Feasibility of comparing medical management and surgery (with neurosurgery or stereotactic radiosurgery) with medical management alone in people with symptomatic brain cavernoma - protocol for the Cavernomas: A Randomised Effectiveness (CARE) pilot trial.

INTRODUCTION: The top research priority for cavernoma, identified by a James Lind Alliance Priority setting partnership was 'Does treatment (with neurosurgery or stereotactic radiosurgery) or no treatment improve outcome for people diagnosed with a cavernoma?' This pilot randomised controlled trial (RCT) aims to determine the feasibility of answering this question in a main phase RCT. METHODS AND ANALYSIS: We will perform a pilot phase, parallel group, pragmatic RCT involving approximately 60 children or adults with mental capacity, resident in the UK or Ireland, with an unresected symptomatic brain cavernoma. Participants will be randomised by web-based randomisation 1:1 to treatment with medical management and with surgery (neurosurgery or stereotactic radiosurgery) versus medical management alone, stratified by prerandomisation preference for type of surgery. In addition to 13 feasibility outcomes, the primary clinical outcome is symptomatic intracranial haemorrhage or new persistent/progressive focal neurological deficit measured at 6 monthly intervals. An integrated QuinteT Recruitment Intervention (QRI) evaluates screening logs, audio recordings of recruitment discussions, and interviews with recruiters and patients/parents/carers to identify and address barriers to participation. A Patient Advisory Group has codesigned the study and will oversee its progress. ETHICS AND DISSEMINATION: This study was approved by the Yorkshire and The Humber-Leeds East Research Ethics Committee (21/YH/0046). We will submit manuscripts to peer-reviewed journals, describing the findings of the QRI and the Cavernomas: A Randomised Evaluation (CARE) pilot trial. We will present at national specialty meetings. We will disseminate a plain English summary of the findings of the CARE pilot trial to participants and public audiences with input from, and acknowledgement of, the Patient Advisory Group. TRIAL REGISTRATION NUMBER: ISRCTN41647111.

A prospective study of shared decision-making in brain tumor surgery.

PURPOSE: Shared decision-making (SDM) is a key tenet of personalized care and is becoming an essential component of informed consent in an increasing number of countries. The aim of this study is to analyze patient and healthcare staff satisfaction with the SDM process before and after SDM was officially introduced as the standard of care. Decision grids are important tools in the SDM process, and we developed them for three different types of intracranial tumors. METHODS: This prospective study was conducted in a high-volume neuro-oncological center on all consecutive eligible patients undergoing consideration of treatment for intracranial glioma and metastases. Twenty-two patients participated before and 74 after the introduction of SDM. Six and 5 staff members respectively participated in the analysis before and after team training and the introduction of SDM. The main outcome was patient and healthcare staff satisfaction with the SDM process. RESULTS: Patients reported high satisfaction with the SDM process before (mean CollaboRATE score 26 of 27 points) and after (mean CollaboRATE score 26.3 of 27 points, p = 0.23) the introduction of SDM. Interestingly, staff attitude toward SDM improved significantly from 61.68 before to 90.95% after the introduction of SDM (p-value < 0.001). Decision grids that were developed for three different types of intracranial tumors are presented. CONCLUSIONS: Team training in SDM and the introduction of techniques into daily practice can increase staff satisfaction with the SDM process. High levels of patient satisfaction were observed before, with a non-significant increase after the introduction of SDM. Decision grids are an important tool to facilitate the conveyance and understanding of complex information and to achieve SDM in daily clinical practice.

Gamma Knife Stereotactic Radiosurgery for the treatment of chordomas and chondrosarcomas.

