MerTK is a mediator of alpha-synuclein fibril uptake by human microglia.

Mer tyrosine kinase (MerTK) is a receptor tyrosine kinase that mediates non-inflammatory, homeostatic phagocytosis of diverse types of cellular debris. Highly expressed on the surface of microglial cells, MerTK is of importance in brain development, homeostasis, plasticity and disease. Yet, involvement of this receptor in the clearance of protein aggregates that accumulate with ageing and in neurodegenerative diseases has yet to be defined. The current study explored the function of MerTK in the microglial uptake of alpha-synuclein fibrils which play a causative role in the pathobiology of synucleinopathies. Using human primary and induced pluripotent stem cell-derived microglia, the MerTK-dependence of alpha-synuclein fibril internalization was investigated in vitro. Relevance of this pathway in synucleinopathies was assessed through burden analysis of MERTK variants and analysis of MerTK expression in patient-derived cells and tissues. Pharmacological inhibition of MerTK and siRNA-mediated MERTK knockdown both caused a decreased rate of alpha-synuclein fibril internalization by human microglia. Consistent with the non-inflammatory nature of MerTK-mediated phagocytosis, alpha-synuclein fibril internalization was not observed to induce secretion of pro-inflammatory cytokines such as IL-6 or TNF, and downmodulated IL-1ß secretion from microglia. Burden analysis in two independent patient cohorts revealed a significant association between rare functionally deleterious MERTK variants and Parkinson's disease in one of the cohorts (P = 0.002). Despite a small upregulation in MERTK mRNA expression in nigral microglia from Parkinson's disease/Lewy body dementia patients compared to those from non-neurological control donors in a single-nuclei RNA-sequencing dataset (P = 5.08 × 10-21), no significant upregulation in MerTK protein expression was observed in human cortex and substantia nigra lysates from Lewy body dementia patients compared to controls. Taken together, our findings define a novel role for MerTK in mediating the uptake of alpha-synuclein fibrils by human microglia, with possible involvement in limiting alpha-synuclein spread in synucleinopathies such as Parkinson's disease. Upregulation of this pathway in synucleinopathies could have therapeutic values in enhancing alpha-synuclein fibril clearance in the brain.

Development of an online calculator for the prediction of seizure freedom following pediatric hemispherectomy using the Hemispherectomy Outcome Prediction Scale (HOPS).

OBJECTIVES: Although hemispheric surgeries are among the most effective procedures for drug-resistant epilepsy (DRE) in the pediatric population, there is a large variability in seizure outcomes at the group level. A recently developed HOPS score provides individualized estimation of likelihood of seizure freedom to complement clinical judgement. The objective of this study was to develop a freely accessible online calculator that accurately predicts the probability of seizure freedom for any patient at 1-, 2-, and 5-years post-hemispherectomy. METHODS: Retrospective data of all pediatric patients with DRE and seizure outcome data from the original Hemispherectomy Outcome Prediction Scale (HOPS) study were included. The primary outcome of interest was time-to-seizure recurrence. A multivariate Cox proportional-hazards regression model was developed to predict the likelihood of post-hemispheric surgery seizure freedom at three time points (1-, 2- and 5- years) based on a combination of variables identified by clinical judgment and inferential statistics predictive of the primary outcome. The final model from this study was encoded in a publicly accessible online calculator on the International Network for Epilepsy Surgery and Treatment (iNEST) website (https://hops-calculator.com/). RESULTS: The selected variables for inclusion in the final model included the five original HOPS variables (age at seizure onset, etiologic substrate, seizure semiology, prior non-hemispheric resective surgery, and contralateral fluorodeoxyglucose-positron emission tomography [FDG-PET] hypometabolism) and three additional variables (age at surgery, history of infantile spasms, and magnetic resonance imaging [MRI] lesion). Predictors of shorter time-to-seizure recurrence included younger age at seizure onset, prior resective surgery, generalized seizure semiology, FDG-PET hypometabolism contralateral to the side of surgery, contralateral MRI lesion, non-lesional MRI, non-stroke etiologies, and a history of infantile spasms. The area under the curve (AUC) of the final model was 73.0%. SIGNIFICANCE: Online calculators are useful, cost-free tools that can assist physicians in risk estimation and inform joint decision-making processes with patients and families, potentially leading to greater satisfaction. Although the HOPS data was validated in the original analysis, the authors encourage external validation of this new calculator.

Systematic comparison of culture media uncovers phenotypic shift of primary human microglia defined by reduced reliance to CSF1R signaling.

