BackgroundDravet syndrome is a severe developmental and epileptic encephalopathy caused primarily by SCN1A haploinsufficiency. Risks of sudden unexpected death in epilepsy and cognitive deficits are higher among patients with this syndrome than in the general population with epilepsy. The effects of zorevunersen, an antisense oligonucleotide designed to up-regulate NaV1.1 sodium channels, in patients with Dravet syndrome are not known.MethodsWe enrolled patients 2 to 18 years of age with Dravet syndrome who were receiving standard antiseizure medications in two phase 1–2a, open-label, multicenter studies (MONARCH and ADMIRAL). Patients were included in either a single-ascending-dose cohort, in which zorevunersen (10 to 70 mg) was administered on day 1 only, or a multiple-ascending-dose cohort, in which zorevunersen (20 to 70 mg) was administered two or three times in a 3-month period. Patients eligible for rollover to the two open-label extension studies (SWALLOWTAIL and LONGWING) continued to receive zorevunersen (≤45 mg) every 4 months. The safety and pharmacokinetics of zorevunersen were assessed in the primary analysis; clinical effects were also evaluated.ResultsA total of 81 patients were enrolled in the phase 1–2a studies. As of May 30, 2025, a total of 75 patients had entered the extension studies. Most adverse events were mild or moderate. The most common adverse event was post–lumbar puncture syndrome (in 25% of patients) in the phase 1–2a studies and was an elevated protein level in cerebrospinal fluid (in 45%) in the extension studies. One patient had suspected unexpected serious adverse reactions, 1 had an adverse event that led to study withdrawal, 2 died from sudden unexpected death in epilepsy, and 1 died from malnutrition. Patients who received 70 mg of zorevunersen (one, two, or three doses) in the phase 1–2a studies, followed by up to 45 mg in the extension studies, had a median change from baseline in convulsive-seizure frequency ranging from −58.82% to −90.91% across 1-month intervals during the first 20 months of the extension studies. The data supported improvements in overall clinical status, quality of life, and adaptive behavior with continued treatment for up to 36 months in the extension studies.ConclusionsThe safety profile and initial clinical improvement support the continued development of zorevunersen as a potential disease-modifying treatment for Dravet syndrome. (Supported by Stoke Therapeutics; MONARCH and SWALLOWTAIL ClinicalTrials.gov numbers, NCT04442295 and NCT04740476, respectively; ADMIRAL and LONGWING ISRCTN Registry numbers, ISRCTN99651026 and ISRCTN12811235, respectively.)

The lymphatic system, traditionally regarded as a unidirectional conduit for interstitial fluid and immune cell transport, has recently been redefined through the discovery of lymphatic networks along the spinal axis. These spinal lymphatic vessels, encompassing the spinal cord, vertebral bones, and intervertebral discs, challenge long-standing anatomical dogmas and introduce new perspectives on the interplay between the central nervous system (CNS) and the vertebral column. This review systematically summarizes the distribution and dual functions of the spinal lymphatic system in regulating cerebrospinal fluid drainage, maintaining tissue homeostasis, and mediating immune responses. Furthermore, we highlight emerging evidence linking spinal lymphatic dysfunction to spinal pathologies, neurological disorders, and vertebral degeneration. Based on these findings, we propose that the spinal lymphatic system constitutes a previously underappreciated pathway integrating spinal cord and vertebral physiology, with potential implications for both disease progression and therapeutic intervention. While research on the cranial lymphatic system has rapidly advanced, the spinal lymphatic system remains comparatively underexplored. We hope this review will catalyze further investigation into spinal lymphatic biology and inform the development of novel therapeutic strategies targeting spinal and neurological diseases.

