Safety and effectiveness of evicel® fibrin sealant as an adjunct to sutured dural repair in children undergoing cranial neurosurgery.

PURPOSE: Cerebrospinal fluid (CSF) leakage is a challenging complication of intradural cranial surgery, and children are particularly at risk. The use of dural sealants confers protection in adults, but pediatric studies are scarce. We evaluated the safety and efficacy of Evicel® fibrin sealant as an adjunct to primary dural suturing in children undergoing cranial surgery. METHODS: A multicenter trial prospectively enrolled pediatric subjects (< 18 years) undergoing cranial neurosurgery who, upon completion of primary sutured dural repair, experienced CSF leakage. As agreed by the EMA Evicel® Pediatric Investigation Plan, 40 subjects were intra-operatively randomized 2:1 to Evicel® or additional sutures ('Sutures'). Data analysis was descriptive. The efficacy endpoint was treatment success rate, with success defined as intra-operative watertight closure after provocative Valsalva maneuver (primary endpoint). Safety endpoints were postoperative CSF leakage (incisional CSF leakage, pseudomeningocele or both) and surgical site complications (secondary endpoints). RESULTS: Forty subjects (0.6-17 years) were randomized to Evicel® (N = 25) or Sutures (N = 15) (intention-to-treat). Intracranial tumor was the most common indication and procedures were mostly supratentorial craniotomies. Success rates were 92.0% for Evicel® and 33.3% for Sutures, with a 2.76 estimated ratio of success rates (Farrington-Manning 95% CI [1.53, 6.16]). Sensitivity analyses in per-protocol and safety sets showed similar results. Despite a higher rescue treatment rate, the frequencies of postoperative CSF leakage and wound complications were higher for Sutures than for Evicel®. CONCLUSION: This small-scale prospective study shows Evicel® treatment to be safe and effective as an adjunct to primary sutured dura mater closure in a pediatric population. Compared to additional sutures, Evicel® was associated with reduced postoperative CSF leakage and surgical site complications. (Trial registration: The trial was registered as NCT02309645 and EudraCT 2013-003558-26).

Manchester Arena Attack: management of paediatric penetrating brain injuries.

PURPOSE: The Manchester Arena bombing on 22 May 2017 resulted in 22 deaths and over 160 casualties requiring medical attention. Given the threat of modern- era terrorist attacks in civilian environments, it is important that we are able to anticipate and appropriately manage neurological injuries associated with these events. This article describes our experience of managing paediatric neurosurgical blast injuries, from initial triage and operative management to longer-term considerations. MATERIALS AND METHODS: Case study and literature review. RESULTS: Paediatric traumatic and penetrating brain injury patients often make a good neurological recovery despite low GCS at time of injury; this should be accounted for during triage and operative decision making in major trauma, mass casualty events. Conservative management of retained shrapnel is advocated in view of low long-term infection rates with retained shrapnel and worsened neurological outcome with shrapnel retrieval. All penetrating brain injuries should receive a prolonged course of broad-spectrum antibiotics and undergo long term follow-up imaging to monitor for the development of cerebral abscesses. MRI should never be utilised in penetrating brain injury cases, even in the absence of macroscopically visible fragments, due to the effect of MRI ferromagnetic field torque on shrapnel fragments. Anti-epileptic drugs should only be prescribed for the initial seven days after injury, as continuing beyond this does not incur any benefit in the reduction of long term post-traumatic epilepsy. CONCLUSION: All receiving neurosurgical units should become familiar with optimum management of these thankfully rare, but complex injuries from their initial presentation to long term follow up considerations. All neurosurgical units should have well-rehearsed local plans to follow in the event of such incidents, ensuring timely deliverance of appropriate neurosurgical care in such extreme settings.

Genetic regulation of gene expression in the epileptic human hippocampus.

