Beyond seizure freedom: Dissecting long-term seizure control after surgical resection for drug-resistant epilepsy.

OBJECTIVE: This study was undertaken to better understand the long-term palliative and disease-modifying effects of surgical resection beyond seizure freedom, including frequency reduction and both late recurrence and remission, in patients with drug-resistant epilepsy. METHODS: This retrospective database-driven cohort study included all patients with >9 years of follow-up at a single high-volume epilepsy center. We included patients who underwent lobectomy, multilobar resection, or lesionectomies for drug-resistant epilepsy; we excluded patients who underwent hemispherectomies. Our main outcomes were (1) reduction in frequency of disabling seizures (at 6 months, each year up to 9 years postoperatively, and at last follow-up), (2) achievement of seizure remission (>6 months, >1 year, and longest duration), and (3) seizure freedom at last follow-up. RESULTS: We included 251 patients; 234 (93.2%) achieved 6 months and 232 (92.4%) experienced 1 year of seizure freedom. Of these, the average period of seizure freedom was 10.3 years. A total of 182 (72.5%) patients were seizure-free at last follow-up (defined as >1 year without seizures), with a median 11.9 years since remission. For patients not completely seizure-free, the mean seizure frequency reduction at each time point was 76.2%, and ranged from 66.6% to 85.0%. Patients decreased their number of antiseizure medications on average by .58, and 53 (21.2%) patients were on no antiseizure medication at last follow-up. Nearly half (47.1%) of those seizure-free at last follow-up were not seizure-free immediately postoperatively. SIGNIFICANCE: Patients who continue to have seizures after resection often have considerable reductions in seizure frequency, and many are able to achieve seizure freedom in a delayed manner.

The Association Between Mild Intraoperative Hypotension and Stroke in General Surgery Patients.

BACKGROUND: Intraoperative hypotension may contribute to perioperative strokes. We therefore tested the hypothesis that intraoperative hypotension is associated with perioperative stroke. METHODS: After institutional review board approval for this case-control study, we identified patients who had nonneurological, noncardiac, and noncarotid surgery under general anesthesia at the Cleveland Clinic between 2005 and 2011 and experienced a postoperative stroke. Control patients not experiencing postoperative stroke were matched in a 4-to-1 ratio using propensity scores and restriction to the same procedure type as stroke patients. The association between intraoperative hypotension, measured as time-integrated area under a mean arterial pressure (MAP) of 70 mm Hg, and postoperative stroke was assessed using zero-inflated negative binomial regression. RESULTS: Among 106 337 patients meeting inclusion criteria, we identified 120 who had confirmed postoperative stroke events based on manual chart review. Four-to-one propensity matching yielded a final matched sample of 104 stroke cases and 398 controls. There was no association between stroke and intraoperative hypotension. Stroke patients were not more likely than controls to have been hypotensive (odds ratio, 0.49 [0.18-1.38]), and among patients with intraoperative hypotension, stroke patients did not experience a greater degree of hypotension than controls (ratio of geometric means, 1.07 [0.76-1.53]). CONCLUSIONS: In our propensity score-matched case-control study, we did not find an association between intraoperative hypotension, defined as MAP < 70 mm Hg, and postoperative stroke.

IDH mutations may not preclude distant, trans-tentorial spread in gliomas: a case report and review of the literature.

BACKGROUND: IDH mutations have been demonstrated to confer prolonged survival in patients suffering from gliomas, but the mechanisms underlying the improved prognosis are unclear. While some studies have attributed these observations to an enhanced sensitivity to genotoxic therapies, others have postulated that IDH-mutated gliomas exhibit less aggressive intrinsic biological behavior, including the propensity to invade distant sites. Although most gliomas recur local to the site of initial presentation, some tumors demonstrate distant recurrence, the vast majority of which involve the contralateral hemisphere. Trans-tentorial spread has been described once before, in which a supratentorial glioblastoma was reported to recur infratentorially in the cerebellum. CASE PRESENTATION: We describe a patient who underwent surgical resection, followed by adjuvant radiation and temozolomide of a World Health Organization (WHO) III anaplastic astrocytoma in the right temporal lobe, exhibiting an IDH1 (R132H) mutation. Twenty-two months after surgery, he developed a second lesion, located in the right cerebellum, suspicious for recurrent tumor versus radiation necrosis. A second surgery was performed, and pathology demonstrated recurrent tumor, consistent with IDH1-mutated anaplastic astrocytoma. CONCLUSIONS: This is the first example of trans-tentorial spread in an IDH-mutated glioma, suggesting that despite improved survival, IDH mutations may not preclude gliomas from exhibiting the ability to invade distant sites of the brain.

