Comparison of Stereotactic Radiosurgery and Radiofrequency Ablation for Trigeminal Neuralgia in Multiple Sclerosis Patients.

BACKGROUND: The optimal treatment for medically refractory trigeminal neuralgia in multiple sclerosis (MS-TN) patients is unknown. OBJECTIVE: To compare treatment outcomes between stereotactic radiosurgery (SRS) and radiofrequency ablation (RFA). METHODS: We performed a retrospective study of MS-TN patients treated with SRS or RFA between 2002 and 2019. Outcomes included degree of pain relief, pain recurrence, and sensory changes, segregated based on initial treatment, final treatment following retreatment with the same modality, and crossover patients. RESULTS: Sixty surgical cases for 42 MS-TN patients were reviewed. Initial pain freedom outcomes and rates of retreatment were similar (SRS: 30%; RFA: 42%). RFA resulted in faster onset of pain freedom (RFA: <1 week; SRS: 15 weeks; p < 0.001). SRS patients with pain relief had longer intervals to pain recurrence at 2 years (p = 0.044). Final treatment outcomes favored RFA for pain freedom/off-medication outcomes (RFA: 44%; SRS: 11%; p = 0.031), though RFA resulted in more paresthesia (RFA: 81%; SRS: 39%; p = 0.012). Both provided at least 80% of adequate pain relief. Crossover patients did not have improved pain relief. CONCLUSIONS: SRS and RFA are both valid surgical options for MS-TN. Discussion with providers will need to balance patient preference with their unique treatment characteristics.

Long-term pain outcomes in elderly patients with trigeminal neuralgia: comparison of first-time microvascular decompression and stereotactic radiosurgery.

OBJECTIVE: Common surgical treatments for trigeminal neuralgia (TN) include microvascular decompression (MVD) and stereotactic radiosurgery (SRS). The use of MVD in elderly patients has been described but has yet to be prospectively compared to SRS, which is well-tolerated and noninvasive. The authors aimed to directly compare long-term pain control and adverse event rates for first-time surgical treatments for idiopathic TN in the elderly. METHODS: A prospectively collected database was reviewed for TN patients who had undergone treatment between 1997 and 2017 at a single institution. Standardized collection of preoperative demographics, surgical procedure, and postoperative outcomes was performed. Data analysis was limited to patients over the age of 65 years who had undergone a first-time procedure for the treatment of idiopathic TN with at least 1 year of follow-up. RESULTS: One hundred ninety-three patients meeting the study inclusion criteria underwent surgical procedures for TN during the study period (54 MVD, 24 MVD+Rhiz, 115 SRS). In patients in whom an artery was not compressing the trigeminal nerve during MVD, a partial sensory rhizotomy (MVD+Rhiz) was performed. Patients in the SRS cohort were older than those in the MVD and MVD+Rhiz cohorts (mean ± SD, 79.2 ± 7.8 vs 72.9 ± 5.7 and 70.9 ± 4.8 years, respectively; p < 0.0001) and had a higher mean Charlson Comorbidity Index (3.8 ± 1.1 vs 3.0 ± 0.9 and 2.9 ± 1.0, respectively; p < 0.0001). Immediate or short-term postoperative pain-free rates (Barrow Neurological Institute [BNI] pain intensity score I) were 98.1% for MVD, 95.8% for MVD+Rhiz, and 78.3% for SRS (p = 0.0008). At the last follow-up, 72.2% of MVD patients had a favorable outcome (BNI score I-IIIa) compared to 54.2% and 49.6% of MVD+Rhiz and SRS patients, respectively (p = 0.02). In total, 0 (0%) SRS, 5 (9.3%) MVD, and 1 (4.2%) MVD+Rhiz patients developed any adverse event. Multivariate Cox proportional hazards analysis demonstrated that procedure type (p = 0.001) and postprocedure sensory change (p = 0.003) were statistically significantly associated with pain control. CONCLUSIONS: In this study cohort, patients who had undergone MVD had a statistically significantly longer duration of pain freedom than those who had undergone MVD+Rhiz or SRS as their first procedure. Fewer adverse events were seen after SRS, though the MVD-associated complication rate was comparable to published rates in younger patients. Overall, the results suggest that both MVD and SRS are effective options for the elderly, despite their advanced age. Treatment choice can be tailored to a patient's unique condition and wishes.

