Systematic 1 Hz direct electrical stimulation for seizure induction: A reliable method for localizing seizure onset zone and predicting seizure freedom.

OBJECTIVE: To prospectively investigate the utility of seizure induction using systematic 1 Hz stimulation by exploring its concordance with the spontaneous seizure onset zone (SOZ) and relation to surgical outcome; comparison with seizures induced by non-systematic 50 Hz stimulation was attempted as well. METHODS: Prospective cohort study from 2018 to 2021 with ≥ 1 y post-surgery follow up at Yale New Haven Hospital. With 1 Hz, all or most of the gray matter contacts were stimulated at 1, 5, and 10 mA for 30-60s. With 50 Hz, selected gray matter contacts outside of the medial temporal regions were stimulated at 1-5 mA for 0.5-3s. Stimulation was bipolar, biphasic with 0.3 ms pulse width. The Yale Brain Atlas was used for data visualization. Variables were analyzed using Fisher's exact, χ2, or Mann-Whitney test. RESULTS: Forty-one consecutive patients with refractory epilepsy undergoing intracranial EEG for localization of SOZ were included. Fifty-six percent (23/41) of patients undergoing 1 Hz stimulation had seizures induced, 83% (19/23) habitual (clinically and electrographically). Eighty two percent (23/28) of patients undergoing 50 Hz stimulation had seizures, 65% (15/23) habitual. Stimulation of medial temporal or insular regions with 1 Hz was more likely to induce seizures compared to other regions [15/32 (47%) vs. 2/41 (5%), p < 0.001]. Sixteen patients underwent resection; 11/16 were seizure free at one year and all 11 had habitual seizures induced by 1 Hz; 5/16 were not seizure free at one year and none of those 5 had seizures with 1 Hz (11/11 vs 0/5, p < 0.0001). No patients had convulsions with 1 Hz stimulation, but four did with 50 Hz (0/41 vs. 4/28, p = 0.02). SIGNIFICANCE: Induction of habitual seizures with 1 Hz stimulation can reliably identify the SOZ, correlates with excellent surgical outcome if that area is resected, and may be superior (and safer) than 50 Hz for this purpose. However, seizure induction with 1 Hz was infrequent outside of the medial temporal and insular regions in this study.

Synthesis of the Indolizidine Core of Virosinine A via a Microwave-Promoted Cascade Cyclization Involving Iminyl Radicals.

The indolizidine core of virosinine A was synthesized by means of a microwave-promoted cascade reaction featuring 5-exo-trig iminyl radical cyclization, thiyl radical elimination, and intramolecular imine alkylation. The resulting bicyclic iminium ion underwent stereoselective reduction by Red-Al to deliver the target compound. DFT calculations suggested that both the radical cyclization and thiyl radical elimination steps are reversible at high reaction temperatures.

Responsive neurostimulation as a treatment for super-refractory focal status epilepticus: a systematic review and case series.

