Following a traumatic brain injury (TBI), intracranial pressure (ICP) increases, often resulting in secondary brain insults. After a spinal cord injury, here the cord may be swollen, leading to a local increase in intraspinal pressure (ISP). We hypothesised that waveform analysis methodology similar to that used for ICP after TBI may be applicable for the monitoring of patients with spinal cord injury.An initial cohort of 10 patients with spinal cord injury, as presented by the first author at a meeting in Cambridge in May 2012, were included in this observational study. The whole group (18 patients) was recently presented in the context of clinically oriented findings (Werndle et al., Crit Care Med, 42(3): 646-655, 2014, PMID: 24231762). Mean pressure, pulse and respiratory waveform were analysed along slow vasogenic waves.Slow, respiratory and pulse components of ISP were characterised in the time and frequency domains. Mean ISP was 22.5 +/- 5.1, mean pulse amplitude 1.57 +/- 0.97, mean respiratory amplitude 0.65 +/- 0.45 and mean magnitude of slow waves (a 20-s to 3-min period) was 3.97 +/- 3.1 (all in millimetres of mercury). With increasing mean ISP, the pulse amplitude increased in all cases. This suggests that the ISP signal is of a similar character to ICP recorded after TBI. Therefore, the methods of ICP analysis can be helpful in ISP analysis.

Intracranial pressure (ICP) is routinely measured in patients with severe traumatic brain injury (TBI). We describe a novel technique that allowed us to monitor intraspinal pressure (ISP) at the injury site in 14 patients who had severe acute traumatic spinal cord injury (TSCI), analogous to monitoring ICP after brain injury. A Codman probe was inserted subdurally to measure the pressure of the injured spinal cord compressed against the surrounding dura. Our key finding is that it is feasible and safe to monitor ISP for up to a week in patients after TSCI, starting within 72 h of the injury. With practice, probe insertion and calibration take less than 10 min. The ISP signal characteristics after TSCI were similar to the ICP signal characteristics recorded after TBI. Importantly, there were no associated complications. Future studies are required to determine whether reducing ISP improves neurological outcome after severe TSCI.

OBJECT:In contrast to intracranial pressure (ICP) in traumatic brain injury (TBI), intraspinal pressure (ISP) after traumatic spinal cord injury (TSCI) has not received the same attention in terms of waveform analysis. Based on a recently introduced technique for continuous monitoring of ISP, here the morphological characteristics of ISP are observationally described. It was hypothesized that the waveform analysis method used to assess ICP could be similarly applied to ISP.METHODS:Data included continuous recordings of ISP and arterial blood pressure (ABP) in 18 patients with severe TSCI.RESULTS:The morphology of the ISP pulse waveform resembled the ICP waveform shape and was composed of 3 peaks representing percussion, tidal, and dicrotic waves. Spectral analysis demonstrated the presence of slow, respiratory, and pulse waves at different frequencies. The pulse amplitude of ISP was proportional to the mean ISP, suggesting a similar exponential pressure-volume relationship as in the intracerebral space. The interaction between the slow waves of ISP and ABP is capable of characterizing the spinal autoregulatory capacity.CONCLUSIONS:This preliminary observational study confirms morphological and spectral similarities between ISP in TSCI and ICP. Therefore, the known methods used for ICP waveform analysis could be transferred to ISP analysis and, upon verification, potentially used for monitoring TSCI patients.

The NHS is entering a third decade of administrative turbulence and cost pressures and many view the new NHS structure and systems as complex and confusing. Health and social care budgets are being merged in some geographical areas and large efficiency savings are needed by 2020. There are risks that lie ahead for neurosurgery and our patients if the specialty becomes further fragmented and opportunities for positive change are missed. One of the new care models proposed in the NHS five year plan is specialist care provided across multiple hospital sites by a single overarching specialist trust, mirroring ophthalmology where the Moorfields trust provides specialist eye services in over 20 locations in London and the South East. This model lends itself to adoption by neurosurgery and has the potential to increase standards, efficiency, training and research.

