Development of a "Geo-Tagged" tumor sample registry: intra-operative linkage of sample location to imaging.

PURPOSE: There is a growing body of literature documenting glioma heterogeneity in terms of radiographic, histologic, molecular, and genetic characteristics. Incomplete spatial specification of intraoperative tumor samples may contribute to variability in the results of pathological and biological investigations. We have developed a system, termed geo-tagging, for routine intraoperative linkage of each tumor sample to its location via neuronavigation. METHODS: This is a single-institution, IRB approved, prospective database of undergoing clinically indicated surgery. We evaluated relevant factors affecting data collection by this registry, including tumor and surgical factors (e.g. tumor volume, location, grade and surgeon). RESULTS: Over a 2-year period, 487 patients underwent craniotomy for an intra-axial tumor. Of those, 214 underwent surgery for a newly diagnosed or recurrent glioma. There was significant variation in the average number of samples collected per registered case, with a range of samples from 2.53 to 4.75 per tumor type. Histology and grade impacted on sampling with a range of 2.0 samples per tumor in Grade four, IDH-WT gliomas to 4.5 samples in grade four, IDH-mutant gliomas. The range of cases with sampling per surgeon was 6 to 99 with a mean of 47.6 cases and there was a statistically significant differences between surgeons. Tumor grade did not have a statistically significant impact on number of samples per case. No significant correlation was found between the number of samples collected and enhancing tumor volume, EOR, or volume of tumor resected. CONCLUSION: We are using the results of this analysis to develop a prospective sample collection protocol.

NTRK3 gene fusion in an adult ganglioglioma: illustrative case.

BACKGROUND: Gangliogliomas are well-differentiated, slow-growing glioneuronal neoplasms frequently reported to harbor upregulating alterations in the mitogen-activated protein kinase pathway, particularly serine-threonine protein kinase B-RAF alterations. Fusions involving neurotrophin tyrosine receptor kinase (NTRK) genes have rarely been reported in ganglioglioma. Similarly, echinoderm microtubule-associated protein-like (EML) 4 gene fusion has been described in lung cancer, but none has been reported in ganglioglioma. OBSERVATIONS: This report discusses the care of a 72-year-old man presenting with medication-refractory, left-sided focal seizures who was found to have a nongadolinium-enhancing, T2-hyperintense, right frontoparietal lesion. The patient received resection, and histological analysis found a World Health Organization grade I ganglioglioma, with genetic analysis demonstrating an EML4-NTRK3 gene fusion protein. LESSONS: To our knowledge, this is the first report of an NTRK3 fusion, EML4-NTRK3, in an adult ganglioglioma, which is otherwise mostly associated with BRAF alterations and activation of the mitogen-activated protein kinase signaling pathway. Further studies are needed to elucidate the function of the resultant fusion protein and determine whether it may serve as a future therapeutic target.

Molecular determinants of outcomes in meningiomas.

Meningiomas are the most common intracranial primary tumor in adults. Surgery is the predominant therapeutic modality for symptomatic meningiomas. Although the majority of meningiomas are benign, there exists a subset of meningiomas that are clinically aggressive. Recent advances in genetics and epigenetics have uncovered molecular alterations that drive tumor meningioma biology with prognostic and therapeutic implications. In this review, we will discuss the advances on molecular determinants of therapeutic response in meningiomas to date and discuss findings of targeted therapies in meningiomas.

Spontaneous Spinal Subdural Hematoma Secondary to Hemophilia A and Zanubrutinib.

Spontaneous spinal subdural hematomas (SSH) are rare occurrences that can occur most commonly secondary to vascular malformations or coagulopathies. Only a small fraction of spontaneous SSHs are caused by acquired coagulation disorders such as leukemia, hemophilia, and thrombocytopenia. This case report describes a patient with a history of Guillain-Barré syndrome (GBS), hemophilia A, and mantle cell lymphoma, on zanubrutinib therapy, a Bruton tyrosine kinase inhibitor associated with a risk of spontaneous hemorrhage. This patient developed a spontaneous spinal subdural hematoma, most likely due to the zanubrutinib therapy and exacerbated due to hemophilia. Treatment was delayed due to the patient's history of GBS that confounded the clinical diagnosis. This case is the first report of a spontaneous SSH in a patient on zanubrutinib, highlighting the need for a high index of suspicion for CNS hemorrhage in patients on Bruton's tyrosine kinase (BTK) inhibitor therapy.

