Haemostatic studies in subarachnoid haemorrhage.

Object. The primary objective of this thesis was to establish the pattern of change in haemostatic systems in patients following a subarachnoid haemorrhage (SAH). I hypothesise that following a SAH there is an undefined period of increasing hypercoagulability, which if present would predispose to ischaemic stroke. Methods. This was a prospective, observational study on 67 consecutive patients admitted with a primary diagnosis of SAH. There were 24 males, median age 47.5 years (25-75) and 43 females, median age 53 years (23- 80). Blood was taken at 4 time periods (<48hours, 4-5, 9-10 and 15-16 days) following the ictus depending on the day of hospital admission, and on regular intervals during the hospital stay. In addition, a sample was taken at 3 months from the ictus. A Thromboelastograph (TEG) profile performed at 37 C, and the routine coagulation studies, International Normalised Ratio (INR) and Activated Partial Thromboplastin Time Ratio (APTR) were obtained at each of these time points. In addition a full blood count, biochemical profile, and plasma for coagulation and fibrinolytic assays was also taken. Results. The results demonstrated that SAH patients were hypercoagulable immediately following the ictus, when compared with the blood sample taken 3 months later. In addition we observed the development of an increasingly hypercoagulable state for the first 21 days following the ictus. This increase in coagulation was demonstrated against a background of haemodilution during this time. Conclusions. This highly significant data demonstrates that SAH patients become increasingly hypercoagulable over time (maximum 21 days) following the ictus. This prothrombotic tendency has reversed by 3 months. This may provide a new direction in the treatment of symptomatic vasospasm. In addition, an in-vitro study using TEG has been performed in 20 volunteer subjects to assess whether haemodilution 'per se' has an intrinsic affect on coagulation specific to the dilutent itself. This study demonstrates that haemodilution does alter coagulation profiles measured using TEG. Different crystalloid and colloid fluids used to achieve haemodilution produce qualitatively consistent but quantitatively very different effects on coagulation in-vitro

Feasibility of simultaneous intracranial EEG-fMRI in humans: a safety study

In epilepsy patients who have electrodes implanted in their brains as part of their pre-surgical assessment, simultaneous intracranial EEG and fMRI (icEEG-fMRI) may provide important localising information and improve understanding of the underlying neuropathology. However, patient safety during icEEG-fMRI has not been addressed. Here the potential health hazards associated with icEEG-fMRI were evaluated theoretically and the main risks identified as: mechanical forces on electrodes from transient magnetic effects, tissue heating due to interaction with the pulsed RF fields and tissue stimulation due to interactions with the switched magnetic gradient fields. These potential hazards were examined experimentally in vitro on a Siemens 3 T Trio, 1.5 T Avanto and a GE 3 T Signa Excite scanner using a Brain Products MR compatible EEG system. No electrode flexion was observed. Temperature measurements demonstrated that heating well above guideline limits can occur. However heating could be kept within safe limits (< 1.0 °C) by using a head transmit RF coil, ensuring EEG cable placement to exit the RF coil along its central z-axis, using specific EEG cable lengths and limiting MRI sequence specific absorption rates (SARs). We found that the risk of tissue damage due to RF-induced heating is low provided implant and scanner specific SAR limits are observed with a safety margin used to account for uncertainties (e.g. in scanner-reported SAR). The observed scanner gradient switching induced current (0.08 mA) and charge density (0.2 μC/cm2) were well within safety limits (0.5 mA and 30 μC/cm2, respectively). Site-specific testing and a conservative approach to safety are required to avoid the risk of adverse events

Simultaneous intracranial EEG and fMRI of interictal epileptic discharges in humans

Simultaneous scalp EEG–fMRI measurements allow the study of epileptic networks and more generally, of the coupling between neuronal activity and haemodynamic changes in the brain. Intracranial EEG (icEEG) has greater sensitivity and spatial specificity than scalp EEG but limited spatial sampling. We performed simultaneous icEEG and functional MRI recordings in epileptic patients to study the haemodynamic correlates of intracranial interictal epileptic discharges (IED). Two patients undergoing icEEG with subdural and depth electrodes as part of the presurgical assessment of their pharmaco-resistant epilepsy participated in the study. They were scanned on a 1.5 T MR scanner following a strict safety protocol. Simultaneous recordings of fMRI and icEEG were obtained at rest. IED were subsequently visually identified on icEEG and their fMRI correlates were mapped using a general linear model (GLM). On scalp EEG–fMRI recordings performed prior to the implantation, no IED were detected. icEEG–fMRI was well tolerated and no adverse health effect was observed. intra-MR icEEG was comparable to that obtained outside the scanner. In both cases, significant haemodynamic changes were revealed in relation to IED, both close to the most active electrode contacts and at distant sites. In one case, results showed an epileptic network including regions that could not be sampled by icEEG, in agreement with findings from magneto-encephalography, offering some explanation for the persistence of seizures after surgery. Hence, icEEG–fMRI allows the study of whole-brain human epileptic networks with unprecedented sensitivity and specificity. This could help improve our understanding of epileptic networks with possible implications for epilepsy surgery

Premature mortality in refractory partial epilepsy: does surgical treatment make a difference?

