Christos M. Tolias

Cortical spreading ischaemia is a novel process involved in ischaemic damage in patients with aneurysmal subarachnoid haemorrhage

The term cortical spreading depolarization (CSD) describes a wave of mass neuronal depolarization associated with net influx of cations and water. Clusters of prolonged CSDs were measured time-locked to progressive ischaemic damage in human cortex. CSD induces tone alterations in resistance vessels, causing either transient hyperperfusion (physiological haemodynamic response) in healthy tissue; or hypoperfusion [inverse haemodynamic response = cortical spreading ischaemia (CSI)] in tissue at risk for progressive damage, which has so far only been shown experimentally. Here, we performed a prospective, multicentre study in 13 patients with aneurysmal subarachnoid haemorrhage, using novel subdural opto-electrode technology for simultaneous laser-Doppler flowmetry (LDF) and direct current-electrocorticography, combined with measurements of tissue partial pressure of oxygen (ptiO2). Regional cerebral blood flow and electrocorticography were simultaneously recorded in 417 CSDs. Isolated CSDs occurred in 12 patients and were associated with either physiological, absent or inverse haemodynamic responses. Whereas the physiological haemodynamic response caused tissue hyperoxia, the inverse response led to tissue hypoxia. Clusters of prolonged CSDs were measured in five patients in close proximity to structural brain damage as assessed by neuroimaging. Clusters were associated with CSD-induced spreading hypoperfusions, which were significantly longer in duration (up to 144 min) than those of isolated CSDs. Thus, oxygen depletion caused by the inverse haemodynamic response may contribute to the establishment of clusters of prolonged CSDs and lesion progression. Combined electrocorticography and perfusion monitoring also revealed a characteristic vascular signature that might be used for non-invasive detection of CSD. Low-frequency vascular fluctuations (LF-VF) (f < 0.1 Hz), detectable by functional imaging methods, are determined by the brains resting neuronal activity. CSD provides a depolarization block of the resting activity, recorded electrophysiologically as spreading depression of high-frequency-electrocorticography activity. Accordingly, we observed a spreading suppression of LF-VF, which accompanied spreading depression of high-frequency-electrocorticography activity, independently of whether CSD was associated with a physiological, absent or inverse haemodynamic response. Spreading suppressions of LF-VF thus allow the differentiation of progressive ischaemia and repair phases in a fashion similar to that shown previously for spreading depressions of high-frequency-electrocorticography activity. In conclusion, it is suggested that (i) CSI is a novel human disease mechanism associated with lesion development and a potential target for therapeutic intervention in stroke; and that (ii) prolonged spreading suppressions of LF-VF are a novel ‘functional marker’ for progressive ischaemia.

Mural destabilization after aneurysm treatment with a flow-diverting device: a report of two cases

Background Flow-diverting stents have demonstrated great promise for the treatment of cerebral aneurysms; however, clinical experience with the devices remains very preliminary. We present two cases of spontaneous delayed complications—one fatal aneurysm rupture and one symptomatic increase in aneurysm volume—following the treatment of intradural aneurysms with the Pipeline Embolization Device (PED). Presentation/intervention Two patients with unruptured, intradural aneurysms of the carotid artery underwent uneventful treatment with the PED (eV3, Irvine, California, USA). One patient, with a giant aneurysm of the carotid terminus, experienced worsening headache 5 days after the procedure and ultimately collapsed and became unresponsive. CT of the head demonstrated acute subarachnoid and intraventricular hemorrhage. The patient died the following day. A second patient with a large left posterior communicating artery aneurysm presented with progressive memory loss 3 months after PED reconstruction of the carotid artery. Although serial CT angiograms showed progressive thrombosis of the aneurysm to near-complete occlusion, MR of the brain demonstrated marked interval growth of the collective aneurysm–intra-aneurysmal thrombus mass with extensive edema throughout the adjacent left temporal lobe. Conclusions Flow-diverting devices have demonstrated tremendous promise for the treatment of complex, unruptured cerebral aneurysms. However, experience with this novel approach to aneurysm treatment is preliminary and the consequences of its application within the cerebrovasculature remain incompletely defined. Mural destabilization resulting in delayed, spontaneous, aneurysm growth and/or rupture may occur in the days to weeks following the application of flow-diverting devices to treat previously unruptured intracranial aneurysms. A better understanding of the incidence and etiology of these complications is essential for this technology to be optimally applied.

