, Italian Ministry of University and Research, and FISM.

OPR‐069

Neurologic, psychiatric and sleep investigations after initial treatment of anti‐LGI1 encephalitis: A prospective study

A. Muñoz‐Lopeteti ¹ ; M. Guasp¹; L. Prades²; E. Martinez‐Hernandez¹ ; M. Rosa‐Justicia² ; V. Patricio²; T. Armangué³; L. Rami²; R. Borràs⁴; J. Castro‐Fornieles⁵ ; A. Compte²; C. Gaig¹; J. Santamaria²; J. Dalmau²

¹Neurology Department, Institute of Neurosciences, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain; ²Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; ³Pediatric Neuroimmunology Unit, Department of Neurology, Sant Joan de Déu Children Hospital, University of Barcelona, Barcelona, Spain; ⁴Medical Statistics Core Facility, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain; ⁵Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain

Background and aims: Anti‐LGI1 encephalitis responds well to immunotherapy, but the symptoms that remain after treatment have not been well described. We aimed to characterize the clinical features of these patients over more than 1 year after initial immunotherapy.

Methods: This prospective cohort study included individuals with anti‐LGI1 encephalitis who received immunotherapy within the past year and sex and age matched healthy participants (HP). At study entry, at 6 months (not in HP), and at 12 months, participants underwent neuropsychiatric and video‐polysomnography (VPSG) assessments.

Results: Between 2019 and 2022, 24 (57%) patients with anti‐LGI1 encephalitis and 18 (43%) healthy participants were recruited. At study entry (median 88 days [IQR 67–155] from initial immunotherapy), all 24 patients had one or more symptoms: cognitive (83%), psychiatric (83%), insomnia (58%), REM sleep behaviour disorder (50%), faciobrachial dystonic seizures (FBDS 38%), and focal onset seizures (29%). FBDS were unnoticed in 17% and focal onset seizures in 21%. VPSG alterations included disruption of sleep structure (79% patients; 0 HP; p = 0.013]), excessive fragmentary myoclonus (63% patients; 22% HP; p = 0.039) and myokymic discharges (38% patients; 0 HP; p = 0.0051). These findings led to additional immunotherapy in 63% of the patients, resulting in improvement or resolution in all cases, however at 12 months 65% remained with cognitive deficits.

Conclusion: Unsuspected but ongoing clinical and video‐polysomnography alterations are common in patients with anti‐LGI1 encephalitis during the year that follows initial immunotherapy. Recognition of these alterations is important because they are treatable, can be used as outcome measures in clinical trials, and may influence cognitive outcome.

Disclosure: Nothing to disclose.

OPR‐070

Clinical characterization and long‐term outcome of children and adults with anti‐AMPAR encephalitis

C. Milano ¹; E. Saylam²; C. Papi³; A. Sankovic²; J. Honnorat⁴; T. Iizuka⁵; R. Höftberger⁶; R. Reinecke⁶; M. Titulaer⁷; J. Kerstens⁷; M. Simabukuro⁸; M. Benaiteau⁴; B. Joubert⁴; M. Gastaldi⁹; L. Almeida Dutra¹⁰; F. Leypoldt¹¹; M. Jansen¹¹; I. Kawachi¹²; F. Graus¹³; J. Dalmau¹³; S. Magana²; M. Spatola¹³

¹Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; ²Department of Pediatrics, Division of Neurology, Nationwide Children's Hospital, Columbus, OH, USA; ³Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Department of Neuroscience, Catholic University of the Sacred Heart, Rome, Italy; ⁴Reference Centre on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, MELIS institute UMR Inserm 1314, CNRS 5284, Université Claude Bernard Lyon 1, Lyon, France; ⁵Department of Neurology. Kitasato University School of Medicine, Japan; ⁶Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria; ⁷Department of Neurology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands; ⁸Division of Neurology, Hospital das Clinicas (HCFMUSP), Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil; ⁹Neuroimmunology Laboratory, IRCCS Mondino Foundation, Pavia, Italy; ¹⁰Hospital Israelita Albert Einstein, São Paulo, Brazil; ¹¹Institute of Clinical Chemistry, University Hospital Schleswig‐Holstein, Germany; ¹²Department of Neurology, Brain Research institute, Niigata University, Japan; ¹³Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain

Background and aims: Anti‐α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionic acid (anti‐AMPAR) encephalitis manifest with limbic encephalitis (LE) associated with cancer. The full clinical spectrum, prognostic factors and outcome are not well established, especially in children. We compared clinical features of children and adults and characterized the long‐term outcome of anti‐AMPAR encephalitis.

Methods: Clinical information of adults and children with anti‐AMPAR encephalitis were reviewed from medical records.

Results: Eighty‐four patients with AMPAR antibodies were included (13 children, 71 adults). Patients with other concomitant neuronal antibodies were excluded. Overall, 62% of patients presented with LE (7 children, 45 adults, p = 0.539). Compared to adults, children experienced more frequently prodromal symptoms (p = 0.035), movement abnormalities (p = 0.032) and cerebellar symptoms (p = 0.025). Brain MRI was abnormal in 68% of patients, restricted to mesio‐temporal lobes (50%) or associated with extratemporal abnormalities (34%). Exclusive involvement of extratemporal areas (16%) was more frequent in children than adults (44% vs. 11%, p = 0.035). Tumours were found only in adults (56%, mainly lung cancer and thymoma). A follow‐up >24 months was available for 34 patients (4 children, 30 adults): 64% showed neurological sequelae, including cognitive (83%), psychiatric (33%), sleep (11%), and movement (6%) disorders. Twenty‐two patients (65%) had a good outcome (modified Rankin scale [mRS] < 2) whereas 12 (35%) a bad outcome (mRS >2). At multivariate analysis, failure to respond to first‐line immunotherapy was the only predictor of bad outcome (OR 8.8, 95% CI 1.3–59.5, p = 0.025).

Conclusion: Children with anti‐AMPAR encephalitis present distinct clinical and radiological features compared to adults. Despite most patients respond to immunotherapy, neurological sequelae are frequent.

Disclosure: M. Spatola receives research support from La Caixa Foundation and Spanish National Research Institute (Carlos III).

OPR‐071

Brain MRI changes and their impact on cognition in the post‐acute stage of anti‐NMDA receptor encephalitis

M. Guasp ¹; F. Vivó²; E. Martinez‐Heras² ; E. Solana²; E. Martinez‐Hernandez¹ ; A. Muñoz‐Lopetegi² ; T. Armangué²; M. Rosa‐Justicia² ; L. Prades²; E. Fonseca²; G. Sugranyes³; A. Calvi²; E. López‐Soley² ; S. Albà‐Arbalat¹ ; J. Castro‐Fornieles³ ; A. Compte²; J. Dalmau²; S. Llufriu¹

¹Neurology Department, Institute of Neuroscience, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain; ²Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; ³Psychiatry Department, Institute of Neuroscience, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain

Background and aims: We aimed to characterize the course of alterations in brain grey matter (GM) volumetry and diffusion‐based white matter (WM) connectivity and their association with cognitive performance during the post‐acute stage of anti‐NMDAR encephalitis (NMDARe).

Methods: NMDARe patients were prospectively studied at 4, 8, 12 and 12–24 months from disease onset with paired cognitive and MRI assessments that quantified whole brain volume, regional GM changes, and structural integrity of WM connectivity. Differences between NMDARe patients and healthy controls (HC), similarly studied, in the longitudinal follow‐up were analyzed using multilevel linear mixed‐effect models.

Results: Twenty‐one post‐acute NMDARe patients and 19 HC were included. Compared with HC, patients showed similar global brain volume, but specific regional changes: atrophy of the middle frontal cortex, and enlargement of bilateral hippocampus and right amygdala, mainly during the first 8 months, which improved over time. NMDARe patients showed differences in 76/2020 (3.8%; p < 0.05, family‐wise error rate) WM connections, following two distinct dynamic patterns: reduced connectivity in 63/76 (83%) connections, involving bilateral cingulate, parietal cortex and deep GM, which improved rapidly (first 8 months), and increased connectivity in 13/76 (17%) connections, mainly subcortical areas, which stabilized over time. Regional atrophy and decreased WM connectivity largely explained variability in working memory (87%) and learning and memory (86%) outcomes.

Conclusion: The first 8 months of post‐acute NMDARe were dominated by regional vulnerability to damage and rapid MRI improvements. In subsequent months (8–24), MRI changes slowed and mild residual volumetric and connectivity abnormalities persisted alongside protracted cognitive deficits in NMDARe patients.

Disclosure: J.D. holds patents for the use of NMDAR as autoantibody tests. GS received speaker fees from Angelini Pharma. SL received compensation for consulting services and speaker honoraria from Biogen Idec, Novartis, TEVA, Genzyme, Sanofi and Merck. S.L. received compensation for consulting services and speaker honoraria from Biogen Idec, Novartis, Janssen, Merck and Bristol‐Myers Squibb, and holds grants from the Instituto de Salud Carlos III. E.S. received travel reimbursement from Merck and Sanofi‐Aventis S.A. The rest of the authors declare no conflicts of interest related to this work.

OPR‐072

How to retreat patients with anti‐MAG polyneuropathy after a course of rituximab? A comparison between two regimens

M. Bellucci¹; F. Massa¹; E. Baroncelli ¹; C. Castellano¹; L. Marinelli¹; C. Cabona²; E. Mobilia³; A. Lechiara³; F. Bozzano³; G. Pesce³; A. Schenone¹; L. Benedetti⁴

¹Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy; ²Department of Neurophysiopathology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy; ³Immunology lab, IRCCS Ospedale Policlinico San Martino, Genoa, Italy; ⁴Department of Neurology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy

Background and aims: Rituximab represents an effective therapy in anti‐MAG polyneuropathy. However, a well‐established retreatment strategy is currently lacking. We aim to compare two different retreatment protocols, upon clinical relapse vs. upon memory B cell reappearance, to evaluate whether they could be associated with an increased long‐term disability.

Methods: We retrospectively evaluated 29 patients who were responsive to an initial cycle of rituximab (375/mg/m²/week for 4 weeks), and retreated according to two different protocols: full course at the time of clinical relapse (n = 20), or a single infusion of rituximab (375 mg/m²) whenever the frequency of reemerging CD27+ memory B cells exceeded 0.05% in the first 2 years and 0.1% thereafter (n = 9). The scores obtained in the validated clinical scales INCAT, MRC, ISS scales were evaluated at baseline, after 9 months and at the last follow‐up visit.

Results: Comparing the scores obtained in the three clinical scales between baseline and the last follow‐up, we found that patients treated upon relapse disclosed a progressively more disabling clinical course, whereas none of the patients treated upon memory B cells reappearance had a significant clinical decline compared to baseline (statistical data not presented for shortness).

Conclusion: Our findings reveal that patients treated upon clinical relapse exhibit greater levels of long‐term disability than patients treated upon CD27+ lymphocyte reappearance, suggesting that the latter protocol may be an effective maintenance treatment strategy in patients with anti‐MAG polyneuropathy.

Disclosure: Nothing to disclose.

OPR‐073

Detailed characterization and evolution of brainstem tau pathology in anti‐IgLON5 disease

R. Reinecke ¹; E. Gelpi¹; M. Blaabjerg²; E. Erro³; J. Ferrari⁴; M. Glatzel⁵; A. Heidbreder⁶; B. Högl⁷; J. Lewerenz⁸; L. Myllykangas⁹; M. Popovic¹⁰; P. Schnider¹¹; D. Yilmazer‐Hanke¹² ; L. Sabater¹³; C. Gaig¹⁴; R. Höftberger¹

¹Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Austria; ²Department of Neurology, Odense University Hospital, Odense, Denmark; ³Department of Neurology, Hospital Universitario de Navarra, Health Research Institute of Navarra (IdisNA), Pamplona, Spain; ⁴Department of Neurology, Hospital Barmherzige Brüder Vienna, Vienna, Austria; ⁵Institute of Neuropathology, University Medical Center Hamburg‐Eppendorf, Hamburg, Germany; ⁶Department of Neurology, Johannes Kepler University Linz, Linz, Austria; ⁷Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria; ⁸German Center for Neurodegenerative Diseases (DZNE), Campus Ulm, Ulm, Germany; ⁹Department of Pathology, University of Helsinki, and HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland; ¹⁰Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia; ¹¹Department of Neurology, Landesklinikum Wiener Neustadt, Wiener Neustadt, Austria; ¹²Clinical Neuroanatomy, Department of Neurology, Institute for Biomedical Research, Ulm University, Ulm, Germany; ¹³Neuroimmunology Program, Fundació de Recerca Clínic Barcelona‐Institut d'Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain; ¹⁴Department of Neurology, Hospital Clínic, Barcelona, Spain

Background and aims: Anti‐IgLON5 disease is a newly identified rare form of autoimmune disorder characterized by anti‐IgLON5 antibodies that, via an as‐yet‐unidentified mechanism, are associated with a brainstem‐dominant tau pathology. Recent research indicates that the tau pathology may develop in a time‐dependent manner, being absent or mild at early disease stages and very prominent after years of disease progression. This study aimed to precisely characterize the different tau phosphorylation steps and establish a sequence of markers at the different severity stages in an autopsy cohort.

Methods: We used immunohistochemistry to analyze the medullary region of 14 autopsy cases of anti‐IgLON5 disease with different severity grades of tau pathology and varying disease durations, from 6 to 180 months. We used 13 antibodies for different tau phosphorylation sites. The presence and severity of tau pathology were assessed semi‐quantitatively and compared to one PSP case and two neurologically healthy controls.

Results: We identified different tau phosphorylation sites in anti‐IgLON5 disease and were able to determine a sequence of phosphorylation steps based on the disease duration. The development of cytoplasmic tau pathology seems to occur only in later disease stages, whereas alterations of the nuclear envelope were evident in the early stages.

Conclusion: Different tau phosphorylation steps occur during the progression of anti‐IgLON5 disease. The establishment of a sequence of pathological disease markers adds support to the hypothesis that tauopathy might indeed be a time‐dependent phenomenon. Furthermore, it may aid in the neuropathological identification of cases with mild pathology, and provides insight into the earliest stages of tauopathy.

Disclosure: This work was supported by the Austrian Science Fund (FWF), project number I6565‐B (SYNABSII).

OPR‐074

High relapse rate influences the long‐term clinical outcome in anti‐CASPR2 encephalitis

T. Brand ¹; S. Franken¹; M. Vermeiren¹; A. Van Sonderen¹; M. de Bruijn¹; Y. Crijnen¹; J. Brenner¹; R. Van Steenhoven¹; J. Kerstens¹; P. Sillevis Smitt¹; S. Veenbergen²; M. Titulaer¹; J. De Vries¹

¹Department of Neurology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands; ²Department of Immunology, Laboratory Medical Immunology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands

Background and aims: Anti‐contactin‐associated protein‐like 2 (CASPR2) encephalitis is a young disease entity, and information on long‐term clinical outcome and relapse rate are limited. We aim to describe long‐term clinical outcome, relapse rate and treatment efficacy to guide treatment decisions.

Methods: In this nationwide observational cohort study, patients with a confirmed diagnosis of anti‐CASPR2 encephalitis were included. Clinical data were collected at diagnosis and during follow‐up, both retrospectively and prospectively. In all patients, written informed consent was obtained.

Results: Forty‐four patients with anti‐CASPR2 encephalitis were included (42/44 [95%] male; median age at onset 65 years, range 40–86). The median follow‐up time was 46.5 months, range 7–113. Relapses were present in 23/44 patients (52%). Compared to the initial disease episode, patients experienced similar but fewer symptoms during the relapse(s). However, peripheral symptoms occurred newly during a relapse in five patients. The median time to relapse was 11 months (range 3–58). At relapse, one patient was tapering prednisone, eight patients had maintenance immunotherapy, three had received Rituximab induction therapy, while 11 patients had no immunotherapy anymore. VGKC RIA titre fluctuations in serum correlated well (84%) with relapse and remission. Nine patients (24%) suffered multiple relapses. In 10 patients, a tumour was present, of which two were only discovered during a relapse.

