The Role of Blood Biomarkers for Magnetic Resonance Imaging Diagnosis of Traumatic Brain Injury.

Background and Objectives: The annual global incidence of traumatic brain injury (TBI) is over 10 million. An estimated 29% of TBI patients with negative computed tomography (CT-) have positive magnetic resonance imaging (MRI+) findings. Judicious use of serum biomarkers with MRI may aid in diagnosis of CT-occult TBI. The current manuscript aimed to evaluate the diagnostic, therapeutic and risk-stratification utility of known biomarkers and intracranial MRI pathology. Materials and Methods: The PubMed database was queried with keywords (plasma OR serum) AND (biomarker OR marker OR protein) AND (brain injury/trauma OR head injury/trauma OR concussion) AND (magnetic resonance imaging/MRI) (title/abstract) in English. Seventeen articles on TBI biomarkers and MRI were included: S100 calcium-binding protein B (S100B; N = 6), glial fibrillary acidic protein (GFAP; N = 3), GFAP/ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1; N = 2), Tau (N = 2), neurofilament-light (NF-L; N = 2), alpha-synuclein (N = 1), and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor peptide (AMPAR; N = 1). Results: Acute GFAP distinguished CT-/MRI+ from CT-/MRI- (AUC = 0.777, 0.852 at 9-16 h). GFAP discriminated CT-/diffuse axonal injury (DAI+) from controls (AUC = 0.903). Tau correlated directly with number of head strikes and inversely with white matter fractional anisotropy (FA), and a cutoff > 1.5 pg/mL discriminated between DAI+ and DAI- (sensitivity = 74%/specificity = 69%). NF-L had 100% discrimination of DAI in severe TBI and correlated with FA. Low alpha-synuclein was associated with poorer functional connectivity. AMPAR cutoff > 0.4 ng/mL had a sensitivity of 91% and a specificity of 92% for concussion and was associated with minor MRI findings. Low/undetectable S100B had a high negative predictive value for CT/MRI pathology. UCH-L1 showed no notable correlations with MRI. Conclusions: An acute circulating biomarker capable of discriminating intracranial MRI abnormalities is critical to establishing diagnosis for CT-occult TBI and can triage patients who may benefit from outpatient MRI, surveillance and/or follow up with TBI specialists. GFAP has shown diagnostic potential for MRI findings such as DAI and awaits further validation. Tau shows promise in detecting DAI and disrupted functional connectivity. Candidate biomarkers should be evaluated within the context of analytical performance of the assays used, as well as the post-injury timeframe for blood collection relative to MRI abnormalities.

Analysis of upfront resection or stereotactic radiosurgery for local control of solid and cystic cerebellar hemangioblastomas.

OBJECTIVE: The purpose of this study was to identify rates of and risk factors for local tumor progression in patients who had undergone surgery or radiosurgery for the management of cerebellar hemangioblastoma and to describe treatments pursued following tumor progression. METHODS: The authors conducted a retrospective single-center review of patients who had undergone treatment of a cerebellar hemangioblastoma with either surgery or stereotactic radiosurgery (SRS) between 1996 and 2019. Univariate and multivariate regression analyses were performed to examine factors associated with local tumor control. RESULTS: One hundred nine patients met the study inclusion criteria. Overall, these patients had a total of 577 hemangioblastomas, 229 of which were located in the cerebellum. The surgical and SRS cohorts consisted of 106 and 123 cerebellar hemangioblastomas, respectively. For patients undergoing surgery, tumors were treated with subtotal resection and gross-total resection in 5.7% and 94.3% of cases, respectively. For patients receiving SRS, the mean target volume was 0.71 cm3 and the mean margin dose was 18.0 Gy. Five-year freedom from lesion progression for the surgical and SRS groups was 99% and 82%, respectively. The surgical and SRS cohorts contained 32% versus 97% von Hippel-Lindau tumors, 78% versus 7% cystic hemangioblastomas, and 12.8- versus 0.56-cm3 mean tumor volumes, respectively. On multivariate analysis, factors associated with local tumor progression in the SRS group included older patient age (HR 1.06, 95% CI 1.03-1.09, p < 0.001) and a cystic component (HR 9.0, 95% CI 2.03-32.0, p = 0.001). Repeat SRS as salvage therapy was used more often for smaller tumor recurrences, and no tumor recurrences of < 1.0 cm3 required additional salvage surgery following repeat SRS. CONCLUSIONS: Both surgery and SRS achieve high rates of local control of hemangioblastomas. Age and cystic features are associated with local progression after SRS treatment for cerebellar hemangioblastomas. In cases of local tumor recurrence, salvage surgery and repeat SRS are valid forms of treatment to achieve local tumor control, although resection may be preferable for larger recurrences.

