Faculty Bibliography

BACKGROUND AND PURPOSE/OBJECTIVE:Mild traumatic brain injury (MTBI) is a common public health concern with potential long-term consequences, yet its underlying pathophysiology remains poorly understood. Clinical heterogeneity of individuals having diverse extent and array of symptoms has impeded the identification of reliable imaging biomarkers. Traditional group-level analyses may obscure biologically meaningful subtypes. This study uses latent class analysis (LCA) to classify MTBI subjects into symptom-defined subgroups and examines corresponding WM microstructural alterations using advanced diffusion MRI. MATERIALS AND METHODS/METHODS:Sixty-one MTBI patients within one month of injury completed the Rivermead Post-Concussion Symptoms Questionnaire (RPQ). LCA was used to identify symptom-based subgroups. Of these, 54 MTBI patients underwent multi-shell diffusion MRI and were compared with 31 controls. WM changes were assessed across subgroups using ROI-based diffusion analyses. RESULTS:LCA identified three distinct MTBI subgroups: those with minimal to no symptoms (31.5%), the cognitively symptomatic (38.9%), and the more globally symptomatic (29.6%). The three groups were associated with different patterns of diffusion MRI differences compared with controls. The cognitively symptomatic subgroup showed predominantly central WM differences, the globally symptomatic subgroup exhibited more peripheral differences with right-hemisphere predominance and sparing the corpus callosum, marked by reduced fractional anisotropy and kurtosis and elevated diffusivities, the less symptomatic subgroup demonstrated focal differences in the callosal genu, with increased fractional anisotropy and kurtosis and decreased diffusivity measures. CONCLUSIONS:MTBI comprises biologically distinct phenotypes with subgroup-specific WM signatures on diffusion MRI. Even individuals with minimal to no symptoms show WM differences compared with controls, underscoring the limitations of symptom reporting alone. Integrating symptom-based classification with advanced diffusion MRI may improve diagnostic precision to help risk stratification and provide insight into mechanisms of injury. ABBREVIATIONS/BACKGROUND:LCA = latent class analysis; MTBI = mild traumatic brain injury; RPQ = Rivermead post-concussion symptoms questionnaire.

INTRODUCTION/BACKGROUND:The Curing Coma Campaign Ethics Working Group sought to understand informed consent practices for research involving persons with disorders of consciousness (DoC) to establish an empirical foundation to formulate common consent elements for research regarding this vulnerable population. METHODS:Consent forms for research involving persons with DoC were collected from the Curing Coma Campaign members and Clinicaltrials.gov in the fall of 2024. We abstracted data about study specifics, the consent process, and unique considerations related to persons with DoC and then reviewed and collated them using descriptive statistics. RESULTS:The collection process yielded 58 consent forms: 40 (69%) from member submissions and 18 (31%) from Clinicaltrials.gov. After excluding duplicates and studies that did not pertain to persons with DoC, there were 43 forms, which included 62 unique terms to describe acute brain injury/consciousness/DoC. Of 41 studies that enrolled persons with DoC, there were 4 (10%) that mentioned an evaluation for covert consciousness. Although only 3 (7%) forms mentioned an evaluation for capacity of the person with DoC/recovered from DoC, 16 (39%) referenced first-person consent if the person with DoC regained capacity. Most studies that involved study-specific medications/interventions/tests included some mention of experiential risks (26/32, 81%), but only 2 (6%) specifically addressed the challenges associated with these risks in a person with DoC. CONCLUSIONS:Consent forms for research involving persons with DoC include inconsistent terminology to describe acute brain injury/consciousness/DoC, the capacity to consent, and the potential experiential risks of study participation in the context of a DoC. There are opportunities to improve transparency and consistency of communication about research involving persons with DoC via creation of common consent elements to ensure the informed consent process protects individual autonomy.

