Background: Treatment of generalized myasthenia gravis (gMG) with reduced steroid dosages may minimize steroid-associated AEs. Corticosteroid dosage changes were not permitted during the 26-week, CHAMPION MG study of ravulizumab in adults with anti-acetylcholine receptor antibody-positive (AChRAb+) gMG. Participants who completed the study could receive ravulizumab in the open-label extension (OLE; NCT03920293); corticosteroid adjustments were permitted. Methods: Patients could receive intravenous ravulizumab (blind induction or bridging dose at Week 26 [OLE start] for those previously receiving placebo or ravulizumab, respectively, then 3000–3600 mg at Week 28 and every 8 weeks thereafter) for ≤4 years. Results: Among 161 patients (78 ravulizumab, 83 placebo) who entered the OLE and received ravulizumab for ≤164 weeks, 113 received oral or enteral corticosteroids during the OLE; the proportion treated with >10 mg/day corticosteroids decreased from 58% (n=66) at first OLE dose to 37% (n=42) (35 [31%] received ≤5 mg/day and 71 [63%] received ≤10 mg/day) at last reported dose. Fourteen patients (12%) discontinued corticosteroids. The mean (SD) corticosteroid dosage/patient decreased from 17.5 (11.9) mg/day at first OLE dose to 11.7 (10.9) mg/day at last assessment. Conclusions: Ravulizumab decreased corticosteroid use in patients with AChRAb+ gMG, suggesting a steroid-sparing role for ravulizumab.

Background: Blood loss quantification and management are important facets of cranial surgery, having been linked with adverse outcomes if management is inadequate. While many studies report estimated blood loss (EBL) as an outcome measure, inconsistencies exist in EBL quantification and management strategies Methods: A systematic review of cranial surgery literature on blood loss measurement and management was conducted according to PRISMA guidelines utilizing a novel software platform, Nested Knowledge Results: Initial search yielded 1029 non-duplicated. 107 full-text studies were included. 70% of studies were retrospective. Most common treatment conditions were 41% craniosynostosis (44/107) and 36% tumor (39/107). Most common EBL measurement methods were comparison of pre-operative and post-operative hemoglobin/hematocrit in 46.7% (50/107), anesthesia record in 26.2% (28/107), and surgeon estimation in 9.3% (10/107). 53.3% of studies did not specify a quantification methodology. Blood loss management strategies also varied, with transfusion being the most common method in 64.5% (69/107) of studies Conclusions: EBL quantification and blood loss management remain important clinical and research metrics. Despite this, significant heterogeneity exists in blood loss quantification and management strategies, with most studies providing no data on EBL quantification. Standardization of EBL quantification/reporting should be undertaken to improve comparability and consistency across studies.

Markwelchite, ideally TlPbSbS3, is a new mineral from the hydrothermal deposit of Jas Roux, Hautes-Alpes, France. It occurs as a black anhedral crystal associated closely with protochabournéite. Microhardness measurements (VHN15) gave a mean value of 197 kg/mm2 corresponding to a Mohs hardness of ~3–4. In plane-polarised incident light, markwelchite is grey in colour. Under crossed polars, it is distinctly anisotropic with greyish white to bluish rotation tints, with bright red internal reflections. Reflectance percentages (Rmin and Rmax) are: 28.5, 31.5 (471.1 nm); 28.3, 30.7 (548.3 nm); 27.9, 30.3 (586.6 nm); and 27.6, 29.8 (652.3 nm). The mean of 5 electron microprobe spot analyses gave Tl 34.67(45), Pb 31.86(25), Sb 15.06(15), As 2.37(5), S 15.35(20), total 99.31 wt.%, corresponding, on the basis of a total of 6 atoms per formula unit and structural results, to Tl1.063Pb0.964(Sb0.775As0.198)Σ0.973S3.000. Single-crystal X-ray diffraction studies revealed that markwelchite is isotypic with richardsollyite, TlPbAsS3. It is monoclinic, space group P21/c, with the following unit-cell parameters: a = 8.9144(3), b = 8.4513(3), c = 8.6511(3) Å, β = 108.723(4)°, V = 617.27(4) Å3 and Z = 4. The five strongest observed powder-diffraction lines [d in Å (Irel)(hkl)] are: 3.88 (100)($\bar{2}$11); 3.78 (90)(210); 3.29 (90)(102); 2.73 (85)($\bar{1}$13); and 2.93 (75)(022). The crystal structure can be described as formed by (100) [Me2(SbS3)]– layers sandwiching the Me1+ cations. The Me1 site has a seven-fold coordination, whereas the Me2 site has an 6+2 coordination corresponding to a distorted, bicapped trigonal prismatic coordination, and the Sb site displays a trigonal pyramidal coordination with three S atoms and Sb at the apex.

