Eligibility to drive and neurology: the how and the why.

Driving is an integral part of adult life and losing a driving licence is potentially a major problem. Many neurological conditions may impact on driving, either by increasing the risk of a sudden disabling event or by affecting cognition, vision, reaction speed, motor coordination, peripheral sensation or visuospatial processing. In the UK, the Drivers Medical Group of the Driver and Vehicle Licensing Agency (DVLA) decides whether an individual's medical condition meets the appropriate standards for driving. The licensing decision rests with the DVLA and is not at the clinician's discretion. However, clinicians must inform patients of their legal obligations towards the DVLA and how their neurological symptoms may restrict their driving. We discuss risk assessment, how chronic disabling neurological disease may impact on driving and the general principles of applying medical standards for fitness to drive. We also highlight how legal driving eligibility varies around the world. Finally, we discuss the practical applications relating to a specific case.

Stability of the CpG island methylator phenotype during glioma progression and identification of methylated loci in secondary glioblastomas.

BACKGROUND: Grade IV glioblastomas exist in two forms, primary (de novo) glioblastomas (pGBM) that arise without precursor lesions, and the less common secondary glioblastomas (sGBM) which develop from earlier lower grade lesions. Genetic heterogeneity between pGBM and sGBM has been documented as have differences in the methylation of individual genes. A hypermethylator phenotype in grade IV GBMs is now well documented however there has been little comparison between global methylation profiles of pGBM and sGBM samples or of methylation profiles between paired early and late sGBM samples. METHODS: We performed genome-wide methylation profiling of 20 matched pairs of early and late gliomas using the Infinium HumanMethylation450 BeadChips to assess methylation at >485,000 cytosine positions within the human genome. RESULTS: Clustering of our data demonstrated a frequent hypermethylator phenotype that associated with IDH1 mutation in sGBM tumors. In 80% of cases, the hypermethylator status was retained in both the early and late tumor of the same patient, indicating limited alterations to genome-wide methylation during progression and that the CIMP phenotype is an early event. Analysis of hypermethylated loci identified 218 genes frequently methylated across grade II, III and IV tumors indicating a possible role in sGBM tumorigenesis. Comparison of our sGBM data with TCGA pGBM data indicate that IDH1 mutated GBM samples have very similar hypermethylator phenotypes, however the methylation profiles of the majority of samples with WT IDH1 that do not demonstrate a hypermethylator phenotype cluster separately from sGBM samples, indicating underlying differences in methylation profiles. We also identified 180 genes that were methylated only in sGBM. Further analysis of these genes may lead to a better understanding of the pathology of sGBM vs pGBM. CONCLUSION: This is the first study to have documented genome-wide methylation changes within paired early/late astrocytic gliomas on such a large CpG probe set, revealing a number of genes that maybe relevant to secondary gliomagenesis.

The intrathecal CD163-haptoglobin-hemoglobin scavenging system in subarachnoid hemorrhage.

Delayed cerebral ischemia resulting from extracellular hemoglobin is an important determinant of outcome in subarachnoid hemorrhage. Hemoglobin is scavenged by the CD163-haptoglobin system in the circulation, but little is known about this scavenging pathway in the human CNS. The components of this system were analyzed in normal cerebrospinal fluid and after subarachnoid hemorrhage. The intrathecal presence of the CD163-haptoglobin-hemoglobin scavenging system was unequivocally demonstrated. The resting capacity of the CD163-haptoglobin-hemoglobin system in the normal CNS was 50 000-fold lower than that of the circulation. After subarachnoid hemorrhage, the intrathecal CD163-haptoglobin-hemoglobin system was saturated, as shown by the presence of extracellular hemoglobin despite detectable haptoglobin. Hemoglobin efflux from the CNS was evident, enabling rescue hemoglobin scavenging by the systemic circulation. Therefore, the CNS is not capable of dealing with significant intrathecal hemolysis. Potential therapeutic options to prevent delayed cerebral ischemia ought to concentrate on augmenting the capacity of the intrathecal CD163-haptoglobin-hemoglobin scavenging system and strategies to encourage hemoglobin efflux from the brain.

NICE guidance on the use of carmustine wafers in high grade gliomas: a national study on variation in practice.

