The Pediatric Epilepsy Surgery Interest Group (PESIG) under the auspice of the ISPN Research Committee: Availability of relevant technology and geographical distribution.

PURPOSE: Epilepsy surgery for pediatric drug-resistant epilepsy has been shown to improve seizure control, enhance patient and family QoL, and reduce mortality. However, diagnostic tools and surgical capacity are less accessible worldwide. The International Society Pediatric Neurosurgery (ISPN) has established a Pediatric Epilepsy Surgery Interest Group (PESIG), aiming to enhance global collaboration in research and educational aspects. The goals of this manuscript are to introduce PESIG and analyze geographical differences of epilepsy surgery and technology availability. METHODS: PESIG was established (2022) following an ISPN executive board decision. Using a standardized form, we surveyed the PESIG members, collecting and analyzing data regarding geographical distribution, and availability of various epilepsy treatment-related technologies. RESULTS: Two hundred eighty-two members registered in PESIG from 70 countries, over 6 continents, were included. We categorized the countries by GDP as follows: low, lower-medium, upper-medium, and high income. The most commonly available technology was vagus nerve stimulation 68%. Stereoelectroencephalography was available for 58%. North America had statistically significant greater availability compared to other continents. Europe had greater availability compared to Africa, Asia, and South (Latin) America. Asia had greater availability compared to Africa. High-income countries had statistically significant greater availability compared to other income groups; there was no significant difference between the other income-level subgroups. CONCLUSION: There is a clear discrepancy between countries and continents regarding access to epilepsy surgery technologies. This strengthens the need for collaboration between neurologists and neurosurgeons from around the world, to enhance medical education and training, as well as to increase technological availability.

Role of Interventional Radiology (IR) in vascular emergencies among cirrhotic patients.

Gastrointestinal hemorrhage remains one of the most common causes of morbidity and mortality among patients with liver cirrhosis. Mostly, these patients bleed from the gastroesophageal varices. However, nonvariceal bleeding is also more likely to occur in these patients. Because of frequent co-existing coagulopathy, cirrhotics are more prone to bleed from a minor vascular injury while performing percutaneous interventions. Ultrasound-guided bedside vascular access is an essential procedure in liver critical care units. Transjugular portosystemic shunts (TIPS) with/without variceal embolization is a life-saving measure in patients with refractory variceal bleeding. Whenever feasible, balloon-assisted retrograde transvenous obliteration (BRTO) is an alternative to TIPS in managing gastric variceal bleeding, but without a risk of hepatic encephalopathy. In cases of failed or unfeasible endotherapy, transarterial embolization using various embolic agents remains the cornerstone therapy in patients with nonvariceal bleeding such as ruptured hepatocellular carcinoma, gastroduodenal ulcer bleeding, and procedure-related hemorrhagic complications. Among various embolic agents, N-butyl cyanoacrylate (NBCA) enables better vascular occlusion in cirrhotics, even in coagulopathy, making it a more suitable embolic agent in an expert hand. This article briefly entails the different interventional radiological procedures in vascular emergencies among patients with liver cirrhosis.

Is salvage Plug-Assisted Retrograde Transvenous Obliteration (PARTO) safe and effective for bleeding gastric varices ?- A preliminary single-center experience.

