Towards improved outcome in children treated surgically for spontaneous intracranial suppuration in South Wales.

INTRODUCTION: Spontaneous central nervous system (CNS) infections in children are rare. Treatment involves surgical intervention and antibiotic therapy. We describe a single centre experience of managing this condition in South Wales. METHODS: We performed a retrospective review of surgically managed cases in our unit for patients under 18 years of age between 2008 and 2018. Data were collected regarding aetiology, location, microbiology examination, treatment and outcomes. RESULTS: Twenty-six patients were identified of which 25 case notes were available. Fifteen were male and 10 were female. Median age was 12 years (age range 0.3-17 years). Seven patients (28%) had a burr-hole aspiration and 18 (72%) underwent craniotomy. A second procedure was performed in 10 (40%) and a third procedure in two (8%). Fourteen (56%) had a brain abscess, 10 (40%) had subdural empyema (one was bilateral) and one (4%) had an extradural empyema. Fifteen (60%) had a raised WCC (>11.5 × 109/L) and 22 (88%) had a CRP of >10 mg/L at presentation. Three (12%) patients had a normal WCC and CRP at presentation. Overall, 12 (48%) were secondary to sinus infection, with the most common organism being Streptococcus. Seven (28%) were due to otitis media or mastoiditis, six (24%) had no cause identified. The mean number of CT/MRI scans was 6.7 (range 3-13). The mean follow-up period was 16.7 months (range 1-117 months). At last follow up, 19 (76%) had a GOS of 5, five (20%) had a GOS of 4 and one (12%) had GOS of 3. There were no deaths. CONCLUSIONS: In Wales, outcomes have improved over time in keeping with other paediatric neurosurgical units in England. Increased availability of imaging resources in our hospital and use of neuro-navigation for all cases in our unit as well as earlier identification of sepsis, communication with microbiologists with dedicated ward rounds and, enhanced identification of causative organisms and contemporary anti-microbials have also contributed towards the improved management of this condition.

Pre-operative dosing of dexamethasone for the management of children with posterior fossa tumours: are we getting it right?

INTRODUCTION: Posterior fossa (PF) tumours are associated with vasogenic oedema causing symptoms of raised intracranial pressure. Preoperatively this is managed with dexamethasone. To minimise steroid related complications, the lowest effective dose should be administered. No neurosurgical guidelines exist for pre-operative dosing of dexamethasone in PF tumours. METHODS: A retrospective review was performed of surgically managed cases for patients under 16 years of age between 2013 and 2018 to ascertain the initial dose of dexamethasone with symptomatic PF tumours. RESULTS: Thirty-six patients were identified of which 30 notes were available. Sixteen were male. Median age was 6 years (range 10 months - 15 years). Twenty-two (73%) were referrals from DGH and 8 (27%) presented to our neurosurgical centre. All patients presented with symptomatic PF tumours including headache (97%), vomiting (93%), gait disturbance (43%), and nystagmus (17%). Four (13%) had papilloedema. Average initial stat dexamethasone dose was 9.15 mg; 0.31 mg/kg (range 1-16.7 mg; 0.05 - 1.77 mg/kg). Stratified according to weight, average dose (and range) was 8.8 mg; 0.94 mg/kg (1-16.6 mg; 0.13 - 1.77 mg/kg) in those weighing <10 kg; 9.7 mg; 0.66 mg/kg (4-16.7 mg; 0.21 - 1.35 mg/kg) in 10-20 kg; 12.3 mg;0.52 mg/kg (8-16.7 mg; 0.27 - 0.73mg/kg) in 20-30 kg and 7.8 mg; 0.17mg/kg (2-16.7 mg; 0.0 - 0.39 mg/kg) in >30 kg up to a maximum of 16.6 mg in any 24h period. These results suggest that dosage was higher in those children weighing less. PPI was used in 24 (80%) of cases. All doses were reduced after review by the neurosurgical team and a PPI added. CONCLUSION: Pre-operative dexamethasone dosing does not always reflect the severity of clinical symptoms for PF tumours. Guidelines are required to correlate clinical symptoms with a suggested suitable dose of dexamethasone to prevent overdose and complications associated with corticosteroid use. We recommend a weight-based regimen as provided by the Food and Drug Administration. The current advice is for 0.02-0.3mg/kg/day in 3-4 divided doses.

