Opciones quirúrgicas para la cobertura de defectos del cierre del tubo neural. Serie de casos / Surgical options for coverage of neural tube closure defects. Case series

Introducción. Los defectos del tubo neural (DNT) son la segunda causa más prevalente de malformaciones congénitas, solo detrás de las cardiopatías congénitas. Los DTN abiertos comprenden el 80% de estas malformaciones. El mielomeningocele es el defecto abierto más común del tubo neural. La mayoría de los defectos son lo suficientemente pequeños como para soportar un cierre por primera o por segunda intención, pero el cierre primario puede no ser posible en aproximadamente 25% de los casos, lo cual es evidente en defectos grandes. Pacientes y métodos. El trabajo a continuación tiene como objetivo mostrar la experiencia en el manejo quirúrgico posnatal a través de una serie de caso con 3 pacientes con diagnóstico de defectos de cierre del tubo neural en distintas localizaciones anatómicas sometidos a cirugía en forma conjunta entre el Servicio de Neurocirugía y Cirugía Plástica del Parque de la Salud en la ciudad de Posadas Misiones. Resultados. En nuestra serie los colgajos realizados para la cobertura de mielomeningoceles fueron eficaces, evolucionando en primera instancia con complicaciones menores. La resolución del caso de encefalocele occipital con un colgajo miocutáneo de trapecio diferido resultó ser una opción válida y confiable. Conclusión. El uso de colgajos regionales para la reconstrucción de este tipo de malformaciones congénitas es una opción válida y reproducible, con bajo porcentaje de complicaciones.

Introduction. Neural tube defects (NTD) are the second most prevalent cause of congenital malformations, only behind congenital heart defects. Open NTDs comprise 80% of these malformations. Myelomeningocele is the most common open neural tube defect. Most defects are small enough to support a first or second intention closure, but primary closure may not be possible in approximately 25% of cases, being evident in large defects. Patients and methods. The following work aims to show the experience in postnatal surgical management through a case series with 3 patients diagnosed with neural tube closure defects in different anatomical locations undergoing joint surgery between the Neurosurgery and Plastic Surgery Service of Parque de la Salud in the city of Posadas, Misiones. Results. In our series, the flaps made to cover myelomeningoceles were effective, evolving in the first instance with minor complications. Resolution of the occipital encephalocele case with a delayed trapezius myocutaneous flap proved to be a valid and reliable option. Conclusion. The use of regional flaps for the reconstruction of this type of congenital malformations is a valid and reproducible option, with a low percentage of complications.

Double Lumbar Localization of Myelomeningocele: Case Report.

INTRODUCTION: Myelomeningocele (MMC) is a malformation resulting from the neural tube's failure to close during embryonic development, and the majority of the cases of neural tube defects (NTDs) were prevalent as single location lesions along the spine; however, multiple NTDs (MNTDs) are a very rare condition. Only a few cases of MNTDs were found in the literature. CASE PRESENTATION: We report the case of a 2-month-old male infant prenatally diagnosed with MMC, presented with two unconnected lumbar and lumbosacral epidermal, soft, dome-shaped swellings located on both sides of the midline (paravertebral) covered by intact skin. MRI revealed double MMC at the level of L4-L5, with spinal nerve roots. The patient underwent surgical repair of the defects by replacing the spinal cord and its nerve roots inside the thecal sac and recreating a covering layer around the neural structures to resemble thecal sac. The outcome was favorable, and postoperative head CT scan did not show any complication. CONCLUSION: Our case report is considered the first from Algeria to report the condition and the first to report the occurrence of double lesions in the same spine region. MMC can be associated with neurological deficits or other congenital anomalies, thus it is necessary to thoroughly examine such patients. However, there was no antenatal folic acid deficiency in our case. We recommend antenatal care with adequate folic acid supplementation given that its deficiency during pregnancy is considered a ubiquitous risk factor for the condition. The optimal timing for surgery of MMC cases is 8 ± 5 days. Prenatal intrauterine repair of the condition provides favorable outcomes but carries high fetal and maternal risks. Surgical repair should include the sac removal, the reconstruction of the placode, and the closure of the overlying meninges. With early diagnosis and proper repair of such cases, MMC has good prognosis and favorable outcomes.

