Epilepsia Open

Purpose: DNM1-related disorder is a rare developmental and epileptic encephalopathy. The current understanding of the clinical spectrum is based on sparse patient descriptions. Here, we compile the largest DNM1 cohort to date, to characterize the genotypic and phenotypic landscape of the disorder. Methods: Phenotypic data was manually curated from 95 individuals from multiple sources and harmonized using the Human Phenotype Ontology framework. Results: Disease-causing variants in DNM1 cluster in mutational hotspots within the gene, which achieve Strong and Moderate evidence for pathogenicity based on ACMG guidelines. The overall DNM1 phenotype was homogeneous compared to other genetic epilepsy conditions: SCN2A, SCN8A, STXBP1, and SYNGAP1. The p.R237W (n=15) variant was associated with bilateral tonic-clonic seizures, infantile spasms, and dystonia. The p.I398_R399insCR (n=14) variant was associated with severe hypotonia, profound global delay, and cortical visual impairment. Five individuals with homozygous loss-of-function variants were clinically similar to dominant-negative DNM1-related disorder, but microcephaly and brain MRI abnormalities were more common in this group. Conclusion: A harmonized cohort of individuals with DNM1-related disorder was analyzed to define mutational hotspots and reveal novel genotype-phenotype correlations. Due to the homogeneous phenotype, disease mechanism, and high proportion of recurrent variants, DNM1 represents an attractive target for targeted therapy development.

ImportanceEpilepsy is one of the most common neurological disorders globally. A significant proportion of patients fail to achieve effective seizure control with medication and ultimately develop drug-resistant epilepsy, particularly mesial temporal lobe epilepsy (MTLE). While surgical resection and laser interstitial thermal therapy (LITT) are effective treatments for drug-resistant MTLE, these procedures may be associated with severe adverse events. In contrast, allogeneic induced pluripotent stem cell (iPSC)-based therapy is expected to offer a novel, potentially safer therapeutic approach with fewer side effects for patients with drug-resistant MTLE. ObjectiveTo evaluate the safety and preliminary efficacy of a single intracranial injection of ALC05 (iPSC-derived GABAergic interneurons) in patients with unilateral MTLE, and to assess the therapeutic effects of different dosage levels. Design, Setting, and ParticipantsThis single-center, randomized, double-blind, Phase 1 clinical trial will enroll 12 subjects with unilateral MTLE. All subjects will be randomly assigned to either the low-dose or high-dose group in a 1:1 ratio. To minimize risks at each dose level, the first subject in each dose group will be monitored for safety for at least 3 months following ALC05 injection and must demonstrate acceptable safety and tolerability before the remaining subjects are enrolled. The primary outcome will be the incidence and severity of adverse events (AEs) and serious adverse events (SAEs). Secondary outcomes include cell engraftment and survival, responder rate, and seizure frequency. The follow-up period for this study is 1 year. After completing the follow-up period within this study, subjects will enter a 15-year long-term safety follow-up. DiscussionMTLE remains a significant challenge in neurology. The results of this study will provide critical data regarding the feasibility and preliminary efficacy of ALC05 in treating MTLE and may offer a transformative therapeutic option for this condition.

Objective: The postictal state is a major yet underrecognised component of epilepsy burden. We aimed to develop a structured patient-reported instrument to quantify postictal recovery, characterise its multidimensional burden and identify demographic, clinical, psychiatric and treatment-related factors associated with postictal severity and duration. Methods: We conducted a prospective, single-centre observational cohort study (Timone Hospital, Marseille, February 2025 - March 2026). Consecutive patients aged >=15 years admitted for scalp or stereo-EEG video-monitoring were included. Patients completed the Postictal Recovery Scale (PRS), an 11-domain questionnaire assessing fatigue, mood, sensory, motor, language, orientation, time perception and postictal amnesia. Items were rated from 0 (severe impairment) to 3 (no symptoms), yielding a total score of 0-33. Internal consistency was assessed using Cronbach alpha. Associations between PRS scores, subjective postictal duration and covariates were analysed using group comparisons, correlations and regression models. Results: Of 107 enrolled patients, 96 were included. PRS showed good internal consistency (Cronbach alpha; = 0.79). 96% of patients reported experiencing postictal symptoms, with fatigue (80%) and postictal amnesia (79%) being the most frequent and severe manifestations. Recovery exceeded one hour in 21% of patients. Greater postictal impairment was associated with higher interictal anxiety (Spearman {rho} = -0.32, p = 0.0018) and depressive symptoms (Spearman {rho} = -0.40, p = 0.0001), whereas demographic, epilepsy-related and treatment variables showed no significant associations. Altered postictal time perception was reported by 40% of patients and was associated with disorientation, but not psychiatric symptoms. Subjective postictal duration was longer than subjective ictal duration (Wilcoxon test, p < 0.0001). Significance: The postictal state is a frequent and multidimensional patient-reported experience. Greater postictal severity, particularly concerning anxiety and depression, is associated with interictal psychiatric comorbidity, while altered temporal experience emerges as a distinct dimension of postictal dysfunction. These findings support integrating postictal measures into clinical practice and trials.