The name markwelchite honours Dr Mark D. Welch of the Natural History Museum, London, UK.

The new mineral has been approved by the Commission on New Minerals, Nomenclature and Classification of the International Mineralogical Association (IMA2024–001). A discussion on the relationships between markwelchite and synthetic TlPbSbS3 is also provided.

Background: Pilocytic astrocytoma and other circumscribed low-grade brain tumors can exhibit spontaneous enhancement changes despite stable size and clinical status. We aimed to describe this phenomenon in adults. Methods: We performed a retrospective review of our MRI database (2011-2021) to identify cases with enhancement changes in otherwise stable tumors. We searched for reports containing: “pilocytic”, “pilomyxoid”, “RGNT”, “rosette”, “glioneuronal”, “DNET”, and “dysembryoplastic”. Exclusion criteria included WHO grade 3/4 tumors, patients <19 years, equivocal diagnostic findings, and no serial MRIs. We reviewed 238 patients. Results: We identified 12 adult patients with the desired phenomenon: 6 pilocytic astrocytoma, 1 pilomyxoid astrocytoma, 2 rosette-forming glioneuronal tumor, 1 unverified low-grade glioma, and 2 cases without biopsy. Seven were untreated, while five were residual or recurrent tumors. Six showed a pattern of new/increasing and subsequent decreasing/disappearing enhancement over 1-4 years. One exhibited spontaneous regression of enhancement over 1 year. Five showed repeating cycles of increasing and decreasing enhancement over longer monitoring periods of 7-15 years, with mean duration of increasing enhancement prior to decline of 21.4 months (SD 5.9). Conclusions: Spontaneous contrast enhancement fluctuation in adult pilocytic astrocytoma and other circumscribed low-grade brain tumors can occur, and on its own should not be misconstrued as evidence of tumor progression/regression.

This study identified 26 late invasive primary surgical site infection (IP-SSI) within 4–12 months of transplantation among 2073 SOT recipients at Duke University Hospital over the period 2015–2019. Thoracic organ transplants accounted for 25 late IP-SSI. Surveillance for late IP-SSI should be maintained for at least one year following transplant.

Background: We recently identified four molecular subgroups of meningioma with distinct biology and outcomes. While two (MG3/MG4) are associated with poor outcome, they display divergent transcriptional profiles (enriched in metabolic and cell cycling pathways, respectively) and therapeutic vulnerabilities (MG3 has no clear treatment target). We sought to understand drivers of these key differences at a chromatin level. Methods: We profiled MG3/MG4 meningiomas for common histone marks H3K27me3, H3K27Ac, H3K4me1, H3K4me3, H3K9me3, and H3K36me3. Multiple computational approaches were used to compare MG3 and MG4 tumours including superenhancer ranking, differential binding analysis, and unsupervised clustering. Results: Our cohort includes 11-20 meningiomas per histone mark. Clustering revealed striking separation of subgroups based on multiple histone marks, particularly H3K36me3. FOXC1, a known driver of the epithelial to mesenchymal transition, was identified as a recurrent superenhancer in both groups, whereas MG3-specific superenhancers mapped to immune regulatory networks. Integrated differential binding analysis confirmed an immune-rich microenvironment in MG3 tumours driven by multiple histone marks, suggesting a role for targeting novel immune checkpoint genes CD84 and CD48. Conclusions: This study is the first to apply integrated analysis of multiple histone modifications to aggressive meningioma. We further characterize MG3 tumours by identifying an epigenetically-driven immune phenotype and propose novel treatment targets.

