A vascular subtraction method for improving the variability of evoked tympanic membrane displacement measurements.

OBJECTIVE: Evoked tympanic membrane displacement (TMD) measurements show a correlation with intracranial pressure (ICP). Attempts to use these measurements for non-invasive monitoring of ICP in patients have been limited by high measurement variability. Pulsing of the tympanic membrane at the cardiac frequency has been shown to be a significant source of the variability. In this study we describe a post processing method to remove the cardiac pulse waveform and assess the impact of this on the measurement and its repeatability. APPROACH: Three-hundred and sixteen healthy volunteers were recruited for evoked TMD measurements. The measurements were quantified by V m, defined as the mean displacement between the point of maximum inward displacement and the end of the stimulus. A sample of spontaneously pulsing TMDs was measured immediately before the evoked measurements. Simultaneous recording of the ECG allowed a heartbeat template to be extracted from the spontaneous data and subtracted from the evoked data. Intra-subject repeatability of V m was assessed from 20 repeats of the evoked measurement. Results with and without subtraction of the heartbeat template were compared. The difference was tested for significance using the Wilcoxon sign rank test. MAIN RESULTS: In left and right ears, both sitting and supine, application of the pulse correction significantly reduced the intra-subject variability of V m (p value range 4.0 × 10-27 to 2.0 × 10-31). The average improvement was from 98 ± 6 nl to 56 ± 4 nl. SIGNIFICANCE: The pulse subtraction technique substantially improves the repeatability of evoked TMD measurements. This justifies further investigations to assess the use of TMD measurements in clinical applications where non-invasive tracking of changes in ICP would be useful.

How is vasospasm screening using transcranial Doppler associated with delayed cerebral ischemia and outcomes in aneurysmal subarachnoid hemorrhage?

BACKGROUND: Delayed cerebral ischemia (DCI) is an independent predictor of an unfavorable outcome after aneurysmal subarachnoid hemorrhage (aSAH). Many centers, but not all, use transcranial Doppler (TCD) to screen for vasospasm to help predict DCI. We used the United Kingdom and Ireland Subarachnoid Haemorrhage (UKISAH) Registry to see if outcomes were better in centers that used TCD to identify vasospasm compared to those that did not. METHODS: TCD screening practices were ascertained by national survey in 13 participating centers of the UKISAH. The routine use of TCD was reported by 5 "screening" centers, leaving 7 "non-screening" centers. Using a cross-sectional cohort study design, prospectively collected data from the UKISAH Registry was used to compare DCI diagnosis and favorable outcome (Glasgow Outcome Score 4 or 5) at discharge based on reported screening practice. RESULTS: A cohort of 2028 aSAH patients treated ≤ 3 days of hemorrhage was analyzed. DCI was diagnosed in 239/1065 (22.4%) and 220/963 (22.8%) of patients in non-screening and screening centers respectively while 847/1065 (79.5%) and 648/963 (67.2%) achieved a favorable outcome. Odds ratios adjusted for age, injury severity, comorbidities, need for cerebrospinal fluid diversion, and re-bleed returned neutral odds of diagnosing DCI of 0.90 (95% CI 0.72-1.12; p value = 0.347) in screening units compared to those of non-screening units but significantly decreased odds of achieving a favorable outcome 0.56 (95% CI 0.42-0.82; p value < 0.001). CONCLUSIONS: Centers that screened for vasospasm using TCD had poorer in-hospital outcomes and similar rates of DCI diagnosis compared to centers that did not.

Compliance of systematic reviews articles in brain arteriovenous malformation with PRISMA statement guidelines: Review of literature.

BACKGROUND: The knowledge of reporting compliance of systematic reviews with PRISMA guidelines may assist in improving the quality of secondary research in brain AVM management and subsequently application to patient population and clinical practice. This may allow researchers and clinicians to be equipped to appraise existing literatures based on known deficit to look for or expect. The objective of this study was to assess the compliance of systematic reviews and meta-analysis in the management of brain AVM. METHODS: Systematic reviews and meta-analyses articles published in medical journals between 1st of May 2011 and 30th April 2016 (five-year period) were examined. Exclusion criteria were articles that were not systematic reviews and not meta-analyses, narrative literature reviews, historical literature reviews, animal studies, unpublished articles, commentaries and letter to the editor. Electronic database search performed through Medline PubMed on 20th September 2016. RESULTS: This systematic review examined seven systematic review articles on intracranial arteriovenous malformation compliance with PRISMA statement guidelines. The mean percentage of applicable PRISMA items across all studies was 74% (range 67-93%). Protocol registration and declaration, risk of bias and funding sources were the most poorly reported of the PRISMA items (14% each). A significant variance in the total percentages was evident between studies (67-93%). CONCLUSION: Systematic review reporting in medical literature is excessively variable and overall poor. As these papers are being published with increasing frequency, need to fully adhere to PRISMA statement guide for systematic review to ensure high-quality publications. Complete reporting of PRISMA items within systematic reviews in cerebral arteriovenous malformation enhance quality assessment, robust critical appraisal, better judgement and ultimately sound application to practice thereby improving research standards and patients care.

