Single-nucleus expression characterization of non-enhancing region of recurrent high-grade glioma.

Background: Non-enhancing (NE) infiltrating tumor cells beyond the contrast-enhancing (CE) bulk of tumor are potential propagators of recurrence after gross total resection of high-grade glioma. Methods: We leveraged single-nucleus RNA sequencing on 15 specimens from recurrent high-grade gliomas (n = 5) to compare prospectively identified biopsy specimens acquired from CE and NE regions. Additionally, 24 CE and 22 NE biopsies had immunohistochemical staining to validate RNA findings. Results: Tumor cells in NE regions are enriched in neural progenitor cell-like cellular states, while CE regions are enriched in mesenchymal-like states. NE glioma cells have similar proportions of proliferative and putative glioma stem cells relative to CE regions, without significant differences in % Ki-67 staining. Tumor cells in NE regions exhibit upregulation of genes previously associated with lower grade gliomas. Our findings in recurrent GBM paralleled some of the findings in a re-analysis of a dataset from primary GBM. Cell-, gene-, and pathway-level analyses of the tumor microenvironment in the NE region reveal relative downregulation of tumor-mediated neovascularization and cell-mediated immune response, but increased glioma-to-nonpathological cell interactions. Conclusions: This comprehensive analysis illustrates differing tumor and nontumor landscapes of CE and NE regions in high-grade gliomas, highlighting the NE region as an area harboring likely initiators of recurrence in a pro-tumor microenvironment and identifying possible targets for future design of NE-specific adjuvant therapy. These findings also support the aggressive approach to resection of tumor-bearing NE regions.

MRI and pathology comparisons in Rasmussen's encephalitis: a multi-institutional examination of hemispherotomy outcomes relative to imaging and histological severity.

PURPOSE: Rasmussen encephalitis (RE) is a very rare chronic neurological disorder of unilateral inflammation of the cerebral cortex. Hemispherotomy provides the best chance at achieving seizure freedom in RE patients, but with significant risks and variable long-term outcomes. The goal of this study is to utilize our multicenter pediatric cohort to characterize if differences in pathology and/or imaging characterization of RE may provide a window into post-operative seizure outcomes, which in turn could guide decision-making for parents and healthcare providers. METHODS: This multi-institutional retrospective review of medical record, imaging, and pathology samples was approved by each individual institution's review board. Data was collected from all known pediatric cases of peri-insular functional hemispherotomy from the earliest available electronic medical records. Mean follow-up time was 4.9 years. Clinical outcomes were measured by last follow-up visit using both Engel and ILAE scoring systems. Relationships between categorical and continuous variables were analyzed with Pearson correlation values. RESULTS: Twenty-seven patients met study criteria. No statistically significant correlations existed between patient imaging and pathology data. Pathology stage, MRI brain imaging stages, and a combined assessment of pathology and imaging stages showed no statistically significant correlation to post-operative seizure freedom rates. Hemispherectomy Outcome Prediction Scale scoring demonstrated seizure freedom in only 71% of patients receiving a score of 1 and 36% of patients receiving a score of 2 which were substantially lower than predicted. CONCLUSIONS: Our analysis did not find evidence for either independent or combined analysis of imaging and pathology staging being predictive for post peri-insular hemispherotomy seizure outcomes, prompting the need for other biomarkers to be explored. Our data stands in contrast to the recently proposed Hemispherectomy Outcome Prediction Scale and does not externally validate this metric for an RE cohort.

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.

Arterial Bypass in the Treatment of Complex Middle Cerebral Artery Aneurysms: Lessons Learned from Forty Patients.

