Publications by authors named "Stephanie M Robert"

13 Publications

  • Page 1 of 1

Commentary: Feasibility and Morbidity of Magnetic Resonance Imaging-Guided Stereotactic Laser Ablation of Deep Cerebral Cavernous Malformations: A Report of 4 Cases.

Neurosurgery 2021 Jul 22. Epub 2021 Jul 22.

Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut, USA.

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http://dx.doi.org/10.1093/neuros/nyab262DOI Listing
July 2021

Inflammatory hydrocephalus.

Childs Nerv Syst 2021 Jun 23. Epub 2021 Jun 23.

Department of Neurosurgery, Yale School of Medicine, New Haven, CT, 06510, USA.

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.
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http://dx.doi.org/10.1007/s00381-021-05255-zDOI Listing
June 2021

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

JAMA Neurol 2021 Jun 14. Epub 2021 Jun 14.

Yale Center for Genome Analysis, West Haven, Connecticut.

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.
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http://dx.doi.org/10.1001/jamaneurol.2021.1681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204259PMC
June 2021

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

Clin Genet 2021 Aug 2;100(2):176-186. Epub 2021 Jun 2.

Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

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.
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http://dx.doi.org/10.1111/cge.13973DOI Listing
August 2021

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

Expert Opin Investig Drugs 2020 Oct 20;29(10):1099-1105. Epub 2020 Sep 20.

Departments of Neurosurgery, Pediatrics, and Cellular & Molecular Physiology and Yale-Rockefeller NIH Centers for Mendelian Genomics, Yale School of Medicine , New Haven, CT, USA.

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.
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http://dx.doi.org/10.1080/13543784.2020.1813715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104020PMC
October 2020

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

Clin Neurol Neurosurg 2020 08 4;195:105883. Epub 2020 May 4.

Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, United States.

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.
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http://dx.doi.org/10.1016/j.clineuro.2020.105883DOI Listing
August 2020

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

World Neurosurg 2020 07 6;139:e212-e219. Epub 2020 Apr 6.

Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Radiology & Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.wneu.2020.03.168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380544PMC
July 2020

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

Arch Clin Med Case Rep 2019 20;3(3):104-112. Epub 2019 May 20.

Yale University School of Medicine, Department of Neurosurgery, New Haven, CT, USA.

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.
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http://dx.doi.org/10.26502/acmcr.96550068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637955PMC
May 2019

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

Sci Transl Med 2015 May;7(289):289ra86

Department of Neurobiology, Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

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.
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http://dx.doi.org/10.1126/scitranslmed.aaa8103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503260PMC
May 2015

Disruption of astrocyte-vascular coupling and the blood-brain barrier by invading glioma cells.

Nat Commun 2014 Jun 19;5:4196. Epub 2014 Jun 19.

Department of Neurobiology, Center for Glial Biology in Medicine, University of Alabama at Birmingham, 1719 6th Avenue South, CIRC 425, Birmingham, Alabama 35294, USA.

Astrocytic endfeet cover the entire cerebral vasculature and serve as exchange sites for ions, metabolites and energy substrates from the blood to the brain. They maintain endothelial tight junctions that form the blood-brain barrier (BBB) and release vasoactive molecules that regulate vascular tone. Malignant gliomas are highly invasive tumours that use the perivascular space for invasion and co-opt existing vessels as satellite tumour form. Here we use a clinically relevant mouse model of glioma and find that glioma cells, as they populate the perivascular space of preexisting vessels, displace astrocytic endfeet from endothelial or vascular smooth muscle cells. This causes a focal breach in the BBB. Furthermore, astrocyte-mediated gliovascular coupling is lost, and glioma cells seize control over the regulation of vascular tone through Ca(2+)-dependent release of K(+). These findings have important clinical implications regarding blood flow in the tumour-associated brain and the ability to locally deliver chemotherapeutic drugs in disease.
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http://dx.doi.org/10.1038/ncomms5196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127490PMC
June 2014

A proinvasive role for the Ca(2+) -activated K(+) channel KCa3.1 in malignant glioma.

Glia 2014 Jun 2;62(6):971-81. Epub 2014 Mar 2.

Department of Neurobiology and Center for Glial Biology in Medicine, University of Alabama at Birmingham, Alabama.