Epilepsy is a serious and common neurological disorder. Expression quantitative loci (eQTL) analysis is a vital aid for the identification and interpretation of disease-risk loci. Many eQTLs operate in a tissue- and condition-specific manner. We have performed the first genome-wide cis-eQTL analysis of human hippocampal tissue to include not only normal (n = 22) but also epileptic (n = 22) samples. We demonstrate that disease-associated variants from an epilepsy GWAS meta-analysis and a febrile seizures (FS) GWAS are significantly more enriched with epilepsy-eQTLs than with normal hippocampal eQTLs from two larger independent published studies. In contrast, GWAS meta-analyses of two other brain diseases associated with hippocampal pathology (Alzheimer's disease and schizophrenia) are more enriched with normal hippocampal eQTLs than with epilepsy-eQTLs. These observations suggest that an eQTL analysis that includes disease-affected brain tissue is advantageous for detecting additional risk SNPs for the afflicting and closely related disorders, but not for distinct diseases affecting the same brain regions. We also show that epilepsy eQTLs are enriched within epilepsy-causing genes: an epilepsy cis-gene is significantly more likely to be a causal gene for a Mendelian epilepsy syndrome than to be a causal gene for another Mendelian disorder. Epilepsy cis-genes, compared to normal hippocampal cis-genes, are more enriched within epilepsy-causing genes. Hence, we utilize the epilepsy eQTL data for the functional interpretation of epilepsy disease-risk variants and, thereby, highlight novel potential causal genes for sporadic epilepsy. In conclusion, an epilepsy-eQTL analysis is superior to normal hippocampal tissue eQTL analyses for identifying the variants and genes underlying epilepsy.

An integrative in silico system for predicting dysregulated genes in the human epileptic focus: Application to SLC transporters.

OBJECTIVE: Many different gene families are currently being investigated for their potential role in epilepsy and in the response to antiepileptic drugs. A common research challenge is identifying the members of a gene family that are most significantly dysregulated within the human epileptic focus, before taking them forward for resource-intensive functional studies. Published data about transcriptomic changes within the human epileptic focus remains incomplete. A need exists for an accurate in silico system for the prediction of dysregulated genes within the epileptic focus. We present such a bioinformatic system. We demonstrate the validity of our approach by applying it to the solute carrier (SLC) gene family. There are >400 known SLCs. SLCs have never been systematically studied in epilepsy. METHODS: Using our in silico system, we predicted the SLCs likely to be dysregulated in the epileptic focus. We validated our in silico predictions by identifying ex vivo the SLCs dysregulated in epileptic foci, and determining the overlap between our in silico and ex vivo results. For the ex vivo analysis, we used a custom oligonucleotide microarray containing exon probes for all known SLCs to analyze 24 hippocampal samples obtained from surgery for pharmacoresistant mesial temporal lobe epilepsy and 24 hippocampal samples from normal postmortem controls. RESULTS: There was a highly significant (p < 9.99 × 10(-7) ) overlap between the genes identified by our in silico and ex vivo strategies. The SLCs identified were either metal ion exchangers or neurotransmitter transporters, which are likely to play a part in epilepsy by influencing neuronal excitability. SIGNIFICANCE: The identified SLCs are most likely to mediate pharmacoresistance in epilepsy by enhancing the intrinsic severity of epilepsy, but further functional work will be needed to fully evaluate their role. Our successful in silico strategy can be adapted in order to prioritize genes relevant to epilepsy from other gene families.

Histologically proven acute paediatric thoracic disc herniation causing paraparesis: a case report and review of literature.