BACKGROUND: Multidisciplinary team (MDT) working in oncology aims to improve outcomes for patients with cancer. One role is to ensure the implementation of best practice and National Institute for Health and Clinical Excellence (NICE) guidance. In this study, we have assessed the role of MDT in implementing the TA121 appraisal of the use of carmustine wafers in high grade gliomas. METHODS: 296 patients with high-grade glioma suitable for maximal resection were recruited from 17 Neurosurgical Centres. The number of patients treated with carmustine wafers and reasons for not using this were recorded. Complications at 48 hours post-operatively and at 6 weeks post-radiotherapy were recorded. RESULTS: 94/296 (32%) of suitable patients received carmustine wafers. In 55% of cases carmustine was not used due to either surgeon preference or a lack of an MDT decision. There was no increased complication rate with carmustine use at either 48 hours post-surgery or at 6 weeks post radiotherapy. Use of carmustine wafers did not decrease access to and use of chemoradiotherapy. CONCLUSIONS: One third of patients suitable for carmustine wafers received them. Their use was neither associated with more frequent complications, nor decreased use of chemoradiotherapy. Implementation of NICE TA121 Guidance is extremely variable in different MDTs across the United Kingdom.

Vagus Nerve Stimulation as a Potential Therapy in Early Alzheimer's Disease: A Review.

Cognitive dysfunction in Alzheimer's disease (AD) is caused by disturbances in neuronal circuits of the brain underpinned by synapse loss, neuronal dysfunction and neuronal death. Amyloid beta and tau protein cause these pathological changes and enhance neuroinflammation, which in turn modifies disease progression and severity. Vagal nerve stimulation (VNS), via activation of the locus coeruleus (LC), results in the release of catecholamines in the hippocampus and neocortex, which can enhance synaptic plasticity and reduce inflammatory signalling. Vagal nerve stimulation has shown promise to enhance cognitive ability in animal models. Research in rodents has shown that VNS can have positive effects on basal synaptic function and synaptic plasticity, tune inflammatory signalling, and limit the accumulation of amyloid plaques. Research in humans with invasive and non-invasive VNS devices has shown promise for the modulation of cognition. However, the direct stimulation of the vagus nerve afforded with the invasive procedure carries surgical risks. In contrast, non-invasive VNS has the potential to be a broadly available therapy to manage cognitive symptoms in early AD, however, the magnitude and specificity of its effects remains to be elucidated, and the non-inferiority of the effects of non-invasive VNS as compared with invasive VNS still needs to be established. Ongoing clinical trials with healthy individuals and patients with early AD will provide valuable information to clarify the potential benefits of non-invasive VNS in cognition and AD. Whether invasive or non-invasive VNS can produce a significant improvement on memory function and whether its effects can modify the progression of AD will require further investigation.

Development and in vivo evaluation of Irinotecan-loaded Drug Eluting Seeds (iDES) for the localised treatment of recurrent glioblastoma multiforme.

Glioblastoma multiforme (GBM) is impossible to fully remove surgically and almost always recurs at the borders of the resection cavity, while systemic delivery of therapeutic drug levels to the brain tumour is limited by the blood-brain barrier. This research describes the development of a novel formulation of Irinotecan-loaded Drug Eluting Seeds (iDES) for insertion into the margin of the GBM resection cavity to provide a sustained high local dose with reduced systemic toxicities. We used primary GBM cells from both the tumour core and Brain Around the Tumour tissue from recurrent GBM patients to demonstrate that irinotecan is more effective than temozolomide. Irinotecan had a 75% response rate, while only 50% responded to temozolomide. With temozolomide the cell viability was never below 80% whereas irinotecan achieved cell viabilities of less than 44%. The iDES were manufactured using a hot melt extrusion process with accurate irinotecan drug loadings and the same cytotoxicity as unformulated irinotecan. The iDES released irinotecan in a sustained fashion for up to 7 days. However, only the 30, 40 and 50% w/w loaded iDES formulations released the 300 to 1000 µg of irinotecan needed to be effective in vivo. The 30 and 40% w/w iDES formulations containing 10% plasticizer and either 60 or 50% PLGA prolonged survival from 27 to 70 days in a GBM xenograft mouse resection model with no sign of tumour recurrence. The 30% w/w iDES formulations showed equivalent toxicity to a placebo in non-tumour bearing mice. This innovative drug delivery approach could transform the treatment of recurrent GBM patients by improving survival and reducing toxicity.

