Neurological disorders in rural Tanzania

Neurological disorders, especially those of infectious origin, seem to be more frequent in low-income countries like sub-Saharan Africa. But not only the prevalence estimates seem to be higher in low-income countries, mortality rates tend to be higher compared to high-income countries, too. Seizures as well as meningitis are often reported as one of the leading causes for neurological disorders in patients in sub-Saharan Africa. As shown in our studies, symptoms and signs of neurological diseases like febrile seizures (FSs) and meningitis can appear very similar and render an exact diagnosis difficult, as they often include impairment of consciousness, for example. Several African studies reported that neurological diseases, especially epileptic seizures, FSs and meningitis/meningoencephalitis as leading causes of impairment of consciousness, are often accompanied with adverse outcome such as neurological sequelae and especially infectious diseases such as meningitis may contribute to the high mortality in sub-Saharan Africa. The lack of appropriate diagnostic methods and imaging modalities as well as unqualified workers and the often late presentation at medical services and, last but not least, the lack of appropriate vaccination coverage in rural areas complicate the detection of the exact diagnosis and concomitant diseases and the exclusion of important differential diagnoses, and thus impede an appropriate patient management. The studies of the present thesis were performed from 2002 to 2004 in the United Republic of Tanzania and more specifically at Haydom, Mbulu district; Wasso, Ngorongoro district and Mahenge, Ulanga district. The prevalence and characteristics of FSs were assessed in three community-based door-to-door studies in the catchment area of the Haydom Lutheran Hospital (HLH), Wasso Hospital and Mahenge Hospital, complemented with retrospectively collected data from main hospitals and Mother and Child Health Centers (MCHs) of the study area by using screening questionnaires. In a hospital based study (Haydom Lutheran Hospital), we identified patients with meningitis in order to describe their clinical characteristics including laboratory and clinical aspects. Patients with neurological symptoms and/or signs were examined by a neurologist and clinical as well as laboratory data were collected. Our study found a prevalence rate of 20.5/1,000 (95% CI: 17.5-23.9/1,000) FSs in children between 2 months and 7 years at the time of the interview and is in line with other studies about FSs, however, it does not confirm the assumption of a higher prevalence in low-income countries of sub-Saharan Africa. Reasons for this are varied and include superstitious beliefs, higher mortality rates or inaccurate recollection of events in the past. However, our study confirms a trend of a higher proportion of complex FSs in low-income countries. This is important, as complex FSs have been discussed as possible risk factors for the development of later neurological sequelae like epilepsy. In patients with meningitis, fever, meningism and impairment of consciousness represented the most important clinical warning symptoms. Our findings show that bacterial pathogens like Haemophilus influenza (H. influenza), Streptococcus pneumoniae (S. pneumoniae) and Neisseria meningitides (N. meningitides) were, in this order, the most frequent pathogens, especially in pediatric patients. Mycobacterial meningitis prevailed in elderly patients. Compared to other regions, the proportion of patients with meningitis caused by H. influenzae in our study population is disproportionally high, which may be due to the lack of appropriate vaccination coverage in rural and remote areas. This is in line with other study results and demonstrates that the causative pathogens vary a lot regarding the age range, region or pre-existing concomitant diseases. Our study underlines the importance of access to health services for populations of rural areas of low-income countries where appropriate and adapted diagnostic and treatment facilities are available. Beside the detection of the causative organisms, the diagnosis of concomitant diseases like HIV and the exclusion of differential diagnoses like cerebral malaria are indispensable methods to ensure the best treatment. In addition, childhood vaccination coverage needs to be assured, especially in remote and vulnerable populations. The current thesis intends to underline prevalence and characteristics of neurological disorders like FSs and meningitis in low-income countries like sub-Saharan Africa, especially with regard to their infectious etiology. In conclusion, further reliable studies are necessary to ascertain the prevalence, burden and mortality rates as well as appropriate treatment strategies of neurological and psychiatric disorders. In fact, in 2015 the United Nations launched the sustainable development goals to which almost all nations agreed and which also draws attention to Global Mental Health. In that sense, the current thesis seems more than timely and underlines the need for further research as well as education for both health care personnel and patients, in Global Mental Health.Neurologische Erkrankungen, insbesondere infektiösen Ursprungs, scheinen häufiger in Entwicklungsländern wie Subsahara-Afrika vorzukommen. Neben der Prävalenz scheint auch die Mortalität in Entwicklungsländern erhöht zu sein. Epileptische Anfälle und Meningitis werden