Efforts to understand microglia function in health and diseases have been hindered by the lack of culture models that recapitulate in situ cellular properties. In recent years, the use of serum-free media with brain-derived growth factors (colony stimulating factor 1 receptor [CSF1R] ligands and TGF-ß1/2) have been favored for the maintenance of rodent microglia as they promote morphological features observed in situ. Here we study the functional and transcriptomic impacts of such media on human microglia (hMGL). Media formulation had little impact on microglia transcriptome assessed by RNA sequencing which was sufficient to significantly alter microglia capacity to phagocytose myelin debris and to elicit an inflammatory response to lipopolysaccharide. When compared to immediately ex vivo microglia from the same donors, the addition of fetal bovine serum to culture media, but not growth factors, was found to aid in the maintenance of key signature genes including those involved in phagocytic processes. A phenotypic shift characterized by CSF1R downregulation in culture correlated with a lack of reliance on CSF1R signaling for survival. Consequently, no improvement in cell survival was observed following culture supplementation with CSF1R ligands. Our study provides better understanding of hMGL in culture, with observations that diverge from those previously made in rodent microglia.

Analysis of the microglia transcriptome across the human lifespan using single cell RNA sequencing.

BACKGROUND: Microglia are tissue resident macrophages with a wide range of critically important functions in central nervous system development and homeostasis. METHOD: In this study, we aimed to characterize the transcriptional landscape of ex vivo human microglia across different developmental ages using cells derived from pre-natal, pediatric, adolescent, and adult brain samples. We further confirmed our transcriptional observations using ELISA and RNAscope. RESULTS: We showed that pre-natal microglia have a distinct transcriptional and regulatory signature relative to their post-natal counterparts that includes an upregulation of phagocytic pathways. We confirmed upregulation of CD36, a positive regulator of phagocytosis, in pre-natal samples compared to adult samples in situ. Moreover, we showed adult microglia have more pro-inflammatory signature compared to microglia from other developmental ages. We indicated that adult microglia are more immune responsive by secreting increased levels of pro-inflammatory cytokines in response to LPS treatment compared to the pre-natal microglia. We further validated in situ up-regulation of IL18 and CXCR4 in human adult brain section compared to the pre-natal brain section. Finally, trajectory analysis indicated that the transcriptional signatures adopted by microglia throughout development are in response to a changing brain microenvironment and do not reflect predetermined developmental states. CONCLUSION: In all, this study provides unique insight into the development of human microglia and a useful reference for understanding microglial contribution to developmental and age-related human disease.

Human Oligodendrocyte Myelination Potential; Relation to Age and Differentiation.

OBJECTIVE: Myelin regeneration in the human central nervous system relies on progenitor cells within the tissue parenchyma, with possible contribution from previously myelinating oligodendrocytes (OLs). In multiple sclerosis, a demyelinating disorder, variables affecting remyelination efficiency include age, severity of initial injury, and progenitor cell properties. Our aim was to investigate the effects of age and differentiation on the myelination potential of human OL lineage cells. METHODS: We derived viable primary OL lineage cells from surgical resections of pediatric and adult brain tissue. Ensheathment capacity using nanofiber assays and transcriptomic profiles from RNA sequencing were compared between A2B5+ antibody-selected progenitors and mature OLs (non-selected cells). RESULTS: We demonstrate that pediatric progenitor and mature cells ensheathed nanofibers more robustly than did adult progenitor and mature cells, respectively. Within both age groups, the percentage of fibers ensheathed and ensheathment length per fiber were greater for A2B5+ progenitors. Gene expression of OL progenitor markers PDGFRA and PTPRZ1 were higher in A2B5+ versus A2B5- cells and in pediatric A2B5+ versus adult A2B5+ cells. The p38 MAP kinases and actin cytoskeleton-associated pathways were upregulated in pediatric cells; both have been shown to regulate OL process outgrowth. Significant upregulation of "cell senescence" genes was detected in pediatric samples; this could reflect their role in development and the increased susceptibility of pediatric OLs to activating cell death responses to stress. INTERPRETATION: Our findings identify specific biological pathways relevant to myelination that are differentially enriched in human pediatric and adult OL lineage cells and suggest potential targets for remyelination enhancing therapies. ANN NEUROL 2022;91:178-191.

Clinical utility of intraoperative electrocorticography for epilepsy surgery: A systematic review and meta-analysis.