Sex differences are increasingly recognized as modifiers of Alzheimer disease and related dementias, with women exhibiting greater tau burden and faster cognitive decline than men. Even though α-synuclein copathology frequently occurs in Alzheimer disease, its contribution to sex differences in disease progression is unclear. To test whether α-synuclein positivity, measured using cerebrospinal fluid seed amplification assay (SAA), is differentially associated with tau accumulation in women vs men across the Alzheimer disease continuum. This cohort study used longitudinal tau positron emission tomography from the Alzheimer's Disease Neuroimaging Initiative collected between 2015 and 2023, with a median (IQR) follow-up of 1.23 (0.00-3.84) years. Participants were stratified by cerebrospinal fluid α-synuclein seed amplification assay status and sex. Participants were cognitively unimpaired or cognitively impaired (mild cognitive impairment or dementia) at baseline. Cerebrospinal fluid α-synuclein status determined by SAA and dichotomized as SAA negative or SAA positive. Tau burden was quantified as standardized uptake value ratio (SUVr) in the medial temporal composite region of interest. Linear mixed-effects models tested SAA by sex by time interactions on longitudinal tau accumulation, adjusting for baseline age, baseline cognitive status, apolipoprotein E ε4 carrier status, and site. Sample size estimates were calculated to detect 25% and 50% treatment effects with 80% power in those with cognitive impairment. Among 415 participants (mean [SD] age, 72.3 [7.6] years; 220 women [53%]; 69 SAA positive [17%] and 346 SAA negative [83%]), there was a significant interaction between SAA status, sex, and time on tau accumulation (β, 0.061; 95% CI, 0.030-0.093; P < .001). Women with positive SAA results exhibited the fastest tau accumulation compared with other groups (0.066 SUVr per year; 95% CI, 0.043 to 0.089 SUVr per year; P < .001). Clinical trials targeting tau pathology in cognitively impaired individuals with 18-month follow-up would require 129 SAA-positive women to detect a 25% treatment effect with 80% power, compared with 518 SAA-negative women. In this cohort study of participants across the Alzheimer disease continuum, α-synuclein copathology was associated with faster tau accumulation in women than men. These findings may inform sex-specific interpretation of α-synuclein biomarkers and trial design.

Clinical metagenomic next-generation sequencing (mNGS) is a diagnostic tool allowing near-universal pathogen detection directly from clinical specimens. Despite promising clinical data, broad adoption of mNGS has been hindered by high cost and reduced sensitivity relative to targeted nucleic acid amplification tests (NAATs). Recently, Ultima Genomics introduced the UG 100 NGS platform which advertises 10 billion reads per $2,400 sequencing wafer. By lowering costs and improving sequencing depth, the historical value proposition of mNGS may be improved. This study evaluates the UG 100 sequencer's ability to generate reads for metagenomic pathogen detection from cerebrospinal fluid specimens. Ultima reads demonstrated 93% (26/28) positive agreement with orthogonal test results and 63% (10/16) negative agreement against a syndromic panel for meningitis and encephalitis. Near full-length genomes were recovered for three organisms (human herpesvirus-1 [HSV-1], Streptococcus pneumoniae, and Haemophilus influenzae), with the ability to detect putative antimicrobial resistance genes for H. influenzae. Recovery of Borrelia burgdorferi reads (6.1 reads per million [RPM] and 9.03 RPM) was achieved from clinical samples with late cycle threshold values (39.7 and 43.0, respectively). Limit of detection (LoD) studies demonstrated detection of HSV-1 and S. pneumoniae reads at concentrations of 50 genomes/mL each, which is below the reported LoD for the orthogonal NAATs used in this study. Reducing sequencing costs and improving the analytical sensitivity remove two major hurdles for mNGS adoption by clinical laboratories. While these results are preliminary, they demonstrate a future in which mNGS may be more widely implemented.IMPORTANCEClinical metagenomic next-generation sequencing has struggled to gain wider adoption for nearly a decade, due in part to its high cost and reduced performance versus targeted molecular assays. This study demonstrates the ability of the UG100 sequencing platform to reduce per-base metagenomic sequencing costs while producing reads that maintain high positive agreement with existing molecular assays. Further improvements to cost and analytical performance may shift clinical metagenomics from an expensive test of last resort to a front-line diagnostic for identifying infections.