dabei häufig als führende neurologische Erkrankungen in afrikanischen Patienten angegeben. Wie wir in unseren Studien zeigen konnten, äußern sich neurologische Erkrankungen oft mit relativ ähnlichen und unspezifischen Symptomen wie beispielsweise Bewusstseinsverlust. Dies erschwert häufig eine exakte und rasche Diagnosefindung. Verschiedene afrikanische Studien zeigten, dass neurologische Erkrankungen, insbesondere epileptische Anfälle, Fieberkrämpfe und Meningoenzephalitiden, oft Ursache von Bewusstseinsverlust darstellen und häufig mit einer ungünstigen Prognose, wie beispielsweise neurologischen Folgeschäden, einhergehen. Insbesondere infektiöse neurologische Erkrankungen scheinen zu einer höheren Mortalität in Subsahara-Afrika beizutragen. Der Mangel an adäquaten diagnostischen Methoden oder bildgebender Verfahren, unqualifiziertes medizinisches Personal und die oftmals erst späte Vorstellung der Patienten in medizinischen Einrichtungen sowie auch das Fehlen von entsprechendem Impfschutz, insbesondere in abgelegenen Regionen, erschweren die Diagnostik und somit eine angemessene Therapie. Darüber hinaus behindern diese Faktoren auch die Feststellung von relevanten Begleiterkrankungen sowie den Ausschluss anderer wichtiger Differentialdiagnosen. Die Studien, auf denen die vorliegende Arbeit basiert, wurden von 2002 bis 2004 in der Vereinigten Republik Tansania, genauer in Haydom, Mbulu Distrikt, Wasso, Ngorongoro Distrikt und Mahenge, Ulanga district durchgeführt. Informationen zur Berechnung der Prävalenz und Charakteristika von Fieberkrämpfen wurden mithilfe von Screening-Fragebögen in drei Tür-zu-Tür Studien im Einzugsgebiet des Haydom Lutheran Hospital (HLH), Mahenge Hospital und Wasso Hospital gesammelt und durch retrospektiv gesammelte Daten aus den Hauptkrankenhäusern der entsprechenden Distrikte sowie deren Mutter-und-Kind Gesundheitszentren (MCH) ergänzt. In einer krankenhausbasierten Studie (Haydom Lutheran Hospital) identifizierten wir Patienten mit Meningitis und sammelten Informationen über die laborchemischen und klinischen Eigenschaften. Patienten, die aufgrund neurologischer Auffälligkeiten im Krankenhaus aufgenommen wurden, wurden durch einen Neurologen untersucht und die klinischen und laborchemischen Untersuchungsergebnisse zusammengetragen. In unserer Studie ermittelten wir eine Prävalenz von 20.5/1,000 (95% CI: 17.5-23.9/1,000) bei Kindern, die zum Zeitpunkt der Befragung zwischen 2 Monaten und 7 Jahren alt waren. Dieses Ergebnis steht im Einklang mit vielen anderen Studien über Fieberkrämpfe, bestätigt jedoch nicht die Annahme, dass Fieberkrämpfe im Allgemeinen in Entwicklungsländern wie Subsahara Afrika häufiger vorkommen. Aberglaube, eine höhere Mortalität oder Vorfälle, die in der Zwischenzeit in Vergessenheit geraten sind, können Ursachen für die Unterschätzung der Prävalenz in unserer Studie darstellen. Der erhöhte Anteil komplexer Fieberkrämpfe in unserer Studie bestärkt jedoch die Annahme, dass diese häufiger in Entwicklungsländern vorkommen. Dies steht möglicherweise in Verbindung mit einer oftmals ermittelten höheren Prävalenz von Epilepsien in dieser Region, da komplexe Anfälle unter anderem als Risikofaktoren für spätere neurologische Schäden wie Epilepsie bekannt sind. Fieber, Meningismus und Bewusstseinsverlust stellen die wichtigsten Warnsymptome bei Patienten mit Meningitis dar. In unserer Studie konnten wir feststellen, dass bakterielle Erreger wie Haemophilus influenzae (H. influenzae), Streptococcus pneumoniae (S. pneumoniae) und Neisseria meningitidis (N. meningitidis), in absteigender Reihenfolge, die häufigsten Erreger für Meningitis, insbesondere bei pädiatrischen Patienten darstellten. Mykobakterielle Meningitiden traten häufiger in älteren Patienten auf. Im Vergleich zu anderen Studien zeigt sich der Anteil der Patienten mit H. influenzae Meningitiden in unserer Studienpopulation unverhältnismäßig hoch, möglicherweise ist dies das Resultat eines fehlenden Impfschutzes, insbesondere in abgelegenen Regionen. Diese Ergebnisse fanden sich auch in vielen weiteren Studien und zeigen, dass die ursächlichen Erreger je nach Altersgruppe, Region oder Vorerkrankung stark variieren können. Neben der Feststellung der ursächlichen Erreger sind die Diagnosen von Vorerkrankungen wie HIV sowie der Ausschluss von Differentialdiagnosen, wie die der zerebralen Malaria, unerlässliche Methoden, um eine adäquate Behandlung zu gewährleisten. Zusätzlich muss eine Durchimpfungsrate im Kindesalter gewährleistet sein, insbesondere in schwer erreichbaren, abgelegenen und gefährdeten Populationen. Die vorliegende Dissertation hebt die Bedeutung der Prävalenz und klinischer Charakteristika neurologischer Erkrankungen wie Fieberkrämpfe und Meningitis in Entwicklungsländern wie Subsahara Afrika hervor. Weitere Forschungsstudien über die Prävalenz und Mortalität neurologischer Erkrankungen sowie den Zusammenhang mit Infektionskrankheiten wie Meningitis, Fieberkrämpfen und die Entwicklung einer späteren Epilepsie in Entwicklungsländern können dazu beitragen, Erkrankungen in diesen Regionen besser zu verstehen und zu verhindern. In der Tat führten im Jahre 2015 die Vereinten Nationen die sogenannten „Sustainable Development Goals“ ein, die u.a. für ein erhöhtes Bewusstsein der globalen mentalen Gesundheit werben. In diesem Sinne ist die vorliegende Dissertation absolut zeitgemäß, da sie ein höchst aktuelles Thema, die globale mentale Gesundheit, unter unterschiedlichen Gesichtspunkten beleuchtet