Limited dorsal myeloschisis without extradural stalk continuity to coexisting congenital dermal sinus.

Limited dorsal myeloschisis (LDM) is characterized by a fibroneural tethering stalk linking the skin lesion to the underlying spinal cord. LDM without an extradural stalk is rare. A full-term boy was noted at birth to have a dimple in the upper back (dorsal skin of the lower thoracic region). Computed tomographic scan showed spina bifida at the T9-12 vertebral level and osteochondral tissue at the T10 level. Magnetic resonance imaging (MRI) demonstrated a tiny dorsal lipoma at the T8 vertebral level, but the intradural tethering tract was not apparent. At 18 days of age, the congenital dermal sinus (CDS) tract started from the dimple and terminated at the osteochondral tissue, without continuity of the dura mater, and the osteochondral tissues were resected. At age 2 years 8 months, he developed spastic paresis of the right foot. On MRI, the tethering tract from the dorsal lipoma became apparent. During the second surgery at age 2 years 11 months, the intradural stalk started from the dorsal lipoma and joined the inner surface of the dura mater was untethering from the cord. Postoperatively, right spastic paresis was improved. Histological examination of the intradural stalk revealed the distribution of S100-immunopositive peripheral nerve fibers, which is one of the histopathological hallmarks of LDM. We speculated that the extradural stalk with coexisting CDS originally linked from the skin lesion subsequently regressed and was replaced by fibroadipose tissue with osteochondral tissue migration. Intradural exploration should always be seriously considered in these disorders of persisting neurocutaneous connection.

Disorders of Secondary Neurulation: Suggestion of a New Classification According to Pathoembryogenesis.

Recently, advanced knowledge on secondary neurulation and its application to the clinical experience have led to the deeper insight into the pathoembryogenesis of secondary neurulation with new classifications of the caudal spinal dysraphic entities. Here, we summarize the dynamic changes in the concepts of disordered secondary neurulation over the last two decades. In addition, we suggest our new pathoembryogenetic explanations for a few entities based on the literature and the data from our previous animal research. Disordered secondary neurulation at each phase may cause various corresponding lesions, such as (1) failed junction with the primary neural tube (junctional neural tube defect and segmental spinal dysgenesis), (2) dysgenesis or duplication of the caudal cell mass associated with disturbed activity of caudal mesenchymal tissue (caudal agenesis and caudal duplication syndrome), (3) abnormal continuity of medullary cord to the surrounding layers, namely, failed ingression of the primitive streak to the caudal cell mass (myelomeningocele), focal limited dorsal neurocutaneous nondisjunction (limited dorsal myeloschisis and congenital dermal sinus), and neuro-mesenchymal adhesion (lumbosacral lipomatous malformation), and (4) regression failure spectrum of the medullary cord (thickened filum and filar cyst, retained medullary cord and low-lying conus, terminal myelocele, and terminal myelocystocele). It seems that almost every anomalous entity of the primary neural tube may occur in the area of secondary neurulation. Furthermore, the close association of the caudal cell mass with the activity of caudal mesenchymal tissue involves a wider range of surrounding structures in secondary neurulation than in primary neurulation. Although the majority of the data are from animals and many theories are still conjectural, these changing concepts of normal and disordered secondary neurulation will provoke further advancements in our management strategies as well as in the pathoembryogenetic understanding of anomalous lesions in this area.

The Absence of the Neuronal Component in Limited Dorsal Myeloschisis: A Case Report.

