<p dir="ltr">A neurological disorder, hydrocephalus, has an estimated global pediatric prevalence of 380,000 new cases each year [<a href="#_ENREF_1" target="_blank">1</a>]. It is a family of diseases that can occur at any age when cerebrospinal fluid builds up within the ventricles of the brain. Thus, the only available treatments are surgical, invasive, and prone to complications. There is a global need for successful treatment strategies without brain surgery.</p><p><br></p><p dir="ltr">Choroid plexus epithelial cells (CPEC) are responsible for production of cerebrospinal fluid (CSF). Ependymal cells line the ventricles and play roles in CSF maintenance and waste clearance. Astrocytes perform various functions, one being blood-brain barrier (BBB) maintenance. Collectively these cells contribute to brain fluid/electrolyte regulation and barrier integrity. Increased glial fibrillary acidic protein (GFAP) fluorescence, a marker of activated astrocytes, appeared in hydrocephalic (<i>Tmem67</i>^-/-) animals by immunohistochemistry as early as postnatal day (P)10. The tight junction proteins expressed in choroid plexus (CP); claudin-1 (Cl-1) and zona occludin 1 (ZO-1) fluorescent intensity increased in P15 hydrocephalic animals compared to wildtype (<i>Tmem67</i>^+/+). These cells also contain aquaporins (AQP), aquaporin-1 (AQP1) and aquaporin-4 (AQP4), important in regulating CSF and interstitial fluid (ISF). Increased fluorescent intensity of AQP4 in the subventricular zone and increased AQP1 apical localization and protein amount in the CP was observed in hydrocephalic animals at postnatal day (P)15. Many of these may be targeted for the treatment of hydrocephalus. However, there is no consensus in pathological findings between models of hydrocephalus and these finding may not translate to common pharmacological targets.</p><p><br></p><p dir="ltr">A transient receptor potential cation channel, subfamily vanilloid, member 4 (TRPV4) antagonist (RN1734) ameliorates hydrocephalus in a rat model of congenital hydrocephalus (<i>Tmem67</i> model). It was hypothesized that targeting this mechanosensitive ion channel may slow production of CSF by targeting the CP. However, hydrocephalus pathology can have various effects on the brain. Astrocytes were visualized using fluorescent immunohistochemistry of glial fibrillary acidic protein (GFAP) and RN1734 did not seem to change immunoreactivity to wildtype untreated levels. Increased immunoreactivity of TRPV4 and AQP1 was observed in CP of untreated and RN1734 treated <i>Tmem67</i>^-/- rats. AQP4 and TRPV4 immunoreactivity increased in the subventricular zone and periventricular white matter (WM) of hydrocephalic rats. With RN1734, TRPV4 immunoreactivity, but not AQP4, had similar immunoreactivity to wildtype untreated. Increased GFAP and AQP immunoreactivity may indicate residual inflammation in the <i>Tmem67</i>^-/- rats. More experiments must be done to further elucidate TRPV4’s role in hydrocephalus pathology.</p><p><br></p><p dir="ltr">Serum and glucocorticoid-regulated kinase 1 (SGK1) is a kinase implicated in cell volume regulation and CSF production. SI113, an SGK1 inhibitor, ameliorates hydrocephalus in the <i>Tmem67</i> rodent model. The goal of this study was to determine if SI113 could be used with a new solvent other than dimethyl sulfoxide (DMSO), which can have possible toxic effects. 1-methyl-2-pyrrolidinone (NMP) has high solubility and ability to cross the BBB. These studies showed that NMP as a solvent did not have adverse effects on body weight, however thus far, it has not ameliorated hydrocephalus significantly at the concentration used in this study. There is a possibility that the concentration in NMP that we used was not efficacious enough. CSF and blood plasma samples from animals treated with SI113 24 hours and 30 minutes before euthanasia will be used to investigate the concentration of SI113 that remains in the circulation and the amount that crosses the BBB and blood-cerebrospinal fluid (BCSFB) barriers. We hope that the results will inform dosage for our future studies. Future studies may also examine SI113 mechanism of action in hydrocephalus.</p><p><br></p><p dir="ltr">This thesis addresses hydrocephalus cell and molecular pathology in the <i>Tmem67</i> model and examines potential treatment strategies. Future directions include comparing models of hydrocephalus to find common treatment strategies in the hope to find pharmaceutical strategies to better manage human hydrocephalus.</p>

The researcher has a daughter who was born with an encephalocele and her neuropsychological assessment indicates a Nonverbal Learning Disability (NLD). The difficulties of the educational experiences that emerged over time, mainly because her learning profile was not understood, prompted reflection on the consequences for other students who present with this profile. A concern for the long-term implications for students and parents of the frequent misunderstandings of the NLD has inspired this study. A review of the literature suggested a need to raise educator awareness about the subtle but disabling nature of the NLD syndrome. This study explored the perceptions of teachers, teacher aides and parents involved with 5 students who showed hallmark signs of an NLD. The theoretical foundation rests in the understanding that a student's learning experiences are influenced by past and present school experiences, the attitudes of peers, and parental expectations. The purpose of this thesis is to help parents, teachers and others appreciate the school experiences of children at Level 1 risk of developing an NLD, those with a hydrocephalic condition. It does not purport to offer ultimate solutions or to contribute to diagnosis but rather to act as a starting point for a body of theory to guide development of suitable learning environments for such children. Of further importance is emphasis on the need for similar studies to be conducted into the learning experiences of other children who demonstrate specific syndromes or mosaic forms of those syndromes. Naturalistic Inquiry methodology was used to explore the educational experiences of five students who attended different Australian schools. After completion of all interviews, psychological testing assessed general intelligence and the NLD status of each student. All students were found to be severely learning disabled and all were high on the NLD parameter. Educators generally did not reveal understanding of the NLD syndrome &quotNonverbal, what is it? So is it a visual ..." Some teachers devised innovative strategies to help the student cope in class while others expressed frustration ... if the traditional instruction &quotdoesn't work either, what does?" What stood out was an absence of understanding about nonverbal deficits. Frustration about poor organisation, decision making, task completion and problem-solving was expressed and a mixture of concern and criticism was levelled at social incompetence. Students who could not work independently were perceived by some teachers and aides as &quotlazy" or &quotmolly-coddled" and problems with everyday living skills were sometimes blamed on the student's family. Findings revealed a compelling need to raise educator awareness about the range of cognitive, learning and social problems associated with shunted hydrocephalus and spina bifida. They also highlighted a need for teachers to question &quotWhy can't this student do things one would expect they could do" and demand answers that explicate the serious difficulties being experienced.

