RESUMO
BACKGROUND: Congenital hydrocephalus (CH) comprises a heterogeneous group of birth anomalies with a wide-ranging prevalence across geographic regions and registry type. The aim of the present study was to analyze the early neonatal case fatality rate (CFR) and total birth prevalence of newborns diagnosed with CH. METHODS: Data were provided by 25 registries from four continents participating in the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR) on births ascertained between 2000 and 2014. Two CH rates were calculated using a Poisson distribution: early neonatal CFR (death within 7 days) per 100 liveborn CH cases (CFR) and total birth prevalence rate (BPR) per 10,000 births (including live births and stillbirths) (BPR). Heterogeneity between registries was calculated using a meta-analysis approach with random effects. Temporal trends in CFR and BPR within registries were evaluated through Poisson regression modeling. RESULTS: A total of 13,112 CH cases among 19,293,280 total births were analyzed. The early neonatal CFR was 5.9 per 100 liveborn cases, 95% confidence interval (CI): 5.4-6.8. The CFR among syndromic cases was 2.7 times (95% CI: 2.2-3.3) higher than among non-syndromic cases (10.4% [95% CI: 9.3-11.7] and 4.4% [95% CI: 3.7-5.2], respectively). The total BPR was 6.8 per 10,000 births (95% CI: 6.7-6.9). Stratified by elective termination of pregnancy for fetal anomalies (ETOPFA), region and system, higher CFR were observed alongside higher BPR rates. The early neonatal CFR and total BPR did not show temporal variation, with the exception of a CFR decrease in one registry. CONCLUSIONS: Findings of early neonatal CFR and total BPR were highly heterogeneous among registries participating in ICBDSR. Most registries with higher CFR also had higher BPR. Differences were attributable to type of registry (hospital-based vs. population-based), ETOPFA (allowed yes or no) and geographical regions. These findings contribute to the understanding of regional differences of CH occurrence and early neonatal deaths.
Assuntos
Hidrocefalia , Natimorto , Feminino , Humanos , Hidrocefalia/epidemiologia , Recém-Nascido , Nascido Vivo/epidemiologia , Gravidez , Prevalência , Sistema de Registros , Natimorto/epidemiologiaRESUMO
BACKGROUND: Fetal ventriculomegaly (VM) is a frequent finding in prenatal ultrasound. Rather than a proper diagnosis, VM is a sonographic sign, making prenatal counseling a complex and challenging undertaking. VM can range from severe pathologic processes leading to severe neurodevelopmental delay to normal variants. DISCUSSION: A growing number of genetic conditions with different pathophysiological mechanisms, inheritance patterns, and long-term prognosis have been associated both to isolated and complex fetal VM. These include chromosomal abnormalities, copy number variants, and several single gene diseases. In this review, we describe some of the most common genetic conditions associated with fetal VM and provide a simplified diagnostic workflow for the clinician.
Assuntos
Hidrocefalia , Malformações do Sistema Nervoso , Feminino , Feto/diagnóstico por imagem , Humanos , Hidrocefalia/diagnóstico por imagem , Hidrocefalia/genética , Gravidez , Cuidado Pré-Natal , Diagnóstico Pré-Natal , Ultrassonografia Pré-NatalRESUMO
Foetal onset hydrocephalus is a disease starting early in embryonic life; in many cases it results from a cell junction pathology of neural stem (NSC) and neural progenitor (NPC) cells forming the ventricular zone (VZ) and sub-ventricular zone (SVZ) of the developing brain. This pathology results in disassembling of VZ and loss of NSC/NPC, a phenomenon known as VZ disruption. At the cerebral aqueduct, VZ disruption triggers hydrocephalus while in the telencephalon, it results in abnormal neurogenesis. This may explain why derivative surgery does not cure hydrocephalus. NSC grafting appears as a therapeutic opportunity. The present investigation was designed to find out whether this is a likely possibility. HTx rats develop hereditary hydrocephalus; 30-40% of newborns are hydrocephalic (hyHTx) while their littermates are not (nHTx). NSC/NPC from the VZ/SVZ of nHTx rats were cultured into neurospheres that were then grafted into a lateral ventricle of 1-, 2- or 7-day-old hyHTx. Once in the cerebrospinal fluid, neurospheres disassembled and the freed NSC homed at the areas of VZ disruption. A population of homed cells generated new multiciliated ependyma at the sites where the ependyma was missing due to the inherited pathology. Another population of NSC homed at the disrupted VZ differentiated into ßIII-tubulin+ spherical cells likely corresponding to neuroblasts that progressed into the parenchyma. The final fate of these cells could not be established due to the protocol used to label the grafted cells. The functional outcomes of NSC grafting in hydrocephalus remain open. The present study establishes an experimental paradigm of NSC/NPC therapy of foetal onset hydrocephalus, at the etiologic level that needs to be further explored with more analytical methodologies.
