Isolated unilateral alar ligamentous injury: illustrative cases.

BACKGROUND: Isolated unilateral alar ligament injury (IUALI) is a rare and likely underreported occurrence after upper cervical trauma, with only 16 cases documented in the literature to date. Patients generally present with neck pain, and definitive diagnosis is typically made by magnetic resonance imaging (MRI). Unfortunately, likely due in part to its rarity, there are no formal guidelines for the treatment of an IUALI. Furthermore, there is a limited understanding of the long-term consequences associated with its inadequate treatment. OBSERVATIONS: Here, the authors report on three pediatric patients, each found to have an IUALI after significant trauma. All patients presented with neck tenderness, and two of the three had associated pain-limited range of neck motion. Imaging revealed either a laterally deviated odontoid process on cervical radiographs and/or MRI evidence of ligamentous strain or discontinuity. Each patient was placed in a hard cervical collar for 1 to 2 months with excellent resolution of symptoms. A comprehensive review of the literature showed that all patients with IUALI who had undergone external immobilization with either rigid cervical collar or halo fixation had favorable outcomes at follow-up. LESSONS: For patients with IUALI, a moderate course of nonsurgical management with rigid external immobilization appears to be an adequate first-line treatment.

Contribution of Somatic Ras/Raf/Mitogen-Activated Protein Kinase Variants in the Hippocampus in Drug-Resistant Mesial Temporal Lobe Epilepsy.

Importance: Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy subtype and is often refractory to antiseizure medications. While most patients with MTLE do not have pathogenic germline genetic variants, the contribution of postzygotic (ie, somatic) variants in the brain is unknown. Objective: To test the association between pathogenic somatic variants in the hippocampus and MTLE. Design, Setting, and Participants: This case-control genetic association study analyzed the DNA derived from hippocampal tissue of neurosurgically treated patients with MTLE and age-matched and sex-matched neurotypical controls. Participants treated at level 4 epilepsy centers were enrolled from 1988 through 2019, and clinical data were collected retrospectively. Whole-exome and gene-panel sequencing (each genomic region sequenced more than 500 times on average) were used to identify candidate pathogenic somatic variants. A subset of novel variants was functionally evaluated using cellular and molecular assays. Patients with nonlesional and lesional (mesial temporal sclerosis, focal cortical dysplasia, and low-grade epilepsy-associated tumors) drug-resistant MTLE who underwent anterior medial temporal lobectomy were eligible. All patients with available frozen tissue and appropriate consents were included. Control brain tissue was obtained from neurotypical donors at brain banks. Data were analyzed from June 2020 to August 2022. Exposures: Drug-resistant MTLE. Main Outcomes and Measures: Presence and abundance of pathogenic somatic variants in the hippocampus vs the unaffected temporal neocortex. Results: Of 105 included patients with MTLE, 53 (50.5%) were female, and the median (IQR) age was 32 (26-44) years; of 30 neurotypical controls, 11 (36.7%) were female, and the median (IQR) age was 37 (18-53) years. Eleven pathogenic somatic variants enriched in the hippocampus relative to the unaffected temporal neocortex (median [IQR] variant allele frequency, 1.92 [1.5-2.7] vs 0.3 [0-0.9]; P = .01) were detected in patients with MTLE but not in controls. Ten of these variants were in PTPN11, SOS1, KRAS, BRAF, and NF1, all predicted to constitutively activate Ras/Raf/mitogen-activated protein kinase (MAPK) signaling. Immunohistochemical studies of variant-positive hippocampal tissue demonstrated increased Erk1/2 phosphorylation, indicative of Ras/Raf/MAPK activation, predominantly in glial cells. Molecular assays showed abnormal liquid-liquid phase separation for the PTPN11 variants as a possible dominant gain-of-function mechanism. Conclusions and Relevance: Hippocampal somatic variants, particularly those activating Ras/Raf/MAPK signaling, may contribute to the pathogenesis of sporadic, drug-resistant MTLE. These findings may provide a novel genetic mechanism and highlight new therapeutic targets for this common indication for epilepsy surgery.

Surgical strategies for intracranial meningioma in the molecular era.

