Implantable Micro-Device for Epilepsy Seizure Detection and Subsequent Treatment

RÉSUMÉ L’émergence des micro-dispositifs implantables est une voie prometteuse pour le traitement de troubles neurologiques. Ces systèmes biomédicaux ont été exploités comme traitements non-conventionnels sur des patients chez qui les remèdes habituels sont inefficaces. Les récents progrès qui ont été faits sur les interfaces neuronales directes ont permis aux chercheurs d’analyser l’activité EEG intracérébrale (icEEG) en temps réel pour des fins de traitements. Cette thèse présente un dispositif implantable à base de microsystèmes pouvant capter efficacement des signaux neuronaux, détecter des crises d’épilepsie et y apporter un traitement afin de l’arrêter. Les contributions principales présentées ici ont été rapportées dans cinq articles scientifiques, publiés ou acceptés pour publication dans les revues IEEE, et plusieurs autres tels que «Low Power Electronics» et «Emerging Technologies in Computing». Le microsystème proposé inclus un circuit intégré (CI) à faible consommation énergétique permettant la détection de crises d’épilepsie en temps réel. Cet CI comporte une pré-amplification initiale et un détecteur de crises d’épilepsie. Le pré-amplificateur est constitué d’une nouvelle topologie de stabilisateur d’hacheur réduisant le bruit et la puissance dissipée. Les CI fabriqués ont été testés sur des enregistrements d’icEEG provenant de sept patients épileptiques réfractaires au traitement antiépileptique. Le délai moyen de la détection d’une crise est de 13,5 secondes, soit avant le début des manifestations cliniques évidentes. La consommation totale d’énergie mesurée de cette puce est de 51 μW. Un neurostimulateur à boucle fermée (NSBF), quant à lui, détecte automatiquement les crises en se basant sur les signaux icEEG captés par des électrodes intracrâniennes et permet une rétroaction par une stimulation électrique au même endroit afin d’interrompre ces crises. La puce de détection de crises et le stimulateur électrique à base sur FPGA ont été assemblés à des électrodes afin de compléter la prothèse proposée. Ce NSBF a été validé en utilisant des enregistrements d’icEEG de dix patients souffrant d’épilepsie réfractaire. Les résultats révèlent une performance excellente pour la détection précoce de crises et pour l’auto-déclenchement subséquent d’une stimulation électrique. La consommation énergétique totale du NSBF est de 16 mW. Une autre alternative à la stimulation électrique est l’injection locale de médicaments, un traitement prometteur de l’épilepsie. Un système local de livraison de médicament basé sur un nouveau détecteur asynchrone des crises est présenté.----------ABSTRACT Emerging implantable microdevices hold great promise for the treatment of patients with neurological conditions. These biomedical systems have been exploited as unconventional treatment for the conventionally untreatable patients. Recent progress in brain-machine-interface activities has led the researchers to analyze the intracerebral EEG (icEEG) recording in real-time and deliver subsequent treatments. We present in this thesis a long-term safe and reliable low-power microsystem-based implantable device to perform efficient neural signal recording, seizure detection and subsequent treatment for epilepsy. The main contributions presented in this thesis are reported in five journal manuscripts, published or accepted for publication in IEEE Journals, and many others such as Low Power Electronics, and Emerging Technologies in Computing. The proposed microsystem includes a low-power integrated circuit (IC) intended for real-time epileptic seizure detection. This IC integrates a front-end preamplifier and epileptic seizure detector. The preamplifier is based on a new chopper stabilizer topology that reduces noise and power dissipation. The fabricated IC was tested using icEEG recordings from seven patients with drug-resistant epilepsy. The average seizure detection delay was 13.5 sec, well before the onset of clinical manifestations. The measured total power consumption of this chip is 51 µW. A closed-loop neurostimulator (CLNS) is next introduced, which is dedicated to automatically detect seizure based on icEEG recordings from intracranial electrode contacts and provide an electrical stimulation feedback to the same contacts in order to disrupt these seizures. The seizure detector chip and a dedicated FPGA-based electrical stimulator were assembled together with common recording electrodes to complete the proposed prosthesis. This CLNS was validated offline using recording from ten patients with refractory epilepsy, and showed excellent performance for early detection of seizures and subsequent self-triggering electrical stimulation. Total power consumption of the CLNS is 16 mW. Alternatively, focal drug injection is the promising treatment for epilepsy. A responsive focal drug delivery system based on a new asynchronous seizure detector is also presented. The later system with data-dependent computation reduces up to 49% power consumption compared to the previous synchronous neurostimulator

