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Ha Son Nguyen, Ninh B Doan, Michael J Gelsomino, Saman Shabani, Wade M Mueller Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, WI, USA Background: Secondary brain stem injury is associated with transtentorial herniation, and manifests as “Duret” hemorrhages. Such an injury has been considered a terminal brain stem event with a high morbidity and mortality, sometimes discouraging continuation of care. However, there have been rare instances where patients have had reasonable recovery. We report another case, emphasizing that such an injury by itself should not deter aggressive measures, as good outcomes remain a possibility. Case presentation: A 37-year-old male sustained a right subdural hematoma after a mechanical fall while intoxicated. He presented initially with a Glasgow Coma Scale 15. Three days later, he exhibited acute neurological deterioration to Glasgow Coma Scale 4, requiring intubation and mannitol. Repeat scan demonstrated enlarging right subdural hematoma with worsening shift; brain stem hemorrhage was noted at pontomesencephalic junction. Patient was immediately taken for subdural hematoma evacuation. The following day, patient was able to sluggishly follow commands in all four extremities. He had a short stay for inpatient rehabilitation and underwent autologous cranioplasty at 3 months. On examination, he was awake, alert, and oriented to self, time, and location; he exhibited dysarthric speech, right ptosis, but followed commands in all four extremities with no focal motor weakness. Conclusion: In contrast to the common belief, patients suffering from a “Duret” hemorrhage can still have a good outcome. “Duret” hemorrhages may not represent a fatal injury. The finding from this paper suggests the finding of “Duret” hemorrhages on imaging should not deter aggressive measures especially in patients with lesions causing significant mass effects. Overall clinical status should drive surgical options and clinical course. Keywords: Duret hemorrhage, brain stem hemorrhage, subdural hematoma

ObjectiveWe have reported that glucose utilization regulates leptin expression and secretion from isolated rat adipocytes. In this study, we employed two antidiabetic agents that act to increase glucose uptake by peripheral tissues, metformin and vanadium, as pharmacological tools to examine the effects of altering glucose utilization on leptin secretion in primary cultures of rat adipocytes.Research methods and proceduresIsolated adipocytes (100 microL of packed cells per well) were anchored in a defined matrix of basement membrane components (Matrigel) with media containing 5.5 mM glucose and incubated for 96 hours with metformin or vanadium. Leptin secretion, glucose utilization, and lactate production were assessed.ResultsMetformin (0.5 and 1.0 mM) increased glucose uptake in the presence of 0.16 nM insulin by 37 +/- 10% (p < 0.005) and 62 +/- 8% (p < 0.0001) over insulin alone, respectively. Metformin from 0.5 to 5.0 mM increased lactate production by 105 +/- 43% (p < 0.025) to 202 +/- 52% (p < 0.0025) and at 1.0 and 5.0 mM increased the proportional rate of glucose conversion to lactate by 78 +/- 18% (p < 0.005) and 166 +/- 41% (p < 0.0025), respectively. At concentrations less than 0.5 mM, metformin did not affect leptin secretion, but at 0.5 mM, the only concentration that significantly increased glucose utilization without increasing glucose conversion to lactate, leptin secretion was modestly stimulated (by 20 +/- 9%; p < 0.05). Concentrations from 1.0 to 25 mM inhibited leptin secretion by 25 +/- 8% (p < 0.005) to 89 +/- 4% (p < 0.0001). Across metformin doses, leptin secretion was inversely related to the percentage of glucose taken up and released as lactate (r = -0.74; p < 0.0001). Vanadium (5 to 20 microM) increased glucose uptake from 20 +/- 7% (p < 0.01) to 34 +/- 13% (p < 0.02) and increased lactate production at 5 microM by 17 +/- 8% (p < 0.025) and 10 microM by 61 +/- 20% (p < 0.02) but did not alter the conversion of glucose to lactate. Vanadium (5 to 50 microM) inhibited leptin secretion by 33 +/- 6% (p < 0.0025) to 61 +/- 8% (p < 0.0001).DiscussionBoth metformin and vanadium increase glucose uptake and inhibit leptin secretion from cultured adipocytes. The inhibition of leptin secretion by metformin is related to an increase in the metabolism of glucose to lactate. The inhibition by vanadium most likely involves direct effects on cellular phosphatases. We hypothesize that the effect of glucose utilization to stimulate leptin production involves the metabolism of glucose to a fate other than anaerobic lactate production, possibly oxidation or lipogenesis.

Adipose tissue secretes leptin, which interacts with receptors in the hypothalamus. In rodent models of obesity, leptin increases metabolism and decreases food intake, which helps to maintain normal body composition. Accurate and precise methods to quantitate circulating leptin concentrations are needed for physiological studies. We developed an RIA to measure leptin in rat plasma, serum, or adipocyte culture fluids. The working range of the assay, defined by the detection limit and the highest calibrator, was 0.5-50 micrograms/L. Recovery of 1.6-11.6 micrograms/L leptin added to serum was 92-103%. The rat leptin RIA correlated well with a previously developed mouse RIA when rat plasma was assayed with both methods (r = 0.94), but the mouse leptin assay underestimated rat leptin in plasma. Within- and between-run CVs were 2.4% to 5.7%. Plasma leptin concentrations correlated directly with percentage of body fat, and correlation improved when the results were separated by gender (r = 0.796, P < 0.001 for males; r = 0.710, P < 0.001 for females). Leptin concentrations were generally higher in male rats than in females; plasma leptin increased 0.60 microgram/L for each percentage of increase in body fat for males but only 0.22 microgram/L for females. We conclude that rat serum/plasma leptin concentrations are accurately and precisely measured with this new RIA.

Circulating leptin secreted from adipocytes is correlated with fat mass and plasma insulin concentrations in humans and rodents. Plasma leptin, insulin, and glucose decrease during fasting and increase after refeeding; however, the underlying mechanisms regulating the changes of leptin secretion are not known. To investigate the role of insulin-stimulated glucose metabolism in the regulation of leptin secretion, we examined the effects of insulin and inhibitors of glucose transport and metabolism on leptin secretion from rat adipocytes in primary culture. Insulin (0.16-16 nM) increased leptin secretion over 96 h; however, the increase in leptin was more closely related to the amount of glucose taken up by the adipocytes (r = 0.64; P < 0.0001) than to the insulin concentration per se (r = 0.20; P < 0.28), suggesting a role for glucose transport and/or metabolism in regulating leptin secretion. 2-Deoxy-D-glucose (2-DG), a competitive inhibitor of glucose transport and phosphorylation, caused a concentration-dependent (2-50 mg/dl) inhibition of leptin release in the presence of 1.6 nM insulin. The inhibitory effect of 2-DG was reversed by high concentrations of glucose. Two other inhibitors of glucose transport, phloretin (0.05-0.25 mM) and cytochalasin-B (0.5-50 microM), also inhibited leptin secretion. Inhibition of leptin secretion by these agents was proportional to the inhibition of glucose uptake (r = 0.60 to 0.86; all P < 0.01). Two inhibitors of glycolysis, iodoacetate (0.005-1.0 mM) and sodium fluoride (0.1-5 mM), produced concentration-dependent inhibition of leptin secretion in the presence of 1.6 nM insulin. In addition, both 2-DG and sodium fluoride markedly decreased the leptin (ob) messenger RNA content of cultured adipocytes, but did not affect 18S ribosomal RNA content. We conclude that glucose transport and metabolism are important factors in the regulation of leptin expression and secretion and that the effect of insulin to increase adipocyte glucose utilization is likely to contribute to insulin-stimulated leptin secretion. Thus, in vivo, decreased adipose glucose metabolism may be one mechanism by which fasting decreases circulating leptin, whereas increased adipose glucose metabolism would increase leptin after refeeding.

