Profiling biomarkers of traumatic axonal injury: from mouse to man

Traumatic brain injury (TBI) poses a major public health problem on a global scale. Its burden results from high mortality and significant morbidity in survivors. This stems, in part, from an ongoing inadequacy in diagnostic and prognostic indicators despite significant technological advances. Traumatic axonal injury (TAI) is a key driver of the ongoing pathological process following TBI, causing chronic neurological deficits and disability. The science underpinning biomarkers of TAI has been a subject of many reviews in recent literature. However, in this review we provide a comprehensive account of biomarkers from animal models to clinical studies, bridging the gap between experimental science and clinical medicine. We have discussed pathogenesis, temporal kinetics, relationships to neuro-imaging, and, most importantly, clinical applicability in order to provide a holistic perspective of how this could improve TBI diagnosis and predict clinical outcome in a real-life setting. We conclude that early and reliable identification of axonal injury post-TBI with the help of body fluid biomarkers could enhance current care of TBI patients by (i) increasing speed and accuracy of diagnosis, (ii) providing invaluable prognostic information, (iii) allow efficient allocation of rehabilitation services, and (iv) provide potential therapeutic targets. The optimal model for assessing TAI is likely to involve multiple components, including several blood biomarkers and neuro-imaging modalities, at different time points

The efficacy of cysto-peritoneal shunting for the surgical management of intracranial arachnoid cysts in the elderly: a systematic review of the literature

Background: Intracranial arachnoid cysts (AC) are benign, cerebrospinal fluid filled spaces within the arachnoid layer of the meninges. Neurosurgical intervention in children and young adults has been extensively studied, but the optimal strategy in the elderly remains unclear. Therefore, we performed a single center retrospective study combined with a systematic review of the literature to compare cystoperitoneal (CP) shunting with other surgical approaches in the elderly cohort. Methods: Retrospective neurosurgical database search between January 2005 and December 2018, and systematic review of the literature using PRISMA guidelines were performed. Inclusion criteria: Age 60 years or older, radiological diagnosis of intracranial AC, neurosurgical intervention, and neuroradiological (NOG score)/clinical outcome (COG score). Data from both sources were pooled and statistically analyzed. Results: Our literature search yielded 12 studies (34 patients), which were pooled with our institutional data (13 patients). CP shunts (7 patients; 15%), cyst fenestration (28 patients; 60%) and cyst marsupialisation/resection (10 patients; 21%) were the commonest approaches. Average duration of follow-up was 23.6, 26.9, and 9.5 months for each approach, respectively. There was no statistically significant association between choice of surgical intervention and NOG score (P = 0.417), COG score (P = 0.601), or complication rate (P = 0.955). However, CP shunting had the lowest complication rate, with only one patient developing chronic subdural haematoma. Conclusion: CP shunting is a safe and effective surgical treatment strategy for ACs in the elderly. It has similar clinical and radiological outcomes but superior risk profile when compared with other approaches. We advocate CP shunting as first line neurosurgical intervention for the management of intracranial ACs in the elderly

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 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 dose

ERK activation causes epilepsy by stimulating NMDA receptor activity

The ERK MAPK signalling pathway is a highly conserved kinase cascade linking transmembrane receptors to downstream effector mechanisms. To investigate the function of ERK in neurons, a constitutively active form of MEK1 (caMEK1) was conditionally expressed in the murine brain, which resulted in ERK activation and caused spontaneous epileptic seizures. ERK activation stimulated phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) and augmented NMDA receptor 2B (NR2B) protein levels. Pharmacological inhibition of NR2B function impaired synaptic facilitation in area cornus ammonicus region 3 (CA3) in acute hippocampal slices derived from caMEK1-expressing mice and abrogated epilepsy in vivo. In addition, expression of caMEK1 caused phosphorylation of the transcription factor, cAMP response element-binding protein (CREB) and increased transcription of ephrinB2. EphrinB2 overexpression resulted in increased NR2B tyrosine phosphorylation, which was essential for caMEK1-induced epilepsy in vivo, since conditional inactivation of ephrinB2 greatly reduced seizure frequency in caMEK1 transgenic mice. Therefore, our study identifies a mechanism of epileptogenesis that links MAP kinase to Eph/Ephrin and NMDA receptor signalling