Methods for three-dimensional Registration of Multimodal Abdominal Image Data

Multimodal image registration benefits the diagnosis, treatment planning and the performance of image-guided procedures in the liver, since it enables the fusion of complementary information provided by pre- and intrainterventional data about tumor localization and access. Although there exist various registration methods, approaches which are specifically optimized for the registration of multimodal abdominal scans are only scarcely available. The work presented in this thesis aims to tackle this problem by focusing on the development, optimization and evaluation of registration methods specifically for the registration of multimodal liver scans. The contributions to the research field of medical image registration include the development of a registration evaluation methodology that enables the comparison and optimization of linear and non-linear registration algorithms using a point-based accuracy measure. This methodology has been used to benchmark standard registration methods as well as novel approaches that were developed within the frame of this thesis. The results of the methodology showed that the employed similarity measure used during the registration has a major impact on the registration accuracy of the method. Due to this influence, two alternative similarity metrics bearing the potential to be used on multimodal image data are proposed and evaluated. The first metric relies on the use of gradient information in form of Histograms of Oriented Gradients (HOG) whereas the second metric employs a siamese neural network to learn a similarity measure directly on the image data. The evaluation showed, that both metrics could compete with state of the art similarity measures in terms of registration accuracy. The HOG-metric offers the advantage that it does not require ground truth data to learn a similarity estimation, but instead it is applicable to various data sets with the sole requirement of distinct gradients. However, the Siamese metric is characterized by a higher robustness for large rotations than the HOG-metric. To train such a network, registered ground truth data is required which may be critical for multimodal image data. Yet, the results show that it is possible to apply models trained on registered synthetic data on real patient data. The last part of this thesis focuses on methods to learn an entire registration process using neural networks, thereby offering the advantage to replace the traditional, time-consuming iterative registration procedure. Within the frame of this thesis, the so-called VoxelMorph network which was originally proposed for monomodal, non-linear registration learning is extended for affine and multimodal registration learning tasks. This extension includes the consideration of an image mask during metric evaluation as well as loss functions for multimodal data, such as the pretrained Siamese metric and a loss relying on the comparison of deformation fields. Based on the developed registration evaluation methodology, the performance of the original network as well as the extended variants are evaluated for monomodal and multimodal registration tasks using multiple data sets. With the extended network variants, it is possible to learn an entire multimodal registration process for the correction of large image displacements. As for the Siamese metric, the results imply a general transferability of models trained with synthetic data to registration tasks including real patient data. Due to the lack of multimodal ground truth data, this transfer represents an important step towards making Deep Learning based registration procedures clinically usable

Clinical Management and Evolving Novel Therapeutic Strategies for Patients with Brain Tumors

A dramatic increase in knowledge regarding the molecular biology of brain tumors has been established over the past few years, and this has lead to the development of novel therapeutic strategies for these patients. In this book a review of the options available for the clinical management of patients with these tumors are outlined. In addition advances in radiology both for pre-operative diagnostic purposes along with surgical planning are described. Furthermore a review of newer developments in chemotherapy along with the evolving field of photodynamic therapy both for intra-operative management and subsequent therapy is provided. A discussion of certain surgical management issues along with tumor induced epilepsy is included. Finally a discussion of the management of certain unique problems including brain metastases, brainstem glioma, central nervous system lymphoma along with issues involving patients with a brain tumor and pregnancy is provided

