Faculty Bibliography

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.

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.

PURPOSE/OBJECTIVE:Bevacizumab treatment is associated with imaging and hearing responses in progressive vestibular schwannoma (VS) caused by NF2-related schwannomatosis (NF2-SWN). However, its effect on co-existing intracranial non-vestibular schwannomas (NVS) and meningiomas is unclear. METHODS:We retrospectively analyzed tumor volumes of non-target intracranial NVS and meningiomas in patients with NF2-SWN and progressive VS who were prospectively treated with bevacizumab for two years on the Neurofibromatosis Clinical Trials Consortium (NFCTC) trial NF104 (NCT01767792). Radiographic response (RR) or progression (PD) were defined as ≥ 20% decrease or ≥ 20% increase in tumor volume compared to baseline, respectively. All other responses were defined as stable disease. RESULTS:A total of 40 meningiomas in eight patients and 12 NVS in six patients were evaluated across 22 enrolled trial participants. On best response analysis, RR occurred in 13% (5/40) of meningiomas and in 42% (5/12) of NVS. On a per-patient basis, RR for meningioma occurred in 38% (3/8) of patients and for NVS in 67% (4/6) of patients. RR in two NVS were durable throughout the study period. During two years of treatment, PD occurred in 55% (22/40) of meningiomas and in 8% (1/12) of NVS. Median time to tumor progression was 15 months for meningiomas and was not reached for NVS. CONCLUSIONS:We observed greater activity of bevacizumab against intracranial NVS compared to meningioma, evidenced by more favorable RR rates, durability of response, and rates of PD. Potential biological differences between meningiomas and schwannomas that underlie this differential response to bevacizumab warrant further investigation.

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.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Older chronological age is associated with decreased multiple sclerosis (MS) relapse rates and increased risk of progressive disease. Measurement of biological age may be more precise than birthdate in understanding these aging effects. In addition to normal aging, MS-related accelerated aging may contribute. Measurement of biological age in adults may be confounded by the effects of natural aging and age-related comorbidities. Examining age extremes can be informative, and demonstrating accelerated biological aging in children would support a hypothesis of MS driving premature aging. We sought to compare epigenetic age in participants with pediatric-onset MS (POMS) and age-similar controls. METHODS:We performed a multicenter case-control analysis of epigenetic age in a prospectively collected set of whole blood DNA samples and clinical data. Quantitative methylation scores were derived for approximately 850,000 cytosine-phosphate-guanine (CpG) sites. Epigenetic age was calculated based on 4 established epigenetic clock algorithms. Epigenetic age and age acceleration residual (AAR) were compared between participants with POMS and age-similar controls using multivariate regression analysis, adjusted for demographic variables. RESULTS:= 0.004). DISCUSSION/CONCLUSIONS:We observed greater point estimates of epigenetic age in participants with POMS compared with healthy controls in all epigenetic clocks tested. This difference was statistically significant for the Hannum and PhenoAge clocks after multivariable modeling. These results are consistent with those of studies in adult MS and suggest that accelerated aging may be present even in the youngest people living with MS.

BACKGROUND:Due to their anatomical locations, optic pathway gliomas (OPGs) can rarely be cured by resection. Given the importance of preserving visual function, we analyzed radiological and visual acuity (VA) outcomes for the type II RAF inhibitor tovorafenib in the OPG subgroup of the phase 2 FIREFLY-1 trial. METHODS:FIREFLY-1 investigated the efficacy (arm 1, n=77), safety, and tolerability (arms 1/2) of tovorafenib (420 mg/m2 once weekly; 600 mg maximum) in patients with BRAF-altered relapsed/refractory pediatric low-grade glioma (pLGG). In this post hoc analysis, anti-tumor activity and VA were analyzed in arm 1 patients with OPG. Anti-tumor activity was independently assessed per Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG), Response Assessment in Pediatric Neuro-Oncology-LGG (RAPNO) and RANO-LGG criteria. The data cutoff was June 5, 2023. RESULTS:Forty-two of 77 patients had OPGs; 35 of 42 had ≥2 VA assessments. The overall response rate in the OPG subgroup according to RANO-HGG, RAPNO and RANO-LGG criteria were 64%, 50%, and 55%, with clinical benefit rates 95%, 88%, and 90%, respectively. VA per patient was preserved for 80% of patients; 31% demonstrated improved VA; VA per eye was preserved in 87%, with 27% improving. The safety profile in the arm 1 OPG subgroup was similar to the overall FIREFLY-1 safety analysis set. CONCLUSIONS:Tovorafenib demonstrated anti-tumor activity in relapsed/refractory BRAF-altered OPG across radiological assessment criteria and was generally well tolerated. Importantly, vision remained stable or improved in most patients.