Annals of Clinical and Translational Neurology

ObjectiveCognitive motor dissociation (CMD) is associated with long-term recovery in acute brain injury, but CMD testing is only available in few centers. Our objective was to identify surface EEG patterns with high sensitivity or positive predictive value (PPV) for CMD in patients with acute disorders of consciousness to refine allocation of this resource-intensive test. MethodsIn this observational cohort study, we enrolled clinically unresponsive, acutely brain injured patients who underwent continuous surface EEG and CMD assessments. CMD was detected by applying a machine learning algorithm to EEG acquired during a motor command paradigm presentation. Electroencephalographers blinded to CMD test results applied standardized ACNS criteria to the EEGs acquired during CMD assessments. We calculated accuracy measures of surface EEG findings for CMD test results using generalized estimating equations, with an exchangeable matrix and accounting for repeated measures per patient. ResultsWe included 185 patients (mean age: 62 {+/-} 17; 85 [46%] female) and 282 CMD assessments. CMD testing was positive in 39 (14%) assessments. Sensitivity and PPV of normal background voltage, symmetry and continuity were respectively 77% (95%-CI: 60-88%) and 19% (95%-CI: 13-26%), 74% (95%-CI: 58-86%) and 14% (95%-CI: 10-20%), and 74% (95%-CI: 58-86%) and 14% (95%-CI: 9-19%). All EEGs with burst suppression, suppression, sporadic epileptiform discharges, lateralized periodic discharges, bilateral independent periodic discharges, electrographic seizures and brief potentially ictal rhythmic discharges had negative CMD tests. InterpretationSurface EEG findings are not reliable to screen for CMD or to identify patterns conferring higher CMD pretest probability.

Background and ObjectivesSporadic inclusion body myositis (IBM) is the most common acquired myopathy in individuals over age 50. The disorder is slowly progressive and while many therapies have been investigated, response has generally been poor. Clinical heterogeneity may influence treatment responsiveness; however, data regarding heterogeneity in IBM is limited and often conflicting. We aim to identify clinically distinct subgroups within a large IBM cohort, as well as prognostic factors for disease progression. MethodsClinical, histologic, radiologic, and electrophysiologic data were analyzed for all patients with IBM and other forms of myositis enrolled in a longitudinal cohort from The Johns Hopkins Myositis Center from 2003-2018. Univariate, multivariate, and graphical analyses were used to identify prognostic factors in IBM patients. ResultsAmong the 335 IBM patients meeting inclusion criteria, 64% were male with an average age of disease onset of 58.7 years and a delay to diagnosis of 5.2 years. Initial misdiagnosis (52%) and immunosuppressant treatment (42%) were common. Less than half (43%) of muscle biopsies demonstrated all three pathologic hallmarks: endomysial inflammation, mononuclear cell invasion, and rimmed vacuoles. Black patients had significantly weaker arm abductors, hip flexors, and knee flexors compared to non-Black patients but were less likely to develop dysphagia. Female patients had stronger finger flexors and knee extensors compared to their male counterparts but were more likely to develop dysphagia. A significant number (20%) of patients had an age of onset less than 50 years. This group of younger patients was weaker at their first visit; however, this may be accounted for by a longer disease duration at first visit. DiscussionAlthough IBM has long been considered a disorder predominately of older, White men, female, and non-White patients comprise a significant proportion of the IBM population. Our study demonstrates that female and Black patients have distinct clinical phenotypes within the overarching IBM clinical phenotype.

Developmental and epileptic encephalopathies (DEEs) are a group of epilepsies with early onset and severe symptoms that sometimes lead to death. While a number of genes have been successfully implicated, it remains challenging to identify causative mutations within these genes from the background variation present in all individuals due to disease heterogeneity. Our ability to detect likely pathogenic variants has continued to improve as in silico predictors of deleteriousness have advanced. We investigate their use in prioritising likely pathogenic variants in epileptic encephalopathy patient whole exome sequences and show that the inclusion of structure-based predictors of intolerance improve upon previous attempts to demonstrate enrichment within epilepsy genes.