PURPOSE: We describe an extremely rare and previously unreported presentation of acute progressive paraparesis secondary to traumatic thoracic disc herniation in a child presenting to our institution. METHODS: A 12-year-old girl presented with progressive paraparesis 24 h after falling from standing height while playing at school. She was being lifted up by her friends and fell landing on her feet then rolled onto her back initially with no pain or neurological sequelae. Over the next few hours, she developed back pain followed by progressive paraparesis associated with urinary retention and sensory impairment. RESULTS: MR imaging demonstrated an unusual lateral and dorsally based lesion at T7/8 causing cord compression which was thought to represent an epidural haematoma. Urgent posterior decompressive surgery was performed but no evidence of haematoma was seen, a large well-circumscribed solid piece of soft tissue was found in the extradural space causing significant cord compression. This was sent for histological analysis and subsequently reported as showing cartilaginous disc material. Postoperative MR imaging at 2 weeks and 3 months demonstrates complete resection of this disc material with no significant kyphotic deformity on standing X-ray at 18 months. Complete neurological recovery occurred over the subsequent 3 months following emergent surgery, and at 18-month review, the patient remains asymptomatic and fully independent.

Identifying the biological pathways underlying human focal epilepsy: from complexity to coherence to centrality.

Numerous diverse biological pathways are dysregulated in the epileptic focus. Which of these pathways are most critical in producing the biological abnormalities that lead to epilepsy? Answering this question is key to identifying the primary causes of epilepsy and for discovering new therapeutic strategies with greater efficacy than currently available antiepileptics (AEDs). We have performed the largest genome-wide transcriptomic analysis to date comparing epileptic with normal human hippocampi. We have identified 118 differentially expressed and, for the first time, differentially connected pathways in the epileptic focus. Using network mapping techniques, we have shown that these dysregulated pathways, though seemingly disparate, form a coherent interconnected central network. Using closeness centrality analysis, we have identified that the most influential hub pathways in this network are signalling through G protein-coupled receptors, in particular opioid receptors, and their downstream effectors PKA/CREB and DAG/IP3. Next, we have objectively demonstrated that genetic association of gene sets in independent genome-wide association studies (GWASs) can be used to identify causally relevant gene sets: we show that proven causal epilepsy genes, which cause familial Mendelian epilepsy syndromes, are associated in published sporadic epilepsy GWAS results. Using the same technique, we have shown that central pathways identified (opioid receptor and PKA/CREB and DAG/IP3 signalling pathways) are genetically associated with focal epilepsy and, hence, likely causal. Published functional studies in animal models provide evidence of a role for these pathways in epilepsy. Our work shows that these pathways play a central role in human focal epilepsy and that they are important currently unexploited antiepileptic drug targets.

Image-defined resolution following radiosurgery for hypothalamic hamartoma.

The authors present the rare case of complete image-defined resolution of a hypothalamic hamartoma (HH) following Gamma Knife surgery (GKS). A 9-month-old girl presented with an episode of generalized tonic-clonic seizures. Magnetic resonance imaging revealed a left-sided HH, which remained radiologically stable. By 3 years of age the patient had a development delay of 12 months, and experienced 8 gelastic seizures per day while on 2 antiepileptic medications. Thirty-one months after presentation, the patient underwent elective GKS to treat the HH. She has since been seizure free for 22 months, while receiving 3 antiepileptic medications. Twelve months after radiosurgery, MRI revealed complete radiological resolution of the lesion. The authors discuss alternative management options for HH, including microsurgical resection, endoscopic disconnection, stereotactic radiofrequency thermocoagulation, and interstitial radiosurgery. Gamma Knife surgery is a minimally invasive procedure associated with a lower morbidity rate than that of published surgical results. The present case demonstrates the potential for complete image-defined resolution of an HH post-GKS, without long-term neurological sequelae, emphasizing the safety and efficacy of this therapeutic option for the control of epileptic seizures produced by small-volume, surgically inaccessible HHs.

Preoperative vincristine for an inoperable choroid plexus papilloma: a case discussion and review of the literature.

The authors report the case of a 14-month-old boy with a large right intraventricular choroid plexus papilloma (CPP) for which the first attempt at resection resulted in life-threatening intraoperative hemorrhage. The tumor was unsuitable for embolization, and neoadjuvant ifosfamide, carboplatin, etoposide (ICE) chemotherapy had no effect on tumor size. However, chemotherapy with vincristine, although not impacting on CT perfusion parameters, resulted in a significant decrease in tumor size, enabling complete resection with manageable blood loss. The mechanism underlying the effect of vincristine in this case is uncertain, but it is a treatment strategy that warrants further evaluation for the treatment of CPPs that are not amenable to embolization.

