Tesis sobre el tema "Central nervous system Meningitis in children"

Thesis (Master's Diploma(Technology (Medical Technology))-- Cape Technikon, 1997
Meningitis in children is a common and serious disease. Bacterial and tuberculous meningitis often lead to neurological complications. A sensitive marker to predict brain damage in children with meningitis could be of great importance. Frithz F et aI, 1982 suggested that increased adenylate kinase values could indeed be used as a marker for brain damage. Adenylate kinase (AK) is an enzyme present in brain tissue. Low concentrations are present in normal cerebrospinal fluid (CSF) « 1 uti). Increased concentrations were found in cases of ischemic brain damage (Frithz et aI, 1982), malignant brain tumours (Ronquist G et aI, 1977) and bacterial meningitis. As AK has a low molecular weight (22,00 Daltons), in comparison to other kinases (40,000 Daltons) it is one of the first enzymes that can be detected in the CSF after brain damage and it can thus be used as a reliable marker for brain cell damage. The aim of this study was to quantify the AK values in CSF of children with bacterial and tuberculous meningitis and to evaluate their use to predict the neurological outcome in children with bacterial and tuberculous meningitis. Eighty eight children with tuberculous meningitis (TBM) and thirty three children with bacterial meningitis were included in the study. Sixty children with suspected meningitis but who were later diagnosed with urinary tract infections, gasto-enteritis, bronchitis, febrile convulsions or other non-neurological infections were used as controls. The results showed raised AK values in the CSF of children with bacterial- and TB meningitis. There was a statistically significant difference of AK values between stage III and II TBM AK values in patients at week 1 after diagnosis (p=0,03). There was also a statistically significant correlation between CSF AK values and lactate concentrations (P=0,001) which reflected hypoxic brain metabolism. Although AK values did not always correlate directly with the patients’ clinical outcome, there is proof that increased AK values in CSF can be used to predict neurological outcome.

Central Nervous System (CNS) vasculitis is the most common life-threatening complication of coccidioidal meningitis. It is manifested by cerebral ischemia, hemorrhage, and infarction. We report a case of CNS vasculitis in a patient receiving chemotherapy and review of the literature on coccidioidal meningitis. The patient was treated with combination antifungal therapy and a short course of high dose corticosteroids with a modest improvement in her neurological examination after initiation of steroids.

Includes bibliographical references
Aims: To assess the clinical and cerebrospinal fluid characteristics, and the role of tuberculous meningitis (TBM) as a confounder, in a cohort of HIV positive individuals with positive varicella zoster virus (VZV) positive cerebrospinal fluid PCR. Methods: Patients in the NHLS database at Groote Schuur Hospital with positive CSF VZV PCR who were also HIV co-infected and whose folders were available for clinical review were reviewed. Clinical and biochemical data were collected. Patients were divided into two groups based an accepted case definition for TBM. Differences between groups were assessed using Mann-Whitney U or Chi squared tests as appropriate. Results: There were 437 for VZV PCR over three years. Of these 98 were positive and, after exclusions, 31 HIV positive patients were included for further analysis. Median age was 31 and median CD4 count was 146 cells/mm³. 11 (35%) had meningitis and 8 (25%) had encephalitis. 13 (42%) met the case definition for TBM. Patients with CNS varicella were frequently confused whereas those with TBM presented sub-acutely. There were no differences in CSF characteristics. Additional organisms were detected 6 (19%) patients. 4 (13%) patients died in hospital. CSF TB culture was requested in 24 (77%) patients and extra CNS samples were sent in only 4 patients. Conclusion: The clinical and CSF presentation of CNS Varicella and TBM overlap and in this cohort patients were under investigated for TB. In settings of high TB prevalence the possibility of false positive PCR or incidental varicella reactivation should be considered.

INTRODUCTION: Community-acquired bacterial meningitis is a relevant entity related to a high morbidity and mortality, despite of the adjuvant and antibiotic treatments available. Morbidity and mortality are caused by neurological complications, being hydrocephalus one of the less investigated one and related to Listeria monocytogenes meningoencephalitis episodes, which increase have been reported in the last decade. Moreover, the devices used for treatment of hydrocephalus have a high risk of infection. These infections have a high personal and economic costs, and their prevention and treatment management can be optimised. HYPOTHESIS: Studying certain aspects of community-acquired bacterial and device-related infections of the central nervous system might improve management and outcome of these patients. OBJECTIVES: 1. To describe the impact on outcome with hydrocephalus complicating community acquired bacterial meningitis patients. 2. To evaluate prognostic factors related to sequelae and mortality in L. monocytogenes meningoencephalitis. 3. To assess efficacy of different treatment strategies on a cohort of patients with ventriculoperitoneal shunt infections. 4. To evaluate, in vitro, a new antibiotic-impregnated external ventricular drainage catheter to prevent Acinetobacter baumannii infections. METHODS: Observational clinical study of a cohort of community-acquired bacterial meningitis and ventriculoperitoneal shunt infection patients during more than 35 years in a university reference hospital. Experimental study of efficacy of an antibiotic-impregnated external ventricular catheter tested by a dynamic in vitro model. RESULTS: Among 790 community-acquired bacterial meningitis patients, 22 (3%) presented complicating hydrocephalus. 7/22 (32%) episodes were caused by L. monocytogenes and Streptococcus pneumoniae. Mortality of patients with complicating hydrocephalus was 50%. Age, time to illness and L. monocytogenes aetiology were risk factors related to development of hydrocephalus. L. monocytogenes episodes increased in the last decade (from 0.73 episodes/1000 admissions to 1.02/1000 admissions per year). Mortality was 24% and neurological sequelae 18%. Seizures were present in 14% and hydrocephalus in 16% of patients. The addition of gentamicin to ampicillin, use of adjuvant dexamethasone and antiepileptic prophylaxis with phenytoin did not influence outcome. Risk factors related to a worse outcome were the presence of hydrocephalus and the inappropriate empirical antibiotic treatment. Among 86 episodes of ventriculoperitoneal shunt infections: 6 received only antibiotic therapy; 24 were managed with a shunt removal without replacement; 37 were managed with a shunt replacement in 2 steps; and 19 with a shunt replacement in one step. The most effective strategy was shunt replacement in 2 steps (89% cure). 6/9 (67%) external ventricular drainage catheters impregnated with trimethoprim, rifampin and triclosan were free of colonisation at least for 3 weeks after several inoculations with 104 A. baumannii in an in vitro model. CONCLUSIONS: The development of hydrocephalus complicating an episode of community acquired bacterial meningitis causes a worse rate of mortality and sequelae. The outcome of L. monocytogenes patients could be improved if the empirical antibiotic treatment is accurate and if a precise suspicion and management of potential hydrocephalus occurs. Shunt removal, particularly in 2 steps when the patient is not shunt-dependant, is the best strategy in the treatment of a ventriculoperitoneal shunt infection, without increasing morbidity. A new external ventricular drainage catheter impregnated with triclosan, rifampin and trimethoprim might prevent multirresistant A. baumannii ventriculitis.
INTRODUCCIÓN: La meningitis bacteriana adquirida en la comunidad es una enfermedad asociada a una elevada morbimortalidad a pesar de los tratamiento adyuvantes y antibióticos disponibles. Su principal causa son las complicaciones neurológicas. La hidrocefalia secundaria es de las menos estudiadas y además está asociada a la etiología Listeria monocytogenes, de reciente incremento en países desarrollados. Por otra parte, los dispositivos utilizados para el tratamiento de la hidrocefalia, drenajes ventriculares temporales y permanentes, tienen alto riesgo de infección. Cuando esto sucede, las consecuencias de la infección, tanto en el paciente como en el sistema sanitario, son importantes, siendo las estrategias de prevención y tratamiento de estas infecciones mejorables. Hipótesis: Estudiar aspectos concretos de las infecciones bacterianas del sistema nervioso central, tanto comunitarias como asociadas a dispositivos, puede ayudar a mejorar el manejo y pronóstico de los pacientes. OBJETIVOS: 1. Determinar el impacto de la hidrocefalia secundaria en el pronóstico de los pacientes con meningitis bacteriana adquirida en la comunidad. 2. Analizar los factores pronósticos de mortalidad y secuelas en la meningoencefalitis por L. monocytogenes. 3. Evaluar la eficacia de diferentes estrategias de tratamiento en una cohorte de pacientes con infecciones de shunt ventriculoperitoneal. 4. Evaluación in vitro de un nuevo drenaje ventricular externo impregnado con antibióticos para prevenir las infecciones por Acinetobacter baumannii multiresistente. MÉTODOS: Estudio clínico observacional de una cohorte de pacientes con meningitis bacteriana adquirida en la comunidad e infecciones de shunt ventriculoperitoneal durante más de 35 años en un Hospital universitario de referencia para infecciones del sistema nervioso central. Estudio experimental de la evaluación de la eficacia de un drenaje ventricular externo impregnado en antibióticos en un modelo dinámico in vitro. Resultados: De 790 pacientes con meningitis bacteriana adquirida en la comunidad, 22(3%) presentaron hidrocefalia como complicación. 7/22(32%) episodios fueron causados por L. monocytogenes y Streptococcus pneumoniae. La mortalidad de los pacientes que presentaron hidrocefalia fue del 50%. La edad, un tiempo de enfermedad avanzado y la etiología L. monocytogenes fueron factores de riesgo asociados a desarrollar hidrocefalia. Los episodios de meningoencefalitis por L. monocytogenes se incrementaron en los últimos 10 años (de 0.73 episodios/1000 admisiones a 1.02/1000 admisiones). La mortalidad fue 24% y las secuelas neurológicas 18%. La frecuencia de crisis comicial fue del 16% y de hidrocefalia del 14%. La adicción de gentamicina al tratamiento con ampicilina no modificó el pronóstico, al igual que el uso de dexametasona ni de profilaxis con fenitoína. Los factores asociados a mal pronóstico fueron la presencia de hidrocefalia y el tratamiento antibiótico empírico inadecuado. De 86 episodios de infección de shunt ventriculoperitoneal: 6 episodios se manejaron sólo con antibióticos; en 24 se retiró el shunt sin recambio; en 37 se realizó un recambio en 2 tiempos del shunt; y en 19 un recambio en un tiempo. La estrategia más efectiva fue el recambio en 2 tiempos (89% de curación). 6/9(67%) drenajes ventriculares externos impregnados en trimetroprim, rifampicina y triclosan permanecieron libre de colonización al menos 3 semanas tras varias inoculaciones con 104 A. Baumannii en un modelo in vitro. CONCLUSIONES: La hidrocefalia secundaria a un episodio de meningitis bacteriana adquirida en la comunidad conlleva una mayor gravedad neurológica y un peor pronóstico en cuanto a mortalidad y secuelas. El pronóstico de la meningoencefalitis por L. Monocytogenes podría mejorar si se administra un tratamiento antibiótico empírico adecuado y si se sospecha y se maneja correctamente la potencial hidrocefalia secundaria. La retirada del shunt , concretamente en dos tiempos cuando el paciente es shunt dependiente, es la estrategia de elección en el tratamiento en una infección de shunt ventriculoperitoneal, sin aumentar la morbilidad. Un nuevo drenaje ventriuclar externo impregnado con triclosan, rifampicina y trimetroprim podría prevenir las ventriculitis por A. baumannii multiresistente.