OBJECTIVE: Complex middle cerebral artery (MCA) aneurysms incorporating parent or branching vessels are often not amenable to standard microsurgical clipping or endovascular embolization treatments. We aim to discuss the treatment of such aneurysms via a combination of surgical revascularization and aneurysm exclusion based on our institutional experience. METHODS: Thirty-four patients with complex MCA aneurysms were treated with bypass and aneurysm occlusion, 5 with surgical clipping or wrapping only, and 1 with aneurysm excision and primary reanastomosis. Bypasses included superficial temporal artery (STA)-MCA, double-barrel STA-MCA, occipital artery-MCA, and external carotid artery-MCA. After bypass, aneurysms were treated by surgical clipping, Hunterian ligation, trapping, or coil embolization. RESULTS: The average age at diagnosis was 46 years. Of the aneurysms, 67% were large and most involved the MCA bifurcation. Most bypasses performed were STA-MCA bypasses, 12 of which were double-barrel. There were 2 wound-healing complications. All but 2 of the aneurysms treated showed complete occlusion at the last follow-up. There were 3 hemorrhagic complications, 3 graft thromboses, and 4 ischemic insults. The mean follow-up was 73 months. Of patients, 83% reported stable or improved symptoms from presentation and 73% reported a functional status (Glasgow Outcome Scale score 4 or 5) at the latest available follow-up. CONCLUSIONS: Cerebral revascularization by bypass followed by aneurysm or parent artery occlusion is an effective treatment option for complex MCA aneurysms that cannot be safely treated by standard microsurgical or endovascular techniques. Double-barrel bypass consisting of 2 STA branches to 2 MCA branches yields adequate flow replacement in most cases.

Proximal Internal Carotid Artery Occlusion and Extracranial-Intracranial Bypass for Treatment of Fusiform and Giant Internal Carotid Artery Aneurysms.

OBJECTIVE: To discuss the treatment of intracranial fusiform and giant internal carotid artery (ICA) aneurysms via revascularization based on our institutional experience. METHODS: An institutional review board-approved retrospective analysis was performed of patients with unruptured fusiform and giant intracranial ICA aneurysms treated from November 1991 to May 2020. All patients were evaluated for extracranial-intracranial (EC-IC) bypass and ICA occlusion. RESULTS: Thirty-eight patients were identified. Initially, patients failing preoperative balloon test occlusion were treated with superficial temporal artery (STA)-middle cerebral artery (MCA) bypass and concurrent proximal ICA ligation. We then treated them with STA-MCA bypass, followed by staged balloon test occlusion, and, if they passed, endovascular ICA coil occlusion. We treat all surgical medically uncomplicated patients with double-barrel STA-MCA bypass and concurrent proximal ICA ligation. The mean length of follow-up was 99 months. Symptom stability or improvement was noted in 85% of patients. Bypass graft patency was 92.1%, and all surviving patients had patent bypasses at their last angiogram. Aneurysm occlusion was complete in 90.9% of patients completing proximal ICA ligation. Three patients experienced ischemic complications and 4 patients experienced hemorrhagic complications. CONCLUSIONS: Not all fusiform intracranial ICA aneurysms require intervention, except when life-threatening rupture risk is high or symptomatic management is necessary to preserve function and quality of life. EC-IC bypass can augment the safety of proximal ICA occlusion. The rate of complete aneurysm occlusion with this treatment is 90.9%, and long-term bypass graft-related complications are rare. Perioperative stroke is a major risk, and continued evolution of treatment is required.

A Transcriptomic Comparative Study of Cranial Vasculature.

In genetic studies of cerebrovascular diseases, the optimal vessels to use as controls remain unclear. Our goal is to compare the transcriptomic profiles among 3 different types of control vessels: superficial temporal artery (STA), middle cerebral arteries (MCA), and arteries from the circle of Willis obtained from autopsies (AU). We examined the transcriptomic profiles of STA, MCA, and AU using RNAseq. We also investigated the effects of using these control groups on the results of the comparisons between aneurysms and the control arteries. Our study showed that when comparing pathological cerebral arteries to control groups, all control groups presented similar responses in the activation of immunological processes, the regulation of intracellular signaling pathways, and extracellular matrix productions, despite their intrinsic biological differences. When compared to STA, AU exhibited upregulation of stress and apoptosis genes, whereas MCA showed upregulation of genes associated with tRNA/rRNA processing. Moreover, our results suggest that the matched case-control study design, which involves control STA samples collected from the same subjects of matched aneurysm samples in our study, can improve the identification of non-inherited disease-associated genes. Given the challenges associated with obtaining fresh intracranial arteries from healthy individuals, our study suggests that using MCA, AU, or paired STA samples as controls are feasible strategies for future large-scale studies investigating cerebral vasculopathies. However, the intrinsic differences of each type of control should be taken into consideration when interpreting the results. With the limitations of each control type, it may be most optimal to use multiple tissues as controls.

