Unjoined primary and secondary neural tubes: junctional neural tube defect, a new form of spinal dysraphism caused by disturbance of junctional neurulation.

INTRODUCTION: Primary and secondary neurulation are the two known processes that form the central neuraxis of vertebrates. Human phenotypes of neural tube defects (NTDs) mostly fall into two corresponding categories consistent with the two types of developmental sequence: primary NTD features an open skin defect, an exposed, unclosed neural plate (hence an open neural tube defect, or ONTD), and an unformed or poorly formed secondary neural tube, and secondary NTD with no skin abnormality (hence a closed NTD) and a malformed conus caudal to a well-developed primary neural tube. METHODS AND RESULTS: We encountered three cases of a previously unrecorded form of spinal dysraphism in which the primary and secondary neural tubes are individually formed but are physically separated far apart and functionally disconnected from each other. One patient was operated on, in whom both the lumbosacral spinal cord from primary neurulation and the conus from secondary neurulation are each anatomically complete and endowed with functioning segmental motor roots tested by intraoperative triggered electromyography and direct spinal cord stimulation. The remarkable feature is that the two neural tubes are unjoined except by a functionally inert, probably non-neural band. CONCLUSION: The developmental error of this peculiar malformation probably occurs during the critical transition between the end of primary and the beginning of secondary neurulation, in a stage aptly called junctional neurulation. We describe the current knowledge concerning junctional neurulation and speculate on the embryogenesis of this new class of spinal dysraphism, which we call junctional neural tube defect.

Neural tube defects in the Republic of Ireland in 2009-11.

BACKGROUND: Neural tube defects (NTDs) are associated with deficient maternal folic acid peri-conceptionally. In Ireland, there is no mandatory folic acid food fortification, partly due to declining NTD rates in recent years. The aim of this study was to ascertain the incident rate of NTD during the period 2009-11 and describe epidemiologically NTD in Ireland. METHODS: Cases were ascertained through multiple sources, including three regional congenital anomaly registers, all maternity hospitals nationally and paediatric hospitals providing care for children with spina bifida in the Republic of Ireland during the period 2009-11. RESULTS: From 225 998 total births, 236 NTDs were identified, giving an incidence of 1.04/1 000 births, increasing from 0.92/1 000 in 2009 to 1.17/1 000 in 2011. Of all cases, 45% (n = 106) had anencephaly, 49% (n = 115) had spina bifida and 6% (n = 15) had an encephalocoele; 78% (n = 184) were liveborn or stillborn and 22% (n = 52) were terminations abroad. Peri-conceptional folic acid supplement intake was 13.7% among the 52.5% (n = 124) of cases whose folic acid supplement intake was known. CONCLUSION: The incidence of NTDs in the Republic of Ireland appears to be increasing. Renewed public health interventions, including mandatory folic acid food fortification, must be considered to reduce the incidence of NTD.

A practical clinical classification of spinal neural tube defects.

Current commonly used terminology to describe neural tube defects (NTD) is inconsistent, overlapping, contradictory and, at times, inaccurate making it difficult to convey the nature of the malformation and what needs to be done to optimally treat patients with these congenital abnormalities.NTD can be broadly divided into those that are open with exposed neural tissue and leaking cerebrospinal fluid (CSF) and those that are closed with no exposed neural tissue nor loss of CSF. It appears that the loss of CSF during development is the underlying factor that leads to the entire central nervous system involvement with an open NTD and lack thereof with a closed NTD, wherein only the spinal cord is malformed. There are, however, rare transitional cases that bridge the gap between the two forms.Agreeing on a nomenclature that is used in a standard fashion would be of help in addressing this group of congenital anomalies that have a great deal of variability and, at times, can be quite complex.

The outcome and course of pregnancies complicated with fetal neural tube defects.