BackgroundDifferentiating demyelinating from axonal polyneuropathies is essential for accurate diagnosis and treatment. We hypothesized that multiparametric quantitative MRI (qMRI) of peripheral nerves can differentiate demyelination from axonal loss. This retrospective study leveraged genetically defined demyelinating and axonal polyneuropathies to test this concept. MethodsMultiparametric qMRI data of proximal (sciatic) and distal (tibial) nerves were acquired on 3T MRI, including magnetization transfer ratio (MTR), MT saturation index (MTsat), T *, T, proton density (PD), fractional anisotropy (FA), mean/axial/radial diffusivities (MD, AD, RD), and fascicular volume (fVol). Data were analyzed from patients with Charcot-Marie-Tooth type 1 (CMT1, de-/dys-myelinating, n=19), CMT2 (axonal, n=12), hereditary neuropathy with liability to pressure palsies (HNPP, a cohort who often has intermediate changes between the two classifications, n=25), and health controls (HC, n=25). A composite qMRI score, as CMT Imaging Score (CMTIS), was developed to predict disease severity using the CMT Neuropathy Score version-2 (CMTNSv2) as a clinical reference. Receiver operating characteristic (ROC) analyses assessed diagnostic performance. ResultsCMT1 showed significantly increased fVol versus HCs, while CMT2 demonstrated reduced T2*. Both CMT1 and CMT2 exhibited reduced FA, MTsat, and AD, along with elevated T1 and RD, with larger abnormalities in CMT1. ROC analyses demonstrated strong discrimination of CMT1 and CMT2 (AUCs: 0.95 and 0.85 for sciatic; 0.89 and 0.73 for tibial nerves). CMTIS correlated strongly with CMTNSv2 (r=0.67 sciatic; r=0.72 tibial; r=0.79 combined). ConclusionsMultiparametric qMRI identifies distinct imaging signatures of demyelinating versus axonal hereditary polyneuropathies. The CMTIS shows strong potential as a biomarker for disease monitoring. DATA AVAILABILITYAnonymized data used in this study is available from the corresponding author upon request and subject to institutional approvals. KEY MESSAGESO_ST_ABSWhat is already known on this topicC_ST_ABSCurrent electrophysiological tools are limited in their ability to differentiate demyelinating from axonal polyneuropathies when pathology occurs in proximal nerves. Quantitative MRI (qMRI) can assess proximal demyelination and axonal loss; however, individual qMRI metrics lack sufficient sensitivity for reliable differentiation. What this study addsThis proof-of-concept study demonstrates the feasibility of using multiparametric qMRI for patient stratification and for distinguishing demyelinating from axonal inherited polyneuropathies. The proposed composite qMRI score shows a strong correlation with clinical disease severity. How this study might affect research, practice, or policyThis study suggests that multiparametric qMRI of peripheral nerves can serve as a non-invasive adjunct to distal nerve conduction studies for improving diagnosis and treatment management of polyneuropathies. The composite qMRI score also shows potential as a monitoring biomarker for tracking disease progression.

Background and ObjectivesWolfram syndrome (WFS) is a genetic disorder mainly caused by pathogenic variants in the WFS1 gene. It is characterized clinically by optic atrophy (OA), diabetes mellitus (DM), sensorineural hearing loss (SNHL), diabetes insipidus (DI), and variable neurological/psychiatric symptoms. WFS typically manifests before age 20 and progresses into adulthood. Classical neuroradiological features include cerebellar and/or brainstem atrophy as well as white matter abnormalities ranging from small, ovoid lesions to diffuse, symmetrical changes along the visual pathway. Following the identification of multifocal, progressive white matter abnormalities that prompted the consideration of multiple sclerosis (MS) in two molecularly confirmed WFS subjects, we sought to verify whether MS-like lesions constitute a novel WFS-associated MRI pattern. MethodsWe conducted an international multicenter retrospective study of the clinical, genetic, and radiological data from 17 unrelated WFS subjects. ResultsSeven subjects (7/17; 41%) showed at least one focal white matter lesion evocative of MS. Among these seven, three fulfilled the McDonald radiological criteria of dissemination in space and time, suggesting an inflammatory demyelinating process. All subjects reviewed in the study had at least one of the classical WFS MRI features. ConclusionsOur report expands the WFS spectrum of white matter involvement to include progressive, seemingly inflammatory demyelinating lesions. While we cannot exclude the possibility of a WFS-MS dual diagnosis in some cases, the role of WFS1 in myelination suggests a selective white matter vulnerability in WFS. Our findings suggest that follow up MRI should be recommended to adult subjects with WFS. Further identification and longitudinal study of adult WFS subjects is required to confirm whether a WFS molecular diagnosis confers susceptibility to the development of MS.