Objective: Electrical brain stimulations (EBS) are central to epileptic network identification and functional mapping during stereo-electroencephalography (SEEG), yet stimulation frequencies remain empirical, and standardized across patients and brain regions, producing false negatives and false positives, and potentially compromising surgical outcome. We investigated theta-range EBS (7 Hz) in the temporal lobe, a prominent physiological frequency band in this region, and compared it with conventional 1-Hz and 50-Hz protocols. Methods: We analyzed 1,408 temporal EBS in 25 patients with drug-resistant epilepsy. Epileptic responses (afterdischarges, seizures) and clinical signs were assessed across the epileptic network and temporal structures (amygdala, hippocampus, neocortex, parahippocampal gyrus, white matter), and analyzed according to stimulation parameters (frequency, intensity, duration, total charge). Results: At matched intensity and duration, 7-Hz EBS were associated with a higher occurrence of afterdischarges and clinical signs than 1-Hz EBS in several temporal structures (e.g., parahippocampal epileptogenic zone: p=0.014). Effects on usual seizure induction were less consistent. Comparisons with 50 Hz showed no systematic significant differences, with responses observed at one or both frequencies depending on structure and outcome. When controlling for total charge, frequency-related differences were attenuated. Some effects were sporadically observed at both intermediate frequency and charge quantity. No adverse events occured. Significance: Theta-range stimulation modulates electrophysiological and clinical responses during SEEG mapping and may provide complementary information to conventional frequencies. These findings support exploring a broader range of stimulation frequencies, rather than relying solely on standard protocols.

Background: The detection of subtle epileptogenic lesions such as focal cortical dysplasias (FCDs) is a clinical challenge in the management of drug-resistant focal epilepsy (DRFE). Ultra-high field (UHF) MRI offers increased signal-to-noise ratios and spatial resolution compared to 3Tesla (T) MRI and may improve diagnostic yield. Here, we present a 9.4T MRI cohort study of patients with DRFE. Methods: We recruited n=21 DRFE patients (with 3T-MRI findings: 2 positive, 3 equivocal, 16 negative) undergoing presurgical workup, and n=20 healthy controls for 9.4T MRI (0.8 mm isotropic MP2RAGE, slabs of 0.375 x 0.375 x 0.8 mm T2*-weighted GRE) and 3T MRI (MP2RAGE, FLAIR) acquisitions. Visual review for possible epileptogenic lesions was performed by clinical experts. For histopathologically confirmed FCD lesions, we extracted surface-based quantitative features (cortical thickness, qT1, FLAIR, T2*, and QSM values) across cortical depths and distances from the lesion centre and performed high-resolution cortical profiling of 9.4T T2* values. Results: No new epileptogenic lesions were visually identified at 9.4T in 3T MRI negative patients. In the two patients with histopathologically confirmed lesions, the FCD IIb lesions were visible with distinct qualitative and quantitative features at both field strengths. One of these FCD IIb showed a focal cortical T2* reduction at 9.4T that could here be quantified via automated cortical profiling, consistent with the previously described "black line sign". Conclusion: 9.4T MRI findings in epileptogenic lesions underlying DRFE are consistent with those on 3T MRI. While additional lesions were not identified in patients with negative 3T MRI, higher resolution T2*-weighted sequences can reveal a feature not seen at 3T: Cortical profiling of FCDs highlights the black line sign and can possibly help refine surgical or ablation targeting for some FCDs. Further optimization of UHF protocols and analysis methods on larger cohorts may reveal clinically applicable diagnostic benefits.