Improving Brain Metastases Outcomes Through Therapeutic Synergy Between Stereotactic Radiosurgery and Targeted Cancer Therapies.

Brain metastases are the most common form of brain cancer. Increasing knowledge of primary tumor biology, actionable molecular targets and continued improvements in systemic and radiotherapy regimens have helped improve survival but necessitate multidisciplinary collaboration between neurosurgical, medical and radiation oncologists. In this review, we will discuss the advances of targeted therapies to date and discuss findings of studies investigating the synergy between these therapies and stereotactic radiosurgery for non-small cell lung cancer, breast cancer, melanoma, and renal cell carcinoma brain metastases.

The History of Neurosurgical Spinal Oncology: From Inception to Modern-Day Practices.

The neurosurgical management of spinal neoplasms has undergone immense development in parallel with advancements made in general spine surgery. Laminectomies were performed as the first surgical procedures used to treat spinal neoplasms. Since then, neurosurgical spinal oncology has started to incorporate techniques that have developed from recent advances in minimally invasive spine surgery. Neurosurgery has also integrated radiotherapy into the treatment of spine tumors. In this historical vignette, we present a vast timeline spanning from the Byzantine period to the current day and recount the major advancements in the management of spinal neoplasms.

Analysis of shunted hydrocephalus follow-up: What do routine clinic visits yield? What factors affect revision surgery presentation and outcomes?

Frequency and duration of outpatient clinic follow-up for patients with shunted hydrocephalus varies among clinicians and assessment of follow-up regimens is lacking. The aim of this study is to investigate whether routine clinic visits alter care and whether they identify patients requiring shunt revision surgery, as well as, to better understand how patients utilize the outpatient clinic and present for shunt revision evaluation. This is a single-centered retrospective study of 154 patients requiring shunt revision surgery from 2009 to 2018 who had at least one prior clinic evaluation. The median age for shunt placement and revision were 3 months and 11 years old, respectively. Routine clinic visits led to a change in care for 16 patients (10.4%); including additional imaging, follow-up, or a combination of the two. With regards to revision surgery, days from prior shunt surgery, Chiari II/myelomeningocele pathology, and shunt type (p < 0.01) did affect time to presentation. Four patients (2.6%) requiring revision surgery were identified at routine clinic follow-up, while 92 (59.7%) and 47 (30.5%) presented to the emergency department and clinic sick visit, respectively. Presentation to clinic resulted in a statistically significant decrease in shunt revision surgery length-of-stay compared to presentation to the emergency department or inpatient admission for another condition. Even with increased emergency room utilization, increased clinic connectivity, and improved patient education, routine clinic visits remain an important component in the follow-up of patients with shunted hydrocephalus by helping to guide clinical care and identify patients requiring shunt revision surgery.

Vegetation of Ventriculoatrial Shunt Managed via Multidisciplinary Surgical Approach.

INTRODUCTION: The popularity of the ventriculoatrial shunt as a means for cerebrospinal fluid diversion was temporally limited, overcome by the success of the peritoneum as a site for distal drainage. Nevertheless, it remains an important tool for patients for whom ventriculoperitoneal shunting is not an option. CLINICAL PRESENTATION: We present the case of a 9-year-old girl with a ventriculoatrial shunt, who had undergone multiple revisions. Ultimately, she suffered a wound dehiscence, resulting in infectious seeding of the bloodstream and formation of a thrombus, presumed granuloma, at the tip of the distal catheter in the right atrium. She underwent successful removal of the lesion via an open approach by our cardiothoracic colleagues. DISCUSSION: Previous authors have noted a high number of mortalities as a result of these lesions. A collaborative approach resulted in a successful outcome for our patient. Although limited in utility today, the ventriculoatrial shunt remains a common procedure for neurosurgeons today. CONCLUSION: Recognizing the potential for atrial thrombus formation and using a team approach can help avoid a poor outcome.