Adenylosuccinate synthetase 1 (ADSS1) myopathy is an ultra-rare disease characterized by progressive muscle dysfunction. The objective of this investigation was to employ a non-invasive biomarker approach to phenotype (fine-)motor skills, speech production and cognition in adults with ADSS1 myopathy. Five individuals with ADSS1 myopathy and five age-sex-matched healthy controls (HCs) underwent a comprehensive multimodal evaluation. Assessments included, (i) evaluation of motor performance, (ii) speech production and cognitive test batteries, (iii) patient-reported outcomes, (iv) electrical impedance myography (EIM), (v) musculoskeletal magnetic resonance imaging (MRI) and (vi) plasma proteomics. ADSS1 participants vs. HCs demonstrated reduced performance on the 9-Hole Peg and grip strength tests as well as lower self-reported mobility. Speech production analysis revealed asthenia (p=0.02), lower intelligibility (p=0.008), and worse voice quality during the sustained vowel task (p=0.03) in the ADSS1 cohort. Cognitive functioning remained unaffected in patients with ADSS1. On EIM, ADSS1 participants vs. HCs, demonstrated a pattern of higher resistance and lower reactance and phase across upper- and lower-extremity measurements, indicative of poorer muscle health, with large effect sizes (Cliffs 8=0.5-0.9). MRI revealed intramuscular fat infiltration, particularly in posterior compartments of the upper leg (e.g., biceps femoris). Proteomics indicated reduced (p=0.04) Neurotrophin-3 (NTF3; implicated in neuronal development, survival and differentiation) levels in the ADSS1 cohort relative to HCs. Lower NTF3 levels associated with poorer performance on hand-motor tasks as well as higher resistance and lower reactance and phase on EIM. This study highlighted the value of multimodal phenotyping for quantifying disease expression and advancing monitoring strategies in ADSS1 myopathy. Take-home messageThis multimodal investigation demonstrates that integrating electrical impedance myography with quantitative motor, speech, musculoskeletal imaging, and proteomic assessments provides a sensitive and non-invasive research framework for capturing neuromuscular dysfunction and functional disease burden in patients with ADSS1 myopathy, thereby supporting the current biomarker strategy for refined phenotyping and longitudinal disease monitoring in this ultra-rare condition.

BackgroundNeurogenetic disorders caused by pathogenic variants in four genes encoding non-erythrocytic spectrins (SPTAN1, SPTBN1, SPTBN2, SPTBN4) range from peripheral and central nervous system involvement to complex syndromic presentations. Heterozygous pathogenic variants in SPTAN1 are exemplary for this diversity with phenotypes spanning almost the entire spectrum. MethodsThrough international collaboration we identified 14 families with genetically unsolved distal weakness and unreported heterozygous SPTAN1 loss-of-function variants including frameshift, nonsense and splice-acceptor variants. Clinical data, electrophysiology, muscle CT or MRI and muscle biopsy findings were collected and standardized. SPTAN1 protein, mRNA expression analysis and cDNA sequencing was performed on muscle tissue from two patients. ResultsAll 20 patients presented with early childhood onset distal weakness. The severity varied both within families and between different families. Foot abnormalities ranged from hammer toes and pes cavus to distal arthrogryposis. Electrophysiology showed mixed myogenic and neurogenic features. Muscle MRI or CT in 10 patients showed fatty infiltration of the distal lower limb anterior compartment and/or selective involvement of the extensor hallucis longus muscle. Muscle biopsy revealed myopathic changes with mild dystrophic and chronic neurogenic changes in 7 patients. Finally, we provide proof for nonsense mediated decay in tissues derived from two patients. ConclusionsWe provide evidence for the association of SPTAN1 loss-of-function variants with childhood onset distal myopathy in 14 families. This finding extends the phenotypic spectrum of SPTAN1 loss-of-function variants ranging from intellectual disability to distal weakness with a predominant myogenic cause. KEY MESSAGES{diamond} SPTAN1 loss-of-function variants, including frameshift, nonsense and splice site variants cause a novel childhood onset distal weakness syndrome with primarily skeletal muscle involvement. {diamond}Hereditary motor neuropathies and distal myopathic disorders present a well-known diagnostic challenge as they demonstrate substantial clinical and genetic overlap. The emergence of SPTAN1 loss-of-function variants serves as a noteworthy example, highlighting a growing convergence in the spectrum of genotypes linked to both hereditary motor neuropathies and distal myopathies.