Normobaric hyperoxia therapy for traumatic brain injury and stroke: a review.

Traumatic brain injury (TBI) and acute ischaemic stroke are major causes of mortality and morbidity and there is an urgent demand for new neuroprotective strategies following the translational failure of neuroprotective drug trials. Oxygen therapy—especially normobaric, may offer a simple and effective therapeutic strategy which we review in this paper. Firstly we review mechanisms underlying the therapeutic effects of hyperoxia (both normobaric and hyperbaric) including mitochondrial rescue, stabilisation of intracranial pressure, attenuation of cortical spreading depression and inducing favourable endothelial-leukocyte interactions, all effects of which are postulated to decrease secondary injury. Next we survey studies using hyperbaric oxygen therapy for TBI and stroke, which formed the basis for early studies on normobaric hyperoxia. Thirdly, we present clinical studies of the efficacy of normobaric hyperoxia on TBI and stroke, emphasising their safety, efficacy and practicality. Finally we consider safety concerns and side effects, particularly pulmonary pathology, respiratory failure and theoretical risks in paediatric patients. A neuroprotective role of normobaric hyperoxia is extremely promising and further studies are warranted.

In vitro models of neurotrauma

Traumatic brain injury (TBI) continues to be an important cause of mortality and morbidity, but its pathophysiology is no longer considered an instantaneous irreversible event occurring at the time of injury. Therein, neuroprotection is the attempt to salvage sublethally injured neurons which subsequently die in post-primary sequelae. Key to the discovery of neuroprotective strategies is the development of reliable models of brain injury—both in vivo and in vitro. While numerous studies on in vivo animal models have yielded encouraging results, these have largely failed to translate effectively in humans. One approach out of this impasse may be to re-explore in vitro models to dissect out specific pathophysiological mechanisms and only then test clearer hypotheses on in vivo models, which are more likely to subsequently translate into neuroprotective therapies of the future. Moreover, milder forms of TBI are a more realistic target for therapeutic intervention as more is understood about the vulnerability of surviving neurons and the capacity to salvage them. Several types of injury models are described including transection, compression, barotrauma, acceleration, hydrodynamic and cell stretch models with their advantages and disadvantages discussed in turn, as well as a survey of the cell cultures used, namely immortalized cell lines, primary cultures and organotypic (explant) cultures. We emphasize advances in three-dimensional strain simulation and a recent interest in modelling milder injuries, and argue that in vitro models may be a useful complement to in vivo models in studying TBI.

ATP signalling in epilepsy

This paper focuses on a role for ATP neurotransmission and gliotransmission in the pathophysiology of epileptic seizures. ATP along with gap junctions propagates the glial calcium wave, which is an extraneuronal signalling pathway in the central nervous system. Recently astrocyte intercellular calcium waves have been shown to underlie seizures, and conventional antiepileptic drugs have been shown to attenuate these calcium waves. Blocking ATP-mediated gliotransmission, therefore, represents a potential target for antiepileptic drugs. Furthermore, while knowledge of an antiepileptic role for adenosine is not new, a recent study showed that adenosine accumulates from the hydrolysis of accumulated ATP released by astrocytes and is believed to inhibit distant synapses by acting on adenosine receptors. Such a mechanism is consistent with a surround-inhibitory mechanism whose failure would predispose to seizures. Other potential roles for ATP signalling in the initiation and spread of epileptiform discharges may involve synaptic plasticity and coordination of synaptic networks. We conclude by making speculations about future developments.