Novel endovascular transmural technique for pharmacological block of superior cervical ganglion prevents sympathetic-mediated cerebral vasospasm.

BACKGROUND: Sympathetic-mediated vasoconstriction from the superior cervical ganglion (SCG) is a significant contributor to cerebral vasospasm. Inhibition of the SCG has been shown to improve cerebral blood flow and reverse cerebral vasospasm in swine models. We evaluated the efficacy of a novel minimally invasive endovascular approach to target and pharmacologically inhibit the SCG, using a Micro-Infusion Device for transmural drug delivery. METHODS: Eight SCGs in four Yorkshire swine were surgically identified. After confirming appropriate sympathetic-mediated intracranial vasoconstriction response with SCG stimulation, an endovascular Micro-Infusion Device was used for transmural targeting of the SCG and delivery of 1.5-2 mL of 1% lidocaine-contrast mixture to the perivascular space. Digital subtraction angiography was obtained at: (1) baseline; (2) with SCG stimulation; and (3) after lidocaine delivery to the SCG using the Micro-Infusion Device with concurrent SCG stimulation. Vessel diameters were measured and compared. RESULTS: Endovascular transmural delivery of lidocaine to the SCG and carotid perivascular tissue using the Micro-Infusion Device successfully inhibited sympathetic-mediated vasoconstriction response. Measured vessel diameters after lidocaine delivery were comparable to baseline despite SCG stimulation. CONCLUSION: A novel endovascular technique of transmural delivery of lidocaine to the SCG and carotid artery perivascular tissues successfully inhibits the sympathetic input to the cerebral vasculature and modulates sympathetic-mediated cerebral vasospasm. These results suggest promising steps towards translation to potential clinical use for patients suffering from cerebral vasospasm.

An unusual presentation of bilateral optic pathway glioma in Crouzon Syndrome.

Crouzon Syndrome is a genetic craniosynostosis disorder associated with a high risk of ophthalmologic sequelae secondary to structural causes. However, ophthalmologic disorders due to intrinsic nerve aberrations in Crouzon Syndrome have not been described. Optic pathway gliomas (OPGs) are low grade gliomas that are intrinsic to the visual pathway, frequently associated with Neurofibromatosis type 1 (NF-1). OPGs involving both optic nerves without affecting the optic chiasm are rarely seen outside of NF-1. We report an unusual case of bilateral optic nerve glioma without chiasmatic involvement in a 17-month-old male patient with Crouzon Syndrome without any clinical or genetic findings of NF-1. This case suggests that close ophthalmologic follow up and orbital MRIs may benefit patients with Crouzon Syndrome.

Magnetic resonance imaging-guided stereotactic laser ablation therapy for the treatment of pediatric epilepsy: a retrospective multiinstitutional study.

