Augmented Reality-Assisted Placement of Ommaya Reservoir for Cyst Aspiration: A Case Report.

Image guidance technologies can significantly improve the accuracy and safety of intracranial catheter insertions. Augmented reality (AR) allows surgeons to visualize 3D information overlaid onto a patient's head. As such, AR has emerged as a novel image guidance technology that offers unique advantages when navigating intracranial targets. A 71-year-old woman with a history of brain metastasis from breast cancer and prior resection surgery and chemotherapy presented with altered mental status and generalized weakness worse on her left side. Magnetic resonance imaging (MRI) demonstrated right frontotemporoparietal edema with a contrast-enhancing mass. MR perfusion confirmed an active tumor with an enlarging right temporal pole cyst. A cyst aspiration was performed via Ommaya reservoir placement. Neuro-navigation (BrainLab, Munich, Germany) and AR navigation were used to plan the trajectory from the temporal gyrus to the cyst. Post-operative computed tomography (CT) demonstrated good placement of the reservoir, reconstitution of the temporal horn of the lateral ventricle with decreased external mass effect, and no areas of hemorrhage. AR has tremendous potential in the field of neurosurgery for improving the accuracy and safety of procedures. This case demonstrates an encouraging application of AR and can serve as an example to drive expanded clinical use of this technology.

Ocular needlefish injury with cavernous sinus thrombosis and carotid-cavernous fistula: illustrative case.

BACKGROUND: The Belonidae family of fish has been implicated in various penetrating injuries; to date, however, there have been limited reports of brain injury due to this species. OBSERVATIONS: The authors present the case of a young patient who suffered an ocular penetrating injury from a needlefish with a resultant cavernous sinus thrombosis and concomitant carotid-cavernous fistula. This case highlights the interdisciplinary management of this rare condition through a strategy of anticoagulation titration to the endpoint of fistula closure. LESSONS: Through this report the importance of a high index of suspicion for neurovascular injury and fistula formation in penetrating ocular injuries is highlighted as well as the importance of interdisciplinary management of patients with such injuries and their sequelae.

The Evolution of 5-Aminolevulinic Acid Fluorescence Visualization: Time for a Headlamp/Loupe Combination.

BACKGROUND: The use of 5-aminolevulinic acid (5-ALA) for intraoperative protoporphyrin IX fluorescent imaging in the resection of malignant gliomas has been demonstrated to improve tumor visualization, increase the extent of resection, and extend progression-free survival. The current technique for visualization of 5-ALA consists of excitation and emission filters built into the operating microscope. However, there are notable limitations to this process, including low quantum yield, expense, and masking of surrounding anatomy. METHODS: We present 3 cases in which 3 separate methods were employed for visualizing fluorescence. The devices reported are 1) a low-cost blue light flashlight, 2) a low-cost headlamp, and 3) the first reported case of the new Designs for Vision REVEAL Fluorescence-Guided Surgery (FGS) 5-ALA fluorescent headlight and loupes. The aim of the study is to provide confirmation that tumor fluorescence can be observed using commercially available products other than the microscope. RESULTS: We demonstrate through 3 intraoperative cases that a variety of devices can produce visible fluorescence of the high-grade tumor and allow for simultaneous real-time visualization of the adjacent brain parenchyma and vasculature. The REVEAL FGS system appears to offer increased fluorescence emission compared with all other methods, including the microscope. CONCLUSIONS: Our study demonstrates the feasibility of using blue/ultraviolet light supplied by a commercially available, inexpensive flashlight or headlamp to visualize 5-ALA fluorescence in high-grade gliomas. We also provide the first documentation of the intraoperative use of the new Designs for Vision REVEAL FGS 5-ALA fluorescent headlight and loupes and report on the experience. Lack of an operative microscope capable of fluorescent illumination should not be a limiting factor in performing fluorescent-guided glioma resection.