Conclusion: The relapse rate in anti‐CASPR2 encephalitis is much higher than previously anticipated, which provides a clear rationale for prolonged immunotherapy. VGKC RIA titres in serum can guide monitoring for relapses and disease course. It is recommended to repeat tumour screening when patients relapse.

Disclosure: Marienke en Yvette funded by EpilepsieNL (NEF 14–19 & 19–08), Juliette by Dioraphte (2001 0403) Robin funded by ZonMW (VIMP scheme) Peter A.E. Sillevis Smitt holds a patent for the detection of anti‐DNER and received research support from Euroimmun. Maarten J. Titulaer has filed a patent, on behalf of the Erasmus MC, for methods for typing neurological disorders and cancer, and devices for use therein, and has received research funds for serving on a scientific advisory board of Horizon Therapeutics, for consultation at Guidepoint Global LLC, and for consultation at UCB. MT has received an unrestricted research grant from Euroimmun AG, and from CSL Behring. JdV is local investigator for the CIELO satralizumab in anti‐NMDAR and anti‐LGI1 encephalitis (Roche).

OPR‐075

Idebenone treatment for Leber hereditary optic neuropathy: Time to clinically relevant recovery in the LEROS study

C. La Morgia ¹; T. Klopstock²; P. Yu‐Wai‐Man³ ; V. Carelli¹; X. Llòria⁴

¹IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy; ²Department of Neurology with Friedrich‐Baur‐Institute, University Hospital of Ludwig‐Maximilians‐Universität München, Munich, Germany; ³John van Geest Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; ⁴Chiesi Farmaceutici SpA, Parma, Italy

Background and aims: LHON is a mitochondrial disease resulting in bilateral vision loss. In LEROS, a Phase IV, open‐label interventional study (NCT02774005), visual acuity (VA) outcomes following 24 months of idebenone treatment were compared to an external matched Natural History (NH) cohort. Eyes treated with idebenone had significantly higher rates of clinically relevant recovery (CRR) from baseline at 12 and 24 months compared to the NH control group. Here, we present the cumulative percentage of eyes with a CRR from baseline (KM‐estimate) by disease phase and primary mtDNA mutation as a function of treatment duration.

Methods: LEROS included patients with LHON aged ≥12 y and with a disease onset ≤5 y prior. Eyes were stratified by time since symptom onset: subacute/dynamic (≤1 y) and chronic (>1 y). CRR was defined as an improvement from “off‐chart” VA to at least 1.6 logMAR, or a ≥0.2 logMAR improvement if “on‐chart”.

Results: The intention‐to‐treat (ITT) population included 196 patients. The KM‐estimate of a CRR from baseline increased from 18.4% of eyes at Month 6 to 47.3% at Month 24 with idebenone treatment in the subacute/dynamic phase, and from 18.2% to 29.1% in the chronic phase. Improvement of visual acuity was also observed in sub‐analyses by mtDNA mutation in both subacute/dynamic and chronic eyes (Table 1).

TABLE 1 Kaplan–Meier estimates of cumulative CRR [95% CI] from baseline.

Conclusion: Longer duration of idebenone treatment (beyond 1 y) further improved visual outcomes regardless of LHON disease phase. This improvement was most pronounced for eyes with the m.14484T>C mutation.

Disclosure: CLM has acted as a consultant for Chiesi Farmaceutici, Gensight Biologics, Regulatory PharmaNet, and Thenewway srl and has also received speaker honoraria and/or financial support for meetings from these companies, as well as from First Class srl and Biologix. CLM has also acted as a principal or study investigator for clinical trials sponsored by GenSight Biologics, Santhera Pharmaceuticals, Stoke Therapeutics, Reneo Pharmaceuticals and Omeicos. PYWM, VC, and TK received research support and/or personal compensation from Santhera Pharmaceuticals, Chiesi, and GenSight Biologics. XL is an employee of Chiesi Farmaceutici S.p.A. LEROS was funded by Santhera Pharmaceuticals and medical writing support was provided by nspm ltd, Switzerland with financial support from Chiesi Farmaceutici SpA.

OPR‐077

Zebra or Horse: Diagnostic process, misdiagnosis, and bias in suspected idiopathic intracranial hypertension

N. Skadkær Hansen ¹; J. Juhl Korsbæk¹; S. Hamann²; R. Jensen¹

¹Danish Headache Center, Department of Neurology, Rigshospitalet‐Glostrup, University of Copenhagen, Copenhagen, Denmark; ²Department of Ophthalmology, Rigshospitalet‐Glostrup, Copenhagen, Denmark

Background and aims: Misdiagnosis of Idiopathic Intracranial Hypertension (IIH) is prevalent and potentially harmful. We evaluate the diagnostic process in IIH and the impact of National Guideline (NG) on IIH management.

Methods: Retrospective observational study of patients referred to the Danish Headache Center bysuspected IIH,Jan 2020 to Sep 2022. We retrieved data on diagnostic work‐up (DW) and duration, causes for suspecting IIH, and mismanagement, and compared outcomes by final diagnosis (confirmed versus disproven IIH (non‐IIH)) and by period before and after the NG. Level of significance was Bonferroni‐corrected to p < 0.002.

Results: 124 patients were referred. We excluded IIH relapse (n = 22) and secondary intracranial hypertension(n = 6) leaving 96 patients with suspected new‐onset IIH. We confirmed IIH in 28% and disproved IIH in 72% Confirmed IIH was discovered by optic disc swelling in 93%. Neuroimaging indicating intracranial hypertension (n = 1) and clinical phenotype (n = 1) aided little in finding true cases, but often elicited IIH suspicion suggesting anchoring bias with premature closure. False‐positive misdiagnosis affected 9%, false‐negative misdiagnosis affected 2%. DWU was significantly more comprehensive and faster in confirmed IIH compared to non‐IIH. Mismanagement dropped by implementation of the NG (from 44% to 20%, p = 0.022), whereas diagnostic accuracy remained low (38% before vs. 21% after, p = 0.11).

Causes for initial IIH suspicion and final diagnosis.

Conclusion: Optic disc swelling is the main determinant leading to correct IIH diagnostics. Ophthalmic evaluation is urgent and decisive in suspected IIH and should guide DWU to mitigate unnecessary investigations. Neuroimaging and clinical phenotype have little diagnostic value and introduce bias. A national guideline optimizes the diagnostic process.

Disclosure: N. S. Hansen received funding from the Novo Nordic Foundation during the conduction of the work. J. J. Korsbæk received funding from the Lundbeck Foundation, Rigshospitalet‐Glostrup and Odense University Hospital. S. Hamann received funding from the VELUX Foundation. R. Jensen gave lectures for Pfizer, Eli‐Lilly, ATI, Merck, TEVA, Novartis, Lundbeck and Allergan. Investigator in clinical trials with ATI, Eli‐Lilly, Novartis and Lundbeck; received research funding from University of Copenhagen, Rigshospitalet, ATI, Lundbeck Foundation, The Medical Society in Copenhagen, Novo Nordisk Foundation and Tryg Foundation.

OPR‐078

OCT in multiple sclerosis: beyond the optic neuritis versus non‐optic neuritis universe

S. Matos; A. Jorge; I. Pais; A. Martins; I. Correia; C. Nunes; M. Macário; S. Batista; J. Lemos

Neurology Department, Coimbra University Hospital Centre, Coimbra, Portugal

Background and aims: When using optical tomography studies(OCT) in multiple sclerosis(MS) eyes are usually classified as having had clinical optic neuritis(ON), subclinical ON, or as otherwise normal. We believe such approach undermines the importance of further including and classifying eyes with signs indicative of retrochiasmal/chiasmal disease(RCD/CD).

Methods: Objectives. To analyze eyes with OCT, evidence of RCD/CD in a large database of MS patients. Methods. Eyes of MS patients examined with OCT were classified as normal, with clinical ON(diagnosed >6 months prior), subclinical ON(>7 micra inter‐eye retinal nerve fiber layer[RNFL] thickness difference and/or > 4 micra inter‐eye ganglion cell layer[GCL] thickness difference), subclinical or clinical CD(bilateral and congruent nasal GCL loss), subclinical or clinical RCD(bilateral and congruent homonymous GCL loss) and subclinical (non‐localizing) involvement (color and/or statistical RNFL/GCL map abnormalities not fulfilling criteria above).

Results: We included 273 eyes. 177(64.8%) of our MS patients had OCT abnormalities, 32.9% of which were subclinical. Eyes had evidence of ON only (n = 86, 31.5%), RCD/CD (n = 36, 13.1%), and non‐localizing findings (n = 55, 20.1%). When comparing between normal, ON, and RCD/CD eyes, disease duration in the right eye was different between groups (p = 0.020), being greater in RCD/CD (p = 0.019) and ON (p = 0.029), than in normal eyes. Disease duration in the left eye was near‐significantly different between groups (p = 0.076), being greater in RCD/CD (p = 0.037) than in normal eyes. Relapse rate in the 2 years prior in the right eye, was near‐significantly different between groups (p = 0.086), being greater in RCD/CD (p = 0.036) than in ON eyes.

Conclusion: Our work supports the use of OCT for identifying MS‐related damage of chiasmal and retrochiasmal pathways.

Disclosure: Nothing to disclose.

OPR‐079

Clinical features, video‐oculographic profile, and treatment in spinocerebellar ataxia type 27B (SCA27B)

S. Fenu ¹; D. Di Bella²; E. Sarto²; D. Pareyson¹; C. Pisciotta¹; S. Magri²; E. Salsano¹; F. Taroni²

¹Unit of Rare Neurological Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; ²Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy

Background and aims: Spinocerebellar ataxia type 27B (SCA27B) is a late‐onset, autosomal‐dominant disorder caused by a GAA‐repeat expansion in the FGF14 gene and characterized by oculomotor abnormalities. This study aims to detail the oculomotor profiles of SCA27B patients and assess the efficacy of 4‐aminopyridine.

Methods: Eight genetically confirmed SCA27B patients underwent clinical and video‐oculographic examinations using EyeSeeCam. Six received 4‐aminopyridine to evaluate its effect on nystagmus.

Results: The cohort consisted of six males and two females, mean age 69 ± 10.3 years, with disease duration of 6.6 ± 3 years. All displayed oculomotor abnormalities at both clinical and instrumental examination; half reported diplopia. Video‐oculography showed reduced smooth pursuit gain in all tested patients (6/6), but normal saccade metrics (8/8). Nystagmus was present in all, predominantly downbeat (7/8) and gaze‐evoked (3/8), with normal vestibulo‐ocular reflex gains (8/8). Treatment with 4‐aminopyridine led to both subjective and objective improvement in 5/6 cases, which was significant in three patients (see Figure) and mild in two. Only one patient had no benefit.

FIGURE 1 Gaze Holding assessment before and after treatment with 4‐aminopyridyne shows complete disappearance of nystagmus.

Conclusion: SCA27B patients exhibit primarily vestibulocerebellar impairments, with significant smooth pursuit and nystagmus abnormalities but no saccadic or vestibulo‐ocular reflex alterations. 4‐aminopyridine was effective in treating nystagmus in most patients, highlighting the potential of targeted therapy in SCA27B management. Further research is needed to optimize treatment strategies.

Disclosure: Nothing to disclose.

OPR‐080

Efgartigimod in non‐AChR myasthenia gravis: a 24 months experience

C. Antozzi ¹; R. Frangiamore¹; E. Rinaldi¹; F. Vanoli¹; F. Andreetta¹; S. Bonanno¹; L. Maggi¹; R. Arnaboldi²; A. Pinna²; R. Mantegazza¹

¹Neuroimmulogy and Muscle Pathology Unit Fondazione IRCCS Istituto Neurlogico C. Besta, Milan Italy; ²argenx Italy, Milan, Italy

Background and aims: The neonatal Fc receptor (FcRn) inhibitor Efgartigimod (EFG) has been approved for treatment of generalized Myasthenia Gravis (gMG) with anti‐AChR antibodies. We investigated the efficacy of EFG in non‐AChR gMG along a clinical follow‐up of 2 years.

Methods: We treated 13 patients with gMG without anti‐AChR antibodies: 5 MuSK+, 2 LRP4+ and 6 triple‐negative (confirmed by live CBA). EFG was administered according to the GENERATIVE protocol (consisting of a Fixed period of 2 treatment cycles of 4 infusions at weekly intervals, followed by a Flexible period during which EFG was given in case of clinical worsening) starting from November 2021. Outcomes were evaluated by means of the MG‐ADL, QMG, and MGC scores.

Results: The mean follow‐up was 14.5 ± 6.7 months. Meaningful improvement was observed with the clinical scores adopted (MG‐ADL: −5.5 ± 3.64; MGC: −8.5 ± 6.54; QMG: −4.84 ± 4.92). The number of cycles/year was 3.9 ± 0.99. The interval between cycles was 8.9 ± 3.8 weeks. MG‐ADL improvement greater than 5 points was recorded in 49% of patients. 46% of patients required hospitalization during the 2 years before treatment with EFG; during EFG none of the patients was hospitalized or required immunomodulation. No major side effects or infusion related reactions occurred.

Conclusion: EFG was effective in non‐AChR gMG and modified significantly the course of the disease. Our experience strengthens the role of FcRn inhibition as a new effective tool in the management of MG without anti‐AChR antibodies, as demonstrated by RCT in AChR‐associated gMG. A longer follow‐up will be available at the time of the meeting.

Disclosure: C. Antozzi received funding for travel, meeting attendance, or Advisory Board participation from Biogen, Sanofi, Alexion, Momenta, argenx, UCB and Janssen R. Frangiamore received funding for meeting attendance and speaking from argenx, UCB and Alexion. L. Maggi received funding for travel, meeting attendance or Advisory Board participation from Sanofi Genzyme, Roche, Alexion, AmicusTherapeutics and Biogen. S. Bonanno received funding for travel, meeting attendance or Advisory Board participation from Sanofi Genzyme, Biogen and Roche. F. Vanoli received funding for travel or meeting attendance from Alexion Pharmaceuticals and argenx R. Mantegazza received funding for travel, meeting attendance or Advisory Board participation from Alexion, Argenx, Biomarin, Catalyst, Sanofi, Regeneron and UCB A. Pinna and R. Arnaboldi are employees of argenx Italy F. Andreetta and E. Rinaldi have nothing to disclose.

OPR‐081

A real‐life comparison of eculizumab and efgartigimod in generalized myasthenia gravis patients

C. Pane¹; V. Di Stefano²; N. Cuomo¹; A. Sarnataro¹; C. Vinciguerra⁵; L. Bevilacqua⁵; M. Camapnile¹; F. Brighina²; N. Rini²; G. Puorro¹; A. Marsili¹; M. Garibaldi³; L. Fionda⁴; F. Saccà ⁶

¹NSRO Department, Federico II University, Naples, Italy; ²Department of Biomedicine, Neuroscience and Advanced Diagnostic (BIND), University of Palermo, Palermo, Italy; ³Neuromuscular and Rare Disease Centre, Sant'Andrea Hospital, Rome, Italy.; ⁴Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, SAPIENZA University of Rome, Rome, Italy; ⁵Neurology Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, Salerno, Italy; ⁶GENESIS Department, Federico II University, Naples, Italy

Background and aims: Eculizumab (ECU) and Efgartigimod (EFGA) are approved for the treatment of generalized Myasthenia Gravis (gMG). Objective of our study is to describe their clinical response in a real‐life setting.

Methods: We included patients receiving either ECU or EFGA as part of our clinic practice and retrospectively collected data on the MG activities of daily living (MG‐ADL), quantitative MG scale (QMG), MG deterioration/crises, adverse events, and prednisone use.

