Faculty Bibliography

BACKGROUND AND OBJECTIVES/OBJECTIVE:The aim of this study was to identify distinct inflammatory response subtypes in patients with c-NORSE by analyzing their cytokine profiles. Insights into underlying mechanisms were sought to understand the pathophysiology and guide personalized therapies to improve patient outcomes. METHODS:Sixty-two patients with c-NORSE were included. A comprehensive panel of 96 cytokines was analyzed in serum samples. Patients were clustered based on their cytokine profiles using the Louvain algorithm, an unsupervised graph-based clustering method. The identified clusters of patients were compared regarding cytokine levels and clinical features. Protein pathway analysis was used to explore the biological relevance of the inflammatory markers within each cluster. Patients with c-NORSE were compared with control patients (n = 18) and patients with other forms of refractory SE (n = 45). RESULTS:Compared with controls, patients with c-NORSE exhibited significant differences in 33 cytokines. Pathway analysis revealed dysregulations in chemotaxis and neutrophil recruitment and migration, highlighting the importance of innate immunity in patients with c-NORSE. Within the c-NORSE cohort, 3 clusters of patients emerged: cluster A, lacking specific inflammatory markers; cluster B, with a much stronger innate-immunity cytokine-driven inflammatory response compared with clusters A and C; and cluster C, defined by dysregulated autoimmune processes. Notably, patients in cluster B showed a statistically significant elevation of innate immune-related proinflammatory cytokines associated with leukocyte recruitment and degranulation. By contrast, those in cluster C showed activation of Janus kinase signal transducer and activator of transcription (JAK-STAT) pathways, suggesting autoimmune mechanisms. Patients in clusters B and C demonstrated varied responses to immunotherapies, with cluster C patients showing favorable outcomes after multiple immunotherapies. DISCUSSION/CONCLUSIONS:The identification of distinct inflammatory subgroups in c-NORSE suggests that variations in the underlying immune mechanisms contribute to differential treatment responses. These findings underscore the importance of personalized therapeutic strategies, potentially targeting specific inflammatory pathways, to optimize clinical outcomes in this challenging condition.

OBJECTIVE:Reduced-channel wearable electroencephalography (EEG) may overcome the accessibility and patient comfort limitations of traditional ambulatory electrographic seizure monitoring during extended-duration use. Automated algorithms are necessary for review of extended-duration reduced-channel EEG, yet current clinical support software is designed only for full-montage recordings. METHODS:The performance of a novel automated seizure detection algorithm for reduced-channel EEG (Epitel) was evaluated in a clinical validation study involving 50 participants (31 with seizures) with diverse demographic and seizure representation. RESULTS:The algorithm demonstrated an event-level sensitivity of 86.2% (95% confidence interval [CI] = 79.5%-93.2%) and a false detection rate of .162 per hour (95% CI = .116-.221), which is comparable to the performance of current clinical software for full-montage EEG. Performance varied by electrographic seizure type, with 91.4% sensitivity for focal evolving to generalized seizures, 86.7% for generalized seizures, and 77.3% for focal seizures. The algorithm maintained robust performance in both pediatric participants aged 6-21 years (83% sensitivity) and adults aged 22+ years (90% sensitivity), as well as in ambulatory (80%) and epilepsy monitoring unit (EMU) monitoring environments (87.5%). The false detection rate in ambulatory monitoring environments (.290 false positive [FP] detections/h), all of which involved pediatric participants, was notably higher than in the EMU (.136 FP/h), indicating an area with clear need for improvement for unrestricted at-home monitoring. The algorithm's supplemental Confidence metric, designed to engender trust in the algorithm, showed a strong correlation with detection precision. SIGNIFICANCE/CONCLUSIONS:These results suggest that this algorithm can provide crucial support for review of extended-duration reduced-channel wearable EEG, enabling electrographic seizure monitoring with no restrictions on a person's daily life.

OBJECTIVE:Common data elements (CDEs) help harmonize data collection across clinical trials and observational studies, allowing for cross-study and cross-condition comparisons. While CDEs exist for multiple clinical conditions and diseases, this work was extended only recently to neurorehabilitation research. DESIGN/METHODS:Subgroups of clinical neurorehabilitation investigators operationalized a domain definition, selected applicable CDEs from 23 existing National Institute of Neurological Disorders and Stroke (NINDS) CDE projects and NIH CDE repositories, and identified areas needing further development. The subgroups also reviewed public comments on the NeuroRehab specific CDEs, which were provided from 01 September 2021 to 07 October 2021. In March 2022, version 1.0 of the NeuroRehab CDEs was completed and can be found on the NINDS CDE website: https://www.commondataelements.ninds.nih.gov/. SETTING/METHODS:NINDS and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)/National Center for Medical Rehabilitation Research (NCMRR) identified NeuroRehab CDEs across 12 different research domains: 1) assessments and examinations; 2) comorbid and behavioral conditions; 3) motor function; 4) treatment/intervention data: therapies; 5) treatment/intervention data: devices; 6) cognitive; 7) communication; 8) emotion/behavior/neuropsychology; 9) activities of daily living/instrumental activities of daily living; 10) quality of life; 11) participation; and 12) infant and pediatrics. Within each domain, corresponding subdomain experts identified instruments with good psychometric measurement properties. PARTICIPANTS/METHODS:120 experts in rehabilitation across the 12 identified research domains and two Co-Chairs with rehabilitation and measurement expertise provided oversight. INTERVENTIONS/METHODS:N/A. MAIN OUTCOME MEASURES/METHODS:CDEs from 23 existing NINDS CDE projects and NIH CDE repositories RESULTS: Clinical investigators recommended NeuroRehab CDEs within three dimensions of the NINDS CDE Classifications: Core, [Disease] Core, and Supplemental - Highly Recommended. Most measures were categorized as Supplemental - Highly Recommended; few were identified as Core or Disease Core. The subgroups also identified measurement gap areas to guide future initiatives as NeuroRehab CDEs are developed in the future. CONCLUSIONS:These efforts are designed to accelerate rehabilitation research in neurological disorders by allowing for cross-study and cross-condition comparisons and to encourage new CDE development.

