Daniel C. Walsh

The role of the coagulation system in tumour angiogenesis

The coagulation system, which is activated in most cancer patients, has an important role in tumour biology. It may make a substantial contribution to tumour angiogenesis, which represents an imbalance in the normal mechanisms that allow organised healing after injury. The recently recognised, but steadily growing, knowledge of the relationship between the coagulation and angiogenesis pathways has research and clinical implications. Manipulation of these systems may minimise both the neoangiogenesis essential for tumour growth and associated thromboembolic complications. However, since surgery is the primary treatment for most cancers, the angiogenesis of wound healing and haemostatic competence must be maintained. In this article, we summarise the complex interactions between the coagulation system and the angiogenic process that occur in cancer growth. We focus upon the contributions of the vascular endothelium, platelets, and coagulation factors to the angiogenic process and explore the coagulation system as a therapeutic target.

Thromboembolism in brain tumors.

Venous thromboembolism commonly affects patients receiving treatment for primary and secondary cerebral tumors. We review the recent literature on the molecular mechanisms underlying this hypercoagulable state and clinical studies of antithrombotic prophylaxis and therapy in this population. A computerized search of the MEDLINE database for articles from 1966 to the present day. Keywords/search terms used were glioma, astrocytoma, glioblastoma multiforme, cerebral tumor, primary brain tumour, secondary brain tumour, venous thromboembolism, thromboprophylaxis, heparin, warfarin, anticoagulants, and caval filters. Although neurological deficit has been identified as an independent risk factor for thrombosis it is also clear that malignant brain tumors induce changes in the makeup of circulating blood, making it more likely to clot. Concern for the perceived risk of perioperative intracranial bleeding with antithrombotic prophylaxis appears not to be justified by the available evidence. Prospective assessment of low molecular weight heparins for prophylaxis and treatment of established thrombosis is required. Antithrombotic therapy may also offer advantages over intracaval devices in prevention of secondary pulmonary embolism in patients with brain tumors.

Indocyanine green video-angiography as an aid to surgical treatment of spinal dural arteriovenous fistulae

PurposeTo illustrate the use of indocyanine green (ICG) video-angiography to confirm abolition of spinal dural arteriovenous fistula (SDAVF) and preserve the normal vascular anatomy intraoperatively.MethodsA 73-year-old woman presenting with progressive myelopathy was diagnosed with an SDAVF, where the origin of the fistula was in close proximity to the origin of the posterior spinal artery. ICG was injected intravenously. Using a filter on the microscope, dynamic filling of the abnormal vasculature was visualised.ResultsAfter applying a clip to the fistulous connection, we were able to see the successful interruption of the dural fistula, on-table in real time.ConclusionICG video angiography confirmed interruption of the fistula and preservation of the associated posterior spinal artery. We find the application of this relatively new technology has the potential to shorten operating times, gives additional reassurance of completeness of surgical treatment and preservation of normal spinal vasculature.

Time-Resolved Contrast-Enhanced MR Angiography of Spinal Vascular Malformations

BACKGROUND AND PURPOSE: The diagnosis of spinal vascular malformations may be challenging on conventional MR imaging because neither the location of the signal abnormality in the spinal cord nor the level of the abnormal flow voids correlates with the level of the fistula. We conducted a retrospective evaluation of the utility of using a time-resolved imaging of contrast kinetics sequence in the diagnosis, characterization, and localization of spinal vascular malformations, comparing it with the criterion standard of spinal DSA. MATERIALS AND METHODS: Fifty-five consecutive patients with a suspected diagnosis of spinal vascular malformation underwent time-resolved imaging of contrast kinetics followed by spinal DSA. All scans were performed on a 1.5T scanner by using a standard 8-channel spine coil and were reported by a neuroradiologist before the DSA was performed. RESULTS: Forty-seven lesions were confirmed on time-resolved imaging of contrast kinetics and classified as spinal dural arteriovenous fistulas (n = 33, with 1 patient having a type Ib fistula), perimedullary spinal cord arteriovenous fistulas (n = 10), and intramedullary arteriovenous malformations (n = 3). One patient had an extradural spinal vascular malformation. Time-resolved imaging of contrast kinetics identified the location of the arterial feeder to within 1 vertebral level in 27/33 patients (81.8%) with spinal dural arteriovenous fistulas and correctly predicted the side in 22/33 (66.6%) patients. Perimedullary spinal cord arteriovenous fistulas were erroneously considered to represent spinal dural arteriovenous fistulas before spinal DSA. The anatomy of the arterial supply to intramedullary arteriovenous malformations was also poorly characterized on time-resolved contrast-enhanced MR angiography. CONCLUSIONS: It has been our experience that time-resolved imaging of contrast kinetics is a useful confirmatory tool when a spinal vascular malformation is suspected on the basis of clinical and conventional MR imaging findings. As experience with the technique grows and sequences are refined, it may be possible to rely on time-resolved imaging of contrast kinetics as a screening tool for the diagnosis of spinal vascular malformations.

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.