OBJECTIVE: The authors of this study evaluated the safety and efficacy of stereotactic laser ablation (SLA) for the treatment of drug-resistant epilepsy (DRE) in children. METHODS: Seventeen North American centers were enrolled in the study. Data for pediatric patients with DRE who had been treated with SLA between 2008 and 2018 were retrospectively reviewed. RESULTS: A total of 225 patients, mean age 12.8 ± 5.8 years, were identified. Target-of-interest (TOI) locations included extratemporal (44.4%), temporal neocortical (8.4%), mesiotemporal (23.1%), hypothalamic (14.2%), and callosal (9.8%). Visualase and NeuroBlate SLA systems were used in 199 and 26 cases, respectively. Procedure goals included ablation (149 cases), disconnection (63), or both (13). The mean follow-up was 27 ± 20.4 months. Improvement in targeted seizure type (TST) was seen in 179 (84.0%) patients. Engel classification was reported for 167 (74.2%) patients; excluding the palliative cases, 74 (49.7%), 35 (23.5%), 10 (6.7%), and 30 (20.1%) patients had Engel class I, II, III, and IV outcomes, respectively. For patients with a follow-up ≥ 12 months, 25 (51.0%), 18 (36.7%), 3 (6.1%), and 3 (6.1%) had Engel class I, II, III, and IV outcomes, respectively. Patients with a history of pre-SLA surgery related to the TOI, a pathology of malformation of cortical development, and 2+ trajectories per TOI were more likely to experience no improvement in seizure frequency and/or to have an unfavorable outcome. A greater number of smaller thermal lesions was associated with greater improvement in TST. Thirty (13.3%) patients experienced 51 short-term complications including malpositioned catheter (3 cases), intracranial hemorrhage (2), transient neurological deficit (19), permanent neurological deficit (3), symptomatic perilesional edema (6), hydrocephalus (1), CSF leakage (1), wound infection (2), unplanned ICU stay (5), and unplanned 30-day readmission (9). The relative incidence of complications was higher in the hypothalamic target location. Target volume, number of laser trajectories, number or size of thermal lesions, or use of perioperative steroids did not have a significant effect on short-term complications. CONCLUSIONS: SLA appears to be an effective and well-tolerated treatment option for children with DRE. Large-volume prospective studies are needed to better understand the indications for treatment and demonstrate the long-term efficacy of SLA in this population.

Endoscope-Assisted Pedicled Maxillary Artery to Middle Cerebral Artery Bypass: An Anatomic Feasibility Study.

BACKGROUND: Extracranial to intracranial bypass is used to augment and/or replace the intracranial circulation for various pathologies. The superficial temporal artery is the mainstay donor for pedicled bypasses to the anterior circulation but can be limited by its variable size, low native flow rates, and potential scalp complications. Interposition grafts such as the radial artery or greater saphenous vein are alternatives but are sometimes limited by size mismatch, length needed to reach the extracranial circulation, and loss of inherent vascular elasticity. Interposition grafts between the maxillary artery (IMA) and middle cerebral artery (MCA) address these limitations. OBJECTIVE: To explore the feasibility of harvesting the IMA through an endoscopic transnasal, transmaxillary approach to perform a direct IMA to MCA bypass. METHODS: Combined transcranial and endoscopic endonasal dissections were performed in embalmed human cadavers to harvest the IMAs for intracranial transposition and direct anastomosis to the MCA. Donor and recipient vessel calibers were measured and recorded. RESULTS: A total of 8 procedures were performed using the largest and distal-most branches of the IMA (the sphenopalatine branch and the descending palatine branch) as pedicled conduits to second division of middle cerebral artery (M2) recipients. The mean diameter of the IMA donors was 1.89 mm (SD ± 0.42 mm), and the mean diameter of the recipient M2 vessels was 1.90 mm (SD ± 0.46 mm). CONCLUSION: Endoscopic harvest of the IMA using a transnasal, transmaxillary approach is a technically feasible option offering an excellent size match to the M2 divisions of the MCA and the advantages of a relatively short, pedicled donor vessel.

Early Postoperative Opioid Requirement Is Associated With Later Pain Control Needs After Supratentorial Craniotomies.