The world population is expected to increase to approximately 11 billion by 2100. The ageing population (aged 60 and over) is projected to exceed the number of children in 2047. This will be a situation without precedent. The number of citizens with disorders of old age like Dementia will rise to 115 million worldwide by 2050. The estimated cost of Dementia will also increase, from $604 billion in 2010, to $1,117 billion by 2030. At the same time, medical expertise, evidence-driven policymaking and commissioning of services are increasingly evolving the definitive architecture of comprehensive long-term care to account for these changes. Technological advances, such as those provided by computational science and biomedical engineering, will allow for an expansion in our ability to model and simulate an almost limitless variety of complex problems that have long defied traditional methods of medical practice. Numerical methods and simulation offer the prospect of improved clinically relevant predictive information, and of course optimisation, enabling more efficient use of resources for designing treatment protocols, risk assessment and urgently needed management of a long term care system for a wide spectrum of brain disorders. Within this paradigm, the importance of the relationship of senescence of cerebrospinal fluid transport to dementia in the elderly make the cerebral environment notably worthy of investigation through numerical and computational modelling. Hydrocephalus can be succinctly described as the abnormal accumulation (imbalance between production and circulation) of cerebrospinal fluid (CSF) within the brain. Using hydrocephalus as a test bed, one is able to account for the necessary mechanisms involved in the interaction between cerebral fluid production, transport and drainage. The current state of knowledge about hydrocephalus, and more broadly integrative cerebral dynamics and its associated constitutive requirements, advocates that poroelastic theory provides a suitable framework to better understand the disease. In this work, Multiple-network poroelastic Theory (MPET) is used to develop a novel spatio-temporal model of fluid regulation and tissue displacement in various scales within the cerebral environment. The model is discretised in a variety of formats, through the established finite difference method, finite difference – finite volume coupling and also the finite element method. Both chronic and acute hydrocephalus was investigated in a variety of settings, and accompanied by emerging surgical techniques where appropriate. In the coupled finite difference – finite volume model, a key novelty was the amalgamation of anatomically accurate choroid plexuses with their feeding arteries and a simple relationship relaxing the constraint of a unique permeability for the CSF compartment. This was done in order to account for Aquaporin-4 sensitisation. This model is used to demonstrate the impact of aqueductal stenosis and fourth ventricle outlet obstruction. The implications of treating such a clinical condition with the aid of endoscopic third (ETV) and endoscopic fourth ventriculostomy (EFV) are considered. It was observed that CSF velocity in the aqueduct, along with ventricular displacement, CSF pressure, wall shear stress and pressure difference between lateral and fourth ventricles increased with applied stenosis. The application of ETV reduced the aqueductal velocity, ventricular displacement, CSF pressure, wall shear stress and pressure difference within nominal levels. The greatest reversal of the effects of atresia come by opting for ETV rather than the more complicated procedure of EFV. For the finite difference model incorporating nonlinear permeability, qualitatively similar results were obtained in comparison to the pertinent literature, however, there was an overall amplification of ventriculomegaly and transparenchymal pressure difference using this model. A quantitative and qualitative assessment is made of hydrocephalus cases involving aqueductal stenosis, along with the effects to CSF reabsorption in the parenchyma and subarachnoid space. The finite element discretisation template produced for the n^th- dimensional transient MPET system allowed for novel insight into hydrocephalus. In the 1D formulation, imposing the breakdown of the blood-CSF barrier responsible for clearance resulted in an increase in ventricular displacement, transparenchymal venous pressure gradient and transparenchymal CSF pressure gradient, whilst altering the compliance proved to markedly alter the rate of change of displacement and CSF pressure gradient. The influence of Poisson's ratio was investigated through the use of the dual-grid solver in order to distinguish between possible over or under prediction of the ventricular displacement. In the 2D model based on linear triangles, the importance of the MPET boundary conditions is acknowledged, along with the quality of the underlying mesh. Interesting results include that the fluid content is highest in the periventricular region and the skull, whilst after longer time scales, the peak CSF content becomes limited to the periventricular region. Venous fluid content is heavily influenced by the Biot-Willis constant, whilst both the venous and CSF/ISF compartments show to be strongly influenced by breakdown in the blood-CSF barrier. Increasing the venous compliance effects the arterial, capillary and venous compartments. Decreasing the venous compliance shows an accumulation of fluid, possibly helping to explain why the ventricles can be induced to compress rather than expand under decreased compliance. Finally, a successful application of the 3D-MPET template is shown for simple geometries. It is envisaged that future observations into the biology of cerebral fluid flow (such as perivascular CSF-ISF fluid exchange) and its interaction with the surrounding parenchyma, will demand the evolution of the MPET model to reach a level of complexity that could allow for an experimentally guided exploration of areas that would otherwise prove too intricate and intertwined under conventional settings.

