Biomarkers of Sudden Unexpected Death in Epilepsy (SUDEP)

La SUDEP (Sudden Unexpected Death in Epilepsy) è una complicanza devastante dell’epilessia e rappresenta la più comune causa di mortalità prematura in epilessia. Studi volti alla definizione di fattori di rischio clinici hanno permesso di identificare gruppi ad alto rischio. Tuttavia al momento non esistono validati biomarkers genomici, elettrofisiologici o strutturali predittivi di aumentato rischio di SUDEP. Al fine di definire la base genetica della SUDEP, abbiamo condotto una analisi di sequenziamento esomico per esaminare la prevalenza di varianti con effetto deleterio in soggetti deceduti per SUDEP rispetto a pazienti epilettici non deceduti e controlli con altre patologie. Abbiamo riscontrato una prevalenza significativamente aumentata di varianti deleterie diffuse a livello dell’intero genoma nei soggetti deceduti per SUDEP in confronto agli altri gruppi. Un secondo studio di neuroimaging è stato dedicato alla valutazione di anomalie regionali del volume della sostanza grigia in soggetti deceduti per SUDEP, confrontati con soggetti epilettici viventi rispettivamente ad alto e basso rischio per SUDEP, e controlli sani. Abbiamo riscontrato un aumento del volume della sostanza grigia in emisfero destro a livello di amigdala, parte anteriore dell’ippocampo e paraippocampo nei soggetti deceduti per SUDEP e nei soggetti ad alto rischio, rispetto ai soggetti a basso rischio ed ai controlli. Sia il sequenziamento esomico sia il neuroimaging strutturale hanno fornito dati significativi per il profilo di rischio di SUDEP. La definizione dei meccanismi eziologici della SUDEP è fondamentale. La traslazione di tali dati in algoritmi predittivi di rischio individuale consente di promuovere la ‘medicina personalizzata’, allo scopo di adottare strategie preventive e ridurre il rischio individuale di SUDEP in pazienti con epilessia.SUDEP (Sudden Unexpected Death in Epilepsy) is the most devastating outcome in epilepsy and the commonest cause of epilepsy-related premature mortality. Studies of clinical risk factors have allowed identifying high-risk populations. However no genomic, electrophysiological or structural features have emerged as established biomarkers of an increased SUDEP risk. To elucidate the genetic architecture of SUDEP, we used an unbiased whole-exome sequencing approach to examine overall burden and over-representation of deleterious variants in people who died of SUDEP compared to living people with epilepsy and non-epilepsy disease controls. We found significantly increased genome-wide polygenic burden per individual in the SUDEP cohort when compared to epilepsy and non-epilepsy disease controls. The polygenic burden was driven both by the number of variants per individual, and overrepresentation of variants likely to be deleterious in the SUDEP cohort. To elucidate which brain regions may be implicated in SUDEP, we investigated whether regional abnormalities in grey matter volume appear in those who died of SUDEP, compared to subjects at high and low risk for SUDEP, and healthy controls. We identified increased grey matter volume in the right anterior hippocampus/amygdala and parahippocampus in SUDEP cases and people at high risk, when compared to those at low risk and controls. Compared to controls, posterior thalamic grey matter volume, an area mediating oxygen regulation, was reduced in SUDEP cases and subjects at high risk. It is fundamental to understand the range of SUDEP aetiological mechanisms. Our results suggest that both exome sequencing data and structural imaging features may contribute to generate SUDEP risk estimates. Translation of this knowledge into predictive algorithms of individual risk and preventive strategies would promote stratified medicine in epilepsy, with the aim of reducing an individual patient's risk of SUDEP

Brain Injury

The present two volume book "Brain Injury" is distinctive in its presentation and includes a wealth of updated information on many aspects in the field of brain injury. The Book is devoted to the pathogenesis of brain injury, concepts in cerebral blood flow and metabolism, investigative approaches and monitoring of brain injured, different protective mechanisms and recovery and management approach to these individuals, functional and endocrine aspects of brain injuries, approaches to rehabilitation of brain injured and preventive aspects of traumatic brain injuries. The collective contribution from experts in brain injury research area would be successfully conveyed to the readers and readers will find this book to be a valuable guide to further develop their understanding about brain injury

Epilepsy Mortality: Leading Causes of Death, Co-morbidities, Cardiovascular Risk and Prevention

a reuptake inhibitor selectively prevents seizure-induced sudden death in the DBA/1 mouse model of sudden unexpected ... Bilateral lesions of the fastigial nucleus prevent the recovery of blood pressure following hypotension induced by ..