Despite the widespread use of intraoperative electrocorticography (iECoG) during resective epilepsy surgery, there are conflicting data on its overall efficacy and inability to predict benefit per pathology. Given the heterogeneity of iECoG use in resective epilepsy surgery, it is important to assess the utility of interictal-based iECoG. This individual patient data (IPD) meta-analysis seeks to identify the benefit of iECoG during resective epilepsy surgery in achieving seizure freedom for various pathologies. Embase, Scopus, and PubMed were searched from inception to January 31, 2021 using the following terms: "ecog", "electrocorticography", and "epilepsy". Articles were included if they reported seizure freedom at ≥12-month follow-up in cohorts with and without iECoG for epilepsy surgery. Non-English articles, noncomparative iECoG cohorts, and studies with <10% iECoG use were excluded. This meta-analysis followed the PRISMA 2020 guidelines. The primary outcome was seizure freedom at last follow-up and time to seizure recurrence, if applicable. Forest plots with random effects modeling assessed the relationship between iECoG use and seizure freedom. Cox regression of IPD was performed to identify predictors of longer duration of seizure freedom. Kaplan-Meier curves with log-rank test were created to visualize differences in time to seizure recurrence. Of 7504 articles identified, 18 were included for study-level analysis. iECoG was not associated with higher seizure freedom at the study level (relative risk = 1.09, 95% confidence interval [CI] = 0.96-1.23, p = .19, I2  = 64%), but on IPD (n = 7 studies, 231 patients) iECoG use was independently associated with more favorable seizure outcomes (hazard ratio = 0.47, 95% CI = .23-.95, p = .037). In Kaplan-Meier analysis of specific pathologies, iECoG use was significantly associated with longer seizure freedom only for focal cortical dysplasia (FCD; p < .001) etiology. Number needed to treat for iECoG was 8.8, and for iECoG in FCD it was 4.7. We show iECoG seizure freedom is not achieved uniformly across centers. iECoG is particularly beneficial for FCD etiology in improving seizure freedom.

Spontaneous resolution of post-hemorrhagic ventricular dilatation in preterm newborns and neurodevelopment.

BACKGROUND: We investigated the temporal evolution of post-hemorrhagic ventricular dilatation (PHVD) and compared neurodevelopmental impairments (NDI) in newborns with (Group 1) spontaneous resolution of PHVD, (Group 2) persistent PHVD without neurosurgical intervention, and (Group 3) progressive PHVD receiving neurosurgical intervention. METHODS: A multicenter retrospective cohort study of newborns born at ≤34 weeks with PHVD (ventricular index [VI] >97th centile for gestational age and anterior horn width [AHW] >6 mm) from 2012 to 2020. Severe NDI was defined as global developmental delay or cerebral palsy GMFCS III-V at 18 months. RESULTS: Of 88 survivors with PHVD, 39% had a spontaneous resolution, 17% had persistent PHVD without intervention, and 44% had progressive PHVD receiving intervention. The median time between PHVD diagnosis and spontaneous resolution was 14.0 days (IQR 6.8-32.3) and between PHVD diagnosis and first neurosurgical intervention was 12.0 days (IQR 7.0-22.0). Group 1 had smaller median maximal VI (1.8, 3.4, 11.1 mm above p97; p < 0.001) and AHW (7.2, 10.8, 20.3 mm; p < 0.001) than Groups 2 and 3. Neurodevelopmental outcome data were available for 82% of survivors. Group 1 had reduced severe NDI compared to Group 3 (15% vs 66%; p < 0.001). CONCLUSION: Newborns with PHVD without spontaneous resolution are at higher risk for impairments despite neurosurgical interventions, which may be due to larger ventricular dilatation. IMPACT: The natural evolution of post-hemorrhagic ventricular dilatation (PHVD) and developmental implications of spontaneous resolution are not well established. In this study, approximately one in three newborns with PHVD experienced spontaneous resolution and this subset of newborns had reduced rates of neurodevelopmental impairments. More prominent ventricular dilatation was associated with reduced rates of spontaneous resolution and increased rates of severe neurodevelopmental impairment among newborns with PHVD. Understanding clinically relevant time points in the evolution of PHVD and predictors of spontaneous resolution may help inform the discussion around the optimal timing for intervention and allow for more precise prognostication in this population.

Diverse injury responses of human oligodendrocyte to mediators implicated in multiple sclerosis.

Early multiple sclerosis lesions feature relative preservation of oligodendrocyte cell bodies with dying back retraction of their myelinating processes. Cell loss occurs with disease progression. Putative injury mediators include metabolic stress (low glucose/nutrient), pro-inflammatory mediators (interferon γ and tumour necrosis factor α), and excitotoxins (glutamate). Our objective was to compare the impact of these disease relevant mediators on the injury responses of human mature oligodendrocytes. In the current study, we determined the effects of these mediators on process extension and survival of human brain derived mature oligodendrocytes in vitro and used bulk RNA sequencing to identify distinct effector mechanisms that underlie the responses. All mediators induced significant process retraction of the oligodendrocytes in dissociated cell culture. Only metabolic stress (low glucose/nutrient) conditions resulted in delayed (4-6 days) non-apoptotic cell death. Metabolic effects were associated with induction of the integrated stress response, which can be protective or contribute to cell injury dependent on its level and duration of activation. Addition of Sephin1, an agonist of the integrated stress response induced process retraction under control conditions and further enhanced retraction under metabolic stress conditions. The antagonist ISRIB restored process outgrowth under stress conditions, and if added to already stressed cells, reduced delayed cell death and prolonged the period in which recovery could occur. Inflammatory cytokine functional effects were associated with activation of multiple signalling pathways (including Jak/Stat-1) that regulate process outgrowth, without integrated stress response induction. Glutamate application produced limited transcriptional changes suggesting a contribution of effects directly on cell processes. Our comparative studies indicate the need to consider both the specific injury mediators and the distinct cellular mechanisms of responses to them by human oligodendrocytes to identify effective neuroprotective therapies for multiple sclerosis.