Polyhydramnios, Megalencephaly, and Symptomatic Epilepsy syndrome (PMSE/STRADA-related disorder) is a rare neurodevelopmental disorder characterized by megalencephaly (ME), early-onset drug-resistant epilepsy, neurocognitive impairment, and high early mortality, often due to status epilepticus. PMSE is caused by a multi-exon deletion in STRADA, encoding STRADA, which regulates the mechanistic target of rapamycin (mTOR) pathway. GABAergic inhibitory interneurons (INs) critically modulate the excitatory:inhibitory balance in cortical and hippocampal networks, and IN deficits contribute to epileptogenesis in several epileptic encephalopathies. However, no studies have investigated INs in PMSE. We used a multimodal approach to study INs in a Strada-/- mouse model engineered with the same causative 5-exon deletion identified in human PMSE. We demonstrate that Strada/STRADA loss causes a reduction of INs in the somatosensory cortex and a corresponding increase in the striatum, representative of remnant ganglionic eminence progenitor origin, in Strada-/- mice and a single PMSE brain tissue specimen. RNA sequencing comparing wildtype to Strada-/- cortex and striatum corroborated these findings, revealing increased IN-related gene expression (e.g., Dlx2) in the striatum and decreased IN-related gene expression (e.g., Pvalb) in the developing cortex. Cytoskeletal (e.g., Tpp3, Kank4, Map1a) and mTOR-associated genes (e.g., Rictor, Cryab) are differentially expressed in the developing cortex, mature striatum, and mature cortex of Strada-/- mice. Functional validation confirmed enlarged INs in mouse and human Strada/STRADA-deficient brain and enhanced S6 phosphorylation in Strada-/- striatum. Together, these findings suggest STRADA/Strada loss contributes to failed IN migration -- the first such report in a developmental, mTOR-associated megalencephaly syndrome -- highlighting INs as a therapeutic target for seizure prevention in PMSE. Key PointsO_LI- Reduced numbers of cortical inhibitory interneurons were observed in the cerebral cortex of Strada-/- mice, with striatal interneuron aggregation C_LIO_LI- Reduced numbers of cortical inhibitory interneurons, with an aggregation in striatum, were observed in human PMSE brain, supporting the observations in Strada-/- mouse C_LIO_LI- Transcriptomic analysis in Strada-/- mice reveals evidence of early developmental interneuron and cytoskeletal dysfunction C_LIO_LI- We introduce a loss of cortical interneurons as a salient feature of PMSE developmental pathogenesis, potentially contributing to a loss of inhibitory modulation C_LIO_LI- This is the first study proposing interneuron migration impairment in the developmental pathogenesis of an mTOR-associated megalencephaly syndrome C_LI

To date, FBRSL1-related disorder has been reported in five individuals with congenital abnormalities and severe postnatal impairment with or without epilepsy; however, the full extent of the phenotypic and genotypic spectrum remains unclear. Previously reported cases involved small truncating variants apparently escaping nonsense-mediated decay, suggesting either a haploinsufficiency or a dominant-negative mechanism. We report the first case of a complex structural variant at the FBRSL1 locus, resulting in an additional, partially truncated copy of the gene, providing strong evidence for a dominant-negative mechanism. RNA-Seq supported the expression of the additional truncated gene copy. The patient is an infant girl with a profound developmental and epileptic encephalopathy (DEE). The child presented at birth with intrauterine growth restriction, respiratory insufficiency, severe swallowing dysfunction, spasticity, contractures, optic nerve hypoplasia, facial dysmorphism, and atrial septal defect. She developed severe postnatal growth restriction with microcephaly and profound developmental impairment. She has a DEE with frequent neonatal focal seizures evolving to infantile epileptic spasms syndrome (IESS). Our patient has congenital abnormalities in common with previously reported cases, along with a profound DEE, not associated previously with FBRSL1. Our case expands both the phenotypic and genotypic spectrum of FBRSL1-related disorder.

