Faculty Bibliography

BACKGROUND AND OBJECTIVES/OBJECTIVE:While reductions in optical coherence tomography (OCT) pRNFL and ganglion cell-inner plexiform layer thicknesses have been shown to be associated with brain atrophy in adult-onset MS (AOMS) cohorts, the relationship between OCT and brain MRI measures is less established in pediatric-onset MS (POMS). Our aim was to examine the associations of OCT measures with volumetric MRI in a cohort of patients with POMS to determine whether OCT measures reflect CNS neurodegeneration in this patient population, as is seen in AOMS cohorts. METHODS:This was a cross-sectional study with retrospective ascertainment of patients with POMS evaluated at a single center with expertise in POMS and neuro-ophthalmology. As part of routine clinical care, patients with POMS are evaluated by a POMS expert and undergo volumetric brain MRI, including whole-brain (WB), subregional, and gray matter (GM) volume analyses. Patients with POMS are routinely referred to neuro-ophthalmology for evaluation that includes high-contrast visual acuity, color vision testing, and OCT. Generalized estimating equation (GEE) models, accounting for within-patient, intereye correlations (both eyes of each patient were included), MS disease duration, and disease-modifying therapy efficacy, were used to determine the relationship between visual pathway structure and function and volumetric MRI measures. RESULTS:= 0.015, respectively). DISCUSSION/CONCLUSIONS:Our results demonstrate that changes in visual pathway structures are associated with reductions in overall brain volume and GM volumes, as well as greater lesion and black hole burden. Collectively, our results emphasize the importance of visual assessment in POMS and suggest that OCT reflects overall CNS neurodegeneration in this cohort.

OBJECTIVE/UNASSIGNED:The authors sought to determine the relationships among cognitive impairment, psychiatric outcome, and functional status 3 months after a hemorrhagic stroke. METHODS/UNASSIGNED:Patients with nontraumatic intracerebral hemorrhage (ICH) or subarachnoid hemorrhage (SAH) were assessed by telephone 3 months after discharge by using the Quality of Life in Neurological Disorders (Neuro-QoL) cognitive function, anxiety, depression, and sleep disturbance short forms, as well as the modified Rankin Scale (mRS). The relationships between poor cognition (Neuro-QoL T score≤50), functional status, and psychiatric outcome among patients with ICH or SAH and patients with ICH only were evaluated. RESULTS/UNASSIGNED:Of 101 patients (N=62 with ICH and N=39 with SAH), 51% had poor cognition 3 months posthemorrhage, with 61% having mRS scores of 3-5, 43% having anxiety, 28% having depression, and 31% having sleep disturbance. Univariate analysis of the full cohort indicated that poor cognition was significantly associated with anxiety, depression, sleep disturbance, and mRS scores of 3-5 (p<0.05). Multivariate analysis revealed that poor cognition was significantly associated with anxiety (OR=4.38, 95% CI=1.30-14.74, p=0.017) and mRS scores of 3-5 (OR=6.15, 95% CI=1.96-19.32, p=0.002). Univariate analysis of the 62 patients with ICH indicated that poor cognition was significantly associated with anxiety, sleep disturbance, and mRS scores of 3-5 (p<0.05). Multivariate analysis revealed that poor cognition was significantly associated with anxiety (OR=10.98, 95% CI=2.32-51.99, p=0.003). CONCLUSIONS/UNASSIGNED:Poor cognition was associated with anxiety 3 months after hemorrhagic stroke. Additional research is needed to understand whether treatment for anxiety would improve cognition in this population.

OBJECTIVE:Antiseizure medications (ASMs) are the first-line treatment for epilepsy, yet they are ineffective in controlling seizures in about 40% of patients with unpredictable individual response to treatment. This study aimed to develop and validate artificial intelligence (AI) models using clinical and brain magnetic resonance imaging (MRI) data to predict responses to the first two ASMs in people with epilepsy. METHODS:People with recently diagnosed epilepsy treated with ASM monotherapy at the Alfred Hospital, Melbourne, Australia formed the development cohort. We developed AI models employing various combinations of clinical features, prescribed ASMs, and brain multimodal MRI images/features to predict the probability of seizure freedom at 12 months while taking the first or second ASM monotherapy. Five-fold cross-internal validation was performed. External validation was conducted on a validation cohort comprising participants of the Human Epilepsy Project. RESULTS:The development cohort included 154 individuals (36% female, 85% focal epilepsy), of whom 29% had received both the first and second ASM monotherapy. The validation cohort included 301 individuals (61% female, all focal epilepsy), of whom 33% had received both the first and second ASM monotherapy. A fusion deep learning (DL) model comprising an 18-layer 3D videoResNet (for multi-sequence MRI data), a transformer encoder (ASM regimens), and a dual linear neural network (for clinical characteristics) outperformed other models. It achieved an internal cross validation F1 score of 0.75 ± 0.05 (average ± 95% confidence interval), higher than other machine learning (ML) models and DL models with less complex architecture or integration of fewer imaging sequences. This DL model significantly outperformed the best ML model on validation cohort (p < 0.001). SIGNIFICANCE/CONCLUSIONS:AI-based models incorporating brain MRI, clinical, and medication data can efficiently predict seizure freedom in recently diagnosed epilepsy. They may enhance treatment selection in epilepsy and offer a foundation for clinical decision support systems. Further validation in larger cohorts is warranted.

