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Alterations in global histone methylation regulate gene expression and participate in cancer onset and progression. The profile of histone methylation marks in pediatric astrocytomas is currently understudied with limited data on their distribution among grades. The global expression patterns of repressive histone marks H3K9me3, H3K27me3, and H4K20me3 and active H3K4me3 and H3K36me3 along with their writers SUV39H1, SETDB1, EZH2, MLL2, and SETD2 were investigated in 46 pediatric astrocytomas and normal brain tissues. Associations between histone marks and modifying enzymes with clinicopathological characteristics and disease-specific survival were studied along with their functional impact in proliferation and migration of pediatric astrocytoma cell lines using selective inhibitors in vitro. Upregulation of histone methyltransferase gene expression and deregulation of histone code were detected in astrocytomas compared to normal brain tissues, with higher levels of SUV39H1, SETDB1, and SETD2 as well as H4K20me3 and H3K4me3 histone marks. Pilocytic astrocytomas exhibited lower MLL2 levels compared to diffusely infiltrating tumors indicating a differential pattern of epigenetic regulator expression between the two types of astrocytic neoplasms. Moreover, higher H3K9me3, H3K36me3, and SETDB1 expression was detected in grade IIΙ/IV compared to grade II astrocytomas. In univariate analysis, elevated H3K9me3 and MLL2 and diminished SUV39H1 expression adversely affected survival. Upon multivariate survival analysis, only SUV39H1 expression was revealed as an independent prognostic factor of adverse significance. Treatment of pediatric astrocytoma cell lines with SUV39H1 inhibitor reduced proliferation and cell migration. Our data implicate H3K9me3 and SUV39H1 in the pathobiology of pediatric astrocytomas, with SUV39H1 yielding prognostic information independent of other clinicopathologic variables. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-021-01090-x.

Craniosynostosis refers to the premature fusion of one or more cranial sutures leading to skull shape deformities and brain growth restriction. Among the many factors that contribute to abnormal suture fusion, mechanical forces seem to play a major role. Nevertheless, the underlying mechanobiology‐related mechanisms of craniosynostosis still remain unknown. Understanding how aberrant mechanosensation and mechanotransduction drive premature suture fusion will offer important insights into the pathophysiology of craniosynostosis and result in the development of new therapies, which can be used to intervene at an early stage and prevent premature suture fusion. Herein, we provide evidence for the first time on the role of polycystin‐1 (PC1), a key protein in cellular mechanosensitivity, in craniosynostosis, using primary cranial suture cells isolated from patients with trigonocephaly and dolichocephaly, two common types of craniosynostosis. Initially, we showed that PC1 is expressed at the mRNA and protein level in both trigonocephaly and dolichocephaly cranial suture cells. Followingly, by utilizing an antibody against the mechanosensing extracellular N‐terminal domain of PC1, we demonstrated that PC1 regulates runt‐related transcription factor 2 (RUNX2) activation and osteocalcin gene expression via extracellular signal–regulated kinase (ERK) signalling in our human craniosynostosis cell model. Altogether, our study reveals a novel mechanotransduction signalling axis, PC1‐ERK‐RUNX2, which affects osteoblastic differentiation in cranial suture cells from trigonocephaly and dolichocephaly patients.

After the introduction of shunt treatment for the management of childhood hydrocephalus, a wide variety of complications related to this treatment modality have been recognized. The entity of slit ventricle syndrome (alternatively, symptomatic ventricular coaptation) is one of them, is frequently encountered in the pediatric population and its symptom complex resembles that of shunt failure. We conducted research on PubMed®, MEDLINE®, and Web of Science®, using the keywords: "slit ventricles," "slit ventricle syndrome," "SVS" and "ventricular coaptation." The aim of our review was to trace the advances made through the past decades, concerning our knowledge about the clinical characteristics, pathophysiology, and treatment options of this entity. The discrepancy among researchers about the offending etiology and the optimum treatment algorithm of this entity, as well as the necessity of an updated concept regarding shunt over drainage is analyzed. The multiple treatment modalities proposed and pathophysiologic mechanisms implicated for the treatment of slit ventricle syndrome illustrate the complexity of this entity. Consequently, the issue requires more detailed evaluation. In this review, we comment on all the main facets related to shunt over drainage and the resultant slit ventricle syndrome.

An isolated or trapped fourth ventricle is a relatively rare, although serious, adverse effect of hemorrhagic, infectious, or inflammatory processes that involve the central nervous system. This entity usually occurs after successful shunting of the lateral ventricles and may become clinically evident with the development of delayed clinical deterioration. This decline of the neurological status of the patient is evident after an initial period of improvement of the relevant symptoms. Surgical treatment options include cerebrospinal fluid shunting procedures, along with open surgical and endoscopic approaches. Complications related to its management are common and are related with obstruction of the fourth ventricular catheter, along with cranial nerve or brainstem dysfunction. We used the keywords: “isolated fourth ventricle,” and “trapped fourth ventricle,” in PubMed® and Web of Science®. Treatment of the trapped fourth ventricle remains a surgical challenge, although the neurosurgical treatment armamentarium has broadened. However, prompt recognition of the clinical and neurological findings that accompany any individual patient, in conjunction with the relevant imaging findings, is mandatory to organize our treatment plan on an individual basis. The current experience suggests that any individual intervention plan should be mainly based on the underlying pathological substrate of hydrocephalus. This could help us to preserve the patient’s life, on an emergent basis, as well as to ensure an uneventful neurological outcome, maintaining at least the preexisting level of neurological function.