OBJECTIVE: Super-refractory status epilepticus (SRSE) has high rates of morbidity and mortality. Few published studies have investigated neurostimulation treatment options in the setting of SRSE. This systematic literature review and series of 10 cases investigated the safety and efficacy of implanting and activating the responsive neurostimulation (RNS) system acutely during SRSE and discusses the rationale for lead placement and selection of stimulation parameters. METHODS: Through a literature search (of databases and American Epilepsy Society abstracts that were last searched on March 1, 2023) and direct contact with the manufacturer of the RNS system, 10 total cases were identified that utilized RNS acutely during SE (9 SRSE cases and 1 case of refractory SE [RSE]). Nine centers obtained IRB approval for retrospective chart review and completed data collection forms. A tenth case had published data from a case report that were referenced in this study. Data from the collection forms and the published case report were compiled in Excel. RESULTS: All 10 cases presented with focal SE: 9 with SRSE and 1 with RSE. Etiology varied from known lesion (focal cortical dysplasia in 7 cases and recurrent meningioma in 1) to unknown (2 cases, with 1 presenting with new-onset refractory focal SE [NORSE]). Seven of 10 cases exited SRSE after RNS placement and activation, with a time frame ranging from 1 to 27 days. Two patients died of complications due to ongoing SRSE. Another patient's SE never resolved but was subclinical. One of 10 cases had a device-related significant adverse event (trace hemorrhage), which did not require intervention. There was 1 reported recurrence of SE after discharge among the cases in which SRSE resolved up to the defined endpoint. CONCLUSIONS: This case series offers preliminary evidence that RNS is a safe and potentially effective treatment option for SRSE in patients with 1-2 well-defined seizure-onset zone(s) who meet the eligibility criteria for RNS. The unique features of RNS offer multiple benefits in the SRSE setting, including real-time electrocorticography to supplement scalp EEG for monitoring SRSE progress and response to treatment, as well as numerous stimulation options. Further research is indicated to investigate the optimal stimulation settings in this unique clinical scenario.

Combined surgical repair and venous sinus stenting for patients with skull base encephaloceles secondary to dural venous sinus stenosis.

BACKGROUND: Chronically elevated intracranial pressure (ICP) seen in idiopathic intracranial hypertension (IIH) can cause the development of skull base encephaloceles and cerebrospinal fluid (CSF) leaks. Surgical repair and ventriculoperitoneal shunt (VPS) placement are mainstays of treatment. Venous sinus stenting (VSS) is a newly accepted treatment modality. The goal of this study was thus to determine if VSS can be used to treat symptoms and prevent recurrence after surgical encephalocele repair. METHODS: Retrospective chart review of patients that had surgical repair of encephaloceles followed by VSS for symptomatic stenosis with elevated pressure gradient. RESULTS: A total of 13 patients underwent a combined encephalocele repair and VSS. Seventy-two percent were female; 46% had headaches, 69% pulsatile tinnitus, and 92% CSF rhinorrhea or otorrhea. One had seizures. Mean lumbar opening pressure was 23.3 ± 2.6 cm H2O; the average sagittal-to-jugular pressure gradient was 12.7 ± 1.8 cmH2O and was elevated in all patients. Four patients had middle fossa craniotomy for repair of tegmen defect (one bilateral); one had a retrosigmoid craniotomy for repair of a sigmoid plate defect. Eight had an endoscopic endonasal repair for sphenoid or cribriform plate encephalocele. There were no VSS procedural complications or complications associated with dual antiplatelet therapy. One patient had meningitis after endoscopic repair that was treated with antibiotics. One patient had recurrence of both CSF leak and venous stenosis adjacent to the stent requiring repeat repair and VSS. There was no further recurrence. CONCLUSION: In patients with dural sinus stenosis and encephaloceles requiring repair, VSS can be performed safely within weeks of surgery for relief of symptoms, resolution of underlying pathology, and prevention of CSF leak recurrence.

Multidisciplinary management of carotid body tumors: a single-institution case series of 22 patients.