Results: We enrolled 63 patients, 32 treated with ECU and 31 with EFGA (Table 1). Median follow‐up was 234 days. Both treatments were well tolerated. Patients treated with EFGA were more likely to suspend treatment (HR 3.732; CI 1.041, 13.385; p = 0.043; Figure 1A). Main reason was MG deterioration, patient choice, adverse event. ECU decreased the MG deterioration/crises rate more than EFGA (OR 0.545, CI 0.363, 0.818; P = 0.003; Figure 1B). By week 24, MG‐ADL decreased by −6.5 points for ECU and − 5.0 for EFGA (p = 0.188; Figure 2A); the QMG decreased by −8.0 for ECU and − 2.9 for EFGA (p = 0.003; Figure 2B). Mean prednisone reduction at follow‐up was −21.3 mg for ECU and − 8.1 mg for EFGA (p = 0.026). Speed of CS reduction was −13.1 mg/month for ECU and − 3.2 mg/month for EFGA (p = 0.001).

TABLE 1 Patient demographics.

FIGURE 1 Treatment retention and MG deterioration/crisis during treatment.

FIGURE 2 Treatment effect of MG‐ADL, QMG, and Prednisone reduction.

Conclusion: Eculizumab and Efgartigimod proved to be both effective treatments in a real world setting as they reduced MG‐ADL and QMG in difficult to treat gMG patients. Patients treated with ECU were less likely to suspend treatment or show a deterioration/crisis. Prednisone sparing effect and reduction speed was higher with Eculizumab.

Disclosure: F.S. received public speaking honoraria from Alexion, argenx, Biogen, Genpharm, Madison Pharma, Mylan, Novartis, Roche, Sanofi, Teva, Viatris, Zai Lab; he also received compensation for Advisory boards or consultation fees from Alexion, Almirall, argenx, AstraZeneca, Avexis, Biogen, Dianthus, Forward Pharma, Lexeo Therapeutics, Novartis, Reata, Sandoz, Takeda; he is PI in clinical trials for Alexion, argenx, Immunovant, Novartis, Prilenia, Sanofi.

OPR‐082

Childbirth and neonatal outcomes in a nationwide myasthenia gravis cohort

J. Lindroos ¹; M. Bjørk¹; J. Cohen²; K. Danielsson³; O. Hikmat⁴; J. Hoff⁵; N. Gilhus¹

¹Department of Clinical Medicine, University of Bergen, Bergen, Norway/ Department of Neurology, Haukeland University Hospital, Bergen, Norway; ²Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway; ³Department of Obstetrics and Gynaecology, Haukeland University Hospital, Bergen, Norway; ⁴Department of Paediatrics and Adolescent Medicine, Haukeland University Hospital, Bergen, Norway/ Department of Clinical Medicine, University of Bergen, Bergen, Norway; ⁵Faculty of Health Studies at VID Specialized University, Bergen, Norway

Background and aims: Myasthenia Gravis (MG) muscle weakness can complicate childbirth. Transient neonatal myasthenia gravis (TNMG) can result from maternofetally transferred autoantibodies. Our aim was to estimate the risks at childbirth in a maternal MG‐cohort.

Methods: A cohort study using nationwide data from the Medical Birth Registry of Norway. Maternal MG was identified by MG‐diagnosis or pyridostigmine‐use, in current or prior pregnancy. All MG‐exposed and unexposed singleton live births in Norway 1999–2022 were compared. Main outcomes were mode of delivery (caesarean section (CS) vs. vaginal, emergency CS vs. vaginal, elective CS, and operative vaginal vs. non‐operative vaginal), induction of labour, TNMG‐rate and neonatal ward admission. Odds ratios (OR) with robust standard errors adjusted for year of birth, maternal age, parity and co‐habitation were calculated.

FIGURE 1 Inclusion–exclusion flowchart of singleton live births with and without maternal myasthenia gravis (MG) exposure, years 1999–2022 in Norway.

Results: 133 MG‐births and 1,344,520 unexposed births were included. Maternal MG did not significantly increase the risk for CS (aOR 1.32, 95% CI: 0.87–1.99). Elective CS (1.90, 1.10–3.30) and induced labour (1.56, 1.05–2.33) were more common with MG. The emergency CS rate was 10% for both groups (0.97, 0.54–1.76). Among MG‐exposed children, five (4%) had TNMG and 38% were admitted to neonatal ward, compared to 10% of unexposed (5.47, 3.85–7.77).

TABLE 1 Obstetrical and neonatal outcomes with and without maternal MG exposure among all singleton live births in Norway 1999–2022.

Conclusion: The risks for elective CS and induced labour were increased, but not for emergency CS, suggesting that pregnancy planning helps avoid complications in MG‐women. Few MG‐exposed children had TNMG, but 38% were admitted to a neonatal ward. All children of mothers with MG should be observed in‐hospital for minimum 2–3 days as TNMG symptoms often develop with delay.

Disclosure: N.E. Gilhus has received financial support from UCB, Argenx, Janssen, Merck, Roche, Alexion, Immunovant, Huma, Denka, Grifols, and Dianthus. Bjørk, M H. has received speaker honoraria and/or served on scientific advisory boards for Teva, Eisai, AbbVie, Pfizer, Novartis, Lundbeck, Angelini Pharma, Jazz pharmaceuticals, and Lilly during the last 5 years. None of the assignments concerned treatment of Myasthenia Gravis. Lindroos, JLV; Cohen, JM; Danielsson, KC; Hikmat, O; Hoff, JM: Nothing to disclose.

OPR‐083

Automatic method for jitter estimation in electromyographic signals

A. Malanda ¹; C. Valle¹; D. Stashuk²; O. Garnés³; J. Rodríguez¹; J. Navallas¹

¹Electrical, Electronics and Communication Engineering, Public University of Navarra, Pamplona. Spain; ²System Design Engineering Department, University of Waterloo, Waterloo, Canada; ³Neurophysiology Service, Jiménez Díaz Foundation University Hospital

Background and aims: Neurophysiological jitter measurement using concentric needle electrodes is a laborious and difficult task, because potentials from several fibers may appear in the recordings due to the large recording areas of these electrodes. This work presents an automatic method that estimates jitter from motor unit potential (MUP) trains recorded using single‐fiber or concentric needle electrodes.

Methods: MUP intervals likely being formed by only one muscle fiber potential are detected. Then jitter measurement is performed between pairs of these intervals. 132 electromyographic signals were recorded from 8 patients with disorders of the neuromuscular junction or different neuropathies, using a Keypoint system and facial‐concentric electrodes. These signals were decomposed into several MUP trains using DQEMG software. Jitter was then estimated manually, using a home‐made graphical interface (Figure 1A,B) and using the automatic method (Figure 1C,D).

FIGURE 1 Examples of MUP trains analyzed by the manual method, with marked negative peaks and the obtained MCD values (A, B). The same MUP trains analyzed with the automatic method, with highlighted valid intervals and MCD values (C, D).

Results: From 96 MUP trains valid for the analysis, 102 automatic and 84 manual jitter measurements were obtained. Comparative analysis (Figure 2) yielded a mean of jitter differences of 1.74 μs, a mean of absolute differences of 2.73 μs and values of −2.62, −0.35, 2.53 and 7.56 μs for the 5th, 25th, 75th and 95th percentiles of the jitter differences distribution, respectively.

FIGURE 2 Boxplots of MCD values obtained by manual and automatic methods and of the difference in MCD values (A). Histogram of the difference in MCD values (B).

Conclusion: Although more extensive tests are still required, these results suggest that the proposed automatic jitter estimation method may be a valuable technique for clinical practice.

Disclosure: This work has been funded by the Department of Health of the Government of Navarra (project GN2022/29) and by the Spanish Ministry of Science and Innovation (project PID2022‐136620OB‐I00).

OPR‐084

The lifetime outcomes of antiseizure medication in patients with mesial temporal lobe epilepsy and hippocampal sclerosis

A. Dias; P. Henning; W. Ferreira; M. Alvim; C. Yasuda; F. Cendes

Laboratory of Neuroimaging, Department of Neurology, UNICAMP, Campinas, Brazil

Background and aims: To evaluate the lifetime seizure frequency in patients with mesial temporal lobe epilepsy and hippocampal sclerosis (mTLE‐HS).

Methods: We studied 118 patients with mTLE‐HS followed at UNICAMP. We reviewed the seizure frequency, age, duration of epilepsy, dosages and type of antiseizure medications (ASM) used. Patients were split into 3 groups: seizure‐free (no seizures in the last 2 years or more of follow‐up), fluctuating (seizure‐freedom periods of 1 year or longer) or pharmacoresistant (never had a seizure‐free period of more than 1 year). Pharmacoresistant patients did not undergo surgery either because they refused it or had contraindications. Patients who underwent surgery were not included in this study.

Results: The mean age was 56.13 years and mean follow‐up was 20.25 years (range 3–47, SD 9.83). 35.6% (n = 42) had right‐TLE, 50% (n = 59) left‐TLE and 14.4% (n = 17) bilateral‐TLE. Thirty‐six (30.5%) were seizure‐free, 39 (33.05%) had a fluctuating course and 43 (36.45%) were pharmacoresistant. There were no differences among groups in relation to the age they became seizure‐free, age of epilepsy onset, epilepsy duration, epilepsy family history, number of ASM used over the years or number and type of ASM in use at the last follow‐up (p > 0.074). The most common ASM was carbamazepine.

Conclusion: Three clinical evolution patterns were observed among patients with mTLE‐HS who did not underwent surgery: pharmacoresistant, fluctuating seizure control/pharmacoresistant, and seizure‐free. We found no significant differences in the main clinical features among groups. Further studies are necessary to define the factors that could predict these three outcome profiles.

Disclosure: Grants: CEPID ‐ FAPESP: “The Brazilian Institute of Neuroscience and Neurotechnology (BRAINN)” 2013/07559–3; CNPQ 315953/2021–7; Conflicts of interest: Fernando Cendes participated in advisory board for Takeda Pharmaceuticals, Libbs, Eurofarma; Clarissa Yasuda participated in advisory board for Eurofarma. Received honoraria for writing educational material for Torrent and Libbs.

OPR‐085

Exploring the long‐term effects of COVID‐19 in patients with epilepsy: A multicenter Italian observational study

C. Corniello ¹; F. Dono¹; M. Russo¹; F. Lombardo¹; G. Evangelista¹; S. Consoli¹; F. Narducci²; G. Assenza²; C. Liguori³; C. Calvello³; S. Sensi¹

¹Department of Neuroscience, Imaging and Clinical Science, “G. d'Annunzio” University of Chieti‐Pescara, Chieti, Italy; ²Unit of Neurology, Neurophysiology, Neurobiology, Department of Medicine, University Campus Bio‐Medico of Rome, Rome, Italy; ³Neurology Unit, University Hospital of Rome Tor Vergata, Viale Oxford, 81, 00133, Rome, Italy

Background and aims: A growing evidence in the literature support that patients recovered from COVID‐19 may develop novel neurological and psychiatric symptoms lasting from weeks to months. This condition, labeled as “long COVID”, can be observed more frequently in patients with chronic diseases. The aim of this study is to identify the long‐term effects of COVID‐19 in people with epilepsy (PwE).

Methods: PwE aged >18 who accessed to three epilepsy centers in the center of Italy during the first pandemic wave between March 2020 and December 2021 were enrolled. According to a documented clinical and laboratory SARS‐CoV‐2 infection, patients were divided into two groups: COVID+ and COVID‐. Epilepsy features (i.e., seizure frequency, treatment), and neurological and psychiatric symptoms were collected at baseline and at 6‐ and 12‐month follow‐up visits in both groups.

Results: 39 patients in COVID+ group (17/22 M/F, age: 40.6 ± 18.6 years, 33 focal epilepsy, 6 generalized epilepsy) and 91 patients in COVID‐ (42/49 M/F, age: 42.9 ± 19.7 years, 69 focal epilepsy, 22 generalized epilepsy) met the inclusion criteria. At 6‐month, COVID+ group showed a need for antiseizure medication dose adjustment compared to COVID‐ group (p < 0.0001). An increased diagnosis of psychiatric (i.e., anxiety and depression) and neurological (i.e., cognitive) symptoms was observed in the COVID+ group at both 6‐ and 12‐month (p < 0.0001). At 12‐month, up to 40% of patients in the COVID+ group revealed an increased seizure frequency (p = 0.002).

Conclusion: These findings suggest that PwE with previous SARS‐CoV‐2 infection may develop psychiatric and neurological long‐lasting effects.

Disclosure: Nothing to disclose.

OPR‐086

Evolution into electrical status epilepticus during sleep in patients with self‐limited focal epilepsies

M. İriş ¹; M. Atacan Yaşgüçlükal²; C. Yalçınkaya¹; V. Demirbilek¹

¹Department of Neurology, Istanbul University‐Cerrahpasa, Cerrahpasa Faculty of Medicine, Istanbul, Turkey; ²Department of Neurology, Haseki Research and Training Hospital, Health Sciences University, Istanbul, Turkey

Background and aims: Self‐limited focal epilepsies of childhood (SeLFE), while predominantly considered benign, are known to potentially manifest with electrical status epilepticus during sleep (ESES) in a minority of patients.

Methods: The medical records of individuals diagnosed with one of the SeLFE syndromes according to the ILAE 2022 diagnostic criteria, who have been followed in our center between 1989–2023, were retrospectively analyzed. At least two awake and sleep EEGs were performed during a minimum 2‐year follow‐up. ESES is considered as spike and wave discharges occupying ≥50% of NREM sleep with symmetrical or mildly asymmetrical bilateral or unilateral hemispheric distribution.

Results: Among 144 patients with SeLFE, 57(39.6%) were diagnosed with self‐limited epilepsy with centrotemporal spikes (SeLECTS); 65(45.1%) with self‐limited epilepsy with autonomic seizures (SeLEAS); and 22 (15.3%) with childhood occipital visual epilepsy (COVE). The mean age of seizure onset was 7.6 years, 5.6 years, 8.5 years, respectively. Twelve (8.3%) evolved into ESES (5 from SeLECTS, 6 from SeLEAS, 1 from COVE). Time elapsed between onset of first seizure and evolution into ESES ranged from 5.2 to 75 months (mean: 26.8±19.8), 6.2–42.8 months (mean: 20.1±14.7 for patients with SeLECTS; 5.2–75.0 months (mean: 32.7±24.5) with SeLEAS, and 25.0 months with COVE). All except one patient had also cognitive or behavioral regression and one patient was diagnosed with Landau–Kleffner syndrome.

Conclusion: The most recent definition of ILAE highlights that SeLFEs are no longer recognized as “benign” epilepsies. Even with a low incidence rate, clinicians should always be cautious about the risk of ESES development in these syndromes.

Disclosure: Nothing to disclose.

OPR‐087

Thalamic atrophy and parahippocampal cortical surface area may distinguish clinical response in temporal lobe epilepsy

P. Henning; A. Dias; W. Ferreira; B. Campos; M. Alvim; C. Yasuda; F. Cendes

Laboratory of Neuroimaging, Department of Neurology, UNICAMP ‐ Campinas, Brazil

Background and aims: To correlate response to antiseizure medication (ASM) with cortical surface area (CSA) and subcortical volumes (SV) in patients with mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE‐HS).

Methods: 111 patients with mTLE‐HS who did not undergo surgery because they refused it, had contraindications, or had good seizure control with ASM (mean follow‐up of 21.8 years) were categorized in three groups: pharmacoresponsive (seizure‐free in the last 2 years or more), fluctuating‐response (seizure‐freedom periods of 1 year or longer) and pharmacoresistant (never had a seizure‐free period of more than 1 year). T1‐weighted MRIs (1 × 1 × 1 mm) were processed with Freesurfer‐6.0. We analyzed the following regions of interest for CSA: inferior, middle and superior temporal gyrus, parahippocampal gyrus and insula. Volumes of thalamus, hippocampus and amygdala, along with the CSA from each ASM response‐groups were compared with 112 controls.

