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).

Awake craniotomy for high-grade gliomas - a prospective cohort study in a UK tertiary-centre.

BACKGROUND: Studies from the UK reporting on awake craniotomy (AC) include a heterogenous group of patients which limit the evaluation of the true impact of AC in high-grade glioma (HGG) patients. This study aims to report solely the experience and outcomes of AC for HGG surgery from our centre. METHODS: A prospective review of all patients who underwent AC for HGG from 2013 to 2019 were performed. Data on patient characteristics including but not limited to demographics, pre- and post-operative Karnofsky performance status (KPS), tumour location and volume, type of surgery, extent of resection (EOR), tumour histopathology, intra- and post-operative complications, morbidity, mortality, disease recurrence, progression-free survival (PFS) and overall survival (OS) from the time of surgery were collected. RESULTS: Fifteen patients (6 males; 9 females; 17 surgeries) underwent AC for HGG (median age = 55 years). Two patients underwent repeat surgeries due to disease recurrence. Median pre- and post-operative KPS score was 90 (range:80-100) and 90 (range:60-100), respectively. The EOR ranges from 60 to 100 % with a minimum of 80 % achieved in 81.3 % cases. Post-operative complications include focal seizures (17.6 %), transient aphasia/dysphasia (17.6 %), permanent motor deficit (11.8 %), transient motor deficit (5.9 %) and transient sensory disturbance (5.9 %). There were no surgery-related mortality or post-operative infection. The median PFS and OS were 13 (95%CI 5-78) and 30 (95%CI 21-78) months, respectively. CONCLUSION: This is the first study in the UK to solely report outcomes of AC for HGG surgery. Our data demonstrates that AC for HGG in eloquent region is safe, feasible and provides comparable outcomes to those reported in the literature.

'Possible shunt malfunction' pathway for paediatric hydrocephalus-a study of clinical outcomes and cost implications.

BACKGROUND: Shunt insertion for hydrocephalus is a common paediatric neurosurgery procedure. Shunt complications are frequent with an estimated 20-40% failure rate within the first year, and 4.5% per year subsequently. We have an open-door 'possible shunt malfunction' pathway for children treated with a shunt or endoscopic third ventriculostomy, providing direct ward access to ensure rapid assessment and timely management of children. OBJECTIVE: To audit the 'possible shunt malfunction' pathway in terms of clinical outcomes (percentage-confirmed shunt dysfunction and number of re-attendances) and costs. METHODS: Clinical data for patients attending the triage service were prospectively recorded over 7 months-including the number of attendances, previous shunt revisions, shunt type, investigations performed (CT, x-rays), and outcome. Costings (e.g. costs of physician, inpatient stay, investigations) were obtained from the hospital's procurement department. RESULTS: In the study period, there were 81 attendances by 62 patients and only 16% of attendances resulted in surgical management (either shunt revision or ETV). Approximately 17% of patients re-attended at least once. The average cost per attendance in our pathway was £765.57 ($969.63; €858.73). The total expenditure for the pathway over 7 months was £62,011.03 ($78,540.07; €69,556.81), with inpatient stay making up the biggest percentage of cost (49.2%). CONCLUSION: Only 16% (13 attendances) of those attending through our pathway required neurosurgical intervention. Investigations for possible blocked shunt come at significant health, social, and financial cost. High rates of shunt failure, re-attendance, investigations, and inpatient stays incur a sizable financial burden to the healthcare system.

Prognostic value of leukocytosis in pediatric traumatic brain injury.

OBJECTIVE: The purpose of this study was to assess leukocytosis and its prognostic value in pediatric isolated traumatic brain injury (TBI). METHODS: Two hundred one children with isolated TBI admitted to the authors' institution between June 2006 and June 2018 were prospectively followed and their data retrospectively analyzed. Initial blood leukocyte count (i.e., white cell count [WCC]), Glasgow Coma Scale (GCS) score, CT scans, duration of hospital stay, and Pediatric Cerebral Performance Category Scale (PCPCS) scores were analyzed. RESULTS: The mean age was 4.2 years (range 0.2-16 years). Seventy-four, 70, and 57 patients had severe (GCS score 3-8), moderate (GCS score 9-13), and mild (GCS score 14-15) TBI, respectively, with associated WCC of 20, 15.9, and 10.7 × 109/L and neutrophil counts of 15.6, 11.3, and 6.1 × 109/L, respectively (p < 0.01). Higher WCC and neutrophil counts were demonstrated in patients with increased intracranial mass effect on CT, longer hospital stay, and worse 6-month PCPCS score (p < 0.05). Multivariate regression revealed a cutoff leukocyte count of 16.1 × 109/L, neutrophil count of 11.9 × 109/L, and neutrophil-to-lymphocyte ratio (NLR) of 5.2, above which length of hospital stay and PCPCS scores were less favorable. Furthermore, NLR was the second most important independent risk factor for a poor outcome (after GCS score). The IMPACT (International Mission for Prognosis and Analysis of Clinical Trials in TBI) adult TBI prediction model applied to this pediatric cohort demonstrated increased accuracy when WCC was incorporated as a risk factor. CONCLUSIONS: In the largest and first prospective study of isolated pediatric head injury to date, the authors have demonstrated that WCC > 16.1 × 109/L, neutrophil count > 11.9 × 109/L and NLR > 5.2 each have predictive value for lengthy hospital stay and poor PCPCS scores, and NLR is an independent risk factor for poor outcome. Incorporating the initial leukocyte count into TBI prediction models may improve prognostication.