Ferroptosis is a form of non-apoptotic cell death in which iron catalyzes the formation of reactive oxygen species, leading to lipid peroxidation. Experimentally, this process has recently been associated with seizures based on the increased levels of specific markers (4-hydroxynonenal and malondialdehyde) in the brain and plasma. Clinically, iron deposits have been identified in resected tissue from patients with refractory temporal lobe epilepsy. Quantitative susceptibility mapping (QSM) offers an opportunity to detect these accumulations in vivo. In this study, we investigated how pilocarpine-induced status epilepticus contributes to the generation of iron deposits in diverse cerebral regions and whether QSM can detect these deposits longitudinally. We scanned 14 animals (n=10 experimental; n=4 control) at five different time points (pre-status epilepticus induction and 1, 7, 14, 21 days post-induction) using QSM. We identified iron deposits in the caudate putamen, hippocampus, thalamus, and primary somatosensory cortex of experimental animals, which is consistent with histological findings. The initial size of the hippocampal iron deposits significantly increased over the following weeks. None of these effects was observed in the control animals. The presence of cerebral iron depositions in an animal model of pilocarpine-induced status epilepticus suggests that ferroptosis may be involved in the onset, development, and progression of spontaneous recurrent seizures. Furthermore, non-invasive, longitudinal in vivo mapping of brain iron deposits could be a potential imaging marker in neurological disorders such as epilepsy. Future experiments will be required to determine the origin of the iron and avoid its progressive accumulation. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=70 SRC="FIGDIR/small/712677v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@14abf67org.highwire.dtl.DTLVardef@5c08fborg.highwire.dtl.DTLVardef@51c40forg.highwire.dtl.DTLVardef@1eb5f9_HPS_FORMAT_FIGEXP M_FIG C_FIG

Hippocampal sclerosis is a frequent finding in pediatric epilepsy surgery and has traditionally been regarded as an acquired lesion. It commonly co-occurs with focal cortical dysplasia (FCD IIIa), yet whether hippocampal injury is secondary to seizures or reflects a shared underlying etiology remains unresolved. Here we identified somatic variants activating the RAS-MAPK pathway in 40% of patients with hippocampal sclerosis, but in none with non-sclerotic hippocampus. Gain-of-function variants in PTPN11 were the most common finding, with mutations present in both cortex and hippocampus and enriched in hippocampal neurons, consistent with a shared developmental origin. In mice, Ptpn11D61Y mutants developed profound hippocampal degeneration and gliosis following subthreshold kainic acid exposure, whereas wild-type controls were unaffected. p38-dependent stress pathways were upregulated in patients and mice, suggesting a mechanism through which ERK-p38 crosstalk lowers the threshold for seizure-induced injury. These results provide a genetic explanation for FCD IIIa, elucidate the role of somatic mutations within the RAS-MAPK pathway in driving hippocampal sclerosis, and provide a target for pathway-specific interventions for intractable seizures.

Importance: NGLY1 (N-Glycanase 1) Deficiency is an ultra-rare autosomal recessive disorder affecting ~165 patients worldwide, characterized by developmental delay, hyperkinetic movement disorders, and shortened life expectancy. Despite its severe neurological manifestations, comprehensive neuroimaging characterization has been limited to case reports and small descriptive studies. Objective: To investigate alterations in brain morphology in patients with NGLY1 Deficiency and determine whether these metrics associate with clinical phenotypes. Design, Setting, and Participants: This case series analyzed real-world MRI scans performed on 11 patients with NGLY1 Deficiency between 1999-2023 at sites across the globe. Ages ranged from 2 to 19 years at scan time (5 female, 6 male). Exposure: Molecular diagnosis of NGLY1 Deficiency. Main Outcomes and Measures: Cortical and subcortical morphology, including subcortical volume, and cortical thickness, surface area, volume, and curvature, were measured with 3-dimensional T1-weighted magnetic resonance imaging (MRI) scans. Z-scores were calculated using normative models from CentileBrain for patients >3 years old or custom models for patients <3 years old. Clinical phenotypes were matched to Human Phenotype Ontology codes. Results: 16 scans from 11 patients met quality criteria for analysis. Both age groups (under and over 3 years old) showed significantly reduced subcortical volumes, particularly in bilateral thalamus and putamen. Younger patients demonstrated widespread reductions in cortical surface area, volume, and curvature, indicating altered gyrification patterns. Older patients showed thinner dorsal and thicker ventral cortical regions with limited surface area reductions. Thalamic volume reduction in older patients correlated with gait disturbance, dysphagia, and EEG abnormalities, with additional cortical associations with sleep and hearing abnormalities. Seizure presence in younger patients correlated with altered cortical thickness, surface area, and curvature patterns. Conclusions and Relevance: NGLY1 Deficiency is associated with pervasive alterations in brain development affecting both subcortical and cortical morphology. Age-dependent patterns of cortical alterations indicate disrupted neurodevelopmental trajectories that may reflect impaired neuronal migration and/or altered synaptic pruning. Correlations with clinical variables suggest that these measures may serve as useful biomarkers for tracking disease progression and/or treatment efficacy. These findings provide a comprehensive neuroimaging characterization of NGLY1 Deficiency and establish a foundation for understanding brain structure-function relationships in this ultra-rare disorder.