Results: Groups were balanced for age, sex, and side of HS. Each ASM response‐group had 37 patients. Compared with controls, ipsilateral hippocampal volumes were reduced in all groups (p < 0.0001) without difference among groups. There was no difference in the contralateral hippocampal volumes among groups. Volumes of ipsilateral and contralateral thalami were reduced in the pharmacoresistant group (p < 0.003), and the contralateral thalamus was reduced in pharmacoresponsive and fluctuating‐response groups (p < 0.006). Amygdala was reduced in the pharmacoresponsive group (p = 0.03). Ipsilateral parahippocampal CSA was reduced in the pharmacoresistant group (p = 0.013). Other CSA did not differ among groups.

Conclusion: Bilateral thalamic atrophy and reduced ipsilateral parahippocampal CSA appears to distinguish pharmacoresistant mTLE‐HS from those with better response to ASM.

Disclosure: CEPID ‐ FAPESP: “The Brazilian Institute of Neuroscience and Neurotechnology (BRAINN)”, grant 2013/07559–3; CNPQ 315953/2021–7.

OPR‐088

Real‐world data on continuous deep brain stimulation of the anterior nucleus of the thalamus for drug‐resistant epilepsy

R. Morcos ¹; J. Sarto²; M. Carreño²; M. Centeno²

¹Neurology Department, Hospital Universitario Vithas Madrid, Spain; ²Neurology Department, Hospital Clinic Barcelona, Barcelona, Spain

Background and aims: This study aimed to evaluate the efficacy and safety of bilateral deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) in patients with drug‐resistant epilepsy (DRE), focusing on continuous stimulation settings.

Methods: A retrospective review was conducted on eight patients with focal DRE who underwent bilateral ANT‐DBS. Clinical and seizure data were collected, and stimulation parameters were adjusted to maximize clinical benefit. Patients were followed for a mean of 51 months, and changes in seizure frequency were assessed.

Results: Continuous ANT‐DBS demonstrated a significant (>50%) reduction in seizure frequency for all patients, with a mean reduction of 68%. The most severe seizure type showed the greatest response to stimulation. None of the patients achieved seizure freedom, but all experienced a transient post‐implantation seizure‐free period. Psychiatric adverse events were reported in 50% of patients, primarily depression, but they were manageable.

TABLE 1 Summary of results. FAS, focal aware seizure; FIAS, focal impaired awareness seizure, FBTCS, focal to bilateral tonic–clonic seizure.

Image 1 and 2. MRI reconstruction of DBS implantation: 3D (top) and axial planes (bottom).

Conclusion: This study highlights the effectiveness of continuous ANT‐DBS in reducing seizures for patients with DRE who are not candidates for resective surgery. The findings suggest that continuous stimulation may offer a valuable alternative to intermittent settings. The study underscores the importance of precise electrode placement and a network‐focused approach in selecting DBS targets. Overall, ANT‐DBS presents a safe and promising option for improving the quality of life in patients with drug‐resistant epilepsy.

Disclosure: Nothing to disclose.

OPR‐089

Abnormal dopamine transporter imaging in pure autonomic failure – A follow‐up study

G. Chiaro ¹; R. Alnasser Alsukhni¹; G. Ingle¹; K. Bhatia²; C. Mathias³; J. Bomanji⁴; V. Iodice¹

¹Autonomic Unit, National Hospital for Neurology and Neurosurgery, London, UK; ²Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK; ³UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK; ⁴Institute of Nuclear Medicine, UCLH NHS Foundation Trust, London, UK

Background and aims: Abnormal dopaminergic transporter imaging in pure autonomic failure (PAF) is a potential biomarker of central nervous system involvement as described in our pilot study of 10 PAF patients. In this follow‐up study, we evaluated the prevalence of abnormal 123I‐Ioflupane dopamine transporter SPECT (DaTSCAN) in a larger, prospective cohort of patients with PAF and assessed the rate of phenoconversion to more widespread alpha synucleinopathies.

Methods: Consecutive PAF patients underwent a multimodal assessment including cardiovascular autonomic function testing performed with the Finapres NOVA and DaTSCAN, as part of the Queen Square Autonomic Prodromal Project (QSA‐PRODROMAL).

Results: 70 patients with PAF with a median disease duration of 6 (IQR 3–10) years were identified. 22 developed a more widespread synucleinopathy (7 Parkinson's disease, 4 dementia with Lewy bodies, 2 multiple system atrophy‐cerebellar [MSA‐C], 9 multiple system atrophy‐parkinsonian). All phenoconverters had an abnormal DaTSCAN, apart from 2 patients who converted to MSA‐C. In patients who underwent DaTSCAN while still retaining a PAF phenotype, the median lag between imaging and phenoconversion was 8 IQR (4–16) months. 48 patients retained a PAF phenotype at last follow‐up and 4 of them had an abnormal DaTSCAN. These had a clinical REM sleep behaviour disorder. There were no differences in demographics, autonomic function, or plasma catecholamine spillover between PAF patients with normal or an abnormal DaTSCAN.

Conclusion: DaTSCAN is a biomarker of subclinical central nervous system involvement in PAF and can predict phenoconversion to more widespread alpha‐synucleinopathies in patients with a prodromal phase of up to 9 years.

Disclosure: The authors have nothing to disclose.

OPR‐090

The role of plasma norepinephrine level in differential diagnosis of alpha‐synucleinopathies

G. Carrozzo ¹; P. Guaraldi²; I. Cani¹; L. Baldelli¹; G. Giannini¹; L. Sambati²; G. Barletta¹; P. Cortelli¹; G. Calandra‐Buonaura¹

¹Department of Biomedical and NeuroMotor Sciences (DIBINEM), Alma Mater Studiorum, University of Bologna, Bologna, Italy and IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy; ²IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy

Background and aims: The alpha‐synucleinopathies, including Parkinson's Disease (PD), Dementia with Lewy Body (DLB), Multiple System Atrophy (MSA) and Pure Autonomic Failure (PAF), differ for specific configurations of abnormal alpha‐synuclein aggregation across the nervous system. The variation in autonomic dysfunction observed in these conditions is attributed to the differing degrees of involvement of Autonomic Nervous System at central or peripheral level or both. This results in different patterns of plasma level of the neurotransmitter norepinephrine (NE), that could help to differentiate alpha‐synucleinopathies.

Methods: We collected blood samples for NE measurement during supine rest (at 20th and 25th min) and at 10th min of the orthostatic phase or at the occurrence of orthostatic intolerance during Head‐Up Tilt Test (HUTT), from 331 subjects (61 controls, 72 PD/DLB; 147 MSA, 51 PAF).

Results: Preliminary results showed a significant higher increment of plasma NE during HUTT in PD/DLB (mean ± SD; 155.9 ± 130.2 pg/mL) compared to MSA (82.9 ± 101.4 pg/mL) in absence of a significant difference in supine NE levels (PD/DLB, 250.3 ± 137.7 pg/mL; MSA, 259.5 ± 160.5 pg/mL). Comparisons with the other groups and cut‐off values evaluation are ongoing.

Conclusion: Our findings suggest that plasma NE patterns could potentially differentiate alpha‐synucleinopathies in the early stages of the diseases, representing a biomarker for differential diagnosis.

Disclosure: Nothing to disclose.

OPR‐091

Cardiovascular autonomic signature of hereditary transthyretin amyloidosis

I. Cani ¹; M. Gianoli¹; G. Barletta²; R. Rinaldi²; S. Longhi³; C. Gagliardi³; N. Galiè³; P. Cortelli¹; P. Guaraldi²

¹Department of Biomedical and NeuroMotor Sciences (DIBINEM), Alma Mater Studiorum ‐ University of Bologna, Italy; ²UOC Clinica Neurologica Rete Metropolitana NEUROMET, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy; ³UO Cardiologia, IRCCS Policlinico Sant'Orsola‐Malpighi, Bologna, Italy

Background and aims: Autonomic dysfunction is a fundamental hallmark in the neurological presentation of hereditary transthyretin amyloidosis (ATTRv). Despite its diagnostic significance, there is a notable lack of instrumental studies examining the cardiovascular autonomic involvement in ATTRv individuals.

Methods: To characterized cardiovascular autonomic functions in a single‐center cohort of subject with ATTRv through standardized cardiovascular reflex tests (CRTs) including head‐up tilt test (HUTT), Valsalva maneuver (VM), deep breathing, cold face test and handgrip test (Finapres Medical System). For comparative analysis, an equivalent number of healthy controls (HC) with similar age and sex distributions were recruited.

Results: The cohort included 65 ATTRv subjects (age 59.77 (14.56), 42% female). During HUTT, ATTRv subjects displayed decreased BP and HR responses compared to HC; with four patients experiencing orthostatic hypotension. All indexes of VM were reduced in ATTRv compared to HC (overshoot: 20 vs. 41 mmHg; phase IIb‐IIa: 6 vs. 15 mmHg; Valsalva ratio: 1.33 vs. 1.75). BP responses to cold face and hand grip tests were also attenuated in ATTRv compared to HC. Additionally, the inspiration/expiration ratio during deep breathing was reduced in ATTRv subjects. Among ATTRv cohort, 23 subjects were asymptomatic with no neurological or cardiological involvement. ATTRv carriers differed from HC, exhibiting significantly lower BP responses during HUTT and reduced overshoot at VM, indicating early autonomic involvement in ATTRv.

Conclusion: This study represents the largest investigation into autonomic cardiovascular regulation in ATTRv. CRT documented cardiovascular autonomic impairment in ATTRv subjects. Additionally, ATTRv carriers displayed early autonomic dysfunction, preceding the onset of neurological and cardiological manifestation. These findings provide crucial insights for earlier diagnosis and timely intervention.

Disclosure: Nothing to disclose.

OPR‐092

The catastrophic nature of vasovagal syncope in cardiovascular self‐organized criticality

N. Navasiolava¹; A. Robin¹; M. Custaud¹; J. Fortrat ²

¹Univ Angers, Inserm, CNRS, Équipe CARME, SFR ICAT, Angers, France; Centre de Recherches Cliniques, CHU Angers, France; ²Univ Angers, Inserm, CNRS, Équipe CARME, SFR ICAT, Angers, France; Service de Médecine Vasculaire, CHU Angers, France

Background and aims: The recent elucidation of self‐organized criticality dynamics within the cardiovascular system (CV‐SOC) presents a potential explanatory framework for the occurrence of vasovagal syncope. Self‐organized criticality, a universal theory governing natural systems, posits the spontaneous emergence of unexpected large events, termed catastrophes. This study investigates the hypothesis that vasovagal syncope represents a catastrophic manifestation within the CV‐SOC. To test this hypothesis, we conducted assessments of CV‐SOC preceding an orthostatic challenge.

Methods: Thirty‐five healthy volunteers underwent an orthostatic test involving lower body negative pressure (LBNP, −50 mmHg) in the supine position to simulate orthostatic fluid shifts. Tolerance to the test was defined as completion without symptoms or no blood pressure dropping below 80 mmHg. Beat‐by‐beat heart rate was recorded in the supine position for 20 min 2 days before LBNP to determine the slope of the distribution of long bradycardia (aL), a descriptive CV‐SOC index. We compared subjects classified as orthostatic intolerant and tolerant.

Results: Nineteen subjects were intolerant, and 16 were tolerant (10 and 6 female, respectively). Despite similar heart rates between groups (67 ± 2 and 65 ± 2 bpm for intolerant and tolerant, respectively), the aL index significantly differed (0.14 ± 0.01 and 0.18 ± 0.01, T test, p < 0.01) between tolerant and intolerant subjects.

Fig. Slope of the statistical distribution of bradycardia occurrence (no unit) as index of self‐organized criticality dynamics in healthy subjects non‐tolerant and tolerant to an orthostatic test (T− and T+, respectively). **: p < 0.01, unpaired T test.

Conclusion: This study not only affirms the self‐organized criticality nature of cardiovascular dynamics but also provides compelling evidence linking vasovagal syncope to this inherent nature. Vasovagal syncope, within this framework, emerges as a catastrophic event within the self‐organized criticality dynamics of the cardiovascular system.

Disclosure: The VIVALDI study was funded by the European Space Agency (ESA), and the French National Center of Space Studies (Centre National d'Études Spatiales, CNES, funding n° 4800001118.

OPR‐093

Intracranial baroreflex: A review

E. Schmidt ¹; N. Nasr²; M. Kermorgan³; A. Pavy Le Traon³

¹Neurosurgery, Toulouse, France; ²Neurology, Poitiers, France; ³Neurology, Toulouse, France

Background and aims: In 2018, two independent teams demonstrated that intracranial pressure (ICP) influences the level of sympathetic activity. A modest physiological increase in ICP leads to an increase in directly recorded sympathetic nerve activity in mice, sheep and humans. This novel regulatory mechanism represents an intracranial baroreflex, bridging ICP and the autonomic nervous system (ANS). Over the last 6 years, data have been published to investigate the role of intracranial baroreflex in physiology and pathology.

Methods: We analysed the literature published on the intracranial baroreflex in the last 6 years to provide an up‐to‐date review and highlight the most important facts.

Results: 1. Astrocytes seem appear to function as intracranial baroreceptors and may play a role in ANS control. 2. Modest ICP increase induced by head‐down tilt increases sympathetic activity. 3. Intracranial baroreflex is attenuated in an ovine model of renovascular hypertension. 4 Acute ICP rise was associated with a significant increase in heart rate variability and baroreflex sensitivity.

Conclusion: The effect of ICP on the ANS and the concept of a physiological intracranial baroreflex are now supported by convergent and independent data. Intracranial and extracranial (i.e. arterial) baroreflexes behave in opposition, with excitatory and inhibitory effects on the sympathetic activity, respectively. We propose an integrated physiological scheme of ABP regulation, including intracranial and extracranial baroreflexes, which may be involved in the fine‐tuning of ABP. However, the exact role of the intracranial baroreflex in the pathophysiology of sympathetic overactivity and hypertension requires further investigation.

Intracranial baroreflex in ABP regulation.

Disclosure: no.

OPR‐094

Cutaneous phosphorylated‐synuclein: An early diagnostic biomarker for pure autonomic failure

S. Koay ¹; V. Provitera²; G. Caporaso²; E. Vichayanrat¹; F. Valerio¹; S. Johnstone¹; M. Lunn³; M. Nolano⁴; V. Iodice¹

¹Autonomic Unit, The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK; ²Neurology Department, Skin Biopsy Laboratory, Istituti Clinici Scientifici Maugeri IRCCS, Telese Terme, Italy; ³Queen Square Centre of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK; ⁴Department of Neurosciences, Reproductive Sciences and Odontostomatology, University Federico II of Naples, Naples, Italy

Background and aims: Pure autonomic failure (PAF) is a predominantly peripheral alpha‐synucleinopathy, presenting with progressive autonomic failure in the absence of other neurological features. Atypical presentations may lead to diagnostic uncertainty. We studied whether cutaneous phosphorylated‐synuclein (p‐syn) could distinguish between PAF, multiple system atrophy (MSA), and non‐synucleinopathy related autonomic failure, and its correlation with quantitative markers of autonomic failure.

Methods: Patients underwent autonomic questionnaires, cardiovascular autonomic testing (Finapres) and bilateral distal leg skin biopsies. We noted whether p‐syn was present in nerves supplying autonomic adnexa, including sweat glands, blood vessels, arrector pili muscles, and subepidermal fibres, dermal fibres and nerve fascicles (maximum autonomic subscore 3 and total p‐syn score 6 for each sample, average calculated for both sides).

