Standard clinical approaches and emerging modalities for glioblastoma imaging.

Glioblastoma (GBM) is the most common primary adult intracranial malignancy and carries a dismal prognosis despite an aggressive multimodal treatment regimen that consists of surgical resection, radiation, and adjuvant chemotherapy. Radiographic evaluation, largely informed by magnetic resonance imaging (MRI), is a critical component of initial diagnosis, surgical planning, and post-treatment monitoring. However, conventional MRI does not provide information regarding tumor microvasculature, necrosis, or neoangiogenesis. In addition, traditional MRI imaging can be further confounded by treatment-related effects such as pseudoprogression, radiation necrosis, and/or pseudoresponse(s) that preclude clinicians from making fully informed decisions when structuring a therapeutic approach. A myriad of novel imaging modalities have been developed to address these deficits. Herein, we provide a clinically oriented review of standard techniques for imaging GBM and highlight emerging technologies utilized in disease characterization and therapeutic development.

Hannover Classification of Vestibular Schwannomas: A Reliability Study.

BACKGROUND: The Hannover classification of vestibular schwannomas is designed to stratify tumors based on extrameatal extension and compression of the brainstem. We have previously reported the reliability of the Koos system, but to date, no study has assessed the reliability of the similar Hannover classification. OBJECTIVE: We present an assessment of the intrarater and interrater reliability of the Hannover classification system. METHODS: After institutional review board approval was obtained, a cross-sectional group of the magnetic resonance imaging of 40 patients with vestibular schwannomas varying in size comprised the study sample. Four raters were selected to assign a Hannover grade to 50 total scans. Interrater and intrarater reliability was calculated and reported using Fleiss's kappa, Kendall's W, and intraclass correlation coefficient (ICC). RESULTS: Interrater observer reliability was found to be moderate when measured using Fleiss' kappa (0.49), extremely strong using Kendall's W (0.93), and excellent as calculated by ICC (0.88). The results were all statistically significant (P < 0.05). Intrarater reliability for Hannover grade ranged from 0.77 to 1.00 (substantial to perfect). By Kendall's W and ICC, all raters had near perfect or excellent agreement. The results were all statistically significant (P < 0.05). CONCLUSIONS: The Hannover classification is a reliable system for grading the size of vestibular schwannomas. This supports its continued use and previously published results of the literature in studies relying on this classification. Further studies are needed to evaluate its validity and determine its role in preoperative counseling and determining microsurgery and radiosurgery outcomes.

Existence of knowledge silos in the adult blunt cerebrovascular injury literature.

BACKGROUND: Blunt cerebrovascular injuries (BCVI) remain a significant source of disability and mortality among trauma patients. The purpose of the present study was to determine whether knowledge silos exist in the overall BCVI literature. METHODS: An object-oriented programmatic script written in Python programming language was used to extract and categorize articles and references on the topic of BCVI. Additionally, each BCVI article was searched for by digital object identifier in the other BCVI references to build a network analysis and visualize topic reference patterns. Analyses were performed using Stata V.14.2 (StataCorp). RESULTS: A total of 306 articles with 10 282 references were included for analysis. Of these, 24% (74) were published in neurosurgery journals, 45% (137) were published in trauma journals, and 31% (95) were published in a journal of another specialty. Similar proportions were found when categorized by author departmental affiliation. Trauma surgery authors disproportionately referenced articles in the trauma literature, compared with neurosurgeons (73.5% vs. 48.0%, p<0.0001), and other authors. The biggest factor influencing reference proportions was the specialty of the publishing journal. Finally, a network analysis revealed that there are more trauma BCVI articles, and there are more frequently cited trauma BCVI articles by all specialties. CONCLUSIONS: This study revealed the existence of a one-way knowledge silo in the BCVI literature. However, a robust preference by both trauma and neurosurgery to cite trauma references when publishing in trauma journals may indicate a possible conscious curating of citations by authors to increase the likelihood of publication. These observations highlight the need for an active role by journal editors, peer reviewers, and authors to actively foster diversity of citations and cross-specialty collaboration to improve dissemination of information between these specialties. LEVEL OF EVIDENCE: Level IV. Observational study.

