Faculty Bibliography

BACKGROUND:Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL) is associated to BPTF gene haploinsufficiency. Epilepsy was not included in the initial descriptions of NEDDFL, but emerging evidence indicates that epileptic seizures occur in some affected individuals. This study aims to investigate the electroclinical epilepsy features in individuals with NEDDFL. METHODS:We enrolled individuals with BPTF-related seizures or interictal epileptiform discharges (IEDs) on electroencephalography (EEG). Demographic, clinical, genetic, raw EEG, and neuroimaging data as well as response to antiseizure medication were assessed. RESULTS:We studied 11 individuals with a null variant in BPTF, including five previously unpublished ones. Median age at last observation was 9 years (range: 4 to 43 years). Eight individuals had epilepsy, one had a single unprovoked seizure, and two showed IEDs only. Key features included (1) early childhood epilepsy onset (median 4 years, range: 10 months to 7 years), (2) well-organized EEG background (all cases) and brief bursts of spikes and slow waves (50% of individuals), and (3) developmental delay preceding seizure onset. Spectrum of epilepsy severity varied from drug-resistant epilepsy (27%) to isolated IEDs without seizures (18%). Levetiracetam was widely used and reduced seizure frequency in 67% of the cases. CONCLUSIONS:Our study provides the first characterization of BPTF-related epilepsy. Early-childhood-onset epilepsy occurs in 19% of subjects, all presenting with a well-organized EEG background associated with generalized interictal epileptiform abnormalities in half of these cases. Drug resistance is rare.

INTRODUCTION/BACKGROUND:The Accreditation Council for Graduate Medical Education (ACGME) approved the first pain medicine fellowship programs over three decades ago, designed around a pharmacological philosophy. Following that, there has been a rise in the transition of pain medicine education toward a multidisciplinary interventional model based on a tremendous surge of contemporaneous literature in these areas. This trend has created variability in clinical experience and education amongst accredited pain medicine programs with minimal literature evaluating the differences and commonalities in education and experience of different pain medicine fellowships through Program Director (PD) experiences. This study aims to gather insight from pain medicine fellowship program directors across the country to assess clinical and interventional training, providing valuable perspectives on the future of pain medicine education. METHODS:This study involved 56 PDs of ACGME-accredited pain fellowship programs in the United States. The recruitment process included three phases: advanced notification, invitation, and follow-up to maximize response rate. Participants completed a standard online questionnaire, covering various topics such as subcategory fields, online platforms for supplemental education, clinical experience, postgraduate practice success, and training adequacy. RESULTS:Surveys were completed by 39/56 (69%) standing members of the Association of Pain Program Directors (APPD). All PDs allowed fellows to participate in industry-related and professional society-related procedural workshops, with 59% encouraging these workshops. PDs emphasized the importance of integrity, professionalism, and diligence for long-term success. Fifty-four percent of PDs expressed the need for extension of fellowship training to avoid supplemental education by industry or pain/spine societies. CONCLUSION/CONCLUSIONS:This study highlights the challenge of providing adequate training in all Pain Medicine subtopics within a 12-month pain medicine fellowship. PDs suggest the need for additional training for fellows and discuss the importance of curriculum standardization.

Mitochondrial fusion requires the sequential merger of four bilayers to two. The outer-membrane solute carrier protein SLC25A46 interacts with both the outer and inner-membrane dynamin family GTPases Mfn1/2 and Opa1. While SLC25A46 levels are known to affect mitochondrial morphology, how SLC25A46 interacts with Mfn1/2 and Opa1 to regulate membrane fusion is not understood. In this study, we use crosslinking mass-spectrometry and AlphaFold 2 modeling to identify interfaces mediating a SLC25A46 interactions with Opa1 and Mfn2. We reveal that the bundle signaling element of Opa1 interacts with SLC25A46, and present evidence of a Mfn2 interaction involving the SLC25A46 cytosolic face. We validate these newly identified interaction interfaces and show that they play a role in mitochondrial network maintenance.