Nous avons réalisé une étude prospective (nov-2017 à oct-2018) chez des patients boliviens hospitalisés suspectés d'infection du SNC pour identifier les plus courants étiologies et orienter les stratégies de diagnostic, de traitement, de prévention et de santé publique. Nous avons recruté 257 patients hospitalisés (20,2% VIH positifs), une étiologie infectieuse a été confirmée chez 49,8% des patients. Les principales étiologies chez les patients VIH positifs étaient Cryptococcus spp. (41,7%) et M. tuberculosis (27,8%) et chez les patients VIH négatifs, M. tuberculosis (26,1%) et S. pneumoniae (18,5%). La mortalité était de 42,1%. Notre étude appelle à renforcer la politique de santé publique, en particulier en ce qui concerne la tuberculose, la rage et la prévention et les soins du VIH.Le virus Zika (ZIKV) a récemment émergé dans les Amériques, et des complications neurologiques chez le fœtus de femmes infectées pendant la grossesse ont été rapportés. Tout d'abord, nous avons développé un test de neutralisation rentable, automatisé, sensible et spécifique basé sur l'effet cytopathique (CPE) pour effectuer de grandes études de séroprévalence. Deuxièmement, nous avons effectué une étude de séroprévalence en 5 villes de la Bolivie (Décembre 2016 à avril-2017) pour estimer l'immunité collective du ZIKV, confirmant la circulation dans les régions tropicales (Santa Cruz (21,5%) et Beni (39%)) avec Santa Cruz toujours vulnérable aux futures épidémies. Troisièmement, 74 femmes enceintes de Santa Cruz (Bolivie) ont été recrutées (2018), 15 (20,3%) étaient positives pour ZIKV en analysant différent méthodes moléculaires et sérologiques
We performed a prospective study from Nov-2017 to Oct-2018 in Bolivian inpatients with suspected CNS infections to identify the most common aetiologies and to guide diagnosis, treatment, prevention, and public health strategies. We recruited 257 inpatients (20.2% HIV-positive), an infectious aetiology was confirmed in 49.8% of patients. The main aetiologies in HIV-positive patients were Cryptococcus spp. (41.7%) and M. tuberculosis (27.8%), in HIV-negative patients M. tuberculosis (26.1%) and S. pneumoniae (18.5%). The mortality rate was 42.1. Our study calls to reinforced public health policy, in particular regarding tuberculosis, rabies and HIV prevention and care. Zika virus (ZIKV) has recently emerged in the Americas and congenital abnormalities in fetus from women infected during pregnancy have been reported. First, we developed a cost-effective, automatized, sensitive and specific neutralization test based on cytopathic effect (CPE) to perform large seroprevalence studies. Second, we performed a seroprevalence study in 5 cities of Bolivia (Dec-2016 to April-2017) to estimate the ZIKV protective herd immunity, confirming the circulation in the tropical regions (Santa Cruz (21.5%) and Beni (39%)), with Santa Cruz still vulnerable to future outbreaks. Third, 74 pregnant women from Santa Cruz (Bolivia) were recruited (2018), 15 (20.3%) were positive by analyzing different molecular and serological methods

As mortality in childhood decreases due to advances in modern medicine, presence of better nutrition and fresh water supply, the impact of disability has become increasingly important especially in resource poor countries. Children living in sub- Saharan Africa are also exposed to a number of potentially debilitating infections which have been shown to have long-term cognitive effects even in absence of clinical neurological sequelae. The objective of the study is to demonstrate that event related potentials (ERPs) can be used to detect neurocognitive impairment following the most common central nervous (CNS) system infections affecting children in sub-Saharan Africa, namely falciparum malaria, acute bacterial meningitis (ABM) and human immune-deficiency virus (HIV). Four groups of children were recruited: children previously admitted with severe falciparum malaria (n= 50), or acute bacterial meningitis (n = 65), or mY-infected (n= 39) or were unexposed to any of these conditions (n= 177). Passive auditory and visual oddball ERP protocols were used. The results of the group of 50 children aged 6-7 years old with a history of severe falciparum malaria (cerebral malaria, CM= 27, malaria plus seizures, M/S= 14 and prostrated malaria, PM= 9) show that children exposed to CM, MIS and PM had significantly longer auditory N200 and P3a latencies and smaller N200 amplitudes than study controls. The results of 65 children aged between 4-15 years old with a history of pneumococcal meningitis shmved that children with a history of bacterial meningitis had significantly smaller auditory P100 amplitudes, longer N200 latencies and longer visual P200 latencies than community controls. Finally, the results of 40 children aged between 18-40 months infected with IllV showed that they had longer auditory P100 latencies, larger auditory P200 amplitudes and smaller Negative component, Nc, amplitudes than community controls. It is concluded that the CNS infections may result in neuro-developmental delays in childhood. Further, CNS infections may interfere with normal education outcomes by precipitating attention deficit amongst children post infection.