Background: Epilepsy carries an increased risk of premature death. For some people with intractable focal epilepsy, surgery offers hope for a seizure-free life. The authors aimed to see whether epilepsy surgery influenced mortality in people with intractable epilepsy. Methods: The authors audited survival status in two cohorts (those who had surgery and those who had presurgical assessment but did not have surgery). Results: There were 40 known deaths in the non-surgical group (3365 person years of follow-up) and 19 in the surgical group (3905 person-years of follow-up). Non-operated patients were 2.4 times (95% CI 1.4 to 4.2) as likely to die as those who had surgery. They were 4.5 times (95% CI 1.9 to 10.9) as likely to die a probable epilepsy-related death. In the surgical group, those with ongoing seizures 1 year after surgery were 4.0 (95% CI 1.2 to 13.7) times as likely to die as those who were seizure-free or who had only simple partial seizures. Time-dependent Cox analysis showed that the yearly outcome group did not significantly affect mortality (HR 1.3, 95% CI 0.9 to 1.8). Conclusion: Successful epilepsy surgery was associated with a reduced risk of premature mortality, compared with those with refractory focal epilepsy who did not have surgical treatment. To some extent, the reduced mortality is likely to be conferred by inducing freedom from seizures. It is not certain whether better survival is attributable only to surgery, as treatment decisions were not randomised, and there may be inherent differences between the groups.<br/

Doublecortin-expressing cell types in temporal lobe epilepsy

Doublecortin (DCX) is widely regarded as a marker of immature and migrating neurons during development. While DCX expression persists in adults, particularly in the temporal lobe and neurogenic regions, it is unknown how seizures influence its expression. The aim of the present study was to explore the distribution and characteristics of DCX-expressing cells in surgical and postmortem samples from 40 adult and paediatric patients, with epilepsy and with or without hippocampal sclerosis (HS), compared to post mortem controls. The hippocampus (pes and body), parahippocampal gyrus, amygdala, temporal pole and temporal cortex were examined with DCX immunohistochemistry using four commercially-available DCX antibodies, labelled cells were quantified in different regions of interest as well as their co-expression with cell type specific markers (CD68, Iba1, GFAP, GFAP∂, nestin, SOX2, CD34, OLIG2, PDGFRβ, NeuN) and cell cycle marker (MCM2). Histological findings were compared with clinical data, as well as gene expression data obtained from the temporal cortex of 83 temporal lobe epilepsy cases with HS. DCX immunohistochemistry identified immature (Nestin-/NeuN-) neurons in layer II of the temporal neocortex in patients with and without epilepsy. Their number declined significantly with age but was not associated with the presence of hippocampal sclerosis, seizure semiology or memory dysfunction. DCX+ cells were prominent in the paralaminar nuclei and periamygdalar cortex and these declined with age but were not significantly associated with epilepsy history. DCX expressing cells with ramified processes were prominent in all regions, particularly in the hippocampal subgranular zone, where significantly increased numbers were observed in epilepsy samples compared to controls. DCX ramified cells co-expressed Iba1, CD68 and PDGFRβ, and less frequently MCM2, OLIG2 and SOX2, but no co-localization was observed with CD34, nestin or GFAP/GFAP ∂. Gene expression data from neocortical samples in patients with TLE and HS supported ongoing DCX expression in adults. We conclude that DCX identifies a range of morphological cell types in temporal lobe epilepsy, including immature populations, glial and microglial cell types. Their clinical relevance and biological function requires further study but we show some evidence for alteration with age and in epilepsy