FIGURE 1 Summary of structures used for calculating autonomic p‐syn subscore (3 structures in top panel) and total p‐syn score (all 6 structures). Figure adapted from Nolano 2022, with permission from IOS Press.

Results: Thirty‐six individuals were studied (11 PAF, 13 MSA, 12 non‐synucleinopathy related autonomic failure). P‐syn was present in 22/22 (100%) PAF biopsies, 19/26 (73%) MSA biopsies, and 0/22 (0%) non‐synucleinopathy biopsies. Total p‐syn score was significantly higher in PAF (median 4.5) compared to MSA (median 1, p < 0.001). Autonomic p‐syn subscore correlated with quantitative markers of autonomic failure related to impaired control of total peripheral resistance, including orthostatic intolerance ratio on tilt (rho = 0.63; p = 0.0004) and blood pressure recovery time following Valsalva manoeuvre (rho = 0.44; p = 0.03), as well as patient‐reported orthostatic intolerance (rho = 0.57; p = 0.006).

FIGURE 2 Confocal images of cutaneous p‐syn deposits from a patient with PAF. P‐syn is seen to co‐localise along nerve fibres, marked with PGP (protein G peptide), running within dermal nerve bundles.

FIGURE 3 Cutaneous autonomic p‐syn score correlated with orthostatic intolerance ratio on tilt (change in systolic blood pressure in mmHg divided by time tolerated on tilt in minutes, to a maximum of 10 min).

Conclusion: Cutaneous p‐syn was abundant in PAF and represents a promising early diagnostic biomarker to help distinguish between predominantly peripheral and central alpha‐synucleinopathies, and non‐synucleinopathy related autonomic failure. P‐syn deposition on autonomic nerves may impair control of total peripheral resistance giving rise to symptomatic orthostatic hypotension.

Disclosure: This study was supported by the Italian Ministry of Health “Ricerca Finalizzata 2013” – project code PE‐2013‐02359028. SK was supported by the Guarantors of Brain Entry Fellowship. MPL and VI are supported by NIHR UCL Biomedical Research Centre.

OPR‐095

Diagnostic and prognostic biomarkers in immune checkpoint inhibitor‐related encephalitis

A. Farina ¹; M. Villagrán‐García¹ ; A. Fourier²; A. Pinto¹; N. Timestit¹; T. Alberto³; J. Aupy⁴; M. Benaiteau¹; C. Birzu⁵; L. Campetella¹; S. Dalle⁶; C. Fontaine Delaruelle⁶; D. Maillet⁶; A. Pegat⁷; D. Psimaraas⁵; M. Rafiq⁸; G. Picard¹; V. Desestret¹; I. Quadrio²; J. Honnorat¹; B. Joubert¹

¹French Reference Center on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, Hôpital Neurologique, Bron; UMR MELIS team SynatAc, INSERM1314/CNRS5284, Lyon, France; ²Lyon Neuroscience Research Center, HCL, Lyon, France; ³Centre Hospitalier de Lille, Lille, France; ⁴Centre Hospitalier de Bordeaux, Bordeaux, France; ⁵Hospital Group Pitié‐Salpêtrière, Paris, France; ⁶Immucare, Lyon, France; ⁷Service ENMG et Pathologies Neuromusculaires, HCL, Lyon, France; ⁸Centre Hospitalier de Toulouse

Background and aims: Diagnostic and prognostic biomarkers are lacking in immune checkpoint inhibitors (ICI)‐related encephalitis. We aimed to characterize the clinical features of ICI encephalitis patients, and identify diagnostic biomarkers and outcome predictors.

Methods: This retrospective study included all patients with possible or definite ICI‐encephalitis whose samples and clinical data were studied in the Lyon Neurological Hospital (2015–2023). Response to treatment was defined as CTCAE (v5.0) grade <3. S‐100 calcium‐binding protein, neurofilament light chain (NfL) and glial fibrillary acidic protein levels were measured in 27 definite ICI‐encephalitis patients and 16 controls.

Results: Seventy‐six patients were identified, including 67 (88%) with definite ICI‐encephalitis (median age, 67 years, 66% male). A focal syndrome was observed in 43/67 patients (64%; limbic encephalitis, rapidly‐progressive cerebellar ataxia, and/or brainstem encephalitis), while 24 (36%) had meningoencephalitis, a non‐focal syndrome with frequent altered mental status (92%) and pleocytosis (100%). Meningoencephalitis patients had less frequent abnormal brain MRI findings (33% vs. 62%, p = 0.025), PNS‐related antibodies (4% versus 84%, p < 0.001), and neuroendocrine cancers (4% versus 49%; p < 0.001) than focal encephalitis patients. Serum NfL > 273.5 pg/mL discriminated definite ICI‐encephalitis patients from controls with sensitivity of 88% and specificity of 81%. Focal ICI‐encephalitis patients responded less to treatment (15%) than ICI‐meningoencephalitis patients (72%, p < 0.001), and PNS‐related antibodies were negatively associated with treatment response (adjusted OR 0.05; 95% CI [0.01; 0.21]). Thirty‐two patients (48%) died during the study period (median 7 months of follow‐up).

Conclusion: Analysis of serum NfL facilitates the diagnosis of ICI‐encephalitis, and focal encephalitis and PNS‐related antibodies are associated with worse treatment response.

Disclosure: Nothing to disclose.

OPR‐096

Outcome and risk of relapse in GABAAR encephalitis

C. Papi ¹; C. Milano²; T. Iizuka³; M. Simabukuro⁴; L. Marmolejo⁵; E. Aguilar⁵; R. Iorio⁶; T. Armangué⁷; F. Graus⁵; J. Dalmau⁵; M. Spatola⁵

¹Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Department of Neuroscience, Catholic University of the Sacred Heart, Rome, Italy; ²Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; ³Department of Neurology, Kitasato University School of Medicine, Japan; ⁴Division of Neurology, Hospital das Clinicas (HCFMUSP), Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil; ⁵Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; ⁶Department of Neuroscience, Catholic University of the Sacred Heart, Rome, Italy; ⁷Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Pediatric Neuroimmunology Unit, Neurology Service, Sant Joan de Déu (SJD) Children's Hospital, University of Barcelona, Barcelona, Spain

Background and aims: Autoimmune encephalitis with antibodies against γ‐aminobutyric acid type A receptor (GABAAR) is characterized by prominent seizures and multifocal brain lesions. Limited data are available on relapse risk and long‐term outcome. The study aim was to report clinical course and outcome of patients with GABAAR encephalitis.

Methods: Clinical information was obtained retrospectively from medical records. Patients were included if GABAAR antibodies were identified by 2 techniques (rat brain tissue and live cell‐based assays) in serum or cerebrospinal fluid.

Results: Nineteen patients with GABAAR encephalitis were included, 3 (16%) children and 16 (84%) adults. At onset, 17 (89%) patients developed seizures, evolving to status epilepticus in 12 (63%), alone or accompanied by other neurological symptoms, most commonly cognitive disturbances (74%). Tumor (mainly thymoma) was found in 11 (58%) patients. Brain MRI showed cortico‐subcortical T2/FLAIR abnormalities in 15 (79%) patients and isolated cerebellar lesions in 2 (11%). Immunotherapy resulted in clinical improvement in 14/16 (88%) patients. Nine (47%) patients had clinical relapses (median 1, range 1–3 relapses), manifesting with seizures in 7 (78%). Older age was associated with clinical relapses (p = 0.0206). After a median follow‐up of 19 months (range 1–59), 4 (21%) patients were dead, 6 (32%) completely recovered, and 9 (47%) partially recovered. Cognitive disturbances were the most frequent neurological sequelae (5/9, 56%). Overall, 10/11 (91%) patients were seizure‐free at last follow‐up, 9/10 (90%) on antiseizure medications.

Conclusion: In GABAAR encephalitis, relapses are not rare, often manifesting with seizure recurrence. Half of the patients are left with residual neurological deficits, mainly cognitive disturbances.

Disclosure: C. Papi receives support from European Academy of Neurology; M. Spatola receives research support from La Caixa Foundation and Spanish National Research Institute (Carlos III).

OPR‐097

Ataxia and movement disorders in autoimmune encephalitis and paraneoplastic neurological syndromes

J. Kerstens ¹; Y. Crijnen¹; J. Brenner¹; R. van Steenhoven¹; M. de Bruijn¹; A. van Sonderen¹; M. van Coevorden‐Hameete¹ ; D. Bastiaansen¹; M. Vermeiren¹; J. de Vries¹; S. Veenbergen²; P. Sillevis Smitt¹; M. Titulaer¹

¹Department of Neurology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands; ²Department of Immunology, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands

Background and aims: Movement disorders (MD) are well‐recognized symptoms of autoimmune encephalitis (AIE) and paraneoplastic neurological syndromes (PNS). Although a large variety of MD has been described in different antibody‐associated syndromes, the frequency of MD remains unknown for most antibodies. This knowledge is important to aid in early diagnosis and develop rational antibody testing strategies.

Methods: We reviewed a large cohort of all known Dutch patients with antibody‐associated AIE/PNS (n = 927) to describe associated movement disorders (MD) and (cerebellar) ataxia. The most common antibodies were LGI1 (n = 182, 19.6%), NMDAR (n = 166, 17.9%), high‐titer GAD65 (n = 122, 13.2%) and Hu (n = 114, 12.3%). Sensory ataxia and faciobrachiodystonic seizures were not considered MD.

Results: MD were present in 337/901 (37.4%) and were the first and/or predominant symptom in 193/297 (65.0%) and 214/297 (72.1%), respectively. Ataxia was by far the most common (n = 159, mainly Yo and GAD65), followed by stiff‐person syndrome (n = 50, mainly GAD65 and GlyR) and chorea (n = 35, mainly NMDAR, IgLON5 and CV2). AIE/PNS associated with antibodies against Yo and Tr presented (almost) exclusively with MD (more specifically ataxia, in 29/30 and 4/4, respectively), while the lowest MD frequency was observed with GABAbR (7/59, 11.9%) and LGI1 (5/182, 2.7%).

Conclusion: MD are common in AIE and PNS, occurring in over a third of the patients. Their frequency varies greatly between subtypes. MD can be the first, predominant and even the only manifestation of these disorders. AIE and PNS should be in the differential diagnosis of new‐onset MD, especially in the case of cerebellar ataxia and chorea.

Disclosure: JK was supported by a Research Mobility Fellowship from the European Joint Programme on Rare Diseases (EJP RD) and is currently funded by the Erasmus Trustfonds. YC and MdB were funded by EpilepsieNL (NEF 14–19 & 19–08), JB was funded by Dioraphte (2001 0403). DB was funded by ZonMW (Memorabel initiative). RvS was funded by ZonMW (VIMP scheme). PSS holds a patent for the detection of anti‐DNER and received research support from Euroimmun. MT has filed a patent, on behalf of the Erasmus MC, for methods for typing neurological disorders and cancer, and devices for use therein, and has received research funds for serving on a scientific advisory board of Horizon Therapeutics, for consultation at Guidepoint Global LLC, and for consultation at UCB. MT has received an unrestricted research grant from Euroimmun AG, and from CSL Behring. The other authors have nothing to disclose.

OPR‐098

Demographic and HLA‐related specificities in LGI1‐antibody encephalitis

L. Campetella ¹; M. Villagrán‐García¹ ; A. Farina¹; M. Villard¹; M. Benaiteau¹; N. Timestit²; G. Picard¹; V. Rogemond¹; B. Joubert¹; J. Honnorat¹; S. Muñiz‐Castrillo³

¹French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, Lyon, France and MeLiS – UCBL‐CNRS UMR 5284 – INSERM U1314, Université Claude Bernard Lyon 1, Lyon, France; ²Department of Biostatistics, Hospices Civils de Lyon, Lyon, France; ³Stanford Center for Sleep Sciences and Medicine, Stanford University, Palo Alto, CA, USA

Background and aims: Patients with autoimmune encephalitis with leucine‐rich glioma‐inactivated 1 (LGI1) antibodies typically are older men and very often carry HLA‐DRB1*07:01. Herein, we aimed to investigate clinical and prognostic features according to patients age, sex, and HLA carrier status.

Methods: Retrospective chart review of 224 patients with isolated LGI1‐antibody positivity in serum and/or cerebrospinal fluid registered at the French Reference Center database. After computing percentiles of age distribution, patients were divided into three age subgroups: old, ≥79 years; typical, 52–78 years; young, ≤51 years. Poor outcome was defined as modified Rankin scale (mRS) >2.

Results: Among 224 patients, 148 (66%) were male, and 179 (80%) belonged to the typical age subgroup. In three‐way comparisons, female sex (p = 0.003) and temporal lobe seizures (p < 0.001) were more common in the younger subgroup (n = 20, 9%), while older patients (n = 25, 11%) presented more frequently facio‐brachial dystonic seizures (p = 0.034) and had higher mRS both at nadir (p < 0.001) and last follow‐up (p = 0.001). Non‐DRB1*07:01 carriers (n = 19/161, 12%) were more frequently female (p = 0.044, Figure 1) and had poorer outcome (p = 0.021). In a multivariate analysis, older age (odds ratio [OR]:1.12, 95% confidence interval [CI]: [1.05; 1.19]; p = 0.001), female sex (OR: 3.4, 95% CI [1.07; 10.87]; p = 0.039), and higher mRS at nadir (OR: 5.43, 95% CI [2.86; 10.3]; p < 0.001) were independently associated with poor outcome, while carrying DRB1*07:01 was protective (OR: 0.04, 95% CI [0.007; 0.22]; p < 0.001).

Population pyramid of the 161 patients with available HLA‐DRB1*07:01 carrier status.

Conclusion: Clinical manifestations differ among age subgroups, whereas poor outcome is associated with certain demographic (older age and female sex) and genetic (non‐DRB1*07:01 carrier status) features.

Disclosure: Macarena Villagrán‐Garcia is supported by a research grant from Fundación Alfonso Martín Escudero (Spain).

OPR‐099

Predictors of annualized attack rates in AQP4‐IgG+ NMOSD patients treated with rituximab or classical immunosuppression

D. Engels¹; M. Herfurth ²; J. Havla¹; P. Schindler³; C. Schwake⁴; M. Ringelstein⁵; K. Fischer⁵; M. Hümmert⁷; K. Giglhuber⁸; I. Vardakas¹⁰; M. Grothe¹¹; T. Etgen¹²; C. Warnke¹³; J. Naumann¹⁴; F. Hoffmann¹⁵; M. Senel¹⁰; B. Wildemann⁹; A. Berthele⁸; C. Trebst⁷; V. Häußler⁶; O. Aktas⁵; I. Ayzenberg⁴; J. Bellmann‐Strobl³ ; F. Then Bergh²; T. Kümpfel¹

¹Institute of Clinical Neuroimmunology, LMU Hospital, Ludwig‐Maximilians University Munich, Munich, Germany; ²Department of Neurology, University of Leipzig, Leipzig, Germany; ³Neuroscience Clinical Research Center, Charité ‐ Universitätsmedizin Berlin, Berlin, Germany; ⁴Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany; ⁵Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; ⁶Department of Neurology and Institute of Neuroimmunology and MS (INIMS), University Medical Center Hamburg ‐Eppendorf, Hamburg, Germany; ⁷Department of Neurology, Hannover Medical School, Hannover, Germany; ⁸Department of Neurology, School of Medicine, Technical University Munich, Klinikum rechts der Isar, Munich, Germany; ⁹Molecular Neuroimmunology Group, Department of Neurology, University of Heidelberg, Heidelberg, Germany; ¹⁰Department of Neurology, University of Ulm, Ulm, Germany; ¹¹Department of Neurology, University of Greifswald, Greifswald, Germany; ¹²Department of Neurology, Kliniken Südostbayern‐Klinikum Traunstein, Germany; ¹³Department of Neurology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; ¹⁴Department of Neurology, Knappschaftsklinikum Sulzbach, Sulzbach, Germany; ¹⁵Department of Neurology, Martha‐Maria Hospital Halle‐Dölau, 06120 Halle (Saale), Germany

Background and aims: Aquaporin‐4‐IgG‐positive neuromyelitis optica spectrum disorder (AQP4‐IgG+ NMOSD) primarily manifests with attacks of optic neuritis or myelitis. Immunosuppression can prevent attacks but may be associated with risks, e.g. infections. We compared the efficacy and risk of rituximab and classical immunosuppressive agents in AQP4‐IgG+ NMOSD patients.