INTRODUCTION: Primary chordomas and chondrosarcomas of the skull base are difficult tumours to treat successfully. Despite advances in surgical techniques, a gross total resection is often impossible to achieve. In addition, some patients may be deemed unsuitable or not wish to undergo extensive surgery for these conditions. This study examines the role of Gamma Knife Stereotactic Radiosurgery (GKRS) in the treatment of these difficult cases. METHODS: All patients harbouring either a chordoma or chondrosarcoma treated at the National Centre for Stereotactic Radiosurgery, Royal Hallamshire Hospital, Sheffield, UK, between 1985 and 2018, were reviewed with regard to their clinical presentations, pre- and post-treatment imaging, GKRS prescriptions and outcomes. RESULTS: In total, 24 patients with a mean tumour volume of 13 cm3 in the chordoma group (n=15) and 12 cm3 in the chondrosarcoma group (n=9) underwent GKRS. The 5- and 10-year overall survival rates for the chordoma group were 67% and 53% respectively, while for the chondrosarcoma group, they were 78% at both time points. The tumour control rates at 5 and 10 years in the chordoma group were 67% and 49% and for the chondrosarcoma group 78% at both time points. Patients with tumour volumes of less than 7 cm3 before GKRS treatment demonstrated a statistically significant longer overall survival rate (p=0.03). CONCLUSIONS: GKRS offers a comparable option to proton beam therapy for the treatment of these tumours. Early intervention for tumour volumes of less than 7 cm3 gives the best long-term survival rates.

A Retrospective Analysis of the Role of Single-Session Gamma Knife Stereotactic Radiosurgery in Sporadic Vestibular Schwannomas with Tumor Volumes Greater Than 10 cm3: Is It Worth Stretching the Boundaries?

OBJECTIVE: To evaluate the role of single-session Gamma Knife stereotactic radiosurgery (GK-SRS) in the treatment of vestibular schwannomas (VSs) with volumes of greater 10 cm3. METHODS: A retrospective analysis was performed of 103 patients treated with single-session GK-SRS between 1993 and 2011 with a mean follow-up of 6.2 years ± 4.4 SD. Treatment, clinical and outcome details were recorded and assessed. RESULTS: Eighty-one (78.6%) patients achieved radiological control with slow progression in a further 5 (4.9%) patients, who did not require further treatment. Linear measurements did not correlate well with volume, which can predict outcome following treatment more precisely. 2.9% of patients developed a new facial paresis, 5.8% trigeminal numbness and 2.9% facial pain. In all, 26 (25.2%) patients who were tested preserved some level of hearing following treatment. CONCLUSIONS: The overall radiological control rate in this study was 78.6%, while tumor volumes less than 20 cm3 can be safely treated with single-stage GK-SRS with an expected control rate of 83.2% without unacceptable morbidity rates. GK-SRS can be utilized as a first-line treatment option in patients with large-volume VSs especially in whom surgery is unattractive.

Speech bubble: dysphasia secondary to spontaneous intraparenchymal pneumocephalus.

Spontaneous pneumocephalus is exceptionally rare, with few published cases in the literature. We describe a patient presenting with dysphasia, right facial weakness, headache and confusion who was subsequently found to have pneumocephalus due to an encephalocoele herniating into a tegmen tympani defect.

Infected intracranial meningiomas.

OBJECTIVE: Infection associated with an intracranial meningioma is an extremely rare condition. Only six cases have been described in the literature. Because of its dual pathologies, initial radiologic diagnosis can be difficult. We present the first reported case of multiple infected intracranial meningiomas and correlate the radiologic and histologic findings. METHODS: A 70-year-old woman presented with sepsis and a left hemiparesis following ureteroscopy and lithotripsy. A large right parietal lesion and a smaller left frontal lesion were diagnosed on magnetic resonance imaging. Diffusion-weighted imaging and an apparent diffusion coefficient map demonstrated features of cerebral metastases. RESULTS: A 2-stage excision confirmed atypical meningiomas containing an intratumoral abscess secondary to Escherichia coli. The patient made a full neurologic recovery. Despite the additional techniques, the radiologic diagnosis was initially challenging because of the dual pathologies. Nonetheless, the radiologic appearance was consistent with the complex histologic findings. CONCLUSIONS: In the appropriate clinical context, diffusion-weighted imaging and apparent diffusion coefficient map aid the diagnosis of infected intracranial meningiomas.

Early brain injury following aneurysmal subarachnoid hemorrhage: emphasis on cellular apoptosis.

Subarachnoid hemorrhage (SAH) due to intracranial aneurysm rupture is a complex clinical disease with high mortality and morbidity. Recent studies suggest that early brain injury (EBI) rather than vasospasm might be responsible for morbidity and mortality within 24-72 hours after SAH. The rise in intracranial pressure following SAH causes a significant drop in cerebral perfusion pressure that leads to global cerebral ischemia and initiates the acute injury cascade. Various molecular mechanisms have been shown to involve in the pathophysiology of EBI including cellular apoptosis. In this review, we summarize apoptotic molecular mechanisms involved in the etiology of EBI and its potential as a target for future therapeutic intervention.