Objectives: To develop a technique for continuously monitoring intraspinal pressure at the injury site (intraspinal pressure) after traumatic spinal cord injury.Design: A pressure probe was placed subdurally at the injury site in 18 patients who had isolated severe traumatic spinal cord injury (American Spinal Injuries Association grades A-C). Intraspinal pressure monitoring started within 72 hours of the injury and continued for up to a week. In four patients, additional probes were inserted to simultaneously monitor subdural pressure below the injury and extradural pressure. Blood pressure was recorded from a radial artery catheter kept at the same horizontal level as the injured segment of the spinal cord. We determined the effect of various maneuvers on spinal cord perfusion pressure and spinal cord function and assessed using a limb motor score and motor-evoked potentials.Setting: Neurosurgery and neuro-ICU covering a 3 million population in London.Subjects: Patients with severe traumatic spinal cord injury. Control subjects without spinal cord injury (to monitor spinal cerebrospinal fluid signal and motor evoked potentials).Interventions: Insertion of subdural spinal pressure probe.Measurements and Main Results: There were no procedure-related complications. Intraspinal pressure at the injury site was higher than subdural pressure below the injury or extradural pressure. Average intraspinal pressure from the 18 patients with traumatic spinal cord injury was significantly higher than average intraspinal pressure from 12 subjects without traumatic spinal cord injury. Change in arterial Pco(2), change in sevoflurane dose, and mannitol administration had no significant effect on intraspinal pressure or spinal cord perfusion pressure. Increase in inotrope dose significantly increased spinal cord perfusion pressure. Bony realignment and laminectomy did not effectively lower intraspinal pressure. Laminectomy was potentially detrimental by exposing the swollen spinal cord to compression forces applied to the skin. By intervening to increase spinal cord perfusion pressure, we could increase the amplitude of motor-evoked potentials recorded from below or just above the injury level in nine of nine patients with traumatic spinal cord injury. In two of two patients with American Spinal Injuries Association grade C traumatic spinal cord injury, higher spinal cord perfusion pressure correlated with increased limb motor score.Conclusions: Our findings provide proof-of-principle that subdural intraspinal pressure at the injury site can be measured safely after traumatic spinal cord injury.

Background There is an increasing demand for noninvasive brain tumor biomarkers to guide surgery and subsequent oncotherapy. We present a novel whole-brain diffusion tensor imaging (DTI) segmentation (D-SEG) to delineate tumor volumes of interest (VOIs) for subsequent classification of tumor type. D-SEG uses isotropic (p) and anisotropic (q) components of the diffusion tensor to segment regions with similar diffusion characteristics. Methods DTI scans were acquired from 95 patients with low- and high-grade glioma, metastases, and meningioma and from 29 healthy subjects. D-SEG uses k-means clustering of the 2D (p,q) space to generate segments with different isotropic and anisotropic diffusion characteristics. Results Our results are visualized using a novel RGB color scheme incorporating p, q and T2-weighted information within each segment. The volumetric contribution of each segment to gray matter, white matter, and cerebrospinal fluid spaces was used to generate healthy tissue D-SEG spectra. Tumor VOIs were extracted using a semiautomated flood-filling technique and D-SEG spectra were computed within the VOI. Classification of tumor type using D-SEG spectra was performed using support vector machines. D-SEG was computationally fast and stable and delineated regions of healthy tissue from tumor and edema. D-SEG spectra were consistent for each tumor type, with constituent diffusion characteristics potentially reflecting regional differences in tissue microstructure. Support vector machines classified tumor type with an overall accuracy of 94.7%, providing better classification than previously reported. Conclusions D-SEG presents a user-friendly, semiautomated biomarker that may provide a valuable adjunct in noninvasive brain tumor diagnosis and treatment planning.

1696 www.ccmjournal.org July 2014 • Volume 42 • Number 7 Objective: Dexmedetomidine and propofol are commonly used sedatives in neurocritical care as they allow for frequent neurologic examinations. However, both agents are associated with significant hemodynamic side effects. The primary objective of this study is to compare the prevalence of severe hemodynamic effects in neurocritical care patients receiving dexmedetomidine and propofol. Design: Multicenter, retrospective, propensity-matched cohort study. Setting: Neurocritical care units at two academic medical centers with dedicated neurocritical care teams and board-certified neurointensivists. Patients: Neurocritical care patients admitted between July 2009 and September 2012 were evaluated and then matched 1:1 based on propensity scoring of baseline characteristics. Interventions: Continuous sedation with dexmedetomidine or propofol. Measurements and Main Results: A total of 342 patients (105 dexmedetomidine and 237 propofol) were included in the analysis, with 190 matched (95 in each group) by propensity score. The primary outcome of this study was a composite of severe hypotension (mean arterial pressure < 60 mm Hg) and bradycardia (heart rate < 50 beats/min) during sedative infusion. No difference in the primary composite outcome in both the unmatched (30% vs 30%, p = 0.94) or matched cohorts (28% vs 34%, p = 0.35) could be found. When analyzed separately, no differences could be found in the prevalence of severe hypotension or bradycardia in either the unmatched or matched cohorts. Conclusions: Severe hypotension and bradycardia occur at similar prevalence in neurocritical care patients who receive dexmedetomidine or propofol. Providers should similarly consider the likelihood of hypotension or bradycardia before starting either sedative. (Crit Care Med 2014; 42:1696–1702)