Delayed recovery from severe refractory intracranial hypertension due to expansion of skin and pericranium stretch after decompressive craniectomy.

PURPOSE: Decompressive craniectomy immediately reduces intracranial pressure by increasing space to accommodate brain volumes. Any delay in reduction of pressure and signs of severe intracranial hypertension requires explanation. CLINICAL FEATURES: We present the case of a 13-yr-old boy presenting with a ruptured arteriovenous malformation resulting in a massive occipito-parietal hematoma and increased intracranial pressure (ICP) refractory to medical management. This patient ultimately underwent a decompressive craniectomy (DC) for alleviation of increased ICP, despite which the patient's hemorrhage continued to worsen to the point of brainstem areflexia suggestive of possible progression to brain death. Within hours of the decompressive craniectomy, the patient displayed a relatively sudden, marked improvement in clinical status, most notably a return in pupillary reactivity and significant decrease in measured ICP. A review of postoperative images after the decompressive craniectomy suggested increases in brain volume that continued beyond the initial postoperative period. CONCLUSION: We urge caution to be taken in the interpretation of the neurologic examination and measured ICP in the context of a decompressive craniectomy. In the patient described in this Case Report, we propose that ongoing expansion of brain volume following a decompressive craniectomy beyond the initial postoperative period, possibly secondary to the stretch of skin or pericranium (used as a dural substitute for expansile duraplasty), can explain further clinical improvements beyond the initial postoperative period. We call for routine serial analyses of brain volumes after decompressive craniectomy to confirm these findings.

RéSUMé: OBJECTIF: La craniectomie décompressive réduit instantanément la pression intracrânienne en augmentant l'espace pour accueillir le volume du cerveau. Tout retard dans la réduction de la pression et tout signe d'hypertension intracrânienne sévère nécessitent une explication. CARACTéRISTIQUES CLINIQUES: Nous décrivons le cas d'un garçon de 13 ans présentant une malformation artérioveineuse rompue entraînant un hématome occipito-pariétal massif et une augmentation de la pression intracrânienne (PIC) réfractaire à une prise en charge médicale. Ce patient a finalement subi une craniectomie décompressive (CD) pour soulager l'augmentation de la PIC, malgré laquelle l'hémorragie du patient a continué à s'aggraver au point d'entraîner une aréflexie du tronc cérébral, suggérant une progression possible vers la mort cérébrale. Quelques heures après la craniectomie décompressive, le patient a présenté une amélioration relativement soudaine et marquée de son état clinique, notamment un retour de la réactivité pupillaire et une diminution significative de la PIC mesurée. Un examen des images postopératoires après la craniectomie décompressive a suggéré une augmentation du volume cérébral qui s'est poursuivie au-delà de la période postopératoire initiale. CONCLUSION: Nous recommandons de faire preuve de prudence dans l'interprétation de l'examen neurologique et de la PIC mesurée dans le contexte d'une craniectomie décompressive. Chez le patient décrit dans cette présentation de cas, nous proposons que l'expansion continue du volume cérébral suite à une craniectomie décompressive au-delà de la période postopératoire initiale, éventuellement secondaire à l'étirement de la peau ou du péricrâne (utilisé comme substitut dural à la duroplastie d'explansion), peut expliquer d'autres améliorations cliniques au-delà de la période postopératoire initiale. Nous recommandons des analyses de routine en série du volume cérébral après une craniectomie décompressive pour confirmer ces résultats.

Regional and age-related diversity of human mature oligodendrocytes.