The NFTI-QOL: A disease-specific quality of life questionnaire for neurofibromatosis 2

The objective of this study was to develop a reliable, validated disease-specific score measuring quality of life (QOL) in clinical practice and treatment trials in Neurofibromatosis 2 (NF2) individuals. In NF2 patients, qualitative interviews (n = 15) and a focus group session (n = 30) generated items for a pilot questionnaire. This was tested and refined (n = 20). The final version (NFTI-QOL) was validated (n = 50) with two generic QOL questionnaires (SF-36 and EuroQOL). The NFTI-QOL was also administered to patients with solitary vestibular schwannoma (SVS) (n = 30) and normal controls (n = 30). The participants were NF2 patients, SVS patients, and normal controls. NFTI-QOL score, SF-36 score, and EuroQOL score were the main outcome measures. Mean NFTI-QOL score was 9.4 (range: 0 to 20, maximum possible score = 24). The NFTI-QOL score correlated strongly with EuroQOL (r = 0.71, p < 0.001) and SF-36 (r = 0.81, p < 0.001). NF2 individuals were significantly worse than the SVS patients, who in turn were worse than the controls on the NIFTI-QOL. The NFTI-QOL showed good internal reliability (Cronbachs α = 0.87). We developed an eight-item disease-specific QOL score for NF2 patients, validated against SF-36 and EuroQOL. It correlated strongly with clinician-rated disease severity in NF2, with better correlation than the SF-36 in this regard.

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.

Prevalence of recurrence and retreatment of ruptured intracranial aneurysms treated with endovascular coil occlusion

Abstract Object. Endovascular coiling is a common treatment for ruptured intracranial aneurysms. However, concerns have been raised over the durability of this treatment. The aim of this study was to establish the rate of recurrence and retreatment of coiled aneurysms treated in our unit. Methods. We performed a retrospective analysis of 264 surviving patients with ruptured aneurysms treated by endovascular coiling between November 2003 and April 2007. Data was collected on patient age, location of aneurysm, angiogram results and any subsequent retreatment. Results. Follow-up angiography performed at 6 months was available in 239 cases (91%) and revealed 158 (66%) aneurysms completely occluded, 51 (21%) had neck recurrence and 31 (13%) had significant recurrence. Thirty (12.6%) aneurysms required retreatment over a mean follow-up period of 46 (range 24–66) months. Younger age predisposed to a higher risk of recurrence and retreatment. Aneurysms of the anterior communicating and anterior cerebral arteries were less likely to recur or require retreatment (relative risk 0.42 and 0.29, respectively); aneurysms of the posterior communicating arteries were more likely to recur (relative risk 2.22). Aneurysms of the basilar and carotid arteries were more likely to undergo retreatment (relative risk 2.84 and 2.46, respectively). Conclusion. Long-term follow-up is required for ruptured aneurysms treated by coiling. Certain subgroups may require closer follow-up due to the increased risk of recurrence or retreatment, such as younger patients and those with aneurysms of the posterior communicating, basilar or carotid arteries.

Intraoperative indocyanine green video-angiography as an aid to the microsurgical treatment of spinal vascular malformations

Abstract Aims and Objectives. Intra-operative Indocyanine Green (ICG) video-angiography (ICG-VA) has become an established aid to cerebrovascular surgery. We describe our experience using this technique to define angio-architecture intraoperatively in a range of spinal vascular malformations. Methods. A retrospective review of notes and imaging was carried out from a prospectively maintained database. Our series comprises 27 patients who underwent surgical treatment between September 2007 and August 2012. We carried out a retrospective review of data from a prospectively maintained database. Results. For slow-flow Type 1 fistulae the ICG videoangiogram demonstrated conclusively that the arteriovenous shunt was obliterated. This is a consideration on the rare occasions where a second fistula is present, an example of which is included in this series. ICG-VA also helps to demonstrate normal vascular anatomy and distinguish these vessels from pathology. For Type II lesions it allowed orientation to the vascular anatomy as demonstrated by the pre-operative angiogram. In one of two cases in this series it ensured to the complete extirpation of a large arteriovenous malformation (AVM). However a second Type II case demonstrated its limitations, as a diffuse intramedullary component could not be identified. Two cases were explored where digital subtraction spinal angiography was not possible and incomplete understanding of the angio-architectures of the lesions were available from Time Resolved dynamic magnetic resonance angiography and/or multi-detector CT angiography. ICG-VA provided invaluable information on alterations in arterio-venous flow that allowed diagnosis and obliteration of the arteriovenous shunts in each case. Discussion. ICG video-angiography is a time-efficient and safe alternative to intra-operative spinal angiography. It provided useful information on haemodynamic changes intraoperatively and completeness of treatment. We discuss its limitations and role in the management of these lesions.

Clinical audit effectively bridges the evidence-practice gap in chronic subdural haematoma management

BackgroundPlacement of a subdural drain after drainage of chronic subdural haematoma (CSDH) has been shown to reduce the rate of recurrence in several randomised controlled trials (RCT). The most recently published RCT was from Cambridge, UK, in 2009. Despite class I evidence for the use of subdural drains, it is unclear whether these results have been translated into clinical practice. In this clinical audit we review the use of subdural drains in our institution before and after the publication of the 2009 RCT results.MethodsA longitudinal retrospective study was performed on all adults having burr holes for CSDH between January 2009 and January 2014. Case notes were analysed to determine subdural drain use, re-operation for CSDH recurrence and post-operative complications. The audit loop was closed with data collected from August 2015 to January 2016.ResultsThirty-one per cent of patients had subdural drains placed at operation. Drain placement was associated with lower reoperation rates (8% vs. 17%, p = 0.021) without increasing complication rates. Drain usage doubled after publication of the Santarius et al. (2009) trial but we observed persisting and significant variability in drain utilisation by supervising consultants. The use of drains in the department increased from 35% to 75% of all cases after presentation of these results.ConclusionsThe use of subdural drains in our unit reduced recurrence rates following drainage of CSDH and reproduced the results of a 2009 clinical trial. Although the use of subdural drains doubled in the post-trial epoch, significant variability remains in practice. Clinical audit provided an effective tool necessary to drive the implementation of subdural drain placement in our unit.