Chiari I malformation and altered cerebrospinal fluid dynamics-the highs and the lows.

PURPOSE: This paper reviews the altered cerebrospinal fluid dynamics that can be associated with paediatric Chiari I malformation and we present our own institutional experience. METHODS: We conducted a thorough review of the literature and retrospectively analyzed all cases of operatively managed paediatric Chiari 1 malformation at our institution between February 2006 and February 2019. RESULTS: Acquired Chiari malformation (ACM) can radiologically mimic Chiari I and has been associated with both intracranial hypotension (either secondary to lumboperitoneal shunting or spontaneous CSF hypotension) and idiopathic intracranial hypertension (IIH). At our institution, 61 paediatric cases (range, 2-15 years) underwent foramen magnum decompression (FMD) for Chiari I malformation. Whilst 80% (50/61) of cases underwent FMD with no preceding or post-operative problems of CSF dynamics, 8% (5/61) of cases had hydrocephalus at initial presentation requiring CSF diversion followed by FMD for persistent Chiari, and 10% (6/61) developed hydrocephalus following FMD and required long-term CSF diversion. CONCLUSIONS: In paediatric ACM, the management of intracranial hypotension involves thorough radiological assessment and inclusion/adjustment of a valve in the case of lumboperitoneal shunting or epidural blood patch or interventional techniques in the case of spontaneous CSF leak. Thereby, unwarranted posterior fossa decompression surgery is avoided. In the case of IIH and Chiari I malformation, children who have recurrent symptoms despite adequate posterior fossa decompression surgery (failed Chiari), there is a strong role for intracranial pressure monitoring as raised intracranial pressure may indicate long-term CSF diversion.

Multiple system atrophy mimicked by multi-organ pathology.

Both multiple system atrophy and Parkinson's disease may present with parkinsonism and autonomic dysfunction. We describe a patient who initially met the diagnostic criteria for multiple system atrophy and had atypical features for Parkinson's disease including blackouts and pyramidal signs. Ultimately, he was found to have three separate diagnoses rather than a single unifying one.

Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade.

Immune checkpoint inhibitors, including those targeting programmed cell death protein 1 (PD-1), are reshaping cancer therapeutic strategies. Evidence suggests, however, that tumor response and patient survival are determined by tumor programmed death ligand 1 (PD-L1) expression. We hypothesized that preconditioning of the tumor immune microenvironment using targeted, virus-mediated interferon (IFN) stimulation would up-regulate tumor PD-L1 protein expression and increase cytotoxic T cell infiltration, improving the efficacy of subsequent checkpoint blockade. Oncolytic viruses (OVs) represent a promising form of cancer immunotherapy. For brain tumors, almost all studies to date have used direct intralesional injection of OV, because of the largely untested belief that intravenous administration will not deliver virus to this site. We show, in a window-of-opportunity clinical study, that intravenous infusion of oncolytic human Orthoreovirus (referred to herein as reovirus) leads to infection of tumor cells subsequently resected as part of standard clinical care, both in high-grade glioma and in brain metastases, and increases cytotoxic T cell tumor infiltration relative to patients not treated with virus. We further show that reovirus up-regulates IFN-regulated gene expression, as well as the PD-1/PD-L1 axis in tumors, via an IFN-mediated mechanism. Finally, we show that addition of PD-1 blockade to reovirus enhances systemic therapy in a preclinical glioma model. These results support the development of combined systemic immunovirotherapy strategies for the treatment of both primary and secondary tumors in the brain.

5-aminolevulinic acid guidance during awake craniotomy to maximise extent of safe resection of glioblastoma multiforme.

Overall survival for patients with glioblastoma multiforme (GBM) has been consistently shown to improve when the surgeon achieves a gross total resection of the tumour. It has also been demonstrated that surgical adjuncts such as 5-aminolevulinic acid (5-ALA) fluorescence--which delineates malignant tumour tissue--normal brain tissue margin seen using violet-blue excitation under an operating microscope--helps achieve this. We describe the case of a patient with recurrent left frontal GBM encroaching on Broca's area (eloquent brain). Gross total resection of the tumour was achieved by combining two techniques, awake resection to prevent damage to eloquent brain and 5-ALA fluorescence guidance to maximise the extent of tumour resection.This technique led to gross total resection of all T1-enhancing tumour with the avoidance of neurological deficit. The authors recommend this technique in patients when awake surgery can be tolerated and gross total resection is the aim of surgery.

