Ictogenesis proceeds through discrete phases in hippocampal CA1 seizures in mice.

Epilepsy is characterized by spontaneous non-provoked seizures, yet the mechanisms that trigger a seizure and allow its evolution remain underexplored. To dissect out phases of ictogenesis, we evoked hypersynchronous activity with optogenetic stimulation. Focal optogenetic activation of putative excitatory neurons in the mouse hippocampal CA1 reliably evoked convulsive seizures in awake mice. A time-vs-time pulsogram plot characterized the evolution of the EEG pulse response from a light evoked response to induced seizure activity. Our results depict ictogenesis as a stepwise process comprised of three distinctive phases demarcated by two transition points. The induction phase undergoes the first transition to reverberant phase activity, followed by the second transition into the paroxysmal phase or a seizure. Non-seizure responses are confined to either induction or reverberant phases. The pulsogram was then constructed in seizures recorded from a murine model of temporal lobe epilepsy and it depicted a similar reverberance preceding spontaneous seizures. The discovery of these distinct phases of ictogenesis may offer means to abort a seizure before it develops.

Preclinical Immune Response and Safety Evaluation of the Protein Subunit Vaccine Nanocovax for COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global health concern. The development of vaccines with high immunogenicity and safety is crucial for controlling the global COVID-19 pandemic and preventing further illness and fatalities. Here, we report the development of a SARS-CoV-2 vaccine candidate, Nanocovax, based on recombinant protein production of the extracellular (soluble) portion of the spike (S) protein of SARS-CoV-2. The results showed that Nanocovax induced high levels of S protein-specific IgG and neutralizing antibodies in three animal models: BALB/c mouse, Syrian hamster, and a non-human primate (Macaca leonina). In addition, a viral challenge study using the hamster model showed that Nanocovax protected the upper respiratory tract from SARS-CoV-2 infection. Nanocovax did not induce any adverse effects in mice (Mus musculus var. albino) and rats (Rattus norvegicus). These preclinical results indicate that Nanocovax is safe and effective.

Cranioplasty Using Customized 3-Dimensional-Printed Titanium Implants: An International Collaboration Effort to Improve Neurosurgical Care.

BACKGROUND: Evolutions in cranioplasty have allowed for the creation of customized implants via advances in 3-dimensional (3D) printing technology, although the high cost associated with this technique presents a barrier for low-income countries. Through an international collaboration, our team in Da Nang, Vietnam is able to create low-cost, customized titanium implants for patients with skull defects. We discuss the details of our collaboration and present our experience with this procedure. METHODS: We conducted a retrospective review of 35 patients who underwent cranioplasty using custom-made titanium implants. The molding and implant making processes were performed by our neurosurgeons using a 3D printer donated by the United Kingdom-based nongovernmental organization Facing the World. We obtained demographic and preoperative data (reason for skull defect, location, surface area measurement of defect) and postoperative data (complications, cosmetic outcome, and patient satisfaction). RESULTS: The median patient age was 27 years (range, 16-60 years). Primary indications for craniectomy included traumatic brain injury from motor vehicle accident (77.1%), cerebrovascular disease (11.4%), implant failure following previous cranioplasty (5.7%), and fall (5.7%). Postoperatively, all implants were found to have an excellent fit; at 6-month follow-up, none of the implants required removal. Complications included 4 postoperative hematomas and 1 surgical site infection. All the patients had improved aesthetic appearance and high satisfaction. CONCLUSIONS: Cranioplasty using customized titanium implants yields excellent results for patients with skull defects, demonstrating the practicality of this technique for cranioplasty in low-income countries. Our experience highlights the importance of ongoing international collaboration to improve neurosurgical care in these countries.

Suppression of phrenic nerve activity as a potential predictor of imminent sudden unexpected death in epilepsy (SUDEP).