Paediatric lumbar disc herniation in the very young: a case-based update.

BACKGROUND: A lumbar disc prolapse is commonly seen in the adult population and as a result, the signs and symptoms are well recognised and easily treated. A disc prolapse, in the adolescent and particularly the paediatric age group, is very rare indeed. The signs and symptoms are atypical in this age group, and there is often difficulty in recognising the pathology. This can lead to delays in the diagnosis and treatment of a very painful condition. DISCUSSION: Lumbar disc herniation in very young children can be hard to diagnose. There is limited information currently available in the literature on the topic of lumbar disc herniation in very young children. Overall, the surgical option in these children appears to have a favourable outcome. ILLUSTRATIVE CASE: This case highlights an 18-month-old child who was not able to walk, following a fall. The child had a normal neurological examination and normal bladder and bowel function. A magnetic resonance imaging (MRI) scan of her lumbar sacral spine indicated a large right paracentral L4/5 disc prolapse indenting the right anterolateral margin of the thecal sac and abutting the right L5 nerve root. She subsequently underwent a laminoplasty and excision of a sub-ligamentous L4/5 disc prolapse under an operating microscope. CONCLUSIONS: This case report highlights the problems in diagnosing an acute lumbar disc prolapse in an 18-month-old child and reviews the current literature dealing with an acute disc prolapse in very young children.

Venous anastomotic circle, multiple varices and oculomotor palsy--a rare coincidence.

Oculomotor nerve palsy due to a venous varix arising from flow anomalies caused by a dural arteriovenous fistula (AVF) is a rare phenomenon. We report a case of surgical third nerve palsy with a rare underlying AVF as the cause and discuss in detail the patho-anatomy and its significance. A tentorial dural AVF mimicking the arterial circle was found with multiple varix formation causing compressive oculomotor palsy. This was treated successfully with Onyx™ injection with a satisfactory angiographic result and complete resolution of symptoms.

Emergency head CT scans: can neurosurgical registrars be relied upon to interpret them?

Neurosurgical registrars are frequently called upon by A&E staff and physicians to interpret emergency head CT (computed tomography) scans out of hours. This appears to reflect the reduced threshold for scanning patients and the nonavailability of a radiologist to report these scans. This study was undertaken to assess the safety of such practices. Five neurosurgical registrars, blinded to each other and to the radiology reports, interpreted 50 consecutive emergency head CT scans (both trauma and nontrauma) from the hospital's imaging system as a pilot study. These were initially graded as normal or abnormal. Abnormal scans were assessed for the presence of an intracranial bleed, pneumocephalus, skull fractures, cerebral contusions, mass effect, midline shift, ischaemia or hydrocephalus. The agreement of the observers' recordings with the report issued or approved by a consultant radiologist was evaluated using SPSS Version 13.0. Four of the five registrars assessed a further 150 scans in a similar manner to complete the study. There was a good general agreement between the formal reports and the neurosurgical registrars' identification of normal scans (average Kappa 0.79). The radiology reports and the registrars also agreed well on the presence or absence of intracranial blood, contusions and pneumocephalus (Kappa value > 0.70). The agreement was poorer for ischaemia, mass lesions (other than intracranial haematomas), grey white differentiation, evidence of raised intracranial pressure and midline shift (Kappa < 0.5). Neurosurgical registrars compared well with radiologists when it came to assessing emergency head CT scans as normal or detecting a surgical lesion. The agreement was poorer on subtle abnormalities. The practice of neurosurgical registrars informally 'reporting' on emergency head CT scans cannot be recommended.

Granulocyte colony-stimulating factor protects the brain against experimental stroke via inhibition of apoptosis and inflammation.