Apport de l’IRM structurelle multimodale dans la chirurgie d’épilepsie : le cas de l’épilepsie insulaire

L’épilepsie insulaire (ÉI) est une forme rare d’épilepsie focale qui, en raison des défis liés à son diagnostic, est difficilement cernable. De plus, la prise en charge des patients avec ÉI s’avère complexifiée par le fait que cette pathologie est fréquemment résistante aux médicaments anti-crises. Pour ces cas médico-réfractaires, la chirurgie insulaire est une option viable. Cela dit, les patients subissant une telle intervention développent fréquemment des déficits neurologiques postopératoires; heureusement, la grande majorité de ceux-ci récupèrent complètement et rapidement. Or, le mécanisme sous-tendant ce singulier rétablissement fonctionnel demeure à ce jour mal compris. Deux modalités modernes d’IRM structurelle, soit l’analyse d’épaisseur corticale et la tractographie, ont permis, dans les dernières années, de décrire les altérations architecturales caractéristiques et potentiellement diagnostiques de divers types d’épilepsie ainsi que de caractériser les remodelages plastiques qui suivent la chirurgie de l’épilepsie extra-insulaire. Cependant, à ce jour, aucune étude ne s’est encore penchée sur le cas de l’ÉI. De ce fait, les études qui constituent cette thèse exploitent l’IRM structurelle afin, d’une part, de dépeindre les altérations d’épaisseur du cortex et de connectivité de matière blanche associées à l’ÉI et, d’autre part, de définir les réarrangements de connectivité subséquents à la chirurgie insulaire pour contrôle épileptique. Les deux premières études de cette thèse ont révélé que l’ÉI était associée à un pattern majoritairement ipsilatéral d’atrophie corticale et d’hyperconnectivité impliquant principalement des sous-régions insulaires et des régions connectées à l’insula. De manière intéressante, la topologie de ces changements correspondait, au moins en partie, à celle du réseau épileptique de l’ÉI. Ensuite, la troisième étude visait à décrire, par le biais d’une méta-analyse, l’histoire naturelle postopératoire des patients subissant une chirurgie pour ÉI. Cette analyse a, entre autres, confirmé que cette chirurgie était efficace (66.7% de disparition des crises) et qu’elle était fréquemment accompagnée de complications neurologiques (42.5%) qui, dans la plupart des cas, étaient transitoires (78.7% des complications) et récupéraient entièrement dans les trois mois postopératoires (91.6% des complications transitoires). Finalement, la quatrième étude a révélé que la chirurgie pour ÉI était suivie d’altérations de connectivité diffuses et bilatérales. Notamment, les connexions présentant une augmentation de connectivité concernaient particulièrement des régions localisées soit près de la cavité chirurgicale ou dans l’hémisphère controlatéral à l’intervention. De plus, la majorité de ces renforcements structurels se sont produits dans les six premiers mois suivant la chirurgie, un délai comparable à celui durant lequel la majeure partie de la récupération fonctionnelle postopératoire a été observée dans notre méta-analyse. En somme, nos résultats suggèrent que les altérations morphologiques en lien avec l’ÉI peuvent correspondre à son réseau épileptique sous-jacent. La topologie de ces changements pourrait constituer un biomarqueur structurel diagnostique qui aiderait à la reconnaissance de l’ÉI et, concomitamment, favoriserait possiblement un traitement chirurgical plus adapté et plus efficace. De plus, les augmentations de connectivité postopératoires pourraient correspondre à des réponses neuroplastiques permettant de prendre en charge les fonctions altérées par la chirurgie. Nos constats ont ainsi contribué à la caractérisation des mécanismes étayant la singulière récupération fonctionnelle accompagnant la chirurgie pour ÉI. À plus grande échelle, nos travaux offrent un aperçu du potentiel de l’IRM structurelle à assister au diagnostic de l’épilepsie focale ainsi qu’à participer à la description des changements plastiques subséquents à une résection neurochirurgicale.Insular epilepsy (IE) is a rare type of focal epilepsy that is difficult to diagnose. In addition to the challenging nature of IE detection, management of patients with this condition is complicated by the tendency of insular seizures to be resistant to anti-seizure medications. For such medically refractory cases, insular surgery constitutes a viable and long-lasting therapeutic option. That said, patients who undergo an insular resection for seizure control frequently develop postoperative neurological deficits; fortunately, most of these impairments recover fully and rapidly. While this favorable postoperative course contributes to improving the outcome of IE surgery, the mechanism underlying the functional recovery remains unknown. Two contemporary structural MRI modalities, namely cortical thickness analysis and tractography, have recently been used to describe characteristic structural alterations of focal epilepsies and to elucidate the postoperative plastic remodeling associated with surgery for extra-insular epilepsy. While these analyses added to our understanding of several localization-related epilepsies, none specifically studied IE. In this thesis, we exploit structural MRI techniques to, first, depict the alterations of cortical thickness and white matter connectivity in IE and, second, define the progressive rearrangements that follow insular surgery for epilepsy. The first two studies of the current thesis showed that IE is associated with a primarily ipsilateral pattern of cortical thinning and hyperconnectivity that mainly involves insular subregions and insula-connected regions. Interestingly, the topology of these changes corresponded, at least in part, to the epileptic network of IE. Furthermore, the third study aimed to describe, via a meta-analysis, the postoperative outcome of patients undergoing surgery for IE. Among other findings, the analysis revealed that insular surgery was effective (66.7% seizure freedom rate) but was associated with a significant risk of neurological complications (42.5%) which, in most cases, were transient (78.7% of all complications) and recovered fully within three months (91.6% of transient complications). Finally, the fourth study showed that surgery for IE was followed by a diffuse pattern of bilateral structural connectivity changes. Notably, connections exhibiting an increase in connectivity were specifically located near the surgical cavity and in the contralateral healthy hemisphere. In addition, the majority of the structural strengthening occurred in the first six months following surgery, a time course that is consistent with the short delay during which most of the postoperative functional recovery was observed in our meta-analysis. Our results suggest that the morphological alterations in IE may reflect its underlying epileptic network. The topology of these changes may constitute a structural biomarker that could help diagnose IE more readily and, concomitantly, potentially enable a more targeted and more effective surgical treatment. Moreover, the postoperative increases in connectivity may be compatible with compensatory neuroplastic responses, a process that arose to recoup the functions of the injured insular cortex. Our findings have therefore contributed to the characterization of the driving process that supports the striking functional recovery seen following surgery for IE. On a larger scale, our work provides insights into the potential of structural MRI to assist in the diagnosis of focal epilepsy and to describe plastic changes following neurosurgical resections