Background: Glioblastoma multiforme (GBM) is the most aggressive and prevalent type of malignant brain tumor, yet it metastasizes outside the central nervous system (CNS) in only 0.4% of cases. Little is known about what enables this subset of GBMs to take root outside the CNS, but genetic mutations likely play a role., Methods: We conducted a PRISMA-compliant systematic review of metastatic GBM wherein we reviewed 3579 search results and 1080 abstracts, analyzing data from 139 studies and 211 unique patients. In addition, we describe 4 cases of patients with pathologically confirmed GBM metastases outside the CNS treated at our institution., Results: We found that metastases were discovered near previous surgical sites in at least 36.9% of cases. Other sites of metastasis included bone (47.9%), lung (25.6%), lymph nodes (25.1%), scalp (19.2%), and liver (14.2%). On average, metastases were diagnosed 12.1 months after the most recent resection, and the mean survival from discovery was 5.7 months. In our patients, primary GBM lesions showed mutations in NF1, TERT, TP53, CDK4, and RB1/PTEN genes. Unique to the metastatic lesions were amplifications in genes such as p53 and PDGFRA/KIT, as well as increased vimentin and Ki-67 expression., Conclusions: There is strong evidence that GBMs acquire novel mutations to survive outside the CNS. In some cases, tumor cells likely mutate after seeding scalp tissue during surgery, and in others, they mutate and spread without surgery. Future studies and genetic profiling of primary and metastatic lesions may help uncover the mechanisms of spread., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Here we assess whether the volume of cerebral ischemia induced during glioma surgery may negatively impact survival independently of neurological function. We also evaluate the sensitivity of intraoperative MRI (iMRI) in detecting cerebral ischemia during surgery., Methods: We retrospectively reviewed 361 cranial surgeries that used a 3 Tesla iMRI. 165 patients met all inclusion criteria and were included in the final analysis. Diffusion weighted imaging (DWI) obtained during iMRI was compared to postoperative DWI obtained within 7 days of the operation in cases where no further resection occurred after the iMRI., Results: 42 of 165 patients (25%) showed at least some evidence of restricted diffusion on postoperative (poMRI). 37 of these 42 (88%) cases lacked evidence of restricted diffusion on iMRI, meaning iMRI had a false-negative rate of 88% and a sensitivity of 12% in assessing the extent of ischemic brain after surgery. In high-grade gliomas, the volume of restricted diffusion on poMRI was predictive of overall survival, independent of new functional deficits acquired during surgery (p = 0.011)., Conclusion: This study presents the largest case series to date analyzing the sensitivity of iMRI in detecting surgical ischemia. In high-grade gliomas, increased volume of ischemia correlated with worsening median overall survival (OS) irrespective of postoperative neurologic deficits. Future work will focus on improving intraoperative detection of ischemia during the hyperacute phase when interventions such as blood pressure modulation or direct application of vasodilator agents may be effective., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Objectives: This study identified a clinically significant subset of patients with glioma with tumor outside of contrast enhancement present at autopsy and subsequently developed a method for detecting nonenhancing tumor using radio-pathomic mapping. We tested the hypothesis that autopsy-based radio-pathomic tumor probability maps would be able to noninvasively identify areas of infiltrative tumor beyond traditional imaging signatures., Methods: A total of 159 tissue samples from 65 subjects were aligned to MRI acquired nearest to death for this retrospective study. Demographic and survival characteristics for patients with and without tumor beyond the contrast-enhancing margin were computed. An ensemble algorithm was used to predict pixelwise tumor presence from pathological annotations using segmented cellularity (Cell), extracellular fluid, and cytoplasm density as input (6 train/3 test subjects). A second level of ensemble algorithms was used to predict voxelwise Cell, extracellular fluid, and cytoplasm on the full data set (43 train/22 test subjects) using 5-by-5 voxel tiles from T1, T1 + C, fluid-attenuated inversion recovery, and apparent diffusion coefficient as input. The models were then combined to generate noninvasive whole brain maps of tumor probability., Results: Tumor outside of contrast was identified in 41.5% of patients, who showed worse survival outcomes (hazard ratio = 3.90, P < .001). Tumor probability maps reliably tracked nonenhancing tumor on a range of local and external unseen data, identifying tumor outside of contrast in 69% of presurgical cases that also showed reduced survival outcomes (hazard ratio = 1.67, P = .027)., Conclusion: This study developed a multistage model for mapping gliomas using autopsy tissue samples as ground truth, which was able to identify regions of tumor beyond traditional imaging signatures., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Congress of Neurological Surgeons.)

Background and Objectives: Gross-total resection (GTR) and low residual tumor volume (RTV) have been associated with increased survival in glioblastoma. Largely due to the subjectivity involved, the determination of GTR and RTV remains difficult in the postoperative setting. In response, the objective of this study is to evaluate the clinical efficacy of an easy-to-use MRI metric, called delta T1 (dT1), to quantify extent of resection (EOR) and RTV, in comparison to radiologist impression, to predict overall survival (OS) in glioblastoma patients., Methods: 59 patients who underwent resection of glioblastoma were retrospectively identified. Delta T1 (dT1) images, automatically created from the difference between calibrated post- and pre-contrast T1-weighted images, were used to quantify EOR and RTV. Kaplan-Meier survival estimates were determined for EOR categories, an RTV cutoff of 5cm 3 and radiologist interpretation of EOR. Multivariate Cox proportional hazard regression analysis was used to evaluate RTV and EOR along with effects related to sex, KPS, MGMT, and age on OS., Results: Kaplan-Meier analysis revealed a statistically significant difference in median OS for a dT1-determined RTV cutoff of 5 cm 3 (P=.0024, HR=2.18 (1.232-3.856)), but not for radiological impression (P=0.666) or dT1-determined EOR (P=0.0803), which was limited to a comparison between partial and subtotal resections. Furthermore, when covariates were accounted for in multivariate Cox regression, significant differences in OS were retained for dT1-determined RTV. Additionally, a significantly strong yet short-term effect of MGMT methylation status on OS was revealed for each RTV and EOR model., Conclusion: The utility of dT1 maps to quantify EOR and RTV in glioblastoma and predict survival, suggests an emerging role for dT1s with relevance for intraoperative MRI, neuro-navigation and postoperative disease surveillance.

Background: Standard of care for brain metastases involves stereotactic radiosurgery (SRS). For cases that also require surgery because of lesion size, edema, or neurological symptoms, whether to provide pre- or postoperative SRS has become a prevalent debate., Observations: Herein, the unique case of a patient with brain metastases of the same pathology and similar size in two different brain locations at two different times is described. The patient underwent surgery with preoperative SRS for the first lesion and surgery with postoperative SRS for the second lesion. Although both treatments resulted in successful local control, the location that received postoperative SRS developed symptomatic and rapidly progressive radiation necrosis (RN) requiring a third craniotomy., Lessons: Large randomized controlled trials are ongoing to compare pre- versus postoperative SRS for the treatment of symptomatic brain metastases (e.g., study NRG-BN012). Recent interest in preoperative SRS has emerged from its theoretical potential to decrease rates of postoperative RN and leptomeningeal disease. This valuable case in which both therapies were applied in a single patient with a single pathology and similar lesions provides evidence supportive of preoperative SRS.