Methods: We compared annualized attack rates (AAR), infection rates (IR, infections per time) and laboratory parameters during rituximab (RIX), azathioprine (AZA), mycophenolate mofetil (MMF) and methotrexate (MTX) treatment cycles in a multicentric, retrospective cohort from the German Neuromyelitis Optica Study Group (NEMOS) registry.

Results: We analyzed 570 treatment episodes in 251 patients. Mean AAR during RIX treatment episodes was significantly lower than with AZA (0.24 vs. 0.61, p < 0.001, Mann–Whitney U). The IR did not differ between RIX (N = 238) and all other treatment episodes (N = 332, 0.38 versus 0.44, p = 0.81, Mann–Whitney U). We identified the IR, leukocyte count and IgM serum concentration as predictors for (higher) AAR. Time from diagnosis to treatment and sex showed no effect. During rituximab treatment episodes, higher neutrophil and B cell counts, and higher IgM serum concentration were associated with higher AAR.

Conclusion: Rituximab is associated with lower AAR, but not with higher infection rates than classical immunosuppressives. Whether the IR constitutes a risk factor for attacks needs to be evaluated prospectively.

Disclosure: Daniel Engels received speaker honoraria from Alexion and Horizon. Joachim Havla reports a grant for OCT research from the Friedrich‐Baur‐Stiftung and Merck, personal fees and nonfinancial support from Merck, Alexion, Novartis, Roche, Celgene, Biogen, Bayer and Horizon and nonfinancial support of the Sumaira‐Foundation and Guthy‐Jackson Charitable Foundation, all outside the submitted work. Achim Berthele receives funding from the Innovationsausschuss of the German Federal Joint Committee (G‐BA; grant 01VSF23040) and from the German Federal Ministry of Education and Research (BMBF; grant 01ZZ2102B). He has received consulting and/or speaker fees from Alexion, Argenx, Biogen, Horizon, Merck, Novartis, Roche and Sandoz/Hexal, and his institution has received compensation for clinical trials from Alexion, Biogen, Merck, Novartis, Roche, and Sanofi Genzyme; all outside the present work. Martin W. Hümmert received research support from Myelitis e. V., speaker honoraria from selpers og, Horizon and Alexion, and reimbursement of travel expenses and compensation for serving on an advisory board from Alexion. Tania Kümpfel has received speaker honoraria and/or personal fees for advisory boards from Novartis Pharma, Roche Pharma, Alexion/AstraZeneca and Biogen. All other authors have nothing to disclose in relation to this project.

OPR‐100

Topography of NREM oscillations is associated with circadian preference and rhythmicity

I. Filchenko ¹; A. Eberhard‐Moscicka² ; C. Gutierrez Herrera³; S. Bauer‐Gambelli¹ ; S. Duss¹; C. Cajochen⁴; C. Bernasconi¹; M. Schmidt¹; C. Bassetti¹

¹Department of Neurology, University Hospital, Inselspital, Bern, Switzerland; ²Department of Psychology, University of Bern, Bern, Switzerland; ³Department of Biomedical Research (DBMR), Inselspital University Hospital Bern, University of Bern, Bern, Switzerland; ⁴Centre for Chronobiology, University Psychiatric Clinic Basel, Basel, Switzerland

Background and aims: Homeostatic and circadian processes play a pivotal role in sleep regulation. However, little is known about the association of NREM oscillations with circadian rhythm characteristics accessed within clinical routine. This exploratory analysis aimed to comprehensively address this link.

Methods: This analysis is based on the pooled data from two observational studies and includes volunteers in good or excellent health condition (Eastern Cooperative Oncology Group grade of 0–1). Clinical history, circadian parameters (i.e., Morningness‐Eveningness Questionnaire and actigraphy) and NREM sleep architecture (i.e., sleep spindle [SS] and slow wave [SW] density and morphology according to 256‐electride electroencephalography) were assessed at study inclusion (Figure 1A). Association between NREM architecture as dependent variables and circadian parameters as independent variables were explored using multiple linear regression with adjustments for age and arousal index.

Results: Data of 71 participants was analyzed (age: median 29.0 interquartile range (IRQ) [23.0, 35.5] years old; 52% women; Figure 1B). SS were prevalently associated with circadian parameters (Figure 2; e.g., high SS density in posterior and pre‐frontal regions vs. late L5 hour), whereas only limited associations between SW and circadian parameters were identified (Figure 3; e.g., high frontal SW amplitude vs. late M10 hours).

Selected associations between circadian parameters and sleep spindles.

Selected associations between circadian parameters and slow waves.

Conclusion: Circadian rhythm is associated with NREM oscillations in a domain‐ and topography‐specific manner, with evening preference being linked to favourable electroencephalographic markers. This knowledge may serve as a basis for targeted interventions for sleep–wake disorders.

Disclosure: European Stroke Research foundation 2021 and Interfaculty Research Cooperation grant of the University of Bern “Decoding sleep”.

OPR‐101

The impact of physical exercise and ketogenic diet on narcolepsy: A randomized, controlled trial

F. Tepel ¹; H. Cintosun¹; D. Borth¹; G. Lammers²; U. Kallweit³

¹Centre for Narcolepsy and Hypersomnia, Clinical Sleep and Neuroimmunology, Institute of Immunology, University Witten/Herdecke, Germany; ²Leiden University Medical Centre, Department of Neurology, Leiden, The Netherlands, and Sleep Wake Centre SEIN, Heemstede, The Netherlands; ³Center for Narcolepsy and Hypersomnias, Clinical Sleep and Neuroimmunology, Institute of Immunology, University Witten/Herdecke, Germany and ORFEA Sleep Clinic, Witten, Germany

Background and aims: Narcolepsy treatment involves pharmacological and non‐pharmacological therapies. This trial aimed to evaluate the efficacy of two specific non‐pharmacological treatments for narcoleptics: regular physical activity and ketogenic diet, respectively.

Methods: In a 10‐week trial on adults with type 1 narcolepsy (NT1), three groups were studied: regular physical activity, ketogenic diet, and control. Assessment included clinical data, treatments, Power Walking Test, and pre/post questionnaires. The sport group adhered to a training plan, keto group followed a high‐fat, low‐carb diet, and controls maintained routine. Questionnaires covered sleep, life quality, well‐being, fatigue, recovery, and stress.

Results: In total, 60 patients (41 female, mean age: 34 years) with NT1 were randomized; 44 completed the study. ESS improved from 13.9 to 11 points (p < 0.009) in the sports group, and 16.3 to 13.2 points (p < 0.005) in the keto group. For controls, no significant change was found. PSQI improved from 9.3 to 6.6 points (p < 0.005) in the sports group only. Quality of life measures (WHO‐5) improved from 12.3 to 15.8 points (p < 0.027) in the sports groups, and from 9.3 to 13.4 points (p < 0.013) in the keto group. Stress levels were reduced from 13.6 to 10.3 (p < 0.007) in the sports group.

Conclusion: Regular physical training or a ketogenic diet effectively reduce daytime sleepiness in narcolepsy. Quality of quality, well‐being, and physical aspects of life quality are also improved by regular physical training in particular. These treatments offer a convenient, cost‐effective, and efficient therapeutic option alongside pharmacological measures.

Disclosure: No disclosures.

OPR‐102

Widespread white matter axonal loss in narcolepsy type 1

J. Gool ¹; A. de Brouwer¹; L. Shan²; J. Bol³; A. Hoogendoorn⁴; Y. van der Werf³; G. Lammers¹; L. Jonkman³; R. Fronczek⁵; G. Schenk³

¹Stichting Epilepsie Instellingen Nederland (SEIN), Sleep–Wake Centre, Heemstede, the Netherlands; ²Department Neuropsychiatric Disorders, Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands; ³Anatomy&Neurosciences, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; ⁴Department of Psychiatry, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; ⁵Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands

Background and aims: Narcolepsy type 1 (NT1) is a debilitating neurological disorder marked by hypocretin deficiency (or orexin), causing excessive daytime sleepiness and cataplexy. Brain imaging studies have suggested global white matter irregularities in NT1, with unknown underlying histopathological correlates. Consistent with expected hypocretin projection patterns, the cerebellum was least affected. In a globally unique sample of human NT1 postmortem brain tissue, we assessed axonal and myelin integrity through immunohistochemical microscopy.

Methods: Postmortem brain sections from four NT1 donors and 10 controls were assessed for axonal density, axonal injury and myelin integrity. Regions of interest included subregions of the midbrain, corpus callosum, cortical regions (anterior cingulate and occipital cortex), and the cerebellum as a control region (Figure 1). Manual axon count and staining intensity assessed axonal density. Area percentage immunoreactivity of phosphorylated neurofilament chains evaluated axonal injury. Myelin integrity was assessed using staining intensity analyses.

FIGURE 1 The regions of interest: (A) reticular formation and pyramidal tract, (B) proximal and distal corpus callosum, anterior cingulate gyrus and cingulate sulcus, (C) primary and secondary visual cortices, (D) cerebellum. Scale bar is 2 mm.

Results: Significantly reduced axonal density was observed in NT1 compared to controls in the reticular formation, pyramidal tract, corpus callosum and anterior cingulate gyrus (Figure 2). No significantly different axonal density was seen in the cerebellum nor in the axonal staining colour intensity, axonal injury and myelin integrity measures, except for lower secondary visual cortex myelin density in NT1.

FIGURE 2 Axon counting results: (A–C) reticular formation (RF) and pyramidal tract (P), (D–F) proximal corpus callosum (P‐CC), anterior cingulate gyrus (ACC), (G, H) cerebellum (CB). Scale bar is 2 mm for A, D, G and 100 μm for B, C, E, F, H.

Conclusion: In NT1, there is widespread lower axonal density within and outside the ascending reticular activating system. These results align with prior in‐vivo brain imaging reports and typical hypocretin projection patterns, and may contribute to the pathophysiology of NT1, possibly stemming from hypocretin deficiency and/or chronic sleep–wake alterations.

Disclosure: Nothing to disclose.

OPR‐103

Sleep‐related hypermotor epilepsy vs. disorders of arousal: Diagnostic interobserver reliability of homemade videos

L. Vignatelli ¹; L. Licchetta¹; G. Maineri¹; G. Loddo¹; F. Baccari¹; G. Bruschi²; L. Taruffi²; L. Nobili³; P. Tinuper²; F. Provini¹; F. Bisulli¹; on behalf of SHE‐DOA Study Group¹

¹IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy; ²Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; ³Child Neuropsychiatry, IRCCS, G. Gaslini Institute, Department of Neuroscience (DINOGMI), University of Genoa, Genoa, Italy

Background and aims: Video‐polysomnography is the reference standard for diagnosing Sleep‐related Hypermotor Epilepsy (SHE)1. However, it entails high hospitalization costs and it is not exempt from the possibility of failing to capture rare events. Homevideo recording (HVR) can help the diagnosis of SHE2 but its diagnostic value remains uncertain. This study aims to assess the reliability of HVR in distinguishing between SHE and NREM Disorders of arousal (DOA) among neurologists with different clinical expertise.

Methods: We selected HVRs (performed by caregivers in real‐world setting) capturing 20 typical sleep‐related events from 10 patients with SHE and 10 with DOA. Thirteen experts and 20 general neurologists were invited to classified each HVR as “SHE”, “DOA” or “unknown”, based on seizure semiology. The experts was then asked to discuss each case, providing agreed key semeiological features for diagnosis. Baseline interobserver reliability (IR) among raters, and among general neurologists before and after experts' discussion, was calculated using Kappa statistics.

Results: The global raw agreement was 74.9% (“moderate” IR, Kappa 0.54). Agreement among experts was 75.3% (“moderate” IR, Kappa 0.55). Among general neurologists agreement improved from 74.5% at baseline to 83.8% after training, corresponding to IR “moderate” (Kappa 0.54) and “substantial” (Kappa 0.69), respectively.

Conclusion: Baseline reliability of HVR for diagnosing SHE versus DOA was found globally moderate. Educational training, focused on behavior patterns, enhanced agreement among non‐expert neurologists. These data highlight HVR as a reliable diagnostic tool in most cases for differentiating SHE from other paroxysmal non‐epileptic manifestations, thereby reducing health care costs and disparities.

Disclosure: Nothing to disclose.

OPR‐104

Cerebrospinal‐fluid orexin levels: A possible biomarker for early identification of neurodegenerative disorders?

S. Maio ¹; S. Lozano Tovar²; R. Cremascoli³; M. Nuccetelli⁴; G. Sancesario⁵; S. Cattaldo⁶; E. Prina⁷; F. Verde⁸; S. Cappelli⁹; S. Bernardini⁴; N. Mercuri⁵; C. Liguori¹

¹Sleep Medicine Center, Neurology Unit, University Hospital of Rome “Tor Vergata”, Rome, Italy; ²Facultad de Psicología, Universidad Nacional Autónoma de México (UNAM), Circuito Ciudad Universitaria Avenida, C.U., Mexico City, Mexico; ³IRCCS, Istituto Auxologico Italiano, Unit of Neurology and Neurorehabilitation, San Giuseppe Hospital, Verbania, Italy.; ⁴Department of Clinical Biochemistry and Molecular Biology, University of Rome “Tor Vergata”, Rome, Italy; ⁵Department of Systems Medicine, University of Rome “Tor Vergata”, Rome, Italy; ⁶IRCCS, Istituto Auxologico Italiano, Laboratory of Clinical Neurobiology, San Giuseppe Hospital, Verbania, Italy; ⁷IRCCS, Istituto Auxologico Italiano, Department of Neurology and Laboratory of Neuroscience, Milan, Italy; ⁸Department of Pathophysiology and Transplantation, “Dino Ferrari” Center, Università degli Studi di Milano, Milan, Italy; ⁹IRCCS, Istituto Auxologico Italiano, Laboratory of Psychology, San Giuseppe Hospital, Verbania, Italy

Background and aims: Orexin system mainly regulates sleep–wake cycle, but there is also growing evidence of its impairment in neurodegenerative diseases(NDs). In this study, we investigated cerebrospinal‐fluid(CSF) orexin levels in patients with different NDs compared to non‐demented controls. We included patients with mild or moderate–severe Alzheimer's disease(mAD, msAD), behavioral variant of Frontotemporal Dementia(bv‐FTLD), non‐fluent primary aphasia(NFPA) and idiopathic normal pressure hydrocephalus(iNPH).

Methods: Patients and controls underwent between 2012 and 2015 a neurological assessment and a lumbar puncture for CSF biomarker analysis. We evaluated 76 AD(mAD = 45, msAD = 31), 34 FTLD(bv‐FTLD = 12, NFPA = 22), 13 iNPH patients and 91 controls. CSF orexin levels were also correlated with β‐amyloid42(Aβ42), total‐tau(t‐tau), phosphorylated‐tau(p‐tau) and clinical data.

Results: CSF concentrations of Aβ42, t‐tau, p‐tau and orexin were significantly different comparing all groups (p < 0.001). The highest CSF orexin levels were found in the iNPH (263.31 ± 56.89). NFPA (210.86 ± 61.99) and msAD (173.04 ± 19.76) showed higher CSF orexin concentrations compared to controls (145.18 ± 27.01) (p < 0.001). CSF orexin levels were similar between Bv‐FTLD (190.12 ± 100.84), mAD (130.76 ± 21.70) patients and controls. Considering the correlation analysis, only in the controls the CSF levels of Aβ42 and t‐tau correlated with orexin (p = 0.014; p < 0.001). Only in the mAD and msAD groups, Mini Mental State Examination scores correlated with CSF orexin levels (r = −0.54; p < 0.001; r = −0.92; p < 0.001; respectively).