YWHAG Syndrome (Developmental and Epileptic Encephalopathy 56, DEE56) is an ultra- rare childhood epilepsy associated with neurodevelopmental delays, with no therapeutic intervention available. Multiple de novo mutations in the YWHAG gene, encoding for the 14-3-3{gamma} protein, have been identified as causative for YWHAG Syndrome. 14-3-3{gamma} interacts with various targets, including major neurodevelopmental signaling proteins such as components of the ROCK pathway. Despite substantial evidence of the essential role of 14-3-3{gamma} in neurite outgrowth, cytoskeletal rearrangements, and neuronal migration during cortical development, little is known regarding the molecular consequences of YWHAG mutations and their effect on neuronal function and survival. Here, we characterized an isogenic, pluripotent stem cell (iPSC) model of YWHAGR132C/+ cortical neurons. The YWHAGR132C/+iPSC-derived neurons exhibited early cytoskeletal phenotypes, coupled with an elevated calcium baseline, lower frequency of calcium spikes, and reduced network activity. The widespread alterations in the transcriptome of mutant neurons revealed a biphasic dysregulation in the core genes and modulators associated with the ROCK pathway that resulted in maturation-dependent changes to cytoskeletal protein stability and calcium phenotypes. Direct inhibition of ROCK with Y27632 further increased the calcium baseline compared to the isogenic control. Exposure of YWHAGR132C/+ neurons to Trypsin-EDTA revealed underlying cytoskeletal instability, which was partially reversed by lovastatin treatment. Further, lovastatin partially rescued the elevated calcium baseline, but not the frequency or amplitude of calcium spikes. Together, these results suggest decoupling of calcium homeostasis and calcium signaling associated with cytoskeletal instability in YWHAGR132C/+ neurons. These findings lay the groundwork for future mechanistic studies of YWHAG function and molecular therapeutic targets for YWHAG Syndrome and YWHAG-associated conditions.

Background and Purpose: 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography (static PET) has mixed specificity and sensitivity in targeting epileptic zones in the noninvasive stage of epilepsy surgery evaluations. We compared the signal quality of static PET compared to a method of interictal dynamic PET (iD-PET). Materials and Methods: We calculated the signal quality of static PET and iD-PET obtained from a cohort of patients with focal epilepsy. We developed a Bayesian regional estimated signal quality (BRESQ) technique to objectively compare signal-to-noise ratios (SNRs) by region of interest (ROI) within subjects. Results: Adjusted for ROI size and neighboring regions, iDPET was superior to sPET with probability >95% in 8/36 regions; >90% in 21/36 regions; >80% in 29/36 regions. The top five regions with the largest adjusted SNR differences (greatest magnitude of iDPET superiority) were the Temporal Mesial (Left and Right), Occipital Lateral (Left and Right), and the Left Frontal Inferior Base. Conclusions: We found that iDPET yielded a superior SNR in most ROI. BRESQ offers a scalable and generalizable method to quantify signal quality between brain mapping modalities.