BackgroundPlasma exchange is an effective therapy for myasthenic crisis (MC); yet the number of exchanges needed is unknown. We set out to examine the relationship between the number of plasma exchanges and clinical outcome in patients experiencing MC. MethodsWe retrospectively reviewed patient episodes with ICD 9 and ICD 10 codes for myasthenia gravis and myasthenia gravis exacerbation/crisis in patients admitted to a single center tertiary care referral center from July 2008 to July 2017. These episodes were screened for patients with impending myasthenia gravis crisis and manifest crisis who received plasmapheresis during their hospital course. We performed statistical analyses to determine if increased number of plasma exchanges improves the primary outcome (hospital length of stay), as well as the secondary outcome (disposition to home, skilled nursing facility, long term acute care hospital, or death). ResultsThere is neither clinically observable nor statistically significant improvement in length of stay or disposition on discharge in patients who received six or greater sessions of plasmapheresis. ConclusionsThis study provides class IV evidence that extending the number of plasma exchanges beyond five does not correlate with decreased hospital length of stay or improved discharge disposition in patients experiencing myasthenic crisis.

Motor unit number index (MUNIX) of the upper trapezius is a candidate biomarker for lower motor neuron function of the bulbar region; however, only a few studies have explored this measure in neuromuscular diseases and reliability data is incomplete. We conducted a systematic review and meta-analysis of this measure in control participants and assessed its reliability in twenty healthy volunteers. Four studies were included with heterogeneous mean-MUNIX estimates, moderated by variability in the populations age and MUNIX sampling technique. We demonstrated an inter- and intra-rater intraclass correlation of 0.86 and 0.94, respectively. Upper trapezius MUNIX is a reliable measure with in-between study variability moderated by age and MUNIX technique.

Background and Objectives: Deep sequencing of brain tissue in the research setting has established that mosaic variants are a major cause of malformations of cortical development (MCDs) and epilepsy. However, genetic testing in the clinical setting primarily detects germline variants using clinically accessible samples. We aimed to determine the diagnostic yield and clinical utility of deep sequencing in the clinical setting to identify pathogenic mosaic variants for this population. Methods: We performed a retrospective cohort analysis of individuals at Boston Children's Hospital with MCDs with or without epilepsy who received clinical deep sequencing between September 2017 and February 2026. Demographic, clinical, and genetic testing data were abstracted from the medical record. For individuals without systemic features, we classified brain tissue as an affected tissue sample. For individuals with systemic features, we classified brain or relevant non-brain tissue as affected. The primary outcome was the diagnostic yield of clinical deep sequencing performed using affected vs unaffected tissue samples. The secondary outcome was the clinical utility of genetic diagnoses. Results: Our cohort included 37 individuals (19/37 (51%) female, 18/37 (49%) male) with MCDs, of whom 35/37 (95%) had epilepsy (25 with brain tissue samples available from epilepsy surgery) and 8/37 (22%) had systemic features. Most (35/37 (95%)) had dysplasia phenotypes on MRI and 12/27 (44%) with pathology available had Focal Cortical Dysplasia Type I or II. The diagnostic yield was 53% (17/32; 16 mosaic and 1 germline variant) when clinical deep sequencing was performed using an affected tissue sample vs 0% (0/6) using an unaffected tissue sample (p=0.016). Of the diagnosed cases, 13/17 (76%) had testing performed on brain tissue (1 with systemic features) and 4/17 (24%) on non-brain tissue (3 buccal and 1 duodenal tissue, all with systemic features). All but one diagnosis involved the mTOR pathway. All diagnoses had clinical utility. Discussion: Clinical deep sequencing, when performed using an affected tissue sample, has high diagnostic yield and clinical utility for individuals with MCDs, especially dysplasia phenotypes, and epilepsy. Our findings support implementation of clinical deep sequencing for this population, especially as the genetic diagnoses have implications for emerging precision therapies.