OBJECTIVE: Carotid body tumors (CBTs) are rare, slow-growing neoplasms derived from the parasympathetic paraganglia of the carotid bodies. Although inherently vascular lesions, the role of preoperative embolization prior to resection remains controversial. In this report, the authors describe an institutional series of patients with CBT successfully treated via resection following preoperative embolization and compare the results in this series to previously reported outcomes in the treatment of CBT. METHODS: All CBTs resected between 2013 and 2019 at a single institution were retrospectively identified. All patients had undergone preoperative embolization performed by interventional neuroradiologists, and all had been operated on by a combined team of cerebrovascular neurosurgeons and otolaryngology-head and neck surgeons. The clinical, radiographic, endovascular, and perioperative data were collected. All procedural complications were recorded. RESULTS: Among 22 patients with CBT, 63.6% were female and the median age was 55.5 years at the time of surgery. The most common presenting symptoms included a palpable neck mass (59.1%) and voice changes (22.7%). The average tumor volume was 15.01 ± 14.41 cm3. Most of the CBTs were Shamblin group 2 (95.5%). Blood was predominantly supplied from branches of the ascending pharyngeal artery, with an average of 2 vascular pedicles (range 1-4). Fifty percent of the tumors were embolized with more than one material: polyvinyl alcohol, 95.5%; Onyx, 50.0%; and N-butyl cyanoacrylate glue, 9.1%. The average reduction in tumor blush following embolization was 83% (range 40%-95%). No embolization procedural complications occurred. All resections were performed within 30 hours of embolization. The average operative time was 173.9 minutes, average estimated blood loss was 151.8 ml, and median length of hospital stay was 4 days. The rate of permanent postoperative complications was 0%; 2 patients experienced transient hoarseness, and 1 patient had medical complications related to alcohol withdrawal. CONCLUSIONS: This series reveals that endovascular embolization of CBT is a safe and effective technique for tumor devascularization, making preoperative angiography and embolization an important consideration in the management of CBT. Moreover, the successful management of CBT at the authors' institution rests on a multidisciplinary approach whereby endovascular surgeons, neurosurgeons, and ear, nose, and throat-head and neck surgeons work together to optimally manage each patient with CBT.

Intra-arterial chemotherapy for retinoblastoma.

Intra-arterial chemotherapy (IAC) for retinoblastoma is a minimally invasive and chemotherapeutic approach resulting in eye salvage and vision restoration or preservation. Moreover, IAC has proven to effectively treat advanced retinoblastoma while not compromising patient survival. Our institutional experience with IAC for retinoblastoma has included over 500 patients and over 2400 intra-arterial infusions. Each infusion is completed with the use of a micropuncture for arterial access and microcatheter for infusion, eliminating the need for guide catheters and related complications (video 1). This treatment modality has resulted in >95% ocular survival and reduces enucleation to <5% for this population. In addition to local therapy, including cryotherapy, intravitreal chemotherapy, or laser treatments, by the ophthalmologist, IAC has become an important component of comprehensive multidisciplinary and multimodal therapy for this disease. For what used to require a possibly vision-sacrificing procedure, retinoblastoma treated with IAC minimizes the need for enucleation while maximizing both patient and ocular survival.DC1SP110.1136/neurintsurg-2022-018957.supp1Supplementary data neurintsurg;15/3/303/V1F1V1Video 1 .

A multidisciplinary management algorithm for brain metastases.

The incidence of brain metastases continues to present a management issue despite the advent of improved systemic control and overall survival. While the management of oligometastatic disease (ie, 1-4 brain metastases) with surgery and radiation has become fairly straightforward in the era of radiosurgery, the management of patients with multiple metastatic brain lesions can be challenging. Here we review the available evidence and provide a multidisciplinary management algorithm for brain metastases that incorporates the latest advances in surgery, radiation therapy, and systemic therapy while taking into account the latest in precision medicine-guided therapies. In particular, we argue that whole-brain radiation therapy can likely be omitted in most patients as up-front therapy.

Flow diversion for cerebral aneurysms.

The treatment of cerebral aneurysms includes open microsurgical options (e.g., clipping, trapping/bypass) and evolving endovascular techniques. Following the landmark trials that propelled endovascular treatment to the forefront, flow diversion has shown high aneurysm cure rates with minimal complications. Flow diversion stents are placed in the parent vessel, redirecting blood flow from the aneurysm, promoting reendothelization across the neck, and resulting in complete occlusion of the aneurysm. As a result, flow diversion has become increasingly used as the primary treatment for unruptured aneurysms; however, its applications are being pushed to new frontiers. Here, the authors present three cases showcasing the treatment of intracranial aneurysms with flow diversion. The video can be found here: https://stream.cadmore.media/r10.3171/2022.7.FOCVID2253.