OBJECTIVE:This randomized, double-blind, phase 1b/2a clinical trial was designed to evaluate the safety, tolerability, and efficacy of oral bexicaserin versus placebo for the treatment of seizures in adolescents and adults with developmental and epileptic encephalopathies (DEEs). METHODS:Eligible participants had a DEE diagnosis, were aged 12-65 years, and were taking 1-4 concomitant antiseizure medications. Randomization to treatment groups (4:1 bexicaserin:placebo) was stratified by type of DEE (Dravet syndrome [DS], Lennox-Gastaut syndrome [LGS], or DEE Other). Following a 28-day baseline period, the treatment period consisted of a 15-day flexible uptitration period (6, 9, or 12 mg three times daily, 5 days each) and a 60-day maintenance period on the highest tolerated dose. Primary end points were safety (adverse events) and change from baseline in countable motor seizure frequency. RESULTS:Forty-three and nine participants were assigned to bexicaserin treatment and placebo, respectively, and received ≥1 dose (safety set); 35 bexicaserin and nine placebo participants completed titration, entered the maintenance period, and had ≥1 seizure measurement during the maintenance period (full analysis set). Twenty-eight of 43 bexicaserin-treated participants (65.1%) and three of nine (33.3%) in the placebo group reported drug-related treatment-emergent adverse events (TEAEs); seven of 43 participants (16.3%) discontinued bexicaserin due to a TEAE during titration and two of 43 (4.7%) during maintenance, most frequently due to somnolence. Median reductions in countable motor seizure frequencies were -59.8% with bexicaserin and -17.4% with placebo; reductions with bexicaserin were observed across DEEs (DS, -74.6%; LGS, -50.8%; DEE Other, -65.5%). The proportion of participants achieving ≥50% reductions during the treatment period (responder analysis) was 60.0% with bexicaserin versus 33.3% with placebo. SIGNIFICANCE/CONCLUSIONS:Bexicaserin was well tolerated and associated with clinically relevant reductions in countable motor seizure frequencies in participants with a variety of DEEs. This novel trial design may expand treatment access to patients previously excluded from clinical trials.

PURPOSE/OBJECTIVE:Establish the minimally clinically important difference (MCID) for the Orthostatic Hypotension Questionnaire (OHQ). BACKGROUND:Neurogenic orthostatic hypotension (nOH) causes disabling symptoms that impair daily function and quality of life. The OHQ is a validated patient-reported outcome with a symptom assessment (OHSA) and daily activity scale (OHDAS), widely used in clinical trials, despite the MCID being unestablished. METHODS:We analyzed data from two phase 3, randomized placebo-controlled trials (SEQUOIA and REDWOOD), evaluating ampreloxetine for symptomatic nOH in patients with Parkinson disease, multiple system atrophy, and pure autonomic failure. Using anchor-based and distribution-based methods, we calculated the MCID for the total OHQ score, OHSA and OHDAS composite subscales, and for the single dizziness/lightheadedness question (OHSA1). RESULTS:The analysis included 184 subjects from SEQUOIA and 128 from REDWOOD. The total OHQ MCID for improvement was a reduction of 0.9-1.2 points and for worsening was an increase of 0.7-1.1 points. The MCID for the OHSA composite ranged from a reduction of 0.9-1.3 points for improvement and an increase of 0.7-1.1 points for worsening. For the single-item OHSA1, the MCID was a reduction of 2.0-3.0 points for improvement and an increase of 1.0 point for worsening. Owing to poor correlation with the symptom-based anchors, a reliable MCID for the OHDAS component was not established. CONCLUSIONS:These MCID thresholds for the OHQ, OHSA and OHSA item 1 alone, enhance the interpretability of scores and support their use in evaluating clinical benefit.