Sudden unexpected death in epilepsy (SUDEP) is a leading cause of death in patients with refractory epilepsy. Centrally-mediated respiratory dysfunction has been identified as one of the principal mechanisms responsible for SUDEP. Seizures generate a surge in adenosine release. Elevated adenosine levels suppress breathing. Insufficient metabolic clearance of a seizure-induced adenosine surge might be a precipitating factor in SUDEP. In order to deliver targeted therapies to prevent SUDEP, reliable biomarkers must be identified to enable prompt intervention. Because of the integral role of the phrenic nerve in breathing, we hypothesized that suppression of phrenic nerve activity could be utilized as predictive biomarker for imminent SUDEP. We used a rat model of kainic acid-induced seizures in combination with pharmacological suppression of metabolic adenosine clearance to trigger seizure-induced death in tracheostomized rats. Recordings of EEG, blood pressure, and phrenic nerve activity were made concomitant to the seizure. We found suppression of phrenic nerve burst frequency to 58.9% of baseline (p < 0.001, one-way ANOVA) which preceded seizure-induced death; importantly, irregularities of phrenic nerve activity were partly reversible by the adenosine receptor antagonist caffeine. Suppression of phrenic nerve activity may be a useful biomarker for imminent SUDEP. The ability to reliably detect the onset of SUDEP may be instrumental in the timely administration of potentially lifesaving interventions.

Primary intraosseous meningioma of the calvarium: A systematic review.

BACKGROUND: Primary intraosseous meningiomas (PIM) of calvarial origin are a small subset of meningiomas that arise from and occur within the calvarial bone. Its definition is often confused with other forms of non-dural based intracranial meningiomas, which has made previously published retrospective reviews heterogenous, non-specific and sometimes inaccurate. We present a systematic review of calvarial PIM. METHODS: Using a systematic search protocol that included databases such as PubMed, Web of Science and Embase, we extracted all human studies on PIM published from inception to December 2017. This systematic review includes case reports and retrospective reviews that specifically described PIM. RESULTS: On review of 166 articles identified with the systematic search protocol, 69 articles were analyzed. These comprised of 64 case reports, 1 case series and 4 retrospective reviews. 111 patients with PIM of calvarial origin were analyzed, 58 % of which were females and 42 % males. The mean patient age was 51 years and the frontal bone was the most common tumor location, occurring in 26.1 % of the cases. Surgical resection was the predominant modality of treatment in 97.2 % of the cases, and gross total resection was achieved in 84 % of cases that reported extent of resection. There were no recurrences for grade I meningiomas. However, all grade III meningiomas recurred and 33.3 % of grade II meningiomas showed recurrence with a mean postoperative follow-up interval of 20 months. Statistical analysis using Fisher's exact test showed the recurrence rate to be strongly associated with WHO tumor grade (p-value <0.001). CONCLUSION: There is statistically significant increased recurrence rate for calvarial PIM of higher grades, and we recommend close follow-up in those cases. Surgical resection remains the overwhelming treatment of choice for calvarial PIM, and it has a high gross total resection rate and low risk of complications and mortality.

Biomarkers of Seizure Activity in Patients With Intracranial Metastases and Gliomas: A Wide Range Study of Correlated Regions of Interest.

Introduction: Studies quantifying cortical metrics in brain tumor patients who present with seizures are limited. The current investigation assesses morphometric/volumetric differences across a wide range of anatomical regions, including temporal and extra-temporal, in patients with gliomas and intracranial metastases (IMs) presenting with seizures that could serve as a biomarker in the identification of seizure expression and serve as a neuronal target for mitigation. Methods: In a retrospective design, the MR sequences of ninety-two tumor patients [55% gliomas; 45% IM] and 34 controls were subjected to sophisticated morphometric and volumetric assessments using BrainSuite and MATLAB modules. We examined 103 regions of interests (ROIs) across eight distinct cortical categories of interests (COI) [gray matter, white matter; total volume, CSF; cortical areas: inner, mid, pial; cortical thickness]. The primary endpoint was quantifying and identifying ROIs with significant differences in z-scores based upon the presence of seizures. Feature selection employing neighborhood component analysis (NCA) determined the ROI within each COI having the highest significance/weight in the differentiation of seizure vs. non-seizure patients harboring brain tumor. Results: Overall, the mean age of the cohort was 58.0 ± 12.8 years, and 45% were women. The prevalence of seizures in tumor patients was 28%. Forty-two ROIs across the eight pre-defined COIs had significant differences in z-scores between tumor patients presenting with and without seizures. The NCA feature selection noted the volume of pars-orbitalis and right middle temporal gyrus to have the highest weight in differentiating tumor patients based on seizures for three distinct COIs [GM, total volume, and CSF volume] and white matter, respectively. Left-sided transverse temporal gyrus, left precuneus, left transverse temporal, and left supramarginal gyrus were associated with having the highest weight in the differentiation of seizure vs. non-seizure in tumor patients for morphometrics relating to cortical areas in the pial, inner and mid regions and cortical thickness, respectively. Conclusion: Our study elucidates potential biomarkers for seizure targeting in patients with gliomas and IMs based upon morphometric and volumetric assessments. Amongst the widespread brain regions examined in our cohort, pars orbitalis, supramarginal and temporal gyrus (middle, transverse), and the pre-cuneus contribute a maximal potential for differentiation of seizure patients from non-seizure.