Surgical management of traumatic brain injury: a comparative-effectiveness study of 2 centers

OBJECT Mass lesions from traumatic brain injury (TBI) often require surgical evacuation as a life-saving measure and to improve outcomes, but optimal timing and surgical technique, including decompressive craniectomy, have not been fully defined. The authors compared neurosurgical approaches in the treatment of TBI at 2 academic medical centers to document variations in real-world practice and evaluate the efficacies of different approaches on postsurgical course and long-term outcome. METHODS Patients 18 years of age or older who required neurosurgical lesion evacuation or decompression for TBI were enrolled in the Co-Operative Studies on Brain Injury Depolarizations (COSBID) at Kings College Hospital (KCH, n = 27) and Virginia Commonwealth University (VCU, n = 24) from July 2004 to March 2010. Subdural electrode strips were placed at the time of surgery for subsequent electrocorticographic monitoring of spreading depolarizations; injury characteristics, physiological monitoring data, and 6-month outcomes were collected prospectively. CT scans and medical records were reviewed retrospectively to determine lesion characteristics, surgical indications, and procedures performed. RESULTS Patients enrolled at KCH were significantly older than those enrolled at VCU (48 vs 34 years, p < 0.01) and falls were more commonly the cause of TBI in the KCH group than in the VCU group. Otherwise, KCH and VCU patients had similar prognoses, lesion types (subdural hematomas: 30%-35%; parenchymal contusions: 48%-52%), signs of mass effect (midline shift ≥ 5 mm: 43%-52%), and preoperative intracranial pressure (ICP). At VCU, however, surgeries were performed earlier (median 0.51 vs 0.83 days posttrauma, p < 0.05), bone flaps were larger (mean 82 vs 53 cm(2), p < 0.001), and craniectomies were more common (performed in 75% vs 44% of cases, p < 0.05). Postoperatively, maximum ICP values were lower at VCU (mean 22.5 vs 31.4 mm Hg, p < 0.01). Differences in incidence of spreading depolarizations (KCH: 63%, VCU: 42%, p = 0.13) and poor outcomes (KCH: 54%, VCU: 33%, p = 0.14) were not significant. In a subgroup analysis of only those patients who underwent early (< 24 hours) lesion evacuation (KCH: n = 14; VCU: n = 16), however, VCU patients fared significantly better. In the VCU patients, bone flaps were larger (mean 85 vs 48 cm(2) at KCH, p < 0.001), spreading depolarizations were less common (31% vs 86% at KCH, p < 0.01), postoperative ICP values were lower (mean: 20.8 vs 30.2 mm Hg at KCH, p < 0.05), and good outcomes were more common (69% vs 29% at KCH, p < 0.05). Spreading depolarizations were the only significant predictor of outcome in multivariate analysis. CONCLUSIONS This comparative-effectiveness study provides evidence for major practice variation in surgical management of severe TBI. Although ages differed between the 2 cohorts, the results suggest that a more aggressive approach, including earlier surgery, larger craniotomy, and removal of bone flap, may reduce ICP, prevent cortical spreading depolarizations, and improve outcomes. In particular, patients requiring evacuation of subdural hematomas and contusions may benefit from decompressive craniectomy in conjunction with lesion evacuation, even when elevated ICP is not a factor in the decision to perform surgery.

Detection of Spreading Depolarization with Intraparenchymal Electrodes in the Injured Human Brain

BackgroundSpreading depolarization events following ischemic and traumatic brain injury are associated with poor patient outcome. Currently, monitoring these events is limited to patients in whom subdural electrodes can be placed at open craniotomy. This study examined whether these events can be detected using intra-cortical electrodes, opening the way for electrode insertion via burr hole.MethodsAnimal work was carried out on adult Sprague–Dawley rats in a laboratory setting to investigate the feasibility of recording depolarization events. Subsequently, 8 human patients requiring craniotomy for traumatic brain injury or aneurysmal subarachnoid hemorrhage were monitored for depolarization events in an intensive care setting with concurrent strip (subdural) and depth (intra-parenchymal) electrode recordings.Results(1) Depolarization events can be reliably detected from intra-cortically placed electrodes. (2) A reproducible slow potential change (SPC) waveform morphology was identified from intra-cortical electrodes on the depth array. (3) The depression of cortical activity known to follow depolarization events was identified consistently from both intra-cortical and sub-cortical electrodes on the depth array.ConclusionsIntra-parenchymally sited electrodes can be used to consistently identify depolarization events in humans. This technique greatly extends the capability of monitoring for spreading depolarization events in injured patients, as electrodes can be sited without the need for craniotomy. The method provides a new investigative tool for the evaluation of the contribution of these events to secondary brain injury in human patients.