Background: study patients with PNES’ outcome after their diagnosis in the EMU. Methods: Comparative analyses were carried out on several variables before and after diagnosis: number of participants with daily PNES, number of visits to the emergency department, number of participants who took ASMs or psychotropic drugs, and employment status. Results: 61/103 patients (79% female) participated. The median age at PNES onset was 35 years. 62% were receiving ASMs and 40% psychotropic drugs. The mean stay at the EMU was five days. PNES diagnosis was explained to almost all patients (97%) by the end of their EMU stay and was well accepted by most (89%). When contacted, 46% of participants no longer had PNES; 32% mentioned that their PNES had ceased immediately upon communication of the diagnosis. Fewer patients had daily seizures after the diagnosis. Similarly, the median number of emergency department visits was significantly lower. Only 17 patients consulted their general practitioner and 20 a neurologist after a PNES attack. The use of ASMs was also significantly reduced from 70% to 33%, with only one still taking an ASM for its antiseizure properties. Conclusions: significant reductions in PNES frequency, health care utilization and ASM use.

We establish two-term spectral asymptotics for the operator of linear elasticity with mixed boundary conditions on a smooth compact Riemannian manifold of arbitrary dimension. We illustrate our results by explicit examples in dimension two and three, thus verifying our general formulae both analytically and numerically.

Background: Elevated BMI has been proposed as a risk factor for the development of meningioma. The relationship between body mass index (BMI) and disease control in high-grade meningioma has not yet been examined. A retrospective cohort study was performed to assess the relationship between high-grade meningioma recurrence and BMI. Methods: This is a retrospective cohort study of patients with Grade 2 or Grade 3 meningioma at a single tertiary care center between 2008 and 2017. We collected clinical data including age, sex, BMI, location, Simpson grade, brain invasion, and radiation treatments. Disease control was monitored on followup MRI scans. We stratified patients by BMI greater than or less than 25. Results: A total of 45 patients were included. Recurrence was observed in 15 patients (33.3%). There were 32 (71.1%) patients with BMI > 25, and 13 (28.9%) patients with normal BMI. Patients with elevated BMI had higher risk of recurrence (p=0.04). Multivariate analysis identified BMI as an independent predictor of recurrence. Conclusions: Our results suggest that overweight patients with a Grade 2 or Grade 3 meningioma are at higher risk of recurrence than patients with normal BMI. The explanation for this association unknown. Further research is suggested to confirm and better characterize this association.

Background: Managing unruptured cerebral aneurysms involves monitoring or repair, with complex factors influencing decision-making. Geographical distance from treatment centers is an understudied factor. This study explores a potential relationship in Nova Scotia between proximity to the sole neurosurgical center in Halifax and aneurysm management. Methods: A prospectively collected neurosurgery database was used to identify all adults seen for unruptured cerebral aneurysm between Jan 1, 2015 - Dec 31, 2020. Demographic data, aneurysm characteristics, follow-up and treatment information were collected. Univariate and multivariate analyses assessed management differences based on geography, controlling for relevant factors including aneurysm size and location. Results: Among 390 patients, 40% were in Halifax, and 60% were outside. No significant difference existed in elective repair (34% vs. 26%, p=0.143) and imaging follow-up frequency (2.26 vs. 2.22, p=0.858). In-person follow-up was higher within Halifax (1.83 vs. 1.43, p=0.008), while virtual follow-up was significant outside Halifax (1.44 vs. 1.01, p=0.003). Overall, in-person and elective repair frequencies declined with the COVID-19 peak, whereas virtual follow-up increased. Conclusions: No significant association was found between patient location and repair decisions. Patients in closer proximity had more in-person follow-ups, while those farther away had more virtual follow-ups. The COVID-19 pandemic affected follow-up frequencies universally.