Abstract Background Understanding the phenotypic spectrum of disease-associated genes is essential for accurate diagnosis and targeted therapy. FRMPD4 (FERM and PDZ Domain Containing 4) has previously been associated with intellectual disability and epilepsy. However, its potential role in non-syndromic hearing loss has not been explored. Methods We performed genetic analysis in two unrelated families presenting with non-syndromic sensorineural hearing loss, identifying maternally inherited missense variants in FRMPD4. Clinical phenotyping included audiological assessment and evaluation for neurodevelopmental involvement. Cross-species expression analyses were conducted in Drosophila, zebrafish, and mouse. Functional characterization included quantitative evaluation of sound-evoked responses in Drosophila nicht gut hoerend (ngh) mutants, assessment of neuronal development and acoustic startle responses in zebrafish loss of function models, and morphological cochlear analyses with auditory brainstem response measurements in knockout mice. Results Three affected males from two unrelated families presented with prelingual, bilaterally symmetrical sensorineural hearing loss, with confirmed congenital onset in one individual and no evidence of neurodevelopmental abnormalities. Cross-species analyses demonstrated evolutionarily conserved expression of FRMPD4 in auditory structures. In Drosophila, quantitative analysis of sound-evoked responses in ngh mutants revealed impaired auditory function. Zebrafish loss of function models exhibited reduced neuronal populations in the otic vesicle and posterior lateral line, abnormal neuromast development, and diminished acoustic startle responses. In mice, Frmpd4 knockout resulted in high-frequency hearing loss and cochlear abnormalities consistent with the human phenotype. Conclusions Our findings expand the phenotypic spectrum of FRMPD4 to include non-syndromic sensorineural hearing loss and establish its evolutionarily conserved role in auditory function. These results have direct implications for genetic diagnosis and variant interpretation in patients with hearing loss.

BackgroundFunctional neurological disorder (FND) is one of the most common, but least researched, conditions in neurology. Debate exists as to whether the clinical entity referred to as FND is truly a single disorder or is in fact multiple entities which have been erroneously amalgamated into the same condition. We sought to provide empirical evidence on this question by treating it as a problem of model comparison. MethodsWe formulated statistical models equivalent to: (1) FND being a single entity with variation in phenotype, represented by latent trait (binary factor/item response theory) models, and (2) FND being multiple discrete entities, represented by latent class analysis (LCA) models. We fitted these models to data on the symptoms experienced by 697 people with FND from the FND Research Connect database (fnd-research.org) and used Bayesian model comparison methods to compare them. ResultsAll but one of the latent trait models, representing FND as a single entity with heterogeneous phenotype, fit the data better than all the LCA models. Secondary analysis of the LCA models showed results compatible with the models capturing discretisation of continuous variation rather than true discrete categories. DiscussionOur results suggest that the symptom structure of FND is the result of a single pathophysiological process, either as a single entity, or a common pathway preceded by multiple causative processes where the common pathway is solely responsible for the phenotype of the condition.

Background Angelman syndrome (AS) is a rare neurodevelopmental disorder with characteristic electroencephalographic abnormalities caused by loss of function of the maternally inherited UBE3A gene. Converging evidence suggests a disrupted excitation-inhibition (E/I) balance towards hyperexcitability. However, noninvasive approaches capable of characterizing intrinsic cortical excitability and its relationship with large-scale brain dynamics in AS are still lacking. We used resting-state electroencephalography (EEG) to derive cortical excitability, testing the hypothesis that altered local E/I balance in AS is associated with instability of large-scale functional brain networks. Methods We recorded 7 minutes of task-free high-density EEG in 29 individuals with AS and 36 typically developing controls. Source-reconstructed cortical activity was used to compute the excitability index (EI), based on mean spatial phase synchronization in the gamma band. Dynamic functional connectivity was computed and summarized as fluidity index, which estimates temporal variability of network configurations. We assessed group differences and associations between EEG features, clinical variables and caregiver-reported questionnaires. Results AS participants showed increased EI in anterior cingulate, dorsolateral prefrontal, temporoparietal, and occipital regions. Fluidity was larger in AS across frequency bands, indicating greater network instability. EI positively predicted fluidity in widespread regions in AS, whereas the opposite pattern was observed in controls. Higher EI correlated with fewer antiseizure medications and with greater sensory-seeking behavior. Conclusions AS is characterized by cortical hyperexcitability coupled with unstable large-scale network dynamics. The EI provides a biologically meaningful marker linking intrinsic E/I imbalance to behavioral features and treatment-related variables