Factors associated with preoperative and postoperative seizures in patients undergoing resection of brain metastases.

OBJECTIVE: Epileptic seizures are a common and potentially devastating complication of metastatic brain tumors. Although tumor-related seizures have been described in previous case series, most studies have focused on primary brain tumors and have not differentiated between different types of cerebral metastases. The authors analyzed a large surgical cohort of patients with brain metastases to examine risk factors associated with preoperative and postoperative seizures and to better understand the seizure risk factors of metastatic brain tumors. METHODS: Patients who underwent resection of a brain metastasis at the University of California, San Francisco (UCSF), were retrospectively reviewed. Patients included in the study were ≥ 18 years of age, required resection of a brain metastasis, and were treated at UCSF. Primary cancers included melanoma, non-small cell lung adenocarcinoma, breast adenocarcinoma, colorectal adenocarcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, renal cell carcinoma, urothelial carcinoma, ovarian carcinoma, cervical squamous cell carcinoma, and endometrial adenocarcinoma. Patients were evaluated for primary cancer type and seizure occurrence, as well as need for use of antiepileptic drugs preoperatively, at time of discharge, and at 6 months postoperatively. Additionally, Engel classification scores were assigned to those patients who initially presented with seizures preoperatively. Univariate and multivariate regression analyses were used to assess the association of tumor type with preoperative seizures. RESULTS: Data were retrospectively analyzed for 348 consecutive patients who underwent surgical treatment of brain metastases between 1998 and 2019. The cohort had a mean age of 60 years at the time of surgery and was 59% female. The mean and median follow-up durations after the date of surgery for the cohort were 22 months and 10.8 months, respectively. In univariate analysis, frontal lobe location (p = 0.05), melanoma (p = 0.02), KRAS mutation in lung carcinoma (p = 0.04), intratumoral hemorrhage (p = 0.04), and prior radiotherapy (p = 0.04) were associated with seizure presentation. Postoperative checkpoint inhibitor use (p = 0.002), prior radiotherapy (p = 0.05), older age (p = 0.002), distant CNS progression (p = 0.004), and parietal lobe tumor location (p = 0.002) were associated with seizures at 6 months postoperatively. The final multivariate model confirmed the independent effects of tumor location in the frontal lobe and presence of intratumoral hemorrhage as predictors of preoperative seizures, and checkpoint inhibitor use and parietal lobe location were identified as significant predictors of seizures at 6 months postoperatively. CONCLUSIONS: Within this surgical cohort of patients with brain metastases, seizures were seen in almost a quarter of patients preoperatively. Frontal lobe metastases and hemorrhagic tumors were associated with higher risk of preoperative seizures, whereas checkpoint inhibitor use and parietal lobe tumors appeared to be associated with seizures at 6 months postoperatively. Future research should focus on the effect of metastatic lesion-targeting therapeutic interventions on seizure control in these patients.

Hemorrhagic vestibular schwannoma: a case example of vestibular apoplexy syndrome. Illustrative case.