Pharmacokinetics, safety, and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial.

BACKGROUND: The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib potentiated radiation and temozolomide (TMZ) chemotherapy in preclinical glioblastoma models but brain penetration was poor. Clinically, PARP inhibitors exacerbate the hematological side effects of TMZ. The OPARATIC trial was conducted to measure penetration of recurrent glioblastoma by olaparib and assess the safety and tolerability of its combination with TMZ. METHODS: Preclinical pharmacokinetic studies evaluated olaparib tissue distribution in rats and tumor-bearing mice. Adult patients with recurrent glioblastoma received various doses and schedules of olaparib and low-dose TMZ in a 3 + 3 design. Suitable patients received olaparib prior to neurosurgical resection; olaparib concentrations in plasma, tumor core and tumor margin specimens were measured by mass spectrometry. A dose expansion cohort tested tolerability and efficacy of the recommended phase II dose (RP2D). Radiosensitizing effects of olaparib were measured by clonogenic survival in glioblastoma cell lines. RESULTS: Olaparib was a substrate for multidrug resistance protein 1 and showed no brain penetration in rats but was detected in orthotopic glioblastoma xenografts. Clinically, olaparib was detected in 71/71 tumor core specimens (27 patients; median, 496 nM) and 21/21 tumor margin specimens (9 patients; median, 512.3 nM). Olaparib exacerbated TMZ-related hematological toxicity, necessitating intermittent dosing. RP2D was olaparib 150 mg (3 days/week) with TMZ 75 mg/m2 daily for 42 days. Fourteen (36%) of 39 evaluable patients were progression free at 6 months. Olaparib radiosensitized 6 glioblastoma cell lines at clinically relevant concentrations of 100 and 500 nM. CONCLUSION: Olaparib reliably penetrates recurrent glioblastoma at radiosensitizing concentrations, supporting further clinical development and highlighting the need for better preclinical models.

Delayed central nervous system manifestation of Chikungunya virus with magnetic resonance T2 weighted imaging high signal changes-a case report.

CHIKV is a relatively new virus and we are still learning about the illness. Very little is known about CNS its involvement and even less about its delayed or long-term manifestations if any. It therefore behoves us to consider delayed CNS involvement when assessing patients with CHIKV infections that may not have had an acute neurological manifestation at the time of diagnosis coupled with new onset neurological manifestations and MRI abnormalities. It seems likely that patients with CHIKV may experience delayed CNS manifestation of the viral infection. This report highlights the importance of a travel history when assessing patients with a neurological complaint. The pathway to best manage such cases is with repeated imaging to assess if the signal changes either progress, resolve or more importantly if there is any MRI correlation should changes in neurology develop during the surveillance period.

Verteporfin selectively kills hypoxic glioma cells through iron-binding and increased production of reactive oxygen species.

Gliomas are highly malignant brain tumours characterised by extensive areas of poor perfusion which subsequently leads to hypoxia and reduced survival. Therapies that address the hypoxic microenvironment are likely to significantly improve patient outcomes. Verteporfin, a benzoporphyrin-like drug, has been suggested to target the Yes-associated protein (YAP). Increased YAP expression and transcriptional activity has been proposed in other tumour types to promote malignant cell survival and thus YAP-inhibitor, verteporfin, may be predicted to impact glioma cell growth and viability. Due to the extensive hypoxic nature of gliomas, we investigated the effect of hypoxia on YAP expression and found that YAP transcription is increased under these conditions. Treatment of both primary and immortalised glioblastoma cell lines with verteporfin resulted in a significant decrease in viability but strikingly only under hypoxic conditions (1% O2). We discovered that cell death occurs through a YAP-independent mechanism, predominately involving binding of free iron and likely through redox cycling, contributes to production of reactive oxygen species. This results in disruption of normal cellular processes and death in cells already under oxidative stress - such as those in hypoxia. We suggest that through repurposing verteporfin, it represents a novel means of treating highly therapy-resistant, hypoxic cells in glioma.

Investigating the impact of headaches on the quality of life of patients with glioblastoma multiforme: a qualitative study.