The prognosis of children with neuroblastoma (NBL) can be dismal with significant variations depending on the stage and biology of the tumor. We assessed the event-free (EFS) and overall (OS) survival using harmonized data from three Southern-Eastern European (SEE) countries. Data for 520 incident NBL cases (2009-2018) were collected from Greece, Slovenia and Russia. Kaplan-Meier curves were fitted, and EFS/OS were derived from Cox proportional models by study variables including the protocol-based risk-group (low/observation, intermediate, high). Over one-third of cases were coded in the high-risk group, of which 23 children (4.4%) received treatment with anti-ganglioside 2 (GD2) mAb. Survival rates were inferior in older (OS 5-year; 1.5-4.9 years: 61%; EFS 5-year; 1.5-4.9 years: 48%) compared to children younger than 1.5 years (OS 5-year

Background A vast amount of articles centered on brain metastases have been published. Objective To present the 100 most-cited articles dedicated to brain metastasis and to accomplish a broad literature review. Methods In December 2019, we performed a title-focused search using the Thomson Reuters Web of Science database to identify the most cited articles centered on brain metastatic disease. Our search query term was based on using the following algorithm: “brain metastases” OR “brain metastasis” OR “brain metastatic disease” OR “cerebral metastases” OR “cerebral metastasis” OR “cerebral metastatic disease.” Afterward, we reviewed the results to certify that they were relevant to the purposes of our research protocol. The 100 most cited papers were chosen and further analyzed. Results Our search resulted in 11,579 articles, published from 1975 until the completion of our survey. The most cited article, by Patchell et al., was published in 1990, with 1862 citations, and an average of 62.07 citations per year, whereas the last in our list, by Gaspar et al., was published in 2010, with 195 total citations, and an average of 19.50 citations per year. Countries with the highest-cited articles included the United States (75 records), followed by Canada (16 records). Conclusions We discovered the top 100 most-cited articles centered on brain metastasis, all of which show a potentially increased level of interest, because they are meaningful scientific reports. In addition, we reviewed the historical development and advances in brain metastasis research and relevant points of interest, alongside the relevant contributions of different authors, fields of special interest, and countries. Many of the most cited articles were written by authors whose specialty was not neurosurgery or by neurosurgeons who were supported by colleagues from other medical fields. As a consequence, many of these articles were not published in neurosurgery-dedicated journals.

Background Intracerebral hemorrhage (ICH)1 is characterized by the pathological accumulation of blood within the brain parenchyma, most commonly associated with hypertension, arteriovenous malformations, or trauma. However, it can also present in patients receiving antithrombotic drugs, either anticoagulants such as acenocoumarol/warfarin-novel oral anticoagulants or antiplatelets, for the prevention and treatment of thromboembolic disease. Objective The purpose of this review is to present current bibliographic data regarding ICH irrespective of the cause, as well as post-hemorrhage use of antithrombotic agents. Moreover, this review attempts to provide guidelines concerning the termination, inversion, and of course resumption of antithrombotic therapy. Methods and materials We reviewed the most recently presented available data for patients who dealt with intracerebral hemorrhagic events while on antithrombotic agents (due to atrial fibrillation, prosthetic mechanical valves or recent/recurrent deep vein thrombosis). Furthermore, we examined and compared the thromboembolic risk, the bleeding risk, as well as the re-bleeding risk in two groups: patients receiving antithrombotic therapy versus patients not on antithrombotic therapy. Conclusion Antithrombotic therapy is of great importance when indicated, though it does not come without crucial side-effects, such as ICH. Optimal timing of withdrawal, reversal, and resumption of antithrombotic treatment should be determined by a multidisciplinary team consisting of a stroke specialist, a cardiologist, and a neurosurgeon, who will individually approach the needs and risks of each patient.

Background Complex spinal deformities are a common issue in pediatric patients with an underlying neurologic diagnosis or syndrome. Management of neuromuscular scoliosis is an awesome responsibility, because these patients present with the most challenging pathologies of the deformed spine. Along with surgical correction of the underlying deformity, an intrathecal baclofen (ITB) pump is considered effective in managing the associated spasticity. Case Description We present the case of an 11-year-old female who sustained an episode of severe ischemic encephalopathy accompanied by hydrocephalus and severe spastic quadriplegia. An ITB pump was inserted to manage spasticity. Two years later, a very severe decompensated spinal curvature developed. In addition, malfunction of the pump was noted, and the decision was made to perform revision along with open hemilaminectomy at the L3-4 level. The inability of cerebrospinal fluid (CSF) to access the pump was verified intraoperatively, with the absence of CSF glow through the intrathecal space demonstrating blockage of CSF flow. Conclusions The association of cerebral palsy and relevant disorders with the relentless progression of scoliosis is analyzed, along with the possible offending mechanisms. The efficacy of an ITB pump in controlling intractable spasticity associated with neuromuscular scoliosis is reviewed, as well as its potential to accentuate the clinical progression of neuromuscular scoliosis. Although this is an extremely infrequent situation, we must always bear in mind the possibility that malfunction of an ITB pump could be related to obstruction of CSF flow, owing to the extreme severity of the curves established during the course of, most likely untreated, neuromuscular scoliosis.

Simple Summary Epigenetic mechanisms, that are modifications of the genome without the presence of mutations, are known to play a crucial role in central nervous system (CNS) tumors during childhood. Two well-known epigenetic regulatory mechanisms include methylation and miRNA regulatory mechanisms. Therefore, in the present study we have investigated the presence of methylated genes in childhood CNS tumors, along with miRNA expression. We have searched for correlations between gene methylation and miRNA expression. In addition, we have investigated mRNA expression in order to search for possible miRNA targets. Such approaches could prove useful for the improvement of CNS tumor prognosis, as well as for the discovery of new therapeutic targets. Abstract Epigenetic modifications are considered of utmost significance for tumor ontogenesis and progression. Especially, it has been found that miRNA expression, as well as DNA methylation plays a significant role in central nervous system tumors during childhood. A total of 49 resected brain tumors from children were used for further analysis. DNA methylation was identified with methylation-specific MLPA and, in particular, for the tumor suppressor genes CASP8, RASSF1, MGMT, MSH6, GATA5, ATM1, TP53, and CADM1. miRNAs were identified with microarray screening, as well as selected samples, were tested for their mRNA expression levels. CASP8, RASSF1 were the most frequently methylated genes in all tumor samples. Simultaneous methylation of genes manifested significant results with respect to tumor staging, tumor type, and the differentiation of tumor and control samples. There was no significant dependence observed with the methylation of one gene promoter, rather with the simultaneous presence of all detected methylated genes’ promoters. miRNA expression was found to be correlated to gene methylation. Epigenetic regulation appears to be of major importance in tumor progression and pathophysiology, making it an imperative field of study.