Intraoperative aseptic practices and surgical site infections in breast surgery

Background and aims. Operating theatre (OT) personnel implement intraoperative aseptic practices (AP) to control and prevent surgical site infection (SSI). AP is considered important in both infection control (IC) and prevention (IP), despite the challenges of investigating the causality between APs and SSIs. This study introduces a project regarding co-creating intraoperative APs in the OTs of one university hospital, with another hospital functioning as a comparison setting. Objectives for this study were: 1) to investigate the acceptance of and adherence to APs among OT personnel before and after the co-creation of the evidence-based intraoperative APs and during the follow-up study; 2) to introduce assessment tools for the intraoperative APs for further development and improvement; 3) to explore performance of AP-related clinical situations; and 4) to define risk factors for SSIs in breast operations. Methods. Outcomes of the project were measured as changes in the acceptance of and self-reported adherence to the AP recommendations, and as SSIs in breast surgery. A follow-up study was completed 12 years after the cocreation of the AP recommendations. First, the acceptance of and adherence to the AP recommendations were surveyed among OT personnel before (N=211) and after (N=234) the co-creation of the recommended APs. Twelve years after the co-creation, a follow-up survey was completed only for nurses both in the study and comparison hospital (N=242). An initial literature based intraoperative AP model created to facilitate the AP recommendation cocreation process. Descriptive statistics and summation variables were computed for assessing the AP recommendation acceptance and adherence. Second, using the variables of the aforementioned survey, separate AP assessment tools were created for circulating and scrub nurses. The initial AP model served as a structure for the tools. Clinically relevant assessment criteria were selected to achieve a high internal consistency for the scales. Third, qualitative research was completed in the study hospital. Video recordings of 31 operations served as stimulated recalls during interviews of 31 circulating nurses. The APs were observed and feedback discussions completed at the end of interviews using a criteria-based observation tool. Fourth, all breast operation-related patient documents (N=1042) and SSI statistics from infection register in the two hospitals were reviewed before and after the co-creation of the AP recommendations. After removing contaminated and infected operations descriptive statistics and logistic regression analyses computed to define the SSI risk factors for all breast operations (N=982), lumpectomies (n=700) and mastectomies (n=282). Results. Statistically significant differences in recommendation acceptance were found between professions and genders before and after the recommendation co-creation measured according to establishment, maintenance and disestablishment of the sterile field. Between study and comparison hospitals the differences were significant except not during the disestablishment of the sterile field before co-creation. In self-reported prevention of handborne contamination, differences were found between hospitals, professions and those 52 respondents participated in both measurements. In preventing airborne contamination, differences were found between hospitals and among the 52 respondents. In preventing bloodborne contamination, differences were found between professions, genders and the 52 respondents. The self-reported adherence to preventing bloodborne infections was found to be higher among those respondents with no needlestick injuries from used needles than those reporting a needlestick. After the follow-up survey, a 20-item tool with good scale reliability was constructed for assessing the AP of circulating nurses. The three phases of AP–establishment, maintenance, and disestablishment of the sterile field –structured the tool. In testing the tool, differences were found in AP recommendation acceptance according to education and working experience. Three tools were constructed for scrub nurses. One was for preparing to work, one for working in the sterile field and one for reporting adherence to AP recommendations during maintenance of the sterile field. No differences were found in the acceptance and self-reported AP adherence by demographics among day surgery and OT nurses. The stimulated recall interviews (N=31) of the circulating nurses in the study hospital found variation in adherence to recommended intraoperative APs. The circulating nurses expressed working experience-, time- and equipment-related stress in implementing APs. Also working with demanding persons in OT team, challenges with patients, working morals and power related stress reported regarding implementing the intraoperative AP recommendations. The OT nurses managed the stress by both active and withdrawal behaviour. Reactions were individual and situation specific. No improvement was found in postoperative SSI rates after the co-creation of AP recommendations in the study hospital. A multivariate logistic regression model for all the breast operations (N=982), lumpectomies (n=700) and mastectomies (n=282) was built to explain the risks for postoperative infections (6.7%). In all operations, a contaminated or dirty wound, high American Society of Anaesthesiologists’ score, high patient body mass index, use of surgical drains, and re-operation predicted increased SSI risk. High patient body mass index and use of surgical