Faculty Bibliography

RGS8-associated paraneoplastic neurologic syndrome (PNS) is a recently-described disorder associated with lymphomas and typically presenting with severe, rapidly-progressing cerebellar dysfunction. We describe a patient who presented with mild signs of cerebellar dysfunction, including ocular motor abnormalities and impaired tandem gait. CSF showed elevated protein and a neural-restricted antibody pattern. Mesenteric lymphadenopathy on abdominal CT was biopsied and diagnosed as follicular B-cell lymphoma. After four years, the previously-detected antibody pattern was identified as RGS8 antibodies. This case describes the first RGS8-PNS patient presenting with a subtle and ocular motor predominant cerebellar syndrome with low-grade lymphoma.

BACKGROUND:Flow-diverter stents (FDS) have become the standard of care for a wide range of intracranial aneurysms, but their efficacy/safety in the context of recurrent/recanalized aneurysms following stent-assisted coiling (SAC) is not well established. We evaluate the outcomes of FDS retreatment in a large multicenter cohort. METHODS:We retrospectively analyzed data from 118 patients across 22 institutions who underwent FDS retreatment for recurrent/persistent aneurysms after SAC (2008-22). The primary outcome was angiographic occlusion status at last follow-up, categorized as complete (100%), near-complete (90-99%), or incomplete (<90%) occlusion. Secondary outcomes included procedural complications and clinical outcomes measured by the modified Rankin Scale (mRS). RESULTS:A total of 118 patients (median age 57, 74.6% female) with median follow-up of 15.3 months were identified. Complete occlusion was achieved in 62.5% and near-complete occlusion in 25%. FDS deployment within the pre-existing stent was successful in 98.3% of cases. Major complications occurred in 3.4% of cases, including postoperative aneurysmal rupture with resultant mortality (1.6%) and thromboembolic events with long-term disability (1.6%). Favorable clinical outcomes (mRS 0-2) were observed in 95.1% of patients. Wider aneurysm neck diameter was a significant predictor of incomplete occlusion (adjusted OR (aOR) 1.23 per mm, P=0.044), with male sex trending towards association with non-occlusion (aOR 3.2, P=0.07), while baseline hypertension was associated with complete occlusion (aOR 0.32, P=0.048). CONCLUSIONS:FDS treatment for recurrent/residual aneurysms after SAC represents a viable treatment option for these challenging cases with acceptable safety and reasonable occlusion rates, although lower than de novo FDS occlusion rates.

OBJECTIVE:Common data elements (CDEs) help harmonize data collection across clinical trials and observational studies, allowing for cross-study and cross-condition comparisons. While CDEs exist for multiple clinical conditions and diseases, this work was extended only recently to neurorehabilitation research. DESIGN/METHODS:Subgroups of clinical neurorehabilitation investigators operationalized a domain definition, selected applicable CDEs from 23 existing National Institute of Neurological Disorders and Stroke (NINDS) CDE projects and NIH CDE repositories, and identified areas needing further development. The subgroups also reviewed public comments on the NeuroRehab specific CDEs, which were provided from 01 September 2021 to 07 October 2021. In March 2022, version 1.0 of the NeuroRehab CDEs was completed and can be found on the NINDS CDE website: https://www.commondataelements.ninds.nih.gov/. SETTING/METHODS:NINDS and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)/National Center for Medical Rehabilitation Research (NCMRR) identified NeuroRehab CDEs across 12 different research domains: 1) assessments and examinations; 2) comorbid and behavioral conditions; 3) motor function; 4) treatment/intervention data: therapies; 5) treatment/intervention data: devices; 6) cognitive; 7) communication; 8) emotion/behavior/neuropsychology; 9) activities of daily living/instrumental activities of daily living; 10) quality of life; 11) participation; and 12) infant and pediatrics. Within each domain, corresponding subdomain experts identified instruments with good psychometric measurement properties. PARTICIPANTS/METHODS:120 experts in rehabilitation across the 12 identified research domains and two Co-Chairs with rehabilitation and measurement expertise provided oversight. INTERVENTIONS/METHODS:N/A. MAIN OUTCOME MEASURES/METHODS:CDEs from 23 existing NINDS CDE projects and NIH CDE repositories RESULTS: Clinical investigators recommended NeuroRehab CDEs within three dimensions of the NINDS CDE Classifications: Core, [Disease] Core, and Supplemental - Highly Recommended. Most measures were categorized as Supplemental - Highly Recommended; few were identified as Core or Disease Core. The subgroups also identified measurement gap areas to guide future initiatives as NeuroRehab CDEs are developed in the future. CONCLUSIONS:These efforts are designed to accelerate rehabilitation research in neurological disorders by allowing for cross-study and cross-condition comparisons and to encourage new CDE development.

Astrocytes are a highly abundant glial cell type and perform critical homeostatic functions in the central nervous system. Like neurons, astrocytes have many discrete heterogeneous subtypes. The subtype identity and functions are, at least in part, associated with their anatomical location and can be highly restricted to strategically important anatomical domains. Here, we report that astrocytes forming the glia limitans superficialis, the outermost border of the brain and spinal cord, are a highly specialized astrocyte subtype and can be identified by a single marker: myocilin (Myoc). We show that glia limitans superficialis astrocytes cover the entire brain and spinal cord surface, exhibit an atypical morphology, and are evolutionarily conserved from zebrafish, rodents, and non-human primates to humans. Identification of this highly specialized astrocyte subtype will advance our understanding of CNS homeostasis and potentially be targeted for therapeutic intervention to combat peripheral inflammatory effects on the CNS.