INTRODUCTION: The presence of neuroglial tissue is considered a hallmark in limited dorsal myeloschisis (LDM). However, several reports have indicated that the presence of neuroglial tissue in LDM cannot always be demonstrated. Here, we present such a case of LDM and provide an alternative hypothesis for lacking the neuronal component. CASE DESCRIPTION: An antenatal LDM suspected neonate was born with a cystic skin lesion and membranous sac typical for membranous LDM. Three days postpartum the otherwise healthy infant underwent surgery, during which the stalk was resected and the spinal cord was untethered. Histopathologically, no neuroglial tissue could be determined. Noteworthy, S-100 staining revealed numerous peripheral nerves. DISCUSSION: The current paradigm explains the absence of neuroglial tissue in resected stalks of LDM by indicating that it should be present in the unresected part, more proximal to the dorsal spinal cord. We hypothesize a different mechanism in which following reopening of the neural tube, mesodermal invasion causes a tight and persistent strand between the cutaneous- and neuroectoderm. Elongation of this mesodermal strand during embryological development allows for the formation of a mesenchymal stalk without the presence of neuroglial tissue. Hydrodynamic forces can cause fistulation of the poorly differentiated mesodermal tissue and subsequently lead to a saccular defect.

Congenital Sacrococcygeal Neuroblastoma: A Report of Two Cases with Summary of Prior Published Cases.

BackgroundNeuroblastoma can arise from extra-adrenal sites in the paraspinal sympathetic chain, including the presacral region, where they must be differentiated from an immature or malignant neural lesion arising from a teratoma.Case ReportWe describe two congenital presacral neuroblastomas. The main clinical differential diagnoses were sacrococcygeal teratoma and meningomyelocele. Pathologically, they lacked teratomatous tissues, lacked germ cell serum markers, were localized without metastases, and were MYCN non-amplified. Both patients have done well without chemotherapy at 18 and 15 months of follow-up.ConclusionCongenital presacral neuroblastoma should be differentiated from teratomatous lesions, and in general have a good prognosis.

Fetal and Perinatal Expression Profiles of Proinflammatory Cytokines in the Neuroplacodes of Rats with Myelomeningoceles: A Contribution to the Understanding of Secondary Spinal Cord Injury in Open Spinal Dysraphism.

The cellular and molecular mechanisms that presumably underlie the progressive functional decline of the myelomeningocele (MMC) placode are not well understood. We previously identified key players in post-traumatic spinal cord injury cascades in human MMC tissues obtained during postnatal repair. In this study, we conducted experiments to further investigate these mediators in the prenatal time course under standardized conditions in a retinoic acid-induced MMC rat model. A retinoic acid MMC model was established using time-dated Sprague-Dawley rats, which were gavage-fed with all-trans retinoic acid (RA; 60 mg/kg) dissolved in olive oil at E10. Control animals received olive oil only. Fetuses from both groups were obtained at E16, E18, and E22. The spinal cords (SCs) of both groups were formalin-fixed or snap-frozen. Tissues were screened by real-time reverse transcription polymerase chain reaction for the expression of cytokines and chemokines known to play a role in the lesion cascades of the central nervous system after trauma. MMC placodes exhibited inflammatory cells and glial activation in the later gestational stages. At the messenger RNA (mRNA) level, interleukin-1 beta, tumor necrosis factor alpha, and tumor necrosis factor receptor type 1 exhibited significant induction at E22. interleukin-1 beta receptor type 1 mRNA was induced significantly at E16 and E22. Double labeling experiments confirmed the co-staining of these cytokines and their receptors with ionized calcium-binding adapter molecule 1 (i.e., inflammatory cells), vimentin, and nestin in different anatomical SC areas and neuronal nuclear protein in ventral horn neurons. C-X-C motif chemokine 12 mRNA was elevated in control and MMC animals at E16 compared with E18 and E22. C-X3-C motif ligand 1 mRNA was lower in MMC tissues than in control tissues on E16. The presented findings contribute to the concept that pathophysiological mechanisms, such as cytokine induction in the neuroplacode, in addition to the "first hit," promote secondary spinal cord injury with functional loss in the late fetal time course. Further, these mediators should be taken into consideration in the development of new therapeutic approaches for open spinal dysraphism.

Preliminary Evaluation of a Novel Fetal Guinea Pig Myelomeningocele Model.