Stabbing Injury of the Cervical Spinal Cord Resulting in Complete Loss of Bilateral Proprioception.

BACKGROUND: Direct penetrating trauma to the spinal cord as a result of stabbing is rare. The vertebral column is strongly suited to protecting the vital neural structures underneath, especially in the midline. CASE DESCRIPTION: A 25-year-old woman experienced a direct stabbing injury to her spinal cord, through the midline structures, resulting in bilateral dorsal column injury. She remained intact with regard to motor function despite bilateral sensory and proprioception loss. CONCLUSIONS: Owing to the strength of the protective elements of the osseous structures surrounding the spinal cord, direct stabbing injuries usually result in incomplete neurologic deficits. This is generally manifested as a Brown-Sequard syndrome because of the midline ligamentous structures and spinous processes deflecting injuries laterally. Our patient experienced a direct midline puncture, resulting in a unique case of bilateral dorsal column injury. These injuries are generally treated conservatively, in the absence of a retained foreign body. Spinal cord stabbing injuries are a rare entity with interesting clinical and anatomic correlations.

Update on the Physiologic Effects of Ketamine in General Anesthesia and Spinal Blockade: A Review of the Literature.

Ketamine, a phencyclidine analog and dissociative anesthetic, has been used in anesthesia since the 1960s. Serial subanesthetic administration has been explored for treatment of depression and chronic pain; however, there has been a recent surge in its intraoperative and perioperative use among anesthesia providers. As ketamine becomes an important addition to multimodal acute pain regimens, it important that anesthesia providers review the physiologic underpinnings of ketamine administration. Herein, we review the primary scientific literature and discuss recent studies that have implicated ketamine in inflammation and oxidative stress, inhibition of ion channels in dorsal horn neurons, and in disruption of frontoparietal communication. Also discussed are the potential clinical implications these effects may have for patients.

A familial syndrome of hypothalamic hamartomas, polydactyly, and SMO mutations: a clinical report of 2 cases.

Hypothalamic hamartomas are benign tumors known to cause gelastic or dacrystic seizures, precocious puberty, developmental delay, and medically refractory epilepsy. These tumors are most often sporadic but rarely can be associated with Pallister-Hall syndrome, an autosomal dominant familial syndrome caused by truncation of glioblastoma transcription factor 3, a downstream effector in the sonic hedgehog pathway. In this clinical report, the authors describe two brothers with a different familial syndrome. To the best of the authors' knowledge, this is the first report in the literature describing a familial syndrome caused by germline mutations in the Smoothened (SMO) gene and the first familial syndrome associated with hypothalamic hamartomas other than Pallister-Hall syndrome. The authors discuss the endoscopic endonasal biopsy and subtotal resection of a large hypothalamic hamartoma in one of the patients as well as the histopathological findings encountered. Integral to this discussion is the understanding of the hedgehog pathway; therefore, the underpinnings of this pathway and its clinical associations to date are also reviewed.

Downregulation of Leucine-Rich Repeat-Containing 8A Limits Proliferation and Increases Sensitivity of Glioblastoma to Temozolomide and Carmustine.