BACKGROUND: Vascular plug-assisted retrograde transvenous obliteration (PARTO) obliterates the gastric varices and portosystemic shunt, thus resulting in a lower rebleeding rate than endoscopic glue/sclerotherapy. AIMS: To evaluate the safety and efficacy of PARTO as salvage therapy in liver cirrhosis with gastric variceal bleed (GVB) after failed endotherapy. We assessed the clinical success rate and changes in liver function at 6- months. MATERIALS AND METHODS: Patients who underwent salvage PARTO after failed endotherapy for GVB (between December 2021 and November 2022) were searched and analyzed from the hospital database. Clinical success rate and rebleed rate were obtained at six months. Child-Pugh score (CTP) and Model for end-stage liver disease (MELD) score were calculated and compared between baseline and 6-month follow-up. RESULTS: Fourteen patients (n = 14, Child-Pugh class A/B) underwent salvage PARTO. Nine had GOV-2, and five had IGV-1 varices. The mean shunt diameter was 11.6 ± 1.6 mm. The clinical success rate of PARTO was 100% (no recurrent gastric variceal hemorrhage within six months). No significant deterioration in CTP (6.79 ± 0.98 vs. 6.21 ± 1.52; p = 0.12) and MELD scores (11.5 ± 4.05 vs. 10.21 ± 3.19; p = 0.36) was noted at 6 months. All patients were alive at 6 months. One patient (n = 1, 7.1%) bled from esophageal varices after three days of PARTO and was managed with variceal banding. 21.4% (3/14) patients had progression of esophageal varices at 6 months requiring prophylactic band ligation. Three patients (21.4%) had new onset or worsening ascites and responded to low-dose diuretics therapy. CONCLUSIONS: PARTO is a safe and effective procedure for bleeding gastric varices without any deterioration in liver function even after six months. Patient selection is critical to prevent complications. Further prospective studies with larger sample size are required to validate our findings.

Added value of corpus callosotomy following vagus nerve stimulation in children with Lennox-Gastaut syndrome: A multicenter, multinational study.

OBJECTIVE: Lennox-Gastaut syndrome (LGS) is a severe form of epileptic encephalopathy, presenting during the first years of life, and is very resistant to treatment. Once medical therapy has failed, palliative surgeries such as vagus nerve stimulation (VNS) or corpus callosotomy (CC) are considered. Although CC is more effective than VNS as the primary neurosurgical treatment for LGS-associated drop attacks, there are limited data regarding the added value of CC following VNS. This study aimed to assess the effectiveness of CC preceded by VNS. METHODS: This multinational, multicenter retrospective study focuses on LGS children who underwent CC before the age of 18 years, following prior VNS, which failed to achieve satisfactory seizure control. Collected data included epilepsy characteristics, surgical details, epilepsy outcomes, and complications. The primary outcome of this study was a 50% reduction in drop attacks. RESULTS: A total of 127 cases were reviewed (80 males). The median age at epilepsy onset was 6 months (interquartile range [IQR] = 3.12-22.75). The median age at VNS surgery was 7 years (IQR = 4-10), and CC was performed at a median age of 11 years (IQR = 8.76-15). The dominant seizure type was drop attacks (tonic or atonic) in 102 patients. Eighty-six patients underwent a single-stage complete CC, and 41 an anterior callosotomy. Ten patients who did not initially have a complete CC underwent a second surgery for completion of CC due to seizure persistence. Overall, there was at least a 50% reduction in drop attacks and other seizures in 83% and 60%, respectively. Permanent morbidity occurred in 1.5%, with no mortality. SIGNIFICANCE: CC is vital in seizure control in children with LGS in whom VNS has failed. Surgical risks are low. A complete CC has a tendency toward better effectiveness than anterior CC for some seizure types.

Tyrphostin A9 attenuates glioblastoma growth by suppressing PYK2/EGFR-ERK signaling pathway.