Direct and indirect costs associated with stereotactic radiosurgery or open surgery for medial temporal lobe epilepsy: Results from the ROSE trial.

OBJECTIVE: To determine whether a less-invasive approach to surgery for medically refractory temporal lobe epilepsy is associated with lower health care costs and costs of lost productivity over time, compared to open surgery. METHODS: We compared direct medical costs and indirect productivity costs associated with treatment with stereotactic radiosurgery (SRS) or anterior temporal lobectomy (ATL) in the ROSE (Radiosurgery or Open Surgery for Epilepsy) trial. Health care use was abstracted from hospital bills, the study database, and diaries in which participants recorded health care use and time lost from work while seeking care. Costs of use were calculated using a Medicare costing approach used in a prior study of the costs of ATL. The power of many analyses was limited by the sample size and data skewing. RESULTS: Combined treatment and follow-up costs (in thousands of US dollars) did not differ between SRS (n = 20, mean = $76.6, 95% confidence interval [CI] = 50.7-115.6) and ATL (n = 18, mean = $79.0, 95% CI = 60.09-103.8). Indirect costs also did not differ. More ATL than SRS participants were free of consciousness-impairing seizures in each year of follow-up (all P < 0.05). Costs declined following ATL (P = 0.005). Costs tended to increase over the first 18 months following SRS (P = 0.17) and declined thereafter (P = 0.06). This mostly reflected hospitalizations for SRS-related adverse events in the second year of follow-up. SIGNIFICANCE: Lower initial costs of SRS for medial temporal lobe epilepsy were largely offset by hospitalization costs related to adverse events later in the course of follow-up. Future studies of less-invasive alternatives to ATL will need to assess adverse events and major costs systematically and prospectively to understand the economic implications of adopting these technologies.

Radiosurgery versus open surgery for mesial temporal lobe epilepsy: The randomized, controlled ROSE trial.

OBJECTIVE: To compare stereotactic radiosurgery (SRS) versus anterior temporal lobectomy (ATL) for patients with pharmacoresistant unilateral mesial temporal lobe epilepsy (MTLE). METHODS: This randomized, single-blinded, controlled trial recruited adults eligible for open surgery among 14 centers in the USA, UK, and India. Treatment was either SRS at 24 Gy to the 50% isodose targeting mesial structures, or standardized ATL. Outcomes were seizure remission (absence of disabling seizures between 25 and 36 months), verbal memory (VM), and quality of life (QOL) at 36-month follow-up. RESULTS: A total of 58 patients (31 in SRS, 27 in ATL) were treated. Sixteen (52%) SRS and 21 (78%) ATL patients achieved seizure remission (difference between ATL and SRS = 26%, upper 1-sided 95% confidence interval = 46%, P value at the 15% noninferiority margin = .82). Mean VM changes from baseline for 21 English-speaking, dominant-hemisphere patients did not differ between groups; consistent worsening occurred in 36% of SRS and 57% of ATL patients. QOL improved with seizure remission. Adverse events were anticipated cerebral edema and related symptoms for some SRS patients, and cerebritis, subdural hematoma, and others for ATL patients. SIGNIFICANCE: These data suggest that ATL has an advantage over SRS in terms of proportion of seizure remission, and both SRS and ATL appear to have effectiveness and reasonable safety as treatments for MTLE. SRS is an alternative to ATL for patients with contraindications for or with reluctance to undergo open surgery.

SOX11 identified by target gene evaluation of miRNAs differentially expressed in focal and non-focal brain tissue of therapy-resistant epilepsy patients.

MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally control the expression of their target genes via RNA interference. There is increasing evidence that expression of miRNAs is dysregulated in neuronal disorders, including epilepsy, a chronic neurological disorder characterized by spontaneous recurrent seizures. Mesial temporal lobe epilepsy (MTLE) is a common type of focal epilepsy in which disease-induced abnormalities of hippocampal neurogenesis in the subgranular zone as well as gliosis and neuronal cell loss in the cornu ammonis area are reported. We hypothesized that in MTLE altered miRNA-mediated regulation of target genes could be involved in hippocampal cell remodeling. A miRNA screen was performed in hippocampal focal and non-focal brain tissue samples obtained from the temporal neocortex (both n=8) of MTLE patients. Out of 215 detected miRNAs, two were differentially expressed (hsa-miR-34c-5p: mean increase of 5.7 fold (p=0.014), hsa-miR-212-3p: mean decrease of 76.9% (p=0.0014)). After in-silico target gene analysis and filtering, reporter gene assays confirmed RNA interference for hsa-miR-34c-5p with 3'-UTR sequences of GABRA3, GRM7 and GABBR2 and for hsa-miR-212-3p with 3'-UTR sequences of SOX11, MECP2, ADCY1 and ABCG2. Reporter gene assays with mutated 3'-UTR sequences of the transcription factor SOX11 identified two different binding sites for hsa-miR-212-3p and its primary transcript partner hsa-miR-132-3p. Additionally, there was an inverse time-dependent expression of Sox11 and miR-212-3p as well as miR-132-3p in rat neonatal cortical neurons. Transfection of neurons with anti-miRs for miR-212-3p and miR-132-3p suggest that both miRNAs work synergistically to control Sox11 expression. Taken together, these results suggest that differential miRNA expression in neurons could contribute to an altered function of the transcription factor SOX11 and other genes in the setting of epilepsy, resulting not only in impaired neural differentiation, but also in imbalanced neuronal excitability and accelerated drug export.

Association of tumor location, extent of resection, and neurofibromatosis status with clinical outcomes for 221 spinal nerve sheath tumors.

OBJECT Intradural extramedullary spine tumors represent two-thirds of all primary spine neoplasms. Approximately half of these are peripheral nerve sheath tumors, mainly neurofibromas and schwannomas. Given the rarity of this disease and, thus, the limited analyses of clinical outcomes, the authors examined the association of tumor location, extent of resection, and neurofibromatosis (NF) status with clinical outcomes. METHODS Patients were identified through a search of the University of California, San Francisco, neuropathology database and a separate review of current procedural terminology codes. Data recorded included patient age, patient sex, clinical presentation, presence of NF, tumor type, tumor location, extent of resection (gross-total resection [GTR] or subtotal resection [STR]), and clinical follow-up. RESULTS Of 221 tumors in 199 patients (mean age 45 years), 53 were neurofibromas, 163 were schwannomas, and 5 were malignant peripheral nerve sheath tumors. The most common presenting symptom was spinal pain (76%), followed by weakness (36%) and sensory abnormalities (34%). Mean symptom duration was 16 months. In terms of spinal location, neurofibromas were more common in the cervical spine (74% vs 27%, p < 0.001), and schwannomas were more common in the thoracic and lumbosacral spine (73% vs 26%, p < 0.001). Rates of GTR were lower for neurofibromas than schwannomas (51% vs 83%, p < 0.001), regardless of location. Rates of GTR were lower for cervical (54%) than thoracic (90%) and lumbosacral (86%) lesions (p < 0.001). NF was associated with lower rates of GTR among all tumors (43% vs 86%, p < 0.001). The mean follow-up time was 32 months. Recurrence/progression was more common for neurofibromas than schwannomas (17% vs 7%, p = 0.03), although the mean time to recurrence/progression did not differ according to tumor type (45 vs 53 months, p = 0.63). As expected, GTR was associated with lower recurrence rates (4% vs 22%, p < 0.001). According to multivariate analysis, cervical location (OR 0.239, 95% CI 0.110-0.520) and presence of NF (OR 0.166, 95% CI 0.054-0.507) were associated with lower rates of GTR. In a separate model, only GTR (OR 0.141, 95% CI 0.046-0.429) was associated with tumor recurrence. CONCLUSIONS Resection is an effective treatment for spinal nerve sheath tumors. Neurofibromas were found more commonly in the cervical spine than in other regions of the spine and were associated with higher rates of recurrence and lower rates of GTR than other tumor types, particularly in patients with NF Types 1 or 2. According to multivariate analysis, both cervical location and presence of NF were associated with lower rates of GTR. According to a second multivariate model, the only variable associated with tumor recurrence was extent of resection. Maximal safe resection remains ideal for these lesions; however, patients with cervical tumors or NF should be counseled about their increased risk for recurrence.