OBJECTIVES: The molecular mechanisms of the anti-apoptotic and anti-inflammatory properties of granulocyte-colony stimulating factor (G-CSF) following focal cerebral ischemia in rats were examined in this study. METHODS: Sprague-Dawley rats were randomly divided into three groups: sham, middle cerebral artery occlusion (MCAO) non-treatment and MCAO with G-CSF treatment. Focal ischemia was induced with the suture occlusion method for 90 minutes, and treatment was given at the onset of reperfusion. All animals were killed 24 hours after reperfusion. Assessment included neurological scores, infarction volumes, histology, immunofluorescent staining and Western blotting. RESULTS: G-CSF significantly reduced the infarct volume and ameliorated the early neurological outcome scores. Western blot analysis showed that G-CSF treatment significantly elevated the cIAP2 levels and decreased the activation of caspase 3 in the ischemic cortex compared with the non-treated rats. Immunofluorescent works also showed that G-CSF treatment inhibited both neuronal and glial tumor necrosis factor alpha and interleukin 1beta expressions. DISCUSSION: The neuronal anti-apoptotic action of G-CSF may be mediated in part by the anti-apoptotic protein cIAP2. G-CSF also exerts anti-inflammatory actions after focal cerebral ischemia by preventing both neuronal and glial pro-inflammatory cytokine expressions.

Flow dynamics in lumboperitoneal shunts and their implications in vivo.

OBJECT: Lumboperitoneal shunting is the standard treatment for pseudotumour cerebri or idiopathic intracranial hypertension. Complications are common, particularly the problem of overdrainage leading to low pressure symptoms. The authors designed a simple experiment using catheters of different lengths that drained at different pressure heads and with different vertical drops to study the flow characteristics in these shunts and determine the optimal catheter placement and length that would reduce the occurrence of low pressure headaches. METHODS: The flow rates through catheters of 3 different lengths (60, 83, and 100 cm) with the same internal radius, at 3 different pressure heads (15, 25, and 35 cm H2O to simulate 3 different placements in the lumbar theca), and 3 different vertical drops (10, 20, and 30 cm to simulate the possible effect of siphoning) were measured and the results analyzed. RESULTS: Application of Poiseuille's law and Bernoulli's principle to the experimental design shows that the volume of flow is directly proportional to the sum of the pressure head and the vertical drop and inversely proportional to the length of the catheter. The flow rate through the standard catheter lengths over the course of 24 hours can be abnormally high. An attempt to predict the optimal catheter length was made. CONCLUSIONS: Although the catheter position in the theca and abdomen cannot be altered significantly and the internal radius of the tube cannot be reduced further without increasing the risk of blockage, the length of the tube can be increased to combat overdrainage. The authors suggest that currently available catheters are too short.

Subarachnoid hemorrhage: is it time for a new direction?

BACKGROUND AND PURPOSE: Despite recent advances in the treatment of patients after subarachnoid hemorrhage, morbidity and mortality rates have failed to improve significantly. Although this was often blamed on vasospasm, is it time to consider alternative etiologies? Summary of Review- Early brain injury (EBI) is a recently described term that describes the immediate injury to the brain after subarachnoid hemorrhage. A number of pathways have been recognized as having a role in the etiology of EBI. This review provides a brief synopsis of EBI and its implications for the future. CONCLUSIONS: EBI may be responsible for the detrimental effects seen in patients after subarachnoid hemorrhage. Additional studies are needed to determine the pathophysiology of EBI and to explore potential therapeutic options.

Hyperbaric oxygen and cerebral physiology.

Hyperbaric oxygen (HBO) therapy is defined by the Undersea and Hyperbaric Medical Society (UHMS) as a treatment in which a patient intermittingly breathes 100% oxygen under a pressure that is greater than the pressure at sea level [a pressure greater than 1 atmosphere absolute (ATA)]. HBO has been shown to be a potent means to increase the oxygen content of blood and has been advocated for the treatment of various ailments, including air embolism, carbon monoxide poisoning, wound healing and ischemic stroke. However, definitive established mechanisms of action are still lacking. This has led to uncertainty among clinicians, who have understandingly become hesitant in regard to using HBO therapy, even in situations where it could prove beneficial. Therefore, this review will summarize the literature regarding the effects of HBO on brain oxygenation, cerebral blood flow and intracranial pressure in both the healthy and injured brains, as well as discuss how changes in these three factors can impart protection.

p53 may play an orchestrating role in apoptotic cell death after experimental subarachnoid hemorrhage.