Qualitative head-to-head comparison of headlamp and microscope for visualizing 5-ALA fluorescence during resection of glioblastoma.

Fluorescence-guided surgery (FGS) for high-grade gliomas using 5-aminolevulinic acid has become a new standard of care for neurosurgeons in several countries. In this video the authors present the case of a man with glioblastoma who underwent FGS in which similar images of the operative field were acquired alternating between the microscope and a new commercially available headlight, facilitating the comparison of visualization quality between the two devices. The authors also review some of the principles of fluorescence-guidance surgery that may explain the improved brightness and contrast that they observed when using the headlamp versus the microscope. The video can be found here: https://stream.cadmore.media/r10.3171/2021.10.FOCVID21181.

Fusiform Cerebral Aneurysm and Atrial Myxoma.

A 24-year-old woman presented with a seizure-like episode of left hemibody sensory loss. Magnetic resonance imaging and magnetic resonance angiography revealed multiple distal fusiform cerebral aneurysms requiring angiographic evaluation and possible endovascular treatment. On preoperative workup, transthoracic echocardiography revealed a large, 4.1 × 2.1 cm, mobile left atrial mass prolapsing into the left ventricle during diastole. Multidisciplinary discussion among representatives from neurosurgery, cardiology, and cardiothoracic surgery determined the plan to proceed with diagnostic cerebral angiogram and aneurysm embolization before moving forward with heart surgery. Cerebral angiogram revealed several right distal middle cerebral artery fusiform aneurysms and a right distal posterior inferior cerebellar artery fusiform aneurysm. Subsequently, the patient underwent endovascular coil embolization of the largest distal M4 fusiform aneurysm, measuring 3.3 × 3.2 mm in maximal diameter. The patient recovered to baseline in the surgical intensive care unit and was discharged home on postoperative day 7 with close neurosurgical and cardiology follow-up.

Synthesis and evaluation of potent yaku'amide A analogs.

Two full-length analogs of the anticancer peptide yaku'amide A (1a) and four partial structures have been synthesized. These analogs were identified by computational studies in which the three E- and Z-ΔIle residues of the natural product were replaced by the more accessible dehydroamino acids ΔVal and ΔEnv. Of the eight possible analogs, modeling showed that the targeted structures 2a and 2b most closely resembled the three-dimensional structure of 1a. Synthesis of 2a and 2b followed a convergent route that was streamlined by the absence of ΔIle in the targets. Screening of the compounds against various cancer cell lines revealed that 2a and 2b mimic the potent anticancer activity of 1a, thereby validating the computational studies.

Characterization of Hemorrhagic and Ischemic Stroke in a Diverse Cohort of COVID-19 Patients.

BACKGROUND AND PURPOSE: COVID-19 is a known risk factor for stroke. There is limited data on the influence of demographics, risk factors, and hematologic function on outcomes in COVID-19 stroke patients. METHODS: All patients with acute ischemic or hemorrhagic stroke tested for COVID-19 and treated from March 13 through May 19, 2020 were retrospectively analyzed. COVID+ patients were compared to COVID- patients and a historical cohort from 2019. RESULTS: 84 patients with radiographic acute stroke from the 2020 study period and 152 patients in the historical cohort were included. Stroke incidence in COVID+ patients was 1.5%, with a significant decline in total stroke presentations during this period compared to 2019. 37 patients were COVID+ and 47 patients were COVID-. 32% of COVID+ stroke patients were Hispanic compared to 15% and 18% in the COVID- and 2019 cohorts respectively (p = 0.069 and 0.07). COVID+ stroke patients were younger, had higher rates of hemorrhagic conversion (p = 0.034), higher initial NIHSS (p < 0.001), increased cryptogenic stroke mechanism (p = 0.02), and higher mortality independent of COVID-19 severity. COVID+ patients had higher rates of thrombocytopenia (p = 0.02), and were less likely to be on antiplatelet therapy (p = 0.025). In multivariable analysis, only COVID-19 status independently predicted mortality. CONCLUSIONS: COVID status, independent of severity, was significantly associated with higher mortality in stroke patients. COVID+ stroke patients were younger and less likely to be on antiplatelets, with higher rates of thrombocytopenia, suggesting a possible role for antiplatelet use in this population.

