Role of non-receptor tyrosine kinases in epilepsy: significance and potential as therapeutic targets.

INTRODUCTION: Epilepsy is a chronic neurological condition characterized by a persistent propensity for seizure generation. About one-third of patients do not achieve seizure control with the first-line treatment options, which include >20 antiseizure medications. It is therefore imperative that new medications with novel targets and mechanisms of action are developed. AREAS COVERED: Clinical studies and preclinical research increasingly implicate Non-receptor tyrosine kinases (nRTKs) in the pathogenesis of epilepsy. To date, several nRTK members have been linked to processes relevant to the development of epilepsy. Therefore, in this review, we provide insight into the molecular mechanisms by which the various nRTK subfamilies can contribute to the pathogenesis of epilepsy. We further highlight the prospective use of specific nRTK inhibitors in the treatment of epilepsy deriving evidence from existing literature providing a rationale for their use as therapeutic targets. EXPERT OPINION: Specific small-molecule inhibitors of NRTKs can be employed for the targeted therapy as already seen in other diseases by examining the precise molecular pathways regulated by them contributing to the development of epilepsy. However, the evidence supporting NRTKs as therapeutic targets are limiting in nature thus, necessitating more research to fully comprehend their function in the development and propagation of seizures.

The multifaceted role of Wnt canonical signalling in neurogenesis, neuroinflammation, and hyperexcitability in mesial temporal lobe epilepsy.

Epilepsy is a neurological disorder characterised by unprovoked, repetitive seizures caused by abnormal neuronal firing. The Wnt/ß-Catenin signalling pathway is involved in seizure-induced neurogenesis, aberrant neurogenesis, neuroinflammation, and hyperexcitability associated with epileptic disorder. Wnt/ß-Catenin signalling is crucial for early brain development processes including neuronal patterning, synapse formation, and N-methyl-d-aspartate receptor (NMDAR) regulation. Disruption of molecular networks such as Wnt/ß-catenin signalling in epilepsy could offer encouraging anti-epileptogenic targets. So, with a better understanding of the canonical Wnt/-Catenin pathway, we highlight in this review the important elements of Wnt/-Catenin signalling specifically in Mesial Temporal Lobe Epilepsy (MTLE) for potential therapeutic targets.

Cold atmospheric plasma (CAP) treatment increased reactive oxygen and nitrogen species (RONS) levels in tumor samples obtained from patients with low-grade glioma.

Low-grade gliomas (LGGs) are a heterogeneous group of tumors with an average 10-year survival rate of 40%-55%. Current treatment options include chemotherapy, radiotherapy, and gross total resection (GTR) of the tumor. The extent of resection (EOR) plays an important role in improving surgical outcomes. However, the major obstacle in treating low-grade gliomas is their diffused nature and the presence of residual cancer cells at the tumor margins post resection. Cold Atmospheric Plasma (CAP) has shown to be effective in targeted killing of tumor cells in various glioma cell lines without affecting non-tumor cells through Reactive Oxygen and Nitrogen Species (RONS). However, no study on the effectiveness of CAP has been carried out in LGG tissues till date. In this study, we applied helium-based CAP on tumor tissues resected from LGG patients. Our results show that CAP is effective in promoting RONS accumulation in LGG tissues when CAP jet parameters are set at 4 kV voltage, 5 min treatment time and 3 lpm gas flow rate. We also observed that CAP jet is more effective in thinner slice preparations of tumor as compared to thick tumor samples. Our results indicate that CAP could prove to be an effective adjunct therapy in glioma surgery to target residual cancer cells to improve surgical outcome of patients with low-grade glioma.

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.

Dendritic reorganization in the hippocampus, anterior temporal lobe, and frontal neocortex of lithium-pilocarpine induced Status Epilepticus (SE).

Status Epilepticus (SE) is a distributed network disorder, which involves the hippocampus and extra-hippocampal structures. Epileptogenesis in SE is tightly associated with neurogenesis, plastic changes and neural network reorganization facilitating hyper-excitability. On the other hand, dendritic spines are known to be the excitatory synapse in the brain. Therefore, dendritic spine dynamics could play an intricate role in these network alterations. However, the exact reason behind these structural changes in SE are elusive. In the present study, we have investigated the aforementioned hypothesis in the lithium-pilocarpine treated rat model of SE. We have examined cytoarchitectural and morphological changes using hematoxylin-eosin and Golgi-Cox staining in three different brain regions viz. CA1 pyramidal layer of the dorsal hippocampus, layer V pyramidal neurons of anterior temporal lobe (ATL), and frontal neocortex of the same animals. We observed macrostructural and layer-wise alteration of the pyramidal layer mainly in the hippocampus and ATL of SE rats, which is associated with sclerosis in the hippocampus. Sholl analysis exhibited partial dendritic plasticity in apical and basal dendrites of pyramidal cells as compared to the saline-treated weight-/age-matched control group. These findings indicate that region-specific alterations in dendritogenesis may contribute to the development of independent epileptogenic networks in the hippocampus, ATL, and frontal neocortex of SE rats.