PURPOSE: The objectives of this study were as follows: to present the course and outcome of pregnancies complicated with neural tube defects, determine the association between prenatal ultrasound diagnoses, and definitive diagnoses after autopsy. MATERIAL AND METHODS: The survey was designed as a retrospective study and included 24 pregnant women who were attending a regular ultrasound examinations at the Department of Gynecology and Obstetrics, Clinical Center of Serbia, or patients who were referred from other institutions in Serbia. RESULTS: Neural tube defects are divided into five subgroups: spina bifida, meningocele, myelomeningocele, acranius, and anencephaly. The most frequent in the present study was spina bifida with 67%. All pregnancies complicated with neural tube defects were terminated. CONCLUSION: Their clinical severity and uncertain cause make them priorities for further research, whether to better target primary preventive measures, to improve in-utero surgery for prenatal repair, or to identify the causative genes to provide an objective basis for individual genetic counselling.

[A painful occipital mass revealing a posterior encephalocele]. / Une tuméfaction occipitale douloureuse révélant une encéphalocèle postérieure.

Encephalocele is a congenital malformation caused by a neural tube defect during embryonic development. We report a case of posterior encephalocele in a 7-month-old infant with a painful occipital mass known since birth. Pathological examination of the mass showed different mature tissues derived from the brain and its coverings (e.g., neuroglia, ependymal canals and clusters of meningothelial cells). A diagnosis of encephalocele was made. The different forms of neural tube defect will be briefly discussed, especially the "aborted" forms (e.g., non-specific midline mass lesion or angioma) that the pathologist may encounter in his/her daily practice.

Sacrococcygeal dimple: new classification and relationship with spinal lesions.

PURPOSE: This study aims to ascertain which specific types of sacrococcygeal dimples are associated with underlying spinal cord malformations. METHODS: From 2008 to 2011, we prospectively examined children less than 2 years old with sacrococcygeal dimples. Each patient underwent clinical assessment of dimples and magnetic resonance imaging. We devised the following new classification of dimples according to their location: type 1, dimples located within the gluteal crease, including coccygeal pits; type 2, dimples located at the upper edge of the gluteal crease with associated curving or deformity of that crease; and type 3, dimples located well above the gluteal crease. RESULTS: We evaluated 142 patients with sacrococcygeal dimples. Although we identified spinal malformations such as spinal lipomas, filum cysts, and thickened fila terminalia in only 17 % of infants with type 1 dimples, we observed them in 45 % with type 2 and 55 % with type 3. Thus, in terms of the rate of spinal malformations, there are significant differences between types 1 and 2 and between types 1 and 3. CONCLUSIONS: We propose a new classification of sacrococcygeal dimples. Although type 2 dimples have previously been classified as simple dimples that require no further investigation, we have identified that they are strongly associated with spinal deformities, comparable to atypical type 3 dimples. Thus, both types 2 and 3 dimples warrant radiological investigation.

Association between rare variants in specific functional pathways and human neural tube defects multiple subphenotypes.

BACKGROUND: Neural tube defects (NTDs) are failure of neural tube closure, which includes multiple central nervous system phenotypes. More than 300 mouse mutant strains exhibits NTDs phenotypes and give us some clues to establish association between biological functions and subphenotypes. However, the knowledge about association in human remains still very poor. METHODS: High throughput targeted genome DNA sequencing were performed on 280 neural tube closure-related genes in 355 NTDs cases and 225 ethnicity matched controls, RESULTS: We explored that potential damaging rare variants in genes functioning in chromatin modification, apoptosis, retinoid metabolism and lipid metabolism are associated with human NTDs. Importantly, our data indicate that except for planar cell polarity pathway, craniorachischisis is also genetically related with chromatin modification and retinoid metabolism. Furthermore, single phenotype in cranial or spinal regions displays significant association with specific biological function, such as anencephaly is associated with potentially damaging rare variants in genes functioning in chromatin modification, encephalocele is associated with apoptosis, retinoid metabolism and one carbon metabolism, spina bifida aperta and spina bifida cystica are associated with apoptosis; lumbar sacral spina bifida aperta and spina bifida occulta are associated with lipid metabolism. By contrast, complex phenotypes in both cranial and spinal regions display association with various biological functions given the different phenotypes. CONCLUSIONS: Our study links genetic variant to subphenotypes of human NTDs and provides a preliminary but direct clue to investigate pathogenic mechanism for human NTDs.