Immunovirotherapy for the Treatment of Glioblastoma and Other Malignant Gliomas.

Glioblastoma multiforme (GBM) represents one of the most challenging malignancies due to many factors including invasiveness, heterogeneity, and an immunosuppressive microenvironment. Current treatment modalities have resulted in only modest effect on outcomes. The development of viral vectors for oncolytic immunovirotherapy and targeted drug delivery represents a promising therapeutic prospect for GBM and other brain tumors. A host of genetically engineered viruses, herpes simplex virus, poliovirus, measles, and others, have been described and are at various stages of clinical development. Herein we provide a review of the advances and current state of oncolytic virotherapy for the targeted treatment of GBM and malignant gliomas.

Cerebellar talcosis following posterior reversible encephalopathy syndrome in an intravenous methamphetamine abuser.

BACKGROUND: Intravenous (IV) methamphetamine abuse is associated with a variety of short- and long-term effects on the nervous system, some of which have yet to be fully elucidated. One known systemic complication that has not been described in nervous system tissues is the deposition of substrate crystals contained in injectable drugs. CASE DESCRIPTION: An unusual case is presented of a 35-year-old active IV methamphetamine abuser with posterior reversible encephalopathy syndrome (PRES) who subsequently developed multifocal bilateral cerebellar enhancing lesions and leptomeningeal enhancement due to biopsy-proven crystalline deposits. CONCLUSION: Although large crystalline substances will not normally penetrate the blood-brain barrier (BBB), during a state of BBB compromise such as with PRES, talc deposition may occur in the central nervous system.

Posterior communicating artery injury and symptomatic vasospasm after high-energy blunt head injury: illustrative case.

BACKGROUND: Most of the published literature pertaining to blunt traumatic cerebrovascular injury (BCVI) is focused on extracranial arterial injury. Studies of intracranial arterial injury are relatively uncommon. OBSERVATIONS: The clinical course of a patient who sustained an injury to the right posterior communicating artery followed by infarction due to vasospasm after severe traumatic brain injury is presented, along with a focused literature review. LESSONS: Intracranial BCVI is uncommon, and this report may serve to raise awareness of BCVI management and the importance of recognizing symptomatic vasospasm due to BCVI.

Rapid Evolution and Rupture of an Incidental Aneurysm During Hyperdynamic Therapy for Cerebral Vasospasm.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high morbidity and mortality. Among the most common sequelae of aSAH is delayed cerebral ischemia. Hyperdynamic therapy (fluid supplementation and hypertension) is used to increase cerebral perfusion. However, the safety of hyperdynamic therapy in patients with separate unruptured, unsecured intracranial aneurysms is not well-established. Herein, a rare case demonstrating the rapid evolution and rupture of an incidental unsecured aneurysm in the setting of hyperdynamic therapy is presented. CASE DESCRIPTION: A 56-year-old woman without significant medical history presented with aSAH secondary to rupture of a 3-mm left posterior inferior cerebellar artery aneurysm. After endovascular treatment of this aneurysm, she developed symptomatic vasospasm prompting initiation of hyperdynamic therapy. Seven days after initiation of hyperdynamic therapy, she experienced rupture of an incidental pericallosal artery aneurysm that was found to have increased in size during the hyperdynamic therapy. She ultimately survived and was functionally independent approximately 1 year after her initial ictus. CONCLUSIONS: This case demonstrates that enlargement and rupture of an incidental, previously unruptured aneurysm may occur during hyperdynamic therapy.

Risk factors for wound-related complications after microvascular decompression.