Although the entities of venous thromboembolism (VTE), deep venous thrombosis, pulmonary embolus, and thromboprophylaxis in adult patients undergoing brain tumor and spine surgery, traumatic brain injury and elective neurosurgical procedures are widely elucidated, the same is not valid when pediatric patients are under consideration. An attempt to review the peculiarities of these patients through a comprehensive bibliographic review is undertaken. We performed a narrative summary of the relevant literature dedicated to pediatric patients, centered on traumatic brain injury, the general incidence of thromboembolic disease in this patient population, the role of low molecular weight heparin (LMWH) in the treatment and prophylaxis of VTE, and its role in elective neurosurgical procedures, including spinal operations. Additionally, the risk of deep venous thrombosis in elective neurosurgical procedures is reviewed. Due to inherent limitations of the current studies, particularly a restricted number of patients, our data are underpowered to give a definitive protocol and guidelines for all the affected patients. Our current conclusions, based only on pediatric patients, argue that there is limited risk of VTE in pediatric patients suffering from brain tumors and that the possibility of VTE is very low in children undergoing elective neurosurgical procedures. There is no consensus regarding the exact incidence of VTE in traumatic brain injury patients. LMWH seems to be a safe and effective choice for the “at risk” pediatric patient population defined as being older than 15 years, venous catheterization, nonaccidental trauma, increased length of hospital stays, orthopaedic (including spinal) surgery, and cranial surgery.

Emerging evidence from randomized controlled clinical trials (RCTs) suggests that colchicine has cardiovascular benefits for patients with coronary disease, including benefits for stroke prevention. We performed an updated systematic review and meta-analysis of all RCTs reporting on stroke outcomes during the follow-up of patients with a history of cardiovascular disease randomized to colchicine treatment or control (placebo or usual care). We identified 6 RCTs including a total of 11,870 patients (mean age 63 years, 83% males) with a mean follow-up of 2 years. Colchicine treatment was associated with a lower risk of stroke during follow-up, compared to that of placebo or usual care (risk ratio = 0.49, 95% confidence interval: 0.31–0.80, p = 0.004), without heterogeneity across the included studies (I2 = 0%, p for Cochran’s Q = 0.52). In the subgroup analysis, no heterogeneity (p = 0.77) was identified in the effect of colchicine on stroke prevention between patients with recent acute (RR = 0.55, 95% CI: 0.15–2.05) or chronic stable (RR = 0.43, 95% CI: 0.21–0.89) coronary artery syndromes. In conclusion, we found that colchicine treatment decreases the stroke risk in patients with a history of atherosclerotic cardiovascular disease.

BACKGROUND The ventriculoperitoneal shunt remains, despite recent advances, the mainstay of treatment for hydrocephalus. Although it is used as a routine practice, and besides its recorded and documented safety, it often malfunctions due to a variety of reasons, most commonly referred to as obstruction, breakage, migration and infection. A usual finding of those children suspected to magnetic resonance imaging is the detection of a rim of hyperintensity in the periventricular white matter (halo). CASE REPORT We describe the case of a 7-year-old male patient, treated 4 years ago for an infratentorial ependymoma, who developed hydrocephalus at the time of clinical presentation. During his previous follow-up, he was disease-free but developed clinically evident acute shunt malfunction, accompanied by imaging findings on magnetic resonance imaging (MRI) consisting of interstitial edema surrounding the supratentorial ventricular system, with additional involvement of the floor of the fourth ventricle. This peculiar and novel imaging finding subsided after successful management of hydrocephalus. CONCLUSIONS At present, contemporary computed tomography and MRI modalities constitute the gold standard in order to assess and follow-up patients with established hydrocephalus. Periventricular interstitial edema is a well-established imaging feature of acute hydrocephalus and, in cases of ventriculoperitoneal shunt, of shunt malfunction. Besides that, a newly described, to the best of our knowledge, imaging feature could be the distinction of that signal alteration at the floor of the fourth ventricle. It seems to have prognostic significance regarding the adequacy of management of hydrocephalus, as it disappeared after its successful treatment.

Background Primary Ewing sarcoma arising from the calvarial bone and/or underlying dura matter are relatively rarely reported in the literature. Even rarer are considered to be those that originate from the dura and proliferate in both directions, toward the brain parenchyma and through the dura invading the overlying bone. Case Description We report the case of a girl aged 11 years who presented with an ictus of generalized tonic-clonic seizures, without known focal neurologic deficit. Neuroradiologic work-up verified the existence of a tumor in the right fronto-parietal area of the brain, invading both the bone and brain parenchyma and emanating from the dura. No other tumor location was discovered after radiologic work-up, and gross total resection was undertaken followed by adjuvant radiation therapy and chemotherapy. Conclusions The patient had an uneventful neurologic recovery without persistent neurologic deficit. One year after the operation, with the patient under close clinical and radiologic surveillance, no recurrence of the disease was detected. This case illustrates an extremely uncommon location of primary Ewing sarcoma, along with a constellation of clinical signs and symptoms that are fairly uncommon for this location of this rare disease entity.