Impact of the COVID-19 pandemic on neuro-oncology outcomes.

INTRODUCTION: The Coronavirus disease 2019 (COVID-19) pandemic has uprooted healthcare systems worldwide, disrupting care and increasing dependence on alternative forms of health care delivery. It is yet to be determined how the pandemic affected neuro-oncology patient outcomes, given that the majority of even "elective" neurosurgical oncology procedures are time-sensitive. This study quantifies changes in neuro-oncological care during the height of the pandemic and investigates patient outcomes in 2020 compared to a historical control. METHODS: We performed a retrospective review of patients with malignant brain tumor diagnoses who were seen at our institution between March 13 and May 1 of 2020 and 2019. Alterations in care, including shift from in-person to telehealth, delays in evaluation and intervention, and treatment modifications were evaluated. These variables were analyzed with respect to brain tumor control and mortality. RESULTS: 112 patients from 2020 to 166 patients from 2019 were included. There was no significant difference in outcomes between the cohorts, despite significantly more treatment delays (p = 0.0160) and use of telehealth (p < 0.0001) in 2020. Patients in 2020 who utilized telehealth visits had significantly more stable tumor control than those who had office visits (p = 0.0124), consistent with appropriate use of in-person visits for patients with progression. CONCLUSIONS: Our study showed that use of telehealth and selective alterations in neuro-oncological care during the COVID-19 pandemic did not lead to adverse patient outcomes. This suggests that adaptive physician-led changes were successful and may inform management during the ongoing pandemic, especially with the emergence of the Delta variant.

Challenges of Epilepsy Surgery.

Though frequently effective in the management of medically refractory seizures, epilepsy surgery presents numerous challenges. Selection of the appropriate candidate patients who are likely to benefit from surgery is critical to achieving seizure freedom and avoiding neurocognitive morbidity. Identifying the seizure focus and mapping epileptogenic networks involves an interdisciplinary team dedicated to formulating a safe and effective surgical plan. Various strategies can be employed either to eliminate the epileptic focus or to modulate network activity, including resection of the focus with open surgery or laser interstitial thermal therapy; modulation of epileptogenic firing patterns with responsive neurostimulation, deep brain stimulation, or vagus nerve stimulation; or non-invasive disconnection of epileptic circuits with focused ultrasound, which is also discussed in greater detail in the subsequent chapter in our series. We review several challenges of epilepsy surgery that must be thoughtfully addressed in order to ensure its success.

Innovations in the Neurosurgical Management of Epilepsy.

Technical limitations and clinical challenges have historically limited the diagnostic tools and treatment methods available for surgical approaches to the management of epilepsy. By contrast, recent technological innovations in several areas hold significant promise in improving outcomes and decreasing morbidity. We review innovations in the neurosurgical management of epilepsy in several areas, including wireless recording and stimulation systems (particularly responsive neurostimulation [NeuroPace]), conformal electrodes for high-resolution electrocorticography, robot-assisted stereotactic surgery, optogenetics and optical imaging methods, novel positron emission tomography ligands, and new applications of focused ultrasonography. Investigation into genetic causes of and susceptibilities to epilepsy has introduced a new era of precision medicine, enabling the understanding of cell signaling mechanisms underlying epileptic activity as well as patient-specific molecularly targeted treatment options. We discuss the emerging path to individualized treatment plans, predicted outcomes, and improved selection of effective interventions, on the basis of these developments.