BACKGROUND: Despite a renewed focus in recent years on pain management in the inpatient hospital setting, postoperative pain after elective craniotomy remains under investigated. This study aims to identify which perioperative factors associate most strongly with postoperative pain and opioid medication requirements after inpatient craniotomy. MATERIALS AND METHODS: Using an existing dataset, we selected a restricted cohort of patients who underwent elective craniotomy surgery requiring an inpatient postoperative stay during a 7-year period at our institution (n=1832). We examined pain scores and opioid medication usage and analyzed the relative contribution of specific perioperative risk factors to postoperative pain and opioid medication intake (morphine milligram equivalents). RESULTS: Postoperative pain was found to be highest on postoperative day 1 and decreased thereafter (up to day 5). Factors associated with greater postoperative opioid medication requirement were preoperative opioid medication use, duration of anesthesia, degree of pain in the preoperative setting, and patient age. Notably, the most significant factor associated with a higher postoperative pain score and Morphine milligram equivalents requirement was the time elapsed between the end of general anesthesia and a patient's first intravenous opioid medication. CONCLUSION: Postcraniotomy patients are at higher risk for requiring opioid pain medications if they have a history of preoperative opioid use, are of younger age, or undergo a longer surgery. Moreover, early requirement of intravenous opioid medications in the postoperative period should alert treating physicians that a patient's pain may require additional or alternative methods of pain control than routinely administered, to avoid over-reliance on opioid medications.

Endovascular transmural access to carotid artery perivascular tissues: safety assessment of a novel technique.

BACKGROUND: Recent advances in endovascular devices have allowed access and targeting of perivascular tissues of the peripheral circulation. The perivascular tissues of the cervical and cranial circulations have many important structures of clinical significance, yet the feasibility and safety of such an approach has not been demonstrated. OBJECTIVE: To evaluate the safety of a novel endovascular transmural approach to target the perivascular tissues of the common carotid artery in swine. METHODS: A micro-infusion device was positioned in the carotid arteries of three Yorkshire pigs (six carotid arteries in total), and each carotid artery was punctured 10 times in the same location to gain access to the perivascular tissues. Digital subtraction angiography was used to evaluate vessel injury or contrast extravasation. MRI and MR angiography were used to evaluate evidence of cerebral ischemia or vessel injury. Post-mortem tissue analysis was performed to assess the level of extravascular hematoma and intravascular dissection. RESULTS: None of the tested carotid arteries showed evidence of vessel injury (dissection or perforation) or intravascular thrombosis. MRI performed after repeated puncture was negative for neck hematoma and brain ischemia. Post-mortem tissue analysis of the carotid arteries showed mild adventitial staining with blood, but without associated hematoma and without vessel dissection. CONCLUSION: Repeated puncture of the carotid artery to gain access to the perivascular tissues using a novel endovascular transmural approach is safe in a swine model. This represents a novel approach to various tissues in close proximity to the cervical and cranial vasculature.

Somatic Variants in SVIL in Cerebral Aneurysms.

Background and Objectives: While somatic mutations have been well-studied in cancer, their roles in other complex traits are much less understood. Our goal is to identify somatic variants that may contribute to the formation of saccular cerebral aneurysms. Methods: We performed whole-exome sequencing on aneurysm tissues and paired peripheral blood. RNA sequencing and the CRISPR/Cas9 system were then used to perform functional validation of our results. Results: Somatic variants involved in supervillin (SVIL) or its regulation were found in 17% of aneurysm tissues. In the presence of a mutation in the SVIL gene, the expression level of SVIL was downregulated in the aneurysm tissue compared with normal control vessels. Downstream signaling pathways that were induced by knockdown of SVIL via the CRISPR/Cas9 system in vascular smooth muscle cells (vSMCs) were determined by evaluating changes in gene expression and protein kinase phosphorylation. We found that SVIL regulated the phenotypic modulation of vSMCs to the synthetic phenotype via Krüppel-like factor 4 and platelet-derived growth factor and affected cell migration of vSMCs via the RhoA/ROCK pathway. Discussion: We propose that somatic variants form a novel mechanism for the development of cerebral aneurysms. Specifically, somatic variants in SVIL result in the phenotypic modulation of vSMCs, which increases the susceptibility to aneurysm formation. This finding suggests a new avenue for the therapeutic intervention and prevention of cerebral aneurysms.

Extent of Tumor Resection and Survival in Pediatric Patients With High-Grade Gliomas: A Systematic Review and Meta-analysis.