The high incidence of traumatic brain injury (TBI) in children, combined with the challenges in diagnosis and treatment options, the difficulty of predicting the outcome of each case, and also the wide variety of possibly lifelong complications, has led to an extraordinary number of published papers regarding this topic. This bibliometric analysis is aimed at identifying and reviewing the 100 most cited papers in the most challenging and trending aspects of pediatric traumatic brain injury. A search was performed using the Web of Science database in October 2018. Results were organized by citation number, and the 100 most cited papers were further reviewed and analyzed. Our search resulted in 2754 published papers from 1975 until October 2018, of which 1783 (64.74%) had been published in the last decade (2010–2018). The 100 most cited papers about traumatic brain injury in children have an average citation of 140.59 and have been published in 44 different journals. Four hundred thirty-five authors have contributed to these prominent articles, most of them from the USA. By reviewing those highly cited papers, we sought to offer significant help not only for studying this challenging field but also for designing new studies.

Background The childhood peak of brain tumors suggests that early-life exposures might have a role in their etiology. Hence, we examined in the Greek National Registry for Childhood Hematological Malignancies and Solid tumors (NARECHEM-ST) whether perinatal and early-life risk factors influence the risk of childhood brain tumors. Methods In a nationwide case-control study, we included 203 cases (0–14 years) with a diagnosis of brain tumor in NARECHEM-ST (2010–2016) and 406 age-, sex-, and center-matched hospital controls. Information was collected via interviews with the guardians and we analyzed the variables of interest in multivariable conditional logistic regression models. Results Instrument-assisted delivery was associated with higher (OR: 7.82, 95%CI: 2.18–28.03), whereas caesarean delivery with lower (OR: 0.67, 95%CI: 0.45-0.99) risk of childhood brain tumors, as compared to spontaneous vaginal delivery. Maternal alcohol consumption during pregnancy (OR: 2.35, 95%CI: 1.45–3.81) and history of living in a farm (OR: 4.98, 2.40–10.32) increased the odds of childhood brain tumors. Conversely, higher birth order was associated with lower risk (OR for 2nd vs. 1st child: 0.60, 95%CI: 0.40-0.89 and OR for 3rd vs. 1st: 0.34, 95%CI: 0.18-0.63). Birth weight, gestational age, parental age, history of infertility, smoking during pregnancy, allergic diseases, and maternal diseases during pregnancy showed no significant associations. Conclusions Perinatal and early-life risk factors, and specifically indicators of brain trauma, exposure to toxic agents and immune system maturation, might be involved in the pathogenesis of childhood brain tumors. Larger studies should aim to replicate our findings and examine associations with tumor subtypes.

Manifestations of central nervous system involvement are one of the leading causes of morbidity and mortality in patients suffering from systemic lupus erythematosus. It frequently involves the central nervous system and sometimes need to be differentiated from lesions of infectious etiology, thus representing a major diagnostic dilemma. We present the case of a male adolescent with a known history of idiopathic thrombocytopenic purpura who presented with a seizure ictus and a space-occupying lesion, which posed significant diagnostic challenges to specify its characteristics.

Background Transclival meningoceles and related primary spontaneous cerebrospinal fluid leaks at the clivus are extremely rare lesions, with only a few cases reported in the literature. Case Description An infant presented with nasal airway obstruction and meningitis secondary to cerebrospinal fluid leak from a transclival meningocele. The radiologic investigation and surgical repair of the lesion are reported, along with intraoperative findings. Basic anatomy, embryology, and development of the clivus are reviewed to clarify the relationship of anatomic variants with the formation of transclival meningoceles. Conclusions Transclival meningocele should be considered in patients with spontaneous cerebrospinal fluid rhinorrhea. The existing classification of meningoencephaloceles based on the location of the defect in the cranium should probably be reconsidered, taking into consideration the described entity.

Highlights • Modern techniques for treatment of infantile post-hemorrhagic hydrocephalus failed. • This operation is an internal shunt that avoids use of ventriculo-peritoneal shunt. • It is currently generally regarded as an “obsolete surgical procedure”., Introduction Torkildsen operation is a ventriculo-cisternal shunt that diverts the cerebrospinal fluid flow from one of the lateral ventricles, via a ventricular catheter, to the cisterna magna of the posterior fossa. It is the first described operation of CSF diversion for the treatment of hydrocephalus [1] (Scarff, 1963). Presentation of case We present the case of a premature infant who presented with post hemorrhagic hydrocephalus who underwent several failed CSF diversion surgeries before Torkildsen shunt procedure. The patient overcame the irregularities of CSF circulation that were observed before the operation and his post-operative course was uneventful, in terms of CSF –related complications. Discussion We summarize the historical data and the technical aspects of the procedure, and we present a brief literature review of the indications and limitations associated with it. Conclusion Torkildsen shunt can be effective in selected patients with hydrocephalus even in the modern era of computed tomography and magnetic resonance imaging. the procedure enables one to avoid a standard ventriculoperitoneal shunt, especially in cases it is not technically feasible.

An intraparenchymal pericatheter cyst is a rare complication of ventriculoperitoneal shunt, which is not well described yet. Due to its rarity, lack of characteristic symptoms and radiological features that often mimic brain tumors or abscesses, especially in head computed tomography without contrast can be easily misdiagnosed. We report the case of a 9-year-old girl who was admitted to a peripheral hospital due to severe headaches and vomiting. The child had a history of craniotomy and ventriculoperitoneal shunt for posterior fossa tumor, performed in our department, 4 years earlier. The patient underwent a brain magnetic resonance imaging (MRI) scan and transmitted to our hospital with the diagnosis of brain tumor. However, a closer look at the MRI established the diagnosis of intraparenchymal pericatheter cerebrospinal fluid cyst; hence, the patient underwent shunt revision and cyst drainage. We researched the literature and described 20 reported cases, discussing the pathophysiological mechanisms, the radiological features, and the optimal treatment of this interesting, yet a challenging complication.