Is there a role for vagus nerve stimulation therapy as a treatment of traumatic brain injury

Abstract This paper aims to review the current literature on vagus nerve stimulation (VNS) use in animal models of traumatic brain injury (TBI) and explore its potential role in treatment of human TBI. A MEDLINE search yielded four primary papers from the same group that demonstrated VNS mediated improvement following fluid percussion models of TBI in rats, seen as motor and cognitive improvements, reduction of cortical oedema and neuroprotective effects. The underlying mechanisms are elusive and authors attribute these to attenuation of post traumatic seizures, a noradrenergic mechanism and as yet undetermined mechanisms. Reviewing and elaborating on these ideas, we speculate other potential mechanisms including attenuation of peri-infarct depolarisations, attenuation of glutamate mediated excitotoxicity, stabilisation of intracranial pressure, enhancement of synaptic plasticity, upregulation of endogenous neurogenesis and anti-inflammatory effects may have a role. Although this data unequivocally shows that VNS improves outcome from TBI in animal models, it remains to be determined if these findings translate clinically. Further studies are warranted.

Proposal for establishment of the UK Cranial Reconstruction Registry (UKCRR).

Abstract Background. The increasing utilisation of decompressive craniectomy for traumatic brain injury and stroke has led to an increase in the number of cranioplasties undertaken. Cranioplasty is also undertaken following excision of tumours originating from or invading the skull vault, removal of bone flaps due to post-operative infection, and decompressive craniectomy for the management of rarer causes of brain oedema and/or refractory intracranial hypertension. The existing literature which mainly consists of single-centre, retrospective studies, shows a significant variation in practice patterns and a wide range of morbidity. There also exists a need to measure the outcome as perceived by the patients themselves with patient reported outcome measures (PROMs; functional outcome, quality of life, satisfaction with cosmesis). In the UK, the concept of long-term surveillance of neurosurgical implants is well established with the UK shunt registry. Based on this background, we propose to establish the UK Cranial Reconstruction Registry (UKCRR). Aim. The overarching aim of the UKCRR is to collect high-quality data about cranioplasties undertaken across the UK and Ireland in order to improve outcomes for patients. Methods. Any patient undergoing reconstruction of the skull vault with autologous bone, titanium, or synthetic material in participating units will be eligible for inclusion. Data will be submitted directly by participating units to the Outcome Registry Intervention and Operation Network secure platform. A Steering Committee will be responsible for overseeing the strategic direction and running of the UKCRR. Outcome measures. These will include re-operation due to a cranioplasty-related issue, surgical site infection, re-admission due to a cranioplasty-related issue, unplanned post-operative escalation of care, adverse events, length of stay in admitting unit, destination at discharge from admitting unit, mortality at discharge from admitting unit, neurological status and PROMs during routine follow-up. Conclusion. The UKCRR will be an important pillar in the ongoing efforts to optimise the outcomes of patients undergoing cranioplasty.

Simultaneous monitoring of potassium, glucose and lactate during spreading depolarization in the injured human brain – Proof of principle of a novel real-time neurochemical analysis system, continuous online microdialysis:

Spreading depolarizations occur spontaneously and frequently in injured human brain. They propagate slowly through injured tissue often cycling around a local area of damage. Tissue recovery after an spreading depolarization requires greatly augmented energy utilisation to normalise ionic gradients from a virtually complete loss of membrane potential. In the injured brain, this is difficult because local blood flow is often low and unreactive. In this study, we use a new variant of microdialysis, continuous on-line microdialysis, to observe the effects of spreading depolarizations on brain metabolism. The neurochemical changes are dynamic and take place on the timescale of the passage of an spreading depolarization past the microdialysis probe. Dialysate potassium levels provide an ionic correlate of cellular depolarization and show a clear transient increase. Dialysate glucose levels reflect a balance between local tissue glucose supply and utilisation. These show a clear transient decrease of variable magnitude and duration. Dialysate lactate levels indicate non-oxidative metabolism of glucose and show a transient increase. Preliminary data suggest that the transient changes recover more slowly after the passage of a sequence of multiple spreading depolarizations giving rise to a decrease in basal dialysate glucose and an increase in basal dialysate potassium and lactate levels.