Tumor vasculature is a promising therapeutic target in glioblastoma. Imaging tumor blood flow may help assess the efficacy of anti-angiogenic treatments. We determined the clinical usefulness of stable xenon CT performed preoperatively in patients with glioblastoma. This is a prospective cohort study. We determined absolute tumor blood flow before surgery in 38 patients with glioblastoma using stable xenon CT. We also histologically examined tumor specimens obtained from surgery and quantified their vascularity (by CD31 and CD105 immunostain), necrosis (by hematoxylin and eosin stain), and the presence of neuronal processes (by neurofilament immunostain). According to the xenon CT blood flow map, there are 3 types of glioblastoma. Type I glioblastomas have unimodal high blood flow histograms; histologically there is little necrosis and vascular proliferation. Type II glioblastomas have unimodal low blood flow histograms; histologically there is prominent necrosis and vascular proliferation. We propose that in type II glioblastoma, the abnormal vessels induced by hypoxia are inefficient at promoting blood flow. Type III glioblastomas have multimodal blood flow histograms. Histologically there is significant neuronal tissue within the tumor. Patients with type III glioblastomas were more likely to develop a post-surgical deficit, consistent with the inclusion of normal tissue within the tumor. Preoperative measurement of absolute blood flow with stable xenon CT in patients with glioblastoma predicts key biological features of the tumor and may aid surgical planning.

Background and Goal of Study: There is wide variability in the treatment of acute traumatic spinal cord injuries (SCI) within the British Neurosurgical population.1 Our aim was to ascertain the current medical treatment of acute traumatic SCI injuries within the British Neuroanaesthetic community. Materials and Methods: A questionnaire survey via an online survey tool was sent to all full members of the Neuroanaesthetic Society of Great Britain and Ireland (NASGBI). Prior approval was obtained from the NASGBI. We asked about experience of the anaesthetist, intraoperative management during spinal surgery for traumatic SCI, and management in the intensive care unit in the week following injury. A total of 96 responded (37% response rate). Results: Desflurane (35%), TCI propofol and remifentanil (33%) and sevoflurane (27%) were the preferred anaesthetics used. Most neuroanaesthetists (96%) avoided agents known to increase intracranial pressure. Intraoperative monitoring was variable: 15% always measure central venous pressure; 78% invasive arterial blood pressure and 6% non invasive cardiac output. We assessed whether, in the intensive care unit, neuroanaesthetists manage spinal cord injury similar to brain injury. Only 3% consider mannitol or hypertonic saline. No one advocates hypothermia. Most (92%) maintain arterial pCO2 and pO2 within normal ranges. There was uncertainty about optimal mean arterial pressure; 54% aimed for ≥80 mmHg, with the use of inotropes if required. Conclusions: There is variability in the anaesthetic management of SCI. Our data suggests British Neuroanaesthetists assume that the injured spinal cord responds in the same way as injured brain. Intraoperative monitoring, however, is more limited and their intensive care management does not follow the same principles as used for brain injury. ReferencesWerndle MC, Zoumprouli A, Bell BA, Papadopoulos MC. Acute traumatic spinal cord injuries: wide variability of treatment within the UK. British Journal of Neurosurgery. April 2011; 25(2):166.

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system associated with pathogenic autoantibodies against the astrocyte water channel protein aquaporin‐4 (AQP4). The presence of neutrophils is a characteristic feature in NMO lesions in humans. Neutrophils are not generally found in multiple sclerosis lesions. We evaluated the role of neutrophils in a mouse NMO model.

We congratulate Lamb et al. on their recent paper ‘Delays in treating patients with good grade subarachnoid haemorrhage in London’ (Br J Neurosurg 2011;25(2):243–8). They highlight a national problem which may have a local solution in London at least. We do not understand why they concluded that only good grade subarachnoid haemorrhage should be managed by each of the London neurosurgical units on a rotational basis at weekends only. Surely all subarachnoid haemorrhage patients benefit from early admission to a neurosurgical centre where they can access all aspects of care and intervention. We conclude that a London-wide vascular ‘‘super-rota’’ for all grades seven days a week would result in the best possible care for the patients and allow for optimal use of resources in the participating centres. Also we do not think that it was clearly addressed in the paper but it seems they experienced 5 re-bleed deaths in 2 years. Extrapolated to the entire London population this would be approximately 15 young, good grade, re-bleed deaths per year. This does not include the extra morbidity as a result of delays in treatment. Overall, we feel the only conclusion is that a round the clock vascular ‘‘super-rota’’ can only be a big step forward for dealing with this issue and providing more timely management for these patients.