Pathology-MRI correlations in diffuse low-grade epilepsy associated tumors

It is recognized that IDH mutation negative, low-grade epilepsy associated tumors (LEAT) can show diffuse growth patterns and lack the diagnostic hallmarks of either classical dysembryoplastic neuroepithelial tumors (DNT) or typical ganglioglioma. “Nonspecific or diffuse DNT” and more recently “polymorphous low-grade neuroepithelial tumor of the young” have been terms used for these entities. There are few reports on the MRI recognition of these diffuse glioneuronal tumors (dGNT), which is important in planning the extent of surgical resection. In 27 LEATs T1, T2, FLAIR, and postcontrast T1 MRI were evaluated and the pathology reviewed, including immunostaining for NeuN, CD34, MAP2, and IDH1. Each case was then independently classified by pathology or MRI as simple DNT, complex DNT, or dGNT. There was agreement in 23/27 (85%; Kappa score 0.62; p < 0.01). In 4 cases, there was discrepancy in the diagnosis of simple versus complex DNT but 100% agreement achieved for dGNT. DNT showed significantly more expansion of the cortex, cystic change and ventricle extension than dGNT. dGNT showed significantly more subcortical T2w hyperintensity and focal cortical atrophy which correlated on pathology with CD34 expression, cortical neuronal loss and white matter rarefaction. There was no distinct cortical dysplasia component identified by MRI or pathology in any case. This study highlights that dGNT can be reliably discriminated on MRI from DNT

Combined Ex Vivo 9.4T MRI and Quantitative Histopathological Study in Normal and Pathological Neocortical Resections in Focal Epilepsy

High-resolution magnetic resonance imaging (MRI) may improve the preoperative diagnosis of focal cortical dysplasia (FCD) in epilepsy. Quantitative 9.4T MRI was carried out (T1, T2, T2* and magnetization transfer ratio) on 13 cortical resections, representing pathologically confirmed FCD (five cases) and normal cortex. Quantitative immunohistochemistry for myelination (myelin basic protein/SMI94), neuronal populations [microtubule-associated protein 2 (MAP2), neurofilament (SMI31, SMI32), synaptophysin, NeuN, calbindin], reactive glia (GFAP), microglia (CD68) and blood–brain barrier permeability (albumin) was carried out in 43 regions of interest (ROI) from normal and abnormal white matter and cortex. MRI was spatially aligned and quantitative analysis carried out on corresponding ROI. Line profile analysis (LPA) of intensity gradients through the cortex was carried out on MRI and immunostained sections. An inverse correlation was noted between myelin/SMI94 and T1, T2 (P < 0.005) and T2* (P < 0.05; Spearman's correlation) and a positive correlation between neuronal MAP2 and T1 (P < 0.005) and T2* (P < 0.05) over all ROI. Similar pathology–MRI correlations were observed for histologically unremarkable white matter ROI only. LPA showed altered gradient contours in regions of FCD, reflecting abnormal cortical lamination and myelo-architecture, including a preoperatively undetected FCD case. This study demonstrates the ability of quantitative 9.4T MRI to detect subtle differences in neuronal numbers and myelination in histologically normal appearing white matter and LPA in the evaluation of cortical dyslamination. These methods may be translatable to the in vivo detection of mild cortical malformations

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Incidence of hemorrhagic stroke in Black Caribbean, Black African, and White Populations : The South London Stroke Register, 1995-2004

Background and Purpose—Data are lacking on the differences in hemorrhagic stroke incidence between black Caribbean (BC), black African (BA), and white ethnic groups. We estimated the incidence for primary intracerebral hemorrhage (PICH) and subarachnoid hemorrhage (SAH) and the associated risk factors for BCs, BAs, and whites. Methods—First-ever stroke patients were drawn from a prospective community stroke register based in a multi-ethnic population in South London with 9% BCs, 15% BAs, and 63% whites. Incidence rates were standardized to European and world populations and adjusted for age and sex. Incidence rate ratios (IRRs) relative to whites were calculated by Poisson regression. Results—Between 1995 and 2004, 566 incident stroke patients were registered: 395 PICHs and 171 SAHs. For PICH, age and sex-adjusted IRRs were higher in BAs (IRR, 2.80; 95% CI, 2.00 to 3.91) than in BCs (IRR, 1.46; 95% CI, 1.07 to 1.99) and were particularly pronounced for patients age 0 to 64 years: IRR3.95 (95% CI, 2.65 to 5.87) in BAs and 2.38 (95% CI, 1.50 to 3.80) in BCs. For those 65 years, prestroke hypertension was more prevalent in BAs and BCs (P=0.049). For SAH, the IRR was higher in BCs (IRR; 1.62; 95% CI, 1.05 to 2.48) than in BAs (IRR, 0.80; 95% CI, 0.43 to 1.46). Conclusions—The higher incidence of PICH observed in BCs and BAs could be explained by prestroke hypertension being more common among young blacks. The different incidences of SAH in BCs and BAs suggest that the baseline risk of stroke for distinct black ethnic groups is not homogeneous.Peer reviewe