PURPOSE: Glioblastoma (GBM) is a fatal primary brain tumor with extremely poor clinical outcomes. The anticancer efficiency of tyrosine kinase inhibitors (TKIs) has been shown in GBM and other cancer, with limited therapeutic outcomes. In the current study, we aimed to investigate the clinical impact of active proline-rich tyrosine kinase-2 (PYK2) and epidermal growth factor receptor (EGFR) in GBM and evaluate its druggability by a synthetic TKI-Tyrphostin A9 (TYR A9). METHODS: The expression profile of PYK2 and EGFR in astrocytoma biopsies (n = 48) and GBM cell lines were evaluated through quantitative PCR, western blots, and immunohistochemistry. The clinical association of phospho-PYK2 and EGFR was analyzed with various clinicopathological features and the Kaplan-Meier survival curve. The phospho-PYK2 and EGFR druggability and subsequent anticancer efficacy of TYR A9 was evaluated in GBM cell lines and intracranial C6 glioma model. RESULTS: Our expression data revealed an increased phospho-PYK2, and EGFR expression aggravates astrocytoma malignancy and is associated with patients' poor survival. The mRNA and protein correlation analysis showed a positive association between phospho-PYK2 and EGFR in GBM tissues. The in-vitro studies demonstrated that TYR A9 reduced GBM cell growth, cell migration, and induced apoptosis by attenuating PYK2/EGFR-ERK signaling. The in-vivo data showed TYR A9 treatment dramatically reduced glioma growth with augmented animal survival by repressing PYK2/EGFR-ERK signaling. CONCLUSION: Altogether, this study report that increased phospho-PYK2 and EGFR expression in astrocytoma was associated with poor prognosis. The in-vitro and in-vivo evidence underlined translational implication of TYR A9 by suppressing PYK2/EGFR-ERK modulated signaling pathway. The schematic diagram displayed proof of concept of the current study indicating activated PYK2 either through the Ca2+/Calmodulin-dependent protein kinase II (CAMKII) signaling pathway or autophosphorylation at Tyr402 induces association to the SH2 domain of c-Src that leads to c-Src activation. Activated c-Src in turn activates PYK2 at other tyrosine residues that recruit Grb2/SOS complex and trigger ERK½ activation. Besides, PYK2 interaction with c-Src acts as an upstream of EGFR transactivator that can activate the ERK½ signaling pathway, which induces cell proliferation and cell survival by increasing anti-apoptotic proteins or inhibiting pro-apoptotic proteins. TYR A9 treatment attenuate GBM cell proliferation and migration; and induce GBM cell death by inhibiting PYK2 and EGFR-induced ERK activation.

Regulation of Keap1-Nrf2 axis in temporal lobe epilepsy-hippocampal sclerosis patients may limit the seizure outcomes.

BACKGROUND: Accumulation of reactive oxygen species (ROS) exacerbates neuronal loss during seizure-induced excitotoxicity. Keap1 (Kelch-like ECH-associated protein1)-nuclear factor erythroid 2-related factor 2 (Nrf2) axis is one of the known active antioxidant response mechanisms. Our study focused on finding the factors influencing Keap1-Nrf2 axis regulation in temporal lobe epilepsy (TLE) associated with hippocampal sclerosis (HS) patients. METHODS: Based on post-surgical follow-up data, patient samples (n = 26) were categorized into class 1 (completely seizure-free) and class 2 (only focal-aware seizures/auras), as suggested by International League Against Epilepsy (ILAE). For molecular analyses, double immunofluorescence assay and Western blot analysis were employed. RESULTS: A significant decrease in expression of Nrf2 (p < 0.005), HO-1; p < 0.02) and NADPH Quinone oxidoreductase1 (NQO1; p < 0.02) was observed in ILAE class 2. Keap1 (p < 0.02) and histone methyltransferases (HMTs) like SetD7 (SET7/9; SET domain-containing 7 histone lysine methyltransferase) (p < 0.009) and enhancer of zeste homolog 2 (EZH2; p < 0.02) and methylated histones viz., H3K4me1 (p < 0.001), H3K9me3 (p < 0.001), and H3K27me3 (p < 0.001) was upregulated in ILAE class 2. Nrf2-interacting proteins viz., p21 (p < 0.001) and heat shock protein 90 (HSP90; p < 0.03) increased in class 1 compared to class 2 patients. CONCLUSION: Upregulation of HMTs and methylated histones can limit phase II antioxidant enzyme expression. Also, HSP90 and p21 that interfere with Keap1-Nrf2 interaction could contribute to a marginal increase in HO-1 and NQO1 expression despite histone methylation and Keap1. Based on our findings, we conclude that TLE-HS patients prone to seizure recurrence were found to have dysfunctional antioxidant response, in part, owing to Keap1-Nrf2 axis. The significance of Keap1-Nrf2 signaling mechanism in generation of phase II antioxidant response. Keap1-Nrf2 controls antioxidant response through regulation of phase II antioxidant enzymes like HO-1 (heme oxygenase-1), NQO1 (NADPH-Quinone Oxidoreductase1), and glutathione S-transferase (GST). Release of Nrf2 from negative regulation by Keap1 causes its translocation into nucleus, forming a complex with cAMP response-element binding protein (CBP) and small Maf proteins (sMaf). This complex subsequently binds antioxidant response element (ARE) and elicits and antioxidant response involving expression of phase II antioxidant enzymes. Reactive oxygen species (ROS) modify Cysteine 151 residue, p62 (sequsetosome-1), and interacts with Nrf2- binding site in Keap 1. p21 and HSP90 prevent Nrf2 interaction with Keap1. At transcriptional level, histone methyltransferases like EZH2 (enhancer of zeste homologue2), and SetD7 (SET7/9; SET domain-containing 7 histone lysine methyltransferase) and corresponding histone targets viz., H3K27me3, H3K9me3, and H3K4me1 influence Nrf2 and Keap1 expression respectively.