Enterovírus (HEV), herpesvírus 1 e 2 (HHV-1 e HHV-2) e adenovírus (HAdV) são importantes agentes de infecções do SNC. Neste trabalho, técnicas moleculares foram aplicadas para a detecção destes vírus em quadros de infecção do SNC. Amostras de líquor foram colhidas de pacientes atendidos no HU-USP entre agosto e novembro/2010 e fevereiro/2012 a janeiro/2013. Através da Nested-PCR HEV foram detectados em 9,8% das amostras, HAdV em 2,5% e HHV-1 e 2 em 1,1%, além de 3 casos de coinfecção, 2 entre HEV e HHV, e 1 entre HEV e HAdV. O material genético viral foi extraído através dos métodos Qiaamp DNA Blood (Qiagen®) e MagMAXTM Viral RNA Isolation (Ambiom), e este último pareceu mais adequado à aplicação na rotina clínica. A análise quimiocitológica do líquor mostrou-se importante no direcionamento da conduta clínica, mas a detecção do vírus é fundamental para a conclusão do diagnóstico. A PCR em tempo real, cuja padronização foi iniciada neste trabalho, consiste em importante ferramenta para a utilização futura no diagnóstico complementar das infecções virais do SNC.
Enteroviruses (HEV), herpesviruses 1 and 2 (HHV-1 and HHV-2) and adenoviruses (HAdV) are important causative agents of infections of the CNS. In this study, molecular techniques were applied to the detection of these viruses. CSF samples were collected from patients treated at the University Hospital of USP, between August and November, 2010, and February 2012 and January 2013. By the Nested-PCR reaction, HEV were detected in 9.8% of the samples, HAdV in 2.5% and HHV-1 and 2 in 1.1%. There were 3 cases of coinfection: 2 with HEV and HHV and other with HEV and HAdV. The viral genetic materials were extracted by QIAamp DNA Blood kit (Qiagen®) and MagMAXTM Viral RNA Isolation (Ambiom), and the second one showed to be more suitable for the application in clinical diagnosis. The CSF chemocytologic analysis proved to be important in directing the clinical conduct, but the detection of viruses is essential for the diagnosis. The real time PCR, which standardization was initiated in this work, will be an important tool for complementary diagnosis of viral infections of the CNS.

Infecções no sistema nervoso central (SNC) causadas por microrganismos desencadeiam sintomas de moderados a severos, dependendo da região atingida, podendo ser designadas como encefalites ou meningites. Os vírus são os agentes mais comuns nestas infecções. Os agentes virais responsáveis por essas enfermidades que apresentam maior incidência na população mundial são certos herpesvírus, flavivírus, influenza A, enterovírus e vírus da caxumba. Entretanto, essa prevalência varia de acordo com a população, estado imunológico do indivíduo, idade e região estudada. Embora existam dados bem estabelecidos da etiologia dessas doenças em alguns países, ainda há uma carência de informação no que diz respeito à etiologia dessas moléstias no Brasil. Assim, informações mais precisas em relação à prevalência desses agentes em nosso meio são necessárias para o desenvolvimento e aplicação de métodos de diagnósticos mais rápidos e eficientes. Neste trabalho, foram analisadas 120 amostras de liquido cefalorraquidiano (LCR), procedentes de dois centros da cidade de São Paulo (Irmandade Santa Casa de Misericórdia e Hospital das Clínicas da Faculdade de medicina da Universidade de São Paulo), as quais foram submetidas à reação em cadeia de polimerase para o herpesvirus simples 1 e 2 (HSV 1 e 2), vírus da varicela zoster (VZV), herpesvirus humano 6 (HHV-6), influenza A (FLUA), enterovírus, vírus da caxumba, poliomavírus vírus BK (BKV) e vírus JC (JCV) para flavivírus. Do total, 44 amostras (36,7%) apresentaram resultado positivo para algum dos vírus analisados no âmbito desta pesquisa, sendo 15 (12,5%) para poliomavírus BKV, 2 (1,7%) para poliomavírus JCV, 21 (17,5%) para HSV1 e 2, 5 (4,2%) foram positivos para BKV e HSV1 e 2 (coinfecção) e 1 (0,8%) para vírus Epstein-Barr (EBV). Uma parte das amostras negativas foi submetida a sequenciamento direto de nova geração (n=8 amostras), resultando em amostras positivas para vírus (vírus simio 40), protozoários e bactérias. Este estudo mostrou que infelizmente, menos de 50% das encefalites e meningites assépticas puderam ser relacionadas a algum agente viral. Houve uma alta prevalência de HSV no material estudado, de acordo com o esperado, mas a presença de poliomavírus no LCR destes indivíduos foi acima da observada na literatura. Esses, bem como os resultados de sequenciamento direto e sua associação a etiologia das encefalites e meningites, devem ser interpretados com cautela.
Central nervous system (CNS) infections caused by microorganism trigger moderate to severe symptoms, depending on the region affected and may be referred as encephalitis or meningitis. Viruses are the most common agents in these infections. The viral agents responsible for these diseases with highest incidence worldwide are certain herpesviruses, flaviviruses, influenza A, enteroviruses, and mumps virus. However, their prevalence vary according to the population, immunological state of the individual, age and region studied. Although there are well-established data on the etiology of these diseases in some countries, there is little information regarding the etiology of these diseases in Brazil. Thus, data regarding the prevalence of these agents in our environment is necessary for the development and application of faster and more efficient diagnostic methods. In this study, 120 cerebrospinal fluid (CSF) samples from two centers of the city of São Paulo (Hospital Santa Casa de Misericordia and Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo) were investigated by PCRs for herpes simplex virus (HSV 1 and 2), varicela zoster virus (VZV), human herpesvirus 6 (HHV6), influenza A, enterovirus, mumps virus, polyomavirus BK virus and JC virus and flaviviruses. From these, 44 samples (36.7%) presented positive result for one of the viruses analyzed, being 15 (12.5%) for polyomavirus BKV, 2 (1.7%) for polyomavirus JCV, 21 (17.5%) for HSV 1 and 2, 5 (4.2%) samples were positive for BKV and HSV1 and 2 (coinfection) and 1 (0.8%) for Epstein-Barr virus (EBV). A part of the negative samples (n=8) were submitted to next generation direct sequencing and revealed the presence of agents as viruses (simian virus 40), protozoa and bacteria. This study showed that unfortunately, less than 50% of the aseptic encephalitis and meningitis could be related to some viral agent. It was found high prevalence of HSV, as expected, but the presence of polyomavirus in the CSF of these individuals was higher than that observed in the literature. These results, as well as direct sequencing results and its relationship to the etiology of encephalitis and meningitis should be interpreted with caution.

