Extradural hematoma from trauma to midline skull tumour.

We present a case of extradural hematoma resulting from a relatively minor closed injury over the vertex where a plasma cell tumour had invaded the superior sagittal sinus. The patient underwent an emergency craniotomy and evacuation of the hematoma. Hemostasis and prevention of recollection of the hematoma were hampered by the erosion of the sagittal sinus making its direct repair impossible. This was achieved by hitching up the dura lateral to the sinus to become its lateral wall reinforced by hemostatic agents. The patient made a full recovery. Malignant tumours invading the dural venous sinuses and eroding the skull can cause life-threatening intracranial bleeding after relatively minor trauma.

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.

An extended role for CT in the emergency diagnosis of malignant spinal cord compression.

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.

Improved outcome after lumbar microdiscectomy in patients shown their excised disc fragments: a prospective, double blind, randomised, controlled trial.

BACKGROUND: Lumbar microdiscectomy (LMD) is a commonly performed neurosurgical procedure. We set up a prospective, double blind, randomised, controlled trial to test the hypothesis that presenting the removed disc material to patients after LMD improves patient outcome. METHODS: Adult patients undergoing LMD for radiculopathy caused by a prolapsed intervertebral disc were randomised into one of two groups, termed experimental and control. Patients in the experimental group were given their removed disc fragments whereas patients in the control group were not. Patients were unaware of the trial hypothesis and investigators were blinded to patient group allocation. Outcome was assessed between 3 and 6 months after LMD. Primary outcome measures were the degree of improvement in sciatica and back pain reported by the patients. Secondary outcome measures were the degree of improvement in leg weakness, paraesthesia, numbness, walking distance and use of analgesia reported by the patients. RESULTS: Data from 38 patients in the experimental group and 36 patients in the control group were analysed. The two groups were matched for age, sex and preoperative symptoms. More patients in the experimental compared with the control group reported improvements in leg pain (91.5 vs 80.4%; p<0.05), back pain (86.1 vs 75.0%; p<0.05), limb weakness (90.5 vs 56.3%; p<0.02), paraesthesia (88 vs 61.9%; p<0.05) and reduced analgesic use (92.1 vs 69.4%; p<0.02) than preoperatively. CONCLUSION: Presentation of excised disc fragments is a cheap and effective way to improve outcome after LMD.

Giant central lumbar disc herniations: a case for the transdural approach.

Giant central lumbar disc protrusions can pose a significant operative challenge. Clinically, these patients are at risk of permanent disability, due not only to preoperative neural compromise caused by the protrusion itself but also to the potential iatrogenic risks associated with the standard extradural microdiscectomy technique. This is the first report to date of a giant central L3/4 disc protrusion being successfully treated through a transdural microdiscectomy approach. Prior to this report, there have been just two cases describing its application in the lumbar spine. However, neither of these reports has described its use below the level of L2/3. We compare our surgical technique with these authors and discuss the pros and cons of this surgical approach relative to the standard extradural microdiscectomy technique. Overall, we have observed encouraging results from this approach and this report would support a role for further investigation into this rarely used technique.

The electrogenic sodium bicarbonate cotransporter: developmental expression in rat brain and possible role in acid vulnerability.

The electrogenic sodium bicarbonate cotransporter (NBC) is expressed in glial cells in the brain and plays an important role in the regulation of both intracellular and extracellular pH. Differential vulnerability to acidosis between neurons and glia has been noted and may contribute to infarction after cerebral ischemia. Ionic substitution studies and inhibition of injury by 4, 4'-di-isothiocyanostilbene-2,2'-disulfonic acid suggest that NBC is involved in astrocyte vulnerability to acidic injury. Recently two NBC cDNAs differing in 5'-untranslated and N-terminal coding sequence have been cloned from kidney and pancreas. We cloned one of these cDNAs from rat brain and demonstrate here that the clone is functional by expression in Xenopus oocytes. We determined the developmental and regional expression of NBC in the brain by in situ hybridization. Expression was observed in the spinal cord at embryonic day 17, whereas expression in brain was first seen at approximately postnatal day 0 (P0), increased at P15, and persisted in the adult brain. Expression was widespread throughout the cerebellum, cortex, olfactory bulb, and subcortical structures. Cellular resolution of the in situ hybridization signal and double labeling for glial fibrillary acidic protein were consistent with a glial localization for NBC. Expression of NBC in 3T3 cells that do not normally express this transporter rendered them vulnerable to acid injury. The expression profile suggests that this transporter is critical during the later stages of brain development and could be one of the factors contributing to the different patterns of injury seen in perinatal versus adult cerebral ischemia.

No association between seniority of surgeon and postoperative recurrence of chronic subdural haematoma.