The Largest Unethical Medical Experiment in Human History

This monograph describes the largest unethical medical experiment in human history: the implementation and operation of non-ionizing non-visible EMF radiation (hereafter called wireless radiation) infrastructure for communications, surveillance, weaponry, and other applications. It is unethical because it violates the key ethical medical experiment requirement for “informed consent” by the overwhelming majority of the participants. The monograph provides background on unethical medical research/experimentation, and frames the implementation of wireless radiation within that context. The monograph then identifies a wide spectrum of adverse effects of wireless radiation as reported in the premier biomedical literature for over seven decades. Even though many of these reported adverse effects are extremely severe, the true extent of their severity has been grossly underestimated. Most of the reported laboratory experiments that produced these effects are not reflective of the real-life environment in which wireless radiation operates. Many experiments do not include pulsing and modulation of the carrier signal, and most do not account for synergistic effects of other toxic stimuli acting in concert with the wireless radiation. These two additions greatly exacerbate the severity of the adverse effects from wireless radiation, and their neglect in current (and past) experimentation results in substantial under-estimation of the breadth and severity of adverse effects to be expected in a real-life situation. This lack of credible safety testing, combined with depriving the public of the opportunity to provide informed consent, contextualizes the wireless radiation infrastructure operation as an unethical medical experiment