Listeria monocytogenes (Lm) es un bacilo gram-positivo anaerobio facultativo con especial tropismo por el sistema nervioso central (SNC). La principal forma de afectación central en el adulto es la meningitis, siendo la rombencefalitis y el absceso cerebral más infrecuentes, pero de peor pronóstico. La forma de presentación de Lm es muy variable y a menudo se confunde con otras entidades más prevalentes creando una demora en el diagnóstico inicial y por lo tanto en su tratamiento. Las hipótesis de este trabajo se basan en que, los abscesos piógenos causados por Lm presentan determinadas características clínicas, radiológicas y licuorales que permiten la sospecha precoz del diagnóstico etiológico y, por lo tanto, el inicio del tratamiento específico antes de la confirmación microbiológica. Las rombencefalitis por Lm presentan determinadas características clínicas, radiológicas y licuorales que permiten su diferenciación del resto de etiologías de rombencefalitis y, por lo tanto, el inicio precoz del tratamiento específico antes de la confirmación microbiológica. Y, finalmente, la meningitis y la rombencefalitis por Lm constituyen dos entidades clínicas diferentes por sus características clínicas y evolutivas. Los objetivos de este trabajo son los siguientes: 1. Identificar las características demográficas, clínicas y de neuroimagen distintivas de los abscesos cerebrales por Lm. 2. Describir el espectro etiológico de las rombencefalitis. 3. Identificar las características demográficas, clínicas, licuorales o radiológicas distintivas de la rombencefalitis por Lm. 4. Identificar las características clínico-evolutivas, licuorales o radiológicas diferenciales entre las meningitis por Lm y la rombencefalitis por Lm. 5. Identificar los factores clínicos, licuorales o radiológicos relacionados con el pronóstico de las infecciones del SNC por Lm. El presente trabajo se base en tres estudios retrospectivos observacionales sobre: 1) Abscesos cerebrales por Lm, 2) Rombencefalitis y 3) Meningoencefalitis por Lm. Cada estudio incluye una serie consecutiva de pacientes ingresados en un Hospital Universitario en los períodos 1970-2008, 1990-2008 y 1977-2009 respectivamente que cumplan los criterios establecidos para cada entidad. Se realiza una revisión de literatura sobre pacientes publicados con abscesos cerebrales por Lm desde 1970 hasta 2008. Para el análisis estadístico se usan el Test de Chi cuadrada, el test exacto de Fisher, el test de la T de Student y la regresión logística de Cox según se requiera. Tras este trabajo se concluye que: 1. Los abscesos cerebrales por Lm son más frecuentes en pacientes inmunodeprimidos o diabéticos. 2. En la mayoría de pacientes con rombencefalitis no se puede establecer una etiología específica. La esclerosis múltiple, la enfermedad de Behçet y la infección por Lm son las causas de rombencefalitis más frecuentes en nuestro medio. 3. En pacientes con rombencefalitis, la presencia de fiebre, signos meníngeos o disminución del nivel de conciencia obliga a considerar Lm como germen causal. En los pacientes sin fiebre y con IRM craneal normal, prácticamente se puede descartar Lm como causa de la rombencefalitis. 4. La rombencefalitis y la meningitis por Lm se pueden considerar dos entidades clínicas distintas, ya que difieren tanto en los factores de riesgo de huésped como en la evolución clínica. 5. La edad avanzada, la presencia de enfermedad de base y el desarrollo de hidrocefalia se asocian a mayor mortalidad en pacientes con meningitis por Lm. La rombencefaltis por Lm presenta un riesgo de secuelas superior a la meningitis por Lm.
Listeria monocytogenes (Lm) is a gram-positive rod with special tropism for the central nervous system (CNS). Meningitis is the most commom form of central involvement in the adult. Rhombencephalitis and brain abscess are less common but with worse prognosis. The hypotheses of this study are based on the fact that listerial brain abscesses and rhombencephalitis have distinctive clinical, cerebrospinal fluid (CSF) and radiologic features that can lead to a prompt diagnosis and empirical treatment. Also, that meningitis and rhombencephalitis due to Lm are two different entities. The main aim of this study is to conduct an accurate description of a series of cases with listerial CNS infection admitted to a tertiary care hospital over a period of 30 years and also a literature review to deepen in the knowledge on CNS infections due to Lm. For that purpose three observational retrospective studies were conducted based on a consecutive series of patients admitted to a Universitary Hospital over 1970 to 2009 that met the established criteria for each entity. A review of the literature about cerebral abscesses was also performed. Based on this study we can conclude that listerial brain abscesses are more common in inmunocompromised or diabetic patients. In the majority of patients with rhombencephalitis, no specific caused is found. Multiple sclerosis, Behçet’s disease and listerial infection are the most common causes. In patients with rhombencephalitis, fever, meningism and low level of consciousness point towards listerial infection. On the other hand, the lack of fever and a normal neuroimaging practically rule out this possibility. Rhombencephalitis and meningitis due to Lm could be considered as two different entities since they have different host risk factors and outcome. Elderly patients, underlying condition and hydrocephalus are associated with worse prognosis in patients with listerial meningitis. Brainstem involvement is an independent risk factor for sequelae in patients with listerial infection.

Este trabalho tem como objetivo investigar sentidos e significações que a criança com tumor de sistema nervoso central, que já passou pelo tratamento oncológico, tem da doença e das alterações corporais aparentes decorrentes do tumor e seu tratamento. Isso porque, em sua maioria, essas crianças apresentam sequelas visíveis no corpo ocasionadas pela doença e seu tratamento oncológico. Para a realização deste trabalho, recorre-se a uma pesquisa bibliográfica, na área da Oncologia Pediátrica, Psicologia e Psicanálise, e uma pesquisa de campo. Através de uma entrevista individual com onze crianças, todas pacientes do Ambulatório de Oncologia Pediátrica do Hospital Santa Marcelina / São Paulo, é possível refleti sobre alguns temas surgidos nas falas dos pacientes. A interpretação desses temas está apoiada em conceitos da psicanálise Freud-lacaniana e abarca a angústia, o luto, a castração e a imagem inconsciente do corpo. Assim, este trabalho mostra a importância de proporcionar a criança construir sua própria história da doença para poder lidar melhor com seus efeitos. Reflete ainda sobre a especificidade de um trabalho psicanalítico nas equipes multidisciplinares que acompanham os pacientes fora de tratamento oncológico. O psicanalista, ao atuar, deve manter a singularidade do seu trabalho e, quando necessário, fazê-lo junto à equipe
This work has as purpose to investigate senses and meanings that the child with central nervous system tumor, which has already gone through oncological treatment, has of the disease and the visible body alterations due to the tumor and its treatment. This was aim because, in most cases, these children show visible sequelae on their bodies caused by the disease and its oncological treatment. In order to accomplish this work, it is used a bibliography research, over the areas of pediatric oncology, psychology and psychoanalysis, and a field research. Through one individual interview with eleven children, all of them patients from the pediatric oncology ambulatory from Santa Marcelina Hospital / São Paulo, is possible to reflect about some themes brought by the patients\' speeches. The interpretation of these themes is supported in concepts from Freud-lacanian psychoanalysis and embraces the angst, the mourning, the castration and the unconscious image of the body. Therefore, this work shows the importance of provide the child to build his own history of the disease to better deal with its effects. It yet reflects about the specificity of a psychoanalytic work on the multidisciplinaries groups that assists the patients outside the oncological treatment. The psychoanalyst, on his acts, must keep the singularity of his work and, when necessary, execute in crew