AIM: To evaluate the usefulness of computed tomography (CT) for triaging between urgent transfer to a neurosurgical unit and delayed magnetic resonance imaging (MRI) in the local hospital.MATERIALS AND METHODS: Radiologists blinded to the MRI findings scored CT images from 1-5 using a novel grading system based on the degree of cord compression observed in 44 patients. Seventy separate levels were scored. The observers' CT scores were compared with the MRI findings. All scoring radiologists were specialist registrars at different stages of training.RESULTS: Agreement between CT and MRI scores for metastatic spinal cord compression (MSCC) were high with Cohen's weighted Kappa score 0.70 (p < 0.001, 95% CI 0.65 to 0.75). CT has a sensitivity of 89% and specificity of 92% for MSCC. Half the false-positive and false-negative results came from a single junior radiologist who would not normally report CT or MRI studies unsupervised. The best CT-MRI agreement was from the most senior trainee radiologist.CONCLUSIONS: Spinal findings on routine staging whole-body CT combined with clinical findings are sufficient to determine which patients with MSCC can safely wait for MRI the next working day at the local hospital and those who need emergency transfer to a neurosurgical unit for MRI and possible surgical decompression. (C) 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

BACKGROUND:Bone graft substitutes are widely used in spinal surgery. Here, serious complications associated with the bone graft substitute GeneX are presented. GeneX contains tri-calcium phosphate and calcium sulphate. METHODS:GeneX was used in three patients who had spinal decompression and fusion. Mice were also injected with GeneX, demineralised bone matrix (DBX) or saline subcutaneously. After 24 h the extent of tissue damage and inflammation in tissue sections was quantified. To understand the licensing process for bone graft substitutes, the U.S. Food and Drug Administration (FDA) and the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) websites were accessed. RESULTS:All patients developed sterile pus in soft tissues adjacent to the GeneX followed by skin breakdown in two and pharyngeal perforation in one. In mice, GeneX produced moderate or severe skin damage compared with no or mild skin damage after DBX (p<0.05) or saline (p<0.05) injection. GeneX caused more inflammation in mouse dermis (1704±193 leucocytes/mm2, mean ± SE) than DBX (537 ± 266, p<0.01) or saline (136 ± 19, p<0.01). The FDA and MHRA classify bone graft substitutes as medical devices. In contrast with drugs, medical devices do not need to undergo clinical safety tests before obtaining FDA 510(k) clearance for use in patients. CONCLUSION:GeneX may cause soft tissue inflammation and destruction and should not be placed next to thin walled structures, such as skin or pharynx, because it may erode through these tissues. Bone graft substitutes should undergo mandatory detailed safety testing prior to approval. This could be achieved by reclassifying them as drugs.

We reported recently that intracerebral administration of NMO-IgG with human complement produces neuromyelitis optica (NMO) lesions in mice. We examined the role of T cells in the formation of NMO lesions by comparing brain histopathology in wildtype and nude mice. Brains were co-injected with IgG from NMO patients and human complement. At 24h and 5days, wildtype vs. nude mouse brains had comparable inflammation (CD45 immunoreactivity), loss of myelin (Luxol Fast Blue staining) and loss of AQP4 immunoreactivity. We conclude that T cells are not required for the formation of NMO lesions in this mouse model.

In a prospective study, patients with a radiologically proven brain tumour underwent diffusion tensor imaging (DTI) prior to definitive diagnosis and treatment. Twenty‐eight patients with a histologically proven glioblastoma or metastasis were included in the study. Following the definition of regions of interest, DTI metrics [mean diffusivity (MD) and fractional anisotropy (FA)] were calculated for the tumour volume and the surrounding region of peritumoral oedema. These metrics were then subjected to logistic regression to investigate their ability to discriminate between glioblastomas and cerebral metastases. A cross‐validation was performed to investigate the ability of the model to predict tumour. The logistic regression analysis correctly distinguished glioblastoma in 15 of 16 cases (93.8%) and metastasis in 11 of 12 cases (91.7%). Cross‐validation resulted in the model correctly predicting 14 of 16 (87.5%) glioblastomas and 10 of 12 (83.3%) metastases studied. MD was significantly higher (p = 0.02) and FA was significantly lower (p = 0.04) within the oedema surrounding metastases than within the oedema around glioblastomas. MD was significantly higher (p = 0.02) within the tumour volume of the glioblastomas. Our results demonstrate that, when DTI metrics from the tumour volume and surrounding peritumoral oedema are studied in combination, glioblastoma can be reliably discriminated from cerebral metastases. Copyright © 2010 John Wiley & Sons, Ltd.