Epilepsy

Epilepsy is the most common neurological disorder globally, affecting approximately 50 million people of all ages. It is one of the oldest diseases described in literature from remote ancient civilizations 2000-3000 years ago. Despite its long history and wide spread, epilepsy is still surrounded by myth and prejudice, which can only be overcome with great difficulty. The term epilepsy is derived from the Greek verb epilambanein, which by itself means to be seized and to be overwhelmed by surprise or attack. Therefore, epilepsy is a condition of getting over, seized, or attacked. The twelve very interesting chapters of this book cover various aspects of epileptology from the history and milestones of epilepsy as a disease entity, to the most recent advances in understanding and diagnosing epilepsy

The Daily Patterns of Emergency Medical Events

This study examines population level daily patterns of time-stamped emergency medical service (EMS) dispatches to establish their situational predictability. Using visualization, sinusoidal regression, and statistical tests to compare empirical cumulative distributions, we analyzed 311,848,450 emergency medical call records from the U.S. National Emergency Medical Services Information System (NEMSIS) for years 2010 through 2022. The analysis revealed a robust daily pattern in the hourly distribution of distress calls across 33 major categories of medical emergency dispatch types. Sinusoidal regression coefficients for all types were statistically significant, mostly at the p \u3c 0.0001 level. The coefficient of determination ($R^2$) ranged from 0.84 and 0.99 for all models, with most falling in the 0.94 to 0.99 range. The common sinusoidal pattern, peaking in mid-afternoon, demonstrates that all major categories of medical emergency dispatch types appear to be influenced by an underlying daily rhythm that is aligned with daylight hours and common sleep/wake cycles. A comparison of results with previous landmark studies revealed new and contrasting EMS patterns for several long-established peak occurrence hours--specifically for chest pain, heart problems, stroke, convulsions and seizures, and sudden cardiac arrest/death. Upon closer examination, we also found that heart attacks, diagnosed by paramedics in the field via 12-lead cardiac monitoring, followed the identified common daily pattern of a mid-afternoon peak, departing from prior generally accepted morning tendencies. Extended analysis revealed that the normative pattern prevailed across the NEMSIS data when re-organized to consider monthly, seasonal, daylight-savings vs civil time, and pre-/post- COVID-19 periods. The predictable daily EMS patterns provide impetus for more research that links daily variation with causal risk and protective factors. Our methods are straightforward and presented with detail to provide accessible and replicable implementation for researchers and practitioners