Elevated Expression of DNA Methyltransferases and Enhancer of Zeste Homolog 2 in Helicobacter pylori - Gastritis and Gastric Carcinoma.

AIM: The aim of this study was to study the role of key epigenetic regulators pertaining to DNA methylation and histone-modification systems in Helicobacter pylori (HP)-associated gastritis and gastric carcinogenesis. METHODS: The expression of DNA methyltransferase (DNMT-1, 3A, and 3B) and the catalytic subunit of polycomb repressive complex-2 (enhancer of zeste homolog 2 [EZH2]) in gastric carcinomas (n = 104), mucosa adjacent to carcinoma (n = 104), HP-associated gastritis (n = 95), and histologically normal mucosa (n = 31) was assessed by immunohistochemistry and qRT-PCR. RESULTS: The expression of all 3 DNMTs and EZH2 was significantly higher in HP-associated gastritis and carcinoma cases than in those with adjacent and normal mucosa. The expression of DNMT-1 and 3B was maximum in HP-associated gastritis. DNMT-3A showed higher expression in carcinoma-adjacent mucosa than in normal mucosa. Interestingly, the expression of EZH2 was higher in cases of HP-associated gastritis with metaplasia than in those without metaplasia and also in cases of intestinal type of adenocarcinoma. Significant positive correlation of EZH2 was identified with DNMT-1, DNMT-3A, and DNMT-3B. However, none of these markers was associated with survival outcome. CONCLUSION: This study establishes an important role of the key epigenetic regulators in the pathogenesis of both HP-associated gastritis and gastric carcinoma. Higher expression of all the epigenetic markers in the gastritis and their persistence in the carcinoma point toward their implications in HP-driven gastric carcinogenesis. Further, an inter-relation between the 2 arms of epigenetics, namely, DNA methylation and histone-modification in the pathogenesis of gastric carcinoma, is also documented. Given the reversibility of epigenetic phenomenon, these molecules may be of important therapeutic use.

Contralateral Clipping of Multiple Intracranial Aneurysms.

The reported incidence of multiple intracranial aneurysms (MIA) is approximately 7-35% of all intracranial aneurysms. The primary goal in the management of MIAs is to secure the ruptured aneurysm and to treat as many of the remaining lesions as possible without affecting the outcome of the patient. In recent era endovascular treatment is the preferred treatment of multiple bilateral intracranial aneurysms if all aneurysms are amenable to addressed in single stage. But most often all aneurysms were not possible to addressed due to complexity of different aneurysms, technical limitation and infrastructure. In such scenarios options left were two stage sequential craniotomy on either sides and clipping of bilateral aneurysms or unilateral craniotomy and clipping of bilateral MIA. Bilateral two stage surgery or two stage endovascular treatment caries risk of bleeding from one of the untreated aneurysms, morbidity due to two stage and increase the cost of treatment. In properly selected cases of unilateral craniotomy and clipping of bilateral MIA secure the all aneurysm in one stage and decreased morbidity and cost of treatment. When patient selection done meticulously, clipping of MIA including contralateral side aneurysms is feasible and safe.

Minimally invasive esophagectomy: Preservation of arch of Azygos vein in prone position.