Multimodal Analysis of STRADA Function in Brain Development.

mTORopathies are a heterogeneous group of neurological disorders characterized by malformations of cortical development (MCD), enhanced cellular mechanistic target of rapamycin (mTOR) signaling, and epilepsy that results from mutations in mTOR pathway regulatory genes. Homozygous mutations (del exon 9-13) in the pseudokinase STE20-related kinase adaptor alpha (STRAD-α; STRADA), an mTOR modulator, are associated with Pretzel Syndrome (PS), a neurodevelopmental disorder within the Old Order Mennonite Community characterized by megalencephaly, intellectual disability, and intractable epilepsy. To study the cellular mechanisms of STRADA loss, we generated CRISPR-edited Strada mouse N2a cells, a germline mouse Strada knockout (KO-/-) strain, and induced pluripotent stem cell (iPSC)-derived neurons from PS individuals harboring the STRADA founder mutation. Strada KO in vitro leads to enhanced mTOR signaling and iPSC-derived neurons from PS individuals exhibit enhanced cell size and mTOR signaling activation, as well as subtle alterations in electrical firing properties e.g., increased input resistance, a more depolarized resting membrane potential, and decreased threshold for action potential (AP) generation. Strada-/- mice exhibit high rates of perinatal mortality and out of more than 100 litters yielding both WT and heterozygous pups, only eight Strada-/- animals survived past P5. Strada-/- mice are hypotonic and tremulous. Histopathological examination (n = 5 mice) revealed normal gross brain organization and lamination but all had ventriculomegaly. Ectopic neurons were seen in all five Strada-/- brains within the subcortical white matter mirroring what is observed in human PS brain tissue. These distinct experimental platforms demonstrate that STRADA modulates mTOR signaling and is a key regulator of cell size, neuronal excitability, and cortical lamination.

Surgical Management of Intramedullary Spinal Cord Tumors.

Intramedullary spinal cord tumors (IMSCT) comprise a rare subset of CNS tumors that have distinct management strategies based on histopathology. These tumors often present challenges in regards to optimal timing for surgery, invasiveness, and recurrence. Advances in microsurgical techniques and technological adjuncts have improved extent of resection and outcomes with IMSCT. Furthermore, adjuvant therapies including targeted immunotherapies and image-guided radiation therapy have witnessed rapid development over the past decade, further improving survival for many of these patients. In this review, we provide an overview of types, epidemiology, imaging characteristics, surgical management strategies, and future areas of research for IMSCT.

Magnetic resonance-guided focused ultrasound for ablation of mesial temporal epilepsy circuits: modeling and theoretical feasibility of a novel noninvasive approach.

OBJECTIVE: The authors tested the feasibility of magnetic resonance-guided focused ultrasound (MRgFUS) ablation of mesial temporal lobe epilepsy (MTLE) seizure circuits. Up to one-third of patients with mesial temporal sclerosis (MTS) suffer from medically refractory epilepsy requiring surgery. Because current options such as open resection, laser ablation, and Gamma Knife radiosurgery pose potential risks, such as infection, hemorrhage, and ionizing radiation, and because they often produce visual or neuropsychological deficits, the authors developed a noninvasive MRgFUS ablation strategy for mesial temporal disconnection to mitigate these risks. METHODS: The authors retrospectively reviewed 3-T MRI scans obtained with diffusion tensor imaging (DTI). The study group included 10 patients with essential tremor (ET) who underwent pretreatment CT and MRI prior to MRgFUS, and 2 patients with MTS who underwent MRI. Fiber tracking of the fornix-fimbria pathway and inferior optic radiations was performed, ablation sites mimicking targets of open posterior hippocampal disconnection were modeled, and theoretical MRgFUS surgical plans were devised. Distances between the targets and optic radiations were measured, helmet angulations were prescribed, and the numbers of available MRgFUS array elements were calculated. RESULTS: Tractograms of fornix-fimbria and optic radiations were generated in all ET and MTS patients successfully. Of the 10 patients with both the CT and MRI data necessary for the analysis, 8 patients had adequate elements available to target the ablation site. A margin (mean 8.5 mm, range 6.5-9.8 mm) of separation was maintained between the target lesion and optic radiations. CONCLUSIONS: MRgFUS offers a noninvasive option for seizure tract disruption. DTI identifies fornix-fimbria and optic radiations to localize optimal ablation targets and critical surrounding structures, minimizing risk of postoperative visual field deficits. This theoretical modeling study provides the necessary groundwork for future clinical trials to apply this novel neurosurgical technique to patients with refractory MTLE and surgical contraindications, multiple prior surgeries, or other factors favoring noninvasive treatment.