Incidence of vestibular schwannomas in the United States.

There is a paucity of population-based data evaluating the incidence of vestibular schwannomas according to age, gender, race, and ethnicity. Such data are necessary to assess the burden of vestibular schwannomas on varying populations and to inform future research and healthcare planning. The Central Brain Tumor Registry of the United States, which contains the largest aggregation of population-based data on the incidence of primary central nervous system tumors in the US, was used. Age-adjusted incidence rates and incidence rate ratios (IRR) of vestibular schwannomas from 2004 to 2010 were calculated by age at diagnosis, gender, race, and ethnicity. Annual percent change (APC) was calculated using Joinpoint to characterize temporal trends. From 2004 to 2010, there were 23,729 newly diagnosed vestibular schwannomas in the US; overall incidence was 1.09 per 100,000 population. Incidence was stable over time (APC -0.41 %, 95 % confidence interval -3.4, 2.7). Incidence increased with age to a peak of 2.93 per 100,000 in the 65-74 year old age group. Overall, there was no difference in incidence by gender. Compared to Whites, incidence was highest in Asian Pacific Islanders (IRR 1.37, p < 0.001) and lowest in African Americans (IRR 0.36, p < 0.001). Incidence was lower in Hispanics than non-Hispanics (IRR 0.69, p < 0.001). Over 3300 vestibular schwannomas are diagnosed per year in the US and incidence is 1.09 per 100,000 population. Incidence increases with age up to the 65-74 year old age group. Incidence is higher in Asian Pacific Islanders and lower in African Americans and Hispanics.

The role of cancer stem cells in glioblastoma.

Recurrence in glioblastoma is nearly universal, and its prognosis remains dismal despite significant advances in treatment over the past decade. Glioblastoma demonstrates considerable intratumoral phenotypic and molecular heterogeneity and contains a population of cancer stem cells that contributes to tumor propagation, maintenance, and treatment resistance. Cancer stem cells are functionally defined by their ability to self-renew and to differentiate, and they constitute the diverse hierarchy of cells composing a tumor. When xenografted into an appropriate host, they are capable of tumorigenesis. Given the critical role of cancer stem cells in the pathogenesis of glioblastoma, research into their molecular and phenotypic characteristics is a therapeutic priority. In this review, the authors discuss the evolution of the cancer stem cell model of tumorigenesis and describe the specific role of cancer stem cells in the pathogenesis of glioblastoma and their molecular and microenvironmental characteristics. They also discuss recent clinical investigations into targeted therapies against cancer stem cells in the treatment of glioblastoma.

High-Gamma Activity Is Coupled to Low-Gamma Oscillations in Precentral Cortices and Modulates with Movement and Speech.

Planning and executing motor behaviors requires coordinated neural activity among multiple cortical and subcortical regions of the brain. Phase-amplitude coupling between the high-gamma band amplitude and the phase of low frequency oscillations (theta, alpha, beta) has been proposed to reflect neural communication, as has synchronization of low-gamma oscillations. However, coupling between low-gamma and high-gamma bands has not been investigated. Here, we measured phase-amplitude coupling between low- and high-gamma in monkeys performing a reaching task and in humans either performing finger-flexion or word-reading tasks. We found significant coupling between low-gamma phase and high-gamma amplitude in multiple sensorimotor and premotor cortices of both species during all tasks. This coupling modulated with the onset of movement. These findings suggest that interactions between the low and high gamma bands are markers of network dynamics related to movement and speech generation.

Cortical sites critical to language function act as connectors between language subnetworks.

Historically, eloquent functions have been viewed as localized to focal areas of human cerebral cortex, while more recent studies suggest they are encoded by distributed networks. We examined the network properties of cortical sites defined by stimulation to be critical for speech and language, using electrocorticography from sixteen participants during word-reading. We discovered distinct network signatures for sites where stimulation caused speech arrest and language errors. Both demonstrated lower local and global connectivity, whereas sites causing language errors exhibited higher inter-community connectivity, identifying them as connectors between modules in the language network. We used machine learning to classify these site types with reasonably high accuracy, even across participants, suggesting that a site's pattern of connections within the task-activated language network helps determine its importance to function. These findings help to bridge the gap in our understanding of how focal cortical stimulation interacts with complex brain networks to elicit language deficits.