Assuntos
Hidrocefalia/terapia , Células-Tronco Neurais/transplante , Animais , Diferenciação Celular , Proliferação de Células , Neurogênese , RatosRESUMO
INTRODUCCIÓN: La hidrocefalia de inicio fetal, perinatal y neonatal representa un gran reto terapéutico y a menudo cursa con un pronóstico neurológico pobre, debido a su etiología heterogénea, que incluye alteraciones del neurodesarrollo. OBJETIVO: Realizar una recopilación de los avances en terapia celular como propuesta que permite ampliar el espectro de tratamiento en la hidrocefalia congénita-neonatal. DESARROLLO: Las intervenciones terapéuticas disponibles actualmente, como la derivación ventrículo-peritoneal y la tercera ventriculostomía, son insuficientes para resolver por completo la hidrocefalia y para prevenir o revertir los daños neurológicos asociados. Es por esto por lo que ha surgido la necesidad de crear nuevas alternativas terapéuticas a partir del conocimiento de los mecanismos fisiopatológicos que participan en el desarrollo de esta condición. Particularmente, la terapia celular con células madre neuronales y células madre mesenquimales ha demostrado, en estudios con animales y en estudios preclínicos con humanos, ser eficiente y segura para prevenir la hidrocefalia originada a partir de la disrupción de la zona ventricular y secundaria a la hemorragia intraventricular, con la consiguiente prevención de las secuelas neurológicas sensoriomotoras y cognitivas. CONCLUSIONES: Hasta el momento no tenemos un tratamiento eficiente que ofrezca calidad de vida a los pacientes con hidrocefalia, y que esa alternativa terapéutica sea efectiva. INTRODUCTION: Fetal hydrocephalus, perinatal and neonatal represents a major therapeutic challenge and often has with poor neurological prognosis, due to its heterogeneous aetiology, including neurodevelopmental disorders. OBJECTIVE: To make a collection of advances in cell therapy as a proposal that can extend the spectrum of treatment in congenita-neonatal hydrocephalus. DEVELOPMENT: Therapeutic interventions available at present as the ventricle-peritoneal shunt and third ventriculostomy, are insufficient to fully resolve the hydrocephalus and to prevent or reverse the associated neurological damage. This is why what has emerged the need for new therapeutic alternatives based on the knowledge of physiopathological mechanisms involved in the development of this condition. In particular, cell therapy with neural stem cells and mesenchymal stem cells has proven in animal studies and preclinical studies with humans, efficiently and safely to prevent hydrocephalus originated from the disruption of the ventricular zone and secondary to intraventricular hemorrhage, with the consequent prevention of neurological sequelae sensorimotor and cognitive. CONCLUSIONS: So far, we do not have an efficient treatment that offers quality of life to patients with hydrocephalus, and that alternative therapy to be effective.
Assuntos
Hidrocefalia/cirurgia , Transplante de Células-Tronco , Humanos , Recém-NascidoRESUMO
Fetal onset hydrocephalus and abnormal neurogenesis are two inseparable phenomena turned on by a cell junction pathology first affecting neural stem/progenitor cells (NSPCs) and later the multiciliated ependyma. The neurological impairment of children born with hydrocephalus is not reverted by derivative surgery. NSPCs and neurosphere (NE) grafting into the cerebrospinal fluid (CSF) of hydrocephalic fetuses thus appears as a promising therapeutic procedure. There is little information about the cell lineages actually forming the NE as they grow throughout their days in vitro (DIV). Furthermore, there is no information on how good a host the CSF is for grafted NE. Here, we use the HTx rat, a model with hereditary hydrocephalus, with the mutation expressed in about 30% of the litter (hyHTx), while the littermates develop normally (nHTx). The investigation was designed (i) to establish the nature of the cells forming 4 and 6-DIV NE grown from NSPCs collected from PN1/nHTx rats and (ii) to study the effects on these NEs of CSF collected from nHTx and hyHTx. Immunofluorescence analyses showed that 90% of cells forming 4-DIV NEs were non-committed multipotential NSPCs, while in 6-DIV NE, 40% of the NSPCs were already committed into neuronal, glial and ependymal lineages. Six-DIV NE further cultured for 3 weeks in the presence of fetal bovine serum, CSF from nHTx or CSF from hyHTx, differentiated into neurons, astrocytes and ßIV-tubulin+ multiciliated ependymal cells that were joined together by adherent junctions and displayed synchronized cilia beating. This supports the possibility that ependymal cells are born from subpopulations of NSC with their own time table of differentiation. As a whole, the findings indicate that the CSF is a supportive medium to host NE and that NE grafted into the CSF have the potential to produce neurons, glia and ependyma.