drains predicted an increased risk in lumpectomies. In mastectomies, the statistically significant predictor was re-operation. Conclusions. The varying acceptance of and adherence to the intraoperative AP recommendations requires improvement. Stress due to the challenges in implementing the AP recommendations is avoidable by co-created evidence-based APs. The SSI risks in breast operations may be managed by considering the use of antimicrobial prophylaxis in re-operations and obese patients. The assessment of intraoperative IP is possible to improve by including the baseline AP model and relevant criteria in the documentation. More carefully planned and implemented projects are necessary for improving the evidence-based recommendations for intraoperative AP to secure the safety of the surgical patients, personnel and environment among anaesthesia personnel also. The expertise of the personnel is important to develop through participative and strategic training and structured follow-up reporting.Tämän tutkimuksen tarkoituksena oli kehittää leikkauksenaikaista aseptista toimintaa yhden suomalaisen yliopistosairaalan leikkausosastolla toisen osaston toimiessa vertailuosastona. Tutkimusprojektin tavoitteina oli: 1) tutkia leikkausosaston henkilökunnan raportoimaa aseptiseen toimintaan liittyvien suositusten hyväksyntää ja suosituksiin sitoutumista, 2) rakentaa arviontityökaluja leikkauksenaikaisen aseptisen toiminnan arviointiin; 3) tutkia aseptisen toiminnan toteutumista rintaleikkausten aikana, sekä 4) määritellä riskitekijöitä rintaleikkauksen jälkeiselle leikkausalueen infektioille. Projektissa dokumentoitiin tutkimukseen perustuvat leikkauksen aikaisen aseptisen toiminnan suositukset sekä laadittiin kirjallisuuteen perustuva malli. Tuloksia mitattiin muutoksina suositusten hyväksymisessä ja noudattamisessa sekä leikkausalueen infektioiden määrässä ennen ja jälkeen suositusten laatimisen. Seurantatutkimuksen jälkeen laadittiin työkalut sekä valvovan hoitajan että steriilillä leikkausalueella työskentelevien toiminnan arvioimiseen. Stimulated recall interview -menetelmällä haastateltiin 31 leikkausta valvovaa sairaanhoitajaa heidän kokemuksistaan aseptisen toiminnan toteuttamisesta rintaleikkauksissa. Aseptisen toiminnan toteutumista ja leikkausalueen infektioiden esiintymistä rintaleikkauksissa (N=1042) arvioitiin kaikista leikkauksiin liittyvistä asiakirjoista. Logistisen regressioanalyysin avulla määritettiin rintaleikkausten jälkeisiä infektioriskejä kaikissa leikkauksissa (N=982), rintakyhmyn- (n=700) ja rinnanpoistoleikkauksissa (n=282). Tilastollisesti merkitseviä eroja suositusten hyväksymisessä havaittiin eri ammattiryhmien, ja sukupuolten välillä ennen ja jälkeen suositusten laatimisen steriilin alueen luomisen, ylläpitämisen ja purkamisen aikana. Seurantatutkimuksen jälkeen eroja havaittiin suositusten hyväksynnässä koulutuksen ja työkokemuksen suhteen. Päiväkirurgisten ja leikkausosastolla työskentelevien sairaanhoitajien välillä eroja ei havaittu. Sairaanhoitajat (N=31) havaitsivat vaihtelua toteuttamassaan aseptisessa toiminnassa. He kokivat leikkauksen aikaisen aseptisen toiminnan stressaavaksi. Stressi liittyi omaan tai leikkausosastolla työskentelevien työkokemukseen, rajalliseen aikaan, työskentelyvälineisiin, työskentelyyn vaativien henkilöiden kanssa, potilaaseen liittyviin haasteisiin sekä työmoraaliin ja vallankäyttöön. Valvovat sairaanhoitajat käyttivät sekä vetäytyviä että aktiivisia keinoja selviytyäkseen stressistä. Projektin jälkeen leikkausalueen infektioiden määrässä (6.7%) ei havaittu vähenemistä. Logistisen regressioanalyysin avulla tunnistettiin leikkausalueen infektioita ennustavia tekijöitä. Kaikissa rintaleikkauksissa (N=982) infektioriskiä lisäsivät kontaminoitunut (3) tai likainen (4) leikkausalue, korkea anestesiariskiä kuvaava (ASA) pistemäärä, korkea painoindeksi (body mass index), kirurgisten laskuputkien käyttö, ja uusintaleikkaus. Korkea painoindeksi ja leikkausalueen dreeni ennustivat infektioriskiä myös rintapatin poiston (n=700) yhteydessä. Rinnanpoisto-leikkauksissa (n=282) uusintaleikkaus lisäsi leikkausalueen infektioriskiä. Vaihtelevuus leikkauksen aikaisessa aseptisessa toiminnassa ja suositusten hyväksynnässä edellyttävät toiminnan parantamista ja kehittämistä. Suositusten toteuttamiseen liittyvä stressi on vähennettävissä moniammatillisesti laadittujen suositusten toimeenpanon avulla. Infektioita voitaneen vähentää harkitsemalla antibiootti-profylaksia uusintaleikkauksissa ja ylipainoisilla. Suositusten ja laaditun mallin avuilla kehittämistyötä voidaan jatkaa

Redox-Active Molecules as Therapeutic Agents

Oxidative stress and altered redox signaling have been described in a plethora of pathological conditions. Redox-active molecules can thus potentially be used to modulate the etiology/progression of such diseases. Recent advances in molecular biology and pharmacology have strengthened this area of research by providing novel mechanistic insights. This book compiles a collection of 13 articles, covering a range of topics from in vitro studies to clinical research, focused on the potential therapeutic effects of either natural or synthetic compounds, applicable to different redox-related diseases

Treatment of Later Humoral Rejection with Anti-CD20 Monoclonal Antibody Rituximab: A Single Centre Experience

Humoral or vascular rejection is a B cell-mediated production of immunoglobulin (Ig) G antibody against a transplanted organ that results in immune complex deposition on the vascular endothelium, activation of the complement cascade, production of endothelial dysfunction and regional ischaemic injury