Introdução: Pacientes com mielomeningocele apresentam elevada mortalidade e desenvolvem déficits neurológicos que ocorrem, primariamente, pelo desenvolvimento anormal da medula e de raízes nervosas e, secundariamente, por complicações adquiridas no período pós-natal. O desafio no cuidado desses pacientes é o reconhecimento precoce dos recém-nascidos de risco para evolução desfavorável a fim de estabelecer estratégias terapêuticas individualizadas. Objetivo: Este estudo tem como objetivo identificar marcadores prognósticos de curto prazo para recém-nascidos com mielomeningocele. As características anatômicas do defeito medular e da sua correção neurocirúrgica foram analisadas para esta finalidade. Métodos: Foi realizado um estudo de coorte retrospectiva com 70 pacientes com mielomeningocele em topografia torácica, lombar ou sacral nascidos entre janeiro de 2007 a dezembro de 2013 no Centro Neonatal do Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Pacientes com infecção congênita, anomalias cromossômicas e outras malformações maiores não relacionadas à mielomeningocele foram excluídos da análise. As características anatômicas da mielomeningocele e a sua correção neurocirúrgica foram analisadas quanto aos seguintes desfechos: reanimação neonatal, tempo de internação, necessidade de derivação ventricular, deiscência da ferida operatória, infecção da ferida operatória, infecção do sistema nervoso central e sepse. Para a análise bivariada dos desfechos qualitativos com os fatores de interesse foram empregados testes do qui-quadrado e exato de Fisher. Para a análise do desfecho quantitativo, tempo de internação hospitalar, foram empregados testes de Mann-Whitney. Foram estimados os riscos relativos e os respectivos intervalos com 95% de confiança. Foram desenvolvidos modelos de regressão linear múltipla para os desfechos quantitativos e regressão de Poisson para os desfechos qualitativos. Resultados: Durante o período do estudo 12.559 recém-nascidos foram admitidos no Centro Neonatal do Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Oitenta pacientes foram diagnosticados com mielomeningocele, com incidência de 6,4 casos para cada 1.000 nascidos vivos. Dez pacientes foram excluídos da análise devido à mielomeningocele em topografia cervical (n = 1), à cardiopatia congênita (n = 4), à trissomia do cromossomo 13 (n = 1), à onfalocele (n = 3) e à encefalocele (n = 1). Ocorreram três óbitos (4,28%). Mielomeningocele extensa foi associada a infecção do sistema nervoso central, a complicação de ferida operatória e a maior tempo de internação hospitalar. Os pacientes com mielomeningocele em topografia torácica apresentaram tempo de internação, em média, 39 dias maior que aqueles com defeito em topografia lombar ou sacral. Houve maior necessidade de reanimação em sala de parto entre os pacientes com macrocrania ao nascer. A correção cirúrgica realizada após 48 horas de vida aumentou em 5,7 vezes o risco de infecção do sistema nervoso central. Entre os pacientes operados nas primeiras 48 horas de vida não foi observado benefício adicional na correção cirúrgica realizada em \"tempo zero\". A ausência de hidrocefalia antenatal foi um marcador de bom prognóstico. Nestes pacientes, a combinação dos desfechos necessidade de derivação ventricular, complicações infecciosas, complicações de ferida operatória e reanimação em sala de parto foi 70% menos frequente. Conclusão: Este estudo permitiu identificar marcadores prognósticos de curto prazo em recém-nascidos com mielomeningocele. Os defeitos medulares extensos e a correção cirúrgica após 48 horas de vida influenciaram negativamente na evolução de curto prazo. As lesões extensas foram associadas a maiores taxas de infecção do sistema nervoso central, a complicações de ferida operatória e a internação hospitalar prolongada. A correção cirúrgica realizada após 48 horas de vida aumentou significativamente a ocorrência de infecção do sistema nervoso central. Ausência de hidrocefalia antenatal foi associada a menor número de complicações nos primeiros dias de vida / Introduction: Patients with myelomeningocele have a high mortality and develop neurological disabilities that occur primarily by a defective spinal cord and nerve root development and, secondarily, by acquired post-natal complications. The challenge in the post-natal management of myelomeningocele is the early recognition of cases at risk for complications in order to establish individualized treatment strategies. Objective: This study aims to identify short-term prognostic markers for newborns with myelomeningocele. Anatomical characteristics of the spinal defect and technical aspects of the neurosurgical repair were analyzed for this purpose. Methods: A retrospective cohort study was conducted in 70 patients with thoracic, lumbar or sacral myelomeningocele born between January 2007 and December 2013 in the Centro Neonatal do Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Patients with congenital infection, chromosomal abnormalities and other major malformations unrelated to myelomeningocele were excluded from our analysis. Features of myelomeningocele anatomy and neurosurgical treatment were analyzed for the following outcomes: neonatal resuscitation, length of hospital stay, need for ventricular shunt, wound dehiscence, wound infection, central nervous system infection and sepsis. Relationships between qualitative outcomes and factors of interest were examined using chi-square or Fisher\'s exact tests. The relationships with the quantitative outcome duration of hospital stay were evaluated using the Mann-Whitney tests. Relative risks were estimated with 95% confidence intervals. Multivariate linear regression was used to evaluate the quantitative outcomes and a Poisson regression model was used for the qualitative outcomes. Results: During the study period a total of 12,559 neonates were born in Centro Neonatal do Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Eighty patients were diagnosed with myelomeningocele resulting in an incidence of 6.4 cases per 1000 live births. Ten patients were excluded from our analysis due to cervical myelomeningocele (n = 1), congenital heart disease (n = 4), trisomy 13 (n = 1), omphalocele (n = 3) and encephalocele (n = 1). Three deaths were observed in the study period (4,28%). Large myelomeningocele was associated with central nervous system infection, wound complications and longer hospital stay. Patients with thoracic myelomeningocele required longer hospital stay, on average 39 days longer when compared to patients with lumbar or sacral defects. There was a positive correlation between the need for resuscitation at the delivery room and the presence of macrocrania at birth. Late surgical repair performed after 48 hours of life increased in 5.7 times the risk of central nervous system infection. Among patients operated within the first 48 hours, no additional benefit in interventions held in \"time zero\" was observed. Absence of antenatal hydrocephalus was a favorable prognostic marker. In these cases, the combination of need for ventricular drainage, sepsis, central nervous system infection, complications of surgical site and intervention in the delivery room were 70% lower. Conclusion: This study allowed us to identify short-term prognostic markers for newborns with myelomeningocele. Extensive spinal cord defect and surgical repair after 48 hours of life negatively influenced short-term outcomes. Extensive lesions were associated with higher rates of central nervous system infections, surgical wound complications and prolonged hospital stay. Interventions performed 48 hours after birth significantly increased occurrence of central nervous system infections. Absence of antenatal hydrocephalus was associated with fewer complications in the first days of life