Importance: Pediatric patients with high-grade gliomas have a poor prognosis. The association among the extent of resection, tumor location, and survival in these patients remains unclear. Objective: To ascertain whether gross total resection (GTR) in hemispheric, midline, or infratentorial pediatric high-grade gliomas (pHGGs) is independently associated with survival differences compared with subtotal resection (STR) and biopsy at 1 year and 2 years after tumor resection. Data Sources: PubMed, EBMR, Embase, and MEDLINE were systematically reviewed from inception to June 3, 2022, using the keywords high-grade glioma, pediatric, and surgery. No period or language restrictions were applied. Study Selection: Randomized clinical trials and cohort studies of pHGGs that stratified patients by extent of resection and reported postoperative survival were included for study-level and individual patient data meta-analyses. Data Extraction and Synthesis: Study characteristics and mortality rates were extracted from each article. Relative risk ratios (RRs) were pooled using random-effects models. Individual patient data were evaluated using multivariate mixed-effects Cox proportional hazards regression modeling. The PRISMA reporting guideline was followed, and the study was registered a priori. Main Outcomes and Measures: Hazard ratios (HRs) and RRs were extracted to indicate associations among extent of resection, 1-year and 2-year postoperative mortality, and overall survival. Results: A total of 37 studies with 1387 unique patients with pHGGs were included. In study-level meta-analysis, GTR had a lower mortality risk than STR at 1 year (RR, 0.69; 95% CI, 0.56-0.83; P < .001) and 2 years (RR, 0.74; 95% CI, 0.67-0.83; P < .001) after tumor resection. Subtotal resection was not associated with differential survival compared with biopsy at 1 year (RR, 0.82; 95% CI, 0.66-1.01; P = .07) but had decreased mortality risk at 2 years (RR, 0.89; 95% CI, 0.82-0.97; P = .01). The individual patient data meta-analysis of 27 articles included 427 patients (mean [SD] age at diagnosis, 9.3 [5.9] years), most of whom were boys (169 of 317 [53.3%]), had grade IV tumors (246 of 427 [57.7%]), and/or had tumors that were localized to either the cerebral hemispheres (133 of 349 [38.1%]) or midline structures (132 of 349 [37.8%]). In the multivariate Cox proportional hazards regression model, STR (HR, 1.91; 95% CI, 1.34-2.74; P < .001) and biopsy (HR, 2.10; 95% CI, 1.43-3.07; P < .001) had shortened overall survival compared with GTR but no survival differences between them (HR, 0.91; 95% CI, 0.67-1.24; P = .56). Gross total resection was associated with prolonged survival compared with STR for hemispheric (HR, 0.29; 95% CI, 0.15-0.54; P < .001) and infratentorial (HR, 0.44; 95% CI, 0.24-0.83; P = .01) tumors but not midline tumors (HR, 0.63; 95% CI, 0.34-1.19; P = .16). Conclusions and Relevance: Results of this study show that, among patients with pHGG, GTR is independently associated with better overall survival compared with STR and biopsy, especially among patients with hemispheric and infratentorial tumors, and support the pursuit of maximal safe resection in the treatment of pHGGs.

Sympathetic nervous system hyperactivity results in potent cerebral hypoperfusion in swine.

INTRODUCTION: Cerebral vasospasm is a complex disease resulting in reversible narrowing of blood vessels, stroke, and poor patient outcomes. Sympathetic perivascular nerve fibers originate from the superior cervical ganglion (SCG) to innervate the cerebral vasculature, with activation resulting in vasoconstriction. Sympathetic pathways are thought to be a significant contributor to cerebral vasospasm. OBJECTIVE: We sought to demonstrate that stimulation of SCG in swine can cause ipsilateral cerebral perfusion deficit similar to that of significant human cerebral vasospasm. Furthermore, we aimed to show that inhibition of SCG can block the effects of sympathetic-mediated cerebral hypoperfusion. METHODS: SCG were surgically identified in 15 swine and were electrically stimulated to achieve sympathetic activation. CT perfusion scans were performed to assess for changes in cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT) and time-to-maximum (TMax). Syngo.via software was used to determine regions of interest and quantify perfusion measures. RESULTS: SCG stimulation resulted in 20-30% reduction in mean ipsilateral CBF compared to its contralateral unaffected side (p < 0.001). Similar results of hypoperfusion were seen with CBV, MTT and TMax with SCG stimulation. Prior injection of lidocaine to SCG inhibited the effects of SCG stimulation and restored perfusion comparable to baseline (p > 0.05). CONCLUSION: In swine, SCG stimulation resulted in significant cerebral perfusion deficit, and this was inhibited by prior local anesthetic injection into the SCG. Inhibiting sympathetic activation by targeting the SCG may be an effective treatment for sympathetic mediated cerebral hypoperfusion.