RNA Sequencing of Intraoperative Peritumoral Tissues Reveals Potential Pathways Involved in Glioma-Related Seizures.

Tumor-induced changes in the peritumoral neocortex play a crucial role in generation of seizures. This study aimed to investigate the molecular mechanisms potentially involved in peritumoral epilepsy in low-grade gliomas (LGGs). Intraoperative peritumoral brain tissues resected from LGG patients with seizures (pGRS) or without seizures (pGNS) were used for RNA sequencing (RNA-seq). Comparative transcriptomics was performed to identify differentially expressed genes (DEGs) in pGRS compared to pGNS using deseq2 and edgeR packages (R). Gene set enrichment analysis (GSEA) using Gene Ontology terms and Kyoto Encyclopedia of Genes & Genomes (KEGG) pathways was performed using the clusterProfiler package (R). The expression of key genes was validated at the transcript and protein levels in the peritumoral region using real-time PCR and immunohistochemistry, respectively. A total of 1073 DEGs were identified in pGRS compared to pGNS, of which 559 genes were upregulated and 514 genes were downregulated (log2 fold-change ≥ 2, padj < 0.001). The DEGs in pGRS were highly enriched in the "Glutamatergic Synapse" and "Spliceosome" pathways, with increased expression of GRIN2A (NR2A), GRIN2B (NR2B), GRIA1 (GLUR1), GRIA3 (GLUR3), GRM5, CACNA1C, CACNA1A, and ITPR2. Moreover, increased immunoreactivity was observed for NR2A, NR2B, and GLUR1 proteins in the peritumoral tissues of GRS. These findings suggest that altered glutamatergic signaling and perturbed Ca2+ homeostasis may be potential causes of peritumoral epilepsy in gliomas. This explorative study identifies important genes/pathways that merit further characterization for their potential involvement in glioma-related seizures.

Epigenetics in epilepsy.

Epilepsy affects over 50 million individuals globally, making it the most prevalent chronic and serious neurological condition. A precise therapeutic strategy is complicated by poor understanding of the pathological changes in epilepsy thus, 30% of TLE patients are resistant to drug therapy. In the brain, epigenetic processes translate information from transient cellular impulses and adjustments in neuronal activity into long-lasting impacts on gene expression. Research suggests that epigenetic processes can be manipulated in the future to treat or prevent epilepsy as epigenetics has been shown to have a profound influence on how genes are expressed in epilepsy. As well as being potential biomarkers for epilepsy diagnosis, epigenetic changes can also be used as prognostic indicators of treatment response. In this chapter, we review the most recent findings in several molecular pathways linked with the pathogenesis of TLE that are controlled by epigenetic mechanisms highlighting their potential utility as biomarkers for upcoming treatment strategies.

Technique of Distraction, Compression, Extension, Reduction to Reduce and Realign Old Displaced Odontoid Fracture From Posterior Approach: A Novel Technique.

OBJECTIVE: Chronic 'displaced' displaced type II fractures, though uncommon, are difficult to manage. They usually require a transoral procedure followed by a posterior instrumented fusion. We describe here, a new method to reduce the fractured displaced odontoid using a posterior cervical approach only. METHODS: Prospective and observational, n = 14 had a 'displaced and irreducible' old fracture dens causing cord compression (type I, 1; type II, 13). They underwent a novel technique to reduce the fracture. The C1 arch was first drilled and removed. The C1 lateral masses on both sides were then drilled completely and a spacer was placed between the occiput and C2 facet. Following this, an intraoperative reducing maneuver was performed, utilizing the spacer as a fulcrum, and then achieving complete reduction and realignment. RESULTS: All patients improved clinically (mean Nurick preoperative score: 4.07 ± 0.8; the postoperative score was 1.3 ± 0.4). The mean correction in effective canal diameter was 74.3% ± 9.5% and the mean correction in actual canal diameter was 77% ± 8.7%. Solid bone fusion was demonstrated in 12 patients with at least 1-year follow-up (follow-up range, 12-35 months; mean, 21.8 ± 9.8 months). CONCLUSION: The new described modification of distraction, compression extension, and reduction seems to be effective for 'displaced' chronic fracture dens with cord compression. It avoids additional transoral surgery in these patients.

