Citations

Abstract Emotional experiences during focal seizures are often misinterpreted as psychiatric disorders. We aimed to evaluate symptoms involving affective symptoms at seizure onset. We aimed to identify the most prevalent affective symptoms at seizure onset and characterize their localizing and lateralizing value. We performed a scoping review based on Preferred Reporting Items for Systematic reviews and Meta‐Analyses–extension for Scoping Reviews guidelines. A systematic search identified records from 4 databases: PubMed, Embase, CINAHL (via EBSCOhost), and Web of Science. Two reviewers independently screened titles/abstracts and full texts; discrepancies were resolved by consensus. This review focused on patients with focal seizures, as affective symptoms may occur in generalized epilepsies. The affective symptoms: fear, anxiety, panic, sadness, mystic, ecstatic, sexual, and mirth were identified, and semiology was evaluated in accordance with ILAE guidelines. Symptom onset, frequency, brain localization, and video‐EEG monitoring technique were evaluated to assess localization and lateralization of regional networks. Scalp EEG, invasive EEG recordings, and electrical stimulation were analyzed. A total of 1276 documents were identified, with 98 studies included for review. Fear was the most frequently reported ictal emotion, identified in 274 patients (66%), predominantly in temporal lobe epilepsy. Sadness and sexual, ecstatic symptoms were also consistently associated with temporal networks. Mirth was more frequently reported with frontal onset seizures. Evidence, primarily from Class IV studies, reported right hemispheric predominance for ecstasy, mystic, and sexual symptoms at seizure onset. Ictal affective symptoms at seizure onset yield localizing information. The limbic system, especially the temporal lobe, followed by the frontal lobe, was the most common site of origin. Fear was the most common spontaneous and electrically elicited symptom, followed by anxiety. While bi‐hemispheric lateralization occurred, right lateralization predominated. Recognizing paroxysmal affective symptoms as ictal phenomena may reduce misdiagnosis and aid presurgical evaluation in drug‐resistant focal epilepsy.

ABSTRACT Background Few studies have examined pretransplant CD4 count and risk of post‐kidney transplant (KT) infection in persons with HIV (PWH). Methods This multi‐center, retrospective cohort study included adult PWH undergoing KT from 2004 to 2019. The primary outcome was infection in the first year post‐KT in PWH with pretransplant CD4 < 350 cells/µL versus CD4 ≥ 350 cells/µL. Relative risk was assessed using modified Poisson modeling. Restricted mean survival time analysis was used to assess 5‐year posttransplant outcomes. Results Of the 75 patients included, 27% had a pretransplant CD4 < 350 cells/µL. Those with CD4 < 350 versus CD4 ≥ 350 were more likely to be hospitalized for infection in the first year (55% versus 16%, p = 0.001). There were no significant differences in relative risk of infection in the first‐year posttransplant (RR: 1.31, p = 0.053), 5‐year overall survival (87.5% vs. 93%, p = 0.49) or 5‐year graft loss (29.4% vs. 23.1%, p = 0.61) betweengroups. Conclusion These findings suggest that pretransplant CD4 count alone may not reflect the true risk of post‐KT infection in PWH.

Abstract Cerebrospinal fluid (CSF) is the biofluid most proximal to the central nervous system (CNS), yet its proteomic organization across neurological disease remains unresolved. We assembled a meta-atlas of 35 CSF proteomic datasets (2016–2026) comprising 10,560 quality-controlled samples spanning neurodegenerative, neuroinflammatory, neuro-oncological, infectious and structural-injury contexts. Meta-analysis of cross-cohort detection defined a 747-protein core mass-spectrometry-accessible CSF proteome that generalizes to held-out cohorts. We derived thirteen consensus meta-programs that transfer across independent cohorts and span the major neural, barrier, immune and plasma compartments. Unexpectedly, these programs are dominated by a single axis of variation opposing complement- and plasma-associated inflammation against neuronal-synaptic homeostasis. This injury–homeostasis axis is diagnosis-spanning and tracks clinical severity and disease activity across diverse neurological conditions. We show that a two-protein C5–NRCAM model can approximate the injury–homeostasis axis, bridging deep proteomic profiling toward bedside assessment.