INTRODUCTION: Surgical resection has long been the treatment of choice for meningiomas and is considered curative in many cases. Indeed, the extent of resection (EOR) remains a significant factor in determining disease recurrence and outcome optimization for patients undergoing surgery. Although the Simpson Grading Scale continues to be widely accepted as the measure of EOR and is used to predict symptomatic recurrence, its utility is under increasing scrutiny. The influence of surgery in the definitive management of meningioma is being re-appraised considering the rapid evolution of our understanding of the biology of meningioma. DISCUSSION: Although historically considered "benign" lesions, meningioma natural history can vary greatly, behaving with unexpectedly high recurrence rates and growth which do not always behave in accordance with their WHO grade. Histologically confirmed WHO grade 1 tumors may demonstrate unexpected recurrence, malignant transformation, and aggressive behavior, underscoring the molecular complexity and heterogeneity. CONCLUSION: As our understanding of the clinical predictive power of genomic and epigenomic factors matures, we here discuss the importance of surgical decision-making paradigms in the context of our rapidly evolving understanding of these molecular features.

Management of dynamic cervical kyphosis with dorsal epidural lipomatosis: a Hirayama disease variant? Illustrative case.

BACKGROUND: Hirayama disease, a cervical myelopathy characterized most commonly by a self-limiting atrophic weakness of the upper extremities, is a rare entity, scarcely reported in the literature. Diagnosis is made by spinal magnetic resonance imaging (MRI), which typically shows loss of normal cervical lordosis, anterior displacement of the cord during flexion, and a large epidural cervical fat pad. Treatment options include observation or cervical immobilization by collar or surgical decompression and fusion. OBSERVATIONS: Here, the authors report an unusual case of a Hirayama-like disease in a young White male athlete who presented with rapidly progressive paresthesia in all 4 extremities and no weakness. Imaging showed characteristic findings of Hirayama disease as well as worsened cervical kyphosis and spinal cord compression in cervical neck extension, which has not previously been reported. Two-level anterior cervical discectomy and fusion and posterior spinal fusion improved both cervical kyphosis on extension and symptoms. LESSONS: Given the disease's self-limiting nature, and a lack of current reporting, there remains no consensus on how to manage these patients. Such findings presented here demonstrate the potentially heterogeneous MRI findings that can be observed in Hirayama disease and emphasize the utility of aggressive surgical management in young, active patients whereby a cervical collar may not be tolerated.

The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus.

The choroid plexus (ChP) is the blood-cerebrospinal fluid (CSF) barrier and the primary source of CSF. Acquired hydrocephalus, caused by brain infection or hemorrhage, lacks drug treatments due to obscure pathobiology. Our integrated, multi-omic investigation of post-infectious hydrocephalus (PIH) and post-hemorrhagic hydrocephalus (PHH) models revealed that lipopolysaccharide and blood breakdown products trigger highly similar TLR4-dependent immune responses at the ChP-CSF interface. The resulting CSF "cytokine storm", elicited from peripherally derived and border-associated ChP macrophages, causes increased CSF production from ChP epithelial cells via phospho-activation of the TNF-receptor-associated kinase SPAK, which serves as a regulatory scaffold of a multi-ion transporter protein complex. Genetic or pharmacological immunomodulation prevents PIH and PHH by antagonizing SPAK-dependent CSF hypersecretion. These results reveal the ChP as a dynamic, cellularly heterogeneous tissue with highly regulated immune-secretory capacity, expand our understanding of ChP immune-epithelial cell cross talk, and reframe PIH and PHH as related neuroimmune disorders vulnerable to small molecule pharmacotherapy.

A neural stem cell paradigm of pediatric hydrocephalus.

Pediatric hydrocephalus, the leading reason for brain surgery in children, is characterized by enlargement of the cerebral ventricles classically attributed to cerebrospinal fluid (CSF) overaccumulation. Neurosurgical shunting to reduce CSF volume is the default treatment that intends to reinstate normal CSF homeostasis, yet neurodevelopmental disability often persists in hydrocephalic children despite optimal surgical management. Here, we discuss recent human genetic and animal model studies that are shifting the view of pediatric hydrocephalus from an impaired fluid plumbing model to a new paradigm of dysregulated neural stem cell (NSC) fate. NSCs are neuroprogenitor cells that comprise the germinal neuroepithelium lining the prenatal brain ventricles. We propose that heterogenous defects in the development of these cells converge to disrupt cerebrocortical morphogenesis, leading to abnormal brain-CSF biomechanical interactions that facilitate passive pooling of CSF and secondary ventricular distention. A significant subset of pediatric hydrocephalus may thus in fact be due to a developmental brain malformation leading to secondary enlargement of the ventricles rather than a primary defect of CSF circulation. If hydrocephalus is indeed a neuroradiographic presentation of an inborn brain defect, it suggests the need to focus on optimizing neurodevelopment, rather than CSF diversion, as the primary treatment strategy for these children.