Whole issue

ΔΕΝ ΔΙΑΤΙΘΕΤΑΙ ΠΕΡΙΛΗΨΗNO ABSTRACT AVAILABL

Neurological disorders in rural Tanzania

Neurological disorders, especially those of infectious origin, seem to be more frequent in low-income countries like sub-Saharan Africa. But not only the prevalence estimates seem to be higher in low-income countries, mortality rates tend to be higher compared to high-income countries, too. Seizures as well as meningitis are often reported as one of the leading causes for neurological disorders in patients in sub-Saharan Africa. As shown in our studies, symptoms and signs of neurological diseases like febrile seizures (FSs) and meningitis can appear very similar and render an exact diagnosis difficult, as they often include impairment of consciousness, for example. Several African studies reported that neurological diseases, especially epileptic seizures, FSs and meningitis/meningoencephalitis as leading causes of impairment of consciousness, are often accompanied with adverse outcome such as neurological sequelae and especially infectious diseases such as meningitis may contribute to the high mortality in sub-Saharan Africa. The lack of appropriate diagnostic methods and imaging modalities as well as unqualified workers and the often late presentation at medical services and, last but not least, the lack of appropriate vaccination coverage in rural areas complicate the detection of the exact diagnosis and concomitant diseases and the exclusion of important differential diagnoses, and thus impede an appropriate patient management. The studies of the present thesis were performed from 2002 to 2004 in the United Republic of Tanzania and more specifically at Haydom, Mbulu district; Wasso, Ngorongoro district and Mahenge, Ulanga district. The prevalence and characteristics of FSs were assessed in three community-based door-to-door studies in the catchment area of the Haydom Lutheran Hospital (HLH), Wasso Hospital and Mahenge Hospital, complemented with retrospectively collected data from main hospitals and Mother and Child Health Centers (MCHs) of the study area by using screening questionnaires. In a hospital based study (Haydom Lutheran Hospital), we identified patients with meningitis in order to describe their clinical characteristics including laboratory and clinical aspects. Patients with neurological symptoms and/or signs were examined by a neurologist and clinical as well as laboratory data were collected. Our study found a prevalence rate of 20.5/1,000 (95% CI: 17.5-23.9/1,000) FSs in children between 2 months and 7 years at the time of the interview and is in line with other studies about FSs, however, it does not confirm the assumption of a higher prevalence in low-income countries of sub-Saharan Africa. Reasons for this are varied and include superstitious beliefs, higher mortality rates or inaccurate recollection of events in the past. However, our study confirms a trend of a higher proportion of complex FSs in low-income countries. This is important, as complex FSs have been discussed as possible risk factors for the development of later neurological sequelae like epilepsy. In patients with meningitis, fever, meningism and impairment of consciousness represented the most important clinical warning symptoms. Our findings show that bacterial pathogens like Haemophilus influenza (H. influenza), Streptococcus pneumoniae (S. pneumoniae) and Neisseria meningitides (N. meningitides) were, in this order, the most frequent pathogens, especially in pediatric patients. Mycobacterial meningitis prevailed in elderly patients. Compared to other regions, the proportion of patients with meningitis caused by H. influenzae in our study