Background: We evaluated vorasidenib (VOR), a dual inhibitor of mIDH1/2, in patients with mIDH1/2 glioma (Phase 3; NCT04164901). Methods: Patients with residual/recurrent grade 2 mIDH1/2 oligodendroglioma or astrocytoma were enrolled (age ≥12; Karnofsky Performance Score ≥80; measurable non-enhancing disease; surgery as only prior treatment; not in immediate need of chemoradiotherapy). Patients were stratified by 1p19q status and baseline tumor size and randomized 1:1 to VOR 40 mg or placebo (PBO) daily in 28-day cycles. Endpoints included imaging-based progression-free survival (PFS), time to next intervention (TTNI), tumor growth rate (TGR), health-related quality of life (HRQoL), neurocognition and seizure activity. Results: 331 patients were randomized (VOR, 168; PBO, 163). The median age was 40.0 years. 172 and 159 patients had histologically confirmed oligodendroglioma and astrocytoma, respectively. Treatment with VOR significantly improved PFS and TTNI. Median PFS: VOR, 27.7 mos; PBO, 11.1 mos (P=0.000000067). Median TTNI: VOR, not reached; PBO, 17.8 mos (P=0.000000019). Treatment with VOR resulted in shrinkage of tumor volume. Post-treatment TGR: VOR, -2.5% (95% CI: -4.7, -0.2); PBO, 13.9% (95% CI: 11.1, 16.8). HRQoL and neurocognition were preserved and seizure control was maintained. VOR had a manageable safety profile. Conclusions: VOR was effective in mIDH1/2 diffuse glioma not in immediate need of chemoradiotherapy.

Background: Cortical myoclonus originates at cerebral cortex, predominantly occurring on voluntary movements. Few case reports described usage of Acetazolamide (ACZ) for myoclonus. Methods: Chart review of 2 patients was performed. Literature review was conducted on myoclonus and ACZ using Pubmed. Results: 22-year-old female was diagnosed with Progressive Myoclonic Epilepsy (PME) secondary to a KCNC1 mutation. Her symptoms started at 10 years old with bilateral tonic clonic seizures (BTCS), later developing progressive ataxia and myoclonus, involving face and limbs, which worsened with stimulus and menses. Medications included Perampanel, Clonazepam and Levetiracetam, however myoclonus was still limiting. At the age of 19, ACZ 250 mg BID was started for 2 weeks around her menses. Follow up revealed significant improvement of myoclonus, resulting in better ambulation, balance and speech, sustained 2.5 years after. 67-year-old male presented BTCS at the age of 53 along with cortical myoclonus, dementia and ataxia, leading to diagnosis of PME with a mutation on IRF2BPL. Improvement of myoclonus occurred with ACZ 250 mg BID biweekly, although balance and cognition still deteriorated. Conclusions: Previous literature outlines 4 cases of action myoclonus that responded to ACZ. We believe that ACZ should be considered to treat myoclonus, especially in cases with cortical involvement and hormonal fluctuations.

Background: Radiofrequency ablation (RFA) is a minimally-invasive procedure that has been used to treat temporal lobe epilepsy (TLE), however its long-term efficacy is unknown. We aim to characterize the long-term outcomes of patients from the original series by Parrent and Blume (1999). Methods: Consecutive patients who underwent stereotactic RFA for TLE were retrospectively reviewed. Demographics, procedural details, and seizure outcomes until last follow-up were abstracted. Seizure-freedom after initial RFA treatment was estimated with Kaplan-Meier analysis. Results: 27 patients underwent RFA from 1994 to 2002. There were 14 female (52%) patients. 24 (89%) had mesial temporal sclerosis. Mean age at time of RFA was 33.1 years (range 12-45 years). 17 (63%) patients underwent left-sided RFA. 15 (56%) patients had further interventions: 4 (15%) underwent only repeat RFA, 1 (4%) had repeat RFA and anterior temporal lobectomy (ATL), and 10 (37%) underwent subsequent ATL only. Mean follow-up was 9.0 years (range 0.5-22.7 years). At last follow-up, 16 (59%) patients were seizure-free: 5 (19%) received one RFA treatment and 11 (41%) underwent additional procedures. Conclusions: Based on the original series describing the technique, stereotactic RFA for TLE is a safe, minimally-invasive procedure. The role of stereotactic RFA in the treatment of TLE remains to be determined.