Retrosigmoid craniotomy for microvascular decompression (MVD) has been traditionally performed via craniectomy. Various closure techniques have been described, yet factors associated with wound-related complications remain undetermined. Accordingly, herein, we sought to identify risk factors associated with wound-related complications after such procedures. An institutional retrospective case-control study was performed; outcomes of interest were cerebrospinal fluid (CSF) leak, wound dehiscence, wound infection, and pseudomeningocele. Univariate analysis was performed using Wilcoxon rank sum test for non-parametric continuous outcomes and chi-square test for categorical outcomes. Multivariate logistic regression was performed on binomial outcome variables. The study population included 197 patients who underwent MVD for trigeminal neuralgia (83.2%), hemifacial spasm (12.2%), vestibular nerve section (3.0%), and glossopharyngeal neuralgia (1.5%). The overall wound-related complication rate was 14.2% (n = 28), including twelve patients (6.1%) with CSF leak, ten patients (5.1%) with wound infection, ten patients (5.1%) with pseudomeningocele, and nine (4.6%) patients with wound dehiscence. Using multivariate logistic regression, preoperative anemia and current tobacco use were associated with significantly higher rates of complications (OR 6.01 and 4.58, respectively; p < 0.05), including CSF leak (OR 12.83 and 12.40, respectively, p < 0.05). Of note, use of synthetic bone substitute for cranioplasty was associated with a significantly lower rate of complications (OR 0.13, p < 0.01). Preoperative anemia and current tobacco use significantly increased, while synthetic bone substitute cranioplasty significantly decreased, odds of wound-related complications, the need for treatment, and CSF leaks. Additionally, higher BMI, longer operative duration, and prior radiosurgery may increase risk for wound-related complications.

Post-Traumatic Stress Symptoms in Caregivers and Children with Hydrocephalus.

OBJECTIVE: Hydrocephalus is a disorder of cerebrospinal fluid dynamics, traditionally treated by placement of a ventricular shunt. Shunts are effective but imperfect as they fail in an unpredictable pattern, and the patient's well-being is dependent on adequate shunt function. The omnipresent threat of shunt failure along with the potential need for invasive investigations can be stressful for patients and caregivers. Our objective was to measure post-traumatic stress symptoms (PTSS) in children with hydrocephalus and their caregivers. METHODS: A cross-sectional analysis of children with hydrocephalus and their caregivers was conducted. Caregivers completed a measure of their own PTSS (the Post-Traumatic Stress Disorders Checklist for the Diagnostic and Statistical Manual of Mental Disorders-V) and resilience (the Connor Davidson Resilience Scale). Pediatric patients rated their own PTSS and resilience using the Acute Stress Checklist for Kids and Connor Davidson Resilience Scale. RESULTS: Ninety-one caregivers completed the Post-Traumatic Stress Disorders Checklist for the Diagnostic and Statistical Manual of Mental Disorders-V. Mean score was 17.0 (standard deviation 15.7; median 13.0). Fourteen percent scored above 33, the threshold suggestive of a preliminary diagnosis of post-traumatic stress disorder. There was a statistically significant association between caregiver post-traumatic stress and marital status, child's race, and caregiver education. More than half (52%) of caregivers reported their child's hydrocephalus as the most significant source of their PTSS. Children did not have markedly elevated levels of PTSS. Forty-one percent of caregivers and 60% of children scored in the lowest resilience quartile compared with the general population. CONCLUSIONS: Results from this study suggest that post-traumatic stress affects caregivers with hydrocephalus, yet levels of resilience for caregivers and pediatric patients are low.

Impact of Anesthetic Variation in Endovascular Treatment of Acute Ischemic Stroke.

Background Given recent technological advancements leading to better outcomes in endovascular therapy for acute ischemic stroke (AIS), updated guidelines recommend thrombectomy as the standard of care in acute large vessel occlusions. However, use of general anesthesia versus conscious sedation continues to be discussed. Two previous randomized trials have shown no significant difference between the use of conscious sedation compared with general anesthesia. Methods The authors performed a retrospective analysis of all consecutive patients with acute ischemia who underwent intra-arterial thrombectomy between September 2014 and May 2020 at a Level 1 stroke center. Patient characteristics along with clinical and operative data were extracted. Frequency distributions of selected characteristics were obtained and statistical significance of any differences according to the mode of anesthesia was assessed. Results A total of 480 patients were included in this study, 257 underwent general anesthesia and 223 underwent conscious sedation. Length of stay (LOS) in the ICU nor length of hospital stay was significantly different between groups. Change in National Institutes of Health Stroke Scale (NIHSS) score from admission to discharge, procedure times, and discharge disposition were not found to be significantly associated with either group although there was a trend towards longer door to puncture time with general anesthesia. Discharge disposition was found to be significantly associated with admission NIHSS (p=0.04). There was a trend towards longer hospital stay in patients with worse admission NIHSS (p=0.09). Success of thrombectomy was not significantly different between both anesthesia groups (p=0.37). Conclusions This large, single-center retrospective cohort study echoes the results of two previous randomized controlled trials in demonstrating non-inferiority of general anesthesia versus conscious sedation in cases of intra-arterial thrombectomy for AIS. These results contrast those of previously published retrospective studies.