Leukemic infiltration of the optic nerves is an uncommon yet clinically significant manifestation of central nervous system (CNS) involvement in acute lymphoblastic leukemia (ALL). We report an adult male with B-cell ALL who developed progressive bilateral visual loss due to optic nerve infiltration and meningeal involvement, representing CNS relapse. The patient had been previously diagnosed with B-cell ALL and had discontinued therapy after induction chemotherapy. Several months later, he presented with bilateral visual loss and pain on eye movements. Ophthalmologic examination revealed bilateral optic disc edema. Magnetic resonance imaging of the brain and orbits demonstrated bilateral optic nerve thickening with postcontrast enhancement and associated leptomeningeal enhancement. Cerebrospinal fluid analysis confirmed malignant lymphoid cells, establishing CNS relapse. The patient was restarted on CNSdirected chemotherapy with partial visual improvement. This case highlights the optic nerve as a pharmacologic sanctuary site, emphasizes the importance of dedicated orbital imaging in patients with suspected CNS leukemia, and underscores the need for strict treatment compliance and long-term surveillance in ALL.

Gene therapies are promising for diseases previously considered incurable. Adeno-associated virus serotype 9 (AAV9) demonstrates remarkable tropism for motor neurons (MNs) and represents an exciting candidate to target genetic causes of motor neuron diseases like amyotrophic lateral sclerosis (ALS). However, systemic delivery risks immunogenicity and off-target effects, therefore localised delivery to the CNS is advantageous. We assessed MN transduction in wild-type post-natal mice using AAV9-controlled, cytomegalovirus-promoter driven, enhanced GFP expression. Intra-cisterna magna (ICM) and intra-cerebroventricular (ICV) methods were compared. Four weeks post-delivery, GFP positivity in MN and astrocytes were quantified via immunohistochemical approaches and viral genome copy number determined by qPCR. All delivery methods achieved high MN transduction in lumbar spinal cord (> 68%). Unilateral ICV delivery provided the highest and most consistent levels (89 ± 3%), and minimal peripheral viral copies. ICV delivery resulted in higher astrocytic transduction, most notably in the cortex. Brainstem MN transduction was high with all methods (> 55%). We failed to find evidence of neuronal transduction in motor cortex. Viral genome copies trended higher in spinal cord and brainstem with ICV approaches, however further work is required to understand how bilateral repeated dose delivery leads to more profound increases. Whilst several routes of administration into cerebrospinal fluid exist, direct comparisons for targeting MNs in vivo remain limited. Overall, all methods of CNS-directed delivery result in high levels of motor neuron transduction in the lumbar spinal cord and brainstem, but not in motor cortex. Unilateral ICV appears to provide the best balance between consistent, high levels of transduction and low off-target effects. However, ICM might be the better option if seeking to avoid astrocytic transduction.

BackgroundDisorders of autonomic dysregulation appear increasingly prevalent in chronic rhinosinusitis (CRS).ObjectiveThe purpose of this study was to investigate if dysautonomia portends a riskier postoperative course in patients with CRS undergoing sinonasal surgery.MethodsThe TriNetX database was queried for patients with CRS with or without comorbid dysautonomia undergoing functional endoscopic sinus surgery, septoplasty, and/or inferior turbinate reduction. Cohorts were propensity-matched based on age, gender, race, and potentially confounding comorbid conditions. Main outcome measures were emergency department utilization, inpatient admission, incidence of postoperative cerebrospinal fluid leak, epistaxis, or hypotension. The use of opioid, neuropathic, antibiotic, benzodiazepine, muscle relaxant, corticosteroid medications, and intravenous fluids within 90 days of surgery were also recorded.ResultsEach group contained n = 1122 patients. The dysautonomia group had higher risks of epistaxis (odds ratio [OR]: 2.03; confidence interval [CI]: 1.13, 3.66; P = .016) and neuropathic medication use (OR: 2.92; CI: 1.35, 6.31, P = .005) following sinonasal surgery.ConclusionPatients with CRS and comorbid dysautonomia appear at a greater risk of postoperative epistaxis and neuropathic pain medication use following sinonasal surgery. Although further study is necessary, these findings suggest patients with dysautonomia may have a higher rate of postoperative bleeding and increased pain sensitivity.