OBJECTIVES: Headaches and facial pain have been identified as the most prevalent form of pain among patients with glioblastoma multiforme, the most common malignant primary brain tumour. Despite this, minimal research has been undertaken investigating the direct and indirect impact these headaches have on their quality of life. Therefore, in this study, we aimed at gaining a personal insight into the importance and impact that these headaches have on the quality of life of patients with glioblastoma multiforme. DESIGN: Exploratory study using face-to-face semistructured interviews. Interviews were audio-recorded, transcribed verbatim and then qualitatively analysed using thematic analysis. SETTING: Participants recruited from a tertiary referral hospital in Birmingham, UK. PARTICIPANTS: Purposive sampling of 14 registered outpatients recently diagnosed with glioblastoma multiforme. RESULTS: 3 themes were identified: (1) an underlying attitude of determination and positivity; (2) impact of headache unpredictability on social interaction; (3) headaches found to act as a springboard onto thoughts regarding their disease and future. CONCLUSIONS: While the quality of life of patients with glioblastoma multiforme is clearly multifactorial, headaches do indeed play a part for some. However, it is not the direct pain of the headache as one might expect that impacts on the quality of life of these patients, but the indirect effect of headaches through limiting patients' social lives and by serving as a painful psychological reminder of having a life-threatening illness. In clinical practice, using headache diaries for these patients may help provide a more comprehensive assessment and further aid management plans. Alongside acting as an important reminder of the potential secondary implications of this disease, suggestions for future research include quantitatively investigating whether headaches can act as a prognostic indicator for quality of life within this patient demographic and determining whether these conclusions also hold true for a wider spectrum of patients with brain tumour.

DNA methylation profiles of long- and short-term glioblastoma survivors.

Glioblastoma (GBM) is the most common and malignant type of primary brain tumor in adults and prognosis of most GBM patients is poor. However, a small percentage of patients show a long term survival of 36 mo or longer after diagnosis. Epigenetic profiles can provide molecular markers for patient prognosis: recently, a G-CIMP positive phenotype associated with IDH1 mutations has been described for GBMs with good prognosis. In the present analysis we performed genome-wide DNA methylation profiling of short-term survivors (STS; overall survival < 1 y) and long-term survivors (LTS; overall survival > 3 y) by utilizing the HumanMethylation450K BeadChips to assess quantitative methylation at > 480,000 CpG sites. Cluster analysis has shown that a subset of LTS showed a G-CIMP positive phenotype that was tightly associated with IDH1 mutation status and was confirmed by analysis of the G-CIMP signature genes. Using high stringency criteria for differential hypermethylation between non-cancer brain and tumor samples, we identified 2,638 hypermethylated CpG loci (890 genes) in STS GBMs, 3,101 hypermethylated CpG loci (1,062 genes) in LTS (wild type IDH1) and 11,293 hypermethylated CpG loci in LTS (mutated for IDH1), reflecting the CIMP positive phenotype. The location of differentially hypermethylated CpG loci with respect to CpG content, neighborhood context and functional genomic distribution was similar in our sample set, with the majority of CpG loci residing in CpG islands and in gene promoters. Our preliminary study also identified a set of CpG loci differentially hypermethylated between STS and LTS cases, including members of the homeobox gene family (HOXD8, HOXD13 and HOXC4), the transcription factors NR2F2 and TFAP2A, and Dickkopf 2, a negative regulator of the wnt/ß-catenin signaling pathway.

Comparison of time taken from initial presentation to histological diagnosis of Glioblastoma Multiforme (GBM) in Birmingham, United Kingdom and Strasbourg, France.