Morphological and emerging molecular studies have provided evidence for heterogeneity within the oligodendrocyte population. To address the regional and age-related heterogeneity of human mature oligodendrocytes (MOLs) we applied single-cell RNA sequencing to cells isolated from cortical/subcortical, subventricular zone brain tissue samples, and thoracolumbar spinal cord samples. Unsupervised clustering of cells identified transcriptionally distinct MOL subpopulations across regions. Spinal cord MOLs, but not microglia, exhibited cell-type-specific upregulation of immune-related markers compared to the other adult regions. SVZ MOLs showed an upregulation of select number of development-linked transcription factors compared to other regions; however, pseudotime trajectory analyses did not identify a global developmental difference. Age-related analysis of cortical/subcortical samples indicated that pediatric MOLs, especially from under age 5, retain higher expression of genes linked to development and to immune activity with pseudotime analysis favoring a distinct developmental stage. Our regional and age-related studies indicate heterogeneity of MOL populations in the human CNS that may reflect developmental and environmental influences.

Correcting for physiological ripples improves epileptic focus identification and outcome prediction.

OBJECTIVE: The integration of high-frequency oscillations (HFOs; ripples [80-250 Hz], fast ripples [250-500 Hz]) in epilepsy evaluation is hampered by physiological HFOs, which cannot be reliably differentiated from pathological HFOs. We evaluated whether defining abnormal HFO rates by statistical comparison to region-specific physiological HFO rates observed in the healthy brain improves identification of the epileptic focus and surgical outcome prediction. METHODS: We detected HFOs in 151 consecutive patients who underwent stereo-electroencephalography and subsequent resective epilepsy surgery at two tertiary epilepsy centers. We compared how HFOs identified the resection cavity and predicted seizure-free outcome using two thresholds from the literature (HFO rate > 1/min; 50% of the total number of a patient's HFOs) and three thresholds based on normative rates from the Montreal Neurological Institute Open iEEG Atlas (https://mni-open-ieegatlas. RESEARCH: mcgill.ca/): global Atlas threshold, regional Atlas threshold, and regional + 10% threshold after regional Atlas correction. RESULTS: Using ripples, the regional + 10% threshold performed best for focus identification (77.3% accuracy, 27% sensitivity, 97.1% specificity, 80.6% positive predictive value [PPV], 78.2% negative predictive value [NPV]) and outcome prediction (69.5% accuracy, 58.6% sensitivity, 76.3% specificity, 60.7% PPV, 74.7% NPV). This was an improvement for focus identification (+1.1% accuracy, +17.0% PPV; p < .001) and outcome prediction (+12.0% sensitivity, +1.0% PPV; p = .05) compared to the 50% threshold. The improvement was particularly marked for foci in cortex, where physiological ripples are frequent (outcome: +35.3% sensitivity, +5.3% PPV; p = .014). In these cases, the regional + 10% threshold outperformed fast ripple rate > 1/min (+3.6% accuracy, +26.5% sensitivity, +21.6% PPV; p < .001) and seizure onset zone (+13.5% accuracy, +29.4% sensitivity, +17.0% PPV; p < .05-.01) for outcome prediction. Normalization did not improve the performance of fast ripples. SIGNIFICANCE: Defining abnormal HFO rates by statistical comparison to rates in healthy tissue overcomes an important weakness in the clinical use of ripples. It improves focus identification and outcome prediction compared to standard HFO measures, increasing their clinical applicability.

Inhibition of nuclear export restores nuclear localization and residual tumor suppressor function of truncated SMARCB1/INI1 protein in a molecular subset of atypical teratoid/rhabdoid tumors.

Loss of nuclear SMARCB1 (INI1/hSNF5/BAF47) protein expression due to biallelic mutations of the SMARCB1 tumor suppressor gene is a hallmark of atypical teratoid/rhabdoid tumors (ATRT), but the presence of cytoplasmic SMARCB1 protein in these tumors has not yet been described. In a series of 102 primary ATRT, distinct cytoplasmic SMARCB1 staining on immunohistochemistry was encountered in 19 cases (19%) and was highly over-represented in cases showing pathogenic sequence variants leading to truncation or mutation of the C-terminal part of SMARCB1 (15/19 vs. 4/83; Chi-square: 56.04, p = 1.0E-10) and, related to this, in tumors of the molecular subgroup ATRT-TYR (16/36 vs. 3/66; Chi-square: 24.47, p = 7.6E-7). Previous reports have indicated that while SMARCB1 lacks a bona fide nuclear localization signal, it harbors a masked nuclear export signal (NES) and that truncation of the C-terminal region results in unmasking of this NES leading to cytoplasmic localization. To determine if cytoplasmic localization found in ATRT is due to unmasking of NES, we generated GFP fusions of one of the SMARCB1 truncating mutations (p.Q318X) found in the tumors along with a p.L266A mutation, which was shown to disrupt the interaction of SMARCB1-NES with exportin-1. We found that while the GFP-SMARCB1(Q318X) mutant localized to the cytoplasm, the double mutant GFP-SMARCB1(Q318X;L266A) localized to the nucleus, confirming NES requirement for cytoplasmic localization. Furthermore, cytoplasmic SMARCB1(Q318X) was unable to cause senescence as determined by morphological observations and by senescence-associated ß-galactosidase assay, while nuclear SMARCB1(Q318X;L266A) mutant regained this function. Selinexor, a selective exportin-1 inhibitor, was effective in inhibiting the nuclear export of SMARCB1(Q318X) and caused rapid cell death in rhabdoid tumor cells. In conclusion, inhibition of nuclear export restores nuclear localization and residual tumor suppressor function of truncated SMARCB1. Therapies aimed at preventing nuclear export of mutant SMARCB1 protein may represent a promising targeted therapy in ATRT harboring truncating C-terminal SMARCB1 mutations.