BACKGROUND:Whether early use of higher-efficacy disease-modifying therapy (DMT) reduces later risk of disability in multiple sclerosis (MS) has not been studied as a prospective treatment strategy. Herein, we describe the TRaditional versus Early Aggressive Therapy for MS (TREAT-MS) trial design and provide the baseline characteristics of the enrolled population. METHODS:TREAT-MS is a pragmatic, randomized, rater-blinded trial of DMT strategies in treatment-naive people aged 18-60 years with relapsing-remitting MS (RRMS). Participants were randomized (1:1, stratified by site and long-term disability risk classification) to one of two treatment strategies: higher-efficacy or traditional DMT; the specific DMT within the assigned strategy was chosen by the clinician/patient pair. Participants could switch DMT for breakthrough disease occurring after 6 months on DMT. The primary outcome is sustained worsening of the Expanded Disability Status Scale (EDSS)-plus, a composite endpoint that includes the EDSS and the timed 25-ft walk and 9-hole peg tests. RESULTS:TREAT-MS includes 900 people with the following baseline characteristics: mean age 36 ± 10 years; 629 (70 %) female gender; 648 (72 %) white, 168 (19 %) Black/African American race, and 105 (12 %) Hispanic or Latino. Mean time since MS symptom onset was 2.6 (± 4.5) years, and mean EDSS score was 2.5 (± 1.3). CONCLUSION/CONCLUSIONS:TREAT-MS seeks to address how early DMT strategy influences MS disability and related outcomes. The results will be generalizable to future individuals newly diagnosed with RRMS who, with their clinicians, will be able to use them to make data-driven DMT decisions about how to maximize their intermediate-term function.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Pediatric multiple sclerosis (MS) affects children and adolescents at an important time for neurologic and cognitive development. Although cognitive impairment has been described, few longitudinal studies of cognitive functioning in pediatric MS with matched controls are available. Here, we report the 2-year follow-up cognitive results of a cohort of participants with MS and healthy controls (HCs) recruited from multiple regions of the United States. METHODS:Three cohorts-participants with pediatric MS, age-matched pediatric HC, and adults with early-onset MS-were recruited across 7 sites through the United States Network of Pediatric MS Centers. Two cognitive batteries, Cogstate Brief Battery (CBB) and Brief International Cognition Assessment for MS (BICAMS), were administered at baseline and follow-up. The primary outcome was the change in CBB composite z-score compared between groups. Change in BICAMS composite z-score was also compared, as were change in z-scores of individual measures. Reliable change indices (RCIs) were calculated to determine meaningful change over time. RESULTS:= 0.022. DISCUSSION/CONCLUSIONS:Most individuals with pediatric MS early in their disease showed stable cognitive function over a 2-year period and had longitudinal changes that were largely similar to pediatric controls. A subset of participants with pediatric MS declined in cognitive processing speed relative to pediatric controls.

State death determination acts require brain death/death by neurologic criteria (BD/DNC) determination to be in accordance with "accepted medical standards." The American Academy of Neurology/American Academy of Pediatrics/Child Neurology Society/Society of Critical Care Medicine published updated BD/DNC guidelines in October 2023 to replace earlier iterations of separate guidelines for BD/DNC determination in adults and pediatric persons. There are no other medical society guidelines for BD/DNC determination in the United States. As of early 2024, only Nevada, New Jersey, and New York identified the 2023 BD/DNC guidelines as the "accepted medical standards." Delineation of the "accepted medical standards" in state death determination acts or by state health organizations (SHOs) could help facilitate consistency and accuracy in BD/DNC determination, prevent false-positive death determination, and promote public trust. SHOs are comprised of policy experts and medical professionals responsible for addressing medical, ethical, and legislative problems related to health. In April 2024, we began iteratively contacting state health departments, medical boards, medical societies, and hospital associations requesting acknowledgment of the 2023 BD/DNC guidelines as the "accepted medical standards." From April 2024 to March 2025, we contacted 168 SHOs and received responses from 108 of 168 (64%, median: 2 per state, range: 0-4 per state). The effects of this advocacy effort continue to evolve, but as of March 31, 2025, 4 states had an SHO that acknowledged the 2023 BD/DNC guidelines as the "accepted medical standards" (Delaware, Louisiana, Oklahoma, and Vermont), 9 states had an SHO discussing acknowledgment, 4 states had an SHO that would consider a resolution submitted by a member about acknowledgment, and 30 states showed no SHO interest in acknowledgment. The Medical Society of Delaware and the Oklahoma State Medical Association formalized acknowledgment in a resolution while the Louisiana Department of Health and the Vermont Department of Health and Board of Medical Practice disseminated communication about acknowledgment. This effort also prompted discussion about the "accepted medical standards" by the American Medical Association. Ongoing advocacy may expand recognition of the 2023 BD/DNC guidelines as the "accepted medical standards" for BD/DNC determination. Communication to hospitals indicating that adherence to these guidelines is crucial and regulations to ensure adherence are essential.

A 65-year-old woman presented with 3 months of progressive hand weakness, initially with distal-predominant symptoms. EMG was notable for diminished amplitudes in bilateral radial nerves without evidence of conduction block and with normal sensory nerve action potentials. Anti-acetylcholine receptor and antistriated muscle antibodies were positive, but subsequent EMG did not reveal abnormalities on repetitive nerve stimulation. Muscle biopsy was performed, revealing extensive inflammatory infiltrates with significant associated fibrosis. This case discusses the approach to localization within the motor pathway and the use of serologic studies, imaging, and electrodiagnostic testing to supplement history and examination.