Background: The drivers that activate endogenous ependymal-derived neural stem/progenitor cells (epNSPCs) remain unknown. Understanding the mechanisms that govern the biology of these cells is critical in developing a therapeutic strategy to harness their regenerative potential after injury. Methods: FoxJ1-CreER-tdTomato reporter mice were used for epNSPC lineage tracing. A conditional genetic knock-out mouse line of glutamate-subtype AMPA receptor (AMPAR) subunits in epNSPCs was generated. Electrophysiological properties were assessed using single cell patch clamp and slice culture recordings. For in vivo studies, mice underwent cervical SCI. To examine the effect of positive modulation of AMPARs, mice received the ampakine CX546 or vehicle and underwent electrophysiological testing, behavioural assessment and spinal cord extraction. Results: Glutamate excitotoxicity, a hallmark in the pathogenesis of acute SCI, drives epNSPCs activation via AMPARs. Genetic knock-out of AMPARs in epNSPCs inhibits their activation following SCI. Positive pharmacological modulation of AMPARs after SCI enhances the migration and differentiation of epNSPCs, increases neuronal sparing and improves long-term locomotor/forelimb function. SCI decreases the excitability of corticospinal tract projections, which is improved with positive AMPAR modulation. Conclusions: Glutamatergic signaling via AMPARs is an important mediator of epNSPC activation after injury. Pharmacological targeting of this mechanism can be used to enhance endogenous regeneration and improve recovery post-SCI.

Background: Migraine affects more than 1 billion people, with attacks triggered by a variety of factors. Knowledge of environmental triggers for migraine attacks is limited, and has mostly been studied via emergency room (ER) visits. There are significant barriers and delays for attending ER for migraine treatment, which create challenges for estimating causal links to environmental exposures. We assessed whether smartphone app records may have fewer barriers and reduced lags. Methods: American and Canadian participants completed an online survey about their migraine attacks, smartphone app use, and ER visits. Results: Among 308 participants, barriers to visiting ER were similar in both countries, except for financial concerns in the US. About half of participants who attended ER also recorded the attack in a diary or app. Whereas migraine patients often present to ER 7+ days after onset, records in a smartphone app dataset were created within 2 days of onset. Conclusions: Although not all severe migraine attacks are recorded by smartphone users, smartphone app records may have fewer barriers to creation and shorter time lags compared to ER visit records, making them a rich source of data for research on transient neurologic health outcomes and environmental exposures.

Background: Late onset Pompe disease (LOPD), rare autosomal recessive lysosomal storage disease, resulting from mutation in alpha glucosidase enzyme (GAA) can present even in 6th decade of life. Slowly progressive, subtle, limb girdle pattern of weakness (LGPW), with auxiliary features such as ptosis, enlarged tongue, axial rigidity, facial diplegia, variable degree of respiratory weakness is not uncommon. Hypertrophic and electrical cardiac abnormalities are well described in LOPD. Methods: We present a case of 67-year-old male presenting with proximal weakness, subtle ptosis, bilateral quadriceps and shoulder girdle atrophy, and left toe numbness. PMHx: CABG, NSTEMI. Statin use. FMHx: noncontributory. Results: EMG: L5 radiculopathy, with unexpected myopathic units in hip/pelvic/ shoulder girdle muscles with active denervation and muscle irritability. CK, CRP, SPEP, ANA, LFTs, HMG-CoA reductase: normal. GAA enzymatic activity=0.96µmol/L/hr (low), genetics: pathogenic variants in GAA gene: c.-32-13T>G and c.1194+3G>C. ECHO: severe diastolic dysfunction, restrictive left ventricular filling. PFTs: normal. Diagnosed with LOPD, started on therapy. Conclusions: LOPD remains a differential for LGPW especially in older patient population with history of cardiopulmonary features. Age-appropriate conconminant pathologies may confound the diagnostic process.Symptoms may preceed diagnosis for years.GAA enzymatic activity followed by genetic testing remains readily available and can confirm diagnosis, preventing delay of approved therapy.