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.

Individuals with neurofibromatosis type 1 (NF1) are prone to the evolution of neurodevelopmental symptomatology including motor delays, learning disabilities, autism, and attention deficits. Caused by heterozygous germline mutations in the NF1 gene, this monogenic condition offers unique opportunities to study the genetic etiologies for neurodevelopmental disorders and the mechanisms that underlie their formation. Although numerous small animal models have been generated to elucidate the causes of these alterations, there is little consensus on how to align preclinical observations with clinical outcomes, harmonize findings across species, and consolidate these insights to chart a cohesive path forward. Capitalizing on expertise from clinicians; human, animal, and cellular model research scientists; and bioinformatics researchers, the first Cognition and Behavior in NF1 (CABIN) meeting was convened at the Banbury Center of Cold Spring Harbor Laboratory in October 2024. This Perspective summarizes the state of our understanding and a proposed plan for future investigation and exploration to improve the quality of life of those with NF1.

OBJECTIVE:This study compared outcomes in patients with and without preoperative stress testing undergoing carotid revascularization including carotid endarterectomy (CEA), transfemoral carotid artery stenting (TF-CAS), and transcarotid revascularization (TCAR). METHODS:Patients in the Vascular Quality Initiative Vascular Implant Surveillance and Interventional Outcomes Network (VQI VISION) database who underwent elective carotid revascularization 2016-2020 were included. Patients were analyzed by group based upon whether they underwent cardiac stress testing within two years preceding revascularization without subsequent coronary intervention. Subset analysis was performed comparing outcomes between those with negative and positive results (evidence of ischemia or MI). Outcomes of interest were postoperative MI/neurologic events, 90-day re-admission rates, as well as long-term mortality. RESULTS:We analyzed 18,364 patients (78.8% CEA, 9.3% TF-CAS, 11.9% TCAR). Of these, 35.8% underwent preoperative stress testing (37.4% of CEA patients, 27.5% of TF-CAS patients, and 31.9% of TCAR patients). While comorbidities were significantly higher amongst patients undergoing CEA with preoperative stress test compared to those without stress testing, the overall prevalence of co-morbidities was higher amongst patients undergoing TF-CAS or TCAR irrespective of preoperative stress test status. Compared to patients with a negative stress test, patients with positive stress test undergoing any form of carotid revascularization had a significant increase in 90-day re-admission rates (CEA 19.6% vs 15.8%, p=0.003; CAS 33.3% vs. 18.6%, p<0.001; TCAR 25% vs. 17.5%, p=0.04). No group demonstrated a difference in the incidence of in-hospital postoperative neurologic events or CHF, but those undergoing CEA (but not CAS or TCAR) experienced a significant increase in-hospital post-operative MI (1.7% vs 0.6%, p<0.001). In 3-year follow-up, those with a positive compared to negative stress test were more likely to undergo CABG/PCI in the CEA (adjusted HR 1.87 [1.42-2.27], p<0.0001) and CAS groups (adjusted HR 3.89 [1.77-8.57], p<0.01), but not the TCAR cohort. Notably those undergoing CEA with a positive compared to negative stress test, but not CAS or TCAR, exhibited a 28% increase in mortality (adjusted HR 1.28 [1.03-1.58], p=0.03) at 3 years. Conversely, those patients with a negative stress test compared to no stress test undergoing CEA experienced a 14% reduction in mortality at 3 years (adjusted HR 0.86 [0.76-0.98], p=0.02); this mortality difference was not observed in similar stress test cohort undergoing TF-CAS or TCAR. CONCLUSIONS:Our study highlights that a positive stress test in appropriately selected, asymptomatic patients undergoing elective carotid revascularization can predict select perioperative and long-term cardiovascular outcomes. However, given the high follow-up mortality associated with those undergoing CEA for elective carotid revascularization, our findings call into question whether these patients should be preferentially offered optimal medical management and/or stenting.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Neuropsychiatric symptoms (NPS) are common in older people with cognitive impairment and Alzheimer's disease (AD). No biomarkers to detect the related pathology or predict the clinical evolution of NPS are available yet. This study aimed to identify plasma proteins that may serve as biomarkers for NPS and NPS-related clinical disease progression. METHODS:A panel of 190 plasma proteins was quantified using Luminex xMAP in the Alzheimer's Disease Neuroimaging Initiative cohort. NPS and cognitive performance were assessed at baseline and after 1 and 2 years. Logistic regression, receiver operating characteristic analysis and cross-validation were used to address the relations of interest. RESULTS:A total of 507 participants with mild cognitive impairment (n=396) or mild AD dementia (n=111) were considered. Selected plasma proteins improved the prediction of NPS (area under the curve (AUC) from 0.61 to 0.76, p<0.001) and future NPS (AUC from 0.63 to 0.80, p<0.001) when added to a reference model. Distinct protein panels were identified for single symptoms. Among the selected proteins, ANGT, CCL1 and IL3 were associated with NPS at all three time points while CCL1, serum glutamic oxaloacetic transaminase and complement factor H were also associated with cognitive decline. The associations were independent of the presence of cerebral AD pathology as assessed using cerebrospinal fluid biomarkers. CONCLUSIONS:Plasma proteins are associated with NPS and improve prediction of future NPS.

Primary brain tumors are the most common solid tumor and cause of cancer-related deaths in children. Their clinical presentation depends on the age of the child and the location of tumor. Tumors in infancy often present with nonspecific symptoms, while focal neurological symptoms are more evident in older children. In this article, we review the most common acute neurological effects of pediatric primary brain tumors and their treatments.