population is disproportionally high, which may be due to the lack of appropriate vaccination coverage in rural and remote areas. This is in line with other study results and demonstrates that the causative pathogens vary a lot regarding the age range, region or pre-existing concomitant diseases. Our study underlines the importance of access to health services for populations of rural areas of low-income countries where appropriate and adapted diagnostic and treatment facilities are available. Beside the detection of the causative organisms, the diagnosis of concomitant diseases like HIV and the exclusion of differential diagnoses like cerebral malaria are indispensable methods to ensure the best treatment. In addition, childhood vaccination coverage needs to be assured, especially in remote and vulnerable populations. The current thesis intends to underline prevalence and characteristics of neurological disorders like FSs and meningitis in low-income countries like sub-Saharan Africa, especially with regard to their infectious etiology. In conclusion, further reliable studies are necessary to ascertain the prevalence, burden and mortality rates as well as appropriate treatment strategies of neurological and psychiatric disorders. In fact, in 2015 the United Nations launched the sustainable development goals to which almost all nations agreed and which also draws attention to Global Mental Health. In that sense, the current thesis seems more than timely and underlines the need for further research as well as education for both health care personnel and patients, in Global Mental Health.Neurologische Erkrankungen, insbesondere infektiösen Ursprungs, scheinen häufiger in Entwicklungsländern wie Subsahara-Afrika vorzukommen. Neben der Prävalenz scheint auch die Mortalität in Entwicklungsländern erhöht zu sein. Epileptische Anfälle und Meningitis werden dabei häufig als führende neurologische Erkrankungen in afrikanischen Patienten angegeben. Wie wir in unseren Studien zeigen konnten, äußern sich neurologische Erkrankungen oft mit relativ ähnlichen und unspezifischen Symptomen wie beispielsweise Bewusstseinsverlust. Dies erschwert häufig eine exakte und rasche Diagnosefindung. Verschiedene afrikanische Studien zeigten, dass neurologische Erkrankungen, insbesondere epileptische Anfälle, Fieberkrämpfe und Meningoenzephalitiden, oft Ursache von Bewusstseinsverlust darstellen und häufig mit einer ungünstigen Prognose, wie beispielsweise neurologischen Folgeschäden, einhergehen. Insbesondere infektiöse neurologische Erkrankungen scheinen zu einer höheren Mortalität in Subsahara-Afrika beizutragen. Der Mangel an adäquaten diagnostischen Methoden oder bildgebender Verfahren, unqualifiziertes medizinisches Personal und die oftmals erst späte Vorstellung der Patienten in medizinischen Einrichtungen sowie auch das Fehlen von entsprechendem Impfschutz, insbesondere in abgelegenen Regionen, erschweren die Diagnostik und somit eine angemessene Therapie. Darüber hinaus behindern diese Faktoren auch die Feststellung von relevanten Begleiterkrankungen sowie den Ausschluss anderer wichtiger Differentialdiagnosen. Die Studien, auf denen die vorliegende Arbeit basiert, wurden von 2002 bis 2004 in der Vereinigten Republik Tansania, genauer in Haydom, Mbulu Distrikt, Wasso, Ngorongoro Distrikt und Mahenge, Ulanga district durchgeführt. Informationen zur Berechnung der Prävalenz und Charakteristika von Fieberkrämpfen wurden mithilfe von Screening-Fragebögen in drei Tür-zu-Tür Studien im Einzugsgebiet des Haydom Lutheran Hospital (HLH), Mahenge Hospital und Wasso Hospital gesammelt und durch retrospektiv gesammelte Daten aus den Hauptkrankenhäusern der