Purpose: The response of cystic brain metastases (BMets) to radiation therapy is poorly understood, with conflicting results regarding local control, overall survival, and treatment-related toxicity. This study aims to examine the role of Gamma Knife (GK) in managing cystic BMets., Methods and Materials: Volumetric analysis was conducted to measure tumor and edema volume at the time of GK and follow-up magnetic resonance imaging studies. Survival was described using the Kaplan-Meier method, and the cumulative incidence of progression was described using the Aalen-Johansen estimator. We evaluated the association of 4 variables with survival using Cox regression analysis., Results: Between 2016 and 2021, 54 patients with 83 cystic BMets were treated with GK at our institution. Lung cancer was the most common pathology (51.9%), followed by breast cancer (13.0%). The mean target volume was 2.7 cm 3 (range, 0.1-39.0 cm 3 ), and the mean edema volume was 13.9 cm 3 (range, 0-165.5 cm 3 ). The median prescription dose of single-fraction and fractionated GK was 20 Gy (range, 14-27.5 Gy). With a median follow-up of 8.9 months, the median survival time (MST) was 11.1 months, and the 1-year local control rate was 75.9%. Gamma Knife was associated with decreased tumor and edema volumes over time, although 68.5% of patients required steroids after GK. Patients whose tumors grew beyond baseline after GK received significantly more whole-brain radiation therapy (WBRT) before GK than those whose tumors declined after GK. Higher age at diagnosis of BMets and pre-GK systemic therapy were associated with worse survival, with an MST of 7.8 months in patients who received it compared with 23.3 months in those who did not., Conclusions: Pre-GK WBRT may select for BMets with increased radioresistance. This study highlights the ability of GK to control cystic BMets with the cost of high posttreatment steroid use., Competing Interests: Joseph A. Bovi reports a relationship with Imaging Biometrics that includes consulting or advising. Christopher J. Schultz reports a relationship with Elekta AB that includes funding grants and travel reimbursement; a relationship with Siemens Healthineers that includes board membership and funding grants; and relationships with Accuray Inc and Mantia Medical Imaging that include funding grants. Lindsay Puckett reports a relationship with Accuray Inc that includes speaking and lecture fees. The other authors declare no personal, financial, or institutional interests in any of the drugs, materials, or devices described in this article., (© 2023 The Author(s).)

Background and Objectives: Naming decline after left temporal lobe epilepsy (TLE) surgery is common and difficult to predict. Preoperative language fMRI may predict naming decline, but this application is still lacking evidence. We performed a large multicenter cohort study of the effectiveness of fMRI in predicting naming deficits after left TLE surgery., Methods: At 10 US epilepsy centers, 81 patients with left TLE were prospectively recruited and given the Boston Naming Test (BNT) before and ≈7 months after anterior temporal lobectomy. An fMRI language laterality index (LI) was measured with an auditory semantic decision-tone decision task contrast. Correlations and a multiple regression model were built with a priori chosen predictors., Results: Naming decline occurred in 56% of patients and correlated with fMRI LI ( r = -0.41, p < 0.001), age at epilepsy onset ( r = -0.30, p = 0.006), age at surgery ( r = -0.23, p = 0.039), and years of education ( r = 0.24, p = 0.032). Preoperative BNT score and duration of epilepsy were not correlated with naming decline. The regression model explained 31% of the variance, with fMRI contributing 14%, with a 96% sensitivity and 44% specificity for predicting meaningful naming decline. Cross-validation resulted in an average prediction error of 6 points., Discussion: An fMRI-based regression model predicted naming outcome after left TLE surgery in a large, prospective multicenter sample, with fMRI as the strongest predictor. These results provide evidence supporting the use of preoperative language fMRI to predict language outcome in patients undergoing left TLE surgery., Classification of Evidence: This study provides Class I evidence that fMRI language lateralization can help in predicting naming decline after left TLE surgery., (© 2022 American Academy of Neurology.)

Background and Purpose: Currently, contrast-enhancing margins on T1WI are used to guide treatment of gliomas, yet tumor invasion beyond the contrast-enhancing region is a known confounding factor. Therefore, this study used postmortem tissue samples aligned with clinically acquired MRIs to quantify the relationship between intensity values and cellularity as well as to develop a radio-pathomic model to predict cellularity using MR imaging data., Materials and Methods: This single-institution study used 93 samples collected at postmortem examination from 44 patients with brain cancer. Tissue samples were processed, stained with H&E, and digitized for nuclei segmentation and cell density calculation. Pre- and postgadolinium contrast T1WI, T2 FLAIR, and ADC images were collected from each patient's final acquisition before death. In-house software was used to align tissue samples to the FLAIR image via manually defined control points. Mixed-effects models were used to assess the relationship between single-image intensity and cellularity for each image. An ensemble learner was trained to predict cellularity using 5 × 5 voxel tiles from each image, with a two-thirds to one-third train-test split for validation., Results: Single-image analyses found subtle associations between image intensity and cellularity, with a less pronounced relationship in patients with glioblastoma. The radio-pathomic model accurately predicted cellularity in the test set (root mean squared error = 1015 cells/mm 2 ) and identified regions of hypercellularity beyond the contrast-enhancing region., Conclusions: A radio-pathomic model for cellularity trained with tissue samples acquired at postmortem examination is able to identify regions of hypercellular tumor beyond traditional imaging signatures., (© 2022 by American Journal of Neuroradiology.)

Direct electrical stimulation of the brain is the gold standard technique used to define functional-anatomical relationships during neurosurgical procedures. Areas that respond to stimulation are considered "critical nodes" of circuits that must remain intact for the subject to maintain the ability to perform certain functions, like moving and speaking. Despite its routine use, the neurophysiology underlying downstream motor responses to electrical stimulation of the brain, such as muscle contraction or movement arrest, is poorly understood. Furthermore, varying and sometimes counterintuitive responses can be seen depending on how and where the stimulation is applied, even within the human primary motor cortex. Therefore, here we review relevant neuroanatomy of the human motor system, provide a brief historical perspective on electrical brain stimulation, explore mechanistic variations in stimulation applications, examine neurophysiological properties of different parts of the motor system, and suggest areas of future research that can promote a better understanding of the interaction between electrical stimulation of the brain and its function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Aaronson, Martinez Del Campo, Boerger, Conway, Cornell, Tate, Mueller, Chang and Krucoff.)

Purpose: Dismal prognosis and limited treatment options for recurrent high-grade glioma have provoked interest in various forms of reirradiation. Pulsed reduced dose rate radiation therapy (pRDR) is a promising technique that exploits low-dose hyper-radiosensitivity of proliferating tumor cells while sparing adjacent nonproliferating normal brain tissue. Large radiation treatment volumes can thus be used to target both contrast-enhancing and FLAIR abnormalities thought to harbor recurrent gross and microscopic disease, respectively. The aim of this retrospective study was to determine whether the addition of pRDR to bevacizumab improves survival over bevacizumab alone for recurrent high-grade glioma., Methods and Materials: Eighty patients with recurrent high-grade glioma were included in this study; 47 patients received bevacizumab monotherapy (BEV), and 33 patients received pRDR with bevacizumab (BEV/pRDR). Progression-free survival (PFS) and overall survival were compared between the BEV and BEV/pRDR groups. Regression analysis was performed to identify and control for confounding influences on survival analyses., Results: Significant (P < .05) advantages in PFS (12 vs 4 months; hazard ratio = 2.37) and OS (16 vs. 9 months; hazard ratio = 1.68) were observed with BEV/pRDR compared with BEV alone., Conclusions: This retrospective analysis suggests that treatment with pRDR in addition to bevacizumab could significantly prolong PFS and overall survival compared with bevacizumab alone for recurrent high-grade glioma., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To define left temporal lobe regions where surgical resection produces a persistent postoperative decline in naming visual objects., Methods: Pre- and postoperative brain magnetic resonance imaging data and picture naming (Boston Naming Test) scores were obtained prospectively from 59 people with drug-resistant left temporal lobe epilepsy. All patients had left hemisphere language dominance at baseline and underwent surgical resection or ablation in the left temporal lobe. Postoperative naming assessment occurred approximately 7 months after surgery. Surgical lesions were mapped to a standard template, and the relationship between presence or absence of a lesion and the degree of naming decline was tested at each template voxel while controlling for effects of overall lesion size., Results: Patients declined by an average of 15% in their naming score, with wide variation across individuals. Decline was significantly related to damage in a cluster of voxels in the ventral temporal lobe, located mainly in the fusiform gyrus approximately 4-6 cm posterior to the temporal tip. Extent of damage to this region explained roughly 50% of the variance in outcome. Picture naming decline was not related to hippocampal or temporal pole damage., Significance: The results provide the first statistical map relating lesion location in left temporal lobe epilepsy surgery to picture naming decline, and they support previous observations of transient naming deficits from electrical stimulation in the basal temporal cortex. The critical lesion is relatively posterior and could be avoided in many patients undergoing left temporal lobe surgery for intractable epilepsy., (© 2020 International League Against Epilepsy.)