Minimally invasive esophagectomy (MIE) for oesophageal cancer has gained wide popularity in recent years due to its improved morbidity and mortality outcomes. We describe our modified technique of MIE in prone position with preservation of the arch of azygos vein. In our experience with 14 patients, the mean operative duration was 378 min (standard deviation [SD] 378 ± 59 min) and the mean blood loss was 390 ml (SD 390 ± 142 ml). The mean lymph node count was 28 (range 17-54). The Visick score was I in 12 (85.7%) patients and II in 2 (14.3%) patients at follow-up. The preservation of azygos vein arch is a technically feasible procedure and may be associated with a better quality of life outcome.

Expression and clinicopathological significance of Nck1 in human astrocytoma progression.

OBJECTIVES: Astrocytoma represents most noted malignancy of the brain. The overall survival rate of patients with progressive form remains dismal despite of the present clinical advancements. Search for biomarkers can open new avenues of therapeutic measures to curb the progressive astrocytic tumors. Nck1 is reported to be involved in actin cytoskeleton rearrangement and neuronal migration. Here, we have determined prognostic importance of Nck1 protein in astrocytoma progression. Temporal lobe epilepsy tissues were used as control. METHODS: Real time PCR was used to analyze Nck1 transcript expression while western blotting and immunohistochemistry techniques were used to study expression on translational levels. Protein expression in western blots was categorized as Nck1 positive and Nck1 negative. We further seen the prognostic significance of Nck1 in 246 glioblastoma tissue samples as visible from the TCGA database. RESULTS: We find Nck1 RNA and protein was upregulated significantly in high grade tissues as compared to low grade and control tissue samples (p < 0.05). Logrank test and Kaplan-Meier analysis signified the use of Nck1 as independent prognostic marker for astrocytoma progression and its expression levels were correlated with poor survival in surgically resected human tissue samples (Chi square = 10.7, p = 0.001). Further, glioblastoma was noticed to be predominant at frontal and temporal lobe. CONCLUSION: On account of it's over expression, Nck1 appears as possible biomarker for astrocytoma progression and may serve as an important therapeutic target. Prominent origin of glioblastoma at frontal and temporal lobe suggests possible involvement of tissue specific developmental or transcriptional factors in origin of tumors.

Crescent durotomy for midline posterior fossa lesions.

OBJECTIVE: The conventional midline suboccipital craniectomy, the standard approach for posterior fossa lesions, involves ligation of the occipital sinus. Postoperative sequelae that could occur from ligation of the occipital sinus include hydrocephalus, cerebrospinal fluid (CSF) leak, and pseudomeningiocoele formation. The standard of practice of venous pathway preservation, as practiced elsewhere in the cranium, should also be attempted in the posterior fossa. In the current study, we compared postsurgical complications between conventional "Y" durotomy with the proposed crescent durotomy in patients with posterior fossa lesions who underwent midline suboccipital craniectomy. MATERIALS AND METHODS: The prospective data of 104 patients who underwent a midline suboccipital craniotomy for posterior fossa tumors between January 2011 and December 2015 was performed. Comparison of study variables was done between the durotomy techniques used. RESULTS: Of the 104 patients who formed the study population, 39 (37.5%) were women. While 75 patients underwent crescent durotomy, the remaining underwent the conventional "Y" durotomy. Among the postsurgical complications, there were no differences between groups in terms of their surgical site hematoma (2.7% vs 3.4%; P = 1.000) and edema (1.3% vs 0.0%; P = 1.000). The groups were also similar in terms of the incidence of postsurgical CSF leak (1.3% vs 6.9%; P = 0.187) and cranial nerve deficits (4.0% vs 6.9%; P = 0.617). However, more number of patients who underwent the "Y" durotomy had postoperative pseudomeningiocoele (2.7% vs 17.2%; P = 0.017). CONCLUSION: The "crescent" durotomy is a novel dural opening technique which attempts to preserve the normal venous flow physiology. The crescent durotomy reduces the need for a duroplasty, facilitates a comfortable primary closure, thus reducing the risk of developing a postoperative pseudomeningiocoele.

Ictal FDGPET and SPECT in hemifacial seizures due to cerebellar epilepsy-Case report.