The effect of direction of force to the craniofacial skeleton on the severity of brain injury in patients with a fronto-basal fracture.

The skull base is uniquely positioned to absorb force imparted to the craniofacial skeleton, thereby reducing brain injury. Less well understood is the effect of the direction of force imparted to the craniofacial skeleton on the severity of brain injury. Eighty-one patients from two UK major trauma centres who sustained a fronto-basal fracture were divided into two groups: those struck with predominantly anterior force and those by predominantly lateral force. The first recorded Glasgow Coma Score (GCS), requirement for intubation, and requirement for decompressive craniectomy were used as markers of the severity of brain injury. An average GCS of 5 was found in the lateral group and 14 in the anterior group; this difference was statistically significant (P<0.001). There was an increased need for both intubation and decompressive craniectomy in the lateral group compared to the anterior group (absolute risk difference 46.6% and 15.8%, respectively). These results suggest that the skeletal anatomy of the fronto-basal region influences the severity of head injury. The delicate lattice-like structure in the central anterior cranial fossa can act as a crumple zone, absorbing force. Conversely in the lateral aspect of the anterior cranial fossa, there is a lack of collapsible interface, resulting in an increased energy transfer to the brain.

Haemoglobin scavenging after subarachnoid haemorrhage.

Rapid and effective clearance of cell-free haemoglobin after subarachnoid haemorrhage (SAH) is important to prevent vasospasm and neurotoxicity and improve long-term outcome. Haemoglobin is avidly bound by haptoglobin, and the complex is cleared by CD163 expressed on the membrane surface of macrophages. We studied the kinetics of haemoglobin and haptoglobin in cerebrospinal fluid after SAH. We show that haemoglobin levels rise gradually after SAH. Haptoglobin levels rise acutely with aneurysmal rupture as a result of injection of blood into the subarachnoid space. Although levels decline as haemoglobin scavenging occurs, complete depletion of haptoglobin does not occur and levels start rising again, indicating saturation of CD163 sites available for haptoglobin-haemoglobin clearance. In a preliminary neuropathological study we demonstrate that meningeal CD163 expression is upregulated after SAH, in keeping with a proinflammatory state. However, loss of CD163 occurs in meningeal areas with overlying blood compared with areas without overlying blood. Becauses ADAM17 is the enzyme responsible for shedding membrane-bound CD163, its inhibition may be a potential therapeutic strategy after SAH.

Surgical management of acute subdural haematomas: current practice patterns in the United Kingdom and the Republic of Ireland.

INTRODUCTION: Uncertainty remains as to the role of decompressive craniectomy (DC) for primary evacuation of acute subdural haematomas (ASDH). In 2011, a collaborative group was formed in the UK with the aim of answering the following question: "What is the clinical- and cost-effectiveness of decompressive craniectomy, in comparison with craniotomy for adult patients undergoing primary evacuation of an ASDH?" The proposed RESCUE-ASDH trial (Randomised Evaluation of Surgery with Craniectomy for patients Undergoing Evacuation of Acute Subdural Haematoma) is a multicentre, pragmatic, parallel group randomised trial of DC versus craniotomy for adult head-injured patients with an ASDH. In this study, we used an online questionnaire to assess the current practice patterns in the management of ASDH in the UK and the Republic of Ireland, and to gauge neurosurgical opinion regarding the proposed RESCUE-ASDH trial. MATERIALS AND METHODS: A questionnaire survey of full members of the Society of British Neurological Surgeons and members of the British Neurosurgical Trainees Association was undertaken between the beginning of May and the end of July 2012. RESULTS: The online questionnaire was answered by 95 neurosurgeons representing 31 of the 32 neurosurgical units managing adult head-injured patients in the UK and the Republic of Ireland. Forty-five percent of the respondents use primary DC in at least 25% of patients with ASDH. In addition, of the 22 neurosurgical units with at least two Consultant respondents, only three units (14%) showed intradepartmental agreement regarding the proportion of their patients receiving a primary DC for ASDH. CONCLUSION: The survey results demonstrate that there is significant uncertainty as to the optimal surgical technique for primary evacuation of ASDH. The fact that the majority of the respondents are willing to become collaborators in the planned RESCUE-ASDH trial highlights the relevance of this important subject to the neurosurgical community in the UK and Ireland.