Magnetic resonance (MR)-derived radiomic features have shown substantial predictive utility in modeling different prognostic factors of glioblastoma and other brain cancers. However, the biological relationship underpinning these predictive models has been largely unstudied, and the generalizability of these models had been called into question. Here, we examine the localized relationship between MR-derived radiomic features and histology-derived "histomic" features using a data set of 16 patients with brain cancer. Tile-based radiomic features were collected on T1, post-contrast T1, FLAIR, and diffusion-weighted imaging (DWI)-derived apparent diffusion coefficient (ADC) images acquired before patient death, with analogous histomic features collected for autopsy samples coregistered to the magnetic resonance imaging. Features were collected for each original image, as well as a 3D wavelet decomposition of each image, resulting in 837 features per MR and histology image. Correlative analyses were used to assess the degree of association between radiomic-histomic pairs for each magnetic resonance imaging. The influence of several confounds was also assessed using linear mixed-effect models for the normalized radiomic-histomic distance, testing for main effects of different acquisition field strengths. Results as a whole were largely heterogeneous, but several features showed substantial associations with their histomic analogs, particularly those derived from the FLAIR and postcontrast T1W images. These features with the strongest association typically presented as stable across field strengths as well. These data suggest that a subset of radiomic features can consistently capture texture information on underlying tissue histology., Competing Interests: Conflict of Interest: None reported., (© 2020 The Authors. Published by Grapho Publications, LLC.)

Numerous studies have shown that surgical resection of the left anterior temporal lobe (ATL) is associated with a decline in object naming ability (Hermann et al., 1999). In contrast, few studies have examined the effects of left ATL surgery on auditory description naming (ADN) or category-specific naming. Compared with object naming, which loads heavily on visual recognition processes, ADN provides a more specific measure of concept retrieval. The present study examined ADN declines in a large group of patients who were tested before and after left ATL surgery, using a 2 × 2 × 2 factorial manipulation of uniqueness (common vs. proper nouns), taxonomic category (living vs. nonliving things), and time (pre- vs. postsurgery). Significant declines occurred across all categories but were substantially larger for proper living (PL) concepts, i.e., famous individuals. The disproportionate decline in PL noun naming relative to other conditions is consistent with the notion that the left ATL is specialized not only for retrieval of unique entity concepts, but also plays a role in processing social concepts and person-specific features., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to report., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The absence of major progress in the treatment of glioblastoma (GBM) is partly attributable to our poor understanding of both GBM tumor biology and the acquirement of treatment resistance in recurrent GBMs. Recurrent GBMs are characterized by their resistance to radiation. In this study, we used an established stable U87 radioresistant GBM model and total RNA sequencing to shed light on global mRNA expression changes following irradiation. We identified many genes, the expressions of which were altered in our radioresistant GBM model, that have never before been reported to be associated with the development of radioresistant GBM and should be concertedly further investigated to understand their roles in radioresistance. These genes were enriched in various biological processes such as inflammatory response, cell migration, positive regulation of epithelial to mesenchymal transition, angiogenesis, apoptosis, positive regulation of T-cell migration, positive regulation of macrophage chemotaxis, T-cell antigen processing and presentation, and microglial cell activation involved in immune response genes. These findings furnish crucial information for elucidating the molecular mechanisms associated with radioresistance in GBM. Therapeutically, with the global alterations of multiple biological pathways observed in irradiated GBM cells, an effective GBM therapy may require a cocktail carrying multiple agents targeting multiple implicated pathways in order to have a chance at making a substantial impact on improving the overall GBM survival., Competing Interests: CONFLICTS OF INTEREST None declared.

Chronic subdural hematoma (cSDH) is a common neurosurgical pathology associated with older age and complicated by antiplatelet/anticoagulant therapies. With improving medical care in an aging population, the incidence of cSDH will likely increase over the next 25 years, placing a burden on health care costs. Consequently, a simple and inexpensive treatment option is desirable. As such, we report a basic, but novel, technique to drain cSDH with an Integra Camino bolt. This technique was employed in two patients, where the significant resolution of cSDH and associated clinical symptoms were observed without complications., Competing Interests: There are no conflicts of interest.

The goal of this study is to spatially discriminate tumor from treatment effect (TE), within the contrast-enhancing lesion, for brain tumor patients at all stages of treatment. To this end, the diagnostic accuracy of MRI-derived diffusion and perfusion parameters to distinguish pure TE from pure glioblastoma (GBM) was determined utilizing spatially-correlated biopsy samples. From July 2010 through June 2015, brain tumor patients who underwent pre-operative DWI and DSC-MRI and stereotactic image-guided biopsy were considered for inclusion in this IRB-approved study. MRI-derived parameter maps included apparent diffusion coefficient (ADC), normalized cerebral blood flow (nCBF), normalized and standardized relative cerebral blood volume (nRCBV, sRCBV), peak signal-height (PSR) and percent signal-recovery (PSR). These were co-registered to the Stealth MRI and median values extracted from the spatially-matched biopsy regions. A ROC analysis accounting for multiple subject samples was performed, and the optimal threshold for distinguishing TE from GBM determined for each parameter. Histopathologic diagnosis of pure TE (n = 10) or pure GBM (n = 34) was confirmed in tissue samples from 15 consecutive subjects with analyzable data. Perfusion thresholds of sRCBV (3575; SN/SP% = 79.4/90.0), nRCBV (1.13; SN/SP% = 82.1/90.0), and nCBF (1.05; SN/SP% = 79.4/80.0) distinguished TE from GBM (P < 0.05), whereas ADC, PSR, and PH could not (P > 0.05). The thresholds for CBF and CBV can be applied to lesions with any admixture of tumor or treatment effect, enabling the identification of true tumor burden within enhancing lesions. This approach overcomes current limitations of averaging values from both tumor and TE for quantitative assessments.

Glioblastoma remains the most common, malignant primary cancer of the central nervous system with a low life expectancy and an overall survival of less than 1.5 years. The treatment options are limited and there is no cure. Moreover, almost all patients develop recurrent tumors, which typically are more aggressive. Therapeutically resistant glioblastoma or glioblastoma stem-like cells (GSCs) are hypothesized to cause this inevitable recurrence. Identifying prognostic biomarkers of glioblastoma will potentially advance knowledge about glioblastoma tumorigenesis and enable discovery of more effective therapies. Proteomic analysis of more than 600 glioblastoma-specific proteins revealed, for the first time, that expression of acid ceramidase (ASAH1) is associated with poor glioblastoma survival. CD133+ GSCs express significantly higher ASAH1 compared to CD133- GSCs and serum-cultured glioblastoma cell lines, such as U87MG. These findings implicate ASAH1 as a plausible independent prognostic marker, providing a target for a therapy tailored toward GSCs. We further demonstrate that ASAH1 inhibition increases cellular ceramide level and induces apoptosis. Strikingly, U87MG cells, and three different patient-derived glioblastoma stem-like cancer cell lines were efficiently killed, through apoptosis, by three different known ASAH1 inhibitors with IC50's ranging from 11-104 μM. In comparison, the standard glioblastoma chemotherapy agent, temozolomide, had minimal GSC-targeted effects at comparable or even higher concentrations (IC50 > 750 μM against GSCs). ASAH1 is identified as a de novo glioblastoma drug target, and ASAH1 inhibitors, such as carmofur, are shown to be highly effective and to specifically target glioblastoma GSCs. Carmofur is an ASAH1 inhibitor that crosses the blood-brain barrier, a major bottleneck in glioblastoma treatment. It has been approved in Japan since 1981 for colorectal cancer therapy. Therefore, it is poised for repurposing and translation to glioblastoma clinical trials., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Glioblastoma multiforme (GBM) is the most common primary, intracranial malignancy of the central nervous system. The standard treatment protocol, which involves surgical resection, and concurrent radiation with adjuvant temozolomide (TMZ), still imparts a grim prognosis. Ultimately, all GBMs exhibit recurrence or progression, developing resistance to standard treatment. This study demonstrates that GBMs acquire resistance to radiation via upregulation of acid ceramidase (ASAH1) and sphingosine‑1-phosphate (Sph-1P). Moreover, inhibition of ASAH1 and Sph-1P, either with humanized monoclonal antibodies, small molecule drugs (i.e. carmofur), or a combination of both, led to suppression of GBM cell growth. These results suggest that ASAH1 and Sph-1P may be excellent targets for the treatment of new GBMs and recurrent GBMs, especially since the latter overexpresses ASAH1.