The role of cerebellum in seizure generation is debatable. Semiology and electroencephalography (EEG) findings are non-specific and sometimes misleading, posing further difficulty in proving the epileptogenicity in pre-surgical workup. We report two cases of cerebellar lesions who presented with hemifacial seizures since the neonatal period and were refractory to antiepileptic drugs (AEDs). Both inter-ictal and ictal EEGs were non-contributory. Magnetic resonance imaging (MRI) showed a lesion in the cerebellum, in proximity to cerebellar peduncle in both the patients. (18) F-fluorodeoxyglucose-positron emission tomography (FDG-PET) and ictal single photon emission computed tomography (SPECT) showed focal hypermetabolism and hyperperfusion respectively, corresponding to the lesion on MRI in both the cases. Intraoperative electrocorticography showed rhythmic spikes confirming the epileptogenic nature of the lesion. Both patients were operated with a favorable surgical outcome. Histopathology was suggestive of a ganglioglioma in one child and a low-grade glioma in the other. Both cases illustrate that FDG-PET and SPECT can act as surrogate markers for invasive recordings to prove the epileptogenicity of cerebellar lesions, especially in resource limited settings.

Overexpression of aryl hydrocarbon receptor (AHR) signalling pathway in human meningioma.

Aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor and involved in tumorigenesis of many cancers. However there are no reports on AHR in human meningioma. Therefore we examined the status of the AHR and its signalling molecules in human meningioma by using tumor biopsy samples and autopsy control meninges. We report the up regulation of AHR pathway genes like aryl hydrocarbon receptor nuclear translocator (ARNT), aldehyde dehydrogenase1family memberA3 (ALDH1A3), cytochrome P450, family1, subfamily A polypeptide1 (CYP1A1) and TCCD induced poly ADP ribose polymerase (TIPARP) gene expression in human meningioma. Further, AHR protein expression was found to be up regulated in all grades of human meningioma. We found that AHR localized in the nucleus for high grade anaplastic meningioma through immunohistochemical analysis. Since AHR signalling pathway was known to involve in inhibition of apoptosis in cancer cells, we evaluated the cyclophilin D levels which maintains mitochondrial permeability transition pore a critical event during apoptosis. We report that cyclophilin D levels were upregulated in all grades of human meningioma compared to control meninges. Finally we also evaluated c-Fos protein levels as its levels were regulated by AHR. Here we report that c-Fos protein levels were down regulated in all grades of human meningioma compared to control meninges. To sum-up we found that AHR signalling pathway components were upregulated, as the grade of the meningioma progresses from low to high grade, suggesting an important role of AHR signalling pathway in human meningioma.

Profiling of microRNAs modulating cytomegalovirus infection in astrocytoma patients.

Astrocytoma is recognized as the most common neoplasm of the brain with aggressive progression. The therapeutic regime for glioblastoma, the most aggressive astrocytoma, often consists of aggressive chemo and radiotherapy. The present holistic approaches, however, have failed to influence the quality life of patients. Therefore, it is necessary to understand the underlying mechanisms of its progression for updated therapeutic evaluation. Human cytomegalovirus (HCMV) is reported to be associated with glioblastoma progression. The hypothesis still remains controversial due to the lack of concrete evidences. Here, we report the profile of miRNAs encoded by human host and the cytomegalovirus (CMV) involved in modulation of CMV infection in surgically resected human astrocytoma tissue samples of various malignancy grades (n = 24). Total RNA from the control brain and tumor tissues was extracted by TriZol reagent. The expression levels of the mature form of miRNA were detected by real-time PCR. Primarily, we found the upregulation of miR-210-3p, miR-155-5p, miR-UL-112-3p, miR-183-5p, and miR-223-5p in high-grade astrocytic tumors as compared with low-grade tumor tissues. miR-214-3p is significantly expressed in control brain tissues and its expression decreased with astrocytoma grade progression. This miRNA was reported to be associated with antiviral proprieties. Among CMV-encoded miRNA, miR-UL-112-3p was significantly upregulated in glioblastoma tissue samples and may be involved in providing immune escape to the virus as well as involved in modulating the immune microenvironment of glioblastoma. Taken together, we conclude the possible involvement of miRNAs in modulating the CMV dependent astrocytoma progression.