Synchronous complex Chiari malformation and cleft palate-a case-based review.

BACKGROUND: The association between mid-facial clefts and Chiari malformation in the medical literature has been restricted to patients with syndromic craniofacial abnormalities. A common shared developmental pathway including causative factors for facial clefts and "complex" Chiari malformations, both midline skull base pathologies, seems logical but has not been reported. The coincident presentation of these findings in a single patient, and our subsequent discovery of other patients harboring these mutual findings prompted further investigation. CASE ILLUSTRATION: We describe the case of a patient born with a cleft palate which was repaired during his first year of life, subsequently presenting as a teenager to our hospital with a severe and symptomatic complex Chiari malformation. We discuss his treatment strategy, suboccipital decompression with occipitocervical fusion and endoscopic anterior decompression surgeries, as well as his favorable radiological and clinical outcome, demonstrated at long-interval follow-up. Furthermore, we review his two pathologies, cleft palate and Chiari malformation, and posit a common embryological linkage. CONCLUSIONS: The embryologic interaction between the paraxial mesoderm and ectoderm may explain the co-occurrence of cleft palate and complex Chiari malformation in a single patient. Complete radiological, clinical, and genetic evaluation and counseling is advised in this situation and raises the question of whether the presence of a cleft palate independently increases the risk for other skull base developmental abnormalities.

The Rate of Complications after Ventriculoperitoneal Shunt Surgery.

BACKGROUND: Although ventriculoperitoneal shunt (VPS) surgery is the most frequent surgical treatment for patients with hydrocephalus, modern rates of complications in adults are uncertain. METHODS: We performed a retrospective cohort study of adult patients hospitalized at the time of their first recorded procedure code for VPS surgery between 2005 and 2012 at nonfederal acute care hospitals in California, Florida, and New York. We excluded patients who during the index hospitalization for VPS surgery had concomitant codes for VPS revision, central nervous system (CNS) infection, or died during the index hospitalization. Patients were followed for the primary outcome of a VPS complication, defined as the composite of CNS infection or VPS revision. Survival statistics were used to calculate the cumulative rate and incidence rate of VPS complications. RESULTS: A total of 17,035 patients underwent VPS surgery. During a mean follow-up of 3.9 (± 1.8) years, at least 1 VPS complication occurred in 23.8% (95% confidence interval [CI], 22.9%-24.7%) of patients. The cumulative rate of CNS infection was 6.1% (95% CI, 5.7%-6.5%) and of VPS revision 22.0% (95% CI, 21.1%-22.9%). Most complications occurred within the first year of hospitalization for VPS surgery. Complication rates were 21.3 (95% CI, 20.6-22.1) complications per 100 patients per year in the first year after VPS surgery, 5.7 (95% CI, 5.3-6.1) in the second year after VPS surgery, and 2.5 (95% CI, 2.1-3.0) in the fifth year after VPS surgery. CONCLUSIONS: Complications are not infrequent after VPS surgery; however, most complications appear to be clustered in the first year after VPS insertion.

Adverse Outcomes After Initial Non-surgical Management of Subdural Hematoma: A Population-Based Study.

