Faculty Bibliography

Rasmussen syndrome (RS) includes a well-described constellation of refractory focal seizures, often including epilepsia partialis continua, hemiplegia with progressive unilateral cortical atrophy, and cognitive/language decline. However, the precise early pathogenesis and reliable biomarkers remain elusive. In addition, we lack operational management guidelines, including diagnostic evaluation, disease-monitoring assessments, and medical and surgical treatment approaches. We aimed to create an expert consensus statement to guide and standardize the treatment of RS, with the goal of providing recommendations applicable to a global population. An expert panel was convened to complete three rounds of a modified Delphi procedure given the lack of high-level evidence, with a focus on workup to exclude mimicking diagnoses, disease-activity metrics, and treatment. Consensus was defined as ≥75% of responses being agree/strongly agree in either two subsequent rounds or in the third and final round. A total of 122 of 143 statements met consensus. Proposed diagnostic evaluation in patients with possible RS is outlined, including physical examination, blood/cerebrospinal fluid analyses, neuroimaging, electroencephalography (EEG), and biopsy. Suggested disease-monitoring assessments include neuropsychological testing and serial magnetic resonance imaging (MRI). Intravenous corticosteroids are recommended as first-line, acute immunotherapy for seizure exacerbations and status epilepticus, with or without the addition of intravenous immunoglobulin. Options for maintenance immunotherapy are outlined, with lack of evidence noted for comparing efficacy of these treatments. Hemispheric disconnection remains the most effective seizure treatment, with parameters including age, function, seizure burden, and patient values influencing candidacy for surgery. This consensus statement offers a guideline to standardize management, as well as suggests future directions to further elucidate underlying pathophysiology and target more-effective, better-tolerated treatments.

BACKGROUND/OBJECTIVES/OBJECTIVE:Characterizing spinal cord multiple sclerosis (MS) lesions in MRI is critical for diagnosis, monitoring, and treatment evaluation. However, current automated approaches for lesion detection and segmentation are typically designed for specific MRI contrasts or acquisition sites, limiting their generalizability in real-world clinical settings where imaging protocols vary widely. This work proposes a robust multi-site, multi-contrast segmentation framework for spinal cord lesions. METHODS:The segmentation model was trained and evaluated on a large-scale dataset comprising 4428 annotated images from 1849 persons with MS across 23 imaging centers, encompassing six MRI contrasts (T1w, T2w, T2*w, PSIR, STIR, and UNIT1) acquired at 1.5 tesla (T), 3 T, and 7 T. RESULTS: < 0.01). Additional experiments evaluated robustness across spinal levels, acquisition resolutions, binarization thresholds, and quantitative evaluation on external labeled datasets. CONCLUSIONS:https://github.com/ivadomed/seg-sc-ms-lesion-multicontrast.

INTRODUCTION/BACKGROUND:Progression Independent of Relapse Activity (PIRA) is a critical measure of disability progression in multiple sclerosis (MS) independent of relapses but lacks a standardized definition. Current reliance on the Expanded Disability Status Scale (EDSS) limits sensitivity to non-motor domains, necessitating a stratified framework to enhance detection and guide management. OBJECTIVES/OBJECTIVE:To develop a novel seven-level stratified PIRA definition and assess its validity, enhanced sensitivity, clinical relevance, and feasibility through expert consensus, and propose a simplified framework based on feedback. METHODS:A two-stage study: (1) A four-expert panel developed a seven-level PIRA framework (PIRA 1: EDSS-based; PIRA 2: EDSS-plus measures; PIRA 3: stress tests; PIRA 4: patient-reported outcomes [PROs]; PIRA 5: conventional MRI; PIRA 6: advanced MRI; PIRA 7: biomarkers) via literature synthesis. (2) A survey of 90 MS experts (26 responded, 28.9%) from nine countries evaluated each level's validity, sensitivity (vs. EDSS), relevance, and feasibility (1-5 scale), with open-ended comments on barriers and suggestions. High agreement was defined as a score ≥ 4. Qualitative feedback on barriers and improvement suggestions was thematically analyzed. RESULTS:Strong support (24/26; 92.3%) endorsed a stratified PIRA definition. Respondents included primarily clinician-researchers (22/26; 84.6%), with 11/26 (42.3%) reporting more than 20 years of MS experience. High agreement for validity ranged from 15/26 (57.7%) for PIRA 1-23/26 (88.5%) for PIRA 6. Agreement regarding enhanced sensitivity was highest for PIRA 2 (25/26; 96.2%), followed by PIRA 6 (22/26; 84.6%) and PIRA 5 (19/26; 73.1%). Clinical relevance was rated highly for PIRA 1, PIRA 2, and PIRA 6 (each 25/26; 96.2%). Feasibility was highest for PIRA 1 (24/26; 92.3%) and declined for higher levels, particularly PIRA 7. Barriers included inter-rater variability (PIRA 1, 30.8%), subjectivity (PIRA 4, 23.1%), and cost/expertise (PIRA 6-7, 26.9% each). Suggestions included digital tools (PIRA 2-3), AI for MRI (PIRA 5-6), biomarker validation (PIRA 7), and combining PIRA 5-6. PIRA 1-2 were preferred for clinical practice, PIRA 5-7 for research. A three-tier framework was proposed: Probable PIRA (clinical), Definite PIRA (clinical + MRI), and Definite PIRA Plus (clinical + MRI + biomarkers). CONCLUSIONS:The proposed seven-level PIRA framework demonstrates strong expert support for its conceptual validity and clinical relevance but highlights feasibility challenges for advanced assessments. A simplified three-tier model may provide a practical structure for standardized evaluation of relapse-independent progression in MS. Further empirical validation in diverse clinical cohorts is required.