BACKGROUND: Acute intratumoral hemorrhage within a vestibular schwannoma, or vestibular apoplexy, is a rare condition. Unlike the typical insidious vestibulopathy typically caused by vestibular schwannoma growth, patients with vestibular apoplexy have an acute and severe presentation with nausea and emesis in addition to severe vertigo and hearing loss. Here, the authors present an illustrative case demonstrating this rare clinical condition and an operative video detailing the surgical management. OBSERVATIONS: A 76-year-old man presented to the emergency department with acute-onset dizziness, left-ear fullness, double vision, gait ataxia, emesis, and facial numbness. Imaging revealed a 2.8-cm hemorrhagic left cerebellopontine angle lesion extending into the left internal auditory canal, consistent with hemorrhagic vestibular schwannoma. The patient subsequently underwent a retrosigmoid craniotomy for resection of the hemorrhagic mass, and by 1 month after surgery, all his presenting symptoms had resolved, allowing his return to daily activities. LESSONS: Vestibular schwannomas typically present with decreased hearing and chronic vestibulopathy. Acute presentation should raise the suspicion for an apoplectic event, and surgical debulking may lead to improvement in most vestibular symptoms.

Longitudinal MR spectroscopy to detect progression in patients with lower-grade glioma in the surveillance phase.

Background: Monitoring lower-grade gliomas (LrGGs) for disease progression is made difficult by the limits of anatomical MRI to distinguish treatment related tissue changes from tumor progression. MR spectroscopic imaging (MRSI) offers additional metabolic information that can help address these challenges. The goal of this study was to compare longitudinal changes in multiparametric MRI, including diffusion weighted imaging, perfusion imaging, and 3D MRSI, for LrGG patients who progressed at the final time-point and those who remained clinically stable. Methods: Forty-one patients with LrGG who were clinically stable were longitudinally assessed for progression. Changes in anatomical, diffusion, perfusion and MRSI data were acquired and compared between patients who remained clinically stable and those who progressed. Results: Thirty-one patients remained stable, and 10 patients progressed. Over the study period, progressed patients had a significantly greater increase in normalized choline, choline-to-N-acetylaspartic acid index (CNI), normalized creatine, and creatine-to-N-acetylaspartic acid index (CRNI), than stable patients. CRNI was significantly associated with progression status and WHO type. Progressed astrocytoma patients had greater increases in CRNI than stable astrocytoma patients. Conclusions: LrGG patients in surveillance with tumors that progressed had significantly increasing choline and creatine metabolite signals on MRSI, with a trend of increasing T2 FLAIR volumes, compared to LrGG patients who remained stable. These data show that MRSI can be used in conjunction with anatomical imaging studies to gain a clearer picture of LrGG progression, especially in the setting of clinical ambiguity.

Salvage Surgery for Local Control of Brain Metastases After Previous Stereotactic Radiosurgery: A Single-Center Series.

BACKGROUND: Although overall survival (OS) has improved in patients with brain metastases (BMs), control of recurrent BMs remains a therapeutic challenge. Salvage surgery may achieve acceptable control rates in the setting of progression after previous stereotactic radiosurgery (SRS), yet it remains a question how additional adjuvant therapies may affect outcomes and how patient selection for salvage surgery may be optimized. METHODS: Patients receiving salvage surgery for BM progression after previous SRS were retrospectively reviewed from a single center. Outcomes of interest included local tumor progression, leptomeningeal dissemination, and OS. Cox proportional hazard models and nominal logistic regression were applied to determine factors associated with outcomes of interest. RESULTS: A total of 43 patients with 50 BMs were included. After salvage surgery, local progression was observed for 17 BMs (34%), leptomeningeal dissemination was observed in 17 patients (39.5%), and censored median OS was 17.9 months. On multivariate analysis, use of brachytherapy was associated with improved local control (hazard ratio [HR], 0.15; 95% confidence interval [CI], 0.04-0.6; P = 0.008). For patients treated with SRS ≥4.5 months before salvage surgery, both brachytherapy (HR, 0.07; 95% CI, 0.01-0.39; P = 0.002) and postoperative adjuvant SRS (HR, 0.14; 95% CI, 0.02-1.00; P = 0.05) were associated with improved local control compared with no adjuvant radiation therapy. Presence of extracranial malignancy (HR, 6.70; 95% CI, 2.58-17.42; P < 0.0001) was associated with shorter survival. Graded prognostic assessment underestimated survival in 79.1% of patients, with a mean difference of 18.9 months between graded prognostic assessment-estimated and actual OS. CONCLUSIONS: In properly selected patients, salvage surgery may be an appropriate therapy for BM progression after previous SRS. Adjuvant brachytherapy and repeat SRS can offer significant benefit for local control with salvage resection.