Visual field defects after radiosurgery for mesial temporal lobe epilepsy.

PURPOSE: Gamma knife radiosurgery (RS) may be an alternative to open surgery for mesial temporal lobe epilepsy (MTLE), but morbidities and the anticonvulsant mechanisms of RS are unclear. Examination of visual field defects (VFDs) after RS may provide evidence of the extent of a postoperative fixed lesion. VFDs occur in 52-100% of patients following open surgery for MTLE. METHODS: This multicenter prospective trial of RS enrolled patients with unilateral hippocampal sclerosis and concordant video-electroencephalography (EEG) findings. Patients were randomized to low (20 Gy) or high (24 Gy) doses delivered to the amygdala, hippocampal head, and parahippocampal gyrus. Postoperative perimetry were obtained at 24 months after RS. Visual field defect ratios (VFDRs) were calculated to quantify the degree of VFDs. Results were contrasted with age, RS dose and 50% isodose volume, peak volume of radiation-induced change at the surgical target, quality of life measurements, and seizure remission. KEY FINDINGS: No patients reported visual changes and no patients had abnormal bedside visual field examinations. Fifteen (62.5%) of 24 patients had postoperative VFDs, all homonymous superior quadrantanopsias. None of the VFDs were consistent with injury to the optic nerve or chiasm. Clinical diagnosis of VFDs correlated significantly with VFDRs (p = 0.0005). Patients with seizure remission had smaller (more severe) VFDRs (p = 0.04). No other variables had significant correlations. SIGNIFICANCE: VFDs appeared after RS in proportions similar to historical comparisons from open surgery for MTLE. The nature of VFDs was consistent with lesions of the optic radiations. The findings support the hypothesis that the mechanism of RS involves some degree of tissue damage and is not confined entirely to functional changes in neuromodulation.

Predictors of seizure freedom after surgery for malformations of cortical development.

OBJECTIVE: Malformations of cortical development (MCDs) are a major cause of medically refractory epilepsy. Our aim was to examine a surgical series of patients with cortical malformations to determine the prognostic factors associated with long-term seizure control. METHODS: We conducted a retrospective review of 143 patients with MCD who underwent resective surgery for medically refractory epilepsy. Demographic, imaging, histopathologic, and surgical variables were analyzed for potential association with seizure freedom. Preoperative magnetic resonance imaging (MRI) was evaluated in a blind fashion and classified according to a new imaging/embryologic MCD classification system. RESULTS: Gray-white blurring on MRI, smaller lesions, complete resection of structural lesions, complete resection of abnormal electrocorticographic areas, and locally confined electrocorticographic abnormalities are favorable prognosticators of seizure freedom on univariate analysis. Imaging features consistent with abnormal proliferation (Barkovich class I) were associated with better outcome compared to those related to abnormal neuronal migration (class II) or abnormal cortical organization (class III). Multivariate logistic regression revealed complete resection of tissue manifesting electrocorticographic and/or MRI anatomic abnormalities as the main independent predictor of seizure freedom. Other histopathologic or demographic factors were not associated with seizure control. Long-term follow-up of patients demonstrated sustained overall rates of seizure control (72% at 2 years, 65% at 5 years, and 67% at 10 years). INTERPRETATION: Surgery for MCDs can result in high rates of seizure freedom. Complete resection of electrocorticographic and anatomic abnormalities appears to be most predictive of long-term seizure control.

Radiosurgery for epilepsy: clinical experience and potential antiepileptic mechanisms.