Head computed tomography (CT) imaging is a widely used imaging modality with multitudes of medical indications, particularly in assessing pathology of the brain, skull and cerebrovascular system. It is commonly used as the first-line imaging in neurologic emergencies given its rapidity of image acquisition, safety, cost and ubiquity. Deep learning models may facilitate detection of a wide range of diseases. However, the scarcity of high-quality labels and annotations, particularly among less common conditions, substantially hinders the development of powerful models. To address this challenge, we introduce FM-HCT, a Foundation Model for Head CT for generalizable disease detection, trained using self-supervised learning. Our approach pretrains a deep learning model on a large, diverse dataset of 361,663 non-contrast 3D head CT scans without the need for manual annotations, enabling the model to learn robust, generalizable features. Our results demonstrate that the self-supervised foundation model substantially improves performance on downstream diagnostic tasks compared to models trained from scratch and previous 3D CT foundation models trained on scarce annotated datasets.

BACKGROUND:Transcranial electrical stimulation (TES) has limited spatial focus and depth penetration, constraining its therapeutic efficacy. Intersectional Short-Pulse (ISP) stimulation was developed to overcome these limitations by delivering rapidly switching pulses that can be temporally integrated by neuronal membranes. Here, we aimed to establish the biophysical basis of ISP-induced temporal summation and to test whether this mechanism enables effective brain modulation in vivo. METHODS:We combined finite-element modeling, cadaver measurements (n = 2 human cadavers), and biophysically realistic NEURON simulations to characterize the spatial and temporal properties of ISP-induced electric fields. In vivo whole-cell patch-clamp recordings were performed in the rat somatosensory cortex (female Wistar rat) to test the membrane-level integration of sequential electric field pulses. Functional efficacy was evaluated using closed-loop ISP stimulation in a hippocampal kindling model of temporal lobe epilepsy in male Long-Evans rats (n = 11 animals, >500 induced seizures analyzed across conditions). RESULTS:Here we show that neurons integrate sequential ISP pulses in a non-vectorial, temporally accumulative manner, consistent with membrane-level charge integration rather than extracellular field superposition. ISP and conventional TES simulations produced similar instantaneous field magnitudes, but ISP stimulation resulted in more uniform neuronal excitability across brain depths. Closed-loop ISP stimulation significantly outperformed conventional TES in reducing seizure duration and severity. ISP reduced hippocampal seizure duration by 45% and 35% compared to SHAM stimulation and conventional TES, and significantly reduced motor seizure severity. CONCLUSIONS:ISP stimulation provides a non-invasive neuromodulation approach that enhances deep brain engagement through rapid, temporally structured pulse sequences. These findings demonstrate effective seizure suppression in a rodent model and support the translational potential of ISP for disorders involving pathological neural dynamics.