Primary diffuse large B-cell central nervous system lymphoma presenting as an acute space-occupying subdural mass.

Primary dural lymphomas are very rare tumors--usually low-grade B-cell lymphomas of mucosa-associated lymphoid tissue type or marginal zone B-cell lymphomas. Primary dural involvement by diffuse large B-cell lymphoma is extremely rare, with only a few cases reported in the literature. The authors present an unusual case of primary dural involvement by a high-grade diffuse large B-cell lymphoma that presented as an acute subdural space-occupying mass and required emergency neurosurgical intervention.

Cerebellar astrocytoma presenting with precocious puberty in a girl. Case report.

Central precocious puberty in girls is uncommon and tends to be idiopathic in most cases. In about 20 to 30% of cases there is an intracranial mass lesion. The common lesions are hypothalamic hamartomas, optic nerve gliomas, suprasellar arachnoid cysts, hydrocephalus, germinomas, and other sellar/suprasellar lesions. Central precocious puberty secondary to a cerebellar astrocytoma is extremely rare. The authors report the first case in a girl who presented with several episodes of bleeding per vaginum. There was no clinical or radiological evidence of raised intracranial pressure.

Development of a pilocytic astrocytoma in a dysembryoplastic neuroepithelial tumor. Case report.

Dysembryoplastic neuroepithelial tumors (DNETs) are benign supratentorial tumors based in the cerebral cortex. They usually are found in children and young adults with seizures that tend to become refractory to medical treatment. In the vast majority of cases resection results in good seizure control, and adjuvant therapy is not required. When tumors thought to be DNETs are not resected due to their proximity to eloquent cortex, lack of change in the clinical and neuroimaging features over time supports the diagnosis of DNET. The authors report on a patient in whom a pilocytic astrocytoma developed within a DNET, raising questions regarding the classification of these lesions and the need for lifelong clinical and imaging surveillance. This paper adds to the growing body of literature about the biological behavior of these lesions.

Risk factors for developing epilepsy after craniotomy in children.

INTRODUCTION: We performed a retrospective analysis of children undergoing supratentorial craniotomy, attempting to identify possible risk factors for postoperative epilepsy and the need for prophylactic anticonvulsant therapy. MATERIALS AND METHODS: We analysed 107 consecutive patients (55% males) who had supratentorial craniotomy for a variety of diagnoses (tumours, trauma, infection, vascular malformations and others) during 1995-1999. Mean age at operation was 89 months (range: 1-180 months). Patients who presented with epilepsy were excluded. Postoperative epilepsy was considered present if patients required systematic pharmacological treatment, at a minimum follow-up of 6 months. Linear regression was used to analyse the effect of sex, anticonvulsant prophylaxis, duration of operation, closure of dura, postoperative infection, the diagnosis, anatomical region of brain affected, operation type (craniotomy/craniectomy) and the need for brain resection. RESULTS: Prophylactic anticonvulsants were given to 52% of the patients; 97% had craniotomy; in five patients, the dura was left open; in 33%, some kind of brain tissue resection had been performed; two patients (1.8%) developed postoperative infection; one patient died. Only 13 patients (12%) developed postoperative epilepsy. The only two factors with statistical significance were female sex (p=0.045) and the absence of dural closure (p=0.001). All other factors were not significant (p>0.258). CONCLUSIONS: Postoperative epilepsy after supratentorial craniotomy is uncommon in children, incidence being 12%. The administration of prophylactic anticonvulsants does not appear to influence the risk of epilepsy. Surprisingly, females have statistically higher risk. Lack of dural closure has higher risk of epilepsy, but this may reflect the type of pathology.