BACKGROUND: Little is known about the natural history of non-surgically managed subdural hematoma (SDH). The purpose of this study is to determine rates of adverse events after non-surgical management of SDH and whether these outcomes differ depending on traumatic versus nontraumatic etiology. A retrospective cohort study was conducted using administrative claims data on all emergency department visits and acute care hospitalizations at nonfederal facilities in California from 2005 to 2011, Florida from 2005 to 2012, and New York from 2006 to 2011. We included patients who were discharged home after hospitalization with a first-recorded diagnosis of SDH and no record of surgical hematoma evacuation. METHODS: Patients were followed for readmission with SDH, readmission for surgical SDH evacuation, and fatal readmission with SDH. Survival statistics and the log-rank test were used to compare rates of these adverse events after traumatic versus nontraumatic SDH. Multivariable Cox regression analysis was used to compare hazards for traumatic versus nontraumatic etiology while adjusting for age, sex, race, insurance status, presence of dementia, alcohol use, acquired abnormalities in coagulation, acquired abnormalities in platelet function, hypertension, atrial fibrillation, venous thromboembolism, ischemic stroke, coronary heart disease, and valvular disease. RESULTS: We identified 27,502 conservatively treated patients with SDH, of which 70.9% were traumatic and 29.1% nontraumatic. Compared to patients with traumatic SDH, patients with nontraumatic SDH had significantly higher rates of subsequent hospitalization with SDH (cumulative 90-day rates: 15.3 % [95% CI 14.5-16.1%] vs. 10.3% [95% CI 9.9-10.8%]), surgical SDH evacuation (7.8% [95% CI 7.3-8.5%] vs. 5.5% [95% CI 5.2-5.8%]), and SDH-related in-hospital death (1.0% [95% CI 0.8-1.2%] vs. 0.4% [95 % CI 0.3-0.5%]). In multivariable Cox regression analysis, nontraumatic etiology was associated with a higher hazard of readmission with SDH (HR 1.4; 95% CI 1.3-1.5), surgery (HR 1.3; 95% CI 1.2-1.4), and in-hospital mortality (HR 1.9; 95% CI 1.4-2.5). Our findings were unchanged in sensitivity analyses that also adjusted for Elixhauser comorbidities. CONCLUSIONS: Approximately one in eight patients with a conservatively managed SDH was readmitted with SDH within 90 days. A substantial proportion of these readmissions involved surgical hematoma evacuation. These outcomes occurred significantly more often after nontraumatic as compared to traumatic SDH.

Fetal brain mTOR signaling activation in tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is characterized by developmental malformations of the cerebral cortex known as tubers, comprised of cells that exhibit enhanced mammalian target of rapamycin (mTOR) signaling. To date, there are no reports of mTORC1 and mTORC2 activation in fetal tubers or in neural progenitor cells lacking Tsc2. We demonstrate mTORC1 activation by immunohistochemical detection of substrates phospho-p70S6K1 (T389) and phospho-S6 (S235/236), and mTORC2 activation by substrates phospho-PKCα (S657), phospho-Akt (Ser473), and phospho-SGK1 (S422) in fetal tubers. Then, we show that Tsc2 shRNA knockdown (KD) in mouse neural progenitor cells (mNPCs) in vitro results in enhanced mTORC1 (phospho-S6, phospho-4E-BP1) and mTORC2 (phospho-Akt and phospho-NDRG1) signaling, as well as a doubling of cell size that is rescued by rapamycin, an mTORC1 inhibitor. Tsc2 KD in vivo in the fetal mouse brain by in utero electroporation causes disorganized cortical lamination and increased cell volume that is prevented with rapamycin. We demonstrate for the first time that mTORC1 and mTORC2 signaling is activated in fetal tubers and in mNPCs following Tsc2 KD. These results suggest that inhibition of mTOR pathway signaling during embryogenesis could prevent abnormal brain development in TSC.

Microfluidic electro-sonoporation: a multi-modal cell poration methodology through simultaneous application of electric field and ultrasonic wave.