Objective: This study aimed to compare the effects of hydroxyethyl starch (6% HES 130/0.4) administered as preload or coload on the incidence of maternal hypotension and neonatal outcomes in elective cesarean sections performed under spinal anesthesia.Methods: This prospective, randomized trial included 162 parturients aged 18–45 years with American Society of Anesthesiologists physical status II and a gestational age greater than 36 weeks undergoing elective cesarean delivery under spinal anesthesia. Participants received 500 mL of HES either 30 minutes before spinal anesthesia (preload group) or at the onset of cerebrospinal fluid flow (coload group). Maternal hemodynamic parameters were monitored throughout the procedure. Umbilical cord blood gas analysis, Apgar scores at 1 and 5 minutes, and total ephedrine consumption were recorded.Results: The incidence of maternal hypotension was 51.1% in the preload group and 48.9% in the coload group, with no statistically significant difference between groups (p = 0.83). Systolic arterial pressure at the onset of hypotension was 86.41 ± 8.63 mmHg in the preload group and 82.20 ± 9.14 mmHg in the coload group (p = 0.19). Total ephedrine requirement and umbilical cord blood gas parameters were comparable between groups. While 1-minute Apgar scores were similar, the 5-minute Apgar score was significantly higher in the preload group (p = 0.01).Conclusion: Colloid preload and coload administration were associated with comparable effects on maternal hypotension, vasopressor requirements, and neonatal outcomes in cesarean deliveries performed under spinal anesthesia.

Abstract Spontaneous intracranial hypotension (SIH) is commonly caused by cerebrospinal fluid (CSF) leakage, resulting in epidural CSF accumulation. Although bony spurs and disc degeneration are traditionally implicated, SIH frequently affects younger individuals, suggesting that additional anatomical or biomechanical factors may contribute. We hypothesized that cervical spinal alignment, particularly reduced lordosis, may influence CSF retention patterns and contribute to SIH pathophysiology. A retrospective analysis was conducted on 30 SIH patients and 30 age- and sex-matched healthy controls. Cervical Cobb angles were measured from lateral MRI images, and CSF accumulation was evaluated for thickness, distribution (ventral vs. dorsal), and spinal level. Correlations were assessed between these variables. Group comparisons were performed using the Wilcoxon rank sum test. Pearson's correlation coefficient was used to evaluate associations between quantitative variables. A p-value of &lt; 0.05 was considered statistically significant. SIH patients had significantly smaller Cobb angles than controls (p = 0.011), indicating reduced cervical lordosis or a straight neck alignment. A strong association was found between smaller Cobb angles and dorsal CSF accumulation (p &lt; 0.001). Ventral retention was more common in the lower cervical spine, while dorsal retention predominated in the mid-thoracic region. No significant correlation was observed between Cobb angle and CSF thickness or patient age. Reduced cervical lordosis is associated with distinct CSF retention patterns in SIH, particularly dorsal accumulation. Despite the limited sample size due to the rarity of SIH, consistent and statistically significant trends were observed. These findings support the clinical relevance of assessing spinal alignment in SIH and suggest that anatomical factors may influence dural vulnerability. Further research should explore whether alignment-based interventions can mitigate dural stress and reduce CSF leakage risk.