INTRODUCTION: Translational models of myelomeningocele (MMC) are needed to test novel in utero interventions. An ideal animal model for MMC has locomotor function at birth and is low cost enough to allow for high throughput. The rat MMC model is limited by immature locomotor function at birth. The ovine MMC model is a costly surgical model. Guinea pigs are uniquely suited for an MMC model being a small animal model with locomotor function at birth. We aimed to develop a retinoic acid (RA) model of MMC in the guinea pig and to evaluate if pregnant guinea pigs could tolerate uterine manipulation. METHODS: Time-mated Dunkin Hartley guinea pig dams were dosed with 60 mg/kg of RA between gestation age (GA) 12 and 15 days in the development of an RA model. Fetuses were grossly evaluated for MMC lesions at Cesarean section after GA 31 days. Evaluation of the ability of pregnant guinea pig dams to tolerate uterine surgical intervention was performed by hysterotomy of a separated group of time-mated guinea pigs at GA 45, 50, and 55. RESULTS: Forty-two pregnant guinea pigs were dosed with RA, with a total of 189 fetuses. The fetal demise rate was 38% (n = 71). A total of 118 fetuses were viable, 83% (n = 98) were normal fetuses, 8% (n = 10) had a neural tube defect, and 8% (n = 10) had a hematoma or other anomalies. No fetuses developed an MMC defect. None of the fetuses that underwent hysterotomy survived to term. CONCLUSION: RA dosed at 60 mg/kg in guinea pigs between GA 12 and 15 did not result in MMC. Dunkin Hartley guinea pigs did not tolerate a hysterotomy near term in our surgical model. Further work is needed to determine if MMC can be induced in guinea pigs with alternate RA dosing.

Diffusion weighted imaging as a biomarker of retinoic acid induced myelomeningocele.

Neural tube defects are a common congenital anomaly involving incomplete closure of the spinal cord. Myelomeningocele (MMC) is a severe form in which there is complete exposure of neural tissue with a lack of skin, soft tissue, or bony covering to protect the spinal cord. The all-trans retinoic acid (ATRA) induced rat model of (MMC) is a reproducible, cost-effective means of studying this disease; however, there are limited modalities to objectively quantify disease severity, or potential benefits from experimental therapies. We sought to determine the feasibility of detecting differences between MMC and wild type (WT) rat fetuses using diffusion magnetic resonance imaging techniques (MRI). Rat dams were gavage-fed ATRA to produce MMC defects in fetuses, which were surgically delivered prior to term. Average diffusion coefficient (ADC) and fractional anisotropy (FA) maps were obtained for each fetus. Brain volumes and two anatomically defined brain length measurements (D1 and D2) were significantly decreased in MMC compared to WT. Mean ADC signal was significantly increased in MMC compared to WT, but no difference was found for FA signal. In summary, ADC and brain measurements were significantly different between WT and MMC rat fetuses. ADC could be a useful complementary imaging biomarker to current histopathologic analysis of MMC models, and potentially expedite therapeutic research for this disease.

Impact of the volume of the myelomeningocele sac on imaging, prenatal neurosurgery and motor outcomes: a retrospective cohort study.

To investigate the association of the myelomeningocele (MMC) volume with prenatal and postnatal motor function (MF) in cases who underwent a prenatal repair. Retrospective cohort study (11/2011 to 03/2019) of 63 patients who underwent a prenatal MMC repair (37 fetoscopic, 26 open-hysterotomy). At referral, measurements of the volume of MMC was performed based on ultrasound scans. A large MMC was defined as greater than the optimal volume threshold (ROC analysis) for the prediction of intact MF at referral (2.7 cc). Prenatal or postnatal intact motor function (S1) was defined as the observation of plantar flexion of the ankle based on ultrasound scan or postnatal examination. 23/63 participants presented a large MMC. Large MMC lesions was associated with an increased risk of having clubfeet by 9.5 times (CI%95[2.1-41.8], p < 0.01), and reduces the chances of having an intact MF at referral by 0.19 times (CI%95[0.1-0.6], p < 0.01). At birth, a large MMC reduces the chance of having an intact MF by 0.09 times (CI%95[0.01-0.49], p < 0.01), and increases the risk of having clubfeet by 3.7 times (CI%95[0.8-18.3], p = 0.11). A lower proportion of intact MF and a higher proportion of clubfeet pre- or postnatally were observed in cases with a large MMC sac who underwent a prenatal repair.Trial registration: Clinicaltrials.gov NCT02230072 and NCT03794011 registered on September 3rd, 2014 and January 4th, 2019.