Background: Currently, a complete understanding of post-ventriculostomy hemorrhagic complications in subarachnoid hemorrhage due to ruptured aneurysms remains unknown. The present study evaluates the impact of periprocedural risk factors on rates of external ventricular drain (EVD)-associated hemorrhage in the setting of endovascular treatment of intracranial aneurysms., Methods: A retrospective chart review of 107 patients who underwent EVD placement within 24 h of endovascular coiling was performed. CT of head without contrast was obtained after drain placement and before endovascular treatment. Post-procedural CT was also obtained within 48 h of embolization and was reviewed for new/worsened track hemorrhages. Chi-squared test was used in evaluation., Results: Ninety-three of the 107 patients reviewed met the inclusion criteria. Four (25%) of the 16 patients on antiplatelet medications at presentation experienced post-EVD hemorrhage compared to 11 (14.3%) of 77 that were not (p = 0.29). Of the 13 patients given intraprocedural antiplatelets, 3 (23.1%) demonstrated hemorrhage compared to 12 (15%) of 80 not administered these medications (p = 0.46). Further, of 36 patients with intraprocedural anticoagulation, 6 (16.7%) exhibited hemorrhage compared to 9 (15.8%) of 57 in those without (p = 0.91). In 17 patients who received DVT prophylaxis, 2 (11.8%) exhibited hemorrhage compared to 13 (17.1%) of 76 who did not (p = 0.59). No post-EVD hemorrhage had attributable neurologic morbidity., Conclusion: Our results, demonstrating no significant risk factor related to EVD-associated hemorrhage rates, support the safety of EVD placement in the peri-endovascular treatment period.

Pediatric brain tumors are the most common solid tumors in children and are also a leading culprit of cancer-related fatalities in children. Pediatric brain tumors remain hard to treat. In this study, we demonstrated that medulloblastoma, pediatric glioblastoma, and atypical teratoid rhabdoid tumors express significant levels of acid ceramidase, where levels are highest in the radioresistant tumors, suggesting that acid ceramidase may confer radioresistance. More importantly, we also showed that acid ceramidase inhibitors are highly effective at targeting these pediatric brain tumors with low IC50 values (4.6-50 μM). This data suggests acid ceramidase as a novel drug target for adjuvant pediatric brain tumor therapies. Of these acid ceramidase inhibitors, carmofur has seen clinical use in Japan since 1981 for colorectal cancers and is a promising drug to undergo further animal studies and subsequently a clinical trial as a treatment for pediatric patients with brain tumors.

Background and Purpose: Patients with recurrent glioblastoma often exhibit regions of diffusion restriction following the initiation of bevacizumab therapy. Studies suggest that these regions represent either diffusion-restricted necrosis or hypercellular tumor. This study explored postmortem brain specimens and a population analysis of overall survival to determine the identity and implications of such lesions., Materials and Methods: Postmortem examinations were performed on 6 patients with recurrent glioblastoma on bevacizumab with progressively growing regions of diffusion restriction. ADC values were extracted from regions of both hypercellular tumor and necrosis. A receiver operating characteristic analysis was performed to define optimal ADC thresholds for differentiating tissue types. A retrospective population study was also performed comparing the overall survival of 64 patients with recurrent glioblastoma treated with bevacizumab. Patients were separated into 3 groups: no diffusion restriction, diffusion restriction that appeared and progressed within 5 months of bevacizumab initiation, and delayed or stable diffusion restriction. An additional analysis was performed assessing tumor O 6 -methylguanine-DNA-methyltransferase methylation., Results: The optimal ADC threshold for differentiation of hypercellularity and necrosis was 0.736 × 10 -3 mm 2 /s. Progressively expanding diffusion restriction was pathologically confirmed to be coagulative necrosis surrounded by viable tumor. Progressive lesions were associated with the worst overall survival, while stable lesions showed the greatest overall survival (P < .05). Of the 40% of patients with O 6 -methylguanine-DNA-methyltransferase methylated tumors, none developed diffusion-restricted lesions., Conclusions: Progressive diffusion-restricted lesions were pathologically confirmed to be coagulative necrosis surrounded by viable tumor and associated with decreased overall survival. Stable lesions were, however, associated with increased overall survival. All lesions were associated with O 6 -methylguanine-DNA-methyltransferase unmethylated tumors., (© 2016 by American Journal of Neuroradiology.)

Background: Surgical wounds after craniotomy heal with primary closure in most cases; however, significant comorbidities, multiple procedures, and history of tumor increase the risk of wound breakdown. Craniotomy wounds often require sophisticated coverage by a plastic surgeon using regional or microvascular flaps to address exposed intracranial contents. Unfortunately, timely treatment of craniotomy wounds may be difficult as a result of limitations of plastic surgery consultation, specialized operating room staffing, and operating room time. Infected wounds may need serial debridement and antibiotic therapy before definitive closure, and patients with dehisced or infected craniotomy wounds may need medical and nutritional optimization., Objective: To present the first case series of 7 neurosurgical patients with craniotomy wound complications who underwent closure with dermal regeneration template (DRT) at the time of urgent surgical debridement., Methods: Seven adult patients underwent placement of DRT for dehisced or infected craniotomy wounds after treatment for tumor or trauma. Patients had an average of 5.5 operations before definitive closure. Six patients ultimately underwent delayed free flap transfer after DRT placement, and 1 patient had DRT as definitive coverage., Results: All patients had healed craniotomy wounds., Conclusion: DRT has a role in treating complicated craniotomy wounds in patients with cancer or trauma either as a bridge or as definitive coverage. Its ease of application does not require advanced or time-consuming techniques. In some cases, it may even be used as a definitive means of closure in surgical wounds.