Transgenic mouse models of amyotrophic lateral sclerosis, such as the widely used SOD1G93A mouse, enable investigation of disease mechanisms and testing of novel therapeutic interventions. However, treatments that have been considered successful in mice have often failed to translate into human benefit in clinical trials, particularly when relying on the so-called survival read-out. Compound muscle action potentials (CMAPs), are a simple neurophysiological test that measures the summation of muscle fibre depolarisation in response to maximal stimulation of the innervating nerve. CMAPs can be measured in both mice and humans and decline with motor axon loss in ALS, making them a potential translational read-out of disease progression which could help bridge the preclinical and clinical divide. Herein we assess the translational potential of CMAPs and ascertain at what time points human and mouse data aligned most closely. We extracted data from 18 human studies and compared with results generated from SOD1G93A and control mice at different ages across different muscles. We found that the relative CMAP amplitude difference between SOD1G93A and control mice in tibialis anterior and gastrocnemius muscles at 70 days of age was most similar to the relative difference between baseline ALS patient CMAP measurements and healthy controls in the abductor pollicis brevis (APB) muscle. We also found that the relative decline in SOD1G93A tibialis anterior CMAP amplitude between 70-140 days was similar to that observed in 12 month human longitudinal studies in APB. Our findings suggest CMAP amplitudes can provide a translational window, from which to make comparisons between the SOD1G93A model and human ALS patients. CMAPs are easy to perform and can help determine the most clinically relevant starting/end points for preclinical studies and provide a basis for predicting potential clinical effect sizes.

Importance: Leukodystrophies are a heterogeneous group of genetic disorders affecting the white matter of the brain, often presenting with overlapping clinical features but differing in neuroanatomical involvement. There is a critical need for quantitative tools to characterize disease burden and support diagnosis, severity stratification, and clinical trial readiness. Objective: To characterize shared and distinct neuroanatomical patterns across six genetically confirmed leukodystrophies using anatomical MRI-derived phenotypes benchmarked against brain growth charts, and to assess the utility of this methodological approach for identifying imaging biomarkers of disease severity. Design, Setting, and Participants: Cross-sectional neuroimaging study using retrospective clinical MRI data. Setting: Multicenter study incorporating data from the Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN) and control data from the Childrens Hospital of Philadelphia. Participants: The study included 434 MRI scan sessions from 274 patients with genetically confirmed leukodystrophies (Pelizaeus-Merzbacher disease, Metachromatic leukodystrophy, Alexander disease, Aicardi-Goutieres syndrome, TUBB4A-related leukodystrophies, and POLR3-related leukodystrophy). Control MRI data (7628 scans from 7205 subjects) were drawn from the Scans with Limited Imaging Pathology cohort at the Children's Hospital of Philadelphia. Exposures: All MRI scans underwent automated segmentation using deep learning segmentation tools to derive global and regional brain volumes. Normative models of brain development ("brain growth charts") were generated for the control cohort using generalized additive models for location, scale, and shape. Centile scores were then calculated for leukodystrophy subjects to quantify deviations from typical development. Main Outcomes and Measures: Centile scores for global and regional brain volumes were compared across leukodystrophy subtypes to identify disease-specific neuroanatomical patterns and to evaluate their potential utility for severity stratification. Results: Distinct patterns of neuroanatomical deviation were observed across leukodystrophy subtypes. Certain leukodystrophies showed preferential involvement of specific cortical or subcortical regions, while others displayed more diffuse volume loss. Centile scores demonstrated potential for differentiating disease subtypes and stratifying individuals by severity. Preliminary longitudinal data suggest centile scores may also track progression over time. Conclusions and Relevance:This study demonstrates the feasibility and utility of MRI profiling of individuals with leukodystrophy using anatomical MRI-derived phenotypes benchmarked against brain growth charts. The approach enables data-driven, quantitative characterization of structural brain abnormalities, offering a scalable method for phenotyping, diagnosis, and future use in clinical trials.