Impact of the COVID-19 pandemic on neuro-oncology outcomes.

INTRODUCTION: The Coronavirus disease 2019 (COVID-19) pandemic has uprooted healthcare systems worldwide, disrupting care and increasing dependence on alternative forms of health care delivery. It is yet to be determined how the pandemic affected neuro-oncology patient outcomes, given that the majority of even "elective" neurosurgical oncology procedures are time-sensitive. This study quantifies changes in neuro-oncological care during the height of the pandemic and investigates patient outcomes in 2020 compared to a historical control. METHODS: We performed a retrospective review of patients with malignant brain tumor diagnoses who were seen at our institution between March 13 and May 1 of 2020 and 2019. Alterations in care, including shift from in-person to telehealth, delays in evaluation and intervention, and treatment modifications were evaluated. These variables were analyzed with respect to brain tumor control and mortality. RESULTS: 112 patients from 2020 to 166 patients from 2019 were included. There was no significant difference in outcomes between the cohorts, despite significantly more treatment delays (p = 0.0160) and use of telehealth (p < 0.0001) in 2020. Patients in 2020 who utilized telehealth visits had significantly more stable tumor control than those who had office visits (p = 0.0124), consistent with appropriate use of in-person visits for patients with progression. CONCLUSIONS: Our study showed that use of telehealth and selective alterations in neuro-oncological care during the COVID-19 pandemic did not lead to adverse patient outcomes. This suggests that adaptive physician-led changes were successful and may inform management during the ongoing pandemic, especially with the emergence of the Delta variant.

Perioperative prophylactic middle meningeal artery embolization for chronic subdural hematoma: a series of 44 cases.

OBJECTIVE: Chronic subdural hematoma (cSDH) is a common and challenging pathology to treat due to both the historically high recurrence rate following surgical evacuation and the medical comorbidities inherent in the aging patient population that it primarily affects. Middle meningeal artery (MMA) embolization has shown promise in the treatment of cSDHs, most convincingly to avoid surgical evacuation in relatively asymptomatic patients. Symptomatic patients requiring surgical evacuation may also benefit from perioperative MMA embolization to prevent cSDH recurrence. The goal of this study was to determine the utility of perioperative MMA embolization for symptomatic cSDH requiring surgical evacuation and to assess if there is a decrease in the cSDH recurrence rate compared to historical recurrence rates following surgical evacuation alone. METHODS: Symptomatic cSDHs were evacuated using a subdural evacuating port system (SEPS) with 5-mm twist-drill craniostomy in an intensive care unit or by performing a craniotomy in the operating room, using either a small (silver dollar, < 4 cm) or large (≥ 4 cm) craniotomy. MMA embolization was performed perioperatively using angiography, selective catheterization of the MMA, and infusion of polyvinyl particles. Outcomes were assessed clinically and radiographically with interval head CT imaging. RESULTS: There were 44 symptomatic cSDHs in 41 patients, with 3 patients presenting with bilateral symptomatic cSDH. All cSDHs were evacuated using an SEPS (n = 18), a silver-dollar craniotomy (n = 16), or a large craniotomy (n = 10). Prophylactic MMA embolization was performed successfully in all cSDHs soon after surgical evacuation. There were no deaths and no procedural complications. There was an overall reduction of greater than 50% or resolution of cSDH in 40/44 (90.9%) cases, regardless of the evacuation procedure used. Of the 44 prophylactic cases, there were 2 (4.5%) cases of cSDH recurrence that required repeat surgical evacuation at the 1-year follow-up. These 2 cSDHs were initially evacuated using an SEPS and subsequently required a craniotomy, thereby representing an overall 4.5% recurrence rate of treated cSDH requiring repeat evacuation. Most notably, of the 26 patients who underwent surgical evacuation with a craniotomy followed by MMA embolization, none had cSDH recurrence requiring repeat intervention. CONCLUSIONS: Perioperative prophylactic MMA embolization in the setting of surgical evacuation, via either craniotomy or SEPS, may help to lower the recurrence rate of cSDH.