The impact of skull thickness on pediatric stereoencephalography electrode implantation and technical considerations.

OBJECTIVE: One consideration in pediatric stereoencephalography (SEEG) is decreased skull thicknesses compared with adults, which may limit traditional bolt-based anchoring of electrodes. The authors aimed to investigate the safety profile, complication rates, and technical adaptations of placing SEEG electrodes in pediatric patients. METHODS: The authors retrospectively reviewed all patients aged 12 years or younger at the time of SEEG implantation at their institution. Postimplantation CT scans were used to measure skull thickness at the entry point of each SEEG lead. Postimplantation lead accuracy was also assessed. RESULTS: Fifty-three patients were reviewed. The median skull thickness was 4.1 (interquartile range [IQR] 3.15-5.2) mm. There were 5 total complications: 1 retained bolt fragment, 3 asymptomatic subdural hematomas, and 1 asymptomatic intracranial hemorrhage. Median radial error from the lead target was 3.5 (IQR 2.24-5.25) mm. Linear regression analysis revealed that increasing skull thickness decreased the deviation from the intended target, implying an improved accuracy to target at thicker skull entry points; this trended towards improved accuracy, but did not achieve statistical significance (p = 0.54). CONCLUSIONS: This study found a 1.9% hardware complication rate and a 9.4% asymptomatic hemorrhage rate. Suturing electrodes to the scalp may represent a reasonable option if there are concerns of young age or a thin skull. These data indicate that invasive SEEG evaluation is safe among patients 12 years old or younger.

Determinants of epileptogenic zone identification and seizure outcome in children with refractory epilepsy undergoing stereoelectroencephalography.

OBJECTIVE: The objective of this paper was to investigate the factors associated with successful epileptogenic zone (EZ) identification and postsurgical seizure freedom in pediatric patients with drug-resistant epilepsy who underwent first-time stereoelectroencephalography (SEEG). METHODS: The authors conducted a retrospective cohort study of all consecutive patients younger than 18 years of age at the time of recommendation for invasive evaluation with SEEG who were treated from July 2009 to June 2020. The authors excluded patients who had undergone failed prior resective epilepsy surgery or prior intracranial electrode evaluation for seizure localization. For their primary outcome, the authors evaluated the relationship between clinical and radiographic factors and successful identification of a putative EZ. For their secondary outcome, the authors investigated whether these factors had a significant relationship with seizure freedom (according to the Engel classification) at last follow-up. RESULTS: The authors included 101 patients in this study. SEEG was safe, with no major morbidity or mortality experienced. The population was complex, with an MRI lesion present in less than 40% of patients and patients as young as 2.9 years included. A proposed EZ was identified in 88 (87%) patients. Patients with an older onset of epilepsy (OR 1.20/year, p = 0.04) or epilepsy etiology suspected to be due to a developmental lesion (OR 8.38, p = 0.02) were more likely to have proposed EZ identification. Patients with a preimplantation bilateral seizure-onset hypothesis (OR 0.29, p = 0.047) and those who underwent longer periods of monitoring (OR 0.86/day, p = 0.006) were somewhat less likely to have proposed EZ identification. The presence of an MRI lesion was a positive factor on secondary analyses (OR 4.18, p = 0.049; 1-tailed test). Fifty percent of patients who underwent surgical treatment with resection or laser ablation achieved Engel class I outcomes, in contrast to 0% of patients who underwent neuromodulation. Patients with a preimplantation hypothesis in the frontal/parietal lobes had increased odds of seizure freedom compared with patients with a hypothesis in other locations (OR 3.64, p = 0.01). CONCLUSIONS: Pediatric SEEG is safe and often identifies a proposed resectable EZ. These results suggest that SEEG is effective in patients with frontal/parietal preimplantation hypothesis, with or without identified lesions on MRI.

High-gamma activity is coupled to low-gamma oscillations in precentral cortices and modulates with movement and speech.