Toll-like receptor linked cytokine profiles in cerebrospinal fluid discriminate neurological infection from sterile inflammation.

Rapid determination of an infective aetiology causing neurological inflammation in the cerebrospinal fluid can be challenging in clinical practice. Post-surgical nosocomial infection is difficult to diagnose accurately, as it occurs on a background of altered cerebrospinal fluid composition due to the underlying pathologies and surgical procedures involved. There is additional diagnostic difficulty after external ventricular drain or ventriculoperitoneal shunt surgery, as infection is often caused by pathogens growing as biofilms, which may fail to elicit a significant inflammatory response and are challenging to identify by microbiological culture. Despite much research effort, a single sensitive and specific cerebrospinal fluid biomarker has yet to be defined which reliably distinguishes infective from non-infective inflammation. As a result, many patients with suspected infection are treated empirically with broad-spectrum antibiotics in the absence of definitive diagnostic criteria. To begin to address these issues, we examined cerebrospinal fluid taken at the point of clinical equipoise to diagnose cerebrospinal fluid infection in 14 consecutive neurosurgical patients showing signs of inflammatory complications. Using the guidelines of the Infectious Diseases Society of America, six cases were subsequently characterized as infected and eight as sterile inflammation. Twenty-four contemporaneous patients with idiopathic intracranial hypertension or normal pressure hydrocephalus were included as non-inflamed controls. We measured 182 immune and neurological biomarkers in each sample and used pathway analysis to elucidate the biological underpinnings of any biomarker changes. Increased levels of the inflammatory cytokine interleukin-6 and interleukin-6-related mediators such as oncostatin M were excellent indicators of inflammation. However, interleukin-6 levels alone could not distinguish between bacterially infected and uninfected patients. Within the patient cohort with neurological inflammation, a pattern of raised interleukin-17, interleukin-12p40/p70 and interleukin-23 levels delineated nosocomial bacteriological infection from background neuroinflammation. Pathway analysis showed that the observed immune signatures could be explained through a common generic inflammatory response marked by interleukin-6 in both nosocomial and non-infectious inflammation, overlaid with a toll-like receptor-associated and bacterial peptidoglycan-triggered interleukin-17 pathway response that occurred exclusively during infection. This is the first demonstration of a pathway dependent cerebrospinal fluid biomarker differentiation distinguishing nosocomial infection from background neuroinflammation. It is especially relevant to the commonly encountered pathologies in clinical practice, such as subarachnoid haemorrhage and post-cranial neurosurgery. While requiring confirmation in a larger cohort, the current data indicate the potential utility of cerebrospinal fluid biomarker strategies to identify differential initiation of a common downstream interleukin-6 pathway to diagnose nosocomial infection in this challenging clinical cohort.

Survival in melanoma brain metastases in the era of novel systemic therapies.

BACKGROUND: Melanoma brain metastases (MBMs) have historically poor overall survival (OS). Recently introduced systemic anticancer therapies (SACTs), namely targeted therapies such as BRAF inhibitors and immunotherapy, to control advanced disease have shown improved survival. Today, increasingly aggressive strategies are sought for MBM. We review outcomes in MBM after surgery or stereotactic radiosurgery (SRS) and the survival impact in advanced systemic disease when combined with novel anticancer therapies. METHODS: A retrospective cohort study of patients referred to a regional neuro-oncology multidisciplinary team (MDT) meeting with MBM. Demographic data, extent of systemic disease, and data on surgical and oncological management were collected, plus the use of SACT. The primary outcomes were median OS, 12- and 24-month survival, and progression-free survival. RESULTS: Between 2010 and 2018, 142 patients with MBM were referred. Following the introduction of SACT, the rate of referrals to MDT more than doubled from 11.6 to 25.7 patients per year. Focal brain metastasis was treated surgically in 23 (16.2%) patients and by SRS in 29 (20.4%). Fifty-six (39.4%) patients underwent palliative whole-brain radiotherapy and 34 (23.9%) did not receive treatment. Median OS was 11 months for the surgical cohort, 9 months for the SRS cohort, and increased when treatment with or without SACT was considered to 23 and 12 months, respectively. CONCLUSION: In the setting of SACTs, survival in MBM is significantly improved after surgery or SRS even in patients with advanced and uncontrolled systemic disease at the time of presentation, supporting an aggressive approach to MBM management.