Intracranial cerebral revascularization.

Stroke is a heterogeneous disorder. A small number are due to hemodynamic insufficiency. In these cases, blood supply is sufficient at rest but unable to meet increased demand. This is demonstrated by loss of cerebrovascular reactivity (CVR) or increased oxygen extraction fraction (OEF). This may be improved by a superficial temporal artery to middle cerebral artery bypass. Whilst too small to completely replace cerebral blood supply, this is sufficient to augment existing blood flow to meet any increases in demand. Practically it has been difficult to demonstrate any reduction in stroke rate with intracranial revascularization. Only one of three randomized studies has shown a benefit. Two problems have been how hemodynamic insufficiency and symptomatic patients have been defined. Hemodynamic insufficiency can only be reliably demonstrated by changes in OEF and CVR. Symptomatic has traditionally described a patient who was had one or more strokes. However, in most cases these occur at the time of occlusion following which the patient remains stable. These patients are not necessarily at a high risk of future stroke as collaterals develop over time to compensate. We prefer to reserve the term symptomatic for those who have ongoing fluctuating symptoms after demonstration of carotid occlusion. This much smaller subset may still benefit from surgery in our view. Therefore although bypass surgery has relatively low morbidity, and high graft patency, extremely careful patient selection is essential for it to benefit patients, and unless there are both severe hemodynamic insufficiency and ongoing symptoms medical management is preferable.

Chordoma of the anterior skull base presenting as a swelling of the medial canthus of the eye.

Intracranial chordomas are locally infiltrative tumours that usually present with deficits of the cranial nerves. Because of their location in the skull base they are difficult to cure and pose complex problems in management. We report an unusual case of a chordoma that presented as a swelling of the medial canthus. Diagnosis of chordoma might not be considered in this site, which is unfortunate because its superficial location offers the possibility of complete excision and cure.

A prospective study of the time to evacuate acute subdural and extradural haematomas.

We performed a prospective, single-centre study of times to treatment of patients with life-threatening, traumatic, extra- and subdural haematomas requiring surgical evacuation between May 2006 and May 2007. The mean time to surgical decompression was 5.0 h and 32% were performed within 4 h. Patients who initially presented to a district hospital and required transfer for neurosurgery were decompressed in 5.4 h vs 3.7 h for those admitted directly. The current standard of surgical evacuation of all haematomas within 4 h is not being met. Delays were identified in every stage in the management of these patients and no single step was identified as the major cause. Initial treatment in district hospitals led to delays greater than the added driving time. There may be time savings from carrying out treatment steps in parallel instead of in series.

An alternative method of wound pain control following hepatic resection: a preliminary study.

BACKGROUND: Epidural analgesia is considered one of the optimal methods for provision of postoperative pain relief in patients recovering from major upper abdominal operations. Concerns regarding the potential risk of neurological complications prompted an evaluation of an alternative strategy using a continuous intermuscular bupivacaine (CIB) infusion combined with patient-controlled analgesia (PCA). METHODS: Two fine-bore catheters are inserted in the deep intermuscular intercostal neuronal plane during abdominal wound closure, and a continuous infusion of bupivacaine 0.25% is commenced for 72 h postoperatively. Simultaneously, patient-controlled analgesia provided intravenous morphine on demand. The study comprised 10 consecutive patients undergoing liver resection in whom CIB infusion and PCA were employed. The feasibility, safety and efficacy of the technique were investigated, analysing postoperative pain scores, morphine requirements, spirometry and oxygen saturation. RESULTS: There were no postoperative deaths. Postoperative morbidity included one urinary tract infection, one minor chest infection and acute confusional episodes in two patients. Median pain scores and morphine requirements at 12, 24, 48 and 72 h postoperatively were satisfactory. Spirometry and oxygen saturation values also remained within the normal range. DISCUSSION: Preliminary experience with CIB infusion/PCA in the aftermath of major liver resection has demonstrated its simplicity and safety as an alternative method of postoperative pain control. Further study is required to investigate the role of CIB infusion/PCA as a practical alternative to epidural analgesia or PCA alone.