Syfte: Att undersöka om det fanns något samband mellan behandling med centralstimulantia ochavvikande tillväxt hos barn och ungdomar med ADHD, samt att undersöka om eventuellt avvikandetillväxt hade något samband med ålder vid insättande, kön eller olika funktionshinder.Metod: 68 barn med ADHD som behandlats med centralstimulantia i minst två år inkluderades.Journalkopior inhämtades från Habiliteringen för barn och vuxna vid Uppsala läns landsting. Dessakopior innehöll barnens tillväxtkurvor, kön, diagnos och ålder. Kurvorna granskades med hjälp av enutformad granskningsmall. Barnens tillväxt jämfördes mellan åldergrupper, kön och olikafunktionshinder.Resultat: Vid behandlingsstart var åldersgrupperna 6-8 år samt 12-16 år signifikant tyngre ännormalpopulationen i samma åldersgrupper. Det fanns en signifikant skillnad mellan åldergrupperna ilängdavplaning efter ett års behandling, där fler barn i åldrarna 10-16 år avplanade än barn i åldrarna6-10 år. Även mellan funktionshindergrupperna fanns det en signifikant skillnad i längdavplaning eftertvå års behandling. Mellan pojkar och flickor fanns det en signifikant skillnad i viktavplaning efter tvåårs behandling, där fler pojkar avvek nedåt från sin tillväxtkurva.Slutsats: Det framkom få samband mellan behandling med centralstimulantia och avvikande tillväxthos barn och ungdomar med ADHD. Ett litet urval i denna journalgranskning innebar låg power i destatistiska analyserna vilket medförde svårigheter att påvisa signifikanta samband och skillnadermellan de grupper som jämförts. Avplaning i tillväxt vid centralstimulantiabehandling är ett viktigtansvarsområde för sjuksköterskan som bör observera och arbeta förebyggande för att undvika detta.Författarna vidhåller att detta är ett viktigt ämne som berör många barn, föräldrar och sociala instanser,vilket gör det önskvärt med fler större studier som undersöker detta mer grundligt.
Objective: To study whether there was any relation between treatment with stimulants and abnormalgrowth in children and adolescents with ADHD, and to study whether any differences in growth wasrelated to age at initiation, gender or different disabilities.Design: 68 children with ADHD treated with stimulants for at least two years were included. Journalcopies were collected from Habiliteringen vid Uppsala län. These copies contained the children'sgrowth charts, gender, diagnosis and age. These curves were studied using a designed review template.Children's growth was compared between age groups, gender and disabilities.Results: At baseline, the age groups 6-8 years and 12-16 years were significantly heavier than normalpopulation of same age groups. There was a significant difference between age groups in decrease inlength after one year of treatment where more children aged 10-16 years decreases than children aged6-10 years. Also among other disability groups, there was a significant difference in decrease in lengthafter two years of treatment. Between boys and girls, there was a significant difference in decrease inweight after two years of treatment, where more boys departed downward from its growth curve.Conclusion: There were few correlations between treatment with stimulants and abnormal growth inchildren and adolescents with ADHD. A small sample in this journal review meant low power in thestatistical analysis leading to an inability to detect significant correlation and differences between thegroups for comparison. Decrese in growth during treatment with stimulants is an importantresponsibility for the nurse who should observe and work preventively to avoid this. The authorsmaintain that this is an important topic that affects many children, parents and social instances, makingit desirable for more major studies to investigate this more thoroughly.

碩士
中國醫藥大學
醫務管理學系碩士班
100
Goals: Anesthesia is a complex pharmacological reaction. Whether general anesthesia will affect central nervous system in children is always the concern. The purpose of this study is to determine whether the duration of anesthesia have an impact on the certral nervous system at different age group of children under the database analysis from the National Health Insurance. Methods:Under "National Health Insurance Research Database of the year 2000, 1 million samples were collected. From 1997 to 2009,children who underwent anesthesia before the age of six was the sample group.While the control group which who have not underwent anstheaia was matched based on gender and age. Results: Total 6608 children underwent anesthesia before age of six in 1997-2009.Above them, intratracheal intubation which accounts 77.9% of all general anesthesia is the highest method .The mean age of anesthesia is 3.6 years old .The incidence rate of central nervous system diseases in children who have anesthesia is 10.75 per1000 person- years with odds ratio of 1.35 (95% CI= 1.23-1.47)which was higher than children without anesthesia (8.02 per 1000 person- years). In Semi-opened or semi-closed mask method group, the cumulative incidence rate of central nervous system diseases is 10.61 per1000 person- years with risk odds of 1.30 (95% CI = 1.09-1.54).In semi-closed or closed intratracheal intubation method group, the cumulative incidence rate of central nervous system diseases is 10.83 per1000 person- years, with odds ratio of 1.36 (95% CI= 1.23-1.50). Conclusion: The duration of anesthesia is not statistically significant to the incidence rate of central nervous system disease. The smaller group number and the smaller gap of grouping age were considered the cause. Both mask and intubation methods of general anesthesia have the higher odds ratio to central nervous system diseases than those who doesn’t have anesthesia. Recommendation: This study was based on the database of the National Health Insurance database.If more detailed grouping age was disclosed,the statistical result may have the difference. In addition, the Government could advocates more on the campaign of regular health examination below the age of six, so that all parents would take their children to the medical institutions for regular health examination. Anesthesia also should be annotated on the NHI manual. Therefore doctors,who assess the development milestone will notice the abnormalities earlier,and will manage them earlier.Regular follow up of physical and mental development would reduce the severity of central nervous system diseases. In that way,the life quality in those children and their parents would improve.The medical costs would also declined.