Rare pathogenic variants in WNK3 cause X-linked intellectual disability.

PURPOSE: WNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown. METHOD: We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID). RESULTS: We identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.Pro204Arg, p.Leu300Ser, p.Glu607Val) in WNK3 in 14 male individuals from 6 unrelated families. Affected individuals had ID with variable presence of epilepsy and structural brain defects. WNK3 variants cosegregated with the disease in 3 different families with multiple affected individuals. This included 1 large family previously diagnosed with X-linked Prieto syndrome. WNK3 pathogenic missense variants localize to the catalytic domain and impede the inhibitory phosphorylation of the neuronal-specific chloride cotransporter KCC2 at threonine 1007, a site critically regulated during the development of synaptic inhibition. CONCLUSION: Pathogenic WNK3 variants cause a rare form of human X-linked ID with variable epilepsy and structural brain abnormalities and implicate impaired phospho-regulation of KCC2 as a pathogenic mechanism.

Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus.

Hydrocephalus, characterized by cerebral ventricular dilatation, is routinely attributed to primary defects in cerebrospinal fluid (CSF) homeostasis. This fosters CSF shunting as the leading reason for brain surgery in children despite considerable disease heterogeneity. In this study, by integrating human brain transcriptomics with whole-exome sequencing of 483 patients with congenital hydrocephalus (CH), we found convergence of CH risk genes in embryonic neuroepithelial stem cells. Of all CH risk genes, TRIM71/lin-41 harbors the most de novo mutations and is most specifically expressed in neuroepithelial cells. Mice harboring neuroepithelial cell-specific Trim71 deletion or CH-specific Trim71 mutation exhibit prenatal hydrocephalus. CH mutations disrupt TRIM71 binding to its RNA targets, causing premature neuroepithelial cell differentiation and reduced neurogenesis. Cortical hypoplasia leads to a hypercompliant cortex and secondary ventricular enlargement without primary defects in CSF circulation. These data highlight the importance of precisely regulated neuroepithelial cell fate for normal brain-CSF biomechanics and support a clinically relevant neuroprogenitor-based paradigm of CH.

Genomic approaches to improve the clinical diagnosis and management of patients with congenital hydrocephalus.

Congenital hydrocephalus (CH), characterized by incomplete clearance of CSF and subsequent enlargement of brain ventricles, is the most common congenital brain disorder. The lack of curative strategies for CH reflects a poor understanding of the underlying pathogenesis. Herein, the authors present an overview of recent findings in the pathogenesis of CH from human genetic studies and discuss the implications of these findings for treatment of CH. Findings from these omics data have the potential to reclassify CH according to a molecular nomenclature that may increase precision for genetic counseling, outcome prognostication, and treatment stratification. Beyond the immediate patient benefits, genomic data may also inform future clinical trials and catalyze the development of nonsurgical, molecularly targeted therapies. Therefore, the authors advocate for further application of genomic sequencing in clinical practice by the neurosurgical community as a diagnostic adjunct in the evaluation and management of patients diagnosed with CH.

The integrated multiomic diagnosis of sporadic meningiomas: a review of its clinical implications.

INTRODUCTION: Meningiomas are generally considered "benign," however, these tumors can demonstrate variability in behavior and a surprising aggressiveness with elevated rates of recurrence. The advancement of next-generation molecular technologies have led to the understanding of the genomic and epigenomic landscape of meningiomas and more recent correlations with clinical characteristics and behavior. METHODS: Based on a thorough review of recent peer-reviewed publications (PubMed) and edited texts, we provide a molecular overview of meningiomas with a focus on relevant clinical implications. RESULTS: The identification of specific somatic driver mutations has led to the classification of several major genomic subgroups, which account for more than 80% of sporadic meningiomas, and can be distinguished using noninvasive clinical variables to help guide management decisions. Other somatic genomic modifications, including non-coding alterations and copy number variations, have also been correlated with tumor characteristics. Furthermore, epigenomic modifications in meningiomas have recently been described, with DNA methylation being the most widely studied and potentially most clinically relevant. Based on these molecular insights, several clinical trials are currently underway in an effort to establish effective medical therapeutic options for meningioma. CONCLUSION: As we enhance our multiomic understanding of meningiomas, our ability to care for patients with these tumors will continue to improve. Further biological insights will lead to additional progress in precision medicine for meningiomas.