entsprechenden Distrikte sowie deren Mutter-und-Kind Gesundheitszentren (MCH) ergänzt. In einer krankenhausbasierten Studie (Haydom Lutheran Hospital) identifizierten wir Patienten mit Meningitis und sammelten Informationen über die laborchemischen und klinischen Eigenschaften. Patienten, die aufgrund neurologischer Auffälligkeiten im Krankenhaus aufgenommen wurden, wurden durch einen Neurologen untersucht und die klinischen und laborchemischen Untersuchungsergebnisse zusammengetragen. In unserer Studie ermittelten wir eine Prävalenz von 20.5/1,000 (95% CI: 17.5-23.9/1,000) bei Kindern, die zum Zeitpunkt der Befragung zwischen 2 Monaten und 7 Jahren alt waren. Dieses Ergebnis steht im Einklang mit vielen anderen Studien über Fieberkrämpfe, bestätigt jedoch nicht die Annahme, dass Fieberkrämpfe im Allgemeinen in Entwicklungsländern wie Subsahara Afrika häufiger vorkommen. Aberglaube, eine höhere Mortalität oder Vorfälle, die in der Zwischenzeit in Vergessenheit geraten sind, können Ursachen für die Unterschätzung der Prävalenz in unserer Studie darstellen. Der erhöhte Anteil komplexer Fieberkrämpfe in unserer Studie bestärkt jedoch die Annahme, dass diese häufiger in Entwicklungsländern vorkommen. Dies steht möglicherweise in Verbindung mit einer oftmals ermittelten höheren Prävalenz von Epilepsien in dieser Region, da komplexe Anfälle unter anderem als Risikofaktoren für spätere neurologische Schäden wie Epilepsie bekannt sind. Fieber, Meningismus und Bewusstseinsverlust stellen die wichtigsten Warnsymptome bei Patienten mit Meningitis dar. In unserer Studie konnten wir feststellen, dass bakterielle Erreger wie Haemophilus influenzae (H. influenzae), Streptococcus pneumoniae (S. pneumoniae) und Neisseria meningitidis (N. meningitidis), in absteigender Reihenfolge, die häufigsten Erreger für Meningitis, insbesondere bei pädiatrischen Patienten darstellten. Mykobakterielle Meningitiden traten häufiger in älteren Patienten auf. Im Vergleich zu anderen Studien zeigt sich der Anteil der Patienten mit H. influenzae Meningitiden in unserer Studienpopulation unverhältnismäßig hoch, möglicherweise ist dies das Resultat eines fehlenden Impfschutzes, insbesondere in abgelegenen Regionen. Diese Ergebnisse fanden sich auch in vielen weiteren Studien und zeigen, dass die ursächlichen Erreger je nach Altersgruppe, Region oder Vorerkrankung stark variieren können. Neben der Feststellung der ursächlichen Erreger sind die Diagnosen von Vorerkrankungen wie HIV sowie der Ausschluss von Differentialdiagnosen, wie die der zerebralen Malaria, unerlässliche Methoden, um eine adäquate Behandlung zu gewährleisten. Zusätzlich muss eine Durchimpfungsrate im Kindesalter gewährleistet sein, insbesondere in schwer erreichbaren, abgelegenen und gefährdeten Populationen. Die vorliegende Dissertation hebt die Bedeutung der Prävalenz und klinischer Charakteristika neurologischer Erkrankungen wie Fieberkrämpfe und Meningitis in Entwicklungsländern wie Subsahara Afrika hervor. Weitere Forschungsstudien über die Prävalenz und Mortalität neurologischer Erkrankungen sowie den Zusammenhang mit Infektionskrankheiten wie Meningitis, Fieberkrämpfen und die Entwicklung einer späteren Epilepsie in Entwicklungsländern können dazu beitragen, Erkrankungen in diesen Regionen besser zu verstehen und zu verhindern. In der Tat führten im Jahre 2015 die Vereinten Nationen die sogenannten „Sustainable Development Goals“ ein, die u.a. für ein erhöhtes Bewusstsein der globalen mentalen Gesundheit werben. In diesem Sinne ist die vorliegende Dissertation absolut zeitgemäß, da sie ein höchst aktuelles Thema, die globale mentale Gesundheit, unter unterschiedlichen Gesichtspunkten beleuchtet