Streptococcus suis de type 2 est un microorganisme pathogène d’importance chez le porc. Il est la cause de différentes pathologies ayant comme caractéristique commune la méningite. C’est également un agent émergeant de zoonose : des cas cliniques humains ont récemment été rapportés en Asie. Cependant, la pathogénèse de S. suis n’est pas encore complètement élucidée. Jusqu’à présent, la réponse pro-inflammatoire initiée par S. suis n’a été étudiée qu’in vitro. L’étude du choc septique et de la méningite requiert toujours des modèles expérimentaux appropriés. Au cours de cette étude, nous avons développé un modèle in vivo d’infection chez la souris qui utilise la voie d’inoculation intra-péritonéale. Ce modèle a servi à l’étude de la réponse pro-inflammatoire associée à ce pathogène, tant au niveau systémique qu’au niveau du système nerveux central (SNC). Il nous a également permis de déterminer si la sensibilité aux infections à S. suis pouvait être influencée par des prédispositions génétiques de l’hôte. Le modèle d’infection par S. suis a été mis au point sur des souris de lignée CD1. Les résultats ont démontré une bactériémie élevée pendant les trois jours suivant l’infection. Celle-ci était accompagnée d’une libération rapide et importante de différentes cytokines pro-inflammatoires (TNF-α, IL-6, IL-12p40/p70, IFN-ɣ) et de chémokines (KC, MCP-1 and RANTES), qui ont entraîné un choc septique et la mort de 20 % des animaux. Ensuite, pour confirmer le rôle de l’inflammation sur la mortalité et pour déterminer si les caractéristiques génétiques de l’hôte pouvaient influencer la réponse inflammatoire et l’issue de la maladie, le modèle d’infection a été étendu à deux lignées murines consanguines différentes considérées comme résistante : la lignée C57BL/6 (B6), et sensible : la lignée A/J. Les résultats ont démontré une importante différence de sensibilité entre les souris A/J et les souris B6, avec un taux de mortalité atteignant 100 % à 20 h post-infection (p.i.) pour la première lignée et de seulement 16 % à 36 h p.i. pour la seconde. La quantité de bactéries dans le sang et dans les organes internes était similaire pour les deux lignées. Donc, tout comme dans la lignée CD1, la bactériémie ne semblait pas être liée à la mort des souris. La différence entre les taux de mortalité a été attribuée à un choc septique non contrôlé chez les souris A/J infectées par S. suis. Les souris A/J présentaient des taux exceptionnellement élevés de TNF-α, IL-12p40/p70, IL-1β and IFN- γ, significativement supérieurs à ceux retrouvés dans la lignée B6. Par contre, les niveaux de chémokines étaient similaires entre les lignées, ce qui suggère que leur influence est limitée dans le développement du choc septique dû à S. suis. Les souris B6 avaient une production plus élevée d’IL-10, une cytokine anti-inflammatoire, ce qui suppose que la cascade cytokinaire pro-inflammatoire était mieux contrôlée, entraînant un meilleur taux de survie. Le rôle bénéfique potentiel de l’IL-10 chez les souris infectées par S. suis a été confirmé par deux approches : d’une part en bloquant chez les souris B6 le récepteur cellulaire à l’IL-10 (IL-10R) par un anticorps monoclonal anti-IL-10R de souris et d’autre part en complémentant les souris A/J avec de l’IL-10 de souris recombinante. Les souris B6 ayant reçu le anticorps monoclonal anti-IL-10R avant d’être infectées par S. suis ont développé des signes cliniques aigus similaires à ceux observés chez les souris A/J, avec une mortalité rapide et élevée et des taux de TNF-α plus élevés que les souris infectées non traitées. Chez les souris A/J infectées par S. suis, le traitement avec l’IL-10 de souris recombinante a significativement retardé l’apparition du choc septique. Ces résultats montrent que la survie au choc septique dû à S. suis implique un contrôle très précis des mécanismes pro- et anti-inflammatoires et que la réponse anti-inflammatoire doit être activée simultanément ou très rapidement après le début de la réponse pro-inflammatoire. Grâce à ces expériences, nous avons donc fait un premier pas dans l’identification de gènes associés à la résistance envers S. suis chez l’hôte. Une des réussites les plus importantes du modèle d’infection de la souris décrit dans ce projet est le fait que les souris CD1 ayant survécu à la septicémie présentaient dès 4 jours p.i. des signes cliniques neurologiques clairs et un syndrome vestibulaire relativement similaires à ceux observés lors de méningite à S. suis chez le porc et chez l’homme. L’analyse par hybridation in situ combinée à de l’immunohistochimie des cerveaux des souris CD1 infectées a montré que la réponse inflammatoire du SNC débutait avec une augmentation significative de la transcription du Toll-like receptor (TLR)2 et du CD14 dans les microvaisseaux cérébraux et dans les plexus choroïdes, ce qui suggère que S. suis pourrait se servir de ces structures comme portes d’entrée vers le cerveau. Aussi, le NF-κB (suivi par le système rapporteur de l’activation transcriptionnelle de IκBα), le TNF-α, l’IL-1β et le MCP-1 ont été activés, principalement dans des cellules identifiées comme de la microglie et dans une moindre mesure comme des astrocytes. Cette activation a également été observée dans différentes structures du cerveau, principalement le cortex cérébral, le corps calleux, l’hippocampe, les plexus choroïdes, le thalamus, l’hypothalamus et les méninges. Partout, cette réaction pro-inflammatoire était accompagnée de zones extensives d’inflammation et de nécrose, de démyélinisation sévère et de la présence d’antigènes de S. suis dans la microglie. Nous avons mené ensuite des études in vitro pour mieux comprendre l’interaction entre S. suis et la microglie. Pour cela, nous avons infecté des cellules microgliales de souris avec la souche sauvage virulente (WT) de S. suis, ainsi qu’avec deux mutants isogéniques, un pour la capsule (CPS) et un autre pour la production d’hémolysine (suilysine). Nos résultats ont montré que la capsule était un important mécanisme de résistance à la phagocytose pour S. suis et qu’elle modulait la réponse inflammatoire, en dissimulant les composants pro-inflammatoires de la paroi bactérienne. Par contre, l’absence d’hémolysine, qui est un facteur cytotoxique potentiel, n’a pas eu d’impact majeur sur l’interaction de S. suis avec la microglie. Ces études sur les cellules microgliales ont permis de confirmer les résultats obtenus précédemment in vivo. La souche WT a induit une régulation à la hausse du TLR2 ainsi que la production de plusieurs médiateurs pro-inflammatoires, dont le TNF-α et le MCP-1. S. suis a induit la translocation du NF-kB. Cet effet était plus rapide dans les cellules stimulées par le mutant déficient en CPS, ce qui suggère que les composants de la paroi cellulaire représentent de puissants inducteurs du NF-kB. De plus, la souche S. suis WT a stimulé l’expression de la phosphotyrosine, de la PKC et de différentes cascades liées à l’enzyme mitogen-activated protein kinase (MAPK). Cependant, les cellules microgliales infectées par le mutant déficient en CPS ont montré des profils de phosphorylation plus forts et plus soutenus que celles infectées par le WT. Finalement, la capsule a aussi modulé l’expression de l’oxyde nitrique synthétase inductible (iNOS) induite par S. suis et par la production subséquente d’oxyde nitrique par la microglie. Ceci pourrait être lié in vivo à la neurotoxicité et à la vasodilatation. Nous pensons que ces résultats contribueront à une meilleure compréhension des mécanismes sous-tendant l’induction de l’inflammation par S. suis, ce qui devrait permettre, d’établir éventuellement des stratégies plus efficaces de lutte contre la septicémie et la méningite. Enfin, nous pensons que ce modèle expérimental d’infection chez la souris pourra être utilisé dans l’étude de la pathogénèse d’autres bactéries ayant le SNC pour cible.
Streptococcus suis serotype 2 is an important swine pathogen responsible for diverse infections, meningitis being its most striking feature. In addition, it is an emerging agent of zoonosis, which has gained worldwide attention due to important outbreaks in Asia. Understanding the pathogenesis of S. suis infections still represents a challenge. Up to present, the pro-inflammatory response due to S. suis has only been studied in vitro, and there is still a great need of appropriate experimental models for both septic shock and meningitis. In the present study, we successfully developed an in vivo model of S. suis infection in adult mice infected by the intraperitoneal route. This model served to investigate the pro-inflammatory events that take place at both the systemic and Central Nervous System (CNS) levels associated with this important pathogen. In addition, this model was useful to determine if susceptibility to S. suis infection may be influenced by the genetic background of the host. The mouse model of S. suis infection was standardized in CD1 mice. Results showed sustained bacteremia during the 3 days post-infection (p.i.), accompanied by a quick and substantial release of different pro-inflammatory cytokines (TNF-α, IL-6, IL-12p40/p70, IFN-ɣ) and chemokines (KC, MCP-1 and RANTES) that lead to septic shock and 20% mortality in mice. Once the hallmark of the septic phase of S. suis infection was established in CD1 mice, research continued with the objective to confirm the role of inflammation in mortality and to determine if the genetic background of the host may influence the inflammatory response toward this pathogen and the further outcome of the disease. For this, the mouse model of S. suis infection was used with two genetically different inbred mouse strains, this is, C57BL/6 (B6) and A/J mice, which are considered as the prototype of Th1-type and Th2-type mice, respectively. Results demonstrated a striking susceptibility to S. suis infection in A/J mice in comparison to B6 mice, with 100% mortality in the former mice strain at 20 h p.i., and 16 % mortality at 36 h p.i. for the latter. Very interestingly, and similarly to CD1 mice, bacteremia did not seem to be responsible for the death of mice, as both mice strains presented similar amounts of bacteria in blood and organs. Thus, it was postulated that the higher mortality in S. suis-infected A/J mice was due to uncontrolled septic shock. In fact, A/J mice presented very high levels of TNF-α, IL-12p40/p70, IL-1β and IFN-ɣ, that significantly exceeded those found in B6 mice. Remarkably, chemokine levels were similar between strains, suggesting their limited participation in the development of septic shock by S. suis. A greater survival of B6 mice was partially related to a better regulation of the pro-inflammatory cytokine cascade, as they showed a higher production of the anti-inflammatory cytokine IL-10 than A/J mice. The potential beneficial role of the IL-10 in mice infected with S. suis was confirmed using two approaches: the first, by blockage of the cell receptor of IL-10 (IL-10R) with an anti-mouse IL-10R monoclonal antibody (Mab) in B6 mice and the second by administrating recombinant mouse (rm)IL-10 (rmIL-10) to A/J mice. B6 mice that received the IL-10R MAb treatment before challenge with S. suis developed a clinical acute disease similar to that observed with A/J mice, with a striking and rapid increase in mortality and higher levels of TNF-α in comparison to those of infected mice that did not receive the treatment. Controversially, treatment with rmIL-10 significantly delayed the onset of septic shock in A/J mice infected with S. suis. These results show that survival from S. suis septic shock requires a tight regulation of pro- and anti-inflammatory mechanisms, and that the latter should be activated at the same time or soon after the onset of the pro-inflammatory response. This part of the study may represent a first step in the identification of host genes associated with resistance against S. suis. One of the most important achievements of the mouse model of infection described in this project is the development of distinct clinical signs of neurological disease in CD1 mice from 4 days p.i. Indeed, in CD1 mice that survived sepsis due to S. suis infection, clinical signs of neurological disease and vestibular syndrome, which are quite similar to those observed in clinical cases of S. suis meningitis in both pigs and humans, were observed. Studies of the brains of infected CD1 mice using in situ hybridization combined with immunocytochemistry, demonstrated that the CNS inflammatory response began with a significant increase in the transcription of Toll-like receptor (TLR)2 and CD14 initially in the brain microvasculature and choroid plexuses, suggesting that S. suis may use these structures as portals of entry to the brain. There also was activation of NF-κB (as indicated by transcriptional activation of IκBα as a reporter system) and TNF-α, IL-1β and MCP-1, mainly in cells identified as microglia and to a lesser extent in astrocytes. These signals reached different brain structures, mainly the brain cortex, corpus callosum, hippocampus, choroid plexuses, thalamus, hypothalamus and meninges. All of these pro-inflammatory events were associated with extensive areas of inflammation and necrosis, severe demyelination and presence of antigens of S. suis inside microglia. In vitro studies were conducted in order to better understand the interactions of S. suis and microglia. For this, mouse microglia were infected with a virulent wild type (WT) strain of S. suis. Two isogenic mutants deficient in capsule (CPS) or hemolysin production (suilysin, SLY) respectively, were also included for comparative purposes. The CPS was important for S. suis resistance to phagocytosis, and it also modulated the inflammatory response by hiding pro-inflammatory components from the bacterial cell wall. On the other hand, the absence of SLY, a potential cytotoxic factor, did not have a major impact on S. suis interactions with microglia. Studies with microglia helped to confirm previous findings in vivo in mice, as the WT S. suis strain induced the up-regulation of TLR2 and the production of several pro-inflammatory mediators, including TNF-α and MCP-1. As observed in mice, S. suis induced NF-kB translocation, which was more rapid for cells stimulated with the CPS-deficient mutant, suggesting that bacterial cell wall components are potent inducers of NF-kB. Moreover, WT S. suis promoted phosphotyrosine, PKC and different mitogen-activated protein kinase (MAPK) events. However, microglia infected with the CPS-deficient mutant showed overall stronger and more sustained phosphorylation profiles. Finally, the CPS also modulated S. suis-induced inducible nitrogen oxide synthase (iNOS) expression and further nitric oxide production in microglia, which could be related to neurotoxicity and vasodilatation in vivo. We are confident that our results may help to more fully understand the mechanisms underlying S. suis induction of inflammation, leading to the design of more efficient anti-inflammatory strategies for sepsis and meningitis. Finally, we believe this experimental model of infection in mice could also be useful for studying the pathogenesis of infections of the CNS, due to other bacteria.