Study ObjectivesIdiopathic hypersomnia (IH) is a central nervous system hypersomnia frequently accompanied by autonomic symptoms, yet objective physiological data are limited. We sought to characterize autonomic nervous system (ANS) dysfunction in IH using nocturnal heart rate variability (HRV) and diurnal autonomic reflex testing (ART), compared to individuals with type 1 narcolepsy (NT1) and healthy controls (HCs). MethodsTwenty-four adults with IH, 10 with NT1, and 14 HCs underwent overnight video polysomnography with HRV analyses in time and frequency domains during stable slow-wave sleep and REM sleep. Comprehensive ART included sympathetic adrenergic (head-up tilt (HUT), Valsalva BP responses), parasympathetic cardiovagal (HRV to deep breathing, Valsalva ratio), and sudomotor (Q-Sweat) measures. ResultsIH participants were predominantly female, with over half reporting long sleep duration. Compared to NT1 and HC, participants with IH demonstrated a greater magnitude of orthostatic tachycardia on tilt ({Delta}HR 41.0 {+/-} 16.3 vs. 26.3 {+/-} 9.3 vs. 30.8 {+/-} 9.3 bpm, p = 0.0086), as well as frequent sudomotor dysfunction (64.3%). IH participants demonstrated greater nocturnal and REM HR with reduced parasympathetic indices during REM, indicating diminished vagal modulation compared with HCs ConclusionsIH is characterized by a distinct pattern of autonomic dysfunction, including pronounced orthostatic tachycardia, frequent sudomotor abnormalities, and reduced parasympathetic activity during sleep. These findings provide objective physiological evidence of ANS involvement in IH and delineate features that distinguish IH from NT1 and HCs.

Epilepsy is a chronic neurological disorder requiring multi-faceted management, including seizure detection, syndrome diagnosis, prognostication, antiseizure medication recommendation, epileptogenic zone localization, and surgical outcome prediction. Although numerous deep learning approaches have been developed for individual tasks, these models are typically siloed and modality-specific (e.g., EEG for seizure detection, MRI for localization), failing to reflect the multidisciplinary nature of real-world epilepsy care, where epileptologists, neuroradiologists, neurosurgeons, neuropsychologists and neuropsychiatrists jointly interpret heterogeneous evidence to guide decisions. In this work, we propose a clinical guideline-grounded hybrid multi-agent framework for holistic epilepsy management. Heterogeneous patient data is processed through modality-specific discriminative and generative models, where textual interpretations from generative agents are combined with structured predictions from discriminative models as auxiliary guidance. This aggregated evidence is passed to a central orchestrating agent grounded in international epilepsy guidelines, which evaluates multi-modal findings within structured clinical pathways and performs iterative cross-agent coordination for evidence-informed decision-making. We evaluate our framework across two datasets spanning six epilepsy management tasks and also introduce a publicly available multi-modal, multi-task epilepsy benchmark. Results demonstrate that integrating discriminative evidence with guideline-grounded generative coordination yields more reliable and comprehensive decisions compared to conventional LLM-based and task-specific baselines. Our dataset and code is available at URL.

Background: Clinical evidence on the contemporary management and functional outcomes of patients with Wernicke encephalopathy remains limited. This study aimed to clarify the nationwide patterns of thiamine administration and functional outcomes at discharge. Methods: Using the Japanese nationwide inpatient Diagnosis Procedure Combination database, we identified patients hospitalized with Wernicke encephalopathy between July 2010 and March 2024. Initial intravenous thiamine doses were categorized as low ([&le;]300 mg/day), medium (301-900 mg/day), or high (>900 mg/day). Outcomes included in-hospital mortality and functional status (Barthel Index) at discharge. Results: We identified 7856 patients with Wernicke encephalopathy. Over the 13-year study period, the proportion of patients receiving initial high-dose thiamine increased markedly from 5.4% to 49.0%, while the frequency of low-dose therapy decreased from 83.0% to 37.9%. Despite prompt intervention [median time to initial administration: 0 days (interquartile range, 0 to 0 days)], 56.1% of patients were discharged with impaired activities of daily living (Barthel Index <90), and the in-hospital mortality rate was 3.8%. Conclusions: High-dose thiamine treatment is increasingly implemented for Wernicke encephalopathy in Japan. Although in-hospital mortality was relatively low, the high prevalence of functional impairment at discharge, despite early treatment initiation, indicates substantial burden of Wernicke encephalopathy. Given the limited clinical evidence, further research investigating the optimal thiamine dose and develop effective primary prevention strategies for Wernicke encephalopathy is needed.