Stereotactic radiosurgery, well established in the noninvasive treatment of focal lesions that are otherwise difficult to access through open surgery, is an emerging technology in the treatment of focal epileptic lesions. Recent studies suggest that seizures from hypothalamic hamartomas and mesial temporal lobe epilepsy remit at clinically significant rates with radiosurgery, but large variations among different studies have raised questions about appropriate treatment protocols and mechanisms. Proposed anticonvulsant mechanisms include neuromodulatory effects or ischemic necrosis of epileptic tissue. An ongoing trial that directly compares efficacy, morbidities, and cost of radiosurgery versus open surgery for mesial temporal lobe epilepsy is underway.

Factors associated with seizure freedom in the surgical resection of glioneuronal tumors.

PURPOSE: Gangliogliomas (GGs) and dysembryoplastic neuroepithelial tumors (DNETs) are low-grade brain tumors of glioneuronal origin that commonly present with seizures. Achieving seizure control in patients with glioneuronal tumors remains underappreciated, as tumor-related epilepsy significantly affects patients' quality-of-life. METHODS: We performed a quantitative and comprehensive systematic literature review of seizure outcomes after surgical resection of GGs and DNETs associated with seizures. We evaluated 910 patients from 39 studies, and stratified outcomes according to several potential prognostic variables. KEY FINDINGS: Overall, 80% of patients were seizure-free after surgery (Engel class I), whereas 20% continued to have seizures (Engel class II-IV). We observed significantly higher rates of seizure-freedom in patients with ≤1 year duration of epilepsy compared to those with >1 year of seizures [odds ratio (OR) 9.48; 95% confidence interval (CI) 2.26-39.66], and with gross-total resection over subtotal lesionectomy (OR 5.34; 95% CI 3.61-7.89). In addition, the presence of secondarily generalized seizures preoperatively predicted a lower rate of seizure-freedom after surgery (OR 0.40; 95% CI 0.24-0.66). Outcomes did not differ significantly between adults and children, patients with temporal lobe versus extratemporal tumors, pathologic diagnosis of GG versus DNET, medically controlled versus refractory seizures, or with the use of electrocorticography (ECoG). Extended resection of temporal lobe tumors, with hippocampectomy and/or corticectomy, conferred additional benefit. SIGNIFICANCE: These results suggest that early operative intervention and gross-total resection are critically important factors in achieving seizure-freedom, and thus improving quality-of-life, in patients with glioneuronal tumors causing epilepsy.

Neurosurgery residency and fellowship education in the United States: 2 decades of system development by the One Neurosurgery Summit organizations.

The purpose of this report is to chronicle a 2-decade period of educational innovation and improvement, as well as governance reform, across the specialty of neurological surgery. Neurological surgery educational and professional governance systems have evolved substantially over the past 2 decades with the goal of improving training outcomes, patient safety, and the quality of US neurosurgical care. Innovations during this period have included the following: creating a consensus national curriculum; standardizing the length and structure of neurosurgical training; introducing educational outcomes milestones and required case minimums; establishing national skills, safety, and professionalism courses; systematically accrediting subspecialty fellowships; expanding professional development for educators; promoting training in research; and coordinating policy and strategy through the cooperation of national stakeholder organizations. A series of education summits held between 2007 and 2009 restructured some aspects of neurosurgical residency training. Since 2010, ongoing meetings of the One Neurosurgery Summit have provided strategic coordination for specialty definition, neurosurgical education, public policy, and governance. The Summit now includes leadership representatives from the Society of Neurological Surgeons, the American Association of Neurological Surgeons, the Congress of Neurological Surgeons, the American Board of Neurological Surgery, the Review Committee for Neurological Surgery of the Accreditation Council for Graduate Medical Education, the American Academy of Neurological Surgery, and the AANS/CNS Joint Washington Committee. Together, these organizations have increased the effectiveness and efficiency of the specialty of neurosurgery in advancing educational best practices, aligning policymaking, and coordinating strategic planning in order to meet the highest standards of professionalism and promote public health.

Single-trial speech suppression of auditory cortex activity in humans.