Concussion in soccer: a comprehensive review of the literature.

Sports-related concussion has been examined extensively in collision sports such as football and hockey. However, historically, lower-risk contact sports such as soccer have only more recently garnered increased attention. Here, we review articles examining the epidemiology, injury mechanisms, sex differences, as well as the neurochemical, neurostructural and neurocognitive changes associated with soccer-related concussion. From 436 titles and abstracts, 121 full texts were reviewed with a total of 64 articles identified for inclusion. Concussion rates are higher during competitions and in female athletes with purposeful heading rarely resulting in concussion. Given a lack of high-level studies examining sports-related concussion in soccer, clinicians and scientists must focus research efforts on large-scale data gathering and development of improved technologies to better detect and understand concussion.

Intraventricular metastatic melanoma: A case report and review of the literature.

Intraventricular melanoma is a very rare and highly malignant disease. Safe resection is the mainstay of treatment, but no standard guidelines exist for adjuvant therapy. Early histologic and molecular diagnosis is key for improved survival.

An Observational Study Investigating the Need for Decompressive Hemicraniectomy after Thrombectomy in Acute Ischemic Stroke of the Middle Cerebral Artery Territory.

OBJECTIVE: The frequency incidence of decompressive hemicraniectomy following intra-arterial thrombectomy (IAT) in acute ischemic stroke (AIS) involving the middle cerebral artery (MCA) territory was assessed as a surrogate for morbidity. METHODS: A single-institution retrospective chart review was conducted involving 209 consecutive patients between September 2014 and May 2017 with infarctions affecting the MCA territory and who subsequently underwent IAT. The outcomes of interest included the frequency of hemicraniectomy following IAT and the effects of intravenous tissue plasminogen activator (IV tPA) use and primary occlusion site on the Thrombolysis in Cerebral Infarction (TICI) score. RESULTS: Thirty-one patients were excluded for infarctions not involving the MCA territory. A total of 178 patients were included in the study. Sixty-eight patients (38.6%) had infarctions of less than one-third of the MCA territory, 50 (28.4%) had infarctions between one-third and two-thirds, and 58 (33%) had infarctions involving greater than two-thirds with 54.3% suffering infarctions of the left side. Only four patients (2.2%) required a hemicraniectomy with no statistically significant association found between TICI score and hemicraniectomy (p=0.41) or between administration of IV tPA and hemicraniectomy (p=0.36). The primary occlusion site was found to influence TICI score (p=0.045). CONCLUSION: A very small number of patients required hemicraniectomy after IAT as compared to previously published rates in the literature. However, several factors may prevent the patient from being an appropriate hemicraniectomy candidate in the first place and the small number of these patients in this study limits statistical analysis. The variables that determine a patient's candidacy for decompressive hemicraniectomy remains multi-factorial.

Incidence and risk factors for seizures associated with deep brain stimulation surgery.

OBJECTIVE: The objective of this study was to determine the incidence of seizures following deep brain stimulation (DBS) electrode implantation and to evaluate factors associated with postoperative seizures. METHODS: The authors performed a single-center retrospective case-control study. The outcome of interest was seizure associated with DBS implantation. Univariate analyses were performed using the Student t-test for parametric continuous outcomes. The authors used the Kruskal-Wallis test or Wilcoxon rank-sum test for nonparametric continuous outcomes, chi-square statistics for categorical outcomes, and multivariate logistic regression for binomial variables. RESULTS: A total of 814 DBS electrode implantations were performed in 645 patients (478 [58.7%] in men and 520 [63.9%] in patients with Parkinson's disease). In total, 22 (3.4%) patients who had undergone 23 (2.8%) placements experienced seizure. Of the 23 DBS implantation-related seizures, 21 were new-onset seizures (3.3% of 645 patients) and 2 were recurrence or worsening of a prior seizure disorder. Among the 23 cases with postimplantation-related seizure, epilepsy developed in 4 (17.4%) postoperatively; the risk of DBS-associated epilepsy was 0.50% per DBS electrode placement and 0.63% per patient. Nine (39.1%) implantation-related seizures had associated postoperative radiographic abnormalities. Multivariate analyses suggested that age at surgery conferred a modest increased risk for postoperative seizures (OR 1.06, 95% CI 1.02-1.10). Sex, primary diagnosis, electrode location and sidedness, and the number of trajectories were not significantly associated with seizures after DBS surgery. CONCLUSIONS: Seizures associated with DBS electrode placement are uncommon, typically occur early within the postoperative period, and seldom lead to epilepsy. This study suggests that patient characteristics, such as age, may play a greater role than perioperative variables in determining seizure risk. Multiinstitutional studies may help better define and mitigate the risk of seizures after DBS surgery.