OBJECTIVE:To assess real-world effectiveness of switching disease-modifying therapy (DMT) in pediatric multiple sclerosis (MS) and clinically isolated syndrome (CIS) initially treated with platform injectables on disease activity. METHODS:Of 2615 pediatric-onset demyelinating disease patients at 12 clinics in the United States (US) Network of Pediatric MS Centers, those with MS/CIS on initial therapy with a platform injectable who switched to another class of platform injectable, oral or infusion DMT were analyzed. Relapse rate was modeled with negative binomial regression, adjusted for preidentified confounders. RESULTS:A total of 212 children switched DMT before age 18 (67% female, 95% MS). Ninety-three switched from injectable to injectable, 76 injectable to oral, and 43 injectable to infusion. Switchers to oral or infusion were older at onset (injectable 12.3 years, oral 13.5 years, and infusion 14.2 years) and switch (injectable 14.6 years, oral 16.0 years, and infusion 15.7 years). Switchers to infusion DMT were more likely to have enhancing lesions (injectable 45%, oral 28%, and infusion 67%). Compared to injectable (annualized relapse rate [ARR] = 0.88, 95% confidence interval [CI] = 0.52-1.48), relapse rates were lower for injectable to oral (ARR = 0.34, 95% CI = 0.20-0.57; rate ratio: 0.38, 95% CI = 0.21-0.69) and injectable to infusion (ARR = 0.18, 95% CI = 0.09-0.37; rate ratio: 0.21, 95% CI = 0.10-0.44) (p < 0.001). Adjusted number needed to treat in person-years to prevent 1 relapse with oral over injectable was 1.84 (95% CI = 1.03-8.69) and infusion over injectable 1.43 (95% CI = 1.00-3.88). INTERPRETATION/CONCLUSIONS:Switching from platform injectable to oral or infusion compared to other platform injectable DMT led to better disease control in pediatric MS. Long-term safety data are required. ANN NEUROL 2025.

OBJECTIVE:Up to 30% of people with epilepsy are refractory to current antiseizure medications (ASMs). JNJ-40411813 is a positive allosteric modulator of metabotropic glutamate 2 receptor, a presynaptic glutamate release inhibitor, and was hypothesized to reduce glutamate-mediated neuronal toxicity through inhibition of excessive glutamate release during seizures. METHODS:This 12-week, double-blinded, placebo-controlled phase 2a study, which employed a rational polypharmacy approach using a novel time-to-event endpoint for epilepsy clinical trials, evaluated JNJ-40411813 (Cohort 1: 50/100 mg; Cohort 2: 100/200 mg) as adjunctive treatment for focal seizures in participants aged 18-64 years receiving levetiracetam or brivaracetam and ≤3 other ASMs. Participants were stratified as induced or noninduced based on treatment or no treatment with a cytochrome P450 3A4 enzyme-inducing ASM. The primary endpoint was time-to-baseline monthly seizure count. RESULTS:Cohorts 1 and 2 randomized 60 and 50 patients, respectively. No significant clinical benefits were observed in the median time (95% confidence interval [CI]) to reach the baseline monthly seizure count in Cohort 1 (JNJ-40411813: 34 days [27-48], placebo 32 days [28-37], hazard ratio [HR] = .75 [.41-1.38], p = .36) or Cohort 2 (JNJ-40411813: 38 days [28-48], placebo: 29 days [22-69], HR = .83 [.40-1.75], p = .63). Similarly, no clinical benefits of JNJ-40411813 were observed for any of the secondary endpoints. JNJ-40411813 displayed an acceptable safety profile; treatment-emergent adverse events were mild to moderate in severity and not treatment limiting. SIGNIFICANCE/CONCLUSIONS:JNJ-40411813 adjunctive to levetiracetam or brivaracetam showed no significant clinical benefit over placebo in reducing time-to-baseline monthly seizure count or improvement in other key measures in patients with focal onset seizures. The time-to-event study design was successful at reducing participant exposure to ineffective treatment. Despite an acceptable safety profile, the overall efficacy and benefit-risk assessment of JNJ-40411813 does not support its use for patients with focal seizures.