Mutations of the DNA repair gene PNKP in a patient with microcephaly, seizures, and developmental delay (MCSZ) presenting with a high-grade brain tumor.

Polynucleotide Kinase-Phosphatase (PNKP) is a bifunctional enzyme that possesses both DNA 3'-phosphatase and DNA 5'-kinase activities, which are required for processing termini of single- and double-strand breaks generated by reactive oxygen species (ROS), ionizing radiation and topoisomerase I poisons. Even though PNKP is central to DNA repair, there have been no reports linking PNKP mutations in a Microcephaly, Seizures, and Developmental Delay (MSCZ) patient to cancer. Here, we characterized the biochemical significance of 2 germ-line point mutations in the PNKP gene of a 3-year old male with MSCZ who presented with a high-grade brain tumor (glioblastoma multiforme) within the cerebellum. Functional and biochemical studies demonstrated these PNKP mutations significantly diminished DNA kinase/phosphatase activities, altered its cellular distribution, caused defective repair of DNA single/double stranded breaks, and were associated with a higher propensity for oncogenic transformation. Our findings indicate that specific PNKP mutations may contribute to tumor initiation within susceptible cells in the CNS by limiting DNA damage repair and increasing rates of spontaneous mutations resulting in pediatric glioma associated driver mutations such as ATRX and TP53.

Human Astrocytes Exhibit Tumor Microenvironment-, Age-, and Sex-Related Transcriptomic Signatures.

Astrocytes are critical for the development and function of synapses. There are notable species differences between human astrocytes and commonly used animal models. Yet, it is unclear whether astrocytic genes involved in synaptic function are stable or exhibit dynamic changes associated with disease states and age in humans, which is a barrier in understanding human astrocyte biology and its potential involvement in neurologic diseases. To better understand the properties of human astrocytes, we acutely purified astrocytes from the cerebral cortices of over 40 humans across various ages, sexes, and disease states. We performed RNA sequencing to generate transcriptomic profiles of these astrocytes and identified genes associated with these biological variables. We found that human astrocytes in tumor-surrounding regions downregulate genes involved in synaptic function and sensing of signals in the microenvironment, suggesting involvement of peritumor astrocytes in tumor-associated neural circuit dysfunction. In aging, we also found downregulation of synaptic regulators and upregulation of markers of cytokine signaling, while in maturation we identified changes in ionic transport with implications for calcium signaling. In addition, we identified subtle sexual dimorphism in human cortical astrocytes, which has implications for observed sex differences across many neurologic disorders. Overall, genes involved in synaptic function exhibit dynamic changes in the peritumor microenvironment and aging. These data provide powerful new insights into human astrocyte biology in several biologically relevant states that will aid in generating novel testable hypotheses about homeostatic and reactive astrocytes in humans.SIGNIFICANCE STATEMENT Astrocytes are an abundant class of cells playing integral roles at synapses. Astrocyte dysfunction is implicated in a variety of human neurologic diseases. Yet our knowledge of astrocytes is largely based on mouse studies. Direct knowledge of human astrocyte biology remains limited. Here, we present transcriptomic profiles of human cortical astrocytes, and we identified molecular differences associated with age, sex, and disease state. We found that peritumor and aging astrocytes downregulate genes involved in astrocyte-synapse interactions. These data provide necessary insight into human astrocyte biology that will improve our understanding of human disease.