DIAPH1 Variants in Non-East Asian Patients With Sporadic Moyamoya Disease.

Importance: Moyamoya disease (MMD), a progressive vasculopathy leading to narrowing and ultimate occlusion of the intracranial internal carotid arteries, is a cause of childhood stroke. The cause of MMD is poorly understood, but genetic factors play a role. Several familial forms of MMD have been identified, but the cause of most cases remains elusive, especially among non-East Asian individuals. Objective: To assess whether ultrarare de novo and rare, damaging transmitted variants with large effect sizes are associated with MMD risk. Design, Setting, and Participants: A genetic association study was conducted using whole-exome sequencing case-parent MMD trios in a small discovery cohort collected over 3.5 years (2016-2019); data were analyzed in 2020. Medical records from US hospitals spanning a range of 1 month to 1.5 years were reviewed for phenotyping. Exomes from a larger validation cohort were analyzed to identify additional rare, large-effect variants in the top candidate gene. Participants included patients with MMD and, when available, their parents. All participants who met criteria and were presented with the option to join the study agreed to do so; none were excluded. Twenty-four probands (22 trios and 2 singletons) composed the discovery cohort, and 84 probands (29 trios and 55 singletons) composed the validation cohort. Main Outcomes and Measures: Gene variants were identified and filtered using stringent criteria. Enrichment and case-control tests assessed gene-level variant burden. In silico modeling estimated the probability of variant association with protein structure. Integrative genomics assessed expression patterns of MMD risk genes derived from single-cell RNA sequencing data of human and mouse brain tissue. Results: Of the 24 patients in the discovery cohort, 14 (58.3%) were men and 18 (75.0%) were of European ancestry. Three of 24 discovery cohort probands contained 2 do novo (1-tailed Poisson P = 1.1 × 10-6) and 1 rare, transmitted damaging variant (12.5% of cases) in DIAPH1 (mammalian diaphanous-1), a key regulator of actin remodeling in vascular cells and platelets. Four additional ultrarare damaging heterozygous DIAPH1 variants (3 unphased) were identified in 3 other patients in an 84-proband validation cohort (73.8% female, 77.4% European). All 6 patients were non-East Asian. Compound heterozygous variants were identified in ena/vasodilator-stimulated phosphoproteinlike protein EVL, a mammalian diaphanous-1 interactor that regulates actin polymerization. DIAPH1 and EVL mutant probands had severe, bilateral MMD associated with transfusion-dependent thrombocytopenia. DIAPH1 and other MMD risk genes are enriched in mural cells of midgestational human brain. The DIAPH1 coexpression network converges in vascular cell actin cytoskeleton regulatory pathways. Conclusions and Relevance: These findings provide the largest collection to date of non-East Asian individuals with sporadic MMD harboring pathogenic variants in the same gene. The results suggest that DIAPH1 is a novel MMD risk gene and impaired vascular cell actin remodeling in MMD pathogenesis, with diagnostic and therapeutic ramifications.

Inflammatory hydrocephalus.

Reparative inflammation is an important protective response that eliminates foreign organisms, damaged cells, and physical irritants. However, inappropriately triggered or sustained inflammation can respectively initiate, propagate, or prolong disease. Post-hemorrhagic (PHH) and post-infectious hydrocephalus (PIH) are the most common forms of hydrocephalus worldwide. They are treated using neurosurgical cerebrospinal fluid (CSF) diversion techniques with high complication and failure rates. Despite their distinct etiologies, clinical studies in human patients have shown PHH and PIH share similar CSF cytokine and immune cell profiles. Here, in light of recent work in model systems, we discuss the concept of "inflammatory hydrocephalus" to emphasize potential shared mechanisms and potential therapeutic vulnerabilities of these disorders. We propose that this change of emphasis could shift our thinking of PHH and PIH from a framework of life-long neurosurgical disorders to that of preventable conditions amenable to immunomodulation.

Protein kinase D1 variant associated with human epilepsy and peripheral nerve hypermyelination.