ObjectivesReport a case series of new onset small fiber neuropathy (SFN) after COVID-19 treated with intravenous immunoglobulin (IVIG). SFN is a critical objective finding in long COVID and amenable to treatment. MethodsA retrospective chart review was conducted on patients seen in the NeuroCOVID Clinic at Yale who developed new-onset SFN after a documented COVID-19 illness. We documented demographics, symptoms, treatments, diagnostics, and clinical response to treatment. ResultsSixteen patients were diagnosed with length dependent or independent SFN on skin biopsy (median age 47, 75% female, 75% Caucasian). Among the nine patients tested for autoantibodies, six were positive for either trisulfated heparin disaccharide (TS-HDS) or fibroblast growth factor receptor 3 (FGFR3). Eight patients underwent treatment with IVIG and experience significant clinical improvement in their neuropathic symptoms. 92% of patients reported post-exertional malaise characteristic of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and six patients underwent invasive cardiopulmonary exercise testing (iCPET), which demonstrated neurovascular dysregulation and dysautonomia consistent with ME/CFS. DiscussionHere we present preliminary evidence that SFN is responsive to treatment with IVIG and linked with neurovascular dysregulation and dysautonomia. A larger clinical trial is indicated to further demonstrate the clinical utility of IVIG in treating post-infectious small fiber neuropathy.

BackgroundNon-compressive myelopathy can lead to severe disability and death. The diagnosis is often complex and resource-intensive, with regional variation in causes. Data on the epidemiology and etiology of non-compressive myelopathy in Africa remains limited. MethodsA prospective observational study of adults presenting with clinical signs and symptoms of non-compressive myelopathy was conducted. Patients were recruited from 2013-2015 and 2018-2022 in Kampala, Uganda. Participants underwent spinal magnetic resonance imaging (MRI) to exclude extradural spinal cord lesions. Serum and cerebrospinal fluid (CSF) were tested for aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibodies. Metagenomic next-generation sequencing (mNGS) was performed on CSF to detect infectious etiologies. Serum vitamin B12 levels and tissue biopsies were performed at clinician discretion. Participant characteristics and diagnostic findings were summarized using descriptive statistics. FindingsAmong 420 participants screened, 144 were enrolled and included in this analysis. The median age was 33 years (interquartile range 25-44). 79 participants (55%) were male, and 38 (26%) were living with HIV. Intradural abnormalities were identified on spinal MRI in 79 (55%) participants. An etiologic diagnosis was established in 50 (35%) participants, including neuromyelitis optica spectrum disorder (NMOSD, n=10), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD, n=7), Schistosoma mansoni (n=9), cytomegalovirus (n=1), varicella zoster virus (n=1), vitamin B12 myelopathy (n=8), spinal cord tumor (n=12), and arteriovenous malformation (n=2). InterpretationThis study identified a wide range of etiologies for non-compressive myelopathy in Uganda. Autoimmune myelopathies (NMOSD and MOGAD) accounted for 14% of cases, while mNGS identified an infectious cause in 13% of participants. These findings highlight the importance of expanding access to both autoimmune and infectious diagnostic testing in resource-limited settings. FundingThis study was supported by the NIH (R01NS113828, R01AI145437, R25TW009345, K24AI096925, and 1K43TW010718) and the Westridge Foundation (MRW). Sequencing was performed at the UCSF Center for Advanced Technology, supported by UCSF PBBR, RRP IMIA, and NIH 1S10OD028511-01 grants. The K24AI096925 was used in the design of the study and data collection, R25TW009345 was used in data collection while 1K43TW010718 was used in analysis, interpretation of the data and in writing the manuscript.