Comparison of the real-world effectiveness of vertical versus lateral functional hemispherotomy techniques for pediatric drug-resistant epilepsy: A post hoc analysis of the HOPS study.

OBJECTIVE: This study was undertaken to determine whether the vertical parasagittal approach or the lateral peri-insular/peri-Sylvian approach to hemispheric surgery is the superior technique in achieving long-term seizure freedom. METHODS: We conducted a post hoc subgroup analysis of the HOPS (Hemispheric Surgery Outcome Prediction Scale) study, an international, multicenter, retrospective cohort study that identified predictors of seizure freedom through logistic regression modeling. Only patients undergoing vertical parasagittal, lateral peri-insular/peri-Sylvian, or lateral trans-Sylvian hemispherotomy were included in this post hoc analysis. Differences in seizure freedom rates were assessed using a time-to-event method and calculated using the Kaplan-Meier survival method. RESULTS: Data for 672 participants across 23 centers were collected on the specific hemispherotomy approach. Of these, 72 (10.7%) underwent vertical parasagittal hemispherotomy and 600 (89.3%) underwent lateral peri-insular/peri-Sylvian or trans-Sylvian hemispherotomy. Seizure freedom was obtained in 62.4% (95% confidence interval [CI] = 53.5%-70.2%) of the entire cohort at 10-year follow-up. Seizure freedom was 88.8% (95% CI = 78.9%-94.3%) at 1-year follow-up and persisted at 85.5% (95% CI = 74.7%-92.0%) across 5- and 10-year follow-up in the vertical subgroup. In contrast, seizure freedom decreased from 89.2% (95% CI = 86.3%-91.5%) at 1-year to 72.1% (95% CI = 66.9%-76.7%) at 5-year to 57.2% (95% CI = 46.6%-66.4%) at 10-year follow-up for the lateral subgroup. Log-rank test found that vertical hemispherotomy was associated with durable seizure-free progression compared to the lateral approach (p = .01). Patients undergoing the lateral hemispherotomy technique had a shorter time-to-seizure recurrence (hazard ratio = 2.56, 95% CI = 1.08-6.04, p = .03) and increased seizure recurrence odds (odds ratio = 3.67, 95% CI = 1.05-12.86, p = .04) compared to those undergoing the vertical hemispherotomy technique. SIGNIFICANCE: This pilot study demonstrated more durable seizure freedom of the vertical technique compared to lateral hemispherotomy techniques. Further studies, such as prospective expertise-based observational studies or a randomized clinical trial, are required to determine whether a vertical approach to hemispheric surgery provides superior long-term seizure outcomes.

Hemispherectomy Outcome Prediction Scale: Development and validation of a seizure freedom prediction tool.

OBJECTIVE: To develop and validate a model to predict seizure freedom in children undergoing cerebral hemispheric surgery for the treatment of drug-resistant epilepsy. METHODS: We analyzed 1267 hemispheric surgeries performed in pediatric participants across 32 centers and 12 countries to identify predictors of seizure freedom at 3 months after surgery. A multivariate logistic regression model was developed based on 70% of the dataset (training set) and validated on 30% of the dataset (validation set). Missing data were handled using multiple imputation techniques. RESULTS: Overall, 817 of 1237 (66%) hemispheric surgeries led to seizure freedom (median follow-up = 24 months), and 1050 of 1237 (85%) were seizure-free at 12 months after surgery. A simple regression model containing age at seizure onset, presence of generalized seizure semiology, presence of contralateral 18-fluoro-2-deoxyglucose-positron emission tomography hypometabolism, etiologic substrate, and previous nonhemispheric resective surgery is predictive of seizure freedom (area under the curve = .72). A Hemispheric Surgery Outcome Prediction Scale (HOPS) score was devised that can be used to predict seizure freedom. SIGNIFICANCE: Children most likely to benefit from hemispheric surgery can be selected and counseled through the implementation of a scale derived from a multiple regression model. Importantly, children who are unlikely to experience seizure control can be spared from the complications and deficits associated with this surgery. The HOPS score is likely to help physicians in clinical decision-making.