Introduction. Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) accounts for approximately 25% of ALL cases in adults. It typically presents with an aggressive clinical course, but the integration of tyrosine kinase inhibitors (TKIs) into chemotherapy regimens has allowed a notable increase in remissions. Despite the significant progress, some patients relapse in the central nervous system (CNS) after treatment, due to the low blood–brain barrier permeability of TKIs. Currently, CNS relapse monitoring is performed by conventional imaging techniques and cytology analysis of the cerebrospinal fluid (CSF). However, these techniques have limited sensitivity. We describe the usefulness, in terms of non-invasiveness and sensitivity, of cell-free tumor DNA testing (Liquid Biopsy, LB) on CSF in a patient with Ph-positive ALL (M-BCR: BCR-ABL p210 b3a2 transcript) who developed a meningeal recurrence after imatinib-based treatment.Methods. The patient was a 75 year old man with a story of Ph+ LLA, with Complete Hematologic Remission for &gt;5 years. After the development of headache, brain MRI, lumbar puncture and minimal residual disease (MRD) testing on peripheral blood were requested for suspected CNS relapse.Follow-up of (MRD) on peripheral blood was carried out with one-step Real-Time PCR monitoring of the BCR-ABL p210 b3a2 transcript on RNA extracted from buffy coat and with Philadelphia chromosome FISH.Free circulating DNA and RNA were extracted from a sample of CSF to investigate the presence of relapses in the central nervous system and to characterize it from a molecular point of view. The molecular research was conducted through the Next-Generation Sequencing (NGS) analysis, with Ion Torrent technology, of a myeloid panel which simultaneously interrogates 45 DNA target genes and 35 fusion driver genes (RNA). Results. Brain MRI revealed enhancement areas in the subarachnoid space. Lumbar puncture showed high opening pressure an increased cell count, with 468 cells / μL with 51% blasts.FISH and Real-Time PCR on peripheral blood had low positivity (ratio BCR/ABL x 100 (IS) = 0.013%), consistent with complete hematological response. Conversely, Real-Time PCR on CSF was positive, with an imbalance score of 0.0002% for the BCR::ABL1B13A transcript, consistent with brain relapse. Real-Time PCR quantitative monitoring of MRD show in peripheral blood a major molecular response (MMR) constant in time. Meningeal relapse was confirmed in CSF by the presence of the BCR::ABL1B13A transcript with an imbalance score of 0.0002%. Conclusions. Liquid biopsy (LB) of the cerebrospinal fluid has proven to be a very sensitive technique that allows the identification of molecular relapse on of free cell-free tumor DNA (ctDNA) in a less invasive way. The results of the molecular evaluation of the response to therapy by NGS study allowed the therapeutical switch to second generation TKIs Dasatinib.

Bilateral subdural hematomas complicating intracranial hypotension following lumbar spine procedures: two case reports