A system divided: the state of neurosurgical training in modern-day Vietnam.

The current report is the first of its kind in describing the neurosurgical training in modern-day Vietnam. Starting with in-depth face-to-face interviews, followed by electronically distributed questionnaires, a detailed picture of the training systems emerged.Neurosurgical training in Vietnam is multifaceted and dichotomous. The country of nearly 100 million people currently has only one neurosurgery-specific residency program, at the University of Medicine and Pharmacy at Ho Chi Minh City (UMPHCMC). This program lasts for 3 years, and Westerners might recognize many similarities to programs native to their countries. A similar training program exists in the north, at the Hanoi Medical University, but at this institution, trainees focus on neurosurgery only in the final year of their 3-year training. Neurosurgical training that resembles the program in Hanoi permeates the rest of the country, and the goal for all of the programs is to rapidly produce surgeons who can be dispersed throughout the country to treat patients requiring urgent neurosurgical procedures who are medically unsuitable for transfer to large urban centers and multispecialty hospitals. For the privilege of practicing elective neurosurgery, trainees around the country are required to acquire further training in Ho Chi Minh City or Hanoi or during fellowships abroad.A clear description of the neurosurgical training systems in Vietnam is hard to achieve, as there exist many diverse pathways and no standard definition of the endpoint for training. Unification and a clearer certification standard will likely help to elevate the standards of training and the state of neurosurgical practice in Vietnam.

Spontaneous Thrombosis of Giant Dissecting Fusiform Middle Cerebral Aneurysm After Double-Barrel Superficial Temporal Artery-Middle Cerebral Artery Bypass: A Case Report of Decision-Making in a Limited Resource Environment.

BACKGROUND: The treatment of giant fusiform middle cerebral artery (MCA) aneurysms remains daunting owing to their tendency to be associated with precarious end-vessel anatomy and the need for complex microsurgical techniques to appropriately address the aneurysm and the vasculature at risk. Extracranial-intracranial bypass revascularization remains a valuable tool for treating these complex lesions. In the present report, we have described a rare occurrence in which the creation of a double-barrel superficial temporal artery (STA-MCA) bypass facilitated spontaneous obliteration of the aneurysm. We have also highlighted our decision-making process, which was affected by operating in a low-to-middle income country with limited resources. CASE DESCRIPTION: A 32-year-old man had presented with recurrent ischemic events in the left MCA distribution and subsequent subarachnoid hemorrhage due to rupture of a giant complex fusiform MCA aneurysm. The patient underwent double-barrel STA-MCA bypass and was scheduled for second-stage clip reconstruction or partial trapping. Postoperative imaging studies revealed progressive thrombosis of the M1 segment, resulting in occlusion of the aneurysm without subsequent trapping or clipping. The patient recovered remarkably without further repeat hemorrhage or ischemic injury. We also reviewed the reported data. CONCLUSIONS: Double-barrel STA-MCA bypass is a potential salvage surgical technique to treat selected ruptured complex giant fusiform MCA aneurysms. In rare selected cases, the flow alteration induced by the bypass alone can potentially facilitate aneurysm thrombosis.

A Review of the History, Anatomy, and Development of the C1 Spinal Nerve.