Purpose We sought to evaluate the relationship between admission neutrophil-to-lymphocyte ratio (NLR) and functional outcome in aneurysmal subarachnoid hemorrhage (aSAH) patients. Material and methods Consecutive patients with aSAH were treated at two tertiary stroke centers during a five-year period. Functional outcome was defined as discharge modified Rankin score dichotomized at scores 0-2 (good) vs. 3-6 (poor). Results 474 aSAH patients were evaluated with a mean NLR 8.6 (SD 8.3). In multivariable logistic regression analysis, poor functional outcome was independently associated with higher NLR, older age, poorer clinical status on admission, prehospital statin use, and vasospasm. Increasing NLR analyzed as a continuous variable was independently associated with higher odds of poor functional outcome (OR 1.03, 95%CI 1.00-1.07, p=0.05) after adjustment for potential confounders. When dichotomized using ROC curve analysis, a threshold NLR value of greater than 6.48 was independently associated with higher odds of poor functional outcome (OR 1.71, 95%CI 1.07-2.74, p=0.03) after adjustment for potential confounders. Conclusions Higher admission NLR is an independent predictor for poor functional outcome at discharge in aSAH patients. The evaluation of anti-inflammatory targets in the future may allow for improved functional outcome after aSAH.

Introduction: Glycemic variability (GV) has been associated with worse prognosis in critically ill patients. We sought to evaluate the potential association between GV indices and clinical outcomes in acute stroke patients. Methods: Consecutive diabetic and nondiabetic, acute ischemic or hemorrhagic stroke patients underwent regular, standard-of-care finger-prick measurements and continuous glucose monitoring (CGM) for up to 96 h. Thirteen GV indices were obtained from CGM data. Clinical outcomes during hospitalization and follow-up period (90 days) were recorded. Hypoglycemic episodes disclosed by CGM but missed by finger-prick measurements were also documented. Results: A total of 62 acute stroke patients [48 ischemic and 14 hemorrhagic, median NIHSS score: 9 (IQR: 3–16) points, mean age: 65 ± 10 years, women: 47%, nondiabetic: 79%] were enrolled. GV expressed by higher mean absolute glucose (MAG) values was associated with a lower likelihood of neurological improvement during hospitalization before and after adjusting for potential confounders (OR: 0.135, 95% CI: 0.024–0.751, p = 0.022). There was no association of GV indices with 3-month clinical outcomes. During CGM recording, 32 hypoglycemic episodes were detected in 17 nondiabetic patients. None of these episodes were identified by the periodic blood glucose measurements and therefore they were not treated. Conclusions: Greater GV of acute stroke patients may be related to lower odds of neurological improvement during hospitalization. No association was disclosed between GV indices and 3-month clinical outcomes.

Background A large number of published articlesexists, centered on pediatric and adult medulloblastomas. Objective To accomplish a systematic review and meta-analysis concerningmedulloblastoma, focusing on the clinical features, diagnostic and currenttreatment modalities, as well as prognostic factors. Methods In March 2020, we performed a title- focused search using Thomson Reuters Web of Science database in order to identify the most cited articles centered on adult and pediatric medulloblastomas. Results Our search resulted in 4.779 articles, published from 1975 until March 2020. All of them combined have been cited 118,703 times, with an average citation per item of 24.84. The most cited article was published by Pomeroy SL, et al. in 2002 in Nature Journal, whereas the least cited one was published by Huang E., et al, in 2002. Conclusions The aim of the study is, via the presentation of the 100 most cited papers focused on medulloblastoma, to describe their relevant contribution regarding advances in therapeutic prospects, prognosis, molecular characteristics andreconsideration of treatment protocols. We describe how, and to what degree, the treatment guidelines and management of this tumor have changed from 1975 to 2020. We reviewrecent advances in cancer genomics which have revealed 4 distinct subgroups of medulloblastomas, as well asthe importance of molecular biology on the development of new treatment features. We aim not only to answer the question: WHAT were the most cited publications, but also to approach the question of WHY the most-cited sources were so.

Background The entity of pediatric stroke has been recognized for centuries and is defined as a focal neurological deficit, lasting more than 24 h, being attributed only to causes of vascular origin, and it refers to patients from 0 to 18 years old. It is a condition implicated with personal, familial, economic, andsocial consequences and related with a diverse spectrum of risk factors. Methods A bibliometric analysis centered on pediatric stroke was performed along with a broad literature review. Risk factors and modern treatment options, including endovascular techniques and decompressive craniectomy, as a treatment option for life threatening circumstances, are reviewed. Results The search resulted in 410 articles, published from 1975 until now (May 2020). All of them combined have been cited 4.038 times, in 2.351 different articles, with an average citation per item of 80.76. The most cited article was published by Ganesan, V in 2003. It has received 303 citations, with an average 16.83 citations per year, while the last was published by Tsivgoulis, G in 2008, with 26 total citations, and an average of 2 citations per year. Conclusion Asignificant proportion of the published articles relevant to ischemic stroke appeared in the literature during the last decade, with a great amount of them focused on the relevant risk factors. Relatively less studies were concentrated on therapeutic options related to massive cerebral infarction, indicating that there is a relative lack of evidence related to acute therapeutic intervention.