The human auditory cortex is engaged in monitoring the speech of interlocutors as well as self-generated speech. During vocalization, auditory cortex activity is reported to be suppressed, an effect often attributed to the influence of an efference copy from motor cortex. Single-unit studies in non-human primates have demonstrated a rich dynamic range of single-trial auditory responses to self-speech consisting of suppressed, nonsuppressed and excited auditory neurons. However, human research using noninvasive methods has only reported suppression of averaged auditory cortex responses to self-generated speech. We addressed this discrepancy by recording electrocorticographic activity from neurosurgical subjects performing auditory repetition tasks. We observed that the degree of suppression varied across different regions of auditory cortex, revealing a variety of suppressed and nonsuppressed responses during vocalization. Importantly, single-trial high-gamma power (γ(High), 70-150 Hz) robustly tracked individual auditory events and exhibited stable responses across trials for suppressed and nonsuppressed regions.

Cortical spatio-temporal dynamics underlying phonological target detection in humans.

Selective processing of task-relevant stimuli is critical for goal-directed behavior. We used electrocorticography to assess the spatio-temporal dynamics of cortical activation during a simple phonological target detection task, in which subjects press a button when a prespecified target syllable sound is heard. Simultaneous surface potential recordings during this task revealed a highly ordered temporal progression of high gamma (HG, 70-200 Hz) activity across the lateral hemisphere in less than 1 sec. The sequence demonstrated concurrent regional sensory processing of speech syllables in the posterior superior temporal gyrus (STG) and speech motor cortex, and then transitioned to sequential task-dependent processing from prefrontal cortex (PFC), to the final motor response in the hand sensorimotor cortex. STG activation was modestly enhanced for target over nontarget sounds, supporting a selective gain mechanism in early sensory processing, whereas PFC was entirely selective to targets, supporting its role in guiding response behavior. These results reveal that target detection is not a single cognitive event, but rather a process of progressive target selectivity that involves large-scale rapid parallel and serial processing in sensory, cognitive, and motor structures to support goal-directed human behavior.

Neuropsychological outcomes after Gamma Knife radiosurgery for mesial temporal lobe epilepsy: a prospective multicenter study.

PURPOSE: To assess outcomes of language, verbal memory, cognitive efficiency and mental flexibility, mood, and quality of life (QOL) in a prospective, multicenter pilot study of Gamma Knife radiosurgery (RS) for mesial temporal lobe epilepsy (MTLE). METHODS: RS, randomized to 20 Gy or 24 Gy comprising 5.5-7.5 ml at the 50% isodose volume, was performed on mesial temporal structures of patients with unilateral MTLE. Neuropsychological evaluations were performed at preoperative baseline, and mean change scores were described at 12 and 24 months postoperatively. QOL data were also available at 36 months. KEY FINDINGS: Thirty patients were treated and 26 were available for the final 24-month neuropsychological evaluation. Language (Boston Naming Test), verbal memory (California Verbal Learning Test and Logical Memory subtest of the Wechsler Memory Scale-Revised), cognitive efficiency and mental flexibility (Trail Making Test), and mood (Beck Depression Inventory) did not differ from baseline. QOL scores improved at 24 and 36 months, with those patients attaining seizure remission by month 24s accounting for the majority of the improvement. SIGNIFICANCE: The serial changes in cognitive outcomes, mood, and QOL are unremarkable following RS for MTLE. RS may provide an alternative to open surgery, especially in those patients at risk of cognitive impairment or who desire a noninvasive alternative to open surgery.

Common data elements in epilepsy research: development and implementation of the NINDS epilepsy CDE project.