Abstract Introduction Leptomeningeal disease (LMD) is the seeding of tumor cells in the leptomeninges and the cerebrospinal fluid (CSF) and carries a poor prognosis of 2-4 months. CSF sampling is required to study LMD, but genomic analysis may not be able to identify non-genomic and post-translational modifications. Proteomics can address this gap but is limited by reproducibility and disease heterogeneity. Integrating proteomic with genomic data may prioritize driver genes that promote LMD. Methods 23 patients with breast cancer-associated LMD with matched CSF proteomic and genomic data were studied. Variant allele frequencies (VAFs) for genes TP53, NFE2L2, ERBB2 and PIK3CA were derived, and proteomic profiling was performed on matched CSF. Spearman correlations between driver-gene VAF and protein expression were computed, restricting to genes with VAF&gt;0 in ≥ 3 samples, and Benjamini-Hochberg correction was applied across gene-protein pairs. Proteins significantly associated with VAF were analyzed using over representation analysis (ORA) and gene segment enrichment analysis (GSEA) with KEGG, Gene Ontology, and MSigDB. Results TP53 VAF was associated with upregulation of proteins involved in glycolysis and cell proliferation, with enrichment of hallmark glycolysis (FDR=2.6x10-8), mTORC1 signalling (FDR=8.5x10-8), and reactive oxygen species pathways (FDR=2.7x10-3), and downregulation of complement (FDR=6.8 x 10-6) and coagulation cascades (FDR=0.011). NFE2L2 VAF was associated with epithelial-mesenchymal transition by both GSEA (FDR=2.3x10-9) and ORA (FDR=4.6x10-3), TGF-β signalling (FDR=0.015) and glycoprotein metabolism (FDR=1.6x10-7). ERBB2 VAF was associated with an upregulation of cell-cycle regulation (FDR=6.4x10-10), mTORC1 pathway (FDR=3.2x10-4), and a downregulation of proteins involved in cell-cell adhesion (FDR=4.0x10-9), axon guidance (GSEA FDR=0.025), and developmental growth (GOBP FDR=3.4x10-4). Conclusion Distinct CSF proteomic signatures were associated with specific driver mutations, implicating metabolic and oxidative stress pathways (TP53), stromal remodelling (NFE2L2), and disruption of CNS structural pathways (ERBB2). Validation in prospective LMD cohorts is needed to confirm these mutation-specific signatures and inform diagnostic and therapeutic strategies.

Abstract Background Peritumoral brain edema (PTBE) is a frequent complication of CNS tumors and radiation therapy (RT). PTBE is primarily treated with corticosteroids, but prolonged use is associated with severe toxicities including myopathy and immunosuppression. Bevacizumab, an alternative treatment, is not recommended in patients with thromboembolic events and intracerebral hemorrhage. Plasma kallikrein is a key driver of tumor-related edema. By targeting this pathogenic enzyme, the orally delivered inhibitor, RZ402, may provide therapeutic value by controlling edema and decreasing corticosteroid use. Methods In this single-patient investigational new drug protocol, we report results from use of RZ402 for treatment of cerebral edema related to metastatic melanoma and RT. Results A 74-year-old man with BRAF-wildtype melanoma had a right frontal and basal ganglia hemorrhagic metastasis not amenable to resection, treated with stereotactic RT (30 Gy, 5 fractions), followed by ipilimumab and nivolumab. MRI obtained 5 months after RT showed increased edema associated with midline shift. After 12 weeks of treatment with high-dose dexamethasone (16 mg daily), edema remained persistent and patient was unable to tolerate dose reduction below 4 mg daily. Course was complicated by a pulmonary embolus prompting initiation of anticoagulation, leading to deferral of bevacizumab. Patient was treated with RZ402, which was tolerated well with no reported toxicities. Dexamethasone was discontinued over 4 weeks. Follow up imaging 6 weeks after RZ402 initiation and off dexamethasone demonstrated stability without rebound edema. Patient did experience adrenal insufficiency characterized by severe fatigue, managed with low-dose prednisone. RZ402 was discontinued after 8 weeks of treatment with patient remaining clinically stable. Conclusion Despite persistent edema after prolonged use of corticosteroids, the selective plasma kallikrein inhibitor RZ402 was associated with radiographic stabilization and discontinuation of dexamethasone for this patient. These findings support prospective evaluation of RZ402 in treatment of symptomatic cerebral edema related to CNS tumors.