Activation of Ih is necessary for patterning of mGluR and mAChR induced network activity in the hippocampal CA3 region.

Neuronal networks of the hippocampal CA3 region generate stereotyped patterns of electrical activity in response to activation of metabotropic glutamate receptors (mGluRs) or muscarinic acetylcholine receptors (mAChRs) that consist of intermittent episodes of prolonged oscillatory activity. In light of the slow kinetics of such network responses, we investigated the possible contribution of the hyperpolarisation-activated inward current (I(h)) in the generation and maintenance of hippocampal oscillatory states. Hippocampal 'mini-slice' experiments in which the main subfields of the hippocampus were isolated by transection of the connecting afferents revealed that the CA3 region was the primary generator of both mGluR and mAChR-mediated network responses. Subsequent patch-clamp experiments confirmed the presence of a prominent hyperpolarisation-activated inward current in the principal cells of the CA3 region that was sensitive to caesium chloride and the selective I(h) blocker ZD-7288.Furthermore, in the presence of mAChR or mGluR agonists these cells exhibited a slow membrane potential oscillation that was independent of AMPA receptor-mediated synaptic transmission. Blockade of I(h) suppressed this oscillation as well as mGluR and mAChR-induced theta based intermittent network oscillatory behaviour. These data support the idea that the I(h) pacemaker current is important in the generation of patterned neuronal activities in the hippocampus.

Opioid receptor regulation of muscarinic acetylcholine receptor-mediated synaptic responses in the hippocampus.

A common feature of many synapses is their regulation by neurotransmitters other than those released from the presynaptic terminal. This aspect of synaptic transmission is often mediated by activation of G protein coupled receptors (GPCRs) and has been most extensively studied at amino acid-mediated synapses where ligand gated receptors mediate the postsynaptic signal. Here we have investigated how opioid receptors modulate synaptic transmission mediated by muscarinic acetylcholine receptors (mAChRs) in hippocampal CA1 pyramidal neurones. Using a cocktail of glutamate and gamma-amino-butyric acid (GABA) receptor antagonists a slow pirenzepine-sensitive excitatory postsynaptic potential (EPSP(M)) that was associated with a small increase in cell input resistance could be evoked in isolation. This response was enhanced by the acetylcholine (ACh) esterase inhibitor physostigmine (1 microM) and depressed by the vesicular ACh transport inhibitor vesamicol (50 microM). The mu-opioid receptor agonists DAMGO (1-5 microM) and etonitazene (100 nM), but not the delta- and kappa-opioid receptor selective agonists DTLET (1 microM) and U-50488 (1 microM), potentiated this EPSP(M) (up to 327%) without affecting cell membrane potential or input resistance; an effect that was totally reversed by naloxone (5 microM). In contrast, postsynaptic depolarizations and increases in cell input resistance evoked by carbachol (3 microM) were unaffected by DAMGO (1-5 microM) but were abolished by atropine (1 microM). Taken together these data provide good evidence for a mu-opioid receptor-mediated presynaptic enhancement of mAChR-mediated EPSPs in hippocampal CA1 pyramidal neurones.

Regulation of muscarinic acetylcholine receptor-mediated synaptic responses by GABA(B) receptors in the rat hippocampus.