Bilateral Parietal Skull Fractures in Infants Attributable to Accidental Falls.

INTRODUCTION: Multiple skull fractures, including bilateral parietal skull fractures (BPSFs) in infants are considered to be suspicious for abusive head trauma (AHT). The aim of this report is to describe a series of BPSF cases in infants which occurred due to accidental falls. METHODS: We searched our neuroradiology database for BPSF in infants (<1 year old) diagnosed between 2006 and 2019; we reviewed initial presentation, mechanisms of injury, clinical course, head imaging, skeletal survey X-rays, ophthalmology, social work and child abuse physicians (CAP) assessments, and long-term follow-up. "Confirmed accidental BPSF" were strictly defined as having negative skeletal survey and ophthalmology evaluation and a CAP conclusion of accidental injury. RESULTS: Twelve cases of BPSF were found; 3 were confirmed to be accidental, with a mean age at presentation of 3 months. Two infants had single-impact falls, and 1 had a compression injury; all 3 had small intracranial hemorrhages. None had bruises or other injuries, and all remained clinically well. A literature search found 10 similar cases and further biomechanical evidence that these fractures can occur from accidental falls. CONCLUSION: While AHT should be kept in the differential diagnosis whenever BPSFs are seen, these injuries can occur as a result of accidental falls.

Hirayama Disease in a Patient with a History of Late-Onset Symptomatic Vein of Galen Aneurysmal Malformation.

INTRODUCTION: The purpose of this report is to present a rare case of Hirayama disease (HD) in a patient with a history of late-onset symptomatic vein of Galen aneurysmal malformation (VGAM). This report may provide new insights into the pathophysiology of HD, a rare disorder consisting of insidious onset of unilateral weakness and atrophy of the forearm and intrinsic hand muscles. These symptoms are believed to result from cervical myelopathy affecting the anterior horn cells due to abnormal compressive forces on the spinal cord from adjacent anatomical structures (i.e., dura and/or epidural veins), but this has not been proven. VGAM is a rare congenital cerebral vascular malformation, consisting of high-flow arteriovenous shunting between a persistent median prosencephalic vein and arterial feeders, which most frequently presents in the early neonatal period with congestive heart failure. CASE PRESENTATION: We report the case of an otherwise healthy boy who presented with heart failure due to VGAM at 7 years and subsequently presented at 14 years with left-sided HD. His cervical MRI with neck flexion revealed enlarged epidural veins at the C5-C6 spinal level with anterior, leftward displacement of the posterior dura and spinal cord as well as left hemicord flattening and/or atrophy at this level. He underwent successful surgical treatment by C5-C6-C7 osteoplastic laminotomies and tenting and expansile autologous duraplasty, during which enlarged, engorged epidural veins were confirmed and coagulated. This halted the progression of his left hand weakness and atrophy and allowed significant functional improvement. Postoperative catheter angiogram showed no anatomical connection between the persistent VGAM and the engorged epidural veins, and genetic testing revealed no genetic predisposition of vascular malformations. DISCUSSION/CONCLUSION: In this patient, a combined surgical technique was performed that included epidural venous plexus coagulation with posterior autologous duraplasty and dural fixation using tenting sutures. This combined approach led to a favorable clinical and radiographic outcome with no complications or limitations and has not been previously proposed in the literature, to our knowledge. Although not completely ruled out, we found no angiographic connection or genetic predisposition to suggest there is a pathophysiological link between HD and VGAM.

MNI SISCOM: an Open-Source Tool for Computing Subtraction Ictal Single-Photon Emission CT Coregistered to MRI.

Subtraction ictal single-photon emission computed tomography (SPECT) coregistered to MRI (SISCOM) is a well-established technique for quantitative analysis of ictal vs interictal SPECT images that can contribute to the identification of the seizure onset zone in patients with drug-resistant epilepsy. However, there is presently a lack of user-friendly free and open-source software to compute SISCOM results from raw SPECT and MRI images. We aimed to develop a simple graphical desktop application for computing SISCOM. MNI SISCOM is a new free and open-source software application for computing SISCOM and producing practical MRI/SPECT/SISCOM image panels for review and reporting. The graphical interface allows any user to quickly and easily obtain SISCOM images with minimal user interaction. Additionally, MNI SISCOM provides command line and Python interfaces for users who would like to integrate these features into their own scripts and pipelines. MNI SISCOM is freely available for download from: https://github.com/jeremymoreau/mnisiscom .

Developmental trajectory of oligodendrocyte progenitor cells in the human brain revealed by single cell RNA sequencing.