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.

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.

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.

OBJECTIVES/BACKGROUND/OBJECTIVE:This study was undertaken to review the published literature and provide a position statement from the American Headache Society regarding the safety, efficacy, and impact on access to care of telemedicine for the clinical management of patients with headache disorders. Access to specialized care in headache medicine is severely limited in the United States and worldwide. Telemedicine has been used as an approach to care delivery in headache medicine for more than a decade, with accelerated adoption during the COVID-19 pandemic. There is now uncertainty regarding the extent to which telemedicine will be accepted by health systems and reimbursed by payers moving forward. The purpose of this position statement is to summarize evidence and clinical experience supporting the utility of telemedicine in headache medicine. METHODS:Evidence regarding the safety and efficacy of telemedicine, and patient and clinician satisfaction with the use of telemedicine for headache specialty care, was gathered from a variety of sources, including PubMed, Google Scholar, and ClinicalTrials.gov. The results and conclusions based upon these results were reviewed and discussed by the authors and the Board of Directors of the American Headache Society to confirm consistency with clinical experience and to achieve consensus. RESULTS:Several randomized clinical trials and observational studies have been performed to compare telemedicine with in-person visits in the management of patients with headache disorders. These studies showed consistently that telemedicine is noninferior to in-person care based upon multiple outcome measures, including disability measures, patient satisfaction, and clinician satisfaction. In addition, these studies found that telemedicine rarely leads to a missed diagnosis of secondary headache or mismanagement of primary headache. Telemedicine has substantial advantages for patients, including improved access to care and reduced costs associated with obtaining care. Studies evaluating health care utilization indicate no significant differences between patients evaluated and treated virtually versus in person. Obvious limitations of telemedicine include the inability to perform an in-person physical exam or to perform injections. For a substantial number of patients, however, these limitations are outweighed by its advantages. The experience with telemedicine reported in the literature is consistent with the experience of the Board of Directors of the American Headache Society, who endorse its use for patients when feasible and appropriate. CONCLUSION/CONCLUSIONS:Telemedicine has significantly advanced the care of patients with headache disorders. Its further development and deployment should be supported and reimbursed.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Arteriovenous malformations (AVMs) with perinidal aneurysms and single draining vein are associated with an elevated risk of rupture and increased procedural complexity. The role of preoperative embolization in this high-risk anatomical subset remains unclear. This study aimed to evaluate the safety and efficacy of microsurgery with preoperative embolization, compared with microsurgery alone in patients with such AVMs. METHODS:We conducted a multicenter retrospective analysis of an AVM registry from the MISTA (Multicenter International Study for Treatment of Brain AVMs) consortium and included AVMs with perinidal aneurysms and a single draining vein. Baseline characteristics, angiographic outcomes, functional outcomes, and complication rates were compared. Propensity score weighting (PSW) using the covariate balancing method was applied to adjust for baseline differences. RESULTS:Out of a total of 1919 patients, 65 met the inclusion criteria; 45 patients underwent preoperative embolization followed by microsurgery, and 20 underwent microsurgery alone. After adjustment, complete obliteration rates were similar between groups (OR 0.87, 95% CI 0.04 to 16.33, P=0.92), as were rates of functional independence at discharge and follow-up. Overall complication, symptomatic complication, and mortality rates did not differ significantly between groups. However, permanent complications were significantly lower in patients with preoperative embolization (OR 0.06, 95% CI 0.004 to 0.84, P=0.03). DISCUSSION/CONCLUSIONS:In patients with AVMs featuring perinidal aneurysms and single draining vein, preoperative embolization followed by microsurgery was associated with fewer permanent complications and no increase in adverse outcomes compared with microsurgery alone. However, given the small number of events, this finding should be interpreted cautiously.