Planning and executing motor behaviors requires coordinated neural activity among multiple cortical and subcortical regions of the brain. Phase-amplitude coupling between the high-gamma band amplitude and the phase of low frequency oscillations (theta, alpha, beta) has been proposed to reflect neural communication, as has synchronization of low-gamma oscillations. However, coupling between low-gamma and high-gamma bands has not been investigated. Here, we measured phase-amplitude coupling between low- and high-gamma in monkeys performing a reaching task and in humans either performing finger movements or speaking words aloud. We found significant coupling between low-gamma phase and high-gamma amplitude in multiple sensorimotor and premotor cortices of both species during all tasks. This coupling modulated with the onset of movement. These findings suggest that interactions between the low and high gamma bands are markers of network dynamics related to movement and speech generation.

The Clinical Utility of Surgical Histopathology in Predicting Seizure Outcomes in Patients with Rasmussen Encephalitis Undergoing Hemispherectomy.

OBJECTIVE: The objectives of this study were to determine the relationship between the severity of pathology and seizure outcomes in patients who underwent hemispherectomy for Rasmussen encephalitis (RE) and to investigate which clinical factors correlated with severity of pathology. METHODS: In this retrospective cohort study, we collected and reviewed pathology and clinical variables. We ascertained seizure outcomes using Engel's classification, and Pardo stages were used to grade pathology. RESULTS: We included 29 unique patients who underwent 34 hemispherectomy procedures for analysis. There was no statistically significant correlation between Pardo stage and seizure outcome (P = 1). Increasing duration of epilepsy (ß = 0.011, P = 0.02) and duration of hemiparesis (ß = 0.024, P = 0.01) were significantly associated with a more severe Pardo stage. In contrast, the presence of epilepsia partialis continua had a negative relationship with Pardo stage (ß = -0.49, P = 0.04). Twenty-six (89.75%) patients were Engel class I at the last follow-up, including all 5 patients who underwent redo hemispherectomy in our cohort. CONCLUSIONS: Consistent with the progressive nature of RE, more severe pathology was associated with a longer duration of epilepsy and longer duration of hemiparesis, while the presence of epilepsia partialis continua was associated with less severe pathology. Results from this series suggest the degree of cortical involvement with RE as assessed on surgical histopathology does not correlate with seizure outcome after hemispherectomy, which appears to be more dependent on surgical technique/complete disconnection.

Delayed Development of Spinal Subdural Hematoma Following Cranial Trauma: A Case Report and Review of the Literature.

BACKGROUND: Spinal subdural hematomas (SDHs) have been reported secondary to direct trauma or iatrogenic causes associated with coagulopathies. Spinal SDHs found after the development of acute intracranial SDHs, without any evidence of trauma to the spine, are extremely rare. In addition to this rare presentation, there is a lack of consensus regarding whether surgical decompression is the ideal treatment strategy. Depending on the extent of SDH within the spinal canal, surgical decompression may be difficult where diffuse hematoma within the intradural space requires multilevel decompression for treatment. CASE DESCRIPTION: A 46-year-old man initially presented with an acute cranial SDH following isolated head trauma. After a period of full recovery, he developed delayed lower extremity paraparesis secondary to the formation of a thoracolumbar SDH. This hematoma coincided with resolution of the cranial SDH and likely was due to redistribution of blood from the cranial subdural space into the spinal canal. Given the diffuse multilevel nature of the spread of hematoma and lack of a focal area of compression, he was managed conservatively. He demonstrated small signs of neurologic improvement over several days and regained considerable strength over the following several weeks. CONCLUSIONS: This report demonstrates a very rare occurrence of a traumatic intracranial SDH migrating into the thoracic and lumbar spine. This case also highlights that despite acute neurologic deficits, conservative management may be a feasible strategy that can result in recovery of neurologic function.

An IDH1-mutated primary gliosarcoma: case report.

The authors present the case of a primary gliosarcoma with an isocitrate dehydrogenase-1 (IDH1) mutation. A 75-year-old man presented with a 3-day history of multiple focal seizures and was found on MRI to have a 2.2-cm left parietal enhancing mass lesion. Brain MRI for tremor performed 8 years prior to this presentation was normal. En bloc resection revealed a high-grade glioma with sarcomatous components that was immunoreactive for the R132H variant of IDH1 by antibody. Gliosarcoma is a rare variant of glioblastoma that arises most frequently as a primary tumor, and has equal or worse survival and an increased propensity for extracranial metastases compared with other Grade 4 gliomas. In contrast, isocitrate dehydrogenase-1 and -2 mutations are associated with low-grade gliomas with increased survival and less commonly with glioblastoma. To the authors' knowledge, there has been only 1 other published report of a primary gliosarcoma carrying an isocitrate dehydrogenase mutation. This rare genetic-histological combination highlights potential differences between glioblastoma and gliosarcoma and may warrant additional study.