INTRODUCTION: Neurosurgical trainees should achieve competency in chronic subdural haematoma (CSDH) drainage at an early stage in training. The effect of surgeon seniority on recurrence following surgical drainage of CSDH was examined. METHODS: All CSDH cases performed at St George's Hospital in London between March 2009 and March 2012 were analysed. Recurrence was defined as clinical deterioration with computed tomography evidence of CSDH requiring reoperation within six months. The following risk factors were considered: seniority of primary and supervising surgeons, timing of surgery (working hours, outside working hours), patient related factors (age, antiplatelets, warfarin) and operative factors (general vs local anaesthesia, burr holes vs craniotomy, drain use). For recurrent cases, we examined the distance of the cranial opening from the thickest part of the CSDH. RESULTS: A total of 239 patients (median age: 79 years, range: 33-98 years) had 275 CSDH drainage operations. The overall recurrence rate was 13.1%. The median time between the initial procedure and reoperation was 16 days (range: 1-161 days). The only statistically significant risk factor for recurrence was antiplatelets (odds ratio: 2.62, 95% confidence interval: 1.13-6.10, p<0.05). Warfarin, grade of surgeon, timing of surgery, type of anaesthesia, type of operation and use of drains were not significant risk factors. In 26% of recurrent CSDH cases, the burr holes or craniotomy flaps were placed with borderline accuracy. CONCLUSIONS: CSDH drainage is a suitable case for neurosurgical trainees to perform without increasing the chance of recurrence.

New insights into water transport and edema in the central nervous system from phenotype analysis of aquaporin-4 null mice.

Aquaporin-4 (AQP4) is the major water channel in the CNS. Its expression at fluid-tissue barriers (blood-brain and brain-cerebrospinal fluid barriers) throughout the brain and spinal cord suggests a role in water transport under normal and pathological conditions. Phenotype studies of transgenic mice lacking AQP4 have provided evidence for a role of AQP4 in cerebral water balance and neural signal transduction. Primary cultures of astrocytes from AQP4-null mice have greatly reduced osmotic water permeability compared with wild-type astrocytes, indicating that AQP4 is the principal water channel in these cells. AQP4-null mice have reduced brain swelling and improved neurological outcome following water intoxication and focal cerebral ischemia, establishing a role of AQP4 in the development of cytotoxic (cellular) cerebral edema. In contrast, brain swelling and clinical outcome are worse in AQP4-null mice in models of vasogenic (fluid leak) edema caused by freeze-injury and brain tumor, probably due to impaired AQP4-dependent brain water clearance. AQP4-null mice also have markedly reduced acoustic brainstem response potentials and significantly increased seizure threshold in response to chemical convulsants, implicating AQP4 in modulation of neural signal transduction. Pharmacological modulation of AQP4 function may thus provide a novel therapeutic strategy for the treatment of stroke, tumor-associated edema, epilepsy, traumatic brain injury, and other disorders of the CNS associated with altered brain water balance.

Molecular mechanisms of brain tumor edema.

Despite their diverse histological types, most brain tumours cause brain oedema, which is a significant cause of patient morbidity and mortality. Brain tumour oedema occurs when plasma-like fluid enters the brain extracellular space through impaired capillary endothelial tight junctions in tumours. Under-expression of the tight junction proteins occludin, claudin-1 and claudin-5 are key molecular abnormalities responsible for the increased permeability of tumour endothelial tight junctions. Recent evidence suggests that the membrane water channel protein aquaporin-4 (AQP4) also plays a role in brain tumour oedema. AQP4-deficient mice show remarkably altered brain water balance after various insults, including brain tumour implantation. AQP4 expression is strongly upregulated around malignant human brain tumours in association with reduced extracellular volume, which may restrict the flow of extracellular fluid from the tumour bed into the brain parenchyma. Elimination of excess fluid leaking into brain parenchyma requires passage across three AQP4-rich barriers: a) the glia limitans externa, b) the glia limitans interna/ependyma, and c) the blood-brain barrier. Modulation of the expression and/or function of endothelial tight junction proteins and aquaporins may provide novel therapeutic options for reducing brain tumour oedema.

Increasing vulnerability of astrocytes to oxidative injury with age despite constant antioxidant defenses.