Characterizing the developmental trajectory of oligodendrocyte progenitor cells (OPC) is of great interest given the importance of these cells in the remyelination process. However, studies of human OPC development remain limited by the availability of whole cell samples and material that encompasses a wide age range, including time of peak myelination. In this study, we apply single cell RNA sequencing to viable whole cells across the age span and link transcriptomic signatures of oligodendrocyte-lineage cells with stage-specific functional properties. Cells were isolated from surgical tissue samples of second-trimester fetal, 2-year-old pediatric, 13-year-old adolescent, and adult donors by mechanical and enzymatic digestion, followed by percoll gradient centrifugation. Gene expression was analyzed using droplet-based RNA sequencing (10X Chromium). Louvain clustering analysis identified three distinct cellular subpopulations based on 5,613 genes, comprised of an early OPC (e-OPC) group, a late OPC group (l-OPC), and a mature OL (MOL) group. Gene ontology terms enriched for e-OPCs included cell cycle and development, for l-OPCs included extracellular matrix and cell adhesion, and for MOLs included myelination and cytoskeleton. The e-OPCs were mostly confined to the premyelinating fetal group, and the l-OPCs were most highly represented in the pediatric age group, corresponding to the peak age of myelination. Cells expressing a signature characteristic of l-OPCs were identified in the adult brain in situ using RNAScope. These findings highlight the transcriptomic variability in OL-lineage cells before, during, and after peak myelination and contribute to identifying novel pathways required to achieve remyelination.

Eight-Year Experience With 3-T Intraoperative MRI Integration in Focal Pediatric Epilepsy Surgery: Impact on Extent of Resection, Residual Volumes, and Seizure Outcomes.

OBJECTIVE. The purpose of this study was to investigate the influence of 3-T intraoperative MRI (ioMRI) on the extent of resection of pediatric focal epileptogenic lesions, residual lesion volumes, and postoperative seizure outcomes. MATERIALS AND METHODS. All surgical procedures for focal epilepsy from 2003 to 2017 were retrospectively reviewed. Patients were divided into two groups: those who underwent ioMRI and those who did not. Each group was subdivided into two subcategories according to preoperative MRI visualization of the lesion: those with well-defined and those with poorly defined lesions. The volumes of preoperative lesions and postoperative residual lesions were delineated. Outcome data and patient characteristics were reviewed. The results were compared between the two groups and the two subcategories. RESULTS. Eighty patients were included: 45 in the ioMRI group (24 with well-defined lesions, 21 with poorly defined lesions) and 35 in the non-ioMRI group (18 with well-defined lesions, 17 with poorly defined lesions). The well-defined lesions included tumors and vascular lesions. The poorly defined lesions included malformations of cortical development, hippocampal sclerosis, and tuberous sclerosis. The mean follow-up duration was 5.1 ± 3.3 years. The rate of gross total resection was not significantly different between the ioMRI and non-ioMRI groups (p = 0.46). However, ioMRI findings facilitated further resection during surgery, increasing gross total resection by an additional 11.1%. The ioMRI group had a significant reduction in percentage of residual volume (p < 0.001). Outcome data suggested that ioMRI is protective against poor Engel score (p = 0.048). Although ioMRI prolonged the mean operative time by 1.2 hours (p = 0.002), the additional time was not associated with additional complications. CONCLUSION. Integration of ioMRI into focal epilepsy surgery was associated with smaller residual lesions and was protective against poor Engel score. It prolonged the operative time but without increasing the number of complications.

Efficacy of Dabrafenib for three children with brainstem BRAFV600E positive ganglioglioma.

PURPOSE: Children with unresectable brainstem-infiltrated ganglioglioma have poor progression-free survival when treated with conventional chemotherapy and radiation regimens. The BRAFV600E mutation occurs in a large number of gangliogliomas, making them amenable for targeted therapy using mutation-specific kinase inhibitors. However, limited data exists on the effectiveness and best treatment duration of these inhibitors in this tumor setting. METHOD: Retrospective description of three cases of childhood brainstem ganglioglioma with BRAFV600E mutation treated in the long-term with Dabrafenib, a specific BRAFV600E kinase inhibitor. RESULTS: Dabrafenib resulted in rapid tumoral regression and significant and durable clinical and radiological improvement. However, all patients had rapid clinical and radiological relapse within days to weeks following treatment discontinuation but showed similar rapid and sustained therapeutic response when Dabrafenib was re-introduced. This targeted therapy has been well tolerated despite its long-term use of 4.8 to 5.5 years in the three patients. CONCLUSION: Dabrafenib is effective and seemingly safe and well tolerated in our three patients. We observed sustained chemosensitivity even when re-introducing this kinase inhibitor after its discontinuation after 2 years of therapy. These cases indicate the need to re-evaluate the timing and means of Dabrafenib discontinuation in pediatric patients with BRAFV600E mutated gangliogliomas and better assess the future implications of its long-term use.