Background and purpose Independent randomized controlled clinical trials (RCTs) have provided robust evidence for endovascular treatment (EVT) as the standard of care treatment for acute large vessel occlusions in the anterior circulation. We examined available studies specific to posterior cerebral circulation ischemic strokes to see if any conclusions can be drawn regarding EVT options. Methods We performed a systematic literature search to identify studies evaluating the safety and efficacy of EVT versus standard medical treatment for patients with acute basilar artery occlusion (BAO). We extracted data for outcomes of interest and presented associations between the two groups with the use of risk ratios (RRs) or odds ratios (ORs), with corresponding 95% confidence intervals (CIs). We used a random-effects model to pool the effect estimates. Results We identified five studies (two RCTs, three observational cohorts) including a total of 1098 patients. Patients receiving EVT had a higher risk of symptomatic intracranial hemorrhage (sICH) compared to those receiving non-interventional medical management (RR 5.42, 95% CI 2.74-10.71). Nonsignificant trends towards modified Rankin Scale (mRS) scores 0-2 (RR 1.02, 95% CI 0.74-1.41), mRS scores 0-3 (RR = 0.97, 95% CI 0.64-1.47), overall functional improvement (OR 0.93, 95% CI 0.57-1.51), and all-cause mortality (RR 1.03, 95% CI 0.78-1.35) at 3 months were seen. Conclusion Although EVT increases the probability of sICH, the available data do not exclude the possibility of improved functional outcomes over standard therapy. As larger studies are challenged by the perceived lack of equipoise in this vulnerable patient population, results of ongoing RCTs are expected to provide substantial input for future meta-analyses.

ObjectiveTo provide a critical appraisal on the evidence from randomized controlled clinical trials (RCTs) on the utility of direct endovascular treatment (dEVT) compared to the combination of endovascular treatment preceded by IV thrombolysis (bridging therapy [BT]) for patients with acute large vessel occlusion (LVO).MethodsEligible RCTs were identified by searching Medline and Scopus. We calculated the corresponding odds ratios (ORs) and 95% confidence intervals (CIs) and pooled estimates using random-effects models. The primary outcome was the probability of modified Rankin scale (mRS) score of 0 to 2 at 3 months.ResultsWe included 3 studies comprising 1,092 patients. No difference between the dEVT and BT groups was detected for the outcomes of mRS score of 0 to 2 (OR 1.08, 95% CI 0.85–1.38; adjusted OR 1.11, 95% CI 0.76–1.63), mRS score of 0 to 1 (OR 1.10, 95% CI 0.84–1.43; adjusted OR 1.16, 95% CI 0.84–1.61), and functional improvement at 3 months (common OR 1.08, 95% CI 0.88–1.34; adjusted common OR 1.09, 95% CI 0.86–1.37). Patients receiving dEVT had significantly lower likelihood of successful recanalization before the endovascular procedure compared to those receiving BT (OR 0.37, 95% CI 0.18–0.77). Patients receiving dEVT had lower intracranial bleeding rates compared to those receiving BT (OR 0.67, 95% CI 0.49–0.92) but without a significant difference in the probability of symptomatic intracranial hemorrhage. No differences in all-cause mortality, serious adverse events, or procedural complications between the 2 groups were uncovered.ConclusionsWe detected no differences in functional outcomes of IV thrombolysis–eligible patients with an acute LVO receiving dEVT compared to BT. Because uncertainty for most endpoints remains large and the available data are not able to exclude the possibility of overall benefit or harm, further RCTs are needed.

Background There is a vast amount of published articles, centered on tethered cord syndrome, which is related to a constellation of diverse pathological entities, included under the term occult spinal dysraphism. Objective To present the 100 most-cited articles dedicated to the entity of tethered cord syndrome and to present a comprehensive review of the relevant literature. Methods In April 2020, we executed a title- focused search using Thomson Reuters Web of Science database in order to identify the most cited articles relevant to tethered cord syndrome. Consequently, we reviewed the results to certify that they were relevant to the criteria of our research protocol. The 100 most cited papers were chosen and further analyzed. Results Our search resulted in 769 articles, published from 1976 until now. All of them combined, have been cited 5.340 times, in a total of 2.097 different articles, with an average citation per item of 53.4.The most cited article was published by Yamada S., in 1981, while the last in our list was published by Walton, M et al in 1995. Conclusions We distinguished the top 100 most-cited articles dedicated to tethered cord syndrome, all of which are demonstrating important aspects and conclusions, being well-supported and methodologically fully adequate. We also reviewed the relevant evolution of the concept of management and the knowledge of the natural history, as well as new data in tethered cord syndrome research, alongside with the relevant contributions of different authors, fields of special interest, and countries.

Patient: Male, 7-year-old Final Diagnosis: Status epilepticus Symptoms: Local sezure Medication: — Clinical Procedure: Computed tomography • magnetic resonance imaging Specialty: Neurosurgery Objective: Rare co-existance of disease or pathology Background: Advanced imaging is one of the main modalities utilized in the diagnostic investigation of a first-time epileptic ictus, as well as in the evaluation of a patient suspected of having an ischemic stroke. Case Report: We report the case of a 7-year-old boy who was admitted to our hospital because of a depressed skull fracture. Soon after its initial evaluation, he had an episode of generalized tonic-clonic seizures; therefore, a detailed diagnostic work up was scheduled, which raised the diagnostic dilemma of ischemic stroke versus imaging alterations related to status epilepticus. He underwent surgical exploration, and a few days later the repeat MRI verified that the initial signal changes should be attributed to the ictus. Conclusions: Brain edema, most commonly affecting a cerebral hemisphere in its entirety, is a rare post-ictal imaging finding that is causally related to focal-onset status epilepticus. The aforementioned perfusion changes can aid in the differentiation of ictal-related brain abnormalities from acute ischemic stroke, if regional or more diffuse areas of increased perfusion are shown on MRI. Consequently, MRI should be considered the preferred imaging modality when we are confronted with cases of postictal signal changes that could masquerade as acute ischemic stroke.