Cerebral malaria is a major complication of Plasmodium falciparum infection that occurs upon the sequestration of infected red blood cells (iRBCs) in brain capillaries, resulting in the loss of endothelial barrier integrity, brain swelling, and frequently long-term sequelae or death. P. falciparum-iRBCs cause the disruption of human brain microvascular endothelial cell barrier integrity in vitro, mimicking the microenvironment of cerebral malaria, yet the specific mechanisms mediating this process remain unknown. Upon infection of the host RBCs, P. falciparum produces hemozoin, a crystal form of heme generated following the degradation of hemoglobin by the parasite. Here, we show that the endothelial barrier-disrupting activity is found entirely in the hemozoin fraction of P. falciparum-iRBCs. This activity is not caused by the hemozoin crystal itself, which is not able to induce barrier disruption, but by the biomolecules that are associated with it. Treatment of purified P. falciparum hemozoin with proteases inhibits the disruption of endothelial barrier integrity caused by the hemozoin, indicating an important role for proteins in the disruption of the barrier. Conversely, treatment with nucleases did not affect hemozoin barrier-disrupting activity. These results identify a key molecular mechanism in the P. falciparum-mediated brain endothelial barrier disruption during cerebral malaria and may open new avenues for the treatment of this complication.IMPORTANCEWhile several specific biomolecules have been proposed to contribute to the disruption of endothelial barrier integrity in cerebral malaria, no single Plasmodium falciparum- or host-derived factor has been definitively identified as the primary driver of this disruption. Here, we identify the brain endothelial barrier-disruptive P. falciparum-infected red blood cell (iRBC)-derived activity to be caused by biomolecules bound to hemozoin, identifying a key, novel mechanism in the pathogenesis of cerebral malaria. The finding that P. falciparum hemozoin also disrupts a pulmonary endothelial cell barrier opens the possibility that this mechanism underlies other severe malaria complications. The implication of P. falciparum-iRBC-derived proteins in this mechanism is in line with previous reports, providing a novel interpretation of these findings in the context of hemozoin-binding. This knowledge provides a new perspective in the search for specific molecules and mechanisms involved in barrier disruption, which may lead to the development of much-needed specific treatments for cerebral malaria.

The effectiveness of COVID-19 vaccination in children and adolescents with prior SARS-CoV-2 infection remains unclear, particularly for Omicron subvariants. We evaluate vaccine effectiveness against reinfection with Omicron BA.1/BA.2, BA.4/BA.5, XBB, and later subvariants among 5- to 17-year-olds using data from the RECOVER initiative, a national electronic health record database covering 37 U.S. children's hospitals and health institutions. We emulate target trials by age group and variant period, comparing previously infected participants between January 2022 and August 2023. During the BA.1/BA.2 period, vaccination reduces the risk of reinfection, with effectiveness rates of 62% in children and 65% in adolescents. During the BA.4/BA.5 period, protection effectiveness in children was 57%, whereas no statistically significant protection is observed in adolescents. During the XBB and later period, no significant protection is observed in either group. In summary, COVID-19 vaccination provides protection against reinfection during the early and mid-Omicron periods in previously infected pediatric populations, but effectiveness declines for later variants.

OBJECTIVE:To validate the carotid web (CW) risk stratification assessment described in previous works within a larger cohort of patients with symptomatic and incidentally found asymptomatic CWs. METHODS:A retrospective analysis of our institution's electronic medical records identified all patients with a diagnosis of CW from 2017 to 2024. We included symptomatic patients and those with asymptomatic CWs, that is, incidentally found webs without history of stroke or transient ischemic attack. Patient charts were reviewed for demographics, imaging, comorbidities, and a diagnosis of stroke after diagnosis of asymptomatic CW. All angles were measured as described in previous work on a sagittal reconstruction of neck CT angiography in which the common carotid artery (CCA), external carotid artery, and internal carotid artery (ICA) were well visualized, together with the CW itself. Principal component analysis and logistic regression were performed to evaluate the association between high-risk angles and stroke risk.  RESULTS: Twenty-six symptomatic and 26 asymptomatic patients were identified. Of note, the number of patients with hypertension, hyperlipidemia, and smoking history was 17 (65.0%), 16 (62.0%), and 8 (31.0%) for symptomatic patients and 18 (69.0%), 17 (65.0%), and 15 (58.0%) for asymptomatic patients. All angular measurements showed statistically significant associations with stroke status. The CCA-web-pouch angle showed the strongest association (p=2.07×10⁻⁴), followed by the CCA-pouch-tip angle (p=3.23×10⁻⁴), ICA-web-pouch angle (p=0.004), and ICA-pouch-tip angle (p=0.005). Each additional high-risk angle increased the odds of stroke by 9.47-fold (p<0.0001). The associated probability of stroke increased from 6.3% with no high-risk angles to 39.1% with one high-risk angle and further to 85.9% with two high-risk angles. The model demonstrated high sensitivity, correctly identifying 84.6% of positive cases, and high specificity, correctly identifying 88.5% of negative cases. The F1 score was 0.863, indicating good overall model performance.  CONCLUSION: Given this successful stratification of CWs into high- and low-risk groups, the utilization of geometric CW parameters may play a role in improving patient selection for intervention in the setting of incidentally diagnosed CW. .