Functional magnetic resonance imaging (fMRI) is used clinically to map the visual cortex before brain surgery or other invasive treatments to achieve an optimal balance between therapeutic effect and the avoidance of postoperative vision deficits. Clinically optimized stimuli, analyses, and displays permit identification of cortical subregions supporting high-acuity central vision that is critical for reading and other essential visual functions. A novel data display permits instant appreciation of the functional relationship between the pattern of fMRI brain activation and the pattern of vision loss and preservation within the patient׳s field of view. Neurovascular uncoupling and its detection in the visual cortex are key issues for the interpretation of fMRI results in patients with existing brain pathology., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Recent conflicting reports have found both brain tumor hypercellularity and necrosis in regions of restricted diffusion on MRI-derived apparent diffusion coefficient (ADC) images. This study precisely compares ADC and cell density voxel by voxel using postmortem human whole brain samples., Methods: Patients with meningioma were evaluated to determine a normative ADC distribution within benign fluid attenuated inversion recovery (FLAIR) T2/hyperintensity surrounding tumor. This distribution was used to calculate a minimum ADC threshold to define regions of ADC-FLAIR mismatch (AFMM), where restricted diffusion presented in conjunction with T2/FLAIR hyperintensity. Contrast-enhancing voxels were excluded from this analysis. AFMM maps were generated using imaging acquired prior to death in 7 patients with high-grade glioma who eventually donated their brains upon death. Histological samples were taken from numerous regions of abnormal FLAIR and AFMM. Each sample was computationally processed to determine cell density. Custom software was then used to downsample coregistered microscopic histology to the more coarse MRI resolution. A voxel-by-voxel evaluation comparing ADC and cellularity was then performed., Results: An ADC threshold of 0.929 × 10(-3) mm(2)/s was calculated from meningioma-induced edema and was used to define AFMM. Regions of AFMM showed significantly greater cell density in 6 of 7 high-grade glioma cases compared with regions of hyperintense FLAIR alone (P < .0001). Two patients had small regions of diffusion-restricted necrosis that had significantly lower ADC than nearby hypercellularity., Conclusions: Regions of AFMM contain hypercellularity except for regions with extremely restricted diffusion, where necrosis is present., (© The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Preoperative mapping has revolutionized neurosurgical care for brain tumor patients. Maximizing resections has improved diagnosis, optimized treatment algorithms, and decreased potentially devastating postoperative deficits. Although mapping has multiple steps and complimentary localization sources, diffusion tensor imaging (DTI) excels in its essential role in depicting white matter tracts. A thorough understanding of DTI, data visualization methods, and limitations with mastery of functional and dysfunctional white matter anatomy is necessary to realize the potential of DTI. By establishing spatial relationships between lesion borders and functional networks preoperatively and intraoperatively, DTI is central to high-risk neurosurgical resections and becoming the standard of care., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Cancer is a complex disease; glioblastoma (GBM) is no exception. Short survival, poor prognosis, and very limited treatment options make it imperative to unravel the disease pathophysiology. The critically important identification of proteins that mediate various cellular events during disease is made possible with advancements in mass spectrometry (MS)-based proteomics. The objective of our study is to identify and characterize proteins that are differentially expressed in GBM to better understand their interactions and functions that lead to the disease condition. Further identification of upstream regulators will provide new potential therapeutic targets. We analyzed GBM tumors by SDS-PAGE fractionation with internal DNA markers followed by liquid chromatography-tandem mass spectrometry (MS). Brain tissue specimens obtained for clinical purposes during epilepsy surgeries were used as controls, and the quantification of MS data was performed by label-free spectral counting. The differentially expressed proteins were further characterized by Ingenuity Pathway Analysis (IPA) to identify protein interactions, functions, and upstream regulators. Our study identified several important proteins that are involved in GBM progression. The IPA revealed glioma activation with z score 2.236 during unbiased core analysis. Upstream regulators STAT3 and SP1 were activated and CTNNα was inhibited. We verified overexpression of several proteins by immunoblot to complement the MS data. This work represents an important step towards the identification of GBM biomarkers, which could open avenues to identify therapeutic targets for better treatment of GBM patients. The workflow developed represents a powerful and efficient method to identify biomarkers in GBM., (Copyright © 2014 the American Physiological Society.)

Background: Techniques for achieving hemispheric disconnection in patients with epilepsy continue to evolve., Objective: To review the outcomes of the first 50 hemispherectomy surgeries performed by a single surgeon with an emphasis on outcomes, complications, and how these results led to changes in practice., Methods: The first 50 hemispherectomy cases performed by the lead author were identified from a prospectively maintained database. Patient demographics, surgical details, clinical outcomes, and complications were critically reviewed., Results: From 2004 to 2012, 50 patients underwent hemispherectomy surgery (mean follow-up time, 3.5 years). Modified lateral hemispherotomy became the preferred technique and was performed on 44 patients. Forty patients (80%) achieved complete seizure freedom (Engel I). Presurgical and postsurgical neuropsychological evaluations demonstrated cognitive stability. Two cases were performed for palliation only. Previous hemispherectomy surgery was associated with worsened seizure outcome (2 of 6 seizure free; P .005). The use of Avitene was associated with a higher incidence of postoperative hydrocephalus (56% vs 18%; P = .03). In modified lateral hemispherotomy patients without the use of Avitene, the incidence of hydrocephalus was 13%. Complications included infection (n = 3), incomplete disconnection requiring reoperation (n = 1), reversible ischemic neurological deficit (n = 1), and craniosynostosis (n = 1). There were no (unanticipated) permanent neurological deficits or deaths. Minor technique modifications were made in response to specific complications., Conclusion: The modified lateral hemispherotomy is effective and safe for both initial and revision hemispherectomy surgery. Avitene use appears to result in a greater incidence of postoperative hydrocephalus.

Purpose: To characterize the influence of perfusion on the measurement of diffusion changes over time when ADC is computed using standard two-point methods., Materials and Methods: Functional diffusion maps (FDMs), which depict changes in diffusion over time, were compared with rCBV changes in patients with brain tumors. The FDMs were created by coregistering and subtracting ADC maps from two time points and categorizing voxels where ADC significantly increased (iADC), decreased (dADC), or did not change (ncADC). Traditional FDMs (tFDMs) were computed using b = 0,1000 s/mm(2). Flow-compensated FDMs (fcFDMs) were calculated using b = 500,1000 s/mm(2). Perfusion's influence on FDMs was determined by evaluating changes in rCBV in areas where the ADC change significantly differed between the two FDMs., Results: The mean ΔrCBV in voxels that changed from iADC (dADC) on the tFDM to ncADC on the fcFDM was significantly greater (less) than zero. In addition, mean ΔrCBV in iADC (dADC) voxels on the tFDM was significantly higher (lower) than in iADC (dADC) voxels on the fcFDM., Conclusion: The ability to accurately identify changes in diffusion on traditional FDMs is confounded in areas where perfusion and diffusion changes are colocalized. Flow-compensated FDMs, which use only non-zero b-values, should therefore be the standard approach., (Copyright © 2013 Wiley Periodicals, Inc.)

White matter injury is a known complication of whole brain radiation (WBRT). Little is known about the factors that predispose a patient to such injury. The current study used MR volumetrics to examine risk factors, in particular the influence of pre-treatment white matter health, in developing white matter change (WMC) following WBRT. Thirty-four patients with unilateral metastatic disease underwent FLAIR MRI pre-treatment and at several time points following treatment. The volume of abnormal FLAIR signal in the white matter was measured in the hemisphere contralateral to the diseased hemisphere at each time point. Analyses were restricted to the uninvolved hemisphere to allow for the measurement of WBRT effects without the potential confounding effects of the disease on imaging findings. The relationship between select pre-treatment clinical variables and the degree of WMC following treatment was examined using correlational and regression based analyses. Age when treated and volume of abnormal FLAIR prior to treatment were significantly associated with WMC following WBRT; however, pre-treatment FLAIR volume was the strongest predictor of post-treatment WMCs. Age did not add any predictive value once white matter status was considered. No significant relationships were found between biological equivalent dose and select cerebrovascular risk factors (total glucose, blood pressure, BMI) and development of WMCs. The findings from this study identify pre-treatment white matter health as an important risk factor in developing WMC following WBRT. This information can be used to make more informed decisions and counsel patients on their risk for treatment effects.