Descriptive Epidemiology of Spinal Meningiomas in the United States.

STUDY DESIGN: Cross-sectional study of US cancer registry data. OBJECTIVE: To present the current population-based descriptive epidemiology of spinal meningiomas in the United States. SUMMARY OF BACKGROUND DATA: Meningioma is the most common primary spinal tumor, yet there is a paucity of population-based data evaluating incidence according to age, sex, race, and ethnicity. Such data are necessary to assess the burden of spinal meningiomas on varying populations and to inform health care planning and future research. METHODS: The Central Brain Tumor Registry of the United States, which contains the largest aggregation of population-based data on the incidence of primary central nervous system tumors in the United States, was used. Age-adjusted incidence rates of spinal meningiomas from 2004 to 2010 were calculated by age at diagnosis, sex, race, and ethnicity. Annual percent change was calculated using Joinpoint to characterize temporal trends. RESULTS: From 2004 to 2010, there were 7148 newly diagnosed spinal meningiomas, resulting in an overall age-adjusted incidence of 0.33 per 100,000 population. There was a nonsignificant increase in incidence over time (annual percent change: 0.8%, 95% confidence interval: -1.4 to 3.0). The highest incidence occurred in the 75- to 84-year old age group. Females had a much higher incidence than males (incidence rate ratio: 3.37; P < 0.0001). Asian Pacific Islanders and Caucasians had the highest incidence. Compared with Caucasians, African Americans and American Indian/Alaskan Native individuals had a significantly lower incidence (incidence rate ratio: 0.72, P < 0.0001; 0.52, P = 0.0003, respectively). Non-Hispanics had a significantly lower incidence than Hispanics (incidence rate ratio: 0.81, P < 0.0001). CONCLUSION: Approximately 1000 spinal meningiomas were diagnosed in the United States per year, and the incidence was relatively stable. Advanced age, female sex, Asian Pacific Islander and Caucasian race, and Hispanic ethnicity were all associated with an increased incidence of spinal meningioma. This study represents the most comprehensive evaluation of population-based descriptive epidemiology of spinal meningiomas in the United States to date. LEVEL OF EVIDENCE: 2.

Signal integration and gene induction by a functionally distinct STAT3 phosphoform.

Aberrant activation of the ubiquitous transcription factor STAT3 is a major driver of solid tumor progression and pathological angiogenesis. STAT3 activity is regulated by numerous posttranslational modifications (PTMs), including Tyr(705) phosphorylation, which is widely used as an indicator of canonical STAT3 function. Here, we report a noncanonical mechanism of STAT3 activation that occurs independently of Tyr(705) phosphorylation. Using quantitative liquid chromatography-tandem mass spectrometry, we have discovered and characterized a novel STAT3 phosphoform that is simultaneously phosphorylated at Thr(714) and Ser(727) by glycogen synthase kinase 3α and -ß (GSK-3α/ß). Both Thr(714) and Ser(727) are required for STAT3-dependent gene induction in response to simultaneous activation of epidermal growth factor receptor (EGFR) and protease-activated receptor 1 (PAR-1) in endothelial cells. In this combinatorial signaling context, preventing formation of doubly phosphorylated STAT3 by depleting GSK-3α/ß is sufficient to disrupt signal integration and inhibit STAT3-dependent gene expression. Levels of doubly phosphorylated STAT3 but not of Tyr(705)-phosphorylated STAT3 are remarkably elevated in clear-cell renal-cell carcinoma relative to adjacent normal tissue, suggesting that the GSK-3α/ß-STAT3 pathway is active in the disease. Collectively, our results describe a functionally distinct, noncanonical STAT3 phosphoform that positively regulates target gene expression in a combinatorial signaling context and identify GSK-3α/ß-STAT3 signaling as a potential therapeutic target in renal-cell carcinoma.