Predictors of mortality and tumor recurrence in desmoplastic infantile ganglioglioma and astrocytoma-and individual participant data meta-analysis (IPDMA).

PURPOSE: Desmoplastic infantile astrocytoma (DIA) and desmoplastic infantile ganglioglioma (DIG) are classified together as grade I neuronal and mixed neuronal-glial tumor of the central nervous system by the World Health Organization (WHO). These tumors are rare and have not been well characterized in terms of clinical outcomes. We aimed to identify clinical predictors of mortality and tumor recurrence/progression by performing an individual patient data meta-analysis (IPDMA) of the literature. METHODS: A systematic literature review from 1970 to 2020 was performed, and individualized clinical data for patients diagnosed with DIA/DIG were extracted. Aggregated data were excluded from collection. Outcome measures of interest were mortality and tumor recurrence/progression, as well as time-to-event (TTE) for each of these. Participants without information on these outcome measures were excluded. Cox regression survival analyses were performed to determine predictors of mortality and tumor recurrence / progression. RESULTS: We identified 98 articles and extracted individual patient data from 188 patients. The cohort consisted of 58.9% males with a median age of 7 months. The majority (68.1%) were DIGs, while 24.5% were DIAs and 7.5% were non-specific desmoplastic infantile tumors; DIAs presented more commonly in deep locations (p = 0.001), with leptomeningeal metastasis (p = 0.001), and was associated with decreased probability of gross total resection (GTR; p = 0.001). Gender, age, and tumor pathology were not statistically significant predictors of either mortality or tumor recurrence/progression. On multivariate survival analysis, GTR was a predictor of survival (HR = 0.058; p = 0.007) while leptomeningeal metastasis at presentation was a predictor of mortality (HR = 3.27; p = 0.025). Deep tumor location (HR = 2.93; p = 0.001) and chemotherapy administration (HR = 2.02; p = 0.017) were associated with tumor recurrence/progression. CONCLUSION: Our IPDMA of DIA/DIG cases reported in the literature revealed that GTR was a predictor of survival while leptomeningeal metastasis at presentation was associated with mortality. Deep tumor location and chemotherapy were associated with tumor recurrence / progression.

Increased Autoimmunity in Individuals With Down Syndrome and Moyamoya Disease.

Objective: To determine if elevated rates of autoimmune disease are present in children with both Down syndrome and moyamoya disease given the high rates of autoimmune disease reported in both conditions and unknown etiology of angiopathy in this population. Methods: A multi-center retrospective case-control study of children with Down syndrome and moyamoya syndrome, idiopathic moyamoya disease, and Down syndrome without cerebrovascular disease was performed. Outcome measures included presence of autoimmune disease, presence of autoantibodies and angiopathy severity data. Comparisons across groups was performed using the Kruskal-Wallis, χ2 and multivariate Poisson regression. Results: The prevalence of autoimmune disease were 57.7, 20.3, and 35.3% in persons with Down syndrome and moyamoya syndrome, idiopathic moyamoya disease, and Down syndrome only groups, respectively (p < 0.001). The prevalence of autoimmune disease among children with Down syndrome and moyamoya syndrome is 3.2 times (p < 0.001, 95% CI: 1.82-5.58) higher than the idiopathic moyamoya group and 1.5 times (p = 0.002, 95% CI: 1.17-1.99) higher than the Down syndrome only group when adjusting for age and sex. The most common autoimmune diseases were thyroid disorders, type I diabetes and Celiac disease. No individuals with idiopathic moyamoya disease had more than one type of autoimmune disorder while 15.4% of individuals with Down syndrome and moyamoya syndrome and 4.8% of individuals with Down syndrome only had >1 disorder (p = 0.05, 95%CI: 1.08-6.08). Interpretation: This study reports elevated rates of autoimmune disease in persons with Down syndrome and moyamoya syndrome providing a nidus for study of the role of autoimmunity in angiopathy in this population.