The C1 spinal nerve is a fascinating anatomic structure owing to its wide range of variations. Throughout history, understanding of the cranial and spinal nerves has probably influenced the current conception of this nerve among anatomists. Located at the craniocervical junction, the C1 spinal nerve contributes to the motor innervation of deep cervical muscles through the cervical (anterior) and Cruveilhier's (posterior) plexuses. Sensory functions of this nerve are more enigmatic; despite investigations into its dorsal rootlets, a dorsal root ganglion, and the relationships between this nerve and adjacent cranial and spinal nerves, there is still no consensus regarding its true anatomy. In this article, we review the available literature and discuss some of the developmental models that could potentially explain the wide range of variations and functions of the C1 nerve.

Outcome of Microsurgery for Arteriovenous Malformations in a Resource-Restricted Environment: Single-Surgeon Series from Vietnam.

BACKGROUND: The health care expenditure in Vietnam is equivalent to 1% of that in the United States. For most patients with brain arteriovenous malformations (AVM), surgery is the only available treatment modality. This study reports on the outcomes on AVM microsurgery in this resource-restricted environment. METHODS: This is a prospectively collected, retrospectively analyzed case series of consecutive patients who underwent surgical resection of AVM by a single surgeon in Vietnam. All surgeries were performed in a 3-year period in Hanoi. The primary endpoints were obliteration of the AVM and surgical morbidity (modified Rankin Scale [mRS] > 1). RESULTS: There were 86 patients and 62% presented with hemorrhage. Only 2 patients had preoperative embolization, and 47 patients (54%) had preoperative digital subtraction angiography. All patients underwent microsurgical resection of their AVM. Excluding the 4 patients who died, the AVM obliteration rate was 98%. The mean follow-up was 20.1 months. Before surgery, 36% of patients had at least some disability (mRS > 1). Postoperatively, this was reduced to 10% (McNemar P = 0.007). For the overall cohort, neurologic status was improved from initial encounter to final assessment (P = 0.001). Because of resource restrictions, some patients with hemorrhage experienced delays in treatment. There was no difference in outcome between patients who were admitted before or after 24 hours post ictus (P = 0.6). The days spent waiting for surgery did not correlate with final mRS in univariate regression (R2 = 0.01). CONCLUSIONS: Notwithstanding the limitation in health care resources in Vietnam, surgery for AVMs was successful in eliminating the malformation, with obliteration rates and morbidity comparable with international standards.

Wogonin attenuates the deleterious effects of traumatic brain injury in anesthetized Wistar rats.

Wogonin, a flavonoid (5,7-dihydroxy-8-methoxyflavone) with reported neuroprotective properties, is widely used in treating inflammatory diseases. The main goal of this study was to explore the role of wogonin in preventing deleterious cardiovascular effects of traumatic brain injury (TBI). Experiments were carried out in adult male urethane-anesthetized, artificially ventilated, Wistar rats, weighing 300-350 gm. TBI was produced by fluid percussion injury (FPI). A significant decrease in blood pressure (BP), heart rate (HR) and greater splanchnic nerve activity (GSNA), which lasted for up to 4 h, was observed after the application of moderate FPI. Intravenous (i.v.) and intracerebroventricular (i.c.v.) administration of wogonin before and after the moderate FPI significantly attenuated the decreases in BP, HR, and GSNA elicited by FPI. Administration of wogonin also prevented the attenuation of baroreflex-induced bradycardia elicited by FPI. Based on these results, it was concluded that administration of wogonin attenuates the deleterious effects of moderate FPI.

Minipterional and Supraorbital Keyhole Craniotomies for Ruptured Anterior Circulation Aneurysms: Experience at Single Center.

BACKGROUND: Keyhole craniotomy is a type of pterional craniotomy that involves a minimally invasive approach for the treatment of cerebral aneurysms. Currently, the minipterional keyhole craniotomy and supraorbital keyhole craniotomy procedures are frequently performed. METHODS: We evaluated the feasibility and safety of supraorbital keyhole craniotomies and minipterional keyhole craniotomy for the clipping of ruptured intracranial aneurysms in the anterior cerebral circulation as an alternative to the pterional approach in a consecutive series of 25 patients. RESULTS: The rate of intraoperative aneurysmal rupture was 8% (2/25), and all ruptures were safely controlled. CONCLUSION: The success solely depends on careful selection of patients and the experience of the surgical team.