Pediatric Traumatic Brain Injury in the United States: Rural-Urban Disparities and Considerations.

INTRODUCTION: Traumatic brain injury (TBI) remains a primary cause of pediatric morbidity. The improved characterization of healthcare disparities for pediatric TBI in United States (U.S.) rural communities is needed to advance care. METHODS: The PubMed database was queried using keywords (("brain/head trauma" OR "brain/head injury") AND "rural/underserved" AND "pediatric/child"). All qualifying articles focusing on rural pediatric TBI, including the subtopics epidemiology (N = 3), intervention/healthcare cost (N = 6), and prevention (N = 1), were reviewed. RESULTS: Rural pediatric TBIs were more likely to have increased trauma and head injury severity, with higher-velocity mechanisms (e.g., motor vehicle collisions). Rural patients were at risk of delays in care due to protracted transport times, inclement weather, and mis-triage to non-trauma centers. They were also more likely than urban patients to be unnecessarily transferred to another hospital, incurring greater costs. In general, rural centers had decreased access to mental health and/or specialist care, while the average healthcare costs were greater. Prevention efforts, such as mandating bicycle helmet use through education by the police department, showed improved compliance in children aged 5-12 years. CONCLUSIONS: U.S. rural pediatric patients are at higher risk of dangerous injury mechanisms, trauma severity, and TBI severity compared to urban. The barriers to care include protracted transport times, transfer to less-resourced centers, increased healthcare costs, missing data, and decreased access to mental health and/or specialty care during hospitalization and follow-up. Preventative efforts can be successful and will require an improved multidisciplinary awareness and education.

Concussion and Mild-Traumatic Brain Injury in Rural Settings: Epidemiology and Specific Health Care Considerations.

Background Mild-traumatic brain injury (mTBI) and concussions cause significant morbidity. To date, synthesis of specific health care disparities and gaps in care for rural mTBI/concussion patients remains needed. Methods A comprehensive literature search was performed using PubMed database for English articles with keywords "rural" and ("concussion" or "mild traumatic brain injury") from 1991 to 2019. Eighteen articles focusing on rural epidemiology ( n = 5), management/cost ( n = 5), military ( n = 2), and concussion prevention/return to play ( n = 6) were included. Results mTBI/concussion incidence was higher in rural compared with urban areas. Compared with urban patients, rural patients were at increased risk for vehicular injuries, lifetime number of concussions, admissions for observation without neuroimaging, and injury-related costs. Rural patients were less likely to utilize ambulatory and mental health services following mTBI/concussion. Rural secondary schools had decreased access to certified personnel for concussion evaluation, and decreased use of standardized assessment instruments/neurocognitive testing. While school coaches were aware of return-to-play laws, mTBI/concussion education rates for athletes and parents were suboptimal in both settings. Rural veterans were at increased risk for postconcussive symptoms and posttraumatic stress. Telemedicine in rural/low-resource areas is an emerging tool for rapid evaluation, triage, and follow-up. Conclusions Rural patients are at unique risk for mTBI/concussions and health care costs. Barriers to care include lower socioeconomic status, longer distances to regional medical center, and decreased availability of neuroimaging and consultants. Due to socioeconomic and distance barriers, rural schools are less able to recruit personnel certified for concussion evaluation. Telemedicine is an emerging tool for remote triage and evaluation.