A microfluidic device that simultaneously applies the conditions required for microelectroporation and microsonoporation in a flow-through scheme toward high-efficiency and high-throughput molecular delivery into mammalian cells is presented. This multi-modal poration microdevice using simultaneous application of electric field and ultrasonic wave was realized by a three-dimensional (3D) microelectrode scheme where the electrodes function as both electroporation electrodes and cell flow channel so that acoustic wave can be applied perpendicular to the electric field simultaneously to cells flowing through the microfluidic channel. This 3D microelectrode configuration also allows a uniform electric field to be applied while making the device compatible with fluorescent microscopy. It is hypothesized that the simultaneous application of two different fields (electric field and acoustic wave) in perpendicular directions allows formation of transient pores along two axes of the cell membrane at reduced poration intensities, hence maximizing the delivery efficiency while minimizing cell death. The microfluidic electro-sonoporation system was characterized by delivering small molecules into mammalian cells, and showed average poration efficiency of 95.6% and cell viability of 97.3%. This proof of concept result shows that by combining electroporation and sonoporation together, significant improvement in molecule delivery efficiency could be achieved while maintaining high cell viability compared to electroporation or sonoporation alone. The microfluidic electro-sonoporation device presented here is, to the best of our knowledge, the first multi-modal cell poration device using simultaneous application of electric field and ultrasonic wave. This new multi-modal cell poration strategy and system is expected to have broad applications in delivery of small molecule therapeutics and ultimately in large molecule delivery such as gene transfection applications where high delivery efficiency and high viability are crucial.

Rapamycin prevents seizures after depletion of STRADA in a rare neurodevelopmental disorder.

A rare neurodevelopmental disorder in the Old Order Mennonite population called PMSE (polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome; also called Pretzel syndrome) is characterized by infantile-onset epilepsy, neurocognitive delay, craniofacial dysmorphism, and histopathological evidence of heterotopic neurons in subcortical white matter and subependymal regions. PMSE is caused by a homozygous deletion of exons 9 to 13 of the LYK5/STRADA gene, which encodes the pseudokinase STRADA, an upstream inhibitor of mammalian target of rapamycin complex 1 (mTORC1). We show that disrupted pathfinding in migrating mouse neural progenitor cells in vitro caused by STRADA depletion is prevented by mTORC1 inhibition with rapamycin or inhibition of its downstream effector p70 S6 kinase (p70S6K) with the drug PF-4708671 (p70S6Ki). We demonstrate that rapamycin can rescue aberrant cortical lamination and heterotopia associated with STRADA depletion in the mouse cerebral cortex. Constitutive mTORC1 signaling and a migration defect observed in fibroblasts from patients with PMSE were also prevented by mTORC1 inhibition. On the basis of these preclinical findings, we treated five PMSE patients with sirolimus (rapamycin) without complication and observed a reduction in seizure frequency and an improvement in receptive language. Our findings demonstrate a mechanistic link between STRADA loss and mTORC1 hyperactivity in PMSE, and suggest that mTORC1 inhibition may be a potential treatment for PMSE as well as other mTOR-associated neurodevelopmental disorders.

Detection of human papillomavirus in human focal cortical dysplasia type IIB.

OBJECTIVE: Focal cortical dysplasia type IIB (FCDIIB) is a sporadic developmental malformation of the cerebral cortex highly associated with pediatric epilepsy. Balloon cells (BCs) in FCDIIB exhibit constitutive activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. Recently, the high-risk human papillomavirus type 16 oncoprotein E6 was identified as a potent activator of mTORC1 signaling. Here, we test the hypothesis that HPV16 E6 is present in human FCDIIB specimens. METHODS: HPV16 E6 protein expression was assayed by immunohistochemistry in FCDIIB specimens (n = 50) and control brain specimens (n = 36). HPV16 E6 DNA was assayed by polymerase chain reaction (PCR) and in situ hybridization; HPV16 E6 mRNA was assayed by reverse transcriptase PCR. HPV16 E6 was transfected into fetal mouse brains by in utero electroporation to test the effects of E6 on cortical development. RESULTS: HPV16 E6 protein was robustly expressed in all FCDIIB specimens in BCs, but not in regions without BCs or in control tissue specimens including normal brain, lymphoblasts, and fibroblasts, cortical tubers, and U87 glioma cells. E6 expression in FCDIIB colocalized with phosphoactivated S6 protein, a known mTORC1 substrate. HPV16 E6 DNA and mRNA were detected in representative specimens of FCDIIB but not control cortex, and were confirmed by sequencing. Transfection of E6 into fetal mouse brains caused a focal cortical malformation in association with enhanced mTORC1 signaling. INTERPRETATION: Our results indicate a new association between HPV16 E6 and FCDIIB and demonstrate for the first time HPV16 E6 in the human brain. We propose a novel etiology for FCDIIB based on HPV16 E6 expression during fetal brain development.