Patient: Female, 6-year-old Final Diagnosis: Arteriovenous malformation Symptoms: Nausea • vomitting Medication:— Clinical Procedure: Computed tomography • digital subtraction angiography Specialty: Neurosurgery Objective: Unusual clinical course Background: Cerebral arteriovenous malformations (AVMs) are considered to be abnormalities of congenital origin, presumably arising due to a disorder in the process of embryogenesis, in the phase of differentiation of premature vascular domes into mature arteries, capillaries, and veins. The end result of that process is the formation of direct arteriovenous communications, without intervening capillary beds. Case Report: We report the case of a 6-year-old female who suffered an abrupt deterioration of her level of consciousness due to a subarachnoid hemorrhage located in the basal cisterns. Radiological investigation with magnetic resonance arteriography-magnetic resonance venography (MRA-MRV) was negative, but digital subtraction angiography (DSA) revealed a micro-AVM in the vicinity of the brainstem. The patient subsequently developed communicating hydrocephalus and the repeat DSA, performed 1 month later, failed to re-imagine the lesion. Further workup with DSA 1 year after the ictus was negative for pathological findings. Conclusions: There are a lot of controversies regarding the optimal imaging modality for surveillance of pediatric AVMs, the time period needed to follow-up a given lesion, even if it is considered treated, and the underlying mechanism of spontaneous thrombosis of untreated, yet ruptured, AVMs. All these issues, along with the unusual mode of evolution of the clinical picture of this lesion are discussed in detail, along with a review of the available literature.

Background: Subependymal giant cell astrocytomas (SEGAs) appear approximately in 10% of patients with tuberous sclerosis. These tumors are most commonly diagnosed in childhood and adolescence, with in utero diagnosed SEGAs being an extremely rare entity. Case Description: We present the case of a congenital SEGA detected in an antenatal ultrasound and further investigated with fetal magnetic resonance imaging (MRI) scans at 22 and 32 weeks of gestational age. At 9 days of age, the child underwent craniotomy and partial excision of the tumor, followed by a second more extensive operation 13 days later. The patient was subsequently administered mammalian target of rapamycin inhibitor (everolimus). Conclusion: In the latest follow-up MRI, at the age of two, the SEGA remained unchanged. Management of these tumors in neonates is challenging, mainly due to high morbidity and mortality of surgical treatment in these ages.

Introduction Neck pain and torticollis are common symptoms in the pediatric population that rarely requires further investigation. However, in case symptoms persist, then a more meticulously approach should be considered. Underlying conditions such as infections, neck injury, autoimmune disorders or even cervical spine cancer should be excluded from diagnosis. Cervical spine cancer is a rare neurosurgical entity in the pediatric population and even rarer is atlantoaxial Ewing's sarcoma. In this report, we present a rare case of primary Ewing's sarcoma of the axis. Case report A 3.5-year-old female with progressive neck pain and intermittent episodes of torticollis was referred to our outpatient clinic. Imaging studies revealed a malignant tumor located on C2 vertebra. Diagnosis of Ewing's Sarcoma was confirmed via open biopsy and the patient was treated with Euro-EWING 99 chemotherapy. Conclusion Pediatric neck pain and/or torticollis should raise high suspicion for malignancy of cervical spine. Modern diagnostic means and techniques can assist in the screening and diagnosis of these tumors.

Background: Colchicine is an ancient drug. Many uses have been reported in medical books and reports through the centuries. Currently the understanding of its mechanism of action has opened new horizons to its use. Objective: This article aims to discuss the use of colchicine in various neurosurgical conditions. Methods: A pubmed database and clinical trials search was performed, using the key words “colchicine”, “Neurosurgery”, “low back pain”, “stroke” and glioma”. Results: Various reports were found contemplating the use of colchicine in chronic low-back pain. The effect of the drug on neutrophil chemotaxis and its role as an anti-inflammatory agent has been the main argument upon which such use of colchicine has been structured. These characteristics have been the key to initiate colchicine as a preventive agent in vascular conditions. Furthermore, as colchicine is an antimitotic drug, it is currently being studied as a potential anti-glioma agent. However, the narrow therapeutic index of the drug is a discouraging factor in clinical application of colchicine in these entities. Therefore, colchicine derivatives that can exert the same effectiveness in lower doses are being studied, forming a new direction in colchicine use. Conclusion: Colchicine is a drug that over the years has shown promising results in certain neurosurgical entities. Its derivatives or potential colchicine-like agents might have a more significant place in neurosurgical practice.

BACKGROUND Epileptic seizures are a relatively common problem in pediatric neurosurgery that can have physical, mental and/or behavioral implications. Pediatric neurosurgery is involved in the treatment of secondary epilepsy, which is mainly associated with brain tumors, traumatic brain injury and intracranial vascular malformations. OBJECTIVE The aim of this article is to review the current literature for commonly used antiepileptic drugs in pediatric neurosurgery and offer an updated view on epilepsy treatment with antiepileptic drugs in the most commonly encountered neurosurgical entities in the pediatric population. METHODS AND MATERIALS Current literature has been reviewed for epilepsy, antiepileptic drugs and common neurosurgical conditions in children that cause seizures and/or epilepsy. Epidemiological features, epileptogenesis and treatment have been thoroughly examined. CONCLUSION The most common neurosurgical conditions that cause seizures and/or epilepsy in the pediatric population are brain tumors and traumatic brain injury. Newer antiepileptic drugs are powerful instruments in the management of epilepsy and they improve the quality of life of patients as well as decrease the epilepsy associated morbidity.