Modern Telemetry

Telemetry is based on knowledge of various disciplines like Electronics, Measurement, Control and Communication along with their combination. This fact leads to a need of studying and understanding of these principles before the usage of Telemetry on selected problem solving. Spending time is however many times returned in form of obtained data or knowledge which telemetry system can provide. Usage of telemetry can be found in many areas from military through biomedical to real medical applications. Modern way to create a wireless sensors remotely connected to central system with artificial intelligence provide many new, sometimes unusual ways to get a knowledge about remote objects behaviour. This book is intended to present some new up to date accesses to telemetry problems solving by use of new sensors conceptions, new wireless transfer or communication techniques, data collection or processing techniques as well as several real use case scenarios describing model examples. Most of book chapters deals with many real cases of telemetry issues which can be used as a cookbooks for your own telemetry related problems

"Investigation on the role of Cl- homeostasis and GABAergic transmission in sleep disorders of Down syndrome and in Prader Willi syndrome: a possible contributor to cognitive impairment"

GABA is the main inhibitory neurotransmitter of the central nervous system (CNS). Recently, GABAergic transmission has been reported to be depolarizing and possibly excitatory rather than inhibitory in a number of neurodevelopmental disorders both in patients and mouse models. In particular, the Ts65Dn mouse model of Down syndrome (DS) exhibits depolarizing GABA due to upregulation of the Cl- importer NKCC1 both in the hippocampus and in the cortex. Moreover, NKCC1 inhibition by the FDA-approved diuretic bumetanide is able to rescue inhibitory GABAergic transmission, synaptic plasticity and cognitive functions in Ts65Dn mice. Beside cognitive impairment, DS mice and people with DS show sleep disturbaces. Since sleep pattern is regulated by GABAergc transmission, we reasoned that the alteration of GABAergic transmission due to upregulation of NKCC1 might be underlying at least some of the sleep disturbances in DS mice. So, we characterized sleep in Ts65Dn mice and investigated the effects of a chronic treatment with bumetanide. We found that bumetanide ameliorates the quality of sleep in NREM and REM sleep phases before and after sleep deprivation and decreases abnormal wakefulness during light phase at baseline in Ts65Dn mice. Moreover, we also found abnormalities in other parameters, which could contribute to sleep abnormalities of Ts65Dn mice: an increase of food intake and activity (partially rescued by bumetanide) with a reduction of body temperature during dark phase. Because of the association of altered GABAergic signaling by dysregulation of the expression of NKCC1 (but also of the Cl- exporter KCC2) in many neurodevelopmental disorders characterized by cognitive or social impairment, and sleep disorders, we extended our studies to Prader Willi syndrome (PWS). PWS is a neurodevelopmental disorder, caused by defects of genomic imprinting and characterized by cognitive, social and sleep abnormalities. Here, we observed that the Snord116 5 mutant mouse model of PWS, PWScrm+/p 12 show an increased expression of NKCC1, specifically in the hippocampus in comparison to their wild-type mice. Moreover, we report that PWS mice have altered cognition and the circadian period in free-running conditions. In particular, mutant mice present defects of long-term memory and a reduced shortening of their circadian period together with an increase of alpha activity in dark-dark (DD). Moreover, they also show alteration of pain sensitivity, that could be linked to defects in the thermoregulation. Interestingly, in constrast with PWS people, Snord116 mutant mice showed no alterations of anxiety, repetivive, obsessive and social behaviors. In an effort to rescue cognition and the circadian phenotype by rescuing NKCC1 inhibition, we treated Snord116 mutant mice with bumetanide. Remarkably, bumetanide treatment resulted in a complete rescue of the cognitive defects and circadian alteration in DD, with no effects in controls. Our results suggest an important link between GABA transmission and the regulation of cognition and the circadian clock in PWS. In addition, the current study extends the repertoire of disorders in which NKCC1 inhibition attenuates behavioural deficits and proposes a new potential mechanism for the investigation of PWS

Investigating the use of medicines in management of children and young people with epilepsy using data from primary care in the UK