OBJECTIVES/OBJECTIVE:Hospital readmissions are associated with poor health outcomes including illness severity and medical complications. The objective of this study was to identify characteristics associated with 30-day post-stroke readmission in an academic urban hospital network. MATERIALS AND METHODS/METHODS:We collected data on patients admitted with stroke from 2017 through 2022 who were readmitted within 30 days of discharge and compared them to a subset of non-readmitted stroke patients. Chart review was used to collect demographics, characteristics of the stroke, co-morbid conditions, in-hospital complications, and post-discharge care. Univariate analyses followed by regression analysis were used to assess characteristics associated with post-stroke readmission. RESULTS:We identified 4743 patients with stroke (18 % hemorrhagic, mean age 70.1 (standard deviation (SD) 17.2), 47.3 % female) discharged from the stroke services, of whom 282 (5.9 %) patients were readmitted within 30 days of index hospitalization. Univariate analyses identified 18 significantly different features between admitted and readmitted patients. Regression analysis revealed characteristics associated with readmission included private insurance (odds ratio (OR) 0.4, confidence interval (CI) 0.3-0.6, p < 0.001), comorbid peripheral vascular disease (PVD) (OR 2.7, CI 1.3-5.5, p = 0.009), malignancy (OR 1.6, CI 1.0-2.6, p = 0.04), seizure (OR 3.4, CI 1.4-8.2, p = 0.007), thrombolytic administration (OR 0.4, CI 0.2-0.7, p = 0.003), undergoing thrombectomy (OR 5.4, CI 2.9-10.1, p < 0.001), and higher discharge modified Rankin Scale score (OR 1.2, CI 1.0-1.3, p = 0.047). CONCLUSIONS:Our data demonstrate that thrombectomy, high discharge Rankin score, comorbid malignancy, seizure or PVD, and lack of thrombolytic administration or private insurance predict readmission.

An existing scale of personal growth in caregivers of people with multiple sclerosis (MS) was expanded for use with an acquired brain injury (ABI) population, and was modified following additional psychometric analyses. A cross-sectional online survey was administered to 315 caregiving partners of persons with MS and 310 family caregivers of persons with ABI. Principal component analysis (PCA) performed on the original 32-item instrument yielded a 4-component, 17-item solution with correlated subscales with solid psychometric properties. Subscales were labelled Appreciation, Positivity, Adjustment, and Spirituality. Secondary PCA conducted revealed three subscales (five items each) correlated moderately while the fourth, Spirituality, remained distinct. The sum of the three five-item subscales may serve as a total score. Reliability analysis yielded acceptable-to-high internal consistency. Comparisons of the PGS with existing instruments demonstrated its discriminant/convergent validity. Two kinds of latent class analyses were conducted on the 15-item PGS to identify three latent classes that spanned the neurologic groups, revealing that measurement invariance was held for the instrument in this sample. An instrument with sound psychometric properties was established, designed to assess personal growth in caregivers of individuals with ABI or MS. Future work should explore its value in other populations and as a metric of changes over time.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Participants with treatment-resistant epilepsy who are randomized to add-on placebo and remain in a trial for the typical 3 to 5-month maintenance period may be at increased risk of adverse outcomes. A novel trial design has been suggested, time to prerandomization monthly seizure count (T-PSC), which would limit participants' time on ineffective therapy. We reanalyzed 11 completed trials to determine whether the primary efficacy conclusions at T-PSC matched each of the original, longer trials. METHODS:A total of 11 double-blind, placebo-controlled trials of levetiracetam, brivaracetam, lacosamide, topiramate, and lamotrigine for either focal-onset or generalized-onset epilepsy were selected. We evaluated the group-level and individual-level efficacy of treatments including the median percent reduction (MPR) in seizure frequency and 50% responder rate (50RR) at T-PSC, time to second seizure, and time to first seizure compared with the full-length trial. RESULTS:The primary efficacy conclusions of 10 of the 11 trials would have been the same with a T-PSC design compared with the traditional design (the exception of lamotrigine had a very high initial placebo response). As a proportion of the full-length effect size, 90% of the MPR and 85% of the 50RR were seen at T-PSC (95% CI 73%-113% and 65%-110%, respectively). Using the T-PSC design, the time on blinded treatment was at least 312 participant-years shorter (40% of total duration) and 142,000 seizures occurred during this time (60% of total seizures). By contrast, the time to first or second seizure designs reproduced group-level effect size, but the primary efficacy conclusions of each trial and individual-level efficacy correspondence were fair to poor. DISCUSSION/CONCLUSIONS:These results support the use of this trial design for new epilepsy medication trials because this reanalysis of 11 randomized controlled trials demonstrated that observation until T-PSC was sufficient to demonstrate efficacy while potentially improving participant safety by reducing the time of exposure to placebo and inadequate treatment. Despite analysis of 11 trials including 3,619 participants, we did not observe a significant reduction in the group-level effect size, which is directly related to statistical power. The next step is to evaluate whether T-PSC is sufficient to evaluate safety as measured by adverse events.

Cases of isolated spinal cord ischemia resulting in symptoms in neonates are rare, and there are even fewer reported cases in atraumatic births. We present a case of a presumed isolated cervical cord ischemic injury, discuss differentials to consider when evaluating a neonatal spinal cord injury, and highlight the difficulties of diagnosing a spinal cord infarction.