OBJECTIVE: Secondary brain injury after subarachnoid hemorrhage (SAH) is poorly understood. As a result, there are few treatment options. Consequently, SAH is associated with a high rate of morbidity and mortality. In an effort to combat these problems, the role of apoptosis was examined in the whole brain after SAH. In particular, the role of p53 and the three major apoptotic cascades were studied, the caspase-dependent and caspase-independent cascades and the mitochondrial pathway. METHODS: In this study, 195 Sprague-Dawley rats were divided into three groups, including sham, nontreatment, and treatment (Pifithrin-alpha; BIOMOL, Inc., Plymouth Meeting, PA) groups. The monofilament puncture model was used to induce SAH and the animals were subsequently sacrificed at 24 and 72 hours. Western blot analysis, histology, physiological parameters, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling, and immunohistological techniques were used to demonstrate the role of p53 and the apoptotic cascades in the rat brain after SAH. In addition, outcome was determined based on mortality rates and neurological outcome scores. RESULTS: We found that p53 and associated apoptotic proteins were up-regulated after SAH and that downstream mediators of apoptosis were negatively influenced by the inhibition of p53 by Pifithrin-alpha. Furthermore, we found that apoptotic inhibition resulted in less cell death and an overall favorable outcome in the treated animals. CONCLUSION: These results suggest that apoptosis may be an important cause of cell death in the brain after SAH and that p53 may play an orchestrating role regarding apoptosis in SAH.

Limited role of inducible nitric oxide synthase in blood-brain barrier function after experimental subarachnoid hemorrhage.

Excessive nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) may play a pivotal role in blood-brain barrier (BBB) breakdown following subarachnoid hemorrhage (SAH). We investigated if the inhibition of iNOS could reduce BBB breakdown and cerebral edema, thereby leading to improved outcome 24 h after SAH. Forty male rats were assigned to three groups: control, SAH, and treatment groups. SAH was induced by perforating the bifurcation of the internal carotid artery. The neurological score and the mortality were evaluated 24 h after the surgery. The expression of iNOS, the concentration of NO metabolites, morphological changes in neuronal cells, water content, and IgG leakage were also evaluated. The expression of iNOS, as well as the concentration of NO metabolites, was elevated after SAH. Treatment with p-Toluenesulfonate decreased both the expression of iNOS and the concentration of NO metabolites. However, there was no significant change in water content, BBB disruption, or morphological findings between the SAH group and the treatment group. Furthermore no significant differences in neurological score or mortality were observed. The iNOS inhibitor failed to reduce BBB breakdown, brain edema, and neuronal cell death and failed to improve the neurological score and the mortality 24 h after SAH.

Cathepsin and calpain inhibitor E64d attenuates matrix metalloproteinase-9 activity after focal cerebral ischemia in rats.

BACKGROUND AND PURPOSE: Matrix metalloproteinases (MMPs) and cysteine proteases (calpain and cathepsin B) play an important role in cell death and are upregulated after focal cerebral ischemia. Because there is a significant interaction between MMP-9 with calpain and cathepsin B, we investigated the role of E64d (a calpain and cathepsin B inhibitor) on MMP-9 activation in the rat focal ischemia model. METHODS: Male Sprague-Dawley rats were subjected to 2 hours of middle cerebral artery occlusion by using the suture insertion method followed by 22 hours of reperfusion. In the treatment group, a single dose of E64d (5 mg/kg IP) was administrated 30 minutes before the induction of focal ischemia, whereas the nontreatment group received dimethyl sulfoxide only. The neurological deficits, infarct volumes, Evans blue extravasation, brain edema, and MMP-9 activation in the brain were determined. RESULTS: Pretreatment with E64d produced a significant reduction in the cerebral infarction volume (353.1+/-19.8 versus 210.3+/-23.7 mm3) and the neurological deficits. Immunofluorescence studies showed MMP-9, calpain, and cathepsin B activation colocalized to both neurons and the neurovascular endothelial cells after ischemia, which was reduced by E64d. CONCLUSIONS: These results suggest that E64d treatment provides a neuroprotective effect to rats after transient focal cerebral ischemia by inhibiting the upregulation of MMP-9.