Background: Epilepsy is a serious chronic neurological disorder that has a higher incidence in children and young people (CYP) than in adults. Epilepsy negatively impacts physical and psychosocial quality of life of CYP. Good outcomes of epilepsy are associated with optimal choice of drug treatment and adequate adherence to the prescribed medicines. Research on the patterns of medication use and adherence to prescribed medicines in CYP remains limited. The long-term clinical outcomes and costs of treating epilepsy have not been extensively studied in CYP in the UK. Aim of the study: This thesis aimed to investigate the pattern of antiepileptic drug (AED) prescribing and the dynamic of medication adherence in CYP with epilepsy. The long-term clinical outcomes and direct costs of treating epilepsy in CYP were estimated at population level. Methods: This study is an observational cohort study of CYP, age 0-17 years, identified from The Health Improvement Network (THIN) primary care database from the UK between January 1988 and December 2004. Four different analyses were carried out on this cohort. First, a cross-sectional design repeated annually was employed to estimate the incidence and prevalence of epilepsy and the pattern of AED prescribing in this population. Secondly, the long-term adherence to prescribed AEDs was calculated using the medication possession ratio (MPR) method. Applying panel data analysis and the Generalised Estimating Equation (GEE) multivariate regression, factors that may have been associated with adherence to the prescribed AEDs were examined. Thirdly, seizure outcomes in terms of seizure frequency and remission of seizures and potential associated factors were assessed using the method of multiple failure survival analysis. Finally, the direct costs of treating epilepsy in CYP in primary care were estimated and stratified by the number of years after the first recording of epilepsy in THIN data. Results: Of total 528,760 CYP born on or after 1st January 1988 and registered in general practices contributed to THIN until 31st December 2004, 2020 CYP were identified who had a diagnosis of epilepsy, from under 1 up to 16.3 years of age (mean=5.6; SD=4.1). The annual incidence of epilepsy in CYP stratified by calendar years ranged from 44.4 (95% CI=31.9-61.8) to 61.2 (95% CI=50.6 -74.1) per 100,000 person-years. Incidence of epilepsy was significantly higher in children with greater socioeconomic deprivation than those with lower deprivation. Around 60% of CYP with epilepsy were prescribed monotherapy each year. Old AEDs such as carbamazepine and sodium valproate were the most frequently prescribed drugs and often prescribed as monotherapy to control epilepsy throughout 1990-2003. Prescribing of lamotrigine, a new AED, increased from 0.07 per person-years in 1992 to 2 per person-years in 2003. The calculated annual adherence to AEDs showed that around 50% of CYP adhered to at least 80% of the prescribed medications each year. Demographic characteristics of CYP were of little significance to affect adherence levels. The incidence of seizures was 0.73 (95% CI=0.71-0.75) per person-years. Incidence of seizures was higher in younger children up to 2 years and decreased with increasing age. A proportion of 94% (95% CI=93%, 96%) of CYP achieved 1 year remission of seizures, 80% (95% CI= 78%, 83%) achieved 2 years and 47% (95% CI=43%, 50%) achieved 5 years remission of seizures. The mean total direct cost associated with treating epilepsy in CYP, according to information in the general practice records that also indicated specialist and hospital care, was estimated at £ 1,153 (SD=1,808) per child in the first year following epilepsy diagnosis and at £459 (SD=1,633) per child for subsequent years. The costs of hospital care and AEDs represented the highest contribution to the total direct costs of epilepsy. The annual direct cost was significantly higher in younger children up to 2 years old. No significant difference in the annual costs was observed between CYP who adhered to at least 80% of medications and those who adhered to less than 80%. Conclusions: The incidence of epilepsy was highest in young children and CYP of higher socioeconomic deprivation. Old AEDs were most often prescribed as first-line drugs and as monotherapy to control epilepsy. Of newer AEDs, there was an increasing trend of prescribing lamotrigine and topiramate as add-on therapy. Long-term adherence to prescribed AEDs was suboptimal in one-half of CYP and positively associated with higher seizure frequency. Inpatient hospital care and drugs were the major contributors to the direct costs of treating epilepsy in CYP. Non-adherence to prescribed medicines was associated with higher hospital care costs but not with total direct costs as the medicines themselves made large contribution to the direct cost