An overlap syndrome of myositis and/or myocarditis associated with myasthenia gravis (MG) has emerged as a life-threatening immune-related adverse event (irAE) in cancer patients treated with immune checkpoint inhibitors (ICIs). This syndrome closely resembles a rare form of idiopathic inflammatory myopathy (IIM) seen in a subset of MG patients. In this systematic review, we searched PubMed for reports of concurrent MG and IIM as well as ICI-related overlap syndromes. By integrating clinical, serological, and pathological observations, we delineated a previously unrecognized clinicopathological subtype of myositis that overlaps with MG. This entity is defined by a strong association with striational antibodies (StrAbs) and frequent co- occurrence with thymoma as a paraneoplastic process, and we classify it as StrAb-associated myositis. The idiopathic and ICI-induced forms share similar, though not identical, clinical, serological, and histopathological characteristics. We found that AChR antibody positivity, independent of established clinical risk factors such as respiratory or cardiac involvement, predicted more severe ICI-myotoxicity. Together with supporting evidence, our findings suggest a pathogenic model in which thymoma-driven cytotoxic T-cell responses trigger secondary AChR autoimmunity. These results highlight the potential utility of StrAbs and anti-AChR antibodies as practical biomarkers for diagnosis, risk stratification, and early intervention in patients at risk for severe neuromuscular irAEs.

Background and ObjectivesAutoimmune-associated epilepsy (AAE), a condition which responds favorably to immune therapies but not traditional anti-seizure interventions, is emerging as a significant contributor to cases of drug-resistant epilepsy. Current standards for the diagnosis of AAE rely on screening for known neuronal autoantibodies in patient serum or cerebrospinal fluid. However, this diagnostic method fails to capture a subset of drug-resistant epilepsy patients with suspected AAE who respond to immunotherapy yet remain seronegative (snAAE) for known autoantibodies. MethodsTo identify potential biomarkers for snAAE, we evaluated the most comprehensive panel of assayed cytokines and autoantibodies to date, comparing patients with snAAE, anti-seizure medication (ASM) responsive epilepsy, and patients with other neuroinflammatory diseases. ResultsWe found a unique signature of 14 cytokines significantly elevated in snAAE patients including: GM-CSF, MCP-2/CCL8, MIP-1a/CCL3, IL-1RA, IL-6, IL-8, IL-9, IL-10, IL-15, IL-20, VEGF-A, TNF-b, LIF, and TSLP. Based on prior literature, we highlight IL-6, IL-8, IL-10, IL-13, VEGF-A, and TNF-b as potentially actionable cytokine biomarkers for snAAE, which could be of diagnostic utility in clinical evaluations of snAAE patients. Autoantibody-ome screening failed to identify autoantibodies targeting neuronal channel proteins in snAAE patients. Interestingly, ASM-responsive epilepsy patients displayed elevations in the proportion of autoantibodies targeting brain plasma membrane proteins, possibly pointing to the presence of immune hyperactivity/dysfunction despite well-controlled seizure activity and suggesting ASM-responsive patients may experience disease progression independent of seizure activity (PISA). DiscussionOverall, our findings suggest that simply expanding existing autoantibody screens may not sufficiently enhance diagnostic power for snAAE. Instead, we propose that cytokine analysis may serve as a promising diagnostic avenue for identifying immune dysregulation in AAE patients and enabling opportunities for trials of immunotherapies.

Objective: In KCNQ2-related disorders (KCNQ2-RD), neurodevelopmental outcome remains variable despite established genotype-phenotype correlations. Our aim is to improve counselling, by developing and internally validating models predicting neurodevelopmental outcomes based on early clinical and genetic features, universally available to clinicians. Methods: We conducted a multicentric retrospective cohort study including 277 individuals carrying a (likely) pathogenic variant in the KCNQ2 gene, with a minimum follow-up age of three years. Mosaic variants were excluded. The cohort was randomly split into training (70%) and validation (30%) sets. Ten expert selected parameters with minimal missing data were used to train random forest models to predict (i) dichotomous outcomes and (ii) three-category outcomes for cognition, language, and gross motor milestones. Results: Models incorporated seven clinical (neonatal hypotonia, EEG characteristics, age at seizure onset, seizure type, and seizure frequency at onset, prematurity, and sex) and three genetic variables (de novo status, exon localisation, and position within known KCNQ2-developmental and epileptic encephalopathy (DEE) hotspot regions). Dichotomous models showed the highest predictive performance, with accuracies of 0.83 for normal vs. mild-profound intellectual disability (ID), 0.83 for achievement of first words, and 0.86 for achievement of independent walking. Three category models remained clinically informative: accuracies were 0.79 for normal vs. mild vs. moderate-profound ID, 0.70 for first words [≤]16 months vs. >16 months vs. never, and 0.71 for independent walking [≤]18 months vs. >18 months vs. never. The strongest predictors for adverse neurodevelopmental outcomes were presence of hypotonia at birth, seizure onset within the first day of life, multiple seizures per day at onset, tonic seizures at onset, a burst-suppression pattern on EEG at onset, the presence of a de novo variant, and variant location within exons 6-7. Significance: These prediction models demonstrate the feasibility of early prognostication in KCNQ2-RD and support future prospective external validation. They enable more accurate individualised counselling by integrating clinical and genetic information readily available at time of genetic diagnosis and provide an objective foundation for early intervention planning and future precision medicine trial stratification.