We report the case of a patient with severe progressive epilepsy and peripheral neuropathy and a novel de novo inactivating variant (p.E79X) in Protein Kinase D1 (PKD1). Using CRISPR/Cas9, we engineered the homologous variant in mice and showed that in the homozygote mouse, it recapitulated the patient peripheral nerve hypermyelination pathology. The lethality of the homozygote mouse prevented us from performing an assessment of locomotor behavior. The mutant heterozygote mouse; however, exhibited a significant increase in kainate-induced seizure activity over wild-type mice, supporting the hypothesis that the PKD1 variant is a candidate for the cause of the patient epilepsy. Because PKD1 was previously identified in a kinomic screen as an interacting partner of the K-Cl cotransporter 3 (KCC3), and since KCC3 is involved in peripheral nerve disease and brain hyperexcitability, one possible mechanism of action of PKD1 in disease is through KCC3. We show that catalytically inactive PKD1 stimulates KCC3 activity, consistent with tonic relief of inhibitory phosphorylation. Our findings implicate a novel role for PKD1 in the human nervous system, and uncover a mechanism that could serve as a potential target to promote nervous system myelination.

New drugs on the horizon for cerebral edema: what's in the clinical development pipeline?

INTRODUCTION: Research has advanced our understanding of the molecular and cellular mechanisms of cerebral edema and has propelled the development of novel antiedema therapeutics. Current evidence supports aberrant neuro-glial ion transport as a central mechanism that underlies pathological fluid accumulation after central nervous system injury. AREAS COVERED: Novel agents in clinical development show potential in altering the natural history and treatment of cerebral edema. Using the PubMed and Google Scholar databases, we review recent advances in our understanding of cerebral edema and describe agents under active investigation, their mechanism, and their application in recent and ongoing clinical trials. EXPERT OPINION: Pharmacotherapies that target molecular mechanisms underlying the compensatory post-injury response of ion channels and transporters that lead to pathological alteration of osmotic gradients are the most promising therapeutic strategies. Repurposing of drugs such as glyburide that inhibit the aberrant upregulation of ion channels such as SUR1-TRPM4, and novel agents, such as ZT-1a, which reestablish physiological regulation of ion channels such as NKCC1/KCC, could be useful adjuvants to prevent and even reverse fluid accumulation in the brain parenchyma.

Associated risk factors for extended length of stay following anterior cervical discectomy and fusion for cervical spondylotic myelopathy.

OBJECTIVES: There is a paucity of literature describing the predictors associated with extended length of hospital stay (LOS) for patients undergoing anterior cervical discectomy and fusion (ACDF) for cervical spondylotic myelopathy. The aim of this study was to identify the patient- and hospital-level factors associated with extended LOS for patients with cervical spondylotic myelopathy undergoing ACDF. PATIENTS AND METHODS: The National Inpatient Sample database was queried to identify patients with a diagnosis of cervical spondylotic myelopathy undergoing ACDF between 2010 and 2014. Updated trend weights were used to assess patient demographics, comorbidities, complications, LOS, discharge disposition and total cost. Multivariate logistic regression was used to determine the odds ratio for risk-adjusted LOS. The primary outcome was the degree to which patient comorbidities or postoperative complications correlated with extended LOS (>3 days). RESULTS: We identified 144,514 patients with 29,947 (20.7%) experiencing an extended LOS (Normal LOS: 114,567; Extended LOS: 29,947). Comorbidities were overall significantly higher in the extended LOS cohort compared to the normal LOS cohort. Patients with extended LOS had a significantly greater proportion of blood transfusion (p < 0.001) and 2-3 vertebral levels fused (p < 0.001). The overall complication rates were greater in the extended LOS cohort (Normal LOS: 7.4% vs. Extended LOS: 44.8%, p < 0.001). The extended LOS cohort incurred $14,489 more in total cost (Normal LOS: $15,486 [11,787-20,623] vs. Extended LOS: $29,975 [21,286-45,285], p < 0.001) and had more patients discharged to non-routine locations (p < 0.001) compared to the normal LOS cohort. On multivariate logistic regression, several risk-factors were associated with extended LOS including: age, male gender, Black and Hispanic race, patient income, insurance, multiple comorbidities, blood transfusion, and number of complications. The odds ratio for extended LOS was 5.15 (95% CI: 4.68-5.67) for patients with 1 complication and 25.54 (95% CI: 20.54-31.75) for patients with >1 complication. CONCLUSION: Our national cohort study demonstrated multiple patient- and hospital-level factors associated with extended LOS (>3 days) after ACDF for CSM. Specifically, patients with an extended LOS had lower socioeconomic status, higher rate of comorbidities, greater percentage of postoperative complications and non-routine discharges, with greater overall costs. Further investigational studies are necessary to identify quality improvement strategies targeted to better optimizing patients preoperatively and reducing perioperative complications in order to improve quality of patient care and reduce hospital LOS.