This paper investigates the vulnerability of astrocytes to oxidative injury as a function of age in culture in mice. Primary murine cortical astrocyte cultures of different ages were exposed to H2O2, combined oxygen-glucose deprivation or glucose deprivation. Astrocytes became more vulnerable to damage from each injury paradigm with age, showing transitions between 15 and 22 days. Both the antioxidant glutathione and superoxide dismutase activity increased after 30 days in culture, while catalase activity did not change up to 34 days. When the decrease in glutathione with injury was measured, young cells showed no change with H2O2 and decreases of < 20% after oxygen-glucose deprivation or glucose deprivation, while older cultures lost > 50% of their glutathione with the same insults. Since iron can be a catalyst for hydroxyl radical formation, we stained cultures and found both iron staining and ferritin immunoreactivity increased with age. Increased iron correlated with protection by deferoxamine against H2O2 injury. The three injury paradigms each had a unique pattern of protection by antioxidants. Dimethylthiourea, a hydrophilic antioxidant, protected from all three insults. Trolox, a lipophilic antioxidant, protected older astrocytes from oxygen-glucose deprivation and glucose deprivation. Deferoxamine provided near complete protection from H2O2, partial protection from oxygen-glucose deprivation and no protection from glucose deprivation. As evidence of increasing oxidative stress, lipid peroxidation resulting from oxygen-glucose deprivation increased with age, assessed with cis-parinaric acid. The increasing sensitivity of ageing astrocytes to oxidative injury occurs while antioxidant defenses are maintained. Increased sensitivity to H2O2 or oxygen-glucose deprivation correlates with iron accumulation.

Water transport becomes uncoupled from K+ siphoning in brain contusion, bacterial meningitis, and brain tumours: immunohistochemical case review.

Specimens of normal human brain, contused brain, brain with bacterial meningitis, and brain tumours were immunolabelled for aquaporin 4 (AQP4) and Kir4.1. In normal brain tissue, AQP4 and Kir4.1 were detected around the microvessels. In pathological brain tissue, AQP4 was upregulated in astrocytes in oedematous regions and Kir4.1 was upregulated in astrocytes in damaged brain. Changes in alpha syntrophin expression paralleled those of AQP4 and Kir4.1. The following hypothesis is proposed: in astrocytes, under normal conditions, AQP4 couples water transport with Kir4.1 mediated K+ siphoning, but in pathological states, AQP4 facilitates the flow of brain oedema fluid, and Kir4.1 buffers increased extracellular K+.

Role of human papillomavirus in determining the HLA associated risk of cervical carcinogenesis.

AIMS: To investigate the role of human papillomavirus (HPV) in the association between HLA DQw3 and squamous cell cancer of the cervix (SCCC). METHODS: Tissue from 194 cervical samples, ranging from normal, through cervical intraepithelial neoplasia, to SCCC, were typed for HPV by amplification of the L1 gene using degenerate consensus primers, followed by oligonucleotide probing. HLA DQw3 typing was undertaken in the same samples using a new PCR amplification system using primers common to all DQ loci, followed by restriction digestion with Mlu 1 to differentiate HLA DQw3 types--null, heterozygous, and homozygous. The data were analysed using chi 2 analysis and by calculating relative risks with the 95% confidence interval. RESULTS: Samples (n = 188) were successfully typed for HPV and 177 were typed for HLA DQw3. There was a nonsignificant rise in the prevalence of HLA DQw3 in SCCC (64.3%) compared with the group with normal histology (53.2%). Analysis of the prevalence of HLA DQw3 on the basis of HPV infection rather than histology showed that 63 of 95 (66.3%) of the HPV positive samples contained HLA DQw3 alleles, compared with 39 of 78 (50.0%) of the HPV negative samples (chi 2 4.06; p < 0.05). CONCLUSIONS: There was a significant association between HLA DQw3 and cervical HPV infection. This may be because people with HLA DQw3 are less able to mount an effective immune response to HPV, which predisposes them to the development of SCCC.

Over-expression of HSP-70 protects astrocytes from combined oxygen-glucose deprivation.

Pretreatment by a sublethal insult is associated with induction of stress proteins and with protection from subsequent injury. Heat pretreatment protects the brain from subsequent ischemia, and is shown here to protect primary astrocyte cultures from subsequent oxygen-glucose deprivation. To determine whether the expression of a single stress protein, HSP-70, could account for much of this protection, we expressed HSP-70 or beta-galactosidase in astrocytes using retroviral vectors. Only 12% of astrocytes expressing HSP-70 died after 7 hours of oxygen-glucose deprivation compared to 65% of astrocytes expressing beta-galactosidase and 82% of normal astrocytes. Our data provide direct evidence that selective expression of HSP-70 enhances the survival of astrocytes challenged with heat or oxygen-glucose deprivation.

Vulnerability to glucose deprivation injury correlates with glutathione levels in astrocytes.