Background: The central nervous system (CNS) dysfunction resulting from prenatal alcohol exposure (PAE) is the most debilitating aspect of fetal alcohol spectrum disorders (FASDs). Affected children exhibit numerous cognitive and behavioural deficits which can severely affect quality of life. As the diagnosis of FASDs often requires specially trained physicians, there is a need for sensitive and specific tools that screen PAE-related CNS dysfunction in order to identify individuals who require further consultation. Additionally, objective measures of intervention end-points are critical to assess potential treatments for this population. As saccadic eye movement behaviours reflect the integrity of multiple brain structures, a battery of oculomotor tasks may serve both these functions. This study sought to test the hypothesis that oculomotor performance in FASD would differ from typically developing children and would allow the objective measure of cognitive improvements resulting from a strength-based motor skills intervention. Methods: A cohort of 31 children with FASD, and 31 age- and sex-matched controls completed prosaccade, antisaccade, delayed memory-guided sequential (DMS) and predictive eye movement tasks. Additionally, a selection of these children were involved in an intervention study and therefore tested on three separate occasions using the eye movement tasks and computerized neuropsychological tests. Results: Compared to controls, children with FASDs elicited increased direction and anticipatory errors in the antisaccade task, increased timing and sequence errors in the DMS task, and increased anticipatory and decreased express saccades in the predictive task. The FASD group also exhibited an increase in the error of saccade trajectories in the pro- and antisaccade tasks, in addition to increased velocities of visually-guided saccades in the predictive task. Furthermore, those involved in the intervention study improved in measures of response inhibition in the DMS task. Conclusion: This study indicates that frontostriatal and cerebellar dysfunction can be assessed in children with FASDs using a battery of eye movement tasks. In addition, children involved in the strength-based motor skills intervention improved in the ability to perform complex oculomotor tasks. These findings suggest that select eye movement tasks may be utilized to identify CNS dysfunction in FASD and to measure cognitive improvements resulting from behavioural interventions.
Thesis (Master, Neuroscience Studies) -- Queen's University, 2010-08-17 09:55:59.382

碩士
國立臺灣大學
護理學研究所
91
This quantitative study was aimed to investigate differences of cognitive function and school grades of the children with acute lymphoblastic leukemia (ALL). This study focused on the central nervous system prophylaxis during anti-leukemia therapy and compared the subjects’ performance with their peers. The case subjects received 18 Gy cranial radiotherapy (TPOG-ALL-93-HR) or intrathecal methotrexate (TPOG-ALL-93-SR), and each therapy was accompanied with intravenous high-dose methotrexate. The study population consisted of 16 children with leukemia as case group and 32 age-matched peers as control group. All of them aged from 6 to 12 years old. Among the case group, there are 6 children received TPOG-ALL-93-HR protocol and 10 children received TPOG-ALL-93-SR protocol. The match-peers were selected according to body weight of birth, gender, age, family socioeconomic status and school environments. The cognitive function were assessed by Wechsler Intelligence Scale for Children-Ⅲ Chinese (WISC-Ⅲ Chinese), Learning Behavior Scale and school scores (Chinese and Mathematics). WISC-Ⅲ Chinese was administrated for all subjects while Learning Behavior Scale was for all the parents. Descriptive data analysis and inferential statistics was performed with SPSS/ Windows 10.0 software and the StatXact-5 statistical software. The major findings of this study were described as below: 1. Children received TPOG-ALL-93-SR protocol had significantly lower scores in Verbal IQ and Chinese than their peers. The similar result was also found in Performance IQ, Full Scale IQ and Mathematics but didn’t reach significance. In addition, the peers had lower percentiles in Learning Behavior Scale, respectively. 2. Children received TPOG-ALL-93-HR protocol had lower scores in Verbal IQ, Performance IQ, Full Scale IQ and school scores than the peers. The peers had lower percentiles in Learning Behavior Scale than children received TPOG-ALL-93-HR protocol. 3. As compared the 2 subgroups of case subjects, children received TPOG-ALL-93-HR protocol had higher scores in Verbal IQ than children received TPOG-ALL-93-SR protocol. However, it was the latter group that had higher scores in Performance IQ, Full Scale IQ and lower percentiles in Learning Behavior Scale. 4. Significant correlation between the factors of absent days from school, Verbal IQ and Learning Behavior Scale was observed in case subjects. 5. For all case subjects, their cognitive function and school grades was not significantly associated with family status. In conclusion, for children with acute lymphoblastic leukemia, central nervous system prophylaxis might not possess significant impact on cognitive function and school grades as expected. The present study provided useful information about appropriate nursing care as well as promoting the quality of life for children with acute lymphoblastic leukemia.