Background: Peri-lead edema (PLE) occurs in up to 15% of Deep Brain Stimulation (DBS) cases, can cause morbidity, and its etiology remains unknown. We hypothesized that PLE represents a secondary brain injury modulated by hypoxemia, and that patients with obstructive sleep apnea (OSA) are at elevated risk. Methods: We conducted a retrospective case-control study of 121 Parkinson's disease (PD) patients undergoing DBS at a single center (2019-2024). PLE severity was quantified by CT volumetric segmentation and Hounsfield unit (HU) measures. Perioperative SpO2 and PaO2 were recorded. Polysomnography (PSG) was available in 26 patients; and the REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ) was administered retrospectively. Results: Symptomatic PLE occurred in 12 patients (9.9%), with onset at 3.5 (2-9) days postoperatively. PLE patients had higher body mass index (p = 0.022) and higher OSA prevalence (75% vs. 30%; p = 0.002). Perioperative SpO2 was lower in the PLE group in both the operating room and post-anesthesia care unit (PACU; p < 0.05); PaO2 was lower in the PACU (p = 0.037). In the PSG subgroup, REM Sleep Behavior Disorder (RBD) incidence was lower in PLE patients (20% vs. 60%; unadjusted p = 0.048), and PLE severity correlated significantly with sleep-related hypoxemia and respiratory indices. RBDSQ scores were positively associated with edema density (normalized HU: rho = 0.86, p = 0.024). Conclusions: OSA and perioperative hypoxemia are associated with symptomatic PLE following DBS, while RBD appears protective. Preoperative sleep evaluation and optimized perioperative airway management warrant prospective investigation as PLE prevention strategies.

BackgroundNeonatal global hypoxic-ischemic cerebral injury is a leading cause of infant mortality and lifelong disability. Current rodent models do not replicate neonatal global cerebral ischemia (nGCI) and reperfusion injury. Here, we developed and characterized a rodent model of cardiac arrest and cardiopulmonary reperfusion (CA/CPR) to induce nGCI, producing acute systemic ischemia, mild neuronal injury, white matter alterations, and motor and memory deficits. MethodsRat pups underwent CA/CPR or sham procedure on postnatal day 9-11. CA/CPR in rat pups was performed under anesthesia while intubated. Asystole was induced with intravenous (IV) KCl and maintained for 10-14 minutes. Resuscitation included oxygen ventilation, chest compressions, and IV epinephrine. ResultsTwelve minutes of asystole provided an optimal balance between survival and systemic injury. Behavioral testing on postoperative day (POD) 7 revealed memory impairments. Despite the absence of overt neuronal death in the hippocampus or cerebellum, we observed evidence of glial activation and white matter alterations. ConclusionThis novel rodent model of nGCI addresses limitations in existing models while offering clinically relevant features to support future mechanistic and translational research. ImpactO_LIThis study validates cardiac arrest and cardiopulmonary resuscitation (CA/CPR) as a novel model for neonatal global cerebral ischemia (nGCI), complementing existing rodent models of unilateral and permanent injury by enabling investigation of both global ischemia and reperfusion injury. C_LIO_LInGCI results in memory impairment in the absence of overt neuronal cell death. Functional deficits are associated with neuroinflammatory responses in the hippocampus, white matter, and cerebellum. C_LIO_LINeonatal CA/CPR induces global cerebral ischemia which uniquely allows investigation of hindbrain structures, such as cerebellum, which are typically spared in existing rodent models of neonatal hypoxia-ischemia. C_LI