Congenital spinal lipomatous malformations: part I--Classification.

BACKGROUND: Congenital spinal lipomatous malformations constitute a diverse group of lesions. There is considerable confusion in the literature regarding their terminology and a proper classification is long overdue. The first part of this two part report sets out a proposed classification scheme. METHODS: On the basis of this author's experience with 80 patients with a congenital spinal lipomatous malformation treated over a 10 year period, a new classification is proposed. The proposed classification divides congenital spinal lipomatous malformations into two broad groups: 1. Lipomas without dural defect and, 2. Lipomas with dural defect. Within each group, there are several subtypes. These two broad groups differ from one another in their embryology, clinical presentation, operative findings, complications and prognosis FINDINGS: Group I consists of Lipomas without dural defect. Included in this group are: Filum lipoma, caudal lipoma without dural defect, and intramedullary lipoma. Group II consists of lipomas with dural defect. Included in this group are: dorsal lipoma, caudal lipoma with dural defect, transitional lipoma, lipomyelocele, and lipomyelomeningocele. The definitions of the various subtypes and radiological and operative findings of all these lesions are described. CONCLUSIONS: Congenital spinal lipomatous malformations constitute a wide spectrum of lesions ranging from relatively simple lipomas of the filum terminale to complex malformations. These lesions differ from one another in their embryology, clinical presentation, operative strategies, complications and prognosis. Failure to differentiate between the different forms of congenital spinal lipomatous malformations may lead to inaccurate assumptions regarding prognosis and inappropriate management. The proposed classification seeks to address these issues.

Unusual patterns of neural tube defects in a high risk region of northern China.

OBJECTIVE: To study the prevalence of different types of neural tube defects (NTDs) in Luliang Prefecture, Shanxi province, where the prevalence of NTDs is unusually high and the correlation between NTDs prevalence and patterns. METHODS: A surveillance population-based birth defects was performed in Luliang Prefecture, Shanxi province. RESULTS: The results of our study showed that the prevalence of NTDs was 2-fold higher in Luliang Prefecture than in other areas of Shanxi province. Unusual patterns of NTDs were found, however, multiple NTDs were relatively common in Luliang Prefecture, accounting for over 13% of all NTDs cases in China. CONCLUSION: The prevalence of NTDs is associated with its patterns.

Pattern of neural tube defects at Tikur Anbessa Hospital, Addis Ababa, Ethiopia.

BACKGROUND: Neural Tube Defect (NTD) is the most common of the central nervous system malformations. Although there is scarcity of information in Ethiopia, the burden of disease is high in low socioeconomic countries. OBJECTIVE: To assess the pattern and frequency of Neural Tube defects (NTDs). METHODS: Charts of a total of 115 children with neural tube defect (NTD) were reviewed retrospectively from JANUARY, 2001 to June 2005 in Ethio Swedish Children's Hospital. RESULTS: The most common defect seen was myelomeningocele (64.4%); followed by meningocele (18.3%) and encephalocele (13.0%). Associated anomalies like clubfoot undescended testis, different types of hernias, hydroceles etc. were noted in 28.7% of the patients. CONCLUSION: This study showed that the frequency distribution of the different neural tube defects in Tikur Anbessa hospital is not different from previous findings mentioned in the literature. However, overall frequency of neural tube defects could not be calculated from this study since the total live births in the study area during the study period were unknown. Hence, further prospective study is needed to substantiate these facts.

In vitro expression of neural tube pathology in the vl mutant mouse.