Thirty- and 90-Day Readmissions After Treatment of Traumatic Subdural Hematoma: National Trend Analysis.

OBJECTIVE: Subdural hematoma (SDH), a form of traumatic brain injury, is a common disease that requires extensive patient management and resource utilization; however, there remains a paucity of national studies examining the likelihood of readmission in this patient population. The aim of this study is to investigate differences in 30- and 90-day readmissions for treatment of traumatic SDH using a nationwide readmission database. METHODS: The Nationwide Readmission Database years 2013-2015 were queried. Patients with a diagnosis of traumatic SDH and a primary procedure code for incision of cerebral meninges for drainage were identified using the International Classification of Diseases, Ninth Revision, Clinical Modification coding system. Patients were grouped by no readmission (Non-R), readmission within 30 days (30-R), and readmission within 31-90 days (90-R). RESULTS: We identified a total of 14,355 patients, with 3106 (21.6%) patients encountering a readmission (30-R: n = 2193 [15.3%]; 90-R: n = 913 [6.3%]; Non-R: n = 11,249). The most prevalent 30- and 90-day diagnoses seen among the readmitted cohorts were postoperative infection (30-R: 10.5%, 90-R: 13.0%) and epilepsy (30-R: 3.7%, 90-R: 1.1%). On multivariate logistic regression analysis, Medicare, Medicaid, hypertension, diabetes, renal failure, congestive heart failure, and coagulopathy were independently associated with 30-day readmission; Medicare and rheumatoid arthritis/collagen vascular disease were independently associated with 90-day readmission. CONCLUSIONS: In this study, we determine the relationship between readmission rates and complications associated with surgical intervention for traumatic subdural hematoma.

A Severe Episode of Hemolytic Anemia After Amoxicillin Exposure in A G6PD Deficient Patient.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme deficiency worldwide, with genetic variants resulting in a range of phenotypes that vary from asymptomatic to severe hemolysis. We report a case of severe hemolytic anemia in a G6PD deficient patient whose only known exposure was amoxicillin two weeks prior to his episode of severe hemolysis, for which he presented to our hospital. An extensive infectious and hematologic workup resulted negative with the exception of a positive G6PD deficiency result. Although rare, we suggest that the patient's severe hemolytic anemia is possibly related to amoxicillin exposure.

SLC7A11 expression is associated with seizures and predicts poor survival in patients with malignant glioma.

Glioma is the most common malignant primary brain tumor. Its rapid growth is aided by tumor-mediated glutamate release, creating peritumoral excitotoxic cell death and vacating space for tumor expansion. Glioma glutamate release may also be responsible for seizures, which complicate the clinical course for many patients and are often the presenting symptom. A hypothesized glutamate release pathway is the cystine/glutamate transporter System xc (-) (SXC), responsible for the cellular synthesis of glutathione (GSH). However, the relationship of SXC-mediated glutamate release, seizures, and tumor growth remains unclear. Probing expression of SLC7A11/xCT, the catalytic subunit of SXC, in patient and mouse-propagated tissues, we found that ~50% of patient tumors have elevated SLC7A11 expression. Compared with tumors lacking this transporter, in vivo propagated and intracranially implanted SLC7A11-expressing tumors grew faster, produced pronounced peritumoral glutamate excitotoxicity, induced seizures, and shortened overall survival. In agreement with animal data, increased SLC7A11 expression predicted shorter patient survival according to genomic data in the REMBRANDT (National Institutes of Health Repository for Molecular Brain Neoplasia Data) database. In a clinical pilot study, we used magnetic resonance spectroscopy to determine SXC-mediated glutamate release by measuring acute changes in glutamate after administration of the U.S. Food and Drug Administration-approved SXC inhibitor, sulfasalazine (SAS). In nine glioma patients with biopsy-confirmed SXC expression, we found that expression positively correlates with glutamate release, which is acutely inhibited with oral SAS. These data suggest that SXC is the major pathway for glutamate release from gliomas and that SLC7A11 expression predicts accelerated growth and tumor-associated seizures.