Conclusion: This study documented significant differences in CSF orexin levels in NDs patients, with the highest levels in iNPH. Our findings highlight the possibility to add orexin to the CSF biomarker panel for the early identification of NDs causing cognitive impairment and dementia.

Disclosure: Nothing to disclose.

OPR‐105

Burden of illness study among patients with central disorders of hypersomnolence in France, Germany and Italy

Y. Dauvilliers¹; G. Plazzi²; U. Kallweit³; S. Crawford⁴; L. Jönsson⁵; G. Kobelt ⁶

¹Sleep‐Wake Disorders Center, Department of Neurology, Gui‐de‐Chauliac Hospital, University of Montpelier, Montpellier, France; ²IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy; Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy; ³Center for Narcolepsy and Hypersomnias, Professorship for Narcolepsy and Hypersomnolence Research, Department of Medicine, Witten/Herdecke University, Witten, Germany; ⁴Takeda Development Center Americas, Inc., Cambridge, MA, USA; ⁵Karolinska Institutet, Solna, Sweden; ⁶EHE International GmBH, St Moritz, Switzerland

Background and aims: Narcolepsy type 1 (NT1) and 2 (NT2) and idiopathic hypersomnia (IH), are rare, chronic neurological disorders with a high disease burden; however, no studies have attempted to establish the relationship between patient burden and disease severity.

Methods: This cross‐sectional, observational, anonymous online/email survey assessed patient burden for participants with NT1, NT2, and IH. Questions included demographics, work‐force participation, disease symptoms, daily activities, coping strategies, resource consumption, and quality of life (QoL: EQ‐5D‐5L). Disease severity was assessed with a visual analog scale (VAS; range 0–10) and three validated instruments (Epworth Sleepiness Scale [ESS], Narcolepsy Severity Scale [NSS‐CT], and Idiopathic Hypersomnia Severity Scale [IHSS]). Participants were recruited via clinical sites, patient associations, and registries across Europe.

Results: This interim analysis included 487 participants with complete disease severity data from the first three countries reaching enrolment targets. Mean (range) age was 37 (18–89) years. Mean (range) ESS scores were above normal for NT1/NT2 (15.0 [0–24]) and IH (13.2 [0–22]); self‐reported disease severity ranged from 6.2 to 6.9 (VAS). Mean (range) NSS‐CT scores were higher (greater severity) for NT1 (20.1 [0–47]) and NT2 (15.2 [1–34]) vs. IH (13.1 [0–40]); IHSS scores were higher (greater severity) for IH (32.4 [5–48]) vs. NT1 (27.0 [4–49]) or NT2 (28.7 [8–44]). Excessive sleepiness and daily naps were reported by 71% and 73%. 82% of participants were treated. Among 66% working participants, 70% reported disease affecting their work negatively. QoL was inversely related to disease severity.

Conclusion: These results illustrate the effect of narcolepsy/IH disease severity on patient‐reported quality of life.

Disclosure: YD: Received funds for seminars, board engagements and travel to congresses from Avadel, Bioprojet, Idorsia, Jazz, Orexia, and Takeda GP: Received honoraria for board engagements from Bioprojet, Idorsia, Jazz, Orexia, and Takeda. UK: Honoraria for board engagements and scientific lectures from Bioprojet, Jazz and Takeda. SC: Employee of Takeda Development Center Americas, Inc., and stockholder of Takeda Pharmaceutical Company Ltd LJ: Consultant to EHE GmbH GK: President of EHE GmbH and project manager of this study on behalf of Takeda.

OPR‐106

Motor reserve impact on nigrostriatal vulnerability and motor severity in Parkinson's disease

A. Galli ¹; A. Pilotto¹; A. Rizzardi¹; C. Zatti¹; M. Ogliani¹; A. Lupini¹; C. Hansen²; R. Romijnders²; S. Caminiti³; E. Premi⁴; S. Lucchini⁵; F. Bertagna⁵; B. Paghera⁵; W. Maetzler²; M. Nucci⁶; S. Mondini⁶; A. Padovani¹

¹Department of Clinical and Experimental Sciences, University of Brescia, Italy; ²Department of Neurology, University Hospital Schleswig‐Holstein and Kiel University, Kiel, Germany; ³Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy; ⁴Stroke Unit, ASST Spedali Civili of Brescia, Italy; ⁵Nuclear Medicine Unit, University of Brescia, Italy; ⁶Department of General Psychology, University of Padua, Padua, Italy

Background and aims: Increasing evidence supports beneficial effects of lifelong physical activities on cognition or mobility. Recently, motor reserve (MR) has been associated with a greater ability to cope with normal or pathological motor‐skill decline. This study investigated the possible impact of MR on dopamine binding and motor severity in early‐diagnosed patients with Parkinson's Disease (PD).

Methods: Drug‐naïve PD patients underwent cognitive and motor assessment‐ and 123I‐FP‐CIT‐SPECT imaging. Gait parameters were evaluated in normal, fast and dual‐task conditions using Mobile Health Technologies (MHT) in supervised setting. Motor Reserve Index questionnaire (MRIq) was administered and individuals were categorized into high‐MR or low‐MR. The relationship between MR and dopamine binding was assessed using a voxel‐wise regression model. Clinical differences between high and low‐MR patients were assessed using two‐sample t‐test, whereas differences in gait parameters were explored using a MDS‐UPDRS‐III, sex and height‐adjusted ANCOVA model.

Results: Forty drug‐naïve PD patients entered the study (age 68.35 ± 7.5). MR was negatively correlated with dopamine binding in left putamen and pallidum in the voxel‐wise model. High vs.. low‐MR PD had similar demographics, motor, and cognitive severity. Only in motor dual‐task conditions, high‐MR vs. low‐MR PD showed lower step‐time (p = 0.002), motor cost (p < 0.001), step‐time variability (p = 0.045), and higher step‐length (p = 0.045).

Voxel‐wise regression showing negative correlation between MRIq and dopamine binding.

Conclusion: MR emerged as important modulator of dopamine nigrostriatal circuitries at onset of PD, with an impact on motor impairment and performances assessed by MHT. These mechanisms might explain the heterogeneity of progression and response to treatments in early disease phases and need to be verified in ongoing longitudinal studies.

Disclosure: Nothing to disclose.

OPR‐107

Nerve ultrasound in Friedreich's Ataxia

G. Di Pietro¹; P. Falco ¹; E. Ciofffi²; E. Galosi¹; G. De Stefano¹; G. Di Stefano¹; C. Leone¹; V. Martines³; S. Perotti⁴; C. Casali²; A. Truini¹

¹Department of Human Neuroscience, Sapienza University, Rome, Italy; ²Department of Medico‐Surgical Sciences and Biotechnologies, University of Rome Sapienza, Latina, Italy; ³Neuroradiology Department, Policlinico Umberto I, Rome, Italy; ⁴Department of Radiological, Oncological and Anatomo‐Pathological Sciences, Sapienza University of Rome, Italy

Background and aims: Friedreich's Ataxia (FRDA) is the most common hereditary ataxia, it is caused by GAA expansion of the FXN gene. Frataxin mutations lead to a damage of the Peripheral Nervous System producing a sensory neuropathy. The mechanism underling this manifestation is still a matter of debate. It is thought to be a ganglionopathy but alterations along the nerve have also been observed. In this study, we tested the usefulness of nerve ultrasound in the assessment of peripheral neuropathy in FRDA.

Methods: We prospectively enrolled 9 consecutive FRDA patients (39.3 ± 8.3 years, 2 Males). Anamnestic data, neurological examination (Scale for the Assessment and Rating of Ataxia (SARA), Activities of Daily Living (ADL 0–36) and Instrumental Activities of Daily Living (IADL)), Nerve Conduction Study (NCS) and peripheral nerves high‐resolution ultrasound (HRUS) were collected. For each patient, 26 nerve sites were evaluated both quantitatively (Cross Sectional Area (CSA) assessment) and qualitatively. CSA values were compared with 20 healthy volunteers.

Results: In FRDA, HRUS showed a significant nerve enlargement of the Median and Ulnar nerves at the axilla and at the arm (p < 0.001). The cumulative count of affected nerve sites was directly associated with clinical disability, as assessed by SARA, ADL 0–36, and INCAT score, while displaying an inverse correlation with IADL.

Cross Sectional Area of Median and Ulnar nerves as assessed with high resolution nerve ultrasound examination in patients with Friedreich's ataxia (orange) and control participants (blue).

Cross Sectional Area of Tibial, Peroneal and Sural nerves as assessed with high resolution nerve ultrasound examination in patients with Friedreich's ataxia (orange) and control participants (blue).

High resolution nerve ultrasound examination showing an enlarged Median (A) and Ulnar (B) nerves at the arm in Friedreich's ataxia. Yellow circles indicate the nerves and red circles indicate the arteries.

Conclusion: Nerve ultrasound can detect alterations along the nerves in Friedreich's Ataxia. While NCS do not correlate with disease severity, HRUS shows a strong correlation with disease severity scores. Nerve ultrasound is a valuable tool in the assessment of Friedreich's Ataxia.

Disclosure: Nothing to disclose.

OPR‐108

Choroid plexus volume as a novel candidate neuroimaging marker of the Alzheimer's continuum: A prospective cohort study

J. Jiang; W. Li; S. Jiang; J. Xu

Beijing Tiantan Hospital, Capital Medical University, China

Background and aims: The clinical role and potential mechanisms of the choroid plexus (ChP) in Alzheimer's disease (AD) remains unclear.

Methods: This prospective cohort study enrolled 607 participants (110 HCs, 269 MCI, and 228 AD dementia). Relationship between ChP volume and CSF hallmarks (Aβ42, Aβ40, Aβ42/40, tTau, and pTau), neuropsychological tests (MMSE, MoCA, NPI, and ADL scores), and multimodal neuroimaging measures were analyzed. The mediating effects of ChP volume were examined on the relationship between CSF hallmarks and neuropsychological tests. The ChP volume performance to differentiate the presence/absence of cerebral Aβ42 deposition was determined using ROC analysis.

Results: The participants' mean age was 65.99 ± 8.79 years. Patients with AD dementia exhibited a larger baseline ChP volume than the other participants. ChP volume enlargement correlated with decreased Aβ42 and Aβ40 levels; lower MMSE and MoCA and higher NPI and ADL scores; lower volume, cortical thickness, and corrected cerebral blood flow in other cognition‐related regions. ChP volume alone mediated and ChP–hippocampal volume combined chain mediated the association of CSF Aβ42 and Aβ40 levels with the MMSE scores (16.91%, 37.15%, 14.25%, and 27.82%, respectively). ChP volume better identified the presence/absence of cerebral Aβ42 deposition than hippocampal volume (AUC: 0.762 vs. 0.724). Generalized linear mixed‐effects models discerned that baseline ChP volume was associated with subsequent decline and faster worsening in the MMSE, MoCA, and ADL scores with 10.03 ± 4.45 months' follow‐up.

FIGURE 1 Comparisons among three representative 3D‐T1 weighted images of the ChP volume in the three groups.

FIGURE 2 Simple and chain‐mediating effects of ChP volume on the association of CSF hallmarks and neuropsychological tests.

FIGURE 3 Receiver operating characteristic curves for choroid plexus and hippocampal volume for discriminating the absence/presence of cerebral pathological deposition, and distinguishing different disease stages.

Conclusion: ChP volume is a novel, candidate, non‐invasive neuroimaging marker associated with neurodegenerative changes in Alzheimer's continuum. It can detect early cerebral Aβ42 deposition and predict prognosis in clinical practice.

Disclosure: Nothing to disclose.

OPR‐109

A data‐driven and dynamic network connectivity approach differentiates atypical patterns in Alzheimer's disease

L. Pini ¹; L. Brusini²; A. Griffa³; F. Cruciani²; G. Allali³; G. Frisoni⁴; M. Corbetta¹; G. Menegaz²; I. Boscolo Galazzo²

¹Department of Neuroscience, University of Padova, Italy; ²Department of Engineering for Innovation Medicine, University of Verona, Italy; ³Leenaards Memory Center, Department of Clinical Neurosciences, Lausanne University Hospital, Lausanne, Switzerland; ⁴Memory Clinic and LANVIE ‐ Laboratory of Neuroimaging of Aging, University Hospitals and University of Geneva, Switzerland

Background and aims: From a macro‐scale perspective, Alzheimer's disease (AD) can be conceptualized as a network‐based syndrome, characterized by polysynaptic communication abnormalities assessed through functional magnetic resonance imaging (fMRI). The molecular hallmark of AD encompasses abnormalities involving amyloid‐beta (A), tau (T) protein accumulation, and medial temporal lobe neurodegeneration (N).

Methods: In this study, we hypothesized that distinct ATN patterns would demonstrate specific spatiotemporal synchronization patterns measured using resting‐state fMRI (rs‐fMRI). We included individuals from the ADNI project. Dynamic functional connectivity (dFC) outcomes were measured using co‐activation patterns derived from the posterior cingulate cortex in 152 controls (74 ± 9 yrs) and projected to 334 patients (74 ± 10 yrs). ATN patterns were identified through a low‐dimensional approach in conjunction with a K‐means algorithm. Univariate, and multivariate approaches were applied to assess biological, behavioral, and dFC differences. Finally, we applied linear and non‐linear classifiers to investigate whether dFC could predict ATN classifications.

Results: We identified three main ATN clusters. The first group displayed mild pathological alterations. The second cluster exhibited typical behavioral impairment alongside AD pathology. The third cluster demonstrated similar behavioral impairment but a divergent T (low) and N (high) pattern, suggestive of non‐AD pathology. Univariate and multivariate analyses revealed two dFC patterns encompassing the default mode network and the occipito‐temporal cortex linked, respectively, with typical and atypical ATN patterns. DFC exhibited an accuracy of approximately 90% in predicting ATN groups.

Conclusion: These results support the key association between macro‐scale and molecular AD alterations. Notably, dFC markers can assist in identifying patients with AD‐like clinical profiles but with different underlying pathologies.

Disclosure: Nothing to disclose.

OPR‐110

Is it time to utilise nerve ultrasonography in the journey of amyotrophic lateral sclerosis (ALS) diagnosis?

R. Abdelnaby ¹ ; A. Samy Shabib²; M. Hossam El Din Moawad ³ ; T. Salem ⁴; M. Wagih Youssef Awad⁵; P. Dawoud Awad ⁶ ; I. Maallem⁷; H. Atwan ⁸ ; S. Adel Rabie⁹; K. Ashraf Mohamed¹⁰; H. Abdelmageed¹¹; M. Karkour¹²; M. Elsayed ¹³ ; M. S. Cartwright ¹⁴

¹Department of Neurology, RWTH Aachen University, Aachen, Germany; ²Faculty of Medicine, Mansoura university, Mansoura, Egypt; ³Faculty of Pharmacy Clinical Department Alexandria University, Alexandria, Egypt; ⁴Faculty of Medicine, Masaryk University, Brno, Czechia; ⁵Faculty of Medicine, Alexandria University, Alexandria, Egypt; ⁶Department of Public Health, Theodor Bilharz Research Institute, Giza, Egypt; ⁷Faculty of Pharmacy, University Grenoble Alpes, La tronche, France; ⁸Faculty of Medicine, Assiut University, Assiut, Egypt; ⁹Faculty of Medicine, October 6 University, Giza, Egypt; ¹⁰Faculty of Medicine, Cairo University, Cairo, Egypt; ¹¹Neurology Department, University of Greifswald, Greifswald, Germany; ¹²Microbiology Department, Faculty of Science, Tanta University, Tanta, Egypt; ¹³Department of Psychiatry and Psychotherapy III, University of Ulm, Ulm, Germany; ¹⁴Department of Neurology, Wake Forest School of Medicine, Winston‐Salem, North Carolina, USA

Background and aims: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and lower motor neurons, causing progressive atrophy of muscles, hypertonia, and paralysis. This study aimed to assess the difference in CSA of several peripheral nerves, vagus and cervical roots measured via US between ALS patients and healthy controls to identify the main nerves that have atrophy during ALS.