A hidrocefalia é uma doença ocasionada pelo distúrbio na formação, circulação ou absorção do líquido cefalorraquidiano (líquor) que acarreta na elevação da pressão intracraniana. O tratamento mais usual para a disfunção é a derivação ventrículo-peritoneal (DVP) responsável pela drenagem do líquor do ventrículo até o abdômen do paciente, através do implante de um cateter ventricular, uma válvula neurológica e um cateter peritoneal. Desse modo, o presente estudo apresenta o conceito de uma nova válvula neurológica com um mecanismo inovador para alteração da pressão de funcionamento, com um menor custo produtivo e de possível aceitação pelo Sistema Único de Saúde (SUS). A norma ISO 7197 forneceu as diretrizes atendidas no desenvolvimento da válvula neurológica ajustável e as informações para a construção das bancadas de testes, utilizadas para a realização dos ensaios hidrodinâmicos no protótipo do dispositivo valvular. Foram pesquisados os biomateriais empregados na fabricação de válvulas neurológicas comerciais, para a proposição dos materiais necessários para a construção da válvula ajustável por acionamento mecânico proposta. O aparato utilizado nos testes hidrodinâmicos apresentou incertezas experimentais, que não comprometem os resultados e a avaliação do desempenho in vitro do dispositivo testado. O protótipo da válvula resistiu aos testes de vazamento e de refluxo de fluido. As pressões de abertura e de fechamento apresentaram-se adequadas para o início e a interrupção do escoamento na DVP. Também foi obtido o comportamento do diferencial de pressão, em função da vazão, para as quatro classes de funcionamento disponíveis no protótipo testado. A avaliação hidrodinâmica do protótipo da válvula ajustável por acionamento mecânico apresenta resultados satisfatórios no controle da drenagem de líquor, frente a todos os ensaios hidrodinâmicos realizados. / Hydrocephalus is a disease caused by disturbance in formation, circulation or absorption of cerebrospinal fluid (CSF) which causes high intracranial pressure. The most common treatment for the dysfunction is the ventricle-peritoneal shunt responsible for drainage of cerebrospinal fluid from the patient\'s ventricle to the abdomen, through the implant of a ventricular catheter, a neurological valve and a peritoneal catheter. Thus, the present study introduces the concept of a new valve with an innovative mechanism to change the working pressure, with a lower cost of production and possible acceptance by the Brazilian Health System. ISO 7197 provided the guidelines met in the development of adjustable neurological valve and the information for the construction of testing rigs, used for hydrodynamic testing on the valve device prototype. Biomaterials used in manufacturing commercial neurological valves have been researched for proposition of materials needed for the proposed adjustable neurological valve by mechanical drive. The apparatus used in hydrodynamic tests presented experimental uncertainties, which do not compromise the results and evaluation of in vitro performance of the device tested. The prototype of the valve withstood the leak and the fluid backflow testing. The opening and closing pressures were suitable for the beginning and the interruption of the flow in the ventricle-peritoneal shunt. It was also obtained the behavior of the pressure differential, due to the flow, for the four classes of operation available in the prototype tested. Hydrodynamic evaluation of the prototype of the adjustable valve by mechanical drive shows satisfactory results in the control of CSF drain, dealing with all hydrodynamic tests carried out.

Die hier vorliegenden klinischen und experimentellen Arbeiten hatten zum Ziel apoptotische Mechanismen einer Schädigung des unreifen zentralen Nervensystems näher zu charakterisieren. Im tierexperimentellen Teil der Studien wurden apoptotische Faktoren und deren Regulation an zwei unterschiedlichen experimentellen Schädigungsmodellen des unreifen Gehirns (Hypoxie, Trauma) untersucht, mit dem Ziel mögliche neuroprotektive Ansätze zu identifizieren. In einem weiteren Teil der Arbeiten ging es darum, die Darstellung der Hirnschädigung von sehr unreifer Frühgeborenen in der Magnetresonanztomographie (MRT) histologisch an Autopsiematerial zu vergleichen. An Autopsiefällen mit pontosubikulärer Nekrose (PSN) wurde die Bedeutung der pro-apoptotischen Marker CD95/Fas/Fas Ligand bei einer Hypoxie erarbeitet. Der klinische Teil der Untersuchungen hatte die Identifizierung Apoptose-regulierender Faktoren (lösliche Form von Fas/Fas Ligand, Caspase 3) im Liquor von Patienten mit Hydrozephalus zum Ziel. Die in dieser kumulativen Habilitationsschrift aufgeführten Arbeiten haben die weitreichende Rolle apoptotischer Mechanismen, insbesondere des Zelloberflächenrezeptors CD95/Fas, in unterschiedlichen klinischen und experimentellen Schädigungsmodellen des unreifen Gehirns demonstriert und weiterführende Fragestellungen aufgezeigt. Im klinischen Umfeld besteht mit neueren bildgebenden Verfahren und der Untersuchung löslicher apoptotischer Marker die Möglichkeit, Schädigungen des Gehirns näher zu charakterisieren. Mit diesen Untersuchungen wurden zudem Grundlagen zur Identifikation möglicher neuroprotektiver Angriffspunkte erarbeitet. / The studies presented here aimed at the investigation of apoptotic mechanisms in the context of damage to the immature central nervous system. The expression and regulation of apoptotic factors was demonstrated in two experimental animal models of damage to the immature brain (hypoxia, trauma), in order to identify possible neuroprotective strategies. The aim of an additional study was to compare the magnetic resonance imaging (MRI) appearances of the immature brain with neuropathological findings at post-mortem examination. In human autopsy material consisting of cases with pontosubicular necrosis (PSN) the expression of pro-apoptotic markers (CD95/Fas/Fas ligand) was demonstrated. The clinical part of the projected investigations identified apoptosis-regulating elements (soluble Fas /Fas ligand, Caspase-3) in the cerebrospinal fluid (CSF) of children with hydrocephalus. The clinical and experimental studies confirmed the importance of apoptotic mechanisms in the pathophysiology of neurodegeneration in the immature brain. In a clinical setting new MRI imaging procedures and identification of novel biochemical markers have the potential to further characterize damage processes. The investigations presented here identified molecular targets for possible neuroprotective therapies.