Shunt Treatment for Coccidioidomycosis-Related Hydrocephalus: A Single-Center Series.

OBJECTIVE: Coccidioidomycosis is a fungal infection endemic to the southwestern United States. Hydrocephalus can develop after intracranial dissemination, and management of this disease entity is difficult. We present our institutional experience with shunting coccidioidomycosis-related hydrocephalus. METHODS: A cohort of patients with coccidioidomycosis-related hydrocephalus undergoing an intracranial shunt placement were retrospectively identified over a 24-year period. Demographics and treatment characteristics were obtained from the electronic medical record. RESULTS: Thirty patients undergoing 83 procedures were identified, with a median follow-up of 19.4 months. The average age of the cohort was 43 years at the time of initial shunt placement. Most patients (66.7%) had ≥1 shunt failure, and the average number of revisions required was 2.6 for patients who had shunt failure. The average shunt valve pressure threshold required was 5.5 cm H2O, and patients who harbored the disease for a longer period (>7 months) had a lower pressure setting for initial shunt valves. Shunts without an antisiphon component were more likely to be failure free on multivariate analysis (odds ratio, 9.2; 95% confidence interval, 2.4-35.7). Death was associated with a longer diagnosis-to-shunt time interval, and patients having been diagnosed with intracranial disease for more than 10 months before shunt placement had significantly higher rates of death on follow-up. CONCLUSIONS: Patients with coccidioidomycosis-related hydrocephalus typically have normal to low pressure setting requirements, high shunt failure rates, prolonged hospitalizations, and mortality. In this disease context, shunt valves without an antisiphon component are associated with lower shunt failure rates.

Triple motor mapping: transcranial, bipolar, and monopolar mapping for supratentorial glioma resection adjacent to motor pathways.

OBJECTIVE: Maximal safe resection of gliomas near motor pathways is facilitated by intraoperative mapping. The authors and other groups have described the use of bipolar or monopolar direct stimulation to identify functional tissue, as well as transcranial or transcortical motor evoked potentials (MEPs) to monitor motor pathways. Here, the authors describe their initial experience using all 3 modalities to identify, monitor, and preserve cortical and subcortical motor systems during glioma surgery. METHODS: Intraoperative mapping data were extracted from a prospective registry of glioma resections near motor pathways. Additional demographic, clinical, pathological, and imaging data were extracted from the electronic medical record. All patients with new or worsened postoperative motor deficits were followed for at least 6 months. RESULTS: Between January 2018 and August 2019, 59 operations were performed in 58 patients. Overall, patients in 6 cases (10.2%) had new or worse immediate postoperative deficits. Patients with temporary deficits all had at least Medical Research Council grade 4/5 power. Only 2 patients (3.4%) had permanently worsened deficits after 6 months, both of which were associated with diffusion restriction consistent with ischemia within the corticospinal tract. One patient's deficit improved to 4/5 and the other to 4/5 proximally and 3/5 distally in the lower limb, allowing ambulation following rehabilitation. Subcortical motor pathways were identified in 51 cases (86.4%) with monopolar high-frequency stimulation, but only in 6 patients using bipolar stimulation. Transcranial or cortical MEPs were diminished in only 6 cases, 3 of which had new or worsened deficits, with 1 permanent deficit. Insula location (p = 0.001) and reduction in MEPs (p = 0.01) were the only univariate predictors of new or worsened postoperative deficits. Insula location was the only predictor of permanent deficits (p = 0.046). The median extent of resection was 98.0%. CONCLUSIONS: Asleep triple motor mapping is safe and resulted in a low rate of deficits without compromising the extent of resection.