Background: Standard pre- and postcontrast (T1 + C) anatomical MR imaging is proving to be insufficient for accurately monitoring bevacizumab treatment response in recurrent glioblastoma (GBM). We present a novel imaging biomarker that detects abnormal tumor vasculature exhibiting both arterial and venous perfusion characteristics. We hypothesized that a decrease in the extent of this abnormal vasculature after bevacizumab treatment would predict treatment efficacy and overall survival., Methods: Dynamic susceptibility contrast perfusion MRI was gathered in 43 patients with high-grade glioma. Independent component analysis separated vasculature into arterial and venous components. Voxels with perfusion characteristics of both arteries and veins (ie, arterio-venous overlap [AVOL]) were measured in patients with de novo untreated GBM and patients with recurrent high-grade glioma before and after bevacizumab treatment. Treated patients were separated on the basis of an increase or decrease in AVOL volume (+/-ΔAVOL), and overall survival following bevacizumab onset was then compared between +/-ΔAVOL groups., Results: AVOL in untreated GBM was significantly higher than in normal vasculature (P < .001). Kaplan-Meier survival curves revealed a greater median survival (348 days) in patients with GBM with a negative ΔAVOL after bevacizumab treatment than in patients with a positive change (197 days; hazard ratio, 2.51; P < .05). Analysis of patients with combined grade III and IV glioma showed similar results, with median survivals of 399 days and 153 days, respectively (hazard ratio, 2.71; P < .01). Changes in T1+C volume and ΔrCBV after treatment were not significantly different across +/-ΔAVOL groups, and ΔAVOL was not significantly correlated with ΔT1+C or ΔrCBV., Conclusions: The independent component analysis dynamic susceptibility contrast-derived biomarker AVOL adds additional information for determining bevacizumab treatment efficacy.

The purpose of this study was to develop a voxel-wise analytical solution to a glioma growth model using serial diffusion MRI. These cell invasion, motility, and proliferation level estimates (CIMPLE maps) provide quantitative estimates of microscopic tumor growth dynamics. After an analytical solution was found, noise simulations were performed to predict the effects that perturbations in apparent diffusion coefficient values and the time between apparent diffusion coefficient map acquisitions would have on the accuracy of CIMPLE maps. CIMPLE maps were then created for 53 patients with gliomas with WHO grades of II-IV. MR spectroscopy estimates of the choline-to-N-acetylaspartate ratio were compared to cell proliferation estimates in CIMPLE maps using Pearson's correlation analysis. Median differences in cell proliferation and diffusion rates between WHO grades were compared. A strong correlation (R(2) = 0.9714) and good spatial correspondence were observed between MR spectroscopy measurements of the choline-to-N-acetylaspartate ratio and CIMPLE map cell proliferation rate estimates. Estimates of cell proliferation and diffusion rates appear to be significantly different between low- (WHO II) and high-grade (WHO III-IV) gliomas. Cell diffusion rate (motility) estimates are highly dependent on the time interval between apparent diffusion coefficient map acquisitions, whereas cell proliferation rate estimates are additionally influenced by the level of noise present in apparent diffusion coefficient maps., (Copyright © 2010 Wiley-Liss, Inc.)

Anti-angiogenic agents targeting brain tumor neovasculature may increase progression-free survival in patients with recurrent malignant gliomas. However, when these patients do recur it is not always apparent as an increase in enhancing tumor volume on MRI, which has been the standard of practice for following patients with brain tumors. Therefore alternative methods are needed to evaluate patients treated with these novel therapies. Furthermore, a method that can also provide useful information for the evaluation of conventional therapies would provide an important advantage for general applicability. Diffusion-weighted magnetic resonance imaging (DWI) has the potential to serve as a valuable biomarker for these purposes. In the current study, we explore the prognostic ability of functional diffusion maps (fDMs), which examine voxel-wise changes in the apparent diffusion coefficient (ADC) over time, applied to regions of fluid-attenuated inversion recovery (FLAIR) abnormalities in patients with malignant glioma, treated with either anti-angiogenic or cytotoxic therapies. Results indicate that the rate of change in fDMs is an early predictor of tumor progression, time to progression and overall survival for both treatments, suggesting the application of fDMs in FLAIR abnormal regions may be a significant advance in brain tumor biomarker technology.

Object: The object of this study was to evaluate surgical outcome in a select group of patients with medically refractory epilepsy who had undergone corpus callosotomy combined with bilateral subdural electroencephalography (EEG) electrode placement as the initial step in multistage epilepsy surgery., Methods: A retrospective chart review of 18 children (ages 3.5-18 years) with medically refractory symptomatic generalized or localization-related epilepsy was undertaken. A corpus callosotomy with subdural bihemispheric EEG electrode placement was performed as the initial step in multistage epilepsy surgery. All of the patients had tonic and atonic seizures; 6 patients also experienced complex partial seizures. All of the patients had frequent generalized epileptiform discharges as well as multifocal independent epileptiform discharges on surface EEG monitoring. Most of the patients (94%) had either normal (44%) MR imaging studies of the brain or bihemispheric abnormalities (50%). One patient had a suspected unilateral lesion (prominent sylvian fissure)., Results: Of the 18 patients who underwent corpus callosotomy and placement of subdural strips and grids, 12 progressed to further resection based on localizing data obtained during invasive EEG monitoring. The mean patient age was 10.9 years. The duration of invasive monitoring ranged from 3 to 14 days, and the follow-up ranged from 6 to 70 months (mean 35 months). Six (50%) of the 12 patients who had undergone resection had an excellent outcome (Engel Class I or II). There were no permanent neurological deficits or deaths., Conclusions: The addition of invasive monitoring for patients undergoing corpus callosotomy for medically refractory epilepsy may lead to the localization of surgically amenable seizure foci, targeted resections, and improved seizure outcomes in a select group of patients typically believed to be candidates for palliative surgery alone.

Purpose: Language lateralization measured by preoperative functional magnetic resonance imaging (fMRI) was shown recently to be predictive of verbal memory outcome in patients undergoing left anterior temporal lobe (L-ATL) resection. The aim of this study was to determine whether language lateralization or functional lateralization in the hippocampus is a better predictor of outcome in this setting., Methods: Thirty L-ATL patients underwent preoperative language fMRI, preoperative hippocampal fMRI using a scene encoding task, and pre- and postoperative neuropsychological testing. A group of 37 right ATL (R-ATL) surgery patients was included for comparison., Results: Verbal memory decline occurred in roughly half of the L-ATL patients. Preoperative language lateralization was correlated with postoperative verbal memory change. Hippocampal activation asymmetry was strongly related to side of seizure focus and to Wada memory asymmetry but was unrelated to verbal memory outcome., Discussion: Preoperative hippocampal activation asymmetry elicited by a scene encoding task is not predictive of verbal memory outcome. Risk of verbal memory decline is likely to be related to lateralization of material-specific verbal memory networks, which are more closely correlated with language lateralization than with overall asymmetry of episodic memory processes.

A consecutive, retrospective analysis of seizure control and quality of life was performed among 83 pediatric patients undergoing epilepsy surgery at Children's Hospital of Wisconsin. Seizure outcomes were generally favorable, with 68.7% class I outcomes; class II, 12%; and class III, 19.3%. Seizure freedom was highest among temporal lobectomies (84.2%) and hemispherectomies (76.2%). Outcomes among hemispherectomies were substantially superior to those of multilobar resections. Cortical dysplasia was associated with lower seizure freedom, at 57.5%. Among age groups, seizure-free outcomes in infants were lowest, at 50%. The lower infant seizure-free rate was likely attributable to frequency of multilobar resections and type of pathology (cortical dysplasia). Quality-of-life measures generally paralleled seizure outcomes. These results indicate that epilepsy surgery in children with intractable epilepsy can result in significant improvements in seizure control, quality of life, and development. Anticipated type of surgery, presumed location of epileptogenic site, absence of a defined lesion on magnetic resonance imaging scan of the brain, and patient's age should not prevent surgical evaluations of children with intractable epilepsy.