Background: Continuous spike and waves during slow-wave sleep (CSWS) is a childhood-onset epileptic encephalopathy that is characterized by clinical seizures, electrical status epilepticus during sleep (ESES), and neurocognitive regression. Early intervention can preserve neurocognitive development, and vagus nerve stimulator (VNS) therapy had positive outcomes in the few previously reported case reports. We present three patients with intractable CSWS unresponsive to medications, who had a positive response to VNS therapy. Methods: Review of clinical records of three pediatric patients diagnosed with CSWS were compared for selected clinical outcomes and electrographic data both prior to and in the years following the initiation of VNS therapy. Results: Three patients now aged 13, 16 and 20 years, were treated with VNS following intolerance and a lack of response to multiple medications (5-9) for CSWS. The ketogenic diet was not an option. The CSWS resolved in all three patients, resulting in improved cognitive function. Patient 3 had resurgence of CSWS on EEG when the VNS settings inadvertently reset to the factory settings and improved with adjustment in the cycling. Conclusions: In patients who are unresponsive to medication, VNS provides an alternative option for resolving CSWS to preserve and, in some cases, potentially restore neurocognitive function.

Background: Currently there are no disease modifying treatment for Synucleinopathies including Parkinson’s disease Dementia (PDD). Carrying a mutation in the GBA gene (beta-glucocerebrosidase/ GCAse) is a leading risk factor for synucleinopathies. Raising activity GCAse lowers α-synuclein levels in cells and animal models. Ambroxol is a pharmacological chaperone for GCAse and can raise GCAse levels. Our goal is to test Ambroxol as a disease-modifying treatment in PDD. Methods: We randomized fifty-five individuals with PDD to Ambroxol 1050mg/day, 525mg/day, or placebo for 52 weeks. Primary outcome measures included safety, Alzheimer’s disease Assessment Scale-cognitive (ADAS-Cog) subscale and the Clinician’s Global Impression of Change (CGIC). Secondary outcomes included pharmacokinetics, cognitive and motor outcomes and and plasma and CSF biomarkers. Results: Ambroxol was well tolerated. There were 7 serious adverse events (SAEs) none deemed related to Ambroxol. GCase activity was increased in white blood cells by ~1.5 fold. There were no differences between groups on primary outcome measures. Patients receiving high dose Ambroxol appeared better on the Neuropsychiatric Inventory. GBA carriers appeared to improve on some cognitive tests. pTau 181 was reduced in CSF. Conclusions: Ambroxol was safe and well-tolerated in PDD. Ambroxol may improve biomarkers and cognitive outcomes in GBA1 mutation carrie.rs Ambroxol improved some biomarkerss. ClinicalTrials.gov NCT02914366

Background: There is an absence of studies evaluating longitudinal quality of life (QoL) amongst vestibular schwannomas (VS) with matched tumor and patient characteristics between treatment groups. We present novel findings of 12 yearlong follow-up of patient QoL and symptomatology outcomes in this matched cohort study. Methods: Symptomatology and 36-Item Short Form Health Survey (SF36) between 2000-2017 in VS patients managed at a single tertiary centre was conducted. Radiation (R) and active surveillance (A) groups were matched for tumor size and age against the surgery (S) group. Results: 14 A patients, 24 R patients, 49 S patients met matching and inclusion criteria. Mean age, tumor diameter and follow up was 69.1 years, 21.6mm and 12.0 years respectively. Mental component summary (MCS) scores deteriorated significantly in the radiation group (3.1 S, 3.7 A, -3.5 R, p-value 0.008). Physical component summary scores remained stable at follow up (-0.2 S, 0.00 S, -4.0 R, p-value 0.227). Various symptoms resolved statistically in surgery goup, whereas tinnitus on follow up was higher with radiation (40.8% S, 66.7% R, p-value 0.038). Conclusions: Surgery group demonstrated improvements in long term QoL with good symptom resolution, whilst radiation group demonstrated small but significant deterioration over time.