O objetivo do estudo foi medir a acuidade visual (AV) em crianças com diagnóstico de hidrocefalia, apresentando ou não a válvula de derivação ventricular (DVP). Participaram da pesquisa um total de 55 crianças (34 F e 21M) com diagnóstico de hidrocefalia (45 com DVP e 10 sem DVP), com idade entre zero a 291 semanas (média 74 semanas). A AV foi medida pela técnica do Potencial Visual Evocado de Varredura e os resultados foram comparados a valores de referência (Norcia, 1985b). Os diagnósticos etiológicos que levaram à hidrocefalia foram: hemorragia intracraniana (25 crianças), mielomeningocele (20 crianças) e hidrocefalia congênita (10 crianças). O diagnóstico de hidrocefalia foi estabelecido em média no 16° dia de vida. Verificamos que, 31 crianças tiveram o procedimento realizado com menos de 15 dias do diagnóstico de hidrocefalia enquanto que em 14 a válvula foi instalada após 15 dias. Das 55 crianças avaliadas no 1° exame, 18 fizeram o 2° exame, 13 fizeram o 3° exame, 10 completaram quatro exames e apenas cinco completaram as cinco avaliações. Os resultados mostram que dentre as 101 avaliações de AV realizadas em todas as crianças, 95 exames (94%) se mostraram alterados e seis normais. Não há diferença estatística entre a AV das crianças sem derivação em comparação com aquelas crianças cuja DVP foi realizada com tempo de derivação maior que 15 dias (p = 0.699). Houve, todavia, uma diferença estatística na AV, quando comparamos as crianças, cujas derivações foram realizadas em até 15 dias do diagnóstico da hidrocefalia, com aquelas cuja derivação foi realizada após 15 dias (p = 0.038) ou com aquelas que não foram derivadas (p = 0.031). Crianças que não tiveram complicações na DVP tiveram um melhor resultado de AV quando comparado com o grupo com complicação (p = 0.0001). No grupo de crianças com complicação, novamente aquelas que foram derivadas com tempo inferior a 15 dias do diagnóstico da hidrocefalia apresentou melhores resultados de AV quando comparado com aquelas crianças com complicação cuja derivação foi realizada com mais de 15 dias (p = 0.029). Nós concluímos que é possível a medida da acuidade visual de resolução pelos PVEs de varredura em crianças com diagnóstico de hidrocefalia e os valores geralmente são piores comparando aos valores normativos. O tempo da derivação e o número de complicações decorrentes da DVP parecem interferir nesta diferença. Em nosso conhecimento, este foi o primeiro trabalho a avaliar progressivamente, a acuidade visual de crianças, nos primeiros anos de vida, com hidrocefalia, com ou sem DVP e correlacionar o resultado com o tempo de derivações e número de complicações. Apesar da grande evolução tecnológica alcançada pela oftalmologia, ainda não somos capazes de prevenir as alterações visuais detectáveis pelo simples exame de AV nas crianças com hidrocefalia. O tempo para a inserção da válvula de derivação e o tratamento para as complicações ainda são medidas retardadas devido à prematuridade, instabilidade hemodinâmica e a não autorização do familiar. Estes motivos podem comprometer o desenvolvimento visual destas crianças. / The objective was to measure the visual acuity (VA) of children with the diagnosis of hydrocephalus with or without peritoneal-ventricular shunt (PVS). A total of 55 children with the diagnosis of hydrocephalus (45 with PVS and 10 without PVS) were included in the study (34F and 21M), with an age range of 0 to 291 weeks (mean=74 weeks). The VA was measured by the sweep visual evoked potential technique and the results were compared with reference values proposed by Norcia (1985b). Etiological diagnosis of the hydrocephalus was as follows: intracranial hemorrhage (25 children), meningomyelocele (20 children) and congenital hydrocephalus (10 children). The diagnosis of hydrocephalus was made in an average time of 16 days of life. After the diagnosis, the insertion of the PVS, when made, was accomplished in average on the 16th day. Of those with a PVS, in 31 the ventricular valve was inserted before 15 days after the diagnosis whereas in 14 in shunt was inserted after 15 days. Of the 55 children evaluated in the first exam, 18 were evaluated in a second exam, 13 did the third exam, 10 completed 4 exams and only 5 completed the 5 evaluations. The results of the 101 sweep visual evoked potential performed in all children, 95 exams (94%) were abnormal and only 6 were normal. There was no statistical difference in the VA of children without a ventricular shunt in comparison with those in which the shunt was inserted after 15 days of the diagnosis of hydrocephalus (p=0.699). There was, however, a statistical difference in the VA between children with a ventricular shunt inserted before 15 days of the diagnosis and children with a ventricular shunt after 15 days (p=0.038) or those without a shunt (p=0.031). Children with no complications of the ventricular shunt had a better VA as compared to those with shunt complications (p= 0.0001). In the group of children with complications, again those who had a shunt inserted before 15 days bad better VA results in comparison to those in whom the shunt was inserted after 15days (p=0.029). We concluded that measuring visual acuity by sweep visual evoked potential is feasible in children with the diagnosis of hydrocephalus and that results are usually worse comparing with reference values. The timing for insertion of a ventricular shunt and the occurrence of complications of this procedure are factors that may influence the VA. To our knowledge, this is the first study that progressively evaluated the VA in children, of early age, with hydrocephalus, with or without a ventricular shunt and correlated the VA with the timing and complications of the ventricular shunt. Despite the great technological advance in ophthalmology, we are still unable to prevent visual impairments, detectable by simple visual acuity tests, in children with hydrocephalus. The timing of the insertion of the ventricular shunt and the adequate treatment of the potential complications may be delayed due to prematurity, hemodynamic instability and family refusal. This delay may compromise the visual development of these children.