BACKGROUND: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Ubiquitously expressed volume-regulated anion channels (VRAC) are thought to play a role in cell proliferation, migration, and apoptosis. VRAC are heteromeric channel complexes assembled from proteins belonging to the leucine-rich repeat-containing 8A (LRRC8A through E), among which LRRC8A plays an indispensable role. In the present work, we used an RNAi approach to test potential significance of VRAC and LRRC8A in GBM survival and sensitivity to chemotherapeutic agents. METHODS: Primary GBM cells were derived from a human surgical tissue sample. LRRC8A expression was determined with quantitative RT-PCR and downregulated using siRNA. The effects of LRRC8A knockdown on GBM cell viability, proliferation, and sensitivity to chemotherapeutic agents were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and Coulter counter assays. Cell cycle progression was further explored using fluorescence-activated cell sorting analysis of propidium iodide-stained cells. RESULTS: Temozolomide (TMZ), carmustine, and cisplatin reduced GBM cell survival with the IC50 values of ~1,250, 320, and 30 µM, respectively. Two of three tested gene-specific siRNA constructs, siLRRC8A_3 and siLRRC8A_6, downregulated LRRC8A expression by >80% and significantly reduced GBM cell numbers. The most potent siLRRC8A_3 itself reduced viable cell numbers by ≥50%, and significantly increased toxicity of the sub-IC50 concentrations of TMZ (570 µM) and carmustine (167 µM). In contrast, the effects of siLRRC8A_3 and cisplatin (32 µM) were not additive, most likely because cisplatin uptake is VRAC-dependent. The results obtained in primary GBM cells were qualitatively recapitulated in U251 human GBM cell line. CONCLUSION: Downregulation of LRRC8A expression reduces GBM cell proliferation and increases sensitivity to the clinically used TMZ and carmustine. These findings indicate that VRAC represents a potential target for the treatment of GBM, alone or in combination with the current standard-of-care.

Magnetic resonance-guided interstitial high-intensity focused ultrasound for brain tumor ablation.

Currently, treatment of brain tumors is limited to resection, chemotherapy, and radiotherapy. Thermal ablation has been recently explored. High-intensity focused ultrasound (HIFU) is being explored as an alternative. Specifically, the authors propose delivering HIFU internally to the tumor with an MRI-guided robotic assistant (MRgRA). The advantage of the authors' interstitial device over external MRI-guided HIFU (MRgHIFU) is that it allows for conformal, precise ablation and concurrent tissue sampling. The authors describe their workflow for MRgRA HIFU delivery.

MRI Conditionality in Patients with Spinal Cord Stimulation Devices.

BACKGROUND: Because of the commonality of diagnostic magnetic resonance imaging (MRI), MRI conditional technology has increased throughout the device industry. It is often difficult to be aware of MRI specifications for each device. OBJECTIVES: We provide a review of the clinical experience with MRI and spinal cord stimulation (SCS) devices and develop a general reference of current device/MRI specifications. METHODS: We reviewed the available literature on the clinical experience with SCS devices and examined its specifications. RESULTS: We developed a user-friendly table of the specific compatibility of SCS devices in the USA and the European Union, and examined the existing literature on the clinical experience with MRI and SCS devices. We share our experience with obtaining spine MRI with MRI conditional SCS leads. CONCLUSION: By describing SCS device specifications and reviewing the literature, we provide a guide to implanting and treating physicians on obtaining MRIs in patients who have SCS devices.

Prehospital Glasgow Coma Score Predicts Emergent Intervention following Helicopter Transfer for Spontaneous Subarachnoid Hemorrhage.

BACKGROUND: Helicopter transport may shorten transport time to neurosurgical intervention; however, there are few data regarding its utility for nontraumatic emergencies. METHODS: Prehospital and hospital records of all patients transferred via helicopter to Dartmouth-Hitchcock Medical Center for spontaneous subarachnoid hemorrhage between January 2007 and December 2011 were reviewed. Primary outcome measure was emergent tertiary-level care intervention, defined as ventriculostomy, conventional angiography, endovascular treatment, or craniotomy within 3 hours of arrival. RESULTS: Fifty-one patients met inclusion criteria. Median helicopter transport time, defined as time from telephone referral to arrival, was 97 minutes (range, 61-214 minutes). Fifteen patients underwent intervention within 3 hours of arrival (29%), 19 patients underwent intervention between 3 and 6 hours (37%), 9 patients underwent intervention between 6 to 12 hours (18%), and 11 patients underwent intervention greater than 12 hours after arrival (16%). Univariate analysis of pretransfer clinical and radiographic findings showed significant correlations between Glasgow Coma Scale (GCS) score less than 15 (odds ratio [OR], 22.8; 95% confidence interval [CI], 4.2-122.5), World Federation of Neurologic Surgeons (WFNS) scale greater than 2 (OR, 46.75; 95% CI, 7.511-290.99), presence of intraparenchymal hemorrhage (OR, 4.7; 95% CI, 1.3-17.5), and intubation (OR, 12.4; 95% CI, 2.9-51.8) with emergent intervention. On logistic multivariate regression analysis, GCS score less than 15 and WFNS scale score greater than 2 independently predicted emergent intervention. CONCLUSIONS: A majority of patients with spontaneous subarachnoid hemorrhage who were transferred by interfacility helicopter ambulance did not require emergent intervention. GCS score less than 15 at an outside hospital was independently associated with emergent intervention on multivariate analysis.