Perioperative seizure incidence and risk factors in 223 pediatric brain tumor patients without prior seizures.

OBJECT: The incidence of, and risk factors for, perioperative seizures and the need for perioperative antiepileptic drugs (AEDs) in previously seizure-free children with brain tumors remains unclear. The authors have undertaken a review of previously seizure-free pediatric patients with brain tumors undergoing resection to identify the incidence of seizures in the perioperative period, and to characterize risk factors for perioperative seizures in this population. METHODS: A retrospective review was conducted of all patients between 0 and 19 years of age without prior seizures who underwent intracranial tumor resection at the authors' institution between January 2005 and December 2009. RESULTS: Of the 223 patients undergoing 229 operations, 7.4% experienced at least 1 clinical seizure during the surgical admission. Over half of all tumors were supratentorial. Only 4.4% of patients received prophylactic AEDs. Independent factors associated with perioperative seizures included supratentorial tumor, age < 2 years, and hyponatremia due to syndrome of inappropriate antidiuretic hormone or cerebral salt wasting. Tumor type, lobe affected, operative blood loss, and length of surgery were not independently associated with seizure incidence. CONCLUSIONS: Perioperative seizures in previously seizure-free children undergoing resection of brain tumors are associated with supratentorial tumor location, age < 2 years, and postoperative hyponatremia. Perioperative seizures are not associated with tumor pathology, tumor size, or frontotemporal location. Due to the low incidence of seizures in this series in patients more than 2 years old with normal serum sodium, the authors recommend that pediatric patients with brain tumors not routinely receive perioperative prophylactic AEDs. However, the role for prophylaxis in patients younger than 2 years of age deserves further study.

Enhanced epidermal growth factor, hepatocyte growth factor, and vascular endothelial growth factor expression in tuberous sclerosis complex.

Epidermal growth factor (EGF), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF) regulate angiogenesis and cell growth in the developing brain. EGF, HGF, and VEGF modulate the activity of the mammalian target of rapamycin (mTOR) cascade, a pathway regulating cell growth that is aberrantly activated in tuberous sclerosis complex (TSC). We hypothesized that expression of EGF, HGF, VEGF, and their receptors EGFR, c-Met, and Flt-1, respectively, would be altered in TSC. We show by cDNA array and immunohistochemical analysis that EGF, EGFR, HGF, c-Met, and VEGF, but not Flt-1, mRNA, and protein expression was up-regulated in Tsc1 conditional knockout (Tsc1(GFAP)CKO) mouse cortex. Importantly, these alterations closely predicted enhanced expression of these proteins in tuber and subependymal giant cell astrocytoma (SEGA) specimens in TSC. Expression of EGF, EGFR, HGF, c-Met, and VEGF protein, as well as hypoxia inducible factor-1α, a transcription factor that regulates VEGF levels and is also modulated by mTOR cascade activity, was enhanced in SEGAs (n = 6) and tubers (n = 10) from 15 TSC patients. Enhanced expression of these growth factors and growth factor receptors in human SEGAs and tubers and in the Tsc1(GFAP)CKO mouse may account for enhanced cellular growth and proliferation in tubers and SEGAs and provides potential target molecules for therapeutic development in TSC.