Human myelomeningocele risk and ultra-rare deleterious variants in genes associated with cilium, WNT-signaling, ECM, cytoskeleton and cell migration.

Myelomeningocele (MMC) affects one in 1000 newborns annually worldwide and each surviving child faces tremendous lifetime medical and caregiving burdens. Both genetic and environmental factors contribute to disease risk but the mechanism is unclear. This study examined 506 MMC subjects for ultra-rare deleterious variants (URDVs, absent in gnomAD v2.1.1 controls that have Combined Annotation Dependent Depletion score ≥ 20) in candidate genes either known to cause abnormal neural tube closure in animals or previously associated with human MMC in the current study cohort. Approximately 70% of the study subjects carried one to nine URDVs among 302 candidate genes. Half of the study subjects carried heterozygous URDVs in multiple genes involved in the structure and/or function of cilium, cytoskeleton, extracellular matrix, WNT signaling, and/or cell migration. Another 20% of the study subjects carried heterozygous URDVs in candidate genes associated with gene transcription regulation, folate metabolism, or glucose metabolism. Presence of URDVs in the candidate genes involving these biological function groups may elevate the risk of developing myelomeningocele in the study cohort.

Severe and progressive neuronal loss in myelomeningocele begins before 16 weeks of pregnancy.

BACKGROUND: Despite undisputable benefits, midtrimester prenatal surgery is not a cure for myelomeningocele (MMC): residual intracranial and motor deficits leading to lifelong handicap question the timing of prenatal surgery. Indeed, the timing and intensity of intrauterine spinal cord injury remains ill defined. OBJECTIVE: We aimed to describe the natural history of neuronal loss in MMC in utero based on postmortem pathology. STUDY DESIGN: Pathology findings were analyzed in 186 cases of myelomeningocele with lesion level between S1 and T1. Using a case-control, cross-sectional design, we investigated the timewise progression and topographic extension of neuronal loss between 13 and 39 weeks. Motor neurons were counted on histology at several spinal levels in 54 isolated MMC meeting quality criteria for cell counting. These were expressed as observed-to-expected ratios, after matching for gestational age and spinal level with 41 controls. RESULTS: Chiari II malformation increased from 30.7% to 91.6% after 16 weeks. The exposed spinal cord displayed early, severe, and progressive neuronal loss: the observed-to-expected count dropped from 17% to ≤2% after 16 weeks. Neuronal loss extended beyond the lesion to the upper levels: in cases <16 weeks, the observed-to-expected motor neuron count was 60% in the adjacent spinal cord, decreasing at a rate of 16% per week. Progressive loss was also found in the upper thoracic cord, but in much smaller proportions. The observed-over-expected ratio of motor neurons was not correlated with the level of myelomeningocele. CONCLUSIONS: Significant neuronal loss is present ≤16 weeks in the exposed cord and progressively extends cranially. Earlier prenatal repair (<16 weeks) could prevent Chiari II malformation in 69.3% of cases, rescue the 17% remaining motor neurons in the exposed cord, and prevent the extension to the upper spinal cord.

Heritable spina bifida in sheep: A potential model for fetal repair of myelomeningocele.

BACKGROUND/PURPOSE: In 2004, a heritable occurrence of spina bifida was reported in sheep on a farm in the United States. We maintained and characterized the spina bifida phenotype in this flock to assess its potential as an alternative surgical model. METHODS: A breeding strategy was developed in which the sheep were crossed to maintain or increase the occurrence of spina bifida. Measurements and observations were recorded regarding lesion size, birthweight, ambulatory capacity, or urological function, and necropsies were performed on spina bifida afflicted lambs in conjunction with magnetic resonance imaging to determine the character of the spina bifida defects and assess the presence of Chiari-like malformations or hydrocephalus. RESULTS: The defects were observed to be more prevalent in ram lambs, and the rate of spina bifida per litter could be increased through backcrossing or by selection of a productive ewe breed. The lambs displayed a range of ambulatory and urological deficits which could be used to evaluate new fetal repair methodologies. Finally, affected lambs were shown to demonstrate severe Chiari malformations and hydrocephalus. CONCLUSIONS: We have determined that use of these sheep as a natural source for spina bifida fetuses is feasible and could supplement the deficits of current sheep models for myelomeningocele repair. LEVEL OF EVIDENCE: Level IV.