Astrocyte death from glucose deprivation appears to be mediated by free radicals. Reduced glutathione (GSH) was used as a measure of antioxidant defenses in primary cultures of cortical astrocytes. Glucose deprivation caused progressive, near complete loss of reduced glutathione (GSH). Astrocytes were protected by increasing endogenous GSH levels. Depletion of GSH to 21.4 +/- 3.3% of controls by the glutathione synthetase inhibitor buthionine sulfoximine resulted in more rapid injury by glucose deprivation, yet depletion of glutathione alone did not kill astrocytes. Both enhanced lipid peroxidation and membrane rigidification were caused by glucose deprivation, both indicators of oxidative damage. Membrane peroxidation was detected as a 24 +/- 2% decrease in cis-parinaric acid fluorescence, membrane rgidification as a 6.3 +/- 0.8% increase in fluorescence anisotropy using diphenylhexatriene. Glucose deprivation under normoxic conditions may occur clinically in patients such as diabetics. In addition, oxidative damage in the setting of energy depletion occurs with other insults, including ischemic brain injury. Glucose deprivation may thus be a clinically relevant model of hypoglycemic astrocyte injury, and may be useful to investigate the effects of glutathione and redox modulation on second messenger systems and gene regulation.

Is the National Health Service at the edge of chaos?

We used chaos and complexity theory to analyse waiting-list data (1998-2001) pertaining to over 20 000 National Health Service (NHS) patients from general surgical, orthopaedic and neurosurgical units across England. Plots of frequency versus quarter-to-quarter change in waiting times revealed a power relation which seems independent of surgical specialty and hospital location. One interpretation of these findings is that, for the period in question, the NHS was a system at the edge of chaos. This hypothesis might explain why waiting times have resisted attempts at shortening.

Aquaporin-4 in brain and spinal cord oedema.

Brain oedema is a major clinical problem produced by CNS diseases (e.g. stroke, brain tumour, brain abscess) and systemic diseases that secondarily affect the CNS (e.g. hyponatraemia, liver failure). The swollen brain is compressed against the surrounding dura and skull, which causes the intracranial pressure to rise, leading to brain ischaemia, herniation, and ultimately death. A water channel protein, aquaporin-4 (AQP4), is found in astrocyte foot processes (blood-brain border), the glia limitans (subarachnoid cerebrospinal fluid-brain border) and ependyma (ventricular cerebrospinal fluid-brain border). Experiments using mice lacking AQP4 or alpha syntrophin (which secondarily downregulate AQP4) showed that AQP4 facilitates oedema formation in diseases causing cytotoxic (cell swelling) oedema such as cerebral ischaemia, hyponatraemia and meningitis. In contrast, AQP4 facilitates oedema elimination in diseases causing vasogenic (vessel leak) oedema and therefore AQP4 deletion aggravates brain oedema produced by brain tumour and brain abscess. AQP4 is also important in spinal cord oedema. AQP4 deletion was associated with less cord oedema and improved outcome after compression spinal cord injury in mice. Here we consider the possible routes of oedema formation and elimination in the injured cord and speculate about the role of AQP4. Finally we discuss the role of AQP4 in neuromyelitis optica (NMO), an inflammatory demyelinating disease that produces oedema in the spinal cord and optic nerves. NMO patients have circulating AQP4 IgG autoantibody, which is now used for diagnosing NMO. We speculate how NMO-IgG might produce CNS inflammation, demyelination and oedema. Since AQP4 plays a key role in the pathogenesis of CNS oedema, we conclude that AQP4 inhibitors and activators may reduce CNS oedema in many diseases.

Increased brain edema in aqp4-null mice in an experimental model of subarachnoid hemorrhage.

We investigated the role of the glial water channel protein aquaporin-4 in brain edema in a mouse model of subarachnoid hemorrhage in which 30 microl of blood was injected into the basal cisterns. Brain water content, intracranial pressure and neurological score were compared in wildtype and aquaporin-4 null mice. We also measured blood-brain barrier permeability, and the osmotic permeability of the glia limitans, one of the routes of edema elimination. Wildtype and aquaporin-4 null mice had comparable baseline brain water content, intracranial pressure and neurological score. At 6 h after blood injection, aquaporin-4 null mice developed more brain swelling than wildtype mice. Brain water content increased by 1.5+/-0.1% vs. 0.5+/-0.2% (Mean+/-Standard Error, P<0.0005) and intracranial pressure by 36+/-5 vs. 21+/-3 mm Hg (P<0.05) above pre-injection baseline, and neurological score was worse at 18.0 vs. 24.5 (median, P<0.05), respectively. Although subarachnoid hemorrhage produced comparable increases in blood-brain barrier permeability in wildtype and aquaporin-4 null mice, aquaporin-4 null mice had a twofold reduction in glia limitans osmotic permeability. We conclude that aquaporin-4 null mice manifest increased brain edema following subarachnoid hemorrhage as a consequence of reduced elimination of excess brain water.