BackgroundAmyotrophic lateral sclerosis (ALS) is a uniformly fatal neurodegenerative disease characterized by progressive cortical and spinal motor neuron loss, with most patients surviving only 2-5 years post-diagnosis. While approximately 10% of cases are familial (fALS), the remaining 90% are sporadic (sALS) with unknown genetic drivers. Importantly, clinical presentations are heterogeneous in both sporadic and familial ALS, underscoring the complexity of the disease. A pathological hallmark of ALS is the mislocalization of RNA-binding protein TDP-43 from the nucleus to the cytoplasm. This mislocalization produces both loss of function consequences, such as widespread RNA processing and splicing defects, as well as potential toxic gain of function effects associated with cytoplasmic aggregation. ResultsIn this study, we used RT-PCR data from induced pluripotent stem cell-derived motor neurons derived from 180 sALS and C9orf72 fALS patients from the Answer ALS collection to identify biological subgroups based on TDP-43 loss-of-function signatures. Spectral embedding revealed four distinct molecular clusters, including one subgroup genetically similar to controls and another with the most dysregulated mRNA expression, suggesting differing disease severity. Linear mixed models were then used to assess the longitudinal trajectory of over 90 clinical measures, and the between-cluster interaction effects were evaluated. Conclusions36 clinical outcomes showed significant differences across clusters, supporting the presence of biologically and clinically distinct ALS subtypes based on the TDP-43 associated pathogenic cascade. These findings demonstrate a critical role of RNA profiling in uncovering biologically meaningful subtypes of ALS, potentially allowing for more precise prognostic tools and the development of future personalized therapeutic approaches.

In LGMDR1-Calpain-3 related, as in all muscular dystrophies, clinical trial monitoring remains a challenge due to the lack of reliable biomarkers. This study assessed IL-32 concentrations in both serum and urine, uncovering a marked increase in patients compared to healthy controls. Serum IL-32 levels were especially elevated in young adults, suggesting a possible link to the early and more active phases of disease onset. Meanwhile, urinary IL-32 levels showed consistent elevation across all age groups, reinforcing its promise as a stable, non-invasive biomarker. These findings support the potential of IL-32 in monitoring disease progression and therapeutic response in clinical trials, and underscore its potential involvement in LGMDR1.

AimTo determine an objective and clinically-feasible method to predict dystonia in cerebral palsy (CP) using magnetic resonance imaging (MRI) following neonatal hypoxic-ischemic encephalopathy (HIE). MethodsIn this retrospective case-control study, we examined brain MRIs in neonates at age 4-5 days who underwent therapeutic hypothermia for HIE at a single tertiary care center. The lower average apparent diffusion coefficient (ADC) values between the left and right striatum and thalamus were determined using clinically-integrated software (IBM iConnect Access). Neonatal neurology, movement disorder, and cerebral palsy specialist notes were screened through age 5 years for motor abnormality documentation. ResultsIn 50 subjects, ADC values significantly predicted dystonia in CP with receiver operator characteristic areas under the curve of 0.862 (p = 0.0004) in the striatum and 0.838 (p = 0.001) in the thalamus. Striatal ADC values less than 1.014x10-3 mm2/s provided 100% specificity and 70% sensitivity for dystonia. Thalamic ADC values less than 0.973x10-3 mm2/s provided 100% specificity and 80% sensitivity for dystonia. InterpretationIn this small retrospective study, analysis of clinically-acquired MRIs predicted dystonia with high specificity following neonatal HIE. This could be a useful prognostication adjunct guiding when to establish appropriate vigilance for dystonia in CP.