IMPORTANCE/UNASSIGNED:Most research to understand postacute sequelae of SARS-CoV-2 infection (PASC), or long COVID, has focused on adults, with less known about this complex condition in children. Research is needed to characterize pediatric PASC to enable studies of underlying mechanisms that will guide future treatment. OBJECTIVE/UNASSIGNED:To identify the most common prolonged symptoms experienced by children (aged 6 to 17 years) after SARS-CoV-2 infection, how these symptoms differ by age (school-age [6-11 years] vs adolescents [12-17 years]), how they cluster into distinct phenotypes, and what symptoms in combination could be used as an empirically derived index to assist researchers to study the likely presence of PASC. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:Multicenter longitudinal observational cohort study with participants recruited from more than 60 US health care and community settings between March 2022 and December 2023, including school-age children and adolescents with and without SARS-CoV-2 infection history. EXPOSURE/UNASSIGNED:SARS-CoV-2 infection. MAIN OUTCOMES AND MEASURES/UNASSIGNED:PASC and 89 prolonged symptoms across 9 symptom domains. RESULTS/UNASSIGNED:A total of 898 school-age children (751 with previous SARS-CoV-2 infection [referred to as infected] and 147 without [referred to as uninfected]; mean age, 8.6 years; 49% female; 11% were Black or African American, 34% were Hispanic, Latino, or Spanish, and 60% were White) and 4469 adolescents (3109 infected and 1360 uninfected; mean age, 14.8 years; 48% female; 13% were Black or African American, 21% were Hispanic, Latino, or Spanish, and 73% were White) were included. Median time between first infection and symptom survey was 506 days for school-age children and 556 days for adolescents. In models adjusted for sex and race and ethnicity, 14 symptoms in both school-age children and adolescents were more common in those with SARS-CoV-2 infection history compared with those without infection history, with 4 additional symptoms in school-age children only and 3 in adolescents only. These symptoms affected almost every organ system. Combinations of symptoms most associated with infection history were identified to form a PASC research index for each age group; these indices correlated with poorer overall health and quality of life. The index emphasizes neurocognitive, pain, and gastrointestinal symptoms in school-age children but change or loss in smell or taste, pain, and fatigue/malaise-related symptoms in adolescents. Clustering analyses identified 4 PASC symptom phenotypes in school-age children and 3 in adolescents. CONCLUSIONS AND RELEVANCE/UNASSIGNED:This study developed research indices for characterizing PASC in children and adolescents. Symptom patterns were similar but distinguishable between the 2 groups, highlighting the importance of characterizing PASC separately for these age ranges.

OBJECTIVE:The objective of this study was to investigate the use of indocyanine green videoangiography with FLOW 800 hemodynamic parameters intraoperatively during superficial temporal artery-middle cerebral artery (STA-MCA) bypass surgery to predict patency prior to anastomosis performance. METHODS:A retrospective and exploratory data analysis was conducted using FLOW 800 software prior to anastomosis to assess four regions of interest (ROIs; proximal and distal recipients and adjacent and remote gyri) for four hemodynamic parameters (speed, delay, rise time, and time to peak). Medical records were used to classify patients into flow and no-flow groups based on immediate or perioperative anastomosis patency. Hemodynamic parameters were compared using univariate and multivariate analyses. Principal component analysis was used to identify high risk of no flow (HRnf) and low risk of no flow (LRnf) groups, correlated with prospective angiographic follow-ups. Machine learning models were fitted to predict patency using FLOW 800 features, and the a posteriori effect of complication risk of those features was computed. RESULTS:A total of 39 cases underwent STA-MCA bypass surgery with complete FLOW 800 data collection. Thirty-five cases demonstrated flow after anastomosis revascularization and were compared with 4 cases with no flow after revascularization. Proximal and distal recipient speeds were significantly different between the no-flow and flow groups (proximal: 238.3 ± 120.8 and 138.5 ± 93.6, respectively [p < 0.001]; distal: 241.0 ± 117.0 and 142.1 ± 103.8, respectively [p < 0.05]). Based on principal component analysis, the HRnf group (n = 10) was characterized by high-flow speed (> 75th percentile) in all ROIs, whereas the LRnf group (n = 10) had contrasting patterns. In prospective long-term follow-up, 6 of 9 cases in the HRnf group, including the original no-flow cases, had no or low flow, whereas 8 of 8 cases in the LRnf group maintained robust flow. Machine learning models predicted patency failure with a mean F1 score of 0.930 and consistently relied on proximal recipient speed as the most important feature. Computation of posterior likelihood showed a 95.29% chance of patients having long-term patency given a lower proximal speed. CONCLUSIONS:These results suggest that a high proximal speed measured in the recipient vessel prior to anastomosis can elevate the risk of perioperative no flow and long-term reduction of flow. With an increased dataset size, continued FLOW 800-based ROI metric analysis could be used to guide intraoperative anastomosis site selection prior to anastomosis and predict patency outcome.