Introdução: As mucopolissacaridoses (MPS) constituem um grupo de doenças lisossômicas caracterizadas pela deficiência de uma das enzimas responsáveis pela degradação dos glicosaminoglicanos (GAGs). É difícil determinar a incidência precisa de hidrocefalia em pacientes com MPS, pois não possui uma definição formal por consenso. Além disso, é difícil distinguir a hidrocefalia comunicante da dilatação ventricular secundária à atrofia cerebral, porque ambas apresentam características clínicas e neuroradiológicas comuns. Embora várias técnicas sejam usadas para identificar pacientes com MPS com maior probabilidade de ter hidrocefalia e responder ao tratamento cirúrgico, não existe um método definitivo para provar o diagnóstico. Objetivos: Avaliar a relação entre ventriculomegalia, volume cerebral e liquórico, fluxo de líquor aquedutal e cervical e pressão de abertura liquórica em pacientes com MPS, e detectar potenciais biomarcadores para as alterações da circulação liquórica. Métodos: Quarenta e três pacientes com MPS (12 MPS I, 15 MPS II, 5 MPS III, 9 MPS IV A e 2 MPS VI) realizaram testes clínicos e de desenvolvimento neurológico, ressonância magnética (RM) nas sequências T1, T2, FLAIR e por contraste de fase, seguidas por punção lombar para avaliação da pressão de abertura liquórica. Para a análise das variáveis da RM, foram medidos: volume cerebral e liquórico, carga de lesões na substância branca (LSB), índice de Evans, largura do terceiro ventrículo, ângulo do corpo caloso, espaços perivasculares dilatados (EPVD), estenose da junção craniocervical, volume de stroke aquedutal e cervical, e concentração de GAGs no líquor. Resultados: As formas graves e a macrocefalia estiveram significativamente associadas com a ventriculomegalia, principalmente com o índice de Evans (p = 0.004 e p = 0.008, respectivamente). A carga de LSB apresentou uma forte correlação com as medidas ventriculares e o volume liquórico ventricular (rs = 0.51, p = 0.001). A dilatação ventricular supratentorial e o volume de líquor ventricular apresentaram uma correlação moderada com o volume de stroke aquedutal (VSA) (rs = 0.46, p = 0.002). A pressão de abertura liquórica não se correlacionou nem com as três medidas da ventriculomegalia, nem com a volumetria liquórica, nem com o VSA. O prejuízo cognitivo e os EPVD mostraram uma associação significativa com a ventriculomegalia, especialmente com a largura do terceiro ventrículo (p = 0.019 e p = 0.001, respectivamente). Os EPVD em quantidade aumentada também apresentaram uma significativa associação com o VSA elevado (p = 0.007). Conclusões: Nos pacientes com MPS, a ventriculomegalia está associada a um fenótipo grave da doença, maior declínio cognitivo e maior extensão das LSB e EPVD. Existem associações entre as medidas de fluxo liquórico e as medidas relacionadas à volumetria liquórica. Além disso, as medidas volumétricas estão associadas a quantidade de EPVD. / Background: The mucopolysaccharidoses (MPS) are a group of lysosomal diseases characterized by a deficiency in one of the lysosomal enzymes responsible to degrade glycosaminoglycans (GAGs). The precise incidence of hydrocephalus in patients with MPS is hard to determine, because it lacks a formal, consensus-based definition. In addition, it is difficult to distinguish communicating hydrocephalus from ventricular dilatation secondary to brain atrophy, because both share common clinical and neuroradiological features. Although various techniques are used to identify MPS patients who are most likely to have hydrocephalus and respond to surgical treatment, no definitive method exists to prove diagnosis. Objectives: To assess the relationship between ventriculomegaly, brain and cerebrospinal fluid (CSF) volumes, aqueductal and cervical CSF flows, and CSF opening pressure in MPS patients, and to provide potential biomarkers for abnormal CSF circulation. Methods: Forty-three MPS patients (12 MPS I, 15 MPS II, 5 MPS III, 9 MPS IV A and 2 MPS VI) performed clinical and neurodevelopmental tests, and T1, T2, FLAIR and phase-contrast magnetic resonance imaging (MRI) followed by a lumbar puncture with the CSF opening pressure assessment. For the analysis of MRI variables, the following measures were performed: brain and CSF volumes, white matter (WM) lesion load, Evans’ index, third ventricle width, callosal angle, dilated perivascular spaces (PVS), craniocervical junction stenosis, aqueductal and cervical CSF stroke volumes, and CSF GAGs concentration Results: The severe forms and the macrocephaly were significantly associated with the ventriculomegaly, mainly with the Evans’ index (p = 0.004 and p = 0.008, respectively). The WM lesion load presented a high correlation with the ventricular measurements and the ventricular CSF volume (rs = 0.51, p = 0.001). The supratentorial ventricular dilation and the ventricular CSF volume presented a moderate correlation with the aqueductal CSF stroke volume (ACSV) (rs = 0.46, p = 0.002). The CSF opening pressure did not correlate with either the three measures of ventriculomegaly, either with the CSF volumetry or with the ACSV. The cognitive impairment and the dilated PVS showed a significant association with the ventriculomegaly, especially with the width of the third ventricle (p = 0.019 and p = 0.001, respectively). Increased amount of dilated PVS also had a significant association with the elevated ACSV (p = 0.007). Conclusions: In MPS patients ventriculomegaly is associated with a severe phenotype, increased cognitive decline, WM lesion severity and enlarged PVS. There are associations between CSF flow measurements and measurements related to CSF volumetrics. Also, the volumetric measurements are associated with the degree of dilated PVS.