Separator fluid volume requirements in multi-infusion settings

INTRODUCTION. Intravenous (IV) therapy is a widely used method for the administration of medication in hospitals worldwide. ICU and surgical patients in particular often require multiple IV catheters due to incompatibility of certain drugs and the high complexity of medical therapy. This increases discomfort by painful invasive procedures, the risk of infections and costs of medication and disposable considerably. When different drugs are administered through the same lumen, it is common ICU practice to flush with a neutral fluid between the administration of two incompatible drugs in order to optimally use infusion lumens. An important constraint for delivering multiple incompatible drugs is the volume of separator fluid that is sufficient to safely separate them. OBJECTIVES. In this pilot study we investigated whether the choice of separator fluid, solvent, or administration rate affects the separator volume required in a typical ICU infusion setting. METHODS. A standard ICU IV line (2m, 2ml, 1mm internal diameter) was filled with methylene blue (40 mg/l) solution and flushed using an infusion pump with separator fluid. Independent variables were solvent for methylene blue (NaCl 0.9% vs. glucose 5%), separator fluid (NaCl 0.9% vs. glucose 5%), and administration rate (50, 100, or 200 ml/h). Samples were collected using a fraction collector until <2% of the original drug concentration remained and were analyzed using spectrophotometry. RESULTS. We did not find a significant effect of administration rate on separator fluid volume. However, NaCl/G5% (solvent/separator fluid) required significantly less separator fluid than NaCl/NaCl (3.6 ± 0.1 ml vs. 3.9 ± 0.1 ml, p <0.05). Also, G5%/G5% required significantly less separator fluid than NaCl/NaCl (3.6 ± 0.1 ml vs. 3.9 ± 0.1 ml, p <0.05). The significant decrease in required flushing volume might be due to differences in the viscosity of the solutions. However, mean differences were small and were most likely caused by human interactions with the fluid collection setup. The average required flushing volume is 3.7 ml. CONCLUSIONS. The choice of separator fluid, solvent or administration rate had no impact on the required flushing volume in the experiment. Future research should take IV line length, diameter, volume and also drug solution volumes into account in order to provide a full account of variables affecting the required separator fluid volume

Effects of de-enrichment on post-stroke learning and microglial activation in mice

Stroke is a leading cause of death and lasting disability in adults. The extent of recovery is mediated in part by the patient’s environment both before and after stroke. Institutionalisation or loss of work, leisure activities or social contact constitutes a loss of enrichment and impairs recovery, as well as increasing the risk of depression and anxiety. Previous animal studies have not examined the effect of a period of pre-stroke enrichment followed by post-stroke loss of enrichment. Therefore, we aimed to model this situation using three different levels of enrichment after stroke: Continued ‘normal’ environmental enrichment (EE), de-enrichment (DE), or enhanced enrichment (EEE). Further, we aimed to assess the possible interaction of medial prefrontal cortex (mPFC) lesions and changes in environment and stress on recognition learning and microglial activation, as a marker for inflammation. Adult male C57BL/6J mice were housed for three months in an enriched environment prior to receiving photothrombotic lesions to the mPFC. Immediately after stroke, animals were placed into one of the three environmental conditions: EE, DE, or EEE. Behavioural testing was carried out at one and four weeks post-stroke and included grid walking and cylinder tests to measure motor skills, open field to measure activity levels and anxiety, elevated plus maze and light-dark box to measure anxiety, and novel object and object location recognition to measure learning and memory. Following testing, animals were sacrificed and their brains analysed for stroke volume and secondary degeneration through microglial activation. DE animals had smaller lesion volumes one week after stroke. Stroke and housing conditions had mixed effects on activity levels and anxiety, and had no effect on object memory. Similar to what we have shown previously, stroke EE and stroke EEE groups showed delayed spatial memory impairment at four weeks. Stroke decreased IBA1-positive microglial staining in several brain regions, except for some dense cores seen in the thalamus and median eminence. EE and EEE reduced staining in stroke animals in several areas, including the thalamus and median eminence, which was associated with spatial memory impairment, and may indicate secondary neuronal degeneration in spatial memory circuits. Interestingly, the stroke DE group showed no impairment in spatial memory seen at 4-weeks post-stroke. In addition, these animals also showed no decrease in IBA1 staining in the thalamus, indicating that IBA1 activation may be mitigating the secondary neuronal cell loss associated with the spatial memory impairments. In human patients secondary neuronal loss is common and can lead to delayed cognitive decline. This loss may contribute to post-stroke depression and anxiety. The negative effects of early enrichment may be caused by an increase in stress in the enrichment groups, combined with disruption to the hypothalamic-pituitary-adrenal (HPA) axis caused by mPFC damage. These results may indicate that de-enrichment is protective early after stroke, and that treatment is best delayed for some hours or days to maximise recovery and minimise delayed impairments