Abstract Background: Glioma diagnosed during pregnancy and pregnancy following glioma treatment present complex management challenges. The safety of glioma treatment during pregnancy is not well established. The ability to counsel patients on timing of conception after treatment remains limited. The aim of this study was to review our institution’s experience with glioma during and before pregnancy. Methods: In this single-institution study, we retrospectively identified patients diagnosed with glioma during or prior to pregnancy and reviewed treatment course and maternal and neonatal outcomes. Results: Twenty-one female patients were included in our study. Glioma diagnoses included 12 high-grade tumors and 9 low-grade tumors. Cohort A consisted of 8 patients who presented with glioma during pregnancy, of which, 7 underwent glioma treatment during pregnancy. All pregnancies in cohort A were without significant maternal complications and resulted in delivery of a healthy neonate. Cohort B consisted of 13 patients who experienced pregnancy after a prior diagnosis of glioma, totaling 23 pregnancies. Antepartum course was complicated by seizure in three pregnancies. Functionally inconsequential anatomic abnormalities in childhood offspring of cohort B occurred in 5 (27.8%) of the pregnancies. Four of the offspring with anatomic abnormalities had exposure to TMZ prior to conception. Conclusions: In this retrospective series, diagnosis of glioma before or during pregnancy was associated with generally favorable maternal, fetal and childhood outcomes. We observed a higher-than-expected rate of anatomic abnormalities in the post-diagnosis cohort, though none carried meaningful functional consequences. These findings add to the limited literature exploring maternal and fetal outcomes in patients with glioma.

Aim: Despite advances with immune checkpoint inhibitor (ICI)-based regimens in the past decade, patients with metastatic urothelial cancer (mUC) face a poor prognosis with few approved options. Platinum-based chemotherapy with paclitaxel and carboplatin (TC) +/– ICI may be a feasible choice. Methods: We generated an IRB-approved, HIPAA-compliant retrospective database of patients at Mayo Clinic Cancer Center with mUC who started TC +/– ICI after disease progression on ICI from January 2018 through December 2024. Baseline demographics, clinicopathologic features, and treatment outcomes were extracted from the electronic health record. Kaplan-Meier method was used to calculate median duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Results: There were 32 patients who fit inclusion criteria, including 31 patients who had disease progression on ICI in the metastatic setting and 1 patient who developed metastatic disease on adjuvant nivolumab. Patients received a median of 4 cycles (range 1–14) of TC over median 12 weeks (range 3–53). Overall, 81% of patients received TC concurrently with an ICI, and 28% continued maintenance ICI after TC discontinuation (at the treating oncologist’s discretion due to adequate response or toxicity). The best objective response rate was 41% and disease control rate was 75%, with median DOR of 4.8 months (IQR 2.7–10.4), median PFS of 4.6 months (IQR 3.3–10.2), and median OS of 9.4 months (IQR 6.3–15.9). Some patients in this series had very durable responses with PFS > 12 months and OS > 24 months. TC +/– ICI was overall well tolerated with expected type and severity of adverse events. Conclusions: Strategies to overcome ICI resistance are needed, and TC +/– ICI after disease progression on an ICI shows promising tolerability and efficacy in this setting for patients with mUC. Our series was notable for some patients having a durable response. Validation in larger cohorts is warranted.