Background Pediatric nonmissile penetrating head injury (NMPHI) is usually accidental attributed mainly to the softer skulls of growing children. However, it is a rare entity, and therefore no consensus exists regarding treatment to effectively prevent immediate and long-term complications. Throughout the literature, these injuries are mostly discussed in case reviews and case series in the general population. No data originating from randomized studies are available because of ethical and practical limitations. Methods We retrospectively studied and present 5 cases of children with NMPHI treated in the last 6 years in the Neurosurgery Department of Children's Hospital “Aghia Sofia”. We performed a review of the literature in PubMed, using the key words “non-missile,” “penetrating head injury,” and “pediatric.” We included case reports and case series involving pediatric cases since 2008 and selected older reports as well as certain literature reviews focusing on analysis of complications and treatment suggestions. We compared reported practice in various institutions with suggestions from the literature. Results In the last year, 4 literature reviews were published suggesting treatment algorithms of NMPHIs. Surgery timing and method as well as anticonvulsant and antibiotic therapy still remain debatable. The only review concentrating on pediatric populations dates back to 1994, based on patient outcome studies from the 1980s. In our review, treatment steps were similar among various institutions and resembled recently suggested algorithms, with better treatment outcomes than originally reported 30 years ago.

Friedreich’s ataxia (FA) is the most frequent hereditary ataxia syndrome, while painful muscle spasms and spasticity have been reported in 11–15% of FA patients. This report describes the successful management of painful spasms in a 65-year-old woman with FA via intrathecal baclofen (ITB) therapy following unsuccessful medical treatments. To our knowledge, this is the third reported case in the literature. Unfortunately, the pathophysiological characteristics of muscle spasms in FA are not well explored and understood while the therapeutic mechanisms of the different treatments are rather vague. Taking into consideration the suggested spinal atrophy in FA, the clinical resemblance of FA and chronic spinal injury muscle spasms, together with the rapid ITB therapy effectiveness in alleviating FA muscle spasms, we attempted to suggest a putative pathophysiological mechanism acting at the spinal level and possibly explained by the presence of independent spinal locomotor systems producing muscle spasms. Specifically, overexcitement of these centers, due to loss of normal regulation from upper CNS levels, may result in the uncontrolled firing of secondary motor neurons and may be the key to producing muscle spasms. However, further research under experimental and clinical settings seems to be necessary.

Objective The aim of this study was to evaluate the degree of brain tissue injury that could be potentially induced by the introduction of a) microrecording electrodes, b) macrostimulation electrodes, or c) chronic stimulation electrodes. We aimed to evaluate whether the use of five simultaneous microrecording tracks is associated with any brain injury not detectable by conventional imaging such as CT or MRI. Materials and methods The study included 61 patients who underwent surgery for implantation of 121 DBS leads. In all cases, five simultaneous tracts were utilized for microelectrode recordings. All patients underwent measurements of serum S-100b at specific time points as follows: a) prior to the operation, and b) intraoperatively at specific stages of the procedure: 1) after opening the burr hole, 2) after the insertion of microrecording electrodes, 3) during macrostimulation, 4) at the end of the operation, and 5) on the first postoperative day. Results The levels of serum S-100B protein remained within the normal range during the entire period of investigation in all patients with the exception of two cases. In both patients, the procedure was complicated by intraparenchymal hemorrhage visible in neuro-imaging. The first patient developed a small intraparenchymal hemorrhage, visible on the postoperative MRI, with no neurological deficit. The second patient experienced a focal epileptic seizure after the insertion of the right DBS chronic lead and the postoperative CT scan revealed a right frontal lobe hemorrhage. Conclusion These results strongly indicate that the insertion of either multiple recording electrodes or the implantation of chronic electrodes in DBS does not increase the risk of brain hemorrhage or of other intracranial complications, and furthermore it does not cause any biochemically detectable brain tissue damage.

Background: Intracerebral hemorrhage is the pathological accumulation of blood within the brain. It is a type of stroke more likely to be lethal or to severely disable the patient and results from a wide variety of causes. On the other hand antithrombotic therapy is used for the prevention or/and the therapy of thromboembolic episodes. Antithrombotic drugs are very effective in reducing risk or mortality rate after a thromboembolic event, yet they are associated with significant hemorrhages. Objective: The aim of this article is to review current literature for intracerebral hemorrhage and antithrombotic therapy and offer recommendations on the reversal, the discontinuation and the resumption of antithrombotic therapy. Methods and Materials: Current literature has been reviewed for intracerebral hemorrhage associated with three major categories of patients, those with atrial fibrillation, those with prosthetic mechanical valves and those with venous thromboembolism. Antithrombotic therapy is categorized in antiplatelet agents and anticoagulants. The risk of intracerebral hemorrhage, of a thromboembolic event and of a rebleeding with or without antithrombotic therapy was also reported. Conclusion: Although no one can deny the usefulness of antithrombotic therapy a therapeutic strategy should be developed in order to optimize the clinical decision of stopping, reversing and restarting antithrombotic treatment. This review concludes in strong recommendations, yet a multidisciplinary panel by a stroke physician or neurologist, a cardiologist, a neuroradiologist and a neurosurgeon should evaluate the benefits and the risks for each patient and decide the best therapeutic strategy.

Epilepsy has been known since antiquity and trepanation has been documented as a therapeutic option. The Greek born physician Aretaeus of Cappadocia (2nd century BC) was the first to recommend trepanation for the treatment of refractory epilepsy to drugs, pointing out the efficacy of the method (Fig. 1). Trepanation was practiced throughout the Middle Ages, as it is proved by the book of "Quattuor Magistri" and during Renaissance as well. In 19th century, Sir Victor Alexander Horsley (1857-1916), combining analysis of clinical presentation with cortical stimulation, performed a series of craniotomies for the treatment of epilepsy Fig. 2. In the following years the advent of electrophysiology and neurosurgery provided a fertile ground for further progress in epilepsy surgery such as the preoperative use of electroencephalography (EEG) to determine the epileptogenic zone by Otfrid Foerster (1873-1941); the research of Wilder Graves Penfield (1891-1976) in Montreal Neurological Institute and the use of stereoelectroencephalography (SEEG) by the neurosurgeon Jean Talairach (1911-2007) and the neurologist Jean Bancaud (1921-1994)) Fig. 3. Nowadays, epilepsy surgery remains a valuable therapeutic option in cases of drug resistant epilepsy.