BACKGROUND: The aim of this study was to investigate possible delays in referral time for Glioblastoma multiforme (GBM) patients diagnosed at two similar neurosurgical centres (in Birmingham, UK and Strasbourg, France) and their impact on survival. Differences in the referral patterns for GBM patients within these healthcare systems may affect subsequent management and are potential targets to optimise the care of patients with GBM. METHODS: Medical case notes of 105 GBM patients in Birmingham and 81 in Strasbourg, admitted during October 2006 and April 2008, were reviewed. Data regarding demographic details, route of admission, presenting symptoms, date of initial presentation to a medical professional and dates of the first CT or MRI scan, first neurosurgical intervention, histological diagnosis and mortality was recorded. RESULTS: The median time taken from initial presentation to first neurosurgical intervention was lower in Birmingham compared to Strasbourg (13 vs. 21 days, respectively; p=0.026). Similarly, the time taken from initial presentation to histological diagnosis was lower in Birmingham (15 vs. 24 days, respectively; p=0.011). However, survival was poorer in Birmingham than Strasbourg (p=0.001) and age (HR=1.029; 95%CI 1.010-1.048; p=0.003) and time from initial presentation to neurosurgical intervention (HR=0.993; 95%CI 0.988-0.998; p=0.011) were predictors of mortality in these groups. CONCLUSION: Patients in Birmingham are diagnosed with GBM more rapidly than those in Strasbourg but they have poorer survival. Differences in disease severity may partially account for the observed results and further large scale work is required to support this study.

L-amino acid transporter-1 and boronophenylalanine-based boron neutron capture therapy of human brain tumors.

The system l-amino acid transporter-1 (LAT-1) imports p-boronophenylalanine (BPA) into cells and may play a major role in the effectiveness of BPA-based boron neutron capture therapy. The functional status of LAT-1 and its relationship to cell proliferation were simultaneously examined in the same section of human tumor material using a dual-labeling technique. The uptake of BPA (boron inductively coupled plasma mass spectrometry) was profiled in the presence of agonists and antagonists in fresh tumor explants. The number of LAT-1-expressing cells (mean +/- SD) was three times higher than that of proliferating cell nuclear antigen (PCNA)-expressing cells (71.5 +/- 17.02% versus 23.8 +/- 16.5%; P < 0.0001; n = 38 glioblastoma and metastatic tumors). There was no correlation between PCNA cells and the number of LAT-1/PCNA double-stained cells, and not all PCNA-expressing cells coexpressed LAT-1. Boron uptake reached 30 +/- 15 mug/g of wet weight of tissue by 4 hours both in tumor and brain around tumor tissue containing tumor cells compared with time 0 (P < 0.005; n = 4 glioblastoma tumors). This uptake was inhibited by both phenylalanine and 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid. These LAT-1 data indicate that BPA-based boron neutron capture therapy might affect up to 70% of tumor cells, representing a three times higher proportion of tumor cells than their cell cycle status might suggest. Cells expressing PCNA, but not LAT-1, will require a different therapeutic strategy.

Proliferative activity and in vitro replication of HSV1716 in human metastatic brain tumours.

BACKGROUND: The neurotropic herpes simplex virus mutant HSV1716 lacks the gene encoding the virulence factor ICP34.5 and cannot replicate in non-dividing cells where proliferating cell nuclear antigen (PCNA) is not actively engaged in cellular DNA synthesis. In the brain, tumoral expression of PCNA therefore confers on it oncolytic specificity and may determine its efficacy. Three phase I trials in glioma patients and one in metastatic melanoma patients have established that HSV1716 is safe and replicates selectively in tumour tissue. Here we examine the in situ PCNA profiles of common human metastatic brain tumours and determine their in vitro permissivity for HSV1716 replication to ascertain their suitability for HSV1716 therapy. METHODS: Histological sections of tumour biopsies obtained from patients undergoing craniotomies were stained for PCNA expression. The replicative ability of HSV wild-type (17(+)) and mutant (1716) viruses was assessed in tissue cultures of the same tumour biopsies and in cancer cell lines by plaque assay. RESULTS: Biopsies of all 10 metastatic tumours (3 melanoma, 4 carcinoma and 3 adenocarcinoma) as well as 4 glioblastoma multiforme were positive for PCNA immunoexpression and supported the replication of HSV1716. The PCNA-positive cells in the metastatic tumours were distributed comparatively in larger and more contiguous areas than in glioblastoma (1.69 +/- 1.61 mm(2) vs. 0.73 +/- 0.77 mm(2)) and numbered 29.0 +/- 12.4 and 12.6 +/- 4.7%, respectively. CONCLUSIONS: The results show that human cerebral metastatic tumours have generally larger and more contiguous proliferative areas, support efficient HSV1716 replication, and are thus potential candidates for such oncolytic viral therapy.