Outpatient follow-up of nonoperative cerebral contusion and traumatic subarachnoid hemorrhage: does repeat head CT alter clinical decision-making?

OBJECTIVES: Many neurosurgeons obtain repeat head CT at the first clinic follow-up visit for nonoperative cerebral contusion and traumatic subarachnoid hemorrhage (tSAH). The authors undertook a single-center, retrospective study to determine whether outpatient CT altered clinical decision-making. METHODS: The authors evaluated 173 consecutive adult patients admitted to their institution from April 2006 to August 2012 with an admission diagnosis of cerebral contusion or tSAH and at least 1 clinic follow-up visit with CT. Patients with epidural, subdural, aneurysmal subarachnoid, or intraventricular hemorrhage, and those who underwent craniotomy, were excluded. Patient charts were reviewed for new CT findings, new patient symptoms, and changes in treatment plan. Patients were stratified by neurological symptoms into 3 groups: 1) asymptomatic; 2) mild, nonspecific symptoms; and 3) significant symptoms. Mild, nonspecific symptoms included minor headaches, vertigo, fatigue, and mild difficulties with concentration, short-term memory, or sleep; significant symptoms included moderate to severe headaches, nausea, vomiting, focal neurological complaints, impaired consciousness, or new cognitive impairment evident on routine clinical examination. RESULTS: One hundred seventy-three patients met inclusion criteria, with initial clinic follow-up obtained within approximately 6 weeks. Of the 173 patients, 104 (60.1%) were asymptomatic, 68 patients (39.3%) had mild, nonspecific neurological symptoms, and 1 patient (1.0%) had significant neurological symptoms. Of the asymptomatic patients, 3 patients (2.9%) had new CT findings and 1 of these patients (1.0%) underwent a change in treatment plan because of these findings. This change involved an additional clinic appointment and CT to monitor a 12-mm chronic subdural hematoma that ultimately resolved without treatment. Of the patients with mild, nonspecific neurological symptoms, 6 patients (8.8%) had new CT findings and 3 of these patients (4.4%) underwent a change in treatment plan because of these findings; none of these patients required surgical intervention. The single patient with significant neurological symptoms did not have any new CT findings. CONCLUSIONS: Repeat outpatient CT of asymptomatic patients after nonoperative cerebral contusion and tSAH is very unlikely to demonstrate significant new pathology. Given the cost and radiation exposure associated with CT, imaging should be reserved for patients with significant symptoms or focal findings on neurological examination.

The history of brain retractors throughout the development of neurological surgery.

Early neurosurgical procedures dealt mainly with treatment of head trauma, especially skull fractures. Since the early medical writings by Hippocrates, a great deal of respect was given to the dura mater, and many other surgeons warned against violating the dura. It was not until the 19th century that neurosurgeons started venturing beneath the dura, deep into the brain parenchyma. With this advancement, brain retraction became an essential component of intracranial surgery. Over the years brain retractors have been created pragmatically to provide better visualization, increased articulations and degrees of freedom, greater stability, less brain retraction injury, and less user effort. Brain retractors have evolved from simple handheld retractors to intricate brain-retraction systems with hand-rest stabilizers. This paper will focus on the history of brain retractors, the different types of retractors, and the progression from one form to another.