BACKGROUND:Familial adult myoclonus epilepsy (FAME) is a rare autosomal dominant disorder caused by the same intronic TTTTA/TTTCA repeat expansion in seven distinct genes. TTTTA-only expansions are benign, whereas those containing TTTCA insertions are pathogenic. OBJECTIVE:We investigated the genetic basis of dominant cortical myoclonus without seizures in two unrelated families. METHODS:Repeat-primed polymerase chain reaction (PCR), long-range PCR, and nanopore sequencing were used to detect and characterize expansions at known FAME loci. RESULTS:We identified a novel repeat expansion in MARCHF6, comprising 388 to 454 elongated TTTTA repeats and 5 to 11 TTTCA repeats at the 3'-terminus, segregating with cortical myoclonus in 8 affected individuals. This configuration shows meiotic stability but low-level somatic variability in blood. We observed an inverse correlation between the number of TTTCA repeats and the age at myoclonus onset. CONCLUSIONS:These findings indicate that as little as five TTTCA repeats combined with expanded TTTTA repeats can cause cortical myoclonus without epilepsy, highlighting the potential mechanisms underlying FAME pathophysiology. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

OBJECTIVE:Naming difficulty is a common symptom of left (i.e., language dominant) hemisphere epilepsy. As such, in the presurgical evaluation for drug-resistant epilepsy, which aims to localize the epileptogenic region, identification of a naming deficit typically implicates the left temporal region. However, the well-established finding of poor naming in those with left but not right (i.e., nondominant) hemisphere seizures in monolingual patients is unreliable in bilingual adults with epilepsy, despite proficiency in the language tested. We aimed to examine naming performance and its relation with seizure lateralization in bilingual children with epilepsy. METHODS:This multisite study included 57 bilingual and 202 monolingual pediatric epilepsy patients, aged 6-17 years. All patients underwent neuropsychological evaluation including assessment of auditory and visual object naming in English. RESULTS:In the context of age-appropriate English expressive vocabulary skills, bilingual children with epilepsy demonstrated significantly weaker auditory and visual naming than monolingual patients. Additionally, unlike monolingual patients, who showed poorer naming among those with left compared to those with right hemisphere seizures, bilingual children with unilateral left and right hemisphere seizures demonstrated similarly weak naming performances. Furthermore, naming score cutoffs failed to differentiate individual bilingual patients with left versus right hemisphere seizure onset as they did among monolingual patients. SIGNIFICANCE/CONCLUSIONS:Despite conversational proficiency and normal English expressive vocabulary, the relation between seizure laterality and naming performance demonstrated in monolingual children with unilateral seizures was not observed in a comparable group of bilingual children. Consequently, poor naming performance in bilingual children with epilepsy may be misinterpreted, most seriously in those with nondominant hemisphere seizures, as scores may be erroneously interpreted to reflect dominant hemisphere seizure involvement, potentially leading to unnecessary invasive and costly procedures. Results suggest cautious interpretation of naming performance in bilingual children with epilepsy.

INTRODUCTION/UNASSIGNED:Current disability questions used in many US federal surveys exclusively measure disability as having 1 or more of 6 functional limitations. This strategy is at odds with who is disabled as some disabled people do not experience these limitations. METHODS/UNASSIGNED:Using data from a nationally representative survey of 2169 adults, this study describes the potential of a comprehensive disability status question to improve the measurement of disability. RESULTS/UNASSIGNED:Results from this study demonstrate that a comprehensive disability status question successfully identifies disabled people who both do, and do not, experience limitations. CONCLUSION/UNASSIGNED:These findings suggest that a single comprehensive disability status question may provide a viable and more inclusive alternative to identifying the disabled population in US federal surveys.

Since the first description of swelling of the optic nerve head in patients with increased intracranial pressure, our understanding of its pathogenesis has undergone significant changes. Early theories postulated that the swelling was caused by excessive extracellular fluid, but these views were disproved when electron microscopy showed that the swelling arose from dilated optic nerve axons, and autoradiography demonstrated blocked axonal transport at the posterior lamina cribrosa. This led to the currently prevailing view that the axonal swelling is caused by the damming back of axoplasm. However, this theory cannot account for the extent of swelling, its rate of development, and the variety of morphological changes in papilledema. It also cannot explain the differing patterns of swelling in papilledema and acute glaucoma despite identically located blockages of axonal transport. We conducted a biomechanical analysis, in which we calculated the stresses induced in a cylindrical nerve by external compression and the effect of these stresses on the nerve's axons and the axoplasm within them. We propose a new theory in which the axial gradient of tissue pressure causes displacement of axoplasm from the extraocular to the intraocular segment of the nerve, accounting for the intraocular axonal swelling. In addition, a sharply localized axial shear stress disrupts the axonal cytoskeleton to block axonal transport. Although the pressure gradient and the shear stress are both caused by the external compression of the nerve, they differ in their relative magnitudes across the nerve cross-section. The proposed hypothesis resolves the difficulties with the damming back hypothesis.