Purpose: Verbal memory decline is a frequent complication of left anterior temporal lobectomy (L-ATL). The goal of this study was to determine whether preoperative language mapping using functional magnetic resonance imaging (fMRI) is useful for predicting which patients are likely to experience verbal memory decline after L-ATL., Methods: Sixty L-ATL patients underwent preoperative language mapping with fMRI, preoperative intracarotid amobarbital (Wada) testing for language and memory lateralization, and pre- and postoperative neuropsychological testing. Demographic, historical, neuropsychological, and imaging variables were examined for their ability to predict pre- to postoperative memory change., Results: Verbal memory decline occurred in over 30% of patients. Good preoperative performance, late age at onset of epilepsy, left dominance on fMRI, and left dominance on the Wada test were each predictive of memory decline. Preoperative performance and age at onset together accounted for roughly 50% of the variance in memory outcome (p < 0.001), and fMRI explained an additional 10% of this variance (p

We present a 59-year-old woman with recurrent glioblastoma multiforme involving the left medial frontal and cingulate gyri. Diffusion tensor imaging (DTI) showed inferior-lateral tumor border proximity to the superior-medial (supracallosal) portion of the left frontal superior longitudinal fasciculus (SLF). Dissections of the tumor border contacting the dominant SLF caused speech arrests 8 times, with full recovery. At postoperative day 2, edema caused transient mild aphasia and paraphasic errors. Postoperative DTI showed an inferior-lateral resection cavity in immediate proximity to the supracallosal aspect of the left SLF. The case demonstrates excellent correlation between tumor border proximity to the dominant SLF shown at DTI and speech deficits caused by intraoperative dissections and postoperative edema. The case is the first to demonstrate speech arrest associated with lesion proximity to the supracallosal aspect of the SLF. Other SLF-related deficits are reviewed.

This study examined factors affecting object naming decline in patients who have undergone anterior temporal lobectomy (ATL) and the correlation between age of word acquisition and loss of specific object names postoperatively. The Boston Naming Test (BNT) was used to assess changes in object-naming performance in patients who underwent ATL. Correlation analyses were performed by group (dominant or nondominant ATL) on individual items from the BNT to determine if age of acquisition of object names had an effect on postoperative word loss. The influence of age at onset of seizures on naming decline was examined in the dominant ATL group. Only patients who had undergone dominant ATL experienced significant clinical and statistical declines after surgery. Among the patients who underwent dominant ATL, those with late age at onset of seizures declined significantly more than those with early-onset seizures. When individual object names were examined, age of acquisition of words predicted whether words were lost or gained after surgery.

A 43-year-old man presented with a grade II astrocytoma in the left postcentral gyrus and superior parietal lobule. Preoperative functional MR imaging and diffusion tensor imaging mapped distal upper-extremity primary motor cortex and white matter, respectively, adjacent to the tumor, within a congenitally truncated precentral gyrus. Because of the congenital anomaly, this region of primary motor cortex was inaccessible to direct visualization or intraoperative electrocortical stimulation. The integration of preoperative and intraoperative mapping data facilitated resection of the tumor while avoiding a postoperative motor deficit.

Objective: This retrospective study documented long-term outcome of patients receiving vagus nerve stimulation (VNS) therapy for pharmacoresistant epilepsy., Methods: Medical charts of 28 patients implanted for 5 years or longer were reviewed for changes in seizure frequency after 1 year of VNS therapy and at follow up, which ranged from 5 to 7 years. Numbers of antiepileptic drugs (AEDs) taken by the patients were also computed at 1 year and follow up. One patient had died and one had discontinued VNS therapy; data were available for 26 patients., Results: The median percent change in seizure frequency from baseline increased from -28% (P = 0.0053, Wilcoxon signed-rank test) at 12 months to -72% (P < 0.0001) at follow up. Some patients whose seizure frequency was not reduced during the initial 12 months of VNS therapy did experience reductions in seizure frequency during the follow-up period., Conclusion: In this retrospective study, the effectiveness of VNS therapy increased over time. Physicians should be aware that response to VNS therapy may be delayed for some patients.

Diffusion Tensor Imaging (DTI) is a new MRI imaging technique sensitive to directional movements of water molecules, induced by tissue barriers. This provides a new form of contrast that allows the identification of functional white matter tracts within the brain, and has been proposed as a technique suitable for presurgical planning in brain tumor patients. Resection of primary brain tumors improves survival, functional performance, and the effectiveness of adjuvant therapies, provided that surgically-induced neurological deficits can be avoided. Diffusion Tensor Imaging (DTI) has the potential to establish spatial relationships between eloquent white matter and tumor borders, provide information essential to preoperative planning, and improve the accuracy of surgical risk assessments preoperatively. We present our experience in a series of 28 brain tumor patients where the integration of functional magnetic resonance imaging (fMRI) and DTI data was used to determine key anatomic spatial relationships preoperatively. Twice as many functional systems were localized to within 5 mm of tumor borders when DTI and fMRI were utilized for preoperative planning, compared to that afforded by fMRI alone. Our results show that the combined use of fMRI and DTI can provide a better estimation of the proximity of tumor borders to eloquent brain systems sub-serving language, speech, vision, motor and premotor functions. Additionally, a low regional complication rate (4%) observed in our series suggests that preoperative planning with these combined techniques may improve surgical outcomes compared to that previously reported in the literature. Larger studies specifically designed to establish the accuracy and predictive value of DTI in brain tumor patients are warranted to substantiate our preliminary observations.

Objective: To illustrate how lesion-induced neurovascular uncoupling at functional magnetic resonance imaging (fMRI) can mimic hemispheric dominance opposite the side of a lesion preoperatively., Methods: We retrospectively reviewed preoperative fMRI mapping data from 50 patients with focal brain abnormalities to establish patterns of hemispheric dominance of language, speech, visual, or motor system functions. Abnormalities included gliomas (31 patients), arteriovenous malformations (AVMs) (11 patients), other congenital lesions (4 patients), encephalomalacia (3 patients), and tumefactive encephalitis (1 patient). A laterality ratio of fMRI hemispheric dominance was compared with actual hemispheric dominance as verified by electrocortical stimulation, Wada testing, postoperative and posttreatment deficits, and/or lesion-induced deficits. fMRI activation maps were generated with cross-correlation (P < 0.001) or t test (P < 0.001) analysis., Results: In 50 patients, a total of 85 functional areas were within 5 mm of the edge of a potentially resectable lesion. In 23 of these areas (27%), reduced fMRI signal in perilesional eloquent cortex in conjunction with preserved or increased signal in homologous contralateral brain areas revealed functional dominance opposite the side of the lesion. This suggested possible lesion-induced transhemispheric cortical reorganization to homologous brain regions (homotopic reorganization). In seven patients, however, the fMRI data were inconsistent with other methods of functional localization. In two patients with left inferior frontal gyrus gliomas and in one patient with focal tumefactive meningoencephalitis, fMRI incorrectly suggested strong right hemispheric speech dominance. In two patients with lateral precentral gyrus region gliomas and one patient with a left central sulcus AVM, the fMRI pattern incorrectly suggested primary corticobulbar motor dominance contralateral to the side of the lesion. In a patient with a right superior frontal gyrus AVM, fMRI revealed pronounced left dominant supplementary motor area activity in response to a bilateral complex motor task, but right superior frontal gyrus perilesional hemorrhage and edema subsequently caused left upper-extremity plegia. Pathophysiological factors that might have caused neurovascular uncoupling and facilitated pseudo-dominance at fMRI in these patients included direct tumor infiltration, neovascularity, cerebrovascular inflammation, and AVM-induced hemodynamic effects. Sixteen patients had proven (1 patient), probable (2 patients), or possible (13 patients) but unproven lesion-induced homotopic cortical reorganization., Conclusion: Lesion-induced neurovascular uncoupling causing reduced fMRI signal in perilesional eloquent cortex, in conjunction with normal or increased activity in homologous brain regions, may simulate hemispheric dominance and lesion-induced homotopic cortical reorganization.