The pathogenesis of lumbosacral spinal dysraphism was analyzed in vitro in early homozygous embryos of the vl (vacuolated lens) mutant mouse, and comparisons were made between the lag in closure of the posterior neuropore at the beginning of culture and the degree of severity in the spinal defect at the end of culture for each embryo. In the majority of abnormal (vl/vl) embryos, the neural tube closed completely in culture, although mild defects were observed in the spinal roofplate comparable to those that occur in vivo. Although some abnormal embryos did exhibit small openings in the caudal neural tube at the end of the culture period, in none of the cultured embryos was the extent and severity of the defect as great as that observed in some abnormal embryos of comparable age obtained in vivo. Moreover, the degree of delay in closure of the posterior neuropore at the outset of culture did not necessarily correlate with the severity of the defect obtained at the end of culture. Thus, the expression of the neural tube defect in this mutant appears to be modulated and attenuated by biochemical and/or mechanical factors which may be peculiar to the culture milieu.

Neural tube defects: are neurulation and canalization forms causally distinct?

Neural tube defects (NTD) may be separated according to the overall location and probable embryological origin into 2 groups: upper or neurulation defects, and lower or canalization defects. Evidence as to whether these 2 forms are causally related or distinct was sought from 2 sources. Families with more than one NTD individual were studied to examine whether there was concordance within sibships for these 2 types of lesion. Seven of the 38 sibships were discordant (18%). Eight of the 10 cases of NTD that had arisen despite maternal periconceptional vitamin supplementation were neurulation defects and 2 were canalization defects. Both observations suggest that upper and lower types of NTD are causally related, and offer no support for the suggestion that they are distinct.

Sex, neural tube defects, and multisite closure of the human neural tube.

While neural tube defects (NTD) overall have a female sex bias, this does not apply to all sites along the neuraxis. The findings regarding sex and NTD in a series of midtrimester fetuses are reviewed, and then analysed in terms of the recent hypothesis that during embryogenesis of the human neural tube there are multiple closure sites, rather than a single zipping up process. Females more often than males tend to have craniorachischisis, spina bifida involving the thorax, the holoacrania form of anencephaly, anencephaly and cervical spina bifida and encephalocoeles, while males more often than females have spina bifida affecting the lower spine. Meroacrania occurs equally in both sexes. Other sources indicate that there is a male bias in frontoethmoidal encephalocoeles. Since sex seems to be a factor that is differentially associated with lack of closure of specific areas of the neural tube, it would seem to support the notion that there are multiple closure sites in the human neural tube. However, no association was found between a particular sex and either the type of NTD which have an isolated abnormality or those NTD associated with developmental abnormalities of other body systems.

Retinoic acid-induced neural tube defects with multiple canals in the chick: immunohistochemistry with monoclonal antibodies.

When retinoic acid was injected into chicken yolks before incubation, various types of neural tube defect (NTD) were induced in 38-46% of the embryos after 48-96 h of incubation. The cranial NTD consisted of a delay in closing of the neural plate in 48-h embryos and some remained as disorganized, hyperplastic masses in older embryos. In spinal NTD of 48-h embryos the posterior neuropore remained widely open. In older embryos with a closed posterior neuropore, the neural tube appeared dissociated or disorganized locally at the trunk level. The tissue consisted of a dorsally-situated, neural-plate-like structure and a ventrally-located cell mass containing multiple canals. Although the location was different, this arrangement was similar to the overlap zone which appears between primary and secondary neurulation in normal development. Immunohistochemistry was performed using monoclonal antibodies which selectively stained various components of chick tissue. Considering the similarity in neural tube formation between chick and human, this experimental NTD may provide clues to understanding the etiology of human myelomeningocele.

Adult tethered cord syndrome: relative to spinal cord length and filum thickness.