Acute demyelination in children may be a monophasic illness or the sentinel attack of multiple sclerosis (MS) – a chronic inflammatory neurodegenerative demyelinating disease. MS risk is largely determined during childhood and vitamin D may protect against MS. The primary objective of this thesis was to evaluate vitamin D status in children presenting with acute demyelinating syndromes (ADS) as a potential contributor to MS outcome. The LIAISON “25 OH Vitamin D TOTAL” assay was validated to assess the biomarker of vitamin D status – serum 25-hydroxyvitamin D (25(OH)D) concentrations. Consecutive patients (<16 y) were enrolled at presentation with ADS and prospectively evaluated at 23 Canadian centres. MS was defined by a second clinical demyelinating event or by MRI evidence of new lesions over time. Cox proportional hazards regression models assessed risk of MS outcome as a function of serum 25(OH)D tertiles, accounting for factors associated with either MS risk or vitamin D status – age, sex, season, and HLA-DRB1*15 status. Of 211 children with 25(OH)D measured in sera obtained a median of 9 days from onset (interquartile range, 5 – 17 d; maximum 36 days), 20% (n = 41) were diagnosed with MS after 3.7 mos. (3.1 – 7.3 mos.). Risk of MS was lower in children with 25(OH)D levels in the highest tertile (≥ 74 nmol/L) at ADS versus those in the lowest tertile (<50 nmol/L) (HR 0.41; 95% CI 0.18 to 0.97, adjusted model). Children with higher circulating 25(OH)D concentrations at ADS have a lower risk of MS. Further evidence for a role of vitamin D insufficiency during childhood and adolescence contributing to MS risk comes from three MS patients with suboptimally managed pseudo-vitamin D deficiency rickets. Finally, a sun exposure questionnaire was validated in the latter part of this thesis for use in future research into determinants of vitamin D status and their association with risk of MS.

An acute demyelinating syndrome (ADS) in a child may be a monophasic illness or may represent the incident attack of multiple sclerosis (MS) – an inflammatory demyelinating neurodegenerative disorder affecting the brain, spinal cord and optic nerves. The central objective of this dissertation was to identify MRI parameters present at ADS that predict MS diagnosis. A scoring tool was first created containing 14 parameters identified from the literature and demonstrating substantial inter-rater agreement (Cohen’s kappa values ≥0.6). Children aged <16 years were enrolled at incident ADS and are currently followed for five years at 23 Canadian centers. Standardized MRI scans were acquired at onset and serially. MS was defined based on the occurrence of a second demyelinating attack or MRI evidence of new lesions in accordance with McDonald criteria for dissemination in time. Multivariable Cox proportional hazards regression models were used to identify MRI parameters that predicted MS diagnosis. Over 1100 MRI scans in 284 children with ADS were evaluated. To date, 57(20%) children have been diagnosed with MS. For those that developed MS, the median (IQR) time from incident attack to diagnosis was 6.2 (4.7-11.1) months. The presence of ≥1 T1-hypointense lesion (HR 20.6, 95% CI 5.5-78.0) and ≥1 T2 periventricular lesion (3.3, 1.3-8.8) were associated with an increased likelihood for MS diagnosis (sensitivity 84%, specificity 93%, PPV 76%, NPV 96%). The predictive parameters were validated in an independent Dutch cohort of 45 children with ADS (n=15, 33% MS): sensitivity 93%, specificity 87%, PPV 78%, NPV 96%. Finally, it was determined that the 2010 McDonald criteria are applicable for diagnosis of pediatric-onset MS diagnosis in older children with non-ADEM presentations. The work embodied herein emphasizes the value of MRI in predicting MS diagnosis in children with incident ADS. Early identification of children with MS is important for planning clinical care and will be valuable in future pediatric MS treatment trials.

A research report submitted to the Faculty of Health Sciences, the University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Science in Medicine in Child Health Neurodevelopment Johannesburg, 2013
Human Immunodeficiency Virus (HIV) infection in infancy may influence the developing brain and lead to adverse neurodevelopmental consequences. We aim to describe the neurodevelopmental characteristics of a cohort of young children infected with HIV prior to antiretroviral therapy (ART) initiation and after achieving viral suppression. A retrospective analysis of data collected as part of a randomised equivalence trial between April 2005 and May 2009, at a hospital in Johannesburg, South Africa. 195 HIV-infected children under 2 years of age were assessed. A simple, inexpensive screening questionnaire (Ages and Stages Questionnaire - ASQ) was used to identify neurodevelopmental delays. The ASQ was administered prior to ART initiation, and again after viral suppression on a protease inhibitor-based regimen had been achieved. Median age pre-ART was 8.8 months (range 2.2 - 24.9), 53.9% were male. Mean time to viral suppression was 9.4 months (range 5.9 - 14.5) and the ASQ was administered to 108 caregivers at this time. Compared to pre-ART, at viral suppression, there was significant reduction in the proportion of children failing the gross motor (31.5% vs. 13%, p<0.01), fine motor (21.3% vs. 10.2%, p=0.02), problem solving (26.9% vs. 9.3%, p<0.001) and personal social (17.6% vs. 7.4%, p=0.02) domains. The proportion of children failing the communication domain was similar at each time point (14.8% vs. 12%, p=0.61). At time of viral suppression 10.2% failed at least one of the five domains. Achieving viral suppression on ART resulted in significant improvements in the neurodevelopmental function of young HIV-infected children, however, neurodevelopmental problems still persisted in a large proportion. Appropriate screening for neurodevelopmental delay and timely referral could help improve outcomes.

碩士
中國醫藥大學
生物統計研究所碩士班
100
Background The estimation of childhood cancer using Taiwan nationwide data has never been reported. The objective of the current study was to estimate the incidence rates and 5-year survival rates of top three childhood cancers followed up to the 2008: leukemia, lymphoma, and central nervous system (CNS) and brain cancer from birth cohorts of 1996-2002 in Taiwan. Methods We conducted a population-based retrospective cohort study consisting of 1996-2002 birth cohorts for Taiwan between 1996 and 2002 and followed it up to 2008. The datasets of the study were from Taiwan National Health Insurance Research Database (NHIRD). The childhood cancer cases were identified from datasets of severe illness registry. We calculated incidence rates and 5-year survival rates of leukemia, lymphoma, and CNS and brain tumor. We estimated incidence rate ratios (IRRs) to evaluate the independent effects of gender, birth year, parents’ insurance premium and geographic area using Poisson regression analysis. We also explored the 5-year survival rate to find out prognosis factors using Cox’s proportional hazard model. Results A total of 1003 leukemia patients, 260 lymphoma patients, and 578 CNS and brain tumor patients were identified, and the incidences of these corresponding three majority childhood cancers were 4.81 per 105 person year, 2.44 per 105 person year and 2.77 per 105 person year, respectively. The multivariable-adjusted incidence rate of lymphoma was significantly higher in boys than girls (incidence rate ratio (IRR) =1.59, 95% CI, 1.24 to 2.05). For leukemia, the incidence rate of the 2002 birth cohort was significantly higher than that of the 1996 birth cohort. For CNS and brain tumor, the incidence rate of 2005 birth cohort was significantly higher than that of the 1996 birth cohort and Southern area was associated with significantly higher risk than Taipei area. The adjusted HRs for leukemia subtype of ALL and AML, birth year of 2002, geographic areas of central area, southern area, Kao-ping area & eastern area and aboriginal area were significant. After adjusting for the other variables in the lymphoma model, none of them was significant. For CNS & brain tumor, the HRs of 2002 birth year and age of onset at 5-9 years old were significantly. Conclusions This study is the first to demonstrate leukemia, lymphoma, and CNS & brain tumor substantial incidence and survival difference from childhood cancer. It also shows that incidence varies according to birth year, gender, parents’ insurance premium and geographic area, and shows that 5-year survival rates varies according to birth year, gender, parents’ insurance premium, cancer subtype, age of onset and geographic area. Our findings are useful for prioritizing future childhood cancer research needs.