Glioblastoma multiforme are highly motile primary brain tumors. Diffuse tissue invasion hampers surgical resection leading to poor patient prognosis. Recent studies suggest that intracellular Ca(2+) acts as a master regulator for cell motility and engages a number of downstream signals including Ca(2+) -activated ion channels. Querying the REepository of Molecular BRAin Neoplasia DaTa (REMBRANDT), an annotated patient gene database maintained by the National Cancer Institute, we identified the intermediate conductance Ca(2+) -activated K(+) channels, KCa3.1, being overexpressed in 32% of glioma patients where protein expression significantly correlated with poor patient survival. To mechanistically link KCa3.1 expression to glioma invasion, we selected patient gliomas that, when propagated as xenolines in vivo, present with either high or low KCa3.1 expression. In addition, we generated U251 glioma cells that stably express an inducible knockdown shRNA to experimentally eliminate KCa3.1 expression. Subjecting these cells to a combination of in vitro and in situ invasion assays, we demonstrate that KCa3.1 expression significantly enhances glioma invasion and that either specific pharmacological inhibition with TRAM-34 or elimination of the channel impairs invasion. Importantly, after intracranial implantation into SCID mice, ablation of KCa3.1 with inducible shRNA resulted in a significant reduction in tumor invasion into surrounding brain in vivo. These results show that KCa3.1 confers an invasive phenotype that significantly worsens a patient's outlook, and suggests that KCa3.1 represents a viable therapeutic target to reduce glioma invasion.
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http://dx.doi.org/10.1002/glia.22655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006152PMC
June 2014

Role of glutamate transporters in redox homeostasis of the brain.

Neurochem Int 2014 Jul 10;73:181-91. Epub 2014 Jan 10.

Department of Neurobiology, Center for Glial Biology in Medicine, University of Alabama at Birmingham, CIRC 425, 1719 6th Ave S, Birmingham, AL 35294, USA. Electronic address:

Redox homeostasis is especially important in the brain where high oxygen consumption produces an abundance of harmful oxidative by-products. Glutathione (GSH) is a tripeptide non-protein thiol. It is the central nervous system's most abundant antioxidant and the master controller of brain redox homeostasis. The glutamate transporters, System xc(-) (SXC) and the Excitatory Amino Acid Transporters (EAAT), play important, synergistic roles in the synthesis of GSH. In glial cells, SXC mediates the uptake of cystine, which after intracellular reduction to cysteine, reacts with glutamate during the rate-limiting step of GSH synthesis. EAAT3 mediates direct cysteine uptake for neuronal GSH synthesis. SXC and EAAT work in concert in glial cells to provide two intracellular substrates for GSH synthesis, cystine and glutamate. Their cyclical basal function also prevents a buildup of extracellular glutamate, which SXC releases extracellularly in exchange for cystine uptake. Maintaining extracellular glutamate homeostasis is critical to prevent neuronal toxicity, as well as glutamate-mediated SXC inhibition, which could lead to a depletion of intracellular GSH and loss of cellular redox control. Many neurological diseases show evidence of GSH dysfunction, and increased GSH has been widely associated with chemotherapy and radiotherapy resistance of gliomas. We present evidence suggesting that gliomas expressing elevated levels of SXC are more reliant on GSH for growth and survival. They have an increased inherent radiation resistance, however, inhibition of SXC can increase tumor sensitivity at low radiation doses. GSH depletion through SXC inhibition may be a viable mechanism to enhance current glioma treatment strategies and make tumors more sensitive to radiation and chemotherapy protocols.
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http://dx.doi.org/10.1016/j.neuint.2014.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058393PMC
July 2014

Glutamate transporters in the biology of malignant gliomas.

Cell Mol Life Sci 2014 May 27;71(10):1839-54. Epub 2013 Nov 27.

Department of Neurobiology, Center for Glial Biology in Medicine, University of Alabama at Birmingham, CIRC 425, 1719 6th Ave S, Birmingham, AL, 35294, USA,

Malignant gliomas are relentless tumors that offer a dismal clinical prognosis. They develop many biological advantages that allow them to grow and survive in the unique environment of the brain. The glutamate transporters system x c (-) and excitatory amino acid transporters (EAAT) are emerging as key players in the biology and malignancy of these tumors. Gliomas manipulate glutamate transporter expression and function to alter glutamate homeostasis in the brain, which supports their own growth, invasion, and survival. As a consequence, malignant cells are able to quickly destroy and invade surrounding normal brain. Recent findings are painting a larger picture of these transporters in glioma biology, and as such are providing opportunities for clinical intervention for patients. This review will detail the current understanding of glutamate transporters in the biology of malignant gliomas and highlight some of the unique aspects of these tumors that make them so devastating and difficult to treat.
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http://dx.doi.org/10.1007/s00018-013-1521-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3999209PMC
May 2014
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