SignificanceCurrent clinical care following ischemic stroke provides intermittent assessments, potentially missing early detection of neurological deterioration. Optical imaging offers the potential for a continuous, portable alternative to the current combination of physical exams and radiological imaging. However, optical imaging technology has lacked the crucial combination of portability, resolution, and coverage required to assess spatially distributed brain function.AimHere, we present a proof-of-principle study that applies recent advancements in portable high-density diffuse optical tomography (HD-DOT) instrumentation and a functional connectivity analysis strategy to assess spatially distributed brain connectivity. Point-of-care brain health assessments with these tools may inform clinical care and our understanding of brain injury throughout acute stages of stroke recovery.ApproachWe measured spatially distributed cortical oxygenation with HD-DOT within the intensive care unit in N=13 patients with ischemic stroke within the first 72-h since last known normal. To assess brain function integrity, we developed a Similarity metric of functional connectivity (FC) through comparisons to FC in a healthy young adult population. To assess the sensitivity of this FC Similarity metric to disruptions caused by stroke, we compared these data with FC Similarity assessed in an older healthy cohort. We administered the NIH Stroke Scale to stroke patients to evaluate the potential of the FC Similarity metric to inform the severity of functional disruptions.ResultsThe FC Similarity metric applied to HD-DOT data in both acute stroke patients and healthy older controls exhibited a significant sensitivity to the presence of a stroke (Cohen’s d=1.5, p=1.2×10−3) and a significant relationship with the degree of neurological disruption as measured by the NIH Stroke Scale (R2=0.69, p=4.7×10−4).ConclusionsWe present a proof-of-principle for HD-DOT and the FC Similarity metric for assessing brain function during the acute stage of ischemic stroke recovery at the point-of-care.

Background: Pediatric tibial fractures are common long-bone injuries, yet uncertainty remains in the optimal immobilization strategy. The comparative effectiveness and safety of short leg versus long leg casts in achieving stable healing and functional recovery have not been clearly established. Methods: A literature search was conducted across Medline, CINAHL, Embase, and Cochrane Library, from inception to August 2025, following PRISMA guidelines and registered with the International Prospective Register of Systematic Reviews (PROSPERO). Statistical analyses were performed using a random-effects model. Results: The initial search yielded 1236 studies; 6 studies with 413 pediatric patients met the inclusion criteria. A total of 163 underwent short leg casting (SLC) and 250 long leg casting (LLC). No differences were observed between SLC and LLC for coronal angulation (MD=0.12 degrees, 95% CI=−0.89 to 1.12, I 2 =58%) or sagittal angulation (MD=0.18 degrees, 95% CI=−0.71 to 1.07, I 2 =56%). Subgroup analyses showed no differences for tibial shaft fractures or Salter-Harris distal tibial fractures. Cast duration was similar between groups (MD=−0.74 wk, 95% CI=−1.49 to 0.01, I 2 =92%). Overall complication rates did not differ (OR=0.76, 95% CI=0.25 to 2.34, I 2 =0%), with no differences in Salter-Harris subgroup analysis (OR=0.67, 95% CI=0.05 to 9.91; I 2 =54%). SLC was associated with shorter time to weight-bearing (MD=−2.29, 95% CI=−4.49 to −0.08, I 2 =68%) and faster time to union (MD=−1.21, 95% CI=−2.16 to −0.25, I 2 =30%). Conclusion: SLCs may be considered as an alternative to LLCs in pediatric tibial shaft and distal tibial physeal fractures based on currently available retrospective comparative evidence. However, the evidence is limited by the retrospective design, clinical heterogeneity, and risk of confounding. Further prospective comparative studies are needed to define optimal indications for SLC use in this population. Level of Evidence: Level III, systematic review and meta-analysis of retrospective comparative studies.