Comparison of Infection Rates Following Immediate and Delayed Cranioplasty for Postcraniotomy Surgical Site Infections: Results of a Meta-Analysis.

Postoperative surgical site infections (SSIs) in neurosurgery are rare. However, they pose a formidable challenge to the treating neurosurgeon and substantially worsen patient outcomes. These infections require prompt intervention in the form of débridement, including removal of craniotomy bone. Reconstruction of the craniotomy defect can be performed along with the débridement or can be performed at a later time. Although there have been concerns about performing cranioplasty at the same time as débridement, recent studies have advocated performance of cranioplasty at the same time as the débridement, as it avoids the morbidity associated with having a craniectomy defect and avoids the need for another surgical procedure. We conducted a literature review and meta-analysis to examine the data on immediate cranioplasties and delayed cranioplasties performed for postcraniotomy SSIs. We analyzed 15 articles with a total of 353 patients. Our analysis revealed that the pooled proportion of treatment failure was 10.4% (95% confidence interval [CI] 5.9%-17.8%) when an immediate cranioplasty was done and 16.1% (95% CI 7.2%-32.1%) when delayed cranioplasty was done. The pooled proportion of treatment failure was 12% (95% CI 5.9%-22.9%) when the same bone was used for cranioplasty and was 8% (95% CI 3%-20%) when prosthetic material such as titanium was used for cranial vault reconstruction. Thus, the rate of treatment failure was less when an immediate single-stage cranioplasty was done compared with a delayed cranioplasty following SSIs.

Novel variants in GABAA receptor subunits: A possible association with benzodiazepine resistance in patients with drug-resistant epilepsy.

Benzodiazepines (BDZ) such as diazepam and lorazepam are popular as first-line treatment for acute seizures due to their rapid action and high efficacy. However, long-term usage of BDZ leads to benzodiazepine resistance, a phenomenon whose underlying mechanisms are still being investigated. One of the hypothesised mechanisms contributing to BDZ resistance is the presence of mutations in benzodiazepine-sensitive receptors. While a few genetic variants have been reported previously, knowledge of relevant pathogenic variants is still scarce. We used Sanger Sequencing to detect variants in the ligand-binding domain of BDZ-sensitive GABAA receptor subunits α1-3 and 5 expressed in resected brain tissues of drug-resistant epilepsy (DRE) patients with a history of BDZ resistance and found two previously unreported predicted pathogenic frameshifting variants - NM_000807.4(GABRA2):c.367_368insG and NM_000810.4(GABRA5):c.410del - significantly enriched in these patients. The findings were further explored in resected DRE brain tissues through cellular electrophysiological experiments.

Single-Stage Posterior Only Approach for Unilateral Atlantoaxial Spondyloptosis with type-II odontoid Fracture in Pediatric Patients.

Objective: When there is a complete slippage of facet joints of C1 over C2 such that there is no contact between the articulating surfaces of C1 and C2, the condition is known as atlantoaxial spondyloptosis (AAS). AAS represents an extremely rare manifestation of atlantoaxial instability. This study was performed to highlight the presentation, radiological features, and management of unilateral AAS in pediatric patients. Material and Methods: We retrospectively identified four pediatric patients with AAS from our hospital records in the last 6 years (2014-2019). Results: Among the four patients with unilateral AAS, three were posttraumic and one was diagnosed with craniovertebral junction tuberculosis (CVJ TB). All the patients had a varying degree of spastic quadriparesis on presentation. One patient with CVJ TB presented with neck tilt. All patients with traumatic unilateral AAS were associated with an odontoid fracture. These patients underwent C1-C2 fixation with complete reduction of spondyloptosis using the techniques of joint manipulation and joint remodeling with a posterior only approach. Complete reduction of AAS in patients with trauma was also associated with the realignment of the odontoid fracture. All patients improved neurologically after surgery and achieved excellent correction of the deformity on a follow-up imaging. Conclusion: Pediatric unilateral AAS is an extremely rare phenomenon. A single-stage posterior approach with C1-C2 fixation is a feasible technique for the treatment of this seemingly difficult to correct deformity in pediatric patients and the clinical outcomes are excellent.

Craniovertebral Junction Anomalies: An Overlooked Cause of 'Posterior Circulation Stroke'.