Background and purpose. Spontaneous aneurysmal subarachnoid haemorrhage (SAH) is managed as a neurosurgical priority with guidelines and published literature emphasising the identification and the treatment of the ruptured aneurysm within 48 h of ictus. We audited the timing of management of good grade (WFNS 1 & 2) SAH in a neurosurgical unit in Greater London. We also reviewed the available services for treating SAH within Greater London.Materials and methods. Retrospective audit of patients admitted with SAH to St. George's Hospital between 31 May 2007 and 31 May 2009 was performed. Prospective telephone and public record review of the catchment area and neurovascular provisions of the seven London neurosurgical units were assessed.Results. There were 141 WFNS grade 1 and 2 SAH patients admitted. Only a quarter were treated within 48 h of ictus. Patients destined for endovascular treatment waited significantly longer periods until treatment when compared with that of clipping group patients. The day of the week on which diagnostic angiography occurred was critical in determining treatment delays, probably due to the lack of routine provision of clipping at weekends and next day coiling services. We estimated that 440 good grade SAH are admitted per annum in Greater London. There are 20 neurovascular surgeons and 16 interventional neuroradiologists across seven neurosurgical units that routinely treat SAH.Conclusions. We have identified significant delays in treating three quarters of good grade SAH patients in London. This appears to be due to a lack of next day treatment availability. A collaborative strategy between the seven London neurosurgical units could reduce treatment delays.

Angiogenesis plays a key role in glioblastoma biology and antiangiogenic agents are under clinical investigation with promising results. However, the angiogenic profiles of patients with glioblastoma and their clinical significance are not well understood. Here we characterize the serum angiogenic profile of patients with glioblastoma, and examine the prognostic significance of individual angiogenic factors. Serum samples from 36 patients with glioblastoma were collected on admission and simultaneously assayed for 48 angiogenic factors using protein microarrays. The data were analyzed using hierarchical cluster analysis. Vessel morphology was assessed histologically after immunostaining for the pan-endothelial marker CD31. Tumor samples were also immunostained for tissue inhibitor of metalloproteinase-1 (TIMP-1). Cluster analysis of the serum angiogenic profiles revealed 2 distinct subtypes of glioblastoma. The 2 subtypes had markedly different tumor microvessel densities. A low serum level of TIMP-1 was associated with significantly longer survival independent of patient age, performance status, or treatment. The serum angiogenic profile in patients with glioblastoma mirrors tumor biology and has prognostic value. Our data suggest the serum TIMP-1 level as an independent predictor of survival.

Neuromyelitis optica is an inflammatory demyelinating disease of the central nervous system associated with autoantibodies against the glial water channel protein aquaporin-4. It has recently been reported that immunoglobulin from neuromyelitis optica patients injected peripherally does not cause lesions in naive rats, but only when pre-existing central nervous system inflammation is present. Here, we investigated whether immunoglobulin G from aquaporin-4-autoantibody-positive neuromyelitis optica patients has the potential to damage the central nervous system either alone or in the presence of human complement. Immunoglobulin G from neuromyelitis optica patients did not activate mouse complement and was not pathogenic when injected into mouse brain. However, co-injection of immunoglobulin G from neuromyelitis optica patients with human complement produced neuromyelitis optica-like lesions in mice. Within 12 h of co-injecting immunoglobulin G from neuromyelitis optica patients and human complement, there was a striking loss of aquaporin-4 expression, glial cell oedema, myelin breakdown and axonal injury, but little intra-parenchymal inflammation. At 7 days, there was extensive inflammatory cell infiltration, perivascular deposition of activated complement components, extensive demyelination, loss of aquaporin-4 expression, loss of reactive astrocytes and neuronal cell death. In behavioural studies, mice injected with immunoglobulin G from neuromyelitis optica patients and human complement into the right hemisphere preferentially turned to the right at 7 days. No brain inflammation, demyelination or right-turning behaviour was seen in wild-type mice that received immunoglobulin G from non-neuromyelitis optica patients with human complement, or in aquaporin-4-null mice that received immunoglobulin G from neuromyelitis optica patients with human complement. We conclude that co-injection of immunoglobulin G from neuromyelitis optica patients with human complement reproduces the key histological features of neuromyelitis optica and that aquaporin-4 is necessary and sufficient for immunoglobulin G from neuromyelitis optica patients to exert its effect. In our mouse model, immunoglobulin G from neuromyelitis optica patients does not require pre-existing central nervous system inflammation to produce lesions.