The Common Data Element (CDE) Project was initiated in 2006 by the National Institute of Neurological Disorders and Stroke (NINDS) to develop standards for performing funded neuroscience-related clinical research. CDEs are intended to standardize aspects of data collection; decrease study start-up time; and provide more complete, comprehensive, and equivalent data across studies within a particular disease area. Therefore, CDEs will simplify data sharing and data aggregation across NINDS-funded clinical research, and where appropriate, facilitate the development of evidenced-based guidelines and recommendations. Epilepsy-specific CDEs were established in nine content areas: (1) Antiepileptic Drugs (AEDs) and Other Antiepileptic Therapies (AETs), (2) Comorbidities, (3) Electrophysiology, (4) Imaging, (5) Neurological Exam, (6) Neuropsychology, (7) Quality of Life, (8) Seizures and Syndromes, and (9) Surgery and Pathology. CDEs were developed as a dynamic resource that will accommodate recommendations based on investigator use, new technologies, and research findings documenting emerging critical disease characteristics. The epilepsy-specific CDE initiative can be viewed as part of the larger international movement toward "harmonization" of clinical disease characterization and outcome assessment designed to promote communication and research efforts in epilepsy. It will also provide valuable guidance for CDE improvement during further development, refinement, and implementation. This article describes the NINDS CDE Initiative, the process used in developing Epilepsy CDEs, and the benefits of CDEs for the clinical investigator and NINDS.

Molecular Classification of Gliomas is Associated with Seizure Control: A Retrospective Analysis.

Classically, histologic grading of gliomas has been used to predict seizure association, with low-grade gliomas associated with an increased incidence of seizures compared to high-grade gliomas. In 2016, WHO reclassified gliomas based on histology and molecular characteristics. We sought to determine whether molecular classification of gliomas is associated with preoperative seizure presentation and/or post-operative seizure control across multiple glioma subtypes. All gliomas operated at our institution from 2007 to 2017 were identified based on ICD 9 and 10 billing codes and were retrospectively assessed for molecular classification of the IDH1 mutation, and 1p/19q codeletion. Logistic regression models were performed to assess associations of seizures at presentation as well as post-operative seizures with IDH status and the new WHO integrated classification. Our study included 376 patients: 82 IDH mutant and 294 IDH wildtype. The presence of IDH mutation was associated with seizures at presentation [OR 3.135 (1.818-5.404), p < 0.001]. IDH-mutant glioblastomas presented with seizures less often than other IDH-mutant glioma subtypes grade II and III [OR 0.104 (0.032-0.340), p < 0.001]. IDH-mutant tumors were associated with worse post-operative seizure outcomes, demonstrated by Engel Class [OR 2.666 (1.592-4.464), p < 0.001]. IDH mutation in gliomas is associated with an increased risk of seizure development and worse post-operative seizure control, in all grades except for GBM.

Cortical representation of ipsilateral arm movements in monkey and man.

A fundamental organizational principle of the primate motor system is cortical control of contralateral limb movements. Motor areas also appear to play a role in the control of ipsilateral limb movements. Several studies in monkeys have shown that individual neurons in primary motor cortex (M1) may represent, on average, the direction of movements of the ipsilateral arm. Given the increasing body of evidence demonstrating that neural ensembles can reliably represent information with a high temporal resolution, here we characterize the distributed neural representation of ipsilateral upper limb kinematics in both monkey and man. In two macaque monkeys trained to perform center-out reaching movements, we found that the ensemble spiking activity in M1 could continuously represent ipsilateral limb position. Interestingly, this representation was more correlated with joint angles than hand position. Using bilateral electromyography recordings, we excluded the possibility that postural or mirror movements could exclusively account for these findings. In addition, linear methods could decode limb position from cortical field potentials in both monkeys. We also found that M1 spiking activity could control a biomimetic brain-machine interface reflecting ipsilateral kinematics. Finally, we recorded cortical field potentials from three human subjects and also consistently found evidence of a neural representation for ipsilateral movement parameters. Together, our results demonstrate the presence of a high-fidelity neural representation for ipsilateral movement and illustrates that it can be successfully incorporated into a brain-machine interface.

Spatiotemporal imaging of cortical activation during verb generation and picture naming.