Background: Vertebral artery dissection (VAD) is a treatable cause of vertebrobasilar ischemic stroke and can be spontaneous or more commonly traumatic. Craniovertebral junction (CVJ) anomalies are a rare and often overlooked cause of VAD. Objective: The objective of this study was to study cases where CVJ anomaly presented as posterior circulation infarct and to conduct a relevant literature review. Materials and Methods: The medical records of seven patients who were managed for posterior circulation infarct associated with CVJ anomaly at our center from January 2009 through August 2013 were reviewed. PubMed and MEDLINE databases were also searched for similar cases, and the published case reports/series were reviewed. Results: Seven patients met our inclusion criteria and were included in the study. The mean age was 17.4 years (range: 10-35 years). All the patients were males. The most common symptoms were headache, vomiting, and gait ataxia. Slurring of speech was seen in one patient. One patient had repeated episodes of gait ataxia with left-sided weakness with complete recovery in between the episodes. One patient presented in unconscious state. Four patients complained of vertigo. The median duration of symptoms was 7 days (range: 3 days-12 months). Conclusions: CVJ anomalies can present as posterior circulation infarct. One must evaluate all patients with posterior circulation stroke, especially young patients, for possible CVJ anomalies. Dynamic lateral cervical spine X-ray is an important tool to diagnose AAD. CVJ anomalies represent a treatable cause of VAD.

AIIMS Cervical Myelopathy Score - A New Comprehensive and Objective Patient-Reported Modification of mJOA: Results of an Internal Validation Study.

Background: Several scoring systems have been developed for assessment of patients with compressive cervical myelopathy. However, all of these have some shortcomings. We proposed a new modification of the modified Japanese Orthopedic Association (mJOA) score-the AIIMS cervical myelopathy score (ACMS). Objective: The aim of this study was to compare the ACMS with mJOA score and Nurick score. Methods: We prospectively studied patients with cervical compressive myelopathy. The new ACMS, mJOA, Nurick proposed by Benzel, and Nurick scores were recorded preoperatively and at three months postoperatively in patients. Results: Sixty-two patients completed the 3-month follow-up and were included in the final analysis. The mean preoperative and postoperative Nurick, mJOA, and ACMS scores were 3.3 and 3.0, 12.3 and 13.8, and 15.1 and 17.7, respectively. High correlation (Pearson's r > 0.8, 95% CI: 0.94 to 0.97, P < 0.005) was observed between ACMS and mJOA scores for all the individual components of both scales, both in pre- and postoperative assessments. A negative correlation was observed between the occupational ability scores ACMS and the Nurick scale (r = -0.76, 95% CI: -0.83 to - 0.68). No correlation was found with cord/canal ratio on magnetic resonance imaging (MRI) with any of the three scoring systems (preoperative, postoperative, or recovery rates). Conclusions: The ACMS score showed a good correlation with the mJOA score for evaluation of functional disability in the setting of cervical myelopathy. The patients could themselves report the scores using the ACMS scoring chart. The occupational component of the ACMS also correlated well with the Nurick score.

O-Arm Assisted Anterior Odontoid Screw Fixation in Type II and Rostral Type III Odontoid Fractures: Single Center Surgical Series of 50 Patients.

Background: Accuracy of screw placement is one of the important factors necessary for adequate union in odontoid fractures with malposition rates as high as 27.2% with standard techniques. Objective: To evaluate efficacy of intraoperative O-arm assistance in improving accuracy of anterior odontoid screw placement and clinco-radiological outcome in type II and III odontoid fractures. Material and Methods: In this retrospective study, surgery consisted of anterior odontoid screw fixation under intraoperative O-arm assistance over 5 years. Demographical, clinical, radiological, operative details and postoperative events were retrieved from hospital database and evaluated for fusion and surgical outcome. Results: 50 patients (Mean age 34.6 years, SD 14.10, range: 7-70 years; 44 males and 6 females) with Type II and Type III odontoid fracture underwent O-arm assisted anterior screw placement. The mean interval between injury and surgery was 12 days (range 1-65 days). Mean operating time was 132.2 min ± SD 33.56 with average blood loss of 93 ml. ±SD 61.46. With our technique, accurate screw placement was achieved in 100% patients. At the mean follow-up of 26.4 month (SD13.75), overall acceptable fusion rate was 97.8% with non-union in 2.2% patients. Morbidity occurred in two patients; one patient developed fixation failure while other patient had nonunion which was managed with posterior C1-C2 arthrodesis. We had surgical mortality in one patient due to SAH. So overall our procedure was successful in 94% patients and among patients whose follow-up was available, acceptable fusion rates of 97.8% were achieved. Conclusion: We conclude that use of intraoperative three-dimensional imaging using O-arm for anterior odontoid screw fixation improves accuracy and leads to improved radiological and clinical outcomes. It further enables us to extend the indications of odontoid screw fixation to selected complex Type II and rostral Type III odontoid fractures.