Chorioamniotic membrane separation following fetal myelomeningocele repair: incidence, risk factors and impact on perinatal outcome.

OBJECTIVES: Prenatal myelomeningocele (MMC) repair has been shown to provide significant benefits to the infant, decreasing the postnatal need for ventriculoperitoneal shunt and improving motor outcome. Chorioamniotic membrane separation (CAS) is a potential complication following prenatal MMC repair and may increase the risk of preterm prelabor rupture of membranes (PPROM) and preterm birth. The objectives of this study were: (1) to evaluate the incidence of CAS after prenatal MMC repair; (2) to determine risk factors associated with its occurrence; and (3) to assess its association with adverse perinatal outcomes. METHODS: This was a retrospective cohort study of patients who underwent fetal MMC repair between November 2011 and December 2018. Surgery was performed using either a fetoscopic (laparotomy or exteriorized uterus) approach or an open-hysterotomy approach. Eligibility criteria were those reported in the Management of Myelomeningocele Study. If CAS was detected on ultrasound (US), its severity was graded as 'mild' if amnion detachment involved < 25% of the uterine cavity, 'moderate' if it involved 25-50% and 'severe' if it involved > 50%. Evolution of CAS was classified as stable, increasing or decreasing based on the difference in severity grading between the time at first diagnosis and the last US scan before delivery. Logistic regression analysis was performed to identify pre- or perisurgical factors associated with the development of CAS and to determine the risk of adverse perinatal outcome associated with CAS. RESULTS: In total, 91 cases were included. Fetoscopic or open-hysterotomy repair of MMC was performed in 52/91 (57.1%) and 39/91 (42.9%) cases, at a median gestational age (GA) of 25.0 weeks (range, 22.9-26.0 weeks) and 25.0 weeks (range, 21.3-25.9 weeks), respectively. CAS was diagnosed in 31/91 (34.1%) patients, at a median GA of 28.1 weeks (range, 24.4-37.6 weeks). Anterior placenta was identified as a risk factor for the postoperative development of CAS (odds ratio (OR), 3.72 (95% CI, 1.46-9.5); P < 0.01). This risk was dependent on the repair technique. An anterior placenta significantly increased the risk of CAS after fetoscopic repair (OR, 3.94 (95% CI, 1.14-13.6); P = 0.03) but not after open repair (OR, 2.8 (95% CI, 0.6-12.5); P = 0.16). There was no significant difference in the rate of CAS after fetoscopic repair (21/52 (40.4%)) vs open-hysterotomy repair (10/39 (25.6%)) (P = 0.14), nor were there any differences in GA at diagnosis of CAS, interval between surgery and diagnosis, distribution of CAS severity or progression of CAS between the two groups. CAS increased the risk of PPROM (50% in those with vs 12% in those without CAS) (OR, 7.6 (95% CI, 2.5-21.9); P < 0.01) and preterm delivery (70% vs 38%) (OR, 3.2 (95% CI, 1.3-8.1); P < 0.01). Fetoscopically repaired cases with CAS had a higher rate of PPROM (12/20 (60.0%) vs 2/31 (6.5%); P < 0.01) and preterm delivery (13/20 (65.0%) vs 5/31 (16.1%); P < 0.01) than those that did not develop CAS, while the differences were not significant in cases with open-hysterotomy repair. Early detection of CAS (before 30 weeks' gestation) was a risk factor for preterm delivery (90% before 30 weeks vs 36% at or after 30 weeks) (OR, 15.7 (95% CI, 2.3-106.3); P < 0.01). There was no association between PPROM or preterm delivery and the severity or progression of CAS. CONCLUSIONS: The presence of an anterior placenta was the only factor that increased the risk for CAS after fetoscopic MMC repair. Detection of CAS after fetoscopic MMC repair significantly increases the risk for PPROM and preterm delivery. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Congenital Spinal Lipomatous Malformations. Part 1. Spinal Lipomas, Lipomyeloceles, and Lipomyelomeningoceles.