Introdução: Pacientes com mielomeningocele apresentam elevada mortalidade e desenvolvem déficits neurológicos que ocorrem, primariamente, pelo desenvolvimento anormal da medula e de raízes nervosas e, secundariamente, por complicações adquiridas no período pós-natal. O desafio no cuidado desses pacientes é o reconhecimento precoce dos recém-nascidos de risco para evolução desfavorável a fim de estabelecer estratégias terapêuticas individualizadas. Objetivo: Este estudo tem como objetivo identificar marcadores prognósticos de curto prazo para recém-nascidos com mielomeningocele. As características anatômicas do defeito medular e da sua correção neurocirúrgica foram analisadas para esta finalidade. Métodos: Foi realizado um estudo de coorte retrospectiva com 70 pacientes com mielomeningocele em topografia torácica, lombar ou sacral nascidos entre janeiro de 2007 a dezembro de 2013 no Centro Neonatal do Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Pacientes com infecção congênita, anomalias cromossômicas e outras malformações maiores não relacionadas à mielomeningocele foram excluídos da análise. As características anatômicas da mielomeningocele e a sua correção neurocirúrgica foram analisadas quanto aos seguintes desfechos: reanimação neonatal, tempo de internação, necessidade de derivação ventricular, deiscência da ferida operatória, infecção da ferida operatória, infecção do sistema nervoso central e sepse. Para a análise bivariada dos desfechos qualitativos com os fatores de interesse foram empregados testes do qui-quadrado e exato de Fisher. Para a análise do desfecho quantitativo, tempo de internação hospitalar, foram empregados testes de Mann-Whitney. Foram estimados os riscos relativos e os respectivos intervalos com 95% de confiança. Foram desenvolvidos modelos de regressão linear múltipla para os desfechos quantitativos e regressão de Poisson para os desfechos qualitativos. Resultados: Durante o período do estudo 12.559 recém-nascidos foram admitidos no Centro Neonatal do Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Oitenta pacientes foram diagnosticados com mielomeningocele, com incidência de 6,4 casos para cada 1.000 nascidos vivos. Dez pacientes foram excluídos da análise devido à mielomeningocele em topografia cervical (n = 1), à cardiopatia congênita (n = 4), à trissomia do cromossomo 13 (n = 1), à onfalocele (n = 3) e à encefalocele (n = 1). Ocorreram três óbitos (4,28%). Mielomeningocele extensa foi associada a infecção do sistema nervoso central, a complicação de ferida operatória e a maior tempo de internação hospitalar. Os pacientes com mielomeningocele em topografia torácica apresentaram tempo de internação, em média, 39 dias maior que aqueles com defeito em topografia lombar ou sacral. Houve maior necessidade de reanimação em sala de parto entre os pacientes com macrocrania ao nascer. A correção cirúrgica realizada após 48 horas de vida aumentou em 5,7 vezes o risco de infecção do sistema nervoso central. Entre os pacientes operados nas primeiras 48 horas de vida não foi observado benefício adicional na correção cirúrgica realizada em \"tempo zero\". A ausência de hidrocefalia antenatal foi um marcador de bom prognóstico. Nestes pacientes, a combinação dos desfechos necessidade de derivação ventricular, complicações infecciosas, complicações de ferida operatória e reanimação em sala de parto foi 70% menos frequente. Conclusão: Este estudo permitiu identificar marcadores prognósticos de curto prazo em recém-nascidos com mielomeningocele. Os defeitos medulares extensos e a correção cirúrgica após 48 horas de vida influenciaram negativamente na evolução de curto prazo. As lesões extensas foram associadas a maiores taxas de infecção do sistema nervoso central, a complicações de ferida operatória e a internação hospitalar prolongada. A correção cirúrgica realizada após 48 horas de vida aumentou significativamente a ocorrência de infecção do sistema nervoso central. Ausência de hidrocefalia antenatal foi associada a menor número de complicações nos primeiros dias de vida / Introduction: Patients with myelomeningocele have a high mortality and develop neurological disabilities that occur primarily by a defective spinal cord and nerve root development and, secondarily, by acquired post-natal complications. The challenge in the post-natal management of myelomeningocele is the early recognition of cases at risk for complications in order to establish individualized treatment strategies. Objective: This study aims to identify short-term prognostic markers for newborns with myelomeningocele. Anatomical characteristics of the spinal defect and technical aspects of the neurosurgical repair were analyzed for this purpose. Methods: A retrospective cohort study was conducted in 70 patients with thoracic, lumbar or sacral myelomeningocele born between January 2007 and December 2013 in the Centro Neonatal do Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Patients with congenital infection, chromosomal abnormalities and other major malformations unrelated to myelomeningocele were excluded from our analysis. Features of myelomeningocele anatomy and neurosurgical treatment were analyzed for the following outcomes: neonatal resuscitation, length of hospital stay, need for ventricular shunt, wound dehiscence, wound infection, central nervous system infection and sepsis. Relationships between qualitative outcomes and factors of interest were examined using chi-square or Fisher\'s exact tests. The relationships with the quantitative outcome duration of hospital stay were evaluated using the Mann-Whitney tests. Relative risks were estimated with 95% confidence intervals. Multivariate linear regression was used to evaluate the quantitative outcomes and a Poisson regression