Design and Rationale for First-in-Human Phase 1 Immunovirotherapy Clinical Trial of Oncolytic HSV G207 to Treat Malignant Pediatric Cerebellar Brain Tumors.

Brain tumors represent the most common pediatric solid neoplasms and leading cause of childhood cancer-related morbidity and mortality. Although most adult brain tumors are supratentorial and arise in the cerebrum, the majority of pediatric brain tumors are infratentorial and arise in the posterior fossa, specifically the cerebellum. Outcomes from malignant cerebellar tumors are unacceptable despite aggressive treatments (surgery, radiation, and/or chemotherapy) that are harmful to the developing brain. Novel treatments/approaches such as oncolytic virotherapy are urgently needed. Preclinical and prior clinical studies suggest that genetically engineered oncolytic herpes simplex virus (HSV-1) G207 can safely target cerebellar malignancies and has potential to induce an antitumor immune response at local and distant sites of disease, including spinal metastases and leptomeningeal disease. Herein, we outline the rationale, design, and significance of a first-in-human immunotherapy Phase 1 clinical trial targeting recurrent cerebellar malignancies with HSV G207 combined with a single low-dose of radiation (5 Gy), designed to enhance virus replication and innate and adaptive immune responses. We discuss the unique challenges of inoculating virus through intratumoral catheters into cerebellar tumors. The trial utilizes a single arm open-label traditional 3 + 3 design with four dose cohorts. The primary objective is to assess safety and tolerability of G207 with radiation in recurrent/progressive malignant pediatric cerebellar tumors. After biopsy to prove recurrence/progression, one to four intratumoral catheters will be placed followed by a controlled-rate infusion of G207 for 6 h followed by the removal of catheters at the bedside. Radiation will be given within 24 h of virus inoculation. Patients will be monitored closely for toxicity and virus shedding. Efficacy will be assessed by measuring radiographic response, performance score, progression-free and overall survival, and quality of life. The data obtained will be invaluable in our efforts to produce more effective and less toxic therapies for children with high-grade brain tumors.

Hydrocephalus-related quality of life as assessed by children and their caregivers.