Convergent Total Synthesis of Yaku'amide†A.

Total synthesis of the anticancer peptide natural product yaku'amide A is reported. Its ß-tert-hydroxy amino acids were prepared by regioselective aminohydroxylation involving a chiral mesyloxycarbamate reagent. Stereospecific construction of the E- and Z-ΔIle residues was accomplished through a one-pot reaction featuring anti dehydration, azide reduction, and O→N acyl transfer. Alkene isomerization was negligible during this process. These methods enabled a highly convergent and efficient synthetic route to the natural product.

Repeat convection-enhanced delivery for diffuse intrinsic pontine glioma.

OBJECTIVE: While the safety and efficacy of convection-enhanced delivery (CED) have been studied in patients receiving single-dose drug infusions, agents for oncological therapy may require repeated or chronic infusions to maintain therapeutic drug concentrations. Repeat and chronic CED infusions have rarely been described for oncological purposes. Currently available CED devices are not approved for extended indwelling use, and the only potential at this time is for sequential treatments through multiple procedures. The authors report on the safety and experience in a group of pediatric patients who received sequential CED into the brainstem for the treatment of diffuse intrinsic pontine glioma. METHODS: Patients in this study were enrolled in a phase I single-center clinical trial using 124I-8H9 monoclonal antibody (124I-omburtamab) administered by CED (clinicaltrials.gov identifier NCT01502917). A retrospective chart and imaging review were used to assess demographic data, CED infusion data, and postoperative neurological and surgical outcomes. MRI scans were analyzed using iPlan Flow software for volumetric measurements. Target and catheter coordinates as well as radial, depth, and absolute error in MRI space were calculated with the ClearPoint imaging software. RESULTS: Seven patients underwent 2 or more sequential CED infusions. No patients experienced Clinical Terminology Criteria for Adverse Events grade 3 or greater deficits. One patient had a persistent grade 2 cranial nerve deficit after a second infusion. No patient experienced hemorrhage or stroke postoperatively. There was a statistically significant decrease in radial error (p = 0.005) and absolute tip error (p = 0.008) for the second infusion compared with the initial infusion. Sequential infusions did not result in significantly different distribution capacities between the first and second infusions (volume of distribution determined by the PET signal/volume of infusion ratio [mean ± SD]: 2.66 ± 0.35 vs 2.42 ± 0.75; p = 0.45). CONCLUSIONS: This series demonstrates the ability to safely perform sequential CED infusions into the pediatric brainstem. Past treatments did not negatively influence the procedural workflow, technical application of the targeting interface, or distribution capacity. This limited experience provides a foundation for using repeat CED for oncological purposes.

Single arm access venous sinus stenting (SAVeS) technique: Technical note.

Intracranial venous sinus stenting is gaining acceptance as an effective treatment for idiopathic intracranial hypertension (IIH). The typical approach is via femoral venous and arterial access for transvenous stenting with simultaneous angiography. These patients are at an above average risk for groin complications considering obesity is typically associated with IIH and the need for heparinization and dual antiplatelet therapy. Here, we describe cerebral venography, angiography, and venous sinus stenting via a single upper extremity. We utilize a transradial approach for angiography and a venous access via the brachial or basilic vein. Over a series of 28 consecutive procedures, we were able to successfully access the intracranial venous sinuses via the arm without access site complications. This method offers the advantages of immediate patient mobilization after the procedure and more easily monitored and compressible access sites for easier post-procedural care.