Assuntos
Astrócitos/citologia , Líquido Cefalorraquidiano/fisiologia , Epêndima/citologia , Células Ependimogliais/citologia , Hidrocefalia/patologia , Células-Tronco Neurais/metabolismo , Animais , Diferenciação Celular , Proliferação de Células , Cílios/metabolismo , Modelos Animais de Doenças , Humanos , Células-Tronco Multipotentes/citologia , Células-Tronco Multipotentes/metabolismo , Células-Tronco Neurais/citologia , Neurônios/citologia , RatosRESUMO
Fetal-onset hydrocephalus is not only a disorder of cerebrospinal fluid (CSF) dynamics, but also a brain disorder. How can we explain the inborn and, so far, irreparable neurological impairment in children born with hydrocephalus? We hypothesize that a cell junction pathology of neural stem cells (NSC) leads to two inseparable phenomena: hydrocephalus and abnormal neurogenesis. All neurons, glial cells, and ependymal cells of the mammalian central nervous system originate from the NSC forming the ventricular zone (VZ) and the neural progenitor cells (NPC) forming the subventricular zone. Several genetic mutations and certain foreign signals all convey into a final common pathway leading to cell junction pathology of NSC and VZ disruption. VZ disruption follows a temporal and spatial pattern; it leads to aqueduct obliteration and hydrocephalus in the cerebral aqueduct, while it results in abnormal neurogenesis in the telencephalon. The disrupted NSC and NPC are released into the CSF and may transform into neurospheres displaying a junctional pathology similar to that of NSC of the disrupted VZ. These cells can then be utilized to investigate molecular alterations underlying the disease and open an avenue into possible NSC therapy.
Assuntos
Feto/fisiopatologia , Hidrocefalia/patologia , Ventrículos Laterais/patologia , Células-Tronco Neurais/patologia , Animais , Humanos , Neurônios/patologiaRESUMO
BACKGROUND: Mutant rodent models have highlighted the importance of the ventricular ependymal cells and the subcommissural organ (a brain gland secreting glycoproteins into the cerebrospinal fluid) in the development of fetal onset hydrocephalus. Evidence indicates that communicating and non-communicating hydrocephalus can be two sequential phases of a single pathological phenomenon triggered by ependymal disruption and/or abnormal function of the subcommissural organ. We have hypothesized that a similar phenomenon may occur in human cases with fetal onset hydrocephalus. CASE PRESENTATION: We report here on a case of human fetal communicating hydrocephalus with no central nervous system abnormalities other than stenosis of the aqueduct of Sylvius (SA) that became non-communicating hydrocephalus during the first postnatal week due to obliteration of the cerebral aqueduct. The case was followed closely by a team of basic and clinic investigators allowing an early diagnosis and prediction of the evolving pathophysiology. This information prompted neurosurgeons to perform a third ventriculostomy at postnatal day 14. The fetus was monitored by ultrasound, computerized axial tomography and magnetic resonance imaging (MRI). After birth, the follow up was by MRI, electroencephalography and neurological and neurocognitive assessments. Cerebrospinal fluid (CSF) collected at surgery showed abnormalities in the subcommissural organ proteins and the membrane proteins L1-neural cell adhesion molecule and aquaporin-4. The neurological and neurocognitive assessments at 3 and 6 years of age showed neurological impairments (epilepsy and cognitive deficits). CONCLUSIONS: (1) In a hydrocephalic fetus, a stenosed SA can become obliterated at perinatal stages. (2) In the case reported, a close follow up of a communicating hydrocephalus detected in utero allowed a prompt postnatal surgery aiming to avoid as much brain damage as possible. (3) The clinical and pathological evolution of this patient supports the possibility that the progressive stenosis of the SA initiated during the embryonic period may have resulted from ependymal disruption of the cerebral aqueduct and dysfunction of the subcommissural organ. The analysis of subcommissural organ glycoproteins present in the CSF may be a valuable diagnostic tool for the pathogenesis of congenital hydrocephalus.
Assuntos
Aqueduto do Mesencéfalo/patologia , Hidrocefalia/diagnóstico , Órgão Subcomissural/patologia , Constrição Patológica/patologia , Feminino , Feto , Glicoproteínas/metabolismo , Humanos , Imageamento por Ressonância Magnética , GravidezRESUMO
Oligodendroglial cell changes in human traumatic brain injuries and hydrocephalus have been reviewed and compared with experimental brain edema. Resting unreactive oligodendrocytes, reactive oligodendrocytes, anoxic-ischemic oligodendrocytes, hyperthrophic phagocytic oligodendrocytes, and apoptotic oligodendrocytes are found. Anoxic-ischemic oligodendrocytes exhibit enlargement of endoplasmic reticulum, Golgi complex, and enlargement and disassembly of nuclear envelope. They appear in contact with degenerated myelinated axons. Hypertrophic phagocytic oligodendrocytes engulf degenerated myelinated axons exerting myelinolytic effects. A continuum oncotic and apoptotic cell death type leading to necrosis is observed. The vasogenic and cytotoxic components of brain edema are discussed in relation to oligodendroglial cell changes and reactivity.