OBJECTIVE: Hydrocephalus is a chronic medical condition that has a significant impact on children and their caregivers. The objective of this study was to measure the quality of life (QOL) of children with hydrocephalus, as assessed by both caregivers and patients. METHODS: Pediatric patients with hydrocephalus and their caregivers were enrolled during routine neurosurgery clinic visits. The Hydrocephalus Outcomes Questionnaire (HOQ), a report of hydrocephalus-related QOL, was administered to both children with hydrocephalus (self-report) and their caregivers (proxy report about the child). Patients with hydrocephalus also completed measures of anxiety, depression, fatigue, traumatic stress, and headache. Caregivers completed a proxy report of child traumatic stress and a measure of caregiver burden. Demographic information was collected from administration of the Psychosocial Assessment Tool (version 2.0) and from the medical record. Child and caregiver HOQ scores were analyzed and correlated with clinical, demographic, and psychological variables. RESULTS: The mean overall HOQ score (parent assessment of child QOL) was 0.68. HOQ Physical Health, Social-Emotional Health, and Cognitive Health subscore averages were 0.69, 0.73, and 0.54, respectively. The mean overall child self-assessment (cHOQ) score was 0.77, with cHOQ Physical Health, Social-Emotional Health, and Cognitive Health subscore means of 0.84, 0.79, and 0.66, respectively. Thirty-nine dyads were analyzed, in which both a child with hydrocephalus and his or her caregiver completed the cHOQ and HOQ. There was a positive correlation between parent and child scores (p < 0.004 for all subscores). Child scores were consistently higher than parent scores. Variables that showed association with caregiver-assessed QOL in at least one domain included child age, etiology of hydrocephalus, and history of endoscopic third ventriculostomy. There was a significant negative relationship (rho -0.48 to -0.60) between child-reported cHOQ score and child-reported measures of posttraumatic stress, anxiety, depression, and fatigue. There was a similar significant relationship between caregiver report of child's QOL (HOQ) and caregiver assessment of the child's posttraumatic stress symptoms as well as their assessment of burden of care (rho = -0.59 and rho = -0.51, respectively). No relationship between parent-reported HOQ and child-reported psychosocial factors was significant. No clinical or demographic variables were associated with child self-assessed cHOQ. CONCLUSIONS: Pediatric patients with hydrocephalus consistently rate their own QOL higher than their caregivers do. Psychological factors such as anxiety and posttraumatic stress may be associated with lower QOL. These findings warrant further exploration.

Efficacy of osimertinib against EGFRvIII+ glioblastoma.

Epidermal Growth Factor Receptor variant III (EGFRvIII) is an active mutant form of EGFR that drives tumor growth in a subset of glioblastoma (GBM). It occurs in over 20% of GBMs, making it a promising receptor for small molecule targeted therapy. We hypothesize that poor penetration of the blood-brain barrier by previously tested EGFR-tyrosine kinase inhibitors (EGFR-TKIs) such as afateninb, erlotinib, gefitinib, and lapatinib played a role in their limited efficacy. The present study examined the effects of osimertinib (previously known as AZD9291) on EGFRvIII+ GBM models, both in vitro and in vivo. Therefore, a panel of six GBM stem cells (GSCs) expressing EGFRvIII+ was evaluated. The EGFRvIII+ GSC differed in the expression of EGFRvIII and other key genes. The GSC line D317, which expresses high levels of EGFRvIII and has robust tyrosine kinase activity, was selected for assessing osimertinib's efficacy. Herein, we report that osimertinib inhibits the constitutive activity of EGFRvIII tyrosine kinase with high potency (<100 nM) while also inhibiting its downstream signaling. Further, osimertinib inhibited D317's growth in vitro and in both heterotopic and orthotopic xenograft models. Additional preclinical studies are warranted to identify EGFRvIII+ GBM's molecular signature most responsive to osimertinib.

Targeting glioma-initiating cells via the tyrosine metabolic pathway.

OBJECTIVE: Despite an aggressive multimodal therapeutic regimen, glioblastoma (GBM) continues to portend a grave prognosis, which is driven in part by tumor heterogeneity at both the molecular and cellular levels. Accordingly, herein the authors sought to identify metabolic differences between GBM tumor core cells and edge cells and, in so doing, elucidate novel actionable therapeutic targets centered on tumor metabolism. METHODS: Comprehensive metabolic analyses were performed on 20 high-grade glioma (HGG) tissues and 30 glioma-initiating cell (GIC) sphere culture models. The results of the metabolic analyses were combined with the Ivy GBM data set. Differences in tumor metabolism between GBM tumor tissue derived from within the contrast-enhancing region (i.e., tumor core) and that from the peritumoral brain lesions (i.e., tumor edge) were sought and explored. Such changes were ultimately confirmed at the protein level via immunohistochemistry. RESULTS: Metabolic heterogeneity in both HGG tumor tissues and GBM sphere culture models was identified, and analyses suggested that tyrosine metabolism may serve as a possible therapeutic target in GBM, particularly in the tumor core. Furthermore, activation of the enzyme tyrosine aminotransferase (TAT) within the tyrosine metabolic pathway influenced the noted therapeutic resistance of the GBM core. CONCLUSIONS: Selective inhibition of the tyrosine metabolism pathway may prove highly beneficial as an adjuvant to multimodal GBM therapies.