1. Both GABA(B) and muscarinic acetylcholine receptors (mAChRs) influence hippocampal-dependent mnemonic processing. Here the possibility of a direct interaction between GABA(B) receptors and mAChR-mediated synaptic responses has been studied using intracellular recording in rat hippocampal slices. 2. The GABA(B) receptor agonist (-)-baclofen (5-10 microM) depressed an atropine-sensitive slow EPSP (EPSP(M)) and occluded the GABA(B)-receptor-mediated IPSP (IPSP(B)) which preceded it. These inhibitory effects were accompanied by postsynaptic hyperpolarization (9 +/- 2 mV) and a reduction in cell input resistance (12 +/- 3 %). 3. The selective GABA(B) receptor antagonist CGP 55845A (1 microM) fully reversed the depressant effects of (-)-baclofen (5-10 microM) such that in the combined presence of (-)-baclofen and CGP 55845A the EPSP(M) was 134 +/- 21 % of control. 4. (-)-Baclofen (5-10 microM) caused a small (28 +/- 11 %) inhibition of carbachol-induced (3.0 microM) postsynaptic depolarizations and increases in input resistance. 5. CGP 55845A (1 microM) alone caused an increase in the amplitude of the EPSP(M) (253 +/- 74 % of control) and blocked the IPSP(B) that preceded it. 6. In contrast, the selective GABA uptake inhibitor NNC 05-0711 (10 microM) increased the amplitude of the IPSP(B) by 141 +/- 38 % and depressed the amplitude of the EPSP(M) by 58 +/- 10 %. This inhibition was abolished by CGP 55845A (1 microM). 7. Taken together these data provide good evidence that synaptically released GABA activates GABA(B) receptors that inhibit mAChR-mediated EPSPs in hippocampal CA1 pyramidal neurones. The mechanism of inhibition may involve both pre- and postsynaptic elements.

Coincident activation of mGluRs and mAChRs imposes theta frequency patterning on synchronised network activity in the hippocampal CA3 region.

Activation of metabotropic glutamate receptors (mGluRs) with the broad spectrum mGluR agonist 1S,3R ACPD (10-50 microM) induced spontaneous field potentials at low frequencies ('burst-mode' activity; <1 Hz) in the CA3 region of rat hippocampal slices. At higher concentrations (100-400 microM) ACPD switched this form of activity to a second, more complex pattern of activity in which intermittent episodes of theta frequency oscillations predominated ('theta-mode' activity; 4-14 Hz). Both patterns of activity were evoked by selective activation of group I mGluRs and, in particular, could be induced by activation of mGluR5 alone using the subtype selective agonist CHPG (0.5-5 mM). In contrast, activation of group II mGluRs (DCG IV; 100 microM) produced only burst-mode behaviour whilst activation of group III mGluRs (L-AP4; 100 microM) did not result in synchronised network activity. Concurrent extra- and intracellular recordings demonstrated that this mGluR-induced theta-mode activity represented the synchronous firing of CA3 pyramidal cells and that it shared a similar temporal signature to that generated by activation of muscarinic acetylcholine receptors (mAChRs). Furthermore, application of mGluR and mAChR agonists at concentrations sufficient to produce only burst-mode activity when applied individually, produced theta-mode activity when co-applied. These data suggest that the level of activation of different mGluRs and mAChRs crucially determine the pattern of rhythmical network activity generated in the hippocampal CA3 network. These results also indicate that individual receptor subtypes (i.e. mGluR5) can initiate patterns of coherent network activity but that interactions between the cholinergic and glutamatergic transmitter systems may also be important factors in governing the temporal patterning of hippocampal network activity.

Activation of nicotinic acetylcholine receptors patterns network activity in the rodent hippocampus.

1. Intracellular and extracellular recordings from area CA3 of rat and mouse hippocampal slices revealed two distinct modes of synchronous network activity in response to continuous application of muscarinic acetylcholine receptor (mAChR) agonists. At low concentrations (e.g. 0.1-1 microM oxotremorine-M), 'burst-mode' activity comprised regular individual AMPA receptor-mediated depolarizing events, each generating several action potentials. At higher concentrations (5-50 microM), 'theta-mode' prevailed in which ordered clusters of depolarizing theta-frequency oscillations occurred. 2. Whilst theta-mode activity was abolished by the mAChR antagonist atropine (5 microM), the nicotinic acetylcholine receptor (nAChR) antagonists tubocurarine (100 microM), mecamylamine (100-500 microM) and dihydro-beta-erythroidine (250 microM) converted this mode of activity to burst-mode. 3. Likewise, disruption of synaptically available ACh using inhibitors of choline uptake (hemicholinium-3; 20-50 microM) or vesicular ACh transport (vesamicol; 50 microM) converted theta-mode into burst-mode activity. 4. Hippocampal slices prepared 2-3 weeks after transection of the primary cholinergic efferent pathway from the medial septum exhibited reduced vesicular ACh transporter immunoreactivity but still supported nAChR-dependent theta-mode activity suggesting that ACh released from this pathway was not critical for the activation of these receptors. 5. In summary, ACh-mediated activation of nAChRs tailors the pattern of network activity into theta-frequency depolarizing episodes as opposed to synchronized individual events at much lower frequencies.