Intra-operative acidosis during 5-aminolevulinic acid assisted glioma resection.

A 47-year-old man underwent 5-aminolevulinic acid assisted resection of high grade glioma. Intraoperatively, he developed a compensated lactic acidosis that was managed medically and did not cause long term complications.

Monitoring the changing pattern of delivery of paediatric epilepsy surgery in England--an audit of a regional service and examination of national trends.

PURPOSE: The demand for paediatric epilepsy surgery in the UK greatly exceeds the number of operations performed. Hence, Children's Epilepsy Surgery Service (CESS) was commenced in 2012. This study is aimed to characterise the changes in service delivery in the North East of England Paediatric Neuroscience Network and nationally. METHODS: A retrospective cohort study of paediatric epilepsy surgery in Leeds between 2005 and 2012 is presented followed by analysis of British Paediatric Neurosurgical Group (BPNG) data before and after CESS commissioning. RESULTS: During the study period, 42 children underwent epilepsy surgery in Leeds. The commonest aetiologies were neoplasm (33%), focal cortical dysplasia (19%) and mesial temporal sclerosis (19%). Seizure outcome was 71 % EngelI and 83% EngelI+II. Complications included one infection (2%), two temporary (5%) and one permanent (2%) motor deficits, three new/worsened visual field deficits (7%). There were six re-craniotomies (14%). The BPNG data show a 48% increase in paediatric epilepsy surgery in England between 2009 (90 cases) and 2012 (133 cases), and a 20% fall in 2013 (106 cases)--the first calendar year for CESS. On average, 64% of all operations were performed in London. CONCLUSIONS: The number of children receiving surgery for epilepsy in England had increased annually up to, and declined after, the establishment of CESS centres. The yearly caseload in neurosurgical units outside of London is small. The outcomes from Leeds are comparable to those published elsewhere. Other UK units are encouraged to publish outcomes to facilitate patient, commissioner and provider decision making.

A simple method to ease insertion and removal of vertebral body distractor pins in anterior cervical surgery.

Soft tissue injuries and visceral perforation are rare but potentially lethal complications of anterior cervical spine surgery. We describe a cheap and simple technique for guarding para-vertebral soft tissues, making insertion and removal of vertebral body distractor screws easier and safer with or without an assistant.

Spontaneous extradural aerocele following cardiopulmonary resuscitation - an unrecognised complication.

We present a case report of a 61-year-old gentleman who had a cardiac arrest and was delivered cardiopulmonary resuscitation (CPR) by a bystander. After resuscitation, he regained cardiac output and was breathing spontaneously. CT scan of the head showed spontaneous right frontal extradural aerocele with fracture of the posterior wall of the frontal sinus with no sign of head injury. We discuss the pathophysiology of this unrecognised complication due to CPR.

Intrathecal baclofen therapy--how we do it.

Intrathecal baclofen has become an invaluable tool to treat spasticity of various etiologies. Children who benefit from intrathecal baclofen are often significantly underweight due to underlying disease pathology, and they lack adequate soft-tissue mass to effectively provide cover to the pump. Thus, in this population, subfascial implantation is favored over the subcutaneous technique in view of the high frequency of wound dehiscence and subsequent explantation of the pump associated with the latter method. The authors describe and review their unit's adapted subfascial implantation technique that has been performed over a period of 10 years in 182 children. This technique provides better tissue coverage for the pump and has resulted in lowering the risk of complications as compared with the subcutaneous technique.

Intrathecal baclofen therapy for spasticity of cerebral origin--does the position of the intrathecal catheter matter?

OBJECTIVE: To assess the correlation between the position of the intrathecal baclofen therapy catheter with the clinical outcome and response to the spasticity. METHODS AND RESULTS: A prospective cohort study was done by reviewing the paediatric group of patients with spasticity of cerebral origin who had insertion of a programmable baclofen pump for intrathecal administration in the last 10 years (August 1998 to September 2007). A total of 190 procedures were carried out in 166 patients, under a single paediatric neurosurgeon, with an age range of 18 months-16 years (mean 8.75 years) with follow up of 1-10 years (mean 5 years). The routine post-operative X-rays, which were done as per protocol, were reviewed, and the position of the intrathecal catheter tip was documented in relation to the vertebral bodies. The maintenance intrathecal baclofen dose was 25 microgms to 1,000 microgms (mean 255.8 microgms) based on the clinical response to spasticity. Statistical analysis was carried out to assess the correlation of the position of the tip of the intrathecal catheter with the outcome in spasticity based on GMFCS (Gross Motor Function Classification System) and Ashworth score. CONCLUSION: In our series, there was no statistically significant correlation between the position of the intrathecal catheter and the clinical response to the spasticity.