model was used for the qualitative outcomes. Results: During the study period a total of 12,559 neonates were born in Centro Neonatal do Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Eighty patients were diagnosed with myelomeningocele resulting in an incidence of 6.4 cases per 1000 live births. Ten patients were excluded from our analysis due to cervical myelomeningocele (n = 1), congenital heart disease (n = 4), trisomy 13 (n = 1), omphalocele (n = 3) and encephalocele (n = 1). Three deaths were observed in the study period (4,28%). Large myelomeningocele was associated with central nervous system infection, wound complications and longer hospital stay. Patients with thoracic myelomeningocele required longer hospital stay, on average 39 days longer when compared to patients with lumbar or sacral defects. There was a positive correlation between the need for resuscitation at the delivery room and the presence of macrocrania at birth. Late surgical repair performed after 48 hours of life increased in 5.7 times the risk of central nervous system infection. Among patients operated within the first 48 hours, no additional benefit in interventions held in \"time zero\" was observed. Absence of antenatal hydrocephalus was a favorable prognostic marker. In these cases, the combination of need for ventricular drainage, sepsis, central nervous system infection, complications of surgical site and intervention in the delivery room were 70% lower. Conclusion: This study allowed us to identify short-term prognostic markers for newborns with myelomeningocele. Extensive spinal cord defect and surgical repair after 48 hours of life negatively influenced short-term outcomes. Extensive lesions were associated with higher rates of central nervous system infections, surgical wound complications and prolonged hospital stay. Interventions performed 48 hours after birth significantly increased occurrence of central nervous system infections. Absence of antenatal hydrocephalus was associated with fewer complications in the first days of life

Bakgrund: Det har i vissa fall varit märkbart att patienter med idiopatisk normaltrycks hydrocefalus (iNPH) upplever att förväntat shuntbehandlingsresultat inte uppnåtts och de rapporterar försämring vid den postoperativa uppföljningen trots att standardiserade tester inte visar i den riktningen. Det har också visat sig att rehabiliteringsinsatserna varierat för patienterna allt från strukturerade rehabiliteringsperioder på exempelvis geriatrisk rehabiliteringsenhet till i princip ingen rehabilitering alls. Syfte: Att beskriva vilka förväntningar personer med iNPH har på behandling med shunt och hur de ser på sin egen roll i rehabiliteringsprocessen. Metod: Kvalitativ, deskriptiv design med manifest och induktiv ansats. Datainsamlingen skedde genom semistrukturerade intervjuer med sju patienter med iNPH preoperativt. Resultat: Det fanns en samstämmighet bland informanterna kring förväntningar på shuntbehandlingsresultatet. De rörde den symtomtriad (gång och balansstörning, överaktiv urinblåsa samt kognitiv nedsättning) som ofta finns vid iNPH. Varierade beskrivningar gavs på hur symtomen påverkade informanterna. Det fanns också en uppfattning bland informanterna att de hade ett eget ansvar i rehabiliteringsprocessen och förslag framkom på vad de själva kunde bidra med i processen men också olika hinder för att utöva fysisk aktivitet beskrevs. Slutsats: Förväntningar på shuntbehandlingsresultat behöver diskuteras med patienten (ibland även anhörig) inför shuntbehandling redan vid beslut om operation men också då patienten läggs in för behandlingen. Rehabiliteringsprocessen behöver också diskuteras med patienten såväl före shuntoperation som tidigt postoperativt. Detta är troligtvis mycket viktigt för att uppnå ett så optimalt behandlingsresultat som möjligt. / Background: It has been noticeable that some patients with idiopathic normal pressure hydrocephalus (iNPH) find the expected result of shunt treatment not  achieved and they report detoriation at postoperative follow-up even though standardized tests do not show results in that direction. It has also been shown that rehabilitation possibilities for patients varied, ranging from structured rehabilitation periods, e.g. at geriatric rehabilitation units to basically no rehabilitation at all. Objective: To describe what expectations patients with iNPH have on treatment with shunt and how they view their own role in the rehabilitation process. Method: A quality, descriptive design with manifest and inductive approach. The data collection was done by semi-structured interviews with seven patients with iNPH preoperative. Results: There was consensus among informants regarding the expectations on the result of shunt treatment. The expectations concerned the symptom triad (gait-and balance disturbance, urgency bladder and cognitive dysfunction) which often occurs in iNPH. Varied descriptions were given on how the symptoms had affected the informants. There was also an opinion among the informants that they had own responsibility for the rehabilitation process and suggestions were given on what they could contribute with in the process but also different obstacles for performing physical activities were described. Conclusion: Expectations on shunt treatment results need to be discussed with the patient (sometimes together with a relative) prior to shunt treatment, already when the patient is offered a shunt operation and also on the day before operation when the patient is in the neurosurgery clinic. The rehabilitation process also needs to be discussed with the patient before the shuntoperation as well as early postoperative. This is probably very important in order to achieve as optimal treatment results as possible.