Background: Lumbosacral spinal lipomas and lipomyeloceles are usually identified in early childhood. Terminology, histopathology, and diagnosis for these malformations can be confusing. Materials and Methods: This is a PubMed review with comparison of embryology, gross, and histopathology, and reporting requisites for these and related closed spinal malformations. Results: The spinal lipoma group (congenital spinal lipomatous malformations) includes subcutaneous, transdural, intradural, and noncontiguous malformations stretching through the entire lower spinal region. This lipomyelocele trajectory overlaps the embryonic tail's caudal eminence. Histopathologically, the lipomyelocele spectrum is a heterogeneous, stereotypical set of findings encountered from dermis to spinal cord. Diagnosis requires detailed correlation of images, intraoperative inspection, and histopathology. Conclusions: Appropriate terminology and clinicopathologic correlation to arrive at a diagnosis is a critical activity shared by pathologist and clinician. Prognostic and management differences depend on specific diagnoses. Familial and genetic influences play little if any role in patient management in closed spinal malformations.

Multiple-site neural tube defects: embryogenesis with complete review of existing literature.

OBJECTIVE: Multiple-site neural tube defects (MNTDs) are very uncommon, with the predominant number of cases being reported in developing countries. The classic theory of neural tube closure fails to explain the occurrence of these defects. Multisite closure theory, first proposed in 1995, explains most of the occurrences with a few modifications specific to a few defects. In this paper, the authors endeavor to explain all the defects, along with their genetic and embryological bases, and to review the available literature and discuss their own experience in the management of these complex cases. METHODS: The authors retrospectively reviewed the data of all the patients treated surgically for MNTDs over that past 14 years. All possible demographic data, clinical details, and radiological imaging data were reviewed. In addition, surgical parameters, complications, and status at follow-up of more than 12 months were evaluated. All previously reported cases of MNTD were analyzed, and comparisons with the present series were made. RESULTS: A total of 3 major series (including the present one) on MNTDs have been from India. A total of 57 such cases (including those of the present series) have been reported in the available literature. While previous series reported a higher incidence of spinal defects, the present series had a higher rate of cephalic defects (55%). Among the reported cases, insertion of a ventriculoperitoneal shunt was necessary in 12 (26%), and only 4 patients were operated on in 2 stages. Neurological status at presentation dictated outcome. CONCLUSIONS: MNTDs are extremely rare, and their embryogenesis is different from that of single neural tube defects. Simultaneous repair of 2 or even 3 defects is possible in a single-stage surgery. The requirement of a shunt is uncommon, and complications following surgery are rare. Folic acid supplementation may reduce the incidence of defects.

In Utero Amniotic Fluid Stem Cell Therapy Protects Against Myelomeningocele via Spinal Cord Coverage and Hepatocyte Growth Factor Secretion.

Despite the poor prognosis associated with myelomeningocele (MMC), the options for prenatal treatments are still limited. Recently, fetal cellular therapy has become a new option for treating birth defects, although the therapeutic effects and mechanisms associated with such treatments remain unclear. The use of human amniotic fluid stem cells (hAFSCs) is ideal with respect to immunoreactivity and cell propagation. The prenatal diagnosis of MMC during early stages of pregnancy could allow for the ex vivo proliferation and modulation of autologous hAFSCs for use in utero stem cell therapy. Therefore, we investigated the therapeutic effects and mechanisms of hAFSCs-based treatment for fetal MMC. hAFSCs were isolated as CD117-positive cells from the amniotic fluid of 15- to 17-week pregnant women who underwent amniocentesis for prenatal diagnosis and consented to this study. Rat dams were exposed to retinoic acid to induce fetal MMC and were subsequently injected with hAFSCs in each amniotic cavity. We measured the exposed area of the spinal cord and hepatocyte growth factor (HGF) levels at the lesion. The exposed spinal area of the hAFSC-treated group was significantly smaller than that of the control group. Immunohistochemical analysis demonstrated a reduction in neuronal damage such as neurodegeneration and astrogliosis in the hAFSC-treated group. Additionally, in lesions of the hAFSC-treated group, HGF expression was upregulated and HGF-positive hAFSCs were identified, suggesting that these cells migrated to the lesion and secreted HGF to suppress neuronal damage and induce neurogenesis. Therefore, in utero hAFSC therapy could become a novel strategy for fetal MMC. Stem Cells Translational Medicine 2019;8:1170-1179.