Vasospasm and p53-induced apoptosis in an experimental model of subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Despite intensive research efforts, the etiology of vasospasm (sustained constriction of the cerebral vessels) remains unknown. In this study, we investigated the role of p53-induced apoptosis in the vasculature at 24 and 72 hours. To completely examine the apoptotic cascades, key proteins of the caspase-dependent, -independent and mitochondrial pathways were examined. METHODS: In this study, adult rats were divided into 3 groups: sham (n=21), nontreatment (subarachnoid hemorrhage [SAH]+dimethyl sulfoxide; n=42), and treatment (SAH+pifithrin-alpha) (n=42) groups. Each animal in the SAH group underwent a surgical procedure to induce SAH, and the basilar artery was harvested at 24 and 72 hours for analysis. RESULTS: We found severe vasospasm at the 24-hour time point, which persisted to 72 hours. Furthermore, we found that the markers of the apoptotic cascades rose significantly at the 24-hour time point but had dissipated by 72 hours. However, the neurological outcome and mortality scores improved at the 72-hour time point. CONCLUSIONS: Apoptosis, and in particular p53, may play an important role in the etiology of vasospasm with relation to SAH, and in this model, vasospasm persisted to 72 hours, despite the fact that apoptosis does not.

Oxygen treatment after experimental hypoxia-ischemia in neonatal rats alters the expression of HIF-1alpha and its downstream target genes.

Recently, mounting evidence has emerged to suggest that hyperbaric oxygenation (HBOT)-induced neuroprotection after experimental global ischemia and subarachnoid hemorrhage entails a decrease in the expression of hypoxia-inducible factor-1alpha (HIF-1alpha). Therefore, the purpose of this study was to test the hypothesis that oxygen-induced neuroprotection after neonatal hypoxia-ischemia involves alterations in the expression of HIF-1alpha. Seven-day-old rat pups were subjected to unilateral carotid artery ligation followed by 2 h of hypoxia (8% O(2) at 37 degrees C). Pups were then treated with HBOT (2.5 ATA) or normobaric oxygenation treatment (NBOT) for 2 h. The expression and phosphorylation status of HIF-1alpha was evaluated at intervals up to 24 h after the insult, as was the expression of glucose transporter (GLUT)-1, GLUT-3, lactate dehydrogenase (LDH), aldolase (Ald), and p53. The protein-protein interaction of HIF-1alpha and p53 was also examined. An elevated expression of HIF-1alpha, GLUT-1, GLUT-3, Ald, and LDH was observed after the insult. An increase in the dephosphorylated form of HIF-1alpha was followed by an increase in the association of HIF-1alpha with p53 and an increase in p53 levels. Both HBOT and NBOT reduced the elevated expression of HIF-1alpha and decreased its dephosphorylated form. Furthermore, both treatments promoted a transient increase in the expression of GLUT-1, GLUT-3, LDH, and Ald, while decreasing the HIF-1alpha-p53 interaction and decreasing the expression of p53. Therefore, the alteration of the HIF-1alpha phenotype by a single oxygen treatment may be one of the underlying mechanisms for the observed oxygen-induced neuroprotection seen when oxygen is administered after a neonatal hypoxic-ischemic insult.

A novel neuroprotectant granulocyte-colony stimulating factor.

BACKGROUND AND PURPOSE: Granulocyte-colony stimulating factor (G-CSF) is a growth factor that orchestrates the proliferation, differentiation, and survival of hematopoietic progenitor cells. It has been used for many years in clinical practice to accelerate the recovery of patients from neutropenia after cytotoxic therapy. However, there is a growing body of evidence from experimental studies suggesting that G-CSF also has important nonhematopoietic functions in the central nervous system. SUMMARY OF REVIEW: The presence of the G-CSF/G-CSF-receptor system in the brain and its role in neuroprotection and neural tissue repair has been investigated in many recent studies. The neuroprotective actions of G-CSF have mainly been attributed to its anti-inflammatory and antiapoptotic effects. Furthermore, it induces neurogenesis and angiogenesis and improves functional recovery. In this review, we summarize the role of G-CSF and the corresponding signal transduction pathways regulated by G-CSF in neuroprotection. CONCLUSIONS: Much additional work is needed to better understand the precise mechanisms of G-CSF-induced neuroprotection. However, there is emerging data suggesting that G-CSF is a potential new agent for neuroprotection.