The adults with tethered cord syndrome (TCS) are divided into two groups: group-1 adult TCS patients with spinal dysraphism; and group-2 patients without dysraphism who develop signs and symptoms in adulthood. A significant number of group-2 patients failed to show elongation of the spinal cord and abnormally thick filum terminale. This paper reports the combinations of the location of the caudal end of the spinal cord and the thickness of the filum terminale in 104 patients with group-2 adult TCS. The caudal end of the spinal cord was found at the L2-3 intervertebral space or above in 37 patients (35.6%) and below L2-3 level in 67 patients (64.4%). The diameter of the filum was <2 mm in 60 patients (57.7%) and > or =2 mm in 44 patients (42.3%). These data clearly indicate that the pre-operative diagnosis of adult TCS must rely primarily on the neurological symptomatology and the specific imaging feature, posterior displacement of the conus and filum that attach the posterior arachnid membrane.

The Chiari malformations: a constellation of anomalies.

The Chiari malformations form a group of abnormalities that are pathogenetically interrelated. The most important member of the group is the Chiari type II malformation, known as the Arnold-Chiari malformation. Its cardinal features are the myelomeningocele in the thoraco-lumbar spine, the venting of the intracranial cerebrospinal fluid through the central canal, the hypoplasia of the posterior fossa, the herniation of hindbrain into the cervical spinal canal, and the compressive damage to cranial nerves. Some of the abnormalities are progressive, and thus treatable. Limitation of progression may improve outcomes. The challenges to our treatment programs involve early diagnosis, delivery by Caesarean section, emergent closure of the neural plaque and prophylaxis of hydrocephalus, anticipatory prevention of the neurological compression syndromes, multidisciplinary teams, and age-appropriate interventions.

Spinal and cranial neural tube defects.

Developmental lesions of the central nervous system with failure of normal midline fusion are often referred to as being dysraphic and vary from inapparent and insignificant to a massive deformity incompatible with survival. Several different schemata are used to classify this wide variety and often complex set of malformations; however, the nomenclature is confusing and even contradictory. As most of these congenital lesions of clinical significance involve an aberration in the formation of the neural tube, it is suggested that the term neural tube defects (NTD) be used to characterize this entire group of anomalies. From a practical clinical standpoint, NTD can be subdivided into three main groupings: open spinal NTD, closed spinal NTD, and cranial NTD. This article briefly covers the epidemiology, embryology, classification, clinical presentation, and management of this group of congenital lesions.

Imaging in spine and spinal cord malformations.

Spinal and spinal cord malformations are collectively named spinal dysraphisms. They arise from defects occurring in the early embryological stages of gastrulation (weeks 2-3), primary neurulation (weeks 3-4), and secondary neurulation (weeks 5-6). Spinal dysraphisms are categorized into open spinal dysraphisms (OSDs), in which there is exposure of abnormal nervous tissues through a skin defect, and closed spinal dysraphisms (CSD), in which there is a continuous skin coverage to the underlying malformation. Open spinal dysraphisms basically include myelomeningocele and other rare abnormalities such as myelocele and hemimyelo(meningo)cele. Closed spinal dysraphisms are further categorized based on the association with low-back subcutaneous masses. Closed spinal dysraphisms with mass are represented by lipomyelocele, lipomyelomeningocele, meningocele, and myelocystocele. Closed spinal dysraphisms without mass comprise simple dysraphic states (tight filum terminale, filar and intradural lipomas, persistent terminal ventricle, and dermal sinuses) and complex dysraphic states. The latter category further comprises defects of midline notochordal integration (basically represented by diastematomyelia) and defects of segmental notochordal formation (represented by caudal agenesis and spinal segmental dysgenesis). Magnetic resonance imaging (MRI) is the preferred modality for imaging these complex abnormalities. The use of the aforementioned classification scheme is greatly helpful to make the diagnosis.

Anomalies of cerebral structures in acranial neonates.

Eleven cases of newborns with acrania and macroscopically diagnosed anencephaly were neuropathologically examined. They presented changes in which 1 group corresponded to the diagnosis of aprosencephaly. In the second group, the development of prosencephalic structures was more advanced. The pathomechanism of the observed anomalies was analyzed in relation to data provided by molecular-genetic classification of nervous system malformations, but that did not exclude the influence of eventual extrinsic factors.