The role of vitamin D replacement therapy in serum FGF23 concentration in children with myelomeningocele compared with healthy children - a preliminary study.

Background Fibroblast growth factor 23 (FGF23) is a recently discovered bone-derived regulator of vitamin D metabolism and phosphate homeostasis. It inhibits phosphate reabsorption and calcitriol production by the kidney. Myelomeningocele (MMC) remains the most severe form of neural tube defects involving serious locomotor disability, osteoporosis and pathologic fractures. We aimed to investigate the influence of vitamin D replacement therapy on serum FGF23 concentration in children with MMC and compare the results with healthy participants. Methods This prospective analysis was conducted on 16 children with MMC and 20 healthy children. Serum FGF23 levels were measured; for the studied group, before and after vitamin D replacement therapy with cholecalciferol (vitamin D3). The children's medical charts were analyzed to determine age, sex, anthropometric measurements, calcium and phosphate, cholecalciferol and renal function parameters. Results There were significant differences in vitamin D and FGF23 serum concentrations between the studied groups. The median vitamin D levels in the MMC group increased during replacement therapy (7 vs. 18.5 ng/mL, p = 0.29) in comparison to the median of 25.5 ng/mL in the control group. In MMC children we found a significant decrease in median serum FGF23 after vitamin D replacement therapy (from 42.1 to 0 RU/mL, p < 0.001). FGF23 correlated positively with albumin, serum and urine phosphate levels and negatively with alkaline phosphatase. Conclusions 1. Serum concentration of FGF-23 is increased in MMC children in comparison to a healthy control group. 2. Vitamin D replacement therapy decreases FGF23 concentrations in MMC children, although further studies are still warranted to gain detailed insight on the FGF23 in the MMC population. 3. Children with MMC present vitamin D deficiency. Nutrition supplemented with low doses of cholecalciferol (vitamin D3) (intakes reaching recommended daily allowances) was insufficient to correct 25(OH)-D level in that population of patients.

Are primary and secondary types of brain anomalies exclusive factors affecting the attention networks in individuals with spina bifida?

OBJECTIVE: Individuals with spina bifida myelomeningocele (SBM) frequently exhibit cognitive impairments on tasks mediated by brain regions involved in the posterior attention network. Although such deficits have been historically assumed to result from primary and secondary brain insults, there is a dearth of literature regarding whether sequential versus simultaneous surgical closure of neural folds and surgical shunt placement affect neuropsychological function and brain structure of attention networks that have been widely studied in individuals with SBM. The current study addressed these gaps in a large cohort of children and adults with SBM. METHOD: White matter pathways and regional brain volumes of anterior and posterior attention networks were quantified through probabilistic tractography and automated segmentation, respectively. The Child Attention Network Test measured behavioral components of posterior and anterior attention networks. RESULTS: Sequential operations were associated with reduced orienting accuracy and smaller left superior parietal and dorsolateral prefrontal cortex volumes compared to simultaneous operations, controlling for a number of shunt revisions and age. Greater number of shunt revisions was associated with higher radial diffusivity values in the parietal tectocortical pathway. Older participants had greater accuracy and faster conflict resolution performance compared to younger participants, across operation type and number of shunt revisions. CONCLUSIONS: Shunt treatment and revision history related to brain structure and functions associated with the posterior attention network. Neurosurgical history also differentiated the harmful effects of early hydrocephalus on brain structure of the posterior from the anterior attention networks in SBM. (PsycINFO Database Record (c) 2019 APA, all rights reserved).