Background To describe our findings in a rare case of secondary triple-hit diffuse large B-cell lymphoma (DLBCL) with choroidal and central nervous system (CNS) involvement, presenting with bilateral serous retinal detachments (SRD) and ophthalmoplegia. Case presentation A 44-year-old male presented with a 4-month history of bilateral vision loss, right-sided headaches radiating to the periorbital area, and oral numbness within the mental nerve distribution. Review of systems was notable for unintentional 25-pound weight loss and chronic back pain. Corrected visual acuities were 20/150 in the right eye and 20/50 in the left. External exam showed remarkable results for right-sided ptosis, diminished pupillary light response without afferent pupillary defect, and limitation of extraocular movements in all gazes. Fundus examination showed bilateral, multifocal SRD with associated increased choroidal thickness. Systemic workup showed right-sided prominence of the cavernous sinus, heterogeneous bone marrow signal throughout the spine, splenomegaly, retroperitoneal lymphadenopathy, and a hypodense hepatic lesion. Cerebrospinal fluid analysis revealed elevated white blood cell count and protein concentration. A lymph node biopsy revealed DLBCL with Bcl6, Bcl2, and c-Myc rearrangements. Treatment with combined intrathecal and systemic chemotherapy resulted in significant improvement in both systemic and ocular symptoms. Conclusion This case underscores the importance of considering secondary lymphoma in patients presenting with bilateral SRD and neuro-ophthalmic deficits, even in the absence of known systemic malignancy. The combination of cavernous sinus syndrome with concomitant mandibular nerve involvement should prompt CNS and systemic evaluation for hematologic malignancy. Patients with triple-hit DLBCL phenotype may achieve dramatic visual recovery following modern targeted chemoimmunotherapy.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease primarily affecting motor neurons. Neurofilament light chain (NfL) is the most established prognostic biomarker; however, its diagnostic resolution is limited, particularly within intermediate concentration ranges, and it does not capture the molecular heterogeneity of ALS. This study aimed to identify complementary cerebrospinal fluid (CSF) biomarkers and pathway-specific signatures through a non-targeted multiomic approach. We performed SWATH-MS-based proteomics and LC-MS/MS lipidomics on CSF from ALS patients stratified by survival (ALS-SS and ALS-LS) and healthy controls. Weighted protein co-expression network analysis (WPCNA) was applied to identify biologically coherent protein modules associated with disease phenotype and progression. Top biomarker candidates were further evaluated using immunoassays in an independent cohort. Post-mortem ALS spinal cord tissues were analyzed to explore the pathophysiological relevance of identified proteins. CSF proteomic profiles robustly distinguished ALS patients from controls and stratified patient subgroups by survival, revealing a molecular signature characterized by inflammation, downregulation of detoxification mechanisms, and synaptic dysregulation in aggressive disease forms. In contrast, lipidomic profiles showed limited discriminatory power. WPCNA identified modular proteomic signatures capturing ALS heterogeneity, and machine learning models based on these profiles yielded optimal biomarker panels for diagnosis and prognosis. CXCL7 emerged as a promising complementary biomarker, and shed light in disease physiopathology. Immunoassay validation supported the diagnostic and prognostic potential of CXCL7 and its association with survival time. Histopathological analysis further confirmed CXCL7 localization in anterior horn motor neurons, despite no detectable changes in whole spinal cord lysates at late disease stages. Comprehensive CSF proteomic profiling, combined with network-based analysis, enhances our understanding of ALS molecular heterogeneity and provides a framework for precision biomarker discovery. CXCL7 complements NfL as a diagnostic and prognostic biomarker, supporting improved patient stratification and advancing the development of personalized therapeutic strategies in ALS.

Listeria monocytogenes (LM) rhombencephalitis is a rare but severe manifestation of neurolisteriosis, typically reported in immunocompromised or elderly patients and often associated with high morbidity and mortality. We describe a 66-year-old immunocompetent man who presented initially with peripheral facial paralysis, an uncommon early manifestation reflecting cranial neuritis, before rapidly developing brainstem dysfunction, respiratory failure, and multiple abscesses. Diagnosis was confirmed by cerebrospinal fluid (CSF) multiplex polymerase chain reaction (PCR) and blood cultures, and despite targeted antimicrobial therapy the patient developed severe neurological sequelae. This case underscores that cranial neuritis may present as an early clue of neurolisteriosis.

Serum but not cerebrospinal fluid biomarkers are associated with domain-specific cognitive performance in PWH.

CSF-venous fistulas Reconsidered: Pressure paradox and the Volume-Elastance Relationship.

Evaluation of blood-brain barrier integrity and clinical characteristics in autoimmune glial fibrillary acidic protein astrocytopathy.

CSF and plasma GFAP and VEGF in adult type 3 spinal muscular atrophy patients treated with nusinersen.

Cellular insights into hydrocephalus: The diverse roles and intricate crosstalk of multiple cell types.

L17E cell-penetrating peptide enhances intranasal delivery of IgG to the cerebrospinal fluid in mice.