One hundred and fifty years of neurolinguistic research has identified the key structures in the human brain that support language. However, neither the classic neuropsychological approaches introduced by Broca (1861) and Wernicke (1874), nor modern neuroimaging employing PET and fMRI has been able to delineate the temporal flow of language processing in the human brain. We recorded the electrocorticogram (ECoG) from indwelling electrodes over left hemisphere language cortices during two common language tasks, verb generation and picture naming. We observed that the very high frequencies of the ECoG (high-gamma, 70-160 Hz) track language processing with spatial and temporal precision. Serial progression of activations is seen at a larger timescale, showing distinct stages of perception, semantic association/selection, and speech production. Within the areas supporting each of these larger processing stages, parallel (or "incremental") processing is observed. In addition to the traditional posterior vs. anterior localization for speech perception vs. production, we provide novel evidence for the role of premotor cortex in speech perception and of Wernicke's and surrounding cortex in speech production. The data are discussed with regards to current leading models of speech perception and production, and a "dual ventral stream" hybrid of leading speech perception models is given.

Soluble endoglin modulates aberrant cerebral vascular remodeling.

OBJECTIVE: Brain arteriovenous malformations (AVMs) are an important cause of neurological morbidity in young adults. The pathophysiology of these lesions is poorly understood. A soluble form of endoglin (sEng) has been shown to cause endothelial dysfunction and induce preeclampsia. We tested if sEng would be elevated in brain AVM tissues relative to epilepsy brain tissues, and also investigated whether sEng overexpression via gene transfer in the mouse brain would induce vascular dysplasia and associated changes in downstream signaling pathways. METHODS: Expression levels of sEng in surgical specimens were determined by Western blot assay and enzyme-linked immunosorbent assay. Vascular dysplasia, levels of matrix metalloproteinase (MMP), and oxidative stress were determined by immunohistochemistry and gelatin zymography. RESULTS: Brain AVMs (n = 33) had higher mean sEng levels (245 +/- 175 vs 100 +/- 60, % of control, p = 0.04) compared with controls (n = 8), as determined by Western blot. In contrast, membrane-bound Eng was not significantly different (108 +/- 79 vs 100 +/- 63, % of control, p = 0.95). sEng gene transduction in the mouse brain induced abnormal vascular structures. It also increased MMP activity by 490 +/- 30% (MMP-9) and 220 +/- 30% (MMP-2), and oxidants by 260 +/- 20% (4-hydroxy-2-nonenal) at 2 weeks after injection, suggesting that MMPs and oxidative radicals may mediate sEng-induced pathological vascular remodeling. INTERPRETATION: The results suggest that elevated sEng may play a role in the generation of sporadic brain AVMs. Our findings may provide new targets for therapeutic intervention for patients with brain AVMs. Ann Neurol 2009;66:19-27.

A multicenter, prospective pilot study of gamma knife radiosurgery for mesial temporal lobe epilepsy: seizure response, adverse events, and verbal memory.

OBJECTIVE: The safety, efficacy, and morbidity of radiosurgery (RS) must be established before it can be offered as an alternative to open surgery for unilateral mesial temporal lobe epilepsy. We report the 3-year outcomes of a multicenter, prospective pilot study of RS. METHODS: RS was randomized to 20 or 24Gy targeting the amygdala, hippocampus, and parahippocampal gyrus. Seizure diaries evaluated the final seizure remission between months 24 and 36. Verbal memory was evaluated at baseline and 24m with the Wechsler Memory Scale-Revised (WMS-R) and California Verbal Learning Test (CVLT). Patients were classified as having "significant improvement," "no change," and "significant impairment" based on relative change indices. RESULTS: Thirteen high-dose and 17 low-dose patients were treated. Both groups showed significant reductions in seizures by 1 year after treatment. At the 36-month follow-up evaluation, 67% of patients were free of seizures for the prior 12 months (high dose: 10/13, 76.9%; low dose: 10/17, 58.8%). Use of steroids, headaches, and visual field defects did not differ by dose or seizure remission. The prevalence of verbal memory impairment was 15% (4/26 patients); none declined on more than one measure. The prevalence of significant verbal memory improvements was 12% (3/26). INTERPRETATION: RS for unilateral mesial temporal lobe epilepsy offers seizure remission rates comparable with those reported previously for open surgery. There were no major safety concerns with high-dose RS compared with low-dose RS. Additional research is required to determine whether RS may be a treatment option for some patients with mesial temporal lobe epilepsy.