Dysfunction of the molecular pathway in ALS. (Figure created by BioRender).

Methods: A systematic search was conducted on Cochrane, Clarivate Web of Science, PubMed, Scopus, and Embase for the mesh terms nerve, ultrasonography, and amyotrophic lateral sclerosis. A quality assessment and a double‐arm meta‐analysis were performed.

Results: 17 studies with a total of 935 ALS patients and 604 controls were included in this review. The overall mean difference showed that individuals with ALS had a significantly smaller CSA in comparison to healthy controls for median, ulnar, C6 root, and phrenic nerves. However, no significant difference in the CSA was found in radial, vagal, sural and tibial nerves.

Mean difference of bilateral median, tibial and radial nerves CSAs between ALS patients and healthy controls.

Mean difference of bilateral ulnar, vagal, C6 root and phrenic nerves CSAs between ALS patients and healthy controls.

Conclusion: Our results confirmed anatomic sites to potentially differentiate individuals with ALS from healthy controls such as the median nerve at the mid‐arm and the ulnar nerve at the wrist and the lower third of the forearm.

Disclosure: Nothing to disclose.

OPR‐111

Evaluating the impact of lacosamide, pregabalin, and tapentadol on spinal biomarkers in human subjects

C. Leone ¹; G. Di Pietro¹; O. Caspani²; A. Mouraux⁴; L. Garcia Larrea³; R. Treede²; A. Truini¹

¹Department of Human Neuroscience, Sapienza University of Rome; ²Mannheim Faculty of Medicine, Heidelberg Univerrsity; ³NeuroPain Lab, Lyon Centre for Neuroscience, INSERM U1028, Neurological Hospital of Lyon & University Claude Bernard, Lyon, France; ⁴Institute Of NeuroScience (IONS), UC Louvain

Background and aims: The BioPain subtopic of IMI‐PainCare project aimed to test the effectiveness of selected biomarkers for evaluating drug effects and target interactions in new analgesic development. Within this framework, the BioPain‐RCT2 assessed the efficacy of lacosamide, pregabalin, and tapentadol against placebo on neurophysiological spinal biomarkers, specifically the RIII flexion reflex and the cervical N13 component of somatosensory evoked potentials, under normal and hyperalgesic conditions induced by high‐frequency electrical skin stimulation (HFS).

Methods: A multi‐center, double‐blind, placebo‐controlled 4‐period, 4‐way crossover pharmacodynamic and pharmacokinetic study in healthy subjects. Spinal biomarkers were measured before and at three time points after administering the three medications and placebo. The study evaluated drug effects on neurophysiological responses in induced hyperalgesia and normal states. It included blood samples for PK analysis. The primary statistical analysis focused on changes in RIII area and N13 amplitudes under tapentadol, with secondary analyses on other treatments' impacts.

Experimental design.

Results: Three different centres enrolled 24 subjects. The blinded analysis showed an effect of tapentadol on the R3 area and a trend towards the significance of pregabalin at the sensitized side, not reaching the set significance level (0.025). No significant effect of drugs on the N13 was observed. Exploratory analysis showed drug effects on the RIII threshold compared to placebo, with tapentadol and PGB also affecting pain ratings.

Conclusion: Tapentadol, and to a lesser extent Pregabalin, prevent the spinal excitability changes induced by secondary hyperalgesia models as assessed with the RIII reflex. This experimental design failed to identify a significant effect of tapentadol on the sensitized N13.

Disclosure: This project has received funding from the Innovative Medicines Initiative 2 Joint undertaking under grant agreement No 777500. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation program and EFPIA. Disclaimer: The statements and opinions presented here reflect the author's view and neither IMI nor the European Union, EFPIA, or any Associated Partners are responsible for any use that may be made of the information contained therein.

OPR‐112

Brain connectivity changes induced by monoclonal antibodies targeting the CGRP pathway in migraine patients

E. Mazzotta ¹; R. De Icco¹; M. Corrado¹; V. Grillo¹; G. Vaghi¹; F. Cammarota¹; F. Bighiani¹; M. Semprini³; A. Putortì¹; D. Martinelli¹; M. Allena²; G. Sances²; C. Tassorelli¹

¹Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy; ²Headache Science & Neurorehabilitation Unit, IRCCS Mondino Foundation, Pavia, Italy; ³Italian Institute of Technology, Genova, Italy

Background and aims: Previous studies demonstrated central and peripheral changes related to monoclonal antibodies directed against the CGRP pathway (mAbs) administration, without reaching a consensus on their mechanism of action. Our study aims to evaluate differences in resting state networks (RSNs) connectivity in migraine patients (MiG) undergoing mAbs treatment.

Methods: This is a prospective, real‐life, open label study based on three HD‐EEG recordings, namely T0 at baseline, T3 and T6 after 3 and 6 months of mAbs treatment. We assessed connectivity for separate frequency bands (alpha, beta, gamma, theta and delta) for six RSNs: default mode network (DMN), dorsal and ventral attention networks (DAN‐VAN), language network (LAN), somatomotor network (SMN) and visual network (VN). We also performed a single HD‐EEG assessment in healthy controls (HCs).

Results: We evaluated 62 migraine patients (age 45.4 ± 12.0 years, 54 females, 56.4% with chronic migraine) and 32 HCs (age 38.0 ± 14.0, 16 females). At T6, 62.9% of patients qualified as Responders (reduction in MMDs ≥50% when compared to baseline). At baseline, migraine patients presented an enhanced connectivity in delta and theta frequency bands compared to HCs for all analysed RSNs. At T6, connectivity in the delta and theta bands became comparable between Responders and HCs, while Non‐responders maintained higher connectivity in the delta and theta bands compared to both HCs and Responders.

Comparison of inter‐network connectivity between migraine patients and healthy controls at baseline. Average RSN connectivity is reported in the box and whiskers plot with median connectivity values for each band and related interquartile ranges.

Longitudinal inter‐network seed‐based connectivity analysis. Comparison between migraine patients in different treatment timepoints (T0: baseline, T3: 3 months of mAbs treatment, T6: 6 months of mAbs treatment). Coding is color‐based ranging from blue, re.

Conclusion: Our study demonstrated an enhanced slow frequencies whole‐brain connectivity in migraine patients. Treatment with anti‐CGRP monoclonal antibodies induced a positive modulation of functional connectivity in the delta and theta bands in Responder patients.

Summary of study findings. Mig: migraine patients, CM: chronic migraine, HFEM: high frequency episodic migraine patients.

Disclosure: Nothing to disclose.

OPR‐113

Role of specific microRNAs in cluster headache: correlation with disease phenotype and neuropeptide levels

F. Cammarota ^1,2; R. De Icco^1,2; F. Bighiani^1,2; M. Corrado^1,2; G. Vaghi^1,2; A. Antoniazzi^1,2; E. Mazzotta^1,2; V. Grillo^1,2; R. Greco^1,2; C. Demartini^1,2; A. Zanaboni^1,2; M. Francavilla^1,2; S. Franchini^1,2; M. Allena^1,2; G. Sances^1,2; C. Tassorelli^1,2

¹Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy; ²Headache Science and Neurorehabilitation Unit, IRCCS Mondino Foundation, Pavia, Italy

Background and aims: The role of specific microRNAs was studied in episodic and chronic migraine, but their possible involvement in cluster headache is yet to be elucidated. Our objective is to evaluate the role of specific microRNAs in episodic cluster headache in active phase (AeCH), remission phase (ReCH), chronic cluster headache (cCH), and healthy controls (HCs).

Methods: In this cross‐sectional study, we assessed gene expression of miR‐382‐5p, miR‐34a‐5p, and miR‐155 in peripheral blood mononuclear cells (Relative Quantification). AeCH and cCH patients were assessed outside of an acute cluster headache attack.

Results: We enrolled 18 AeCH (45.7 ± 12.8 years, 14 males, 16.3 ± 9.6 attacks/week), 7 ReCH (48.6 ± 19.8 years, 5 males), 10 cCH (50.1 ± 16.2 years, 9 males, 21.4 ± 18.8 attacks/week), and 14 HCs (45.4 ± 15.2 years, 2 males). miR‐382‐5p expression was higher in AeCH (1.7 ± 0.8) when compared to ReCH (0.8 ± 0.2) and HCs (0.3 ± 0.1) (p < 0.005 for all comparisons). miR‐34a expression was higher in AeCH (1.7 ± 0.4) when compared with ReCH (1.0 ± 0.3), cCH (1.2 ± 0.3) and HCs (0.5 ± 0.2) (p < 0.001 for all comparisons). miR‐155 expression was lower in HCs (0.4 ± 0.1) compared to all CH subgroups (p = 0.001 for all comparisons), with no difference among AeCH (1.7 ± 0.5), ReCH (1.3 ± 0.3) and cCH (1.3 ± 0.5).

Conclusion: miR‐382‐5p, miR‐34a‐5p and miR‐155 expression is increased in cluster headache when compared to HCs. MiR‐382‐5p and miR‐34a‐5p were associated with disease activity, being higher in AeCH patients when compared to ReCH. MicroRNAs expression of cCH was in‐between active and remission phases of episodic cluster headache patients. Our data supports the role of specific microRNAs in the pathophysiology of different primary headaches.

Disclosure: Cristina Tassorelli has participated in advisory boards for AbbVie, Dompé, Eli Lilly, Lundbeck, Novartis, Pfizer, and Teva; lectured at symposia and is a principal investigator or collaborator in clinical trials sponsored by AbbVie, Eli Lilly, Lundbeck, Novartis, and Teva; received research grants from the European Commission, the Italian Ministry of Health, the Italian Multiple Sclerosis Foundation, and the Migraine Research Foundation; and serves as an associate editor for Cephalalgia and The Journal of Headache and Pain. Roberto Di Icco received speaker honoraria for scientific presentations from Eli‐Lilly, and Teva, and has participated as advisory board for Pfizer. Gloria Vaghi reports consultant fees from Lundbeck.

OPR‐114

Evaluation of perivascular and extracellular space properties in migraine: A potential index for glymphatic clearance

R. Messina ¹; F. Genovese¹; E. Pagani²; I. Cetta¹; L. Zanandrea¹; B. Colombo³; M. Rocca¹; M. Filippi¹

¹Neurology Unit and Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Vita‐Salute San Raffaele University, Milan, Italy; ²Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; ³Neurology Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy

Background and aims: The glymphatic system is a network of perivascular spaces (PVS) that facilitates fluid exchange and peptide clearance in the brain. We aim to investigate if glymphatic dysfunction contributes to migraine pathophysiology, and examine its variations between patients studied during the interictal phase and those studied while experiencing headache.

Methods: One hundred twenty migraine patients (95 interictal, 25 with headache) and 53 controls underwent diffusion tensor (DTI) and susceptibility weighted (SWI) magnetic resonance imaging. Using DTI and SWI, we computed the Diffusion Along Perivascular Space (DTI‐ALPS) index, reflecting diffusivity in the PVS near the left lateral ventricle. This index serves as a proxy for regional glymphatic function. Based on previous evidence showing an association between glymphatic function and changes within intra/extracellular compartments, we employed neurite orientation dispersion and density imaging to evaluate voxel‐wise maps of white matter extracellular (EVF) and intracellular (IVF) volume fraction. Thus, providing a comprehensive insights into the glymphatic system functioning. Age‐ and sex‐adjusted between‐group comparisons were run using R and FSL software.

Results: Compared to controls, migraine patients were older (mean age: patients 39 (12), controls 41 (14), p = 0.02) and had a higher proportion of female subjects (female: patients 82, controls 24, p = 0.006). We found no significant differences between patients and controls, neither concerning the DTI‐ALPS index nor regarding EVF and IVF. No differences were even observed between subgroups of patients.

Conclusion: These results suggest the absence of abnormalities in the PVS and white matter extracellular compartment, indicating normal functioning of the glymphatic system in migraine.

Disclosure: Nothing to disclose in relation to this work.

OPR‐115

Defining mechanisms and new treatments for headache in raised intracranial pressure

O. Grech ¹; E. Rubio‐Beltran² ; E. Stanyer³; A. Labastida‐Ramirez² ; G. Lavery⁴; L. Hill⁵; P. Holland²; A. Sinclair¹

¹Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; ²Headache Group, Wolfson Sensory, Pain and Regeneration Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; ³Sleep and Circadian Neuroscience Institute, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; ⁴Centre for Systems Health and Integrated Metabolic Research, Department of Biosciences, School of Science and Technology, Nottingham Trent University, Clifton Campus, Nottingham, UK; ⁵School of Biomedical Sciences, Institute of Clinical Sciences, University of Birmingham, Birmingham, UK

Background and aims: Elevated intracranial pressure (ICP) is associated with migraine‐like headaches, but the mechanisms are unclear. Glucagon‐like peptide‐1 (GLP‐1) receptor agonism can reduce ICP, while migraines are associated with increased calcitonin gene‐related peptide (CGRP), and therapeutic benefits are observed with CGRP blockade. We investigated migraine mechanisms in a raised ICP rat model, investigating the effects of GLP‐1 receptor agonism and CGRP inhibition on ICP and nociception.

Methods: A validated rat model with intracisternal kaolin injection hindering CSF drainage was used. Mechanical hyperalgesia via von Frey filament testing, steady‐state potential and cortical blood flow responses to cortical spreading depression (CSD) were assessed. Responses were investigated following treatment with GLP‐1 receptor agonist exenatide or CGRP receptor antagonist olcegepant.

Results: Kaolin increased ICP [median(range) 15.96 mmHg (8.97) n = 8] controls [6.02 mmHg (1.79) n = 6 p = 0.0007]. Mechanical thresholds were reduced in raised ICP (mean(SD) hind paw baseline: 5.78 g (2.81), day 7 3.34 g (2.22) p < 0.001, periorbital baseline: 6.13 g (2.07), day 7 2.35 g (1.91) n = 12 p < 0.001). Raised ICP drastically altered CSD responses [depolarisation duration raised ICP: 108.81 s (222.12) n = 11, controls 37.54 s (108.38) n = 9 p = 0.038, repolarisation duration raised ICP: 1824.26 s (3499.54) n = 12, controls 86.96 s (140.05) n = 9 p < 0.0001]. CBF change was also reduced (85.55% (30.84) n = 9) versus controls (217.64% (37.70) n = 8 p < 0.0001).

Conclusion: These data suggest that elevated ICP results in mechanical hyperalgesia, a sign of cutaneous allodynia. GLP‐1 receptor agonism reduced ICP, prevented changes in mechanical thresholds and restored responses to CSD. CGRP receptor antagonism prevented periorbital pain behaviour, indicating a potential role for CGRP in driving pain responses associated with elevated ICP.

Increased ICP resulted in mechanical hyperalgesia and altered CSD responses. Reducing ICP via GLP‐1 receptor agonism restored mechanical thresholds and CSD responses, while CGRP receptor antagonism prevented periorbital pain behaviour.

Disclosure: OG reports scientific consultancy fees from Invex Therapeutics 2020 which were outside the work in this article. AJS reports personal fees from Invex therapeutics in her role as Director with stock holdings, during the conduct of the study (since 28.06.